[Federal Register Volume 81, Number 159 (Wednesday, August 17, 2016)]
[Rules and Regulations]
[Pages 54960-55055]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-19164]



[[Page 54959]]

Vol. 81

Wednesday,

No. 159

August 17, 2016

Part III





Department of Health and Human Services





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Food and Drug Administration





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21 CFR Parts 20, 25, 170, et al.





Substances Generally Recognized as Safe; Final Rule

  Federal Register / Vol. 81 , No. 159 / Wednesday, August 17, 2016 / 
Rules and Regulations  

[[Page 54960]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 25, 170, 184, 186, and 570

[Docket No. FDA-1997-N-0020 (formerly 97N-0103)]
RIN 0910-AH15


Substances Generally Recognized as Safe

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or we) is issuing a 
final rule that amends and clarifies the criteria in our regulations 
for when the use of a substance in food for humans or animals is not 
subject to the premarket approval requirements of the Federal Food, 
Drug, and Cosmetic Act (the FD&C Act) because the substance is 
generally recognized as safe (GRAS) under the conditions of its 
intended use. We also are amending our regulations to replace the 
voluntary GRAS affirmation petition process with a voluntary 
notification procedure under which any person may notify us of a 
conclusion that a substance is GRAS under the conditions of its 
intended use. The clarified criteria for GRAS status should help 
stakeholders draw more informed conclusions about whether the intended 
conditions of use of a substance in food for humans or animals complies 
with the FD&C Act, and the notification procedure will enable 
stakeholders to be aware of whether we have questioned the basis of a 
conclusion of GRAS status.

DATES: This rule is effective October 17, 2016. Submit comments on 
information collection issues under the Paperwork Reduction Act of 1995 
by October 17, 2016 (see section XXIX, the ``Paperwork Reduction Act of 
1995'' section of this document).

ADDRESSES: To ensure that comments on the information collection are 
received, the Office of Management and Budget (OMB) recommends that 
written comments be faxed to the Office of Information and Regulatory 
Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-7285, or emailed to 
[email protected]. All comments should be identified with the 
OMB control number 0910-0342 and titled ``Substances Generally 
Recognized as Safe.'' Also include the FDA docket number found in 
brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Regarding substances that would be 
used in human food: Paulette M. Gaynor, Center for Food Safety and 
Applied Nutrition (HFS-255), Food and Drug Administration, 5001 Campus 
Drive, College Park, MD 20740, 240-402-1192. Regarding substances that 
would be used in animal food: Geoffrey K. Wong, Center for Veterinary 
Medicine (HFV-224), Food and Drug Administration, 7519 Standish Pl., 
Rockville, MD 20855, 240-402-5838.

SUPPLEMENTARY INFORMATION: 

Table of Contents

Executive Summary

Purpose and Coverage of the Rule

Summary of the Major Provisions of the Rule

Costs and Benefits

I. Introduction
    A. History of FDA's Approach to the GRAS Provision of the FD&C 
Act
    B. Report by the Government Accountability Office and How We Are 
Addressing Its Recommendations
    C. Issues Regarding the Legal and Regulatory Framework for 
Substances Added to Food
    D. Recent FDA Actions Related to GRAS Criteria
    E. Moving Forward Under This Final Rule
II. Background
    A. The Proposed Rule
    B. Interim Pilot Program
    C. 2010 Report of the Government Accountability Office
    D. 2010 Notice Reopening the Comment Period
    E. Public Comments
    F. Applicability of Discussions in This Document to Both the 
Human Food Regulations and the Animal Food Regulations
    G. Use of Pronouns in This Document
    H. Summary of Principal Changes to the Proposed Notification 
Procedure
III. Legal Authority
IV. General Comments on the Proposed Rule
V. Comments on the Definition of Scientific Procedures
VI. Comments on the Criteria for Eligibility for Classification as 
GRAS
    A. General Criteria for Eligibility for Classification as GRAS
    B. Criteria for Eligibility for Classification as GRAS Through 
Scientific Procedures
    C. Criteria for Eligibility for Classification as GRAS Through 
Experience Based on Common Use in Food
    D. Other Comments on the Criteria for Eligibility for 
Classification as GRAS
    E. GRAS Status of Certain Food Substances
VII. Comments on the Substitution of a GRAS Notification Procedure 
for the GRAS Affirmation Petition Process
    A. Affirmation on the Initiative of the Commissioner
    B. Deletion of the GRAS Affirmation Petition Process
    C. General Comments on the Proposed GRAS Notification Procedure
    D. Comments on Certain Terms Used in the Proposed Regulatory 
Text
    E. Comments on the Use of ``Plain Language'' in the Regulatory 
Text
VIII. Definitions Applicable to a GRAS Notice
    A. Definitions We Described in the 2010 Notice
    B. Definition of ``GRAS Notice''
    C. Other Terms We Are Defining in the Rule
IX. Opportunity to Submit a GRAS Notice
X. Comments on Administrative Procedures for Submission of a GRAS 
Notice
    A. How to Send a GRAS Notice to FDA
    B. Option for Submission of Electronic or Paper Copies of a GRAS 
Notice
    C. Incorporation into a GRAS Notice
XI. General Requirements Applicable to a GRAS Notice
XII. Comments on Part 1 of a GRAS Notice: Signed Statements and 
Certification
    A. Exclusion of Trade Secret and Confidential Commercial 
Information From the Signed Statements
    B. Name of the Notified Substance, Using an Appropriately 
Descriptive Term
    C. Intended Conditions of Use of the Notified Substance
    D. Statutory Basis for the Conclusion of GRAS Status
    E. Agreement to Make Data and Information Available Upon Request
    F. Statements and Any Applicable Explanation Regarding Data and 
Information That a Notifier Views as Exempt From Disclosure Under 
FOIA
    G. Certification Statement
    H. Person Signing Part 1 of the GRAS Notice
    I. Authorization for FDA to Send Trade Secret Information to 
FSIS
XIII. Comments on Part 2 of a GRAS Notice: Identity, Method of 
Manufacture, Specifications, and Physical or Technical Effect
    A. Scientific Information About the Identity of a Notified 
Substance
    B. Method of Manufacture
    C. Specifications for the Notified Substance
    D. Data and Information Bearing on the Physical or Other 
Technical Effect of the Notified Substance
XIV. Comments on Part 3 of a GRAS Notice: Dietary Exposure
XV. Comments on Part 4 of a GRAS Notice: Self-Limiting Levels of Use
XVI. Comments on Part 5 of a GRAS Notice: Common Use in Food Before 
1958
XVII. Comments on Parts 6 and 7 of a GRAS Notice: Narrative and List 
of Supporting Data and Information
XVIII. Comments on Steps a Notifier May Take Before We Respond to a 
GRAS Notice
    A. Communicating With a Notifier Before We Respond to a GRAS 
Notice
    B. Submitting an Amendment
    C. Notifier's Request That We Cease To Evaluate a GRAS Notice
XIX. Comments on What We Will Do With a GRAS Notice
    A. Filing Decision
    B. Our Response to a GRAS Notice
    C. Additional Correspondence as Circumstances Warrant
    D. Procedures If a Notifier Disagrees With Our Response

[[Page 54961]]

XX. Coordinating Our Evaluation of a GRAS Notice With FSIS
XXI. Comments on Public Disclosure of a GRAS Notice
    A. Data and Information in a GRAS Notice Are Available for 
Public Disclosure on the Date That We Receive It
    B. We Will Make a List of Filed GRAS Notices and Our Responses 
to GRAS Notices Readily Accessible
    C. Public Disclosure of a GRAS Notice Is in Accordance With Our 
Public Information Regulations in Part 20
XXII. Submission of a Supplement
XXIII. Comments on the Administrative Process for Pending GRAS 
Affirmation Petitions
XXIV. Other Comments
    A. GRAS Panels and Conflict of Interest
    B. Guidance on Documenting Conclusions of GRAS Status
    C. Compliance With Other FDA Regulations
    D. Impact on Other Federal Agencies
    E. Impact on International Trade
    F. Audits
    G. Lack of an Environmental Assessment
    H. Substances Affirmed as GRAS With Specific Limitations
XXV. Comments on Substances Intended for Use in Animal Food
    A. Issues in the 2010 Notice Specific to Animal Food
    B. Criteria for Eligibility for Classification as GRAS for a 
Substance Intended for Use in Animal Food (Sec.  570.30)
    C. Part 1 of a GRAS Notice for a Substance Intended for Use in 
Animal Food: Name of the Notified Substance (Sec.  570.225(c)(3))
    D. Part 1 of a GRAS Notice for a Substance Intended for Use in 
Animal Food: Intended Conditions of Use (Sec.  570.225(c)(4))
    E. Part 2 of a GRAS Notice for a Substance Intended for Use in 
Animal Food: Data and Information Bearing on the Physical or Other 
Technical Effect of the Notified Substance (Sec.  570.230(d))
    F. Part 3 of a GRAS Notice for a Substance Intended for Use in 
Animal Food: Target Animal and Human Exposures (Sec.  570.235)
    G. Data and Information in a GRAS Notice About Safety for the 
Target Animal (Sec.  570.250)
    H. Data and Information in a GRAS Notice About the Safety for 
Humans Consuming Human Food Derived From a Food-Producing Animal 
(Sec. Sec.  570.235 and 570.250)
    I. Filing Decision, Opportunity for a Notifier to Submit an 
Amendment, and Asking Us to Cease to Evaluate a GRAS Notice for a 
Substance Intended for Use in Animal Food (Sec. Sec.  570.260 and 
570.265)
    J. Opportunity for a Notifier to Submit a Supplement to a GRAS 
Notice for a Substance Intended for Use in Animal Food (Sec.  
570.280)
    K. GRAS Affirmation Petitions for Substances Used in Animal Food
XXVI. Editorial, Clarifying, and Conforming Amendments
XXVII. Economic Analysis of Impacts
XXVIII. Analysis of Environmental Impact
XXIX. Paperwork Reduction Act of 1995
XXX. Federalism
XXXI. References

Executive Summary

Purpose and Coverage of the Rule

    Although we have premarket review authority over food additives, a 
food manufacturer can intentionally add a substance to human food or 
animal food without our premarket review or approval if the substance 
is generally recognized, among qualified experts, to be safe under the 
conditions of its intended use (GRAS). Since the 1970s, we have had 
regulations clarifying the statutory provision for eligibility for 
classification as GRAS. We also have had regulations governing a 
procedure for any person to voluntarily submit to us a petition asking 
us to affirm the GRAS status of a substance under the conditions of its 
intended use, and for us to engage in an intensive rulemaking process 
in response to that petition. Experience has shown that our regulations 
need further clarification to help stakeholders understand when a 
substance is eligible for classification as GRAS in human food or 
animal food under the conditions of its intended use. Experience also 
has shown that streamlining our evaluation of conclusions of GRAS 
status will enable us to evaluate more, and higher priority, 
substances. We are issuing this final rule to amend and clarify the 
criteria in our regulations for when a substance is GRAS under the 
conditions of its intended use in human food or animal food, and to 
replace the voluntary administrative procedure for petitioning us to 
affirm the GRAS status of a use of a substance in human food or animal 
food with a voluntary administrative procedure for notifying us about a 
conclusion that a substance is GRAS under the conditions of its 
intended use in human food or animal food.

Summary of the Major Provisions of the Rule

    The final rule clarifies the criteria for the use of a substance to 
be eligible for classification as GRAS and establishes a new 
administrative procedure for any person to notify us of the basis for a 
conclusion that a substance is GRAS under the conditions of its 
intended use. With respect to criteria for eligibility for 
classification as GRAS, in the final rule we clarify that:
     A substance cannot be classified as GRAS under the 
conditions of its intended use if the available data and information do 
not satisfy the safety standard for a food additive under the FD&C Act;
     General recognition of safety requires common knowledge, 
throughout the expert scientific community knowledgeable about the 
safety of substances directly or indirectly added to food, that there 
is a reasonable certainty that the substance is not harmful under the 
conditions of its intended use;
     ``Common knowledge'' can be based on either ``scientific 
procedures'' or on experience based on common use of a substance in 
food prior to January 1, 1958; and
     General recognition of safety through scientific 
procedures must be based upon the application of generally available 
and accepted scientific data, information, or methods, which ordinarily 
are published, as well as the application of scientific principles, and 
may be corroborated by the application of unpublished scientific data, 
information, or methods.
    With respect to the procedure for submitting a GRAS notice, we 
provide:
     Definitions for certain terms, including amendment, GRAS 
notice, notified substance, notifier, qualified expert, supplement, we/
our/us, and you/your;
     A clear statement of the opportunity for any person to 
submit a GRAS notice;
     Information on available formats (electronic and paper) 
and where to send a GRAS notice;
     What data and other information may be incorporated into a 
GRAS notice;
     General provisions applicable to a GRAS notice;
     Specific information you must provide in your GRAS notice, 
including:
    [cir] Signed statements and a certification (Part 1);
    [cir] The identity, method of manufacture, specifications, and 
physical or technical effect of the notified substance (Part 2);
    [cir] Dietary exposure (Part 3);
    [cir] Self-limiting levels of use, in circumstances where the 
amount of the notified substance that can be added to human food or 
animal food is limited because the food containing levels of the 
notified substance above a particular level would become unpalatable or 
technologically impractical (Part 4);
    [cir] The history of consumption of the substance for food use by a 
significant number of consumers (or animals in the case of animal food) 
prior to January 1, 1958, if a conclusion of GRAS status is based on 
common use of the substance in food prior to 1958 (Part 5);
    [cir] A narrative that provides the basis for your conclusion of 
GRAS status, including why the scientific data, information, methods, 
and principles

[[Page 54962]]

described in the notice provide a basis for your conclusion that the 
notified substance is generally recognized, among qualified experts, to 
be safe under the conditions of its intended use (Part 6); and
    [cir] A list of the data and information that you discuss in the 
narrative of your GRAS notice, specifying which of these data and 
information are generally available, and which of these data and 
information are not generally available (Part 7); and
     Process for you to submit an amendment to your GRAS 
notice; and
     Process for you to request that we cease to evaluate your 
GRAS notice.
    With respect to our administration of a GRAS notice, we specify:
     Information about how we will file a GRAS notice, respond 
to it, and send subsequent correspondence about it;
     Our commitment to respond within 180 days of filing of a 
GRAS notice, with a potential to extend our response timeframe by 
another 90 days;
     Our procedures in the event the intended conditions of use 
of the notified substance include use in a product subject to 
regulation by the Food Safety and Inspection Service (FSIS) of the U.S. 
Department of Agriculture (USDA); and
     Provisions governing the public disclosure of a GRAS 
notice, including the actions we take to make some information 
regarding a GRAS notice readily accessible to the public.
    As of the effective date of the final rule, we will close the 
docket for any pending GRAS affirmation petition. The petitioner may 
incorporate the applicable petition into a new GRAS notice.
Costs and Benefits
    The final rule eliminates the petition process to affirm that a 
substance is GRAS under the conditions of its intended use and replaces 
that petition process with a GRAS notification procedure. We estimate 
that over 10 years with a 7 percent discount rate, the present value of 
the total costs of the final rule range from $0.9 million to $3.3 
million; with a 3 percent discount rate, the present value of the total 
costs range from $0.9 million to $3.4 million. The annualized costs of 
the rule range from $0.1 million to $0.4 million with a 7 percent 
discount rate and range from $0.1 million to $0.5 million with a 3 
percent discount rate. We do not quantify the benefits of the final 
rule, but assume that firms will only participate in the GRAS 
notification procedure when they expect to receive a non-negative 
private benefit. The GRAS notification procedure will allow us to 
complete our evaluation within the timelines specified in the final 
rule. The following table includes a summary of the benefits and costs 
of the final rule.

                                 Summary of Benefits and Costs of the Final Rule
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                                                                           Total annualized    Total annualized
                                   Present value of    Present value of      costs over 10       costs over 10
         Total benefits           total costs with 7  total costs with 3     years with 7        years with 3
                                   percent  discount   percent  discount   percent discount    percent discount
                                     rate ($ mil)        rate ($ mil)        rate ($ mil)        rate ($ mil)
----------------------------------------------------------------------------------------------------------------
Not estimated...................  $0.9 to $3.3......  $0.9 to $3.4......  $0.1 to $0.4......  $0.1 to $0.5.
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                   Table of Abbreviations and Acronyms
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           Abbreviation/acronym                     What it means
------------------------------------------------------------------------
1958 amendment............................  1958 Food Additives
                                             Amendment to the Federal
                                             Food, Drug, and Cosmetic
                                             Act.
AAFCO.....................................  Association of American Feed
                                             Control Officials.
Affected petitioner.......................  Any person who had submitted
                                             a pending petition.
BATF......................................  Bureau of Alcohol, Tobacco,
                                             and Firearms.
CFSAN.....................................  Center for Food Safety and
                                             Applied Nutrition.
CVM.......................................  Center for Veterinary
                                             Medicine.
EPA.......................................  U.S. Environmental
                                             Protection Agency.
FDA.......................................  U.S. Food and Drug
                                             Administration.
FDAMA.....................................  1997 Food and Drug
                                             Administration
                                             Modernization Act.
FD&C Act..................................  Federal Food, Drug, and
                                             Cosmetic Act.
FOIA......................................  Freedom of Information Act.
FSIS......................................  Food Safety and Inspection
                                             Service of the U.S.
                                             Department of Agriculture.
GAO.......................................  Government Accountability
                                             Office.
GRAS......................................  Generally Recognized as
                                             Safe.
JECFA.....................................  Joint Expert Committee on
                                             Food Additives.
MOU.......................................  Memorandum of Understanding.
N/A.......................................  Not Applicable.
OMB.......................................  Office of Management and
                                             Budget.
Pdf.......................................  Portable document format.
Pending petition..........................  A filed GRAS affirmation
                                             petition that is pending on
                                             the date that the petition
                                             process is replaced with a
                                             notification procedure.
PHO.......................................  Partially hydrogenated oil.
PRA.......................................  Paperwork Reduction Act.
TTB.......................................  Alcohol and Tobacco Tax and
                                             Trade Bureau.
USDA......................................  U.S. Department of
                                             Agriculture.
------------------------------------------------------------------------

I. Introduction

A. History of FDA's Approach to the GRAS Provision of the FD&C Act

    In 1958, in response to public concern about the increased use of 
chemicals in foods and food processing and with the support of the food 
industry, Congress enacted the Food Additives Amendment (the 1958 
amendment) to the FD&C Act. The basic thrust of the 1958 amendment was 
to require that, before a substance could be used in food, its sponsor 
demonstrate the safety of the substance to FDA, and that we establish a 
regulation prescribing the conditions under which the substance may be 
safely used. The 1958 amendment

[[Page 54963]]

defined the terms ``food additive'' (21 U.S.C. 321(s)) and ``unsafe 
food additive'' (21 U.S.C. 348(a)), established a premarket approval 
process for food additives (21 U.S.C. 348(b) through (g)), and amended 
the food adulteration provisions of the FD&C Act to deem adulterated 
any food that is, or bears or contains, any food additive that is 
unsafe within the meaning of 21 U.S.C. 348 (see 21 U.S.C. 
342(a)(2)(C)).
    Congress recognized that, under this scheme, the safety of a food 
additive could not be established with absolute certainty, and thus 
provided for a science-based safety standard that requires sponsors of 
food additives to demonstrate to a reasonable certainty that no harm 
will result from the intended use of an additive (Ref. 1). We have 
incorporated this safety standard into our regulations for food 
additives and GRAS substances (Sec.  170.3(i)) (21 CFR 170.3(i)). (We 
note that although this rule addresses substances intended for use in 
animal food as well as substances intended for use in human food, in 
this introduction we describe the history of the our GRAS regulations 
from the perspective of human food only.) If we find an additive to be 
safe, based ordinarily on data submitted by the sponsor to us in a food 
additive petition, we promulgate a regulation specifying the conditions 
under which the additive may be safely used.
    In enacting the 1958 amendment, Congress recognized that many 
substances intentionally added to food would not require a formal 
premarket review by FDA to assure their safety, either because their 
safety had been established by a long history of use in food or by 
virtue of the nature of the substance, its customary or projected 
conditions of use, and the information generally available to 
scientists about the substance. Congress thus adopted, in section 
201(s) of the FD&C Act (21 U.S.C. 321(s)), a two-step definition of 
``food additive.'' The first step broadly includes any substance, the 
intended use of which results or may reasonably be expected to result, 
directly or indirectly, in its becoming a component or otherwise 
affecting the characteristics of food. The second step, however, 
excludes from the definition of ``food additive'' substances that are 
generally recognized, among experts qualified by scientific training 
and experience to evaluate their safety (``qualified experts''), as 
having been adequately shown through scientific procedures (or, in the 
case of a substance used in food prior to January 1, 1958, through 
either scientific procedures or through experience based on common use 
in food) to be safe under the conditions of their intended use. 
Importantly, under section 201(s) of the FD&C Act, it is the use of a 
substance, rather than the substance itself, that is eligible for GRAS 
status. It is on the basis of the GRAS provision within the food 
additive definition that many substances (such as vinegar, vegetable 
oil, baking powder, and many spices, flavors, gums, and preservatives) 
are lawfully marketed today without a food additive regulation. Under 
the 1958 amendment, a substance that is GRAS for a particular use may 
be marketed for that use without our review and approval. However, when 
a use of a substance does not qualify for GRAS status or other 
exceptions provided under section 201(s) of the FD&C Act, that use of 
the substance is a food additive use subject to the premarket approval 
mandated by the FD&C Act. In such circumstances, we can take 
enforcement action to stop distribution of the food substance and foods 
containing it on the grounds that such foods are or contain an unlawful 
food additive.
    Shortly after passage of the 1958 amendment, we clarified the 
regulatory status of a multitude of food substances that were used in 
food prior to 1958 and amended our regulations to include a list of 
food substances that, when used for the purposes indicated and in 
accordance with good manufacturing practice, are GRAS. This list was 
incorporated into our regulations as Sec.  121.101(d) (21 CFR 
121.101(d)) (now part 182 (21 CFR part 182)) (24 FR 9368; November 20, 
1959). As part of that rulemaking, however, we acknowledged that it 
would be impracticable to list all substances that are GRAS for their 
intended use (Sec.  121.101(a); current Sec.  182.1(a)).
    Section 121.101(d) became commonly referred to as ``the GRAS 
list.'' We added other categories of substances (e.g., spices, 
seasonings, and flavorings) to the GRAS list in subsequent rulemakings 
(25 FR 404, January 19, 1960; and 26 FR 3991, May 9, 1961).
    Many substances that were considered GRAS by the food industry were 
not included in our GRAS list. Under the 1958 amendment, a substance 
that is GRAS under the conditions of its intended use may be marketed 
for that use without Agency review and approval. Nonetheless, as a 
practical matter, manufacturers who concluded on their own initiative 
that use of a substance qualified for GRAS status frequently decided to 
obtain our opinion on whether their conclusion was justified. Many 
manufacturers wrote to us and requested an ``opinion letter,'' in which 
Agency officials would render an informal opinion on the GRAS status of 
use of a substance. Although convenient and expedient, these opinion 
letters were often available only to the requestor. Moreover, these 
opinion letters were not binding on us even at the time they were 
issued and letters issued before April 9, 1970, were in fact revoked 
(21 CFR 170.6; 35 FR 5810; April 9, 1970).
    In 1969 (34 FR 17063; October 21, 1969), we deleted various 
cyclamate salts, a family of nonnutritive sweeteners, from the GRAS 
list because they were implicated in the formation of bladder tumors in 
rats (Ref. 2). In response to the concerns raised by the new 
information on cyclamates, then-President Nixon directed us to 
reexamine the safety of GRAS substances (Ref. 3), and we announced that 
we were conducting a comprehensive study of substances presumed to be 
GRAS (35 FR 18623; December 8, 1970). The purpose of the study was to 
evaluate, by contemporary standards, the available safety information 
regarding substances presumed to be GRAS and to promulgate each item in 
a new (i.e., affirmed) GRAS list, a food additive regulation, or an 
interim food additive regulation pending completion of additional 
studies.
    In the notice announcing the comprehensive review of presumed GRAS 
substances, we proposed criteria that could be used to establish 
whether these substances should be listed as GRAS, become the subject 
of a food additive regulation, or be listed in an interim food additive 
regulation pending completion of additional studies (35 FR 18623). 
These criteria were incorporated into our regulations as Sec.  121.3 
(precursor of current Sec.  170.30) (36 FR 12093; June 25, 1971).
    We made a second announcement that we were conducting a study of 
presumed GRAS substances (36 FR 20546; October 23, 1971) and 
subsequently instituted a rulemaking to establish procedures that we 
could use, on our own initiative, to affirm the GRAS status of 
substances that were the subject of that review and were found to 
satisfy the criteria established in Sec.  121.3 (proposed rule, 37 FR 
6207, March 25, 1972; final rule, 37 FR 25705, December 2, 1972). These 
procedures were subsequently codified at Sec.  170.35(a) and (b). 
Because the GRAS review did not cover all GRAS substances (e.g., it did 
not cover many substances that were marketed based on a manufacturer's 
independent conclusion of GRAS status), that rulemaking included a 
mechanism (the GRAS affirmation petition process; Sec.  170.35(c)) 
whereby

[[Page 54964]]

an individual could petition us to review the GRAS status of substances 
not being considered as part of our GRAS review. We codified our 
affirmations of GRAS status in current parts 184 and 186 (21 CFR parts 
184 and 186).
    In 1974, we proposed to clarify the criteria for GRAS status, the 
differences between GRAS status and food additive status, and the 
procedures being used to conduct the current review of food substances 
(39 FR 34194; September 23, 1974). The final regulations based on this 
proposal amended Sec.  121.3 (now Sec.  170.30) to distinguish a 
conclusion of GRAS status through scientific procedures (Sec.  
170.30(b)) from a conclusion of GRAS status through experience based on 
common use in food (Sec.  170.30(c)) (41 FR 53600; December 7, 1976). 
Those final regulations also established definitions for ``common use 
in food'' (now Sec.  170.3(f)) and ``scientific procedures'' (now Sec.  
170.3(h)). We subsequently added criteria (Sec.  170.30(c)(2)) for the 
determination of GRAS status through experience based on common use in 
food when that use occurred exclusively or primarily outside of the 
United States (53 FR 16544; May 10, 1988).
    To the extent that a person elected to submit a GRAS affirmation 
petition, the GRAS affirmation process could facilitate awareness, by 
us as well as the domestic and international food industry, of 
independent conclusions of GRAS status. However, the GRAS affirmation 
petition process involved the resource-intensive rulemaking process. In 
the Federal Register of April 17, 1997 (62 FR 18938; the proposed 
rule), we proposed to: (1) Clarify the criteria for eligibility for 
classification as GRAS; and (2) replace the GRAS affirmation petition 
process with a notification procedure whereby any person may notify us 
of a conclusion that a particular use of a substance is GRAS. We 
explained that we would evaluate whether the notice provides a 
sufficient basis for a GRAS conclusion and whether information in the 
notice or otherwise available to us raises issues that lead us to 
question whether use of the substance is GRAS. We would respond to the 
notifier in writing and could advise the notifier that we had 
identified a problem with the notice. Although information in a notice 
would be publicly available consistent with the Freedom of Information 
Act (FOIA), we would make readily accessible to the public a basic 
description the notified substance, the conditions of its intended use, 
and the statutory basis for GRAS status (i.e., through scientific 
procedures or through experience based on common use in food), as well 
as our response to the notice. In 2010, we reopened the comment period 
for the proposed rule to update comments and to solicit comment on 
specific issues (75 FR 81536, December 28, 2010; the 2010 notice). (See 
section II.D for additional information about this reopening of the 
comment period).
    In the proposed rule, we invited interested persons to notify us 
about their conclusions of GRAS status as described in the proposed 
rule (62 FR 18938 at 18954; the ``Interim Pilot program''). Our Center 
for Food Safety and Applied Nutrition (CFSAN) filed its first GRAS 
notice in 1998 and has filed 614 GRAS notices as of December 31, 2015. 
Our Center for Veterinary Medicine (CVM) established its Interim Pilot 
program more recently (75 FR 31800, June 4, 2010) and filed its first 
GRAS notice in December 2010. As of December 31, 2015, CVM has filed 18 
GRAS notices.

B. Report by the Government Accountability Office and How We Are 
Addressing Its Recommendations

    From 2008 to 2010, the Government Accountability Office (GAO) 
conducted a study related to ingredients used in human food on the 
basis of the GRAS provision in section 201(s) of the FD&C Act. In 2010, 
GAO issued a report (Ref. 4; the GAO report) that included a number of 
recommendations for FDA. For example, the GAO report recommended that 
we finalize the proposed rule to establish a notification program for 
GRAS substances, strive to minimize the potential for conflict of 
interest on ``GRAS panels,'' issue guidance on how to document GRAS 
conclusions, and obtain more information about the use of engineered 
nanomaterials. (As we note in section VI.B, this document uses the term 
``GRAS panel'' to mean a panel of individuals convened for the purpose 
of evaluating whether the available scientific data, information, and 
methods establish that a substance is safe under the conditions of its 
intended use in food.) Consistent with the recommendations in the GAO 
report, this document finalizes the GRAS notification procedure as 
requested by GAO. It also announces our intent to issue guidance in the 
near future to: (1) Provide recommendations regarding the use of a 
``GRAS panel,'' including the potential for conflict of interest; and 
(2) remind the food industry that the same standards apply to a 
conclusion of GRAS status regardless of whether the conclusion is 
submitted to us as a GRAS notice or is not submitted to us. (See 
Response 125, Response 128, and Response 129).
    In 2012, we made available a draft guidance entitled ``Draft 
Guidance for Industry: Assessing the Effects of Significant 
Manufacturing Process Changes, Including Emerging Technologies, on the 
Safety and Regulatory Status of Food Ingredients and Food Contact 
Substances, Including Food Ingredients That Are Color Additives'' (Ref. 
5) (77 FR 24722, April 25, 2012). We finalized this guidance in 2014 
(Ref. 6) (79 FR 36533, June 27, 2014). The guidance includes 
recommendations for assessing the effect of a significant manufacturing 
process change (including the use of nanotechnology) on the safety and 
regulatory status of substances used in human food, including those 
that are GRAS. In this guidance, we stated that, at present, for 
nanotechnology applications in food substances, there are questions 
related to the technical evidence of safety as well as the general 
recognition of that safety, that are likely to be sufficient to warrant 
formal premarket review and approval by FDA, rather than to satisfy 
criteria for GRAS status. In addition, in 2011, we made available a 
draft guidance entitled ``Considering Whether an FDA-Regulated Product 
Involves the Application of Nanotechnology'' (Ref. 7) (76 FR 34715, 
June 14, 2011). We finalized this guidance in 2014 (Ref. 8) (June 27, 
2014, 79 FR 36534), which describes our thinking on determining whether 
FDA-regulated products involve the application of nanotechnology.

C. Issues Regarding the Legal and Regulatory Framework for Substances 
Added to Food

    The GAO report discussed issues fundamental to the legal and 
regulatory framework for our oversight of the safety of substances 
added to food, such as the voluntary nature of the GRAS affirmation 
petition process and the proposed GRAS notification procedure. In light 
of these issues, the GAO report recommended that we ask any company 
evaluating whether a substance is GRAS under the conditions of its 
intended use to provide us with basic information about any conclusion 
of GRAS status (Ref. 4). Some comments to this rulemaking raise similar 
issues. For example, some comments address the voluntary nature of the 
GRAS notification procedure or assert that we have implied legal 
authority to require that companies notify us of a conclusion of GRAS 
status (see Comment 1 and Comment 28). Some comments ask us to require 
companies to maintain active

[[Page 54965]]

and accurate listings for all GRAS substances, not just those that are 
the subject of a GRAS regulation or a GRAS notice, in a public database 
(see Comment 3). Some comments ask us to require certain postmarket 
submissions of exposure and safety data related to all GRAS substances, 
to require submissions for conclusions of GRAS status that predate the 
final rule, and to require any notifier who ``withdraws'' a GRAS notice 
or receives an ``insufficient basis letter'' to notify us about any use 
of that substance (see Comment 30). One comment asks us to exclude uses 
of ``novel'' substances from consideration for eligibility for 
classification as GRAS (see Comment 19).
    Some comments discuss an industry practice of convening a ``GRAS 
panel'' of ``qualified experts'' to provide an opinion on whether a 
company's evaluation of the available data and information support a 
conclusion that a substance is safe under the conditions of its 
intended use, and express concern that such a ``GRAS panel'' may base 
its opinion partly on confidential data and information that are 
provided to the GRAS panel, but not provided to us in a submitted GRAS 
notice (see Comment 10 through Comment 14, Comment 69, and Comment 78).
    Some comments express concern that the GRAS notification procedure 
would be viewed as a ``fast-track'' option that would tempt a company 
that should submit a food additive petition to submit a GRAS notice 
instead (see Comment 32). A published critique of the GRAS notification 
procedure (Ref. 9) likewise expresses concern that industry is simply 
using the GRAS notification procedure as an alternative to the food 
additive petition process, contrasting the number of food additive 
petitions filed in recent years with the number of GRAS notices filed 
in recent years. This report also expresses concern that there are an 
indeterminate--but not insignificant--number of industry conclusions of 
GRAS status that are not the subject of a GRAS notice to FDA.
    In this document, we respond to such comments in the context of our 
proposed revisions to the criteria for eligibility for classification 
as GRAS and our proposal to replace one voluntary administrative 
procedure, i.e., the GRAS affirmation petition process, with a 
different voluntary administrative procedure, i.e., the GRAS 
notification procedure. (See Response 1, Response 3, Response 10 
through Response 14, Response 19, Response 28, Response 30, Response 
32, Response 69, and Response 78). As we discuss in Response 28, the 
broader issues raised by these comments about the legal and regulatory 
framework for our oversight of the safety of substances added to food 
are outside the scope of this rulemaking. Thus, this final rule does 
not address the possibility that we might enhance our oversight through 
additional rulemaking or other actions based on our current legal 
authority. Nonetheless, we will continue to consider the broader issues 
raised by these comments and take further action as appropriate under 
our existing authority through future rulemaking. Importantly, however, 
this final rule does establish uniform criteria for describing the 
basis for a conclusion that a substance is GRAS under the conditions of 
its intended use, and those uniform criteria apply to all conclusions 
of GRAS status, not just conclusions of GRAS status that are submitted 
to us as a GRAS notice. As discussed in Response 129, we are issuing a 
guidance directed to any person who evaluates whether the available 
data and information regarding the safety of a substance under the 
conditions of its intended use satisfy GRAS criteria. The purpose of 
the guidance is to: (1) Remind such persons of their responsibilities 
under the FD&C Act regarding a conclusion of GRAS status, regardless of 
whether the conclusion of GRAS status is submitted to us as a GRAS 
notice; and (2) refer such persons to key resources, such as those 
discussed in Response 128, for evaluating the safety of the substance 
under the conditions of its intended use and for evaluating whether the 
available data and information regarding safety satisfy the criteria 
for eligibility for classification as GRAS in Sec.  170.30.

D. Recent FDA Actions Related to GRAS Criteria

    In the following paragraphs, we describe two examples of steps we 
have taken to address concerns about the safety of certain substances 
marketed under the GRAS provision. The first example is partially 
hydrogenated oils (PHOs), which are the primary dietary source of 
industrially produced trans fatty acids, or trans fat. The second 
example is certain uses of caffeine.
    Although we had not listed the most commonly used PHOs in either 
part 182 or part 184, they had been used in food for many years based 
on conclusions of GRAS status by industry. In a notice published in the 
Federal Register of November 8, 2013 (78 FR 67169), we described new 
scientific evidence and the findings of expert scientific panels 
regarding trans fat and requested comments and scientific data and 
information on our tentative determination that PHOs are not GRAS for 
any use in food based on current scientific evidence establishing the 
health risks associated with the consumption of trans fat. In the 
Federal Register of June 17, 2015 (80 FR 34650), we issued a 
declaratory order announcing our final determination that there is no 
longer a consensus among qualified experts that PHOs are GRAS for any 
use in human food.
    The GRAS list in part 182 includes the use of caffeine in cola-type 
beverages at a maximum level of 0.02 percent (Sec.  182.1180). In 2010, 
we issued four warning letters regarding the use of caffeine under 
markedly different conditions of use than the use listed in Sec.  
182.1180, i.e., the use of caffeine as an added ingredient in alcoholic 
beverages (Ref. 10 through Ref. 13). In our letters, we stated that, 
based on the publicly available literature, a number of qualified 
experts have concerns about the safety of caffeinated alcoholic 
beverages. We described these concerns, citing published literature. We 
further stated that FDA is not aware of data or other information to 
establish the safety of caffeine as used in these products. We 
therefore informed the companies who were marketing these caffeinated 
alcoholic beverages that caffeine, as used in the companies' products, 
is an unsafe food additive, and therefore the products are adulterated 
under section 402(a)(2)(C) of the FD&C Act (21 U.S.C. 342(a)(2)(C)). 
(The Alcohol and Tobacco Tax and Trade Bureau (TTB) also notified the 
four companies that if we deem their caffeinated alcohol beverage 
products adulterated under the FD&C Act, TTB would consider them to be 
mislabeled under the Federal Alcohol Administration Act, making it a 
violation for industry members to sell or ship the products in 
interstate or foreign commerce (Ref. 14).) The companies subsequently 
ceased distribution of these products.
    In recent years, other food and beverage products containing 
caffeine as an added substance have been introduced into the 
marketplace, including so-called ``energy drinks'' that are frequently 
marketed for their stimulant properties. When there are new uses of an 
added food substance without FDA's premarket engagement, presumably 
because a manufacturer has concluded that such a use is GRAS, we must 
react to the new uses after they emerge. In such cases, it can be 
challenging for FDA to accurately assess consumption patterns and 
intake levels and to determine whether those new uses are safe and 
lawful in light of all of the available safety data. FDA has engaged 
with the National Academies of Science (Ref. 15), trade associations, 
and other industry representatives, some of

[[Page 54966]]

whom are conducting a systematic review on the health effects 
associated with the consumption of caffeine (Ref. 16 and Ref. 17).

E. Moving Forward Under This Final Rule

    We believe that our filing of more than 600 GRAS notices for 
substances used in human food is evidence that the substitution of a 
GRAS notification procedure for the GRAS affirmation petition process 
has benefits for consumers, FDA, the regulated industry, and other 
stakeholders. We have increased our awareness of the composition of the 
nation's food supply and the dietary exposure to GRAS substances, which 
helps us to ensure the safe use of substances added to food. The 
ongoing submission of GRAS notices provides evidence that our response 
to a GRAS notice can support the marketing of a food substance by the 
regulated industry. Notified substances include substances that are 
intended to address food safety problems (e.g., antimicrobial 
substances and substances intended to reduce acrylamide formation) and 
public health issues (e.g., substances that would reduce levels of 
sodium chloride in food). In addition, the letters we issue responding 
to GRAS notices demonstrate that we inform notifiers of any scientific 
or regulatory issues that call into question a notifier's conclusion of 
GRAS status, and stakeholders have ready access to those letters. As 
discussed in Response 81, we intend to increase the transparency of our 
response letters when a notifier asks us to cease to evaluate a GRAS 
notice.
    In the years since we published the proposed rule, we have taken 
important public health actions with respect to substances used in food 
on the basis of the GRAS provision of the FD&C Act. For example, we 
recently announced an initiative to establish voluntary short-term and 
long-term goals for sodium reduction in a variety of identified 
categories of foods to address the excessive intake of sodium in the 
current population and promote improvements in public health (81 FR 
35363, June 2, 2016). In addition, we recently held a public meeting in 
which we invited public comment on what should be included, changed, or 
even excluded from our guidance entitled ``Guidance for Industry and 
Other Stakeholders: Toxicological Principles for the Safety Assessment 
of Food Ingredients'' (79 FR 64603, October 30, 2014); that guidance is 
intended to help interested parties understand our expectations 
regarding how to determine which toxicity studies are appropriate and 
regarding the design, conduct, and reporting of the results of toxicity 
studies and applies to assessing the safety of GRAS substances. As 
discussed in section I.D, we also have taken key postmarket actions 
such as issuing a declaratory order announcing our final determination 
that there is no longer a consensus among qualified experts that PHOs 
are GRAS for any use in human food, as well as issuing warning letters 
regarding the use of caffeine as an added ingredient in alcoholic 
beverages.
    For reasons such as those discussed in this section, and after 
fully considering comments submitted to this rulemaking, this rule 
announces that we are replacing the former GRAS affirmation petition 
process with a GRAS notification procedure.
    We strongly encourage any company considering the addition of a 
substance to any food on the basis of a conclusion of GRAS status to 
contact us and follow the available procedures for FDA oversight of 
such decisions. As we move forward to implement the GRAS notification 
procedure that is the subject of this rulemaking, we intend to continue 
to closely monitor and assess the ramifications of the use of 
substances without food additive approval or evaluation by FDA through 
the GRAS notification procedure. We intend to take action as 
appropriate, such as we did in the case of PHOs and caffeinated 
alcoholic beverages, particularly when the available data and 
information raise a safety concern about the use of a substance.
    We advise any company that intends to market a food substance on 
the basis of an independent conclusion of GRAS status (i.e., a 
conclusion of GRAS status that would remain with the proponent of the 
conclusion rather than be submitted to us as a GRAS notice) to 
carefully consider whether this use fully satisfies the criteria for 
eligibility for classification as GRAS and to carefully review the 
discussions in this document relevant to those criteria. Fundamental to 
all conclusions of GRAS status is the criterion that general 
recognition of safety requires common knowledge throughout the 
scientific community knowledgeable about the safety of substances 
directly or indirectly added to food that there is reasonable certainty 
that the substance is not harmful under the conditions of its intended 
use (see Sec.  170.30(a)). In addition, the criteria for eligibility 
for classification as GRAS through scientific procedures require that 
general recognition of safety through scientific procedures be based 
upon the application of generally available and accepted scientific 
data, information, or methods, which ordinarily are published, as well 
as the application of scientific principles (Sec.  170.30(b)). Although 
general recognition of safety through scientific procedures may be 
corroborated by the application of unpublished scientific data, 
information, or methods (Sec.  170.30(b)), to satisfy GRAS criteria 
qualified experts must be able to conclude that the substance is not 
harmful under the conditions of its intended use without access to 
``corroborative'' information (see, e.g., Response 9). For example, as 
discussed in Response 69 there could be no basis for a conclusion of 
GRAS status if trade secret information (or other non-public 
information) is necessary for qualified experts to reach a conclusion 
that the notified substance is safe under the conditions of its 
intended use.
    We also advise any company who intends to market a food substance 
on the basis of an independent GRAS conclusion that relies, in whole or 
in part, on the opinion of a specially convened ``GRAS panel'' to 
carefully review the discussions in this document regarding whether and 
how the opinion of a GRAS panel can support an independent conclusion 
of GRAS status. For example, as discussed in Response 10 and Response 
11 whether a published ``GRAS panel'' opinion that discusses data and 
information that are available to the members of the GRAS panel, but 
not generally available to qualified experts, could support an 
independent conclusion of GRAS status would depend on factors such as 
whether that publication includes details similar to details that would 
be included in a publication in the primary scientific literature; the 
subject matter expertise of the members of the GRAS panel; and whether 
the members of the GRAS panel would be considered representative of 
experts qualified by scientific training and experience to evaluate the 
safety of the substance under the conditions of its intended use. For 
example, a published GRAS panel opinion that includes a very general 
statement that a study was conducted and reported no adverse findings 
would not suffice to make the study ``generally available'' as required 
by the criteria for eligibility for classification as GRAS and would 
merely be a generally available opinion about data and information that 
are not generally available. As another example, a ``GRAS panel'' 
opinion published by scientists without expertise appropriate to 
address the applicable safety questions could not provide evidence that 
the conclusions in the publication are ``generally

[[Page 54967]]

accepted.'' Unless both criteria, i.e., ``generally available'' as well 
as ``generally accepted'', are satisfied, there would be no basis for a 
conclusion of GRAS status.

II. Background

A. The Proposed Rule

    We proposed to: (1) Clarify the criteria for eligibility for 
classification as GRAS; and (2) replace the GRAS affirmation petition 
process with a notification procedure through which any interested 
person may notify us of a determination that a particular use of a 
substance is GRAS (62 FR 18938). In the proposed rule, we:
     Discussed the 1958 amendment, including judicial decisions 
bearing on GRAS criteria and the burden on the proponent of a 
conclusion of GRAS status to show that there is a consensus of expert 
opinion regarding the safety of the use of the substance (62 FR 18938 
at 18939);
     Described the history of our approach to the GRAS 
provision, including: (1) A GRAS list, first established in 1959, in 
which we clarified the regulatory status of a multitude of food 
substances that were used in food prior to 1958; (2) opinion letters in 
which Agency officials rendered an informal, non-binding opinion on the 
GRAS status of a use of a substance; (3) an FDA-initiated GRAS review 
to evaluate the available safety information regarding substances 
presumed to be GRAS; and (4) GRAS criteria and the GRAS affirmation 
petition process (62 FR 18938 at 18939 to 18940);
     Discussed ``elements of the GRAS standard,'' in which we 
distinguished the ``technical element'' of the GRAS standard (i.e., 
safety) from the ``common knowledge element'' of the GRAS standard 
(i.e., general recognition) (62 FR 18938 at 18940 to 18941);
     Proposed the submission requirements for the GRAS 
notification procedure, including: (1) A ``GRAS exemption claim,'' in 
which a notifier would take responsibility for a GRAS determination; 
(2) information about the identity of the notified substance; (3) 
information about any self-limiting levels of use; and (4) a 
comprehensive discussion of the basis for the GRAS determination 
(proposed Sec. Sec.  170.36 (c) and 570.36(c));
     Proposed what we would do when we received a GRAS notice, 
including: (1) Acknowledge receipt of the GRAS notice; (2) evaluate 
whether the notice provides a sufficient basis for a GRAS determination 
and respond to the notifier in writing; (3) make readily accessible to 
the public the notice's ``GRAS exemption claim'' and our response to 
the notice; and (4) disclose other releasable information in a notice 
in accordance with our regulations, in part 20 (21 CFR part 20), 
implementing the FOIA (proposed Sec. Sec.  170.36 (d) through (f) and 
570.36(d) through (f)); and
     Proposed to: (1) Convert any GRAS affirmation petition 
that was pending on the effective date of the rule establishing the 
notification procedure to a GRAS notice; and (2) require the petitioner 
to submit an amendment to the converted petition to satisfy the 
procedural requirements of the GRAS notification procedure (proposed 
Sec. Sec.  170.36(g) and 570.36(g)).
    We requested comments on the proposed rule by July 16, 1997.

B. Interim Pilot Program

    In the proposed rule, we invited interested persons who determine 
that a use of a substance is GRAS to notify us of those determinations 
as described in the proposed rule (62 FR 18938 at 18954). We explained 
that we would administer the notices as described in the proposed rule 
(i.e., we would acknowledge receipt of the notice, respond in writing 
to the notifier, and make publicly accessible a copy of all ``GRAS 
exemption claims'' and our response). Although we would make a good 
faith effort to respond within the proposed 90-day timeframe, we would 
not be bound by such a timeframe. We stated that we would determine 
whether our experience in administering such notices suggests 
modifications to the proposed procedure.
    CFSAN received its first GRAS notice in 1998. CFSAN wrote a 
memorandum documenting its experience in evaluating GRAS notices during 
the period 1998-2009 (Ref. 18, ``CFSAN's 2010 experience document'') 
and added that memorandum to the docket for this rulemaking in 2010. 
Unless we say otherwise, the discussions in this document referring to 
FDA's experience during the Interim Pilot program refer to CFSAN's 
experience.
    During the Interim Pilot program, CFSAN's response to a GRAS notice 
fell into three categories as shown in table 1 in this document. We 
refer to these categories of response throughout this document. Table 1 
in CFSAN's 2010 experience document shows the category of response for 
CFSAN's GRAS notices that came to closure by December 31, 2009. CFSAN 
has now written an updated memorandum showing the category of response 
for CFSAN's GRAS notices that came to closure by December 31, 2015 
(Ref. 19).

  Table 1--Categories of Letters Responding to a GRAS Notice During the
                          Interim Pilot Program
------------------------------------------------------------------------
    Category of response letter         Typical text of the response
------------------------------------------------------------------------
``No questions letter''...........  Based on the information provided by
                                     the notifier, as well as other
                                     information available to FDA, the
                                     Agency has no questions at this
                                     time regarding the notifier's
                                     conclusion that the notified
                                     substance is GRAS under the
                                     intended conditions of use. The
                                     Agency has not, however, made its
                                     own determination regarding the
                                     GRAS status of the subject use of
                                     the notified substance. As always,
                                     it is the continuing responsibility
                                     of the notifier to ensure that food
                                     ingredients that the firm markets
                                     are safe, and are otherwise in
                                     compliance with all applicable
                                     legal and regulatory requirements.
``Insufficient basis letter''.....  FDA has evaluated the information
                                     that the notifier discusses in its
                                     GRAS notice as well as other data
                                     and information that are available
                                     to us. The notice does not provide
                                     a sufficient basis for a
                                     determination that the notified
                                     substance is GRAS under the
                                     conditions of its intended use.
``Cease to evaluate letter''......  In correspondence dated [month, day,
                                     year], you asked that we cease to
                                     evaluate your notice. We ceased to
                                     evaluate your GRAS notice,
                                     effective the date we received your
                                     correspondence.
------------------------------------------------------------------------

    In this document, we frequently cite CFSAN's experience during the 
Interim Pilot program when responding to comments asking us to clarify 
how we intend to administer various provisions of the rule, as well as 
state our intent to continue the applicable practice in the future, 
because this experience is relevant to our administration of the GRAS 
notification program. Nonetheless, we intend to adapt our practices, 
consistent with the provisions of this rule, as circumstances warrant 
and as necessary to administer the GRAS notification program consistent

[[Page 54968]]

with appropriate public health policy, current scientific information, 
our available resources, and the scientific and regulatory issues 
raised by specific GRAS notices. For example, as discussed in Response 
92 we intend to continue to include standard language such as that 
shown in table 1 in responding to GRAS notices. However, this language 
may evolve over time.
    CVM established its Interim Pilot program in June, 2010 (75 FR 
31800, Docket No. FDA-2010-N-0215) and filed its first GRAS notice in 
December 2010. CVM did not have any experience to document as of 2010 
and, thus, had not written its own experience document at that time. As 
of December 31, 2015, CVM had responded to 18 GRAS notices, and has now 
documented its experience with those 18 GRAS notices with respect to 
some comments specifically directed to the GRAS notification procedure 
administered by CVM (Ref. 20; ``CVM's experience document''). We 
discuss CVM's experience with GRAS notices submitted for substances 
intended for use in animal food in section XXV.
    We are ending both the CFSAN Interim Pilot program announced in the 
proposed rule, and the CVM pilot program announced in Docket No. FDA-
2010-N-0215, as of October 17, 2016. On that date, the final rule 
becomes effective and will govern the GRAS notification procedure.

C. 2010 Report of the Government Accountability Office

    As noted in section I.B, from 2008 to 2010 GAO conducted a study 
related to ingredients used in human food on the basis of the GRAS 
provision of section 201(s) of the FD&C Act. In 2010, GAO issued a 
report (Ref. 4) that included a number of recommendations for FDA. We 
responded to the GAO's recommendations, and that response is also 
included in the GAO report.

D. 2010 Notice Reopening the Comment Period

    As noted in section I.A, we reopened the comment period for the 
proposed rule to update comments (75 FR 81536). We did so because of 
the length of time that had elapsed since publication of the proposed 
rule and because we had identified a number of issues within the scope 
of the proposed rule that may require further clarification based on 
CFSAN's experience with GRAS notices during the Interim Pilot program, 
comments we received on the proposed rule, and GAO's recommendations 
(75 FR 81536 at 81537). These issues related to the proposed revisions 
to the criteria for eligibility for classification as GRAS (Issue 1), 
the proposed establishment of a notification procedure (Issues 2 
through 16), and the effect of the proposed notification procedure on 
existing GRAS affirmation petitions (Issue 17). Accordingly, we 
requested comments, by March 28, 2011, on the entire proposed rule as 
well as on the specific issues identified in the 2010 notice.
    In Issue 2 in the 2010 notice, we explained our reasons for 
tentatively concluding that the terms ``conclude'' and ``conclusion'' 
would be more appropriate in lieu of ``determine'' and 
``determination'' and requested comment on these terms. In the 
remainder of this document, we generally use the terms ``conclude'' and 
``conclusion'' in lieu of ``determine'' and ``determination'' except 
when we are describing provisions of the proposed rule (see Response 
41).

E. Public Comments

    We received submissions, each containing one or more comments, from 
diverse members of the public, including manufacturers; trade 
organizations; consulting firms; law firms; public advocacy groups; 
non-profit organizations; individuals; a Federal Agency; and other 
organizations. In the remainder of this document, we describe these 
comments, respond to them, and explain any revisions we made to the 
proposed rule.
    Some comments address issues that are outside the scope of this 
rule. For example, some comments ask us to add a new definition to part 
170, to define the term ``harm'' that is used in our current definition 
of ``safe'' or ``safety'' (Sec.  170.3(e)(i)) (where ``safe'' or 
``safety'' means that there is a reasonable certainty in the minds of 
competent scientists that the substance is not harmful under the 
intended conditions of use). We did not propose to add a definition of 
the term ``harm'' or ask for comment on whether we should do so, and 
adding a new definition in the final rule for a term that is used in 
the definition of ``safe'' and ``safety'' would broadly affect our 
regulations for food additives and GRAS substances without opportunity 
for public comment. As another example, one comment asks us to prepare 
an alphabetical index of food additive and GRAS regulations and cites 
the alphabetical list in our Investigations Operations Manual as 
evidence that it is feasible to develop such a list. Regardless of 
whether it is feasible to develop such a list, doing so is not within 
the scope of our proposal to establish a notification procedure for 
uses of substances that are not listed in our regulations. We do not 
discuss such comments in this document.

F. Applicability of Discussions in This Document to Both the Human Food 
Regulations and the Animal Food Regulations

    To simplify the discussion in this document, in general we refer to 
provisions of the proposed rule and the 2010 notice from the 
perspective of the regulations that would be established in part 170. 
Unless we say otherwise, however, the issues discussed also apply to 
the corresponding provisions for part 570. Any reference to CFSAN 
documents (such as guidance documents) is specific to CFSAN. See 
section XXV for a discussion of comments and issues specifically 
directed to substances used in animal food.

G. Use of Pronouns in This Document

    In this document, terms such as ``we,'' ``our,'' and ``us'' refer 
to FDA. The regulatory text of the final rule for the GRAS notification 
procedure specifies that the terms ``you'' and ``your'' refer to a 
notifier (i.e., a person who is responsible for a GRAS notice). To 
simplify the discussion in this document, in general we use pronouns 
such as ``you'' and ``your'' to refer to a notifier, even though some 
persons who read this document may not be notifiers.

H. Summary of Principal Changes to the Proposed Notification Procedure

    In table 2, we briefly describe the principal changes to the GRAS 
notification procedure in the final rule compared to the proposed rule. 
In the remainder of this document, we discuss each of these changes in 
more detail, including our response to comments relevant to these 
changes. See table 28 for principal changes that are specific to the 
GRAS notification procedure for substances used in animal food in part 
570.

[[Page 54969]]



   Table 2--Summary of Principal Changes to the Proposed Notification
                                Procedure
------------------------------------------------------------------------
             Proposed rule                          Final rule
------------------------------------------------------------------------
Would not define any terms.............  Defines the terms
                                          ``amendment,'' ``GRAS,''
                                          ``GRAS notice,'' ``notified
                                          substance,'' ``notifier,''
                                          ``qualified expert,''
                                          ``supplement,'' ``we, our, and
                                          us,'' and ``you and your.''
Referred to a ``GRAS determination''...  Refers to a ``GRAS conclusion''
                                          or ``conclusion of GRAS
                                          status.''
Referred to the statutory GRAS           Refers to the statutory GRAS
 provision as an ``exemption''.           provision as an ``exclusion.''
Would not use ``Plain Language''         Uses ``Plain Language''
 techniques as outlined in a              techniques such as pronouns
 Presidential Memorandum dated June 1,    and short regulatory sections.
 1998 (Ref. 21) and in ``Improving
 Electronic Dockets on Regulations.gov
 and the Federal Docket Management
 System: Best Practices for Federal
 Agencies'' (Ref. 22).
Was silent on whether you could          Expressly provides for you to
 incorporate into your GRAS notice        incorporate into your GRAS
 specifically identified data and         notice specifically identified
 information previously submitted to      data and information
 CFSAN or CVM.                            previously submitted to CFSAN
                                          or CVM.
Would not specify individual parts of a  Specifies the seven parts of a
 GRAS notice.                             GRAS notice.
Would require three paper copies of a    Provides that you may submit a
 GRAS notice.                             GRAS notice either in
                                          electronic format that is
                                          accessible for our evaluation
                                          or on paper. If you send your
                                          GRAS notice on paper, a single
                                          paper copy is sufficient.
Referred to dated and signed statements  Refers to dated and signed
 in a GRAS notice as a ``claim''.         statements in a GRAS notice as
                                          ``signed statements.''
Assumed that a notice will not contain   Specifies that you must not
 any information that is protected from   include any information that
 public disclosure under the FOIA.        is trade secret or
                                          confidential commercial
                                          information in certain
                                          sections of the signed
                                          statements in your GRAS
                                          notice, but does not otherwise
                                          prohibit the submission of
                                          information that is protected
                                          from public disclosure under
                                          the FOIA.
Would require that you inform us of the  Requires that you provide an
 ``common or usual name'' of the          ``appropriately descriptive
 notified substance.                      term'' for the notified
                                          substance.
Would not require that you state your    Requires that you state your
 view as to whether any data and          view as to whether any of the
 information in your GRAS notice are      data and information in your
 exempt from disclosure under the FOIA.   GRAS notice are exempt from
                                          disclosure under the FOIA
                                          (e.g., as trade secret or as
                                          commercial or financial
                                          information that is privileged
                                          or confidential).
Would not expressly require a signed     Expressly requires a signed
 certification regarding the              certification that to the best
 representative and balanced nature of    of your knowledge, your GRAS
 the GRAS notice.                         notice is a complete,
                                          representative, and balanced
                                          submission that includes
                                          unfavorable information, as
                                          well as favorable information,
                                          known to you and pertinent to
                                          the evaluation of the safety
                                          and GRAS status of the use of
                                          the substance.
For a notified substance of natural      For a notified substance of
 biological origin, would require         natural biological origin,
 source information such as genus and     requires source information
 species.                                 that includes applicable data
                                          and information at the sub-
                                          species level (e.g., variety,
                                          strain) in addition to genus
                                          and species.
Would require the method of manufacture  Requires a description of the
 (excluding any trade secrets).           method of manufacture of the
                                          notified substance in
                                          sufficient detail to evaluate
                                          the safety of the notified
                                          substance as manufactured; you
                                          may include trade secret
                                          information.
Would not expressly require relevant     When necessary to demonstrate
 data and information bearing on the      safety, expressly requires
 physical or other technical effect the   relevant data and information
 notified substance is intended to        bearing on the physical or
 produce.                                 other technical effect the
                                          notified substance is intended
                                          to produce, including the
                                          quantity of the notified
                                          substance required to produce
                                          such effect.
Would require consideration of dietary   Separates the statutory
 exposure as part of a comprehensive      language of section
 discussion of the data and information   409(c)(5)(A) and (B) of the
 that you rely on to establish safety,    FD&C Act into two distinct
 using the statutory language of          parts of the GRAS notice: (1)
 section 409(c)(5)(A) and (B) of the      Part 3, which addresses how
 FD&C Act.                                much of the notified substance
                                          consumers would eat as part of
                                          the total diet (including
                                          exposure from its intended use
                                          and all sources in the diet),
                                          as well as how much consumers
                                          would eat of other substances
                                          (e.g., contaminants or by-
                                          products); and (2) Part 6,
                                          which requires that you
                                          address, in your narrative,
                                          the safety of the notified
                                          substance, considering all
                                          dietary sources and taking
                                          into account any chemically or
                                          pharmacologically related
                                          substances in such diet.
Would require a ``comprehensive          Requires a narrative (Part 6 of
 discussion'' of, and citations to,       a GRAS notice) and a list of
 generally available and accepted         supporting data and
 scientific data, information, methods,   information (Part 7 of a GRAS
 or principles that you rely on to        notice).
 establish safety.
Would not require consideration of       Expressly requires
 dietary exposure as part of a            consideration of dietary
 comprehensive discussion of the data     exposure, regardless of
 and information that you rely on to      whether your conclusion of
 establish safety for a conclusion of     GRAS status is through
 GRAS status through experience based     scientific procedures or
 on common use in food.                   through experience based on
                                          common use in food.
Would require a comprehensive            Requires that you either: (1)
 discussion of any reports of             Identify, discuss, and place
 investigations or other information      in context, data and
 that may appear to be inconsistent       information that are, or may
 with the GRAS determination.             appear to be, inconsistent
                                          with your conclusion of GRAS
                                          status; or (2) state that you
                                          have reviewed the available
                                          data and information and are
                                          not aware of any data and
                                          information that are, or may
                                          appear to be, inconsistent
                                          with your conclusion of GRAS
                                          status.
Would not require that you identify      If you view any of the data and
 data and information that you view as    information in your notice as
 exempt from disclosure under the FOIA.   exempt from disclosure under
                                          the FOIA, requires that you
                                          identify the specific data and
                                          information.

[[Page 54970]]

 
Would not require that you explain how   Requires that you explain how
 there could be a basis for a             there could be a basis for a
 conclusion of GRAS status if qualified   conclusion of GRAS status if
 experts generally do not have access     qualified experts generally do
 to non-public, safety-related data and   not have access to non-public,
 information.                             safety-related data and
                                          information.
Would require that the comprehensive     Uses the term ``generally
 discussion include the basis for         recognized'' rather than the
 concluding that there is consensus       term ``consensus.''
 among qualified experts that there is
 reasonable certainty that the
 substance is not harmful under the
 intended conditions of use.
Was silent on whether you could submit   Expressly provides for you to
 an amendment to a GRAS notice.           submit a timely ``amendment''
                                          to a GRAS notice before we
                                          respond to your GRAS notice or
                                          cease to evaluate your GRAS
                                          notice.
Considered that it was implicit that     Expressly provides that you may
 you could ask us to cease to evaluate    ask us to cease to evaluate
 a GRAS notice.                           your GRAS notice, and
                                          expressly provides that we
                                          will inform you of our
                                          decision regarding your
                                          request.
We would acknowledge receipt of a GRAS   We will conduct an initial
 notice within 30 days of receipt.        evaluation of your submission
                                          to determine whether to file
                                          it as a GRAS notice for
                                          evaluation of your view that
                                          the notified substance is GRAS
                                          under the conditions of its
                                          intended use. If we file your
                                          submission as a GRAS notice,
                                          we will send you a letter that
                                          informs you of the date of
                                          filing. If we do not file your
                                          submission as a GRAS notice,
                                          we will send you a letter that
                                          informs you of that fact and
                                          provides our reasons for not
                                          filing the submission as a
                                          GRAS notice.
We would respond to you in writing       Within 180 days of filing, we
 within 90 days of receipt of the         will respond to you by letter
 notice.                                  based on our evaluation of
                                          your notice. We may extend the
                                          180 day timeframe by 90 days
                                          on an as needed basis. If we
                                          extend the timeframe, we will
                                          inform you of the extension as
                                          soon as practicable but no
                                          later than within 180 days of
                                          filing.
Was silent on procedures that apply      Specifies procedures that apply
 when the intended conditions of use of   when the intended conditions
 a notified substance include use in a    of use of a notified substance
 product or products subject to           in human food include use in a
 regulation by USDA's FSIS.               product or products subject to
                                          regulation by USDA's FSIS.
We noted that, although the decision to  The regulatory text of the
 submit a GRAS notice would be            final rule specifies that the
 voluntary, the provisions governing      data and information in a GRAS
 the GRAS notification procedure,         notice are considered a
 including the information to be          mandatory, rather than
 submitted, would be mandatory.           voluntary, submission for
                                          purposes of its status under
                                          the FOIA and our public
                                          information requirements in
                                          part 20.
Was silent on whether you could submit   Expressly provides for you to
 additional information to a GRAS         submit a ``supplement'' to a
 notice after we respond to it.           GRAS notice after we respond
                                          to your GRAS notice or cease
                                          to evaluate it.
Would presumptively convert any filed,   On the effective date of the
 pending GRAS affirmation petition to a   rule, we will close the docket
 notice on the effective date of the      for any GRAS affirmation
 rule. If we did not receive an           petition that is still
 amendment from the petitioner within     pending. Any person who
 90 days of the effective date of the     submitted a GRAS affirmation
 rule, with information and statements    petition that is closed may
 analogous to those in the proposed       submit a GRAS notice and
 ``GRAS exemption claim,'' we would       request that we incorporate
 consider the converted petition to be    the GRAS affirmation petition.
 inadequate as a notice and would send
 the petitioner a letter to that
 effect..
------------------------------------------------------------------------

III. Legal Authority

    We are amending our regulations in 21 CFR parts 170 and 570 to 
replace the voluntary GRAS affirmation petition process with a 
voluntary GRAS notification procedure and to clarify when the intended 
conditions of use of a substance are eligible for classification as 
GRAS under our authority in sections 201, 402, 409, and 701 of the FD&C 
Act (21 U.S.C. 321, 342, 348, and 371). Section 701(a) of the FD&C Act 
authorizes the Secretary of the Department of Health and Human Services 
(the Secretary) to issue regulations for the efficient administration 
of the FD&C Act; under section 1003(d) of the FD&C Act (21 U.S.C. 
393(d)), the Secretary is responsible for executing the FD&C Act, 
including section 701(a), through the Commissioner of Food and Drugs. 
The FD&C Act requires that all food additives (as defined by section 
201(s) of the FD&C Act) be approved by FDA before they are marketed 
(sections 402(a)(2)(C) and 409 of the FD&C Act). Section 201(s) 
excludes from the definition of a food additive a substance generally 
recognized, among experts qualified by scientific training and 
experience to evaluate its safety, as having been adequately shown 
through scientific procedures (or, in the case of a substance used in 
food prior to January 1, 1958, through either scientific procedures or 
experience based on common use in food) to be safe under the conditions 
of its intended use.
    These regulations will help FDA administer efficiently the FD&C 
Act's various provisions that apply to the use of substances added to 
food, specifically on the question of whether a substance is GRAS under 
the conditions of its intended use or is a food additive subject to 
FDA's premarket review. These regulations provide clarification of the 
GRAS criteria and provide a more efficient procedure.
    As an error, the authority citation that we listed for the proposed 
amendments to part 570 did not include an existing authority citation, 
i.e., section 408 of the FD&C Act (21 U.S.C. 346a). Nothing in the 
proposed rule would alter the citation to section 408. Therefore, the 
authority citation for 21 CFR part 570 continues to include section 
408.
    As an error, the authority citation that we listed for the proposed 
amendments to part 170 stated that we were revising the authority 
citation. Nothing in the proposed rule would alter the authority 
citation for part 170. Therefore, the authority citation for 21 CFR 
part 170 states that the authority citation ``continues to read'' 
rather than ``is revised to read.''
    (Comment 1) Some comments state that the proposed rule violates the 
1958 amendment because FDA would not be

[[Page 54971]]

fulfilling its statutory duty to oversee food additives, and, 
therefore, FDA's interpretation of the GRAS provision is arbitrary and 
capricious. The comments state that the proposed rule violates the 1958 
amendment because it would not require companies to notify FDA of a 
conclusion that the use of a substance is GRAS. One comment states that 
without mandatory submissions FDA lacks a ``comprehensive catalog'' of 
such substances and their dietary exposure, and therefore cannot 
``police the border between food additives and GRAS substances'' and 
that FDA and food manufacturers do not have access to accurate exposure 
data and cannot assess the cumulative effect of similar substances. The 
comment further states that because the proposed rule ``establishes no 
real oversight over the safety of GRAS substances'' it violates the 
1958 amendment.
    (Response 1) We disagree that the voluntary nature of the GRAS 
notification procedure violates the 1958 amendment. The FD&C Act 
provides for premarket review by FDA of a food additive, and excludes 
from this review any substance that is generally recognized, among 
qualified experts, to be safe under the conditions of its intended use. 
Although the FD&C Act specifically provides for our review of food 
additives, it is silent with respect to industry submissions to us on 
the use of GRAS substances. To administer the provisions of the FD&C 
Act with respect to the use of GRAS substances, we are retaining the 
voluntary nature of the GRAS administrative procedure. This rule 
replaces one longstanding voluntary administrative procedure with a 
different voluntary administrative procedure.

IV. General Comments on the Proposed Rule

    (Comment 2) One comment states that the rule does not give 
consumers an opportunity to participate in the process before a 
substance is used in food. Another comment asserts that the lack of an 
opportunity for public comment or participation is a ``major flaw'' in 
the rule.
    (Response 2) We disagree that the GRAS notification procedure does 
not allow for public participation. We proactively disclose to the 
public information about each GRAS notice that we have filed for 
evaluation, including the name and address of the notifier; the name of 
the notified substance; the intended conditions of use of the notified 
substance; and the statutory basis for the conclusion of GRAS status 
(i.e., through scientific procedures or through experience based on 
common use in food). In the past, outside parties who have accessed 
this information have made us aware of dissenting views about whether 
available data and information support a conclusion that a notified 
substance is safe under the conditions of its intended use (see 
sections III.C.2, III.E, and III.I.1 in CFSAN's 2010 experience 
document) (Ref. 18). We continue to welcome substantive information 
from stakeholders regarding the safety of a notified substance. We 
advise stakeholders who wish to provide us with such substantive 
information to submit it to the same address where a notifier would 
send a GRAS notice and ask us to add it to the administrative file for 
the applicable GRAS notice. This administrative file is maintained by 
the responsible Center (i.e., CFSAN or CVM). We would consider the 
submitted information, along with other information that is available 
to us, on a case-by-case basis.
    (Comment 3) One comment asks us to require companies to maintain 
active and accurate registrations for GRAS substances in a public 
database.
    (Response 3) We decline this request. This comment is suggesting a 
process not within our regulatory framework and does not provide a 
legal basis whereby we could require companies to maintain 
registrations in a public database for substances that are used in food 
on the basis of the GRAS provision in section 201(s) of the FD&C Act. 
We note, however, that the final rule provides a framework for making 
the GRAS notices, and our responses to these notices, available to the 
public.
    (Comment 4) One comment asks us to specify whether the notified 
substance would be for human or animal consumption. Another comment 
notes that specifying whether the notified substance is intended for 
human or animal consumption is important because food for humans is not 
necessarily appropriate for animals and vice versa.
    (Response 4) We agree with these comments. This rule establishes 
requirements for a GRAS notice about the intended use of a notified 
substance in human food in part 170 and establishes separate 
requirements for a GRAS notice about the intended use of a notified 
substance in animal food in part 570. Regardless of whether the 
notified substance would be used in human food or in animal food, the 
notifier must specify the intended conditions of use (see Sec. Sec.  
170.225(c)(4) and 570.225(c)(4)). As discussed in Response 90, we 
include the intended conditions of use in our publicly available 
letters responding to GRAS notices.
    (Comment 5) One comment notes that the experience highlighted in 
CFSAN's experience document (Ref. 18) can provide valuable learning 
that can be of benefit to CVM and asks CFSAN and CVM to strive for 
harmonization of their requirements and policies in all areas, so the 
process is not more stringent for one industry than the other.
    (Response 5) We agree that CFSAN and CVM can learn from each 
other's experience with the implementation of the GRAS notification 
procedure and that procedural and scientific requirements should be 
consistent as much as is feasible and appropriate. As noted in section 
II.B, CVM has now documented its experience with 18 GRAS notices with 
respect to some comments specifically directed to the GRAS notification 
procedure administered by CVM (Ref. 20).
    (Comment 6) One comment urges CFSAN and CVM to put forth similar 
training and resources for staff assigned to evaluate GRAS notices to 
decrease the time necessary to complete the evaluation of a GRAS 
notice.
    (Response 6) We staff, equip, and train our employees consistent 
with our priorities and budgets, which are specific to each Center. As 
a practical matter, our current organizational framework, in which 
CFSAN and CVM are both components of the Office of Foods and Veterinary 
Medicine, promotes interactions between staff in the two Centers.

V. Comments on the Definition of Scientific Procedures

    We proposed to amend the definition of ``scientific procedures'' to 
specify that scientific procedures include scientific data (such as 
human, animal, analytical, or other scientific studies), information, 
methods, and principles, whether published or unpublished, appropriate 
to establish the safety of a substance. In the 2010 notice, we 
described comments relevant to this proposed amendment, including 
comments that support it and a comment that objected to it because, 
under the proposed amendment, an ``unpublished principle'' could 
inappropriately be considered a sufficient scientific procedure for 
demonstrating the safety of a food substance. We also noted that we had 
reviewed our use of the term ``study'' in the proposed companion change 
to the definition of scientific procedures and explained our view that, 
to be a ``procedure,'' data, information, methods, or principles would 
need to be acquired or applied. We stated that we were considering 
whether to revise the

[[Page 54972]]

definition of scientific procedures in Sec.  170.3(h) to include the 
application of scientific data (including, as appropriate, data from 
human, animal, analytical, and other scientific studies), information, 
and methods, whether published or unpublished, as well as the 
application of scientific principles, appropriate to establish the 
safety of a substance (see Issue 1, 75 FR 81536 at 81537-81538). We 
requested comment on this issue.
    Several comments support the proposed amendment to the definition 
of scientific procedures as described in the proposed rule, with the 
potential modifications described in the 2010 notice, because the 
revised definition would more accurately reflect the state of 
contemporary science than the definition it would replace. Some 
comments express the view that specifying that it is ``the 
application'' of unpublished scientific data, information, or methods 
that would corroborate GRAS status would make it clear that a 
submission to us regarding a conclusion of GRAS status may include 
discussions of unpublished studies. In the following paragraphs, we 
discuss comments that suggest additional changes to the definition of 
``scientific procedures.'' After considering these comments, we are 
finalizing the definition of scientific procedures as proposed, with 
the modifications described in the 2010 notice and with editorial 
changes as shown in table 29.
    (Comment 7) One comment that supports the potential modifications 
to the definition of ``scientific procedures'' as described in the 2010 
notice asks us to incorporate an additional clarification that 
``scientific principles appropriate to establishing the safety of a 
substance'' encompass consideration of both the data supporting the 
safety of the substance and the probable dietary exposure.
    (Response 7) To the extent that the comment means that ``scientific 
procedures'' (rather than ``scientific principles'') encompass 
consideration of both the data supporting the safety of the substance 
and the probable dietary exposure, we agree. However, it is not 
necessary to revise the definition of scientific procedures to make 
that clear. The definition of ``scientific procedures'' already 
specifies the application of data from human, animal, analytical, or 
other scientific studies, and the definition of ``safe'' or ``safety'' 
in Sec.  170.3(i) includes probable dietary exposure as a factor that 
must be considered in determining safety.
    As discussed in the 2010 notice, ``principle'' can be defined as a 
fundamental cause or basis of something; a primary element, force, or 
law determining a particular result; or a fundamental truth or 
proposition on which others depend. Thus, a principle is a different 
genre than data, information, and methods. Therefore, although we agree 
that ``scientific procedures'' encompass consideration of both the data 
supporting the safety of the substance and the probable dietary 
exposure, we disagree that the data supporting the safety of the 
substance and the probable dietary exposure are ``scientific 
principles.''

VI. Comments on the Criteria for Eligibility for Classification as GRAS

    Section 170.30 specifies three types of criteria for eligibility 
for classification as GRAS: (1) General criteria; (2) criteria for 
classification as GRAS through scientific procedures; and (3) criteria 
for classification as GRAS through experience based on common use in 
food. We proposed to amend all three criteria to: (1) Clarify that the 
safety standard for a GRAS substance is identical to the safety 
standard for a food additive; (2) clarify the types of technical 
evidence of safety that could form the basis for classification as GRAS 
through scientific procedures, and clarify the role of publication in 
establishing general recognition of safety through scientific 
procedures; and (3) make conforming changes to the criteria for 
eligibility for classification as GRAS through experience based on 
common use in food. We proposed these amendments in association with 
our concurrent proposal to replace the GRAS affirmation petition 
process with a GRAS notification procedure. In the 2010 notice, we 
stated that we were considering an additional revision to correspond 
with the revision to the definition of scientific procedures (see 
section V in this document and Issue 1, 75 FR 81536 at 81537-81538 in 
the 2010 notice).
    In the following sections, we discuss comments that disagree with 
one or more aspects of our proposal to amend the criteria for 
eligibility for classification as GRAS, with the potential 
modifications described in the 2010 notice (see, e.g., Comment 9 and 
Comment 13); ask us to clarify how we will interpret the revised 
criteria or offer suggestions for how we should interpret the revised 
criteria (see, e.g., Comment 12, Comment 16, Comment 17, and Comment 
18); or suggest one or more changes to the revised criteria (see, e.g., 
Comment 10, Comment 19, and Comment 20). After considering these 
comments, we are establishing the criteria for eligibility for 
classification as GRAS for use of a substance in human food as 
proposed, with the modification we described in the 2010 notice and 
with editorial, clarifying, and conforming changes as shown in table 
29. See section XXV.B for a description of additional changes we made 
to the criteria for eligibility for classification as GRAS for use of a 
substance in animal food.

A. General Criteria for Eligibility for Classification as GRAS

    We proposed to revise the final sentence of Sec.  170.30(a) to 
specify that general recognition of safety requires common knowledge 
throughout the scientific community knowledgeable about the safety of 
substances directly or indirectly added to food that there is 
reasonable certainty that the substance is not harmful under the 
intended conditions of use. As discussed in the proposed rule, we 
proposed this revision to clarify that the safety standard for a GRAS 
substance is identical to the safety standard for food additives (see 
Sec.  170.3(i)) and that a GRAS substance is neither more safe, nor 
less safe, than an approved food additive (62 FR 18938 at 18942). We 
received no comments that disagreed with this proposed revision and are 
finalizing Sec.  170.30(a) as proposed with conforming changes as shown 
in table 29.
    See section XXV.B regarding revisions to the general criteria for 
eligibility for classification as GRAS for a substance used in animal 
food.

B. Criteria for Eligibility for Classification as GRAS Through 
Scientific Procedures

    We proposed to amend the criteria for eligibility for 
classification as GRAS through scientific procedures to: (1) Require 
that the data and information for general recognition of safety be 
``generally available and accepted,'' and (2) broaden the types of 
acceptable data and information by replacing ``studies'' with ``data, 
information, methods, or principles.'' In the 2010 notice, we stated 
that we were considering whether to revise these criteria with respect 
to the types of acceptable data and information to include ``the 
application'' of generally available and accepted scientific data, 
information, or methods, as well as ``the application'' of scientific 
principles'' (see section V in this document and Issue 1, 75 FR 81536 
at 81537-81538 in the 2010 notice).
    See section XXV.B regarding revisions to the criteria for 
eligibility for classification as GRAS through scientific procedures 
for a substance used in animal food.

[[Page 54973]]

    (Comment 8) One comment asserts that the criterion for the 
generally available data or information establishing safety to 
ordinarily be published is artificial. Other comments point out that 
information that is not published can nonetheless be considered 
``generally available.'' Some comments object to the proposed amendment 
to the criteria for eligibility for classification as GRAS through 
scientific procedures and assert that it would de-emphasize or 
eliminate the existing criterion for peer-reviewed studies.
    (Response 8) Regardless of whether the data and information are 
published or unpublished, under the revised criteria a GRAS conclusion 
must be based on data and information that are generally available and 
accepted, and as such, are publicly available. As we stated in the 
proposed rule, the common knowledge element of the GRAS standard 
precludes a GRAS conclusion if the data and information (e.g., as 
evaluated by a ``GRAS panel'') are only available in files that are not 
publicly accessible, such as in confidential industry files (62 FR 
18938 at 18943). We disagree that the criterion for the generally 
available data or information establishing safety to ordinarily be 
published is artificial. Publication in a peer-reviewed scientific 
journal is the usual mechanism to establish that scientific information 
is generally available, provided that the journal is representative of 
scientific publications accessed by the expert scientific community (62 
FR 18938 at 18943). Nonetheless, the revised criteria provide 
flexibility for supporting a conclusion of GRAS status through the 
application of scientific data, information, or methods that are 
generally available through a mechanism other than publication in a 
peer-reviewed scientific journal, such as publication in a textbook and 
other sources of technical literature. One example of another source of 
technical literature is the Joint Expert Committee on Food Additives 
(JECFA, a joint committee of the Food and Agriculture Organization/
World Health Organization). We note, however, that the mere fact that 
data and information are published or otherwise publicly available does 
not satisfy the criteria for general recognition of safety. Regardless 
of the mechanism of making data and information generally available to 
qualified experts, it must be plausible that qualified experts would be 
accessing those data and information using that mechanism. For example, 
scientists who routinely access peer-reviewed journals in electronic 
form on the Internet may avoid Internet ``publications'' about a 
scientific topic when the ``publication'' is not associated with a 
reputable scientific institution.
    We have not changed our position on the importance of peer review. 
The basis for GRAS status continues to be the application of generally 
available scientific data, information, and methods, which ordinarily 
are published (and, thus, are subject to peer review as part of the 
scientific publication process for most journals). We continue to 
believe that whether scientific data, information, and methods have 
been peer reviewed before publication in a scientific journal that is 
representative of scientific publications accessed by the expert 
scientific community is a factor that bears on the objectivity and 
scientific merit of study, and is a variable we consider in determining 
whether experts accept the report of a scientific investigation as a 
credible report and whether there is general knowledge of the 
scientific investigation.
    CFSAN's 2010 experience document (Ref. 18) provides factual 
information on how CFSAN already has interpreted the criteria for 
eligibility for classification of GRAS status through scientific 
procedures for GRAS notices CFSAN received during the Interim Pilot 
program (see section III.A.1 of CFSAN's 2010 experience document), and 
we intend to continue this approach in the future. In most cases, a 
submitted GRAS notice described a mixture of information published in 
peer-reviewed journals, information (such as in textbooks) that was 
generally available in a form other than a peer-reviewed journal, and 
unpublished information. As shown in table 1 in CFSAN's 2016 experience 
document, CFSAN had no questions about GRAS status based on this 
mixture of information in approximately 81 percent of the GRAS notices 
CFSAN evaluated between 1998 and 2015 (Ref. 19). Importantly, CFSAN's 
evaluation of the basis for a conclusion that a use of a food substance 
is GRAS in addition to being safe was a case-by-case evaluation. As 
discussed in section III.A.4 of CFSAN's 2010 experience document, in 
some cases it was CFSAN's view that the available data and information 
were sufficient to demonstrate safety, but not GRAS status, and CFSAN 
established a food additive regulation for the use of the substance in 
response to a food additive petition for that use (Ref. 18).
    (Comment 9) Some comments state that all available relevant data, 
including unpublished data, should be used in evaluating GRAS status. 
Some of these comments cited the placement of the word ``ordinarily'' 
in the criteria for classification as GRAS through scientific 
procedures as support for this interpretation. Several comments urge us 
to interpret, in a flexible manner, the proposed criteria for the 
scientific data, information, methods or principles that establish 
safety to be ``generally available and accepted'' and ``ordinarily . . 
. published.''
    (Response 9) We agree that all relevant data should be used in 
evaluating GRAS status, including unpublished data. However, regardless 
of whether data and information are published or unpublished, a GRAS 
conclusion based on scientific procedures must be based on data and 
information that are generally available and accepted, and as such, are 
publicly available (see Response 8). The GRAS criteria for scientific 
procedures, as established in 1976, state that the applicable data and 
information are ``ordinarily'' published and may be ``corroborated'' by 
unpublished data and information, and this rule retains these criteria. 
The common meaning of ``corroborate'' is to make more certain or 
confirm (Ref. 23). Although unpublished data and information can 
confirm a conclusion of GRAS status, to satisfy GRAS criteria qualified 
experts must be able to conclude that the substance is not harmful 
under the conditions of its intended use without access to 
``corroborative'' information (see Sec.  170.30(a)). Under this rule, a 
notifier is required to explain how there could be a basis for a 
conclusion of GRAS status if qualified experts do not have access to 
non-public safety-related data and information considered in reaching a 
conclusion of GRAS status (see Sec.  170.250(e)).
    Whether data and information are corroborative of safety, rather 
than establish safety, depends on what those data and information are 
and how they relate to the safety assessment, not just whether they are 
published or otherwise publicly available. Whereas unpublished data and 
information that have a bearing on a safety conclusion, and therefore 
could help confirm a safety conclusion based on other data and 
information, in general, can only be considered as corroborative in the 
context of a GRAS conclusion, published data and information may be 
either the basis for a safety conclusion or corroborative of a safety 
conclusion, depending on the nature of the data and information. For 
example, a published 90-day toxicology study could be the basis for a 
safety conclusion, but a preliminary toxicology study conducted 
primarily for the purpose of selecting

[[Page 54974]]

the doses to be used in that 90-day toxicology study is unlikely to be 
the basis for a safety conclusion, regardless of whether that 
preliminary toxicology study is published.
    See also the discussion in Response 58 regarding the requirement 
for you to submit a signed statement certifying that, to the best of 
your knowledge, your GRAS notice is a complete, representative, and 
balanced submission that includes unfavorable information, as well as 
favorable information, known to you and pertinent to the evaluation of 
the safety and GRAS status of the use of the substance (Sec.  
170.225(c)(9)). See also the discussion in section XVII regarding the 
requirement for your narrative to identify, and place in context, data 
and information that are, or may appear to be, inconsistent with your 
conclusion of GRAS status, regardless of whether those data and 
information are generally available (Sec.  170.250(c)).
    (Comment 10) One comment asks us to explicitly acknowledge 
publication of information in the secondary scientific literature as a 
mechanism to satisfy the standard for general availability.
    (Response 10) We decline this request. In general, the secondary 
scientific literature includes publications (such as review articles, 
textbooks, and compendia) which disseminate the views of scientists who 
are critically evaluating a primary body of data and information 
already published in peer-reviewed scientific journals that are 
representative of scientific publications accessed by the expert 
scientific community (i.e., the primary scientific literature). Whether 
a publication in the secondary scientific literature satisfies the 
criteria for GRAS status through scientific procedures is a case-by-
case determination that depends on the circumstances. See section 
III.A.1 of CFSAN's 2010 experience document (Ref. 18) for examples of 
how CFSAN considered publications in the secondary scientific 
literature during the Interim Pilot program. When the underlying data 
being reviewed in the secondary scientific literature are themselves 
generally available, a publication in the secondary scientific 
literature can provide evidence that the data and information discussed 
in the publication are generally accepted as well as generally 
available. If a publication in the secondary scientific literature 
discusses data and information that are available to the authors, but 
not previously published in the primary scientific literature, whether 
that publication could satisfy the ``generally available'' aspect of 
the criteria for eligibility for GRAS status through scientific 
procedures would depend on the nature and extent of the discussion in 
the publication. For example, a very general statement that a study was 
conducted and reported no adverse findings would not suffice to make 
the study ``generally available''; instead, such a statement would 
merely be a generally available opinion about data and information, in 
that study, that are not generally available. Such a publication may 
satisfy the ``generally accepted'' aspect of the criteria for GRAS 
status through scientific procedures for that study, but would be 
insufficient, by itself, to satisfy the ``generally available'' aspect 
of those criteria. However, a comprehensive description in the 
secondary scientific literature of a previously unpublished study, 
including details similar to details that would be included in a 
publication in the primary scientific literature, may suffice to make 
the study published in the secondary scientific literature ``generally 
available.'' In such circumstances, the publication in the secondary 
scientific literature may be able to satisfy both the ``generally 
available'' and ``generally accepted'' aspects of the criteria for 
eligibility for GRAS status through scientific procedures for certain 
data and information.
    (Comment 11) One comment asks us to recognize that publication of 
an opinion of a specially convened ``expert panel'' would satisfy the 
standard for general availability because, in the comment's view, 
review by such a panel would be equivalent to, or exceed, peer review. 
(By ``expert panel,'' we assume that the comment is referring to a 
``GRAS panel'', i.e., a panel of individuals convened for the purpose 
of evaluating whether the available scientific data, information, and 
methods establish that a substance is safe under the conditions of its 
intended use in food. See the discussion in section III.A.1 of CFSAN's 
2010 experience document (Ref. 18).)
    (Response 11) We would consider publication of an opinion of a 
specially convened ``GRAS panel'' to be part of the secondary 
scientific literature as discussed in Response 10. As with any 
publication in the secondary scientific literature, when the underlying 
data being reviewed in a published ``GRAS panel'' opinion are 
themselves generally available, a published ``GRAS panel'' opinion 
could provide evidence that the data and information discussed in the 
publication are generally accepted, depending on factors such as the 
subject matter expertise of the members of the GRAS panel and whether 
the members of the GRAS panel would be considered representative of 
experts qualified by scientific training and experience to evaluate the 
safety of the substance under the conditions of its intended use. For 
example, a ``GRAS panel'' opinion published by scientists without 
expertise appropriate to address the applicable safety questions could 
not provide evidence that the conclusions in the publication are 
``generally accepted.''
    If a published ``GRAS panel'' opinion discusses data and 
information that are available to the members of the GRAS panel, but 
not generally available to qualified experts, whether that publication 
could satisfy the ``generally available'' aspect of the criteria for 
eligibility for GRAS status through scientific procedures would depend 
on the nature and extent of the discussion in the publication (see 
Response 10). Unless both criteria, i.e., ``generally available'' and 
``generally accepted'', are satisfied, there would be no basis for a 
conclusion of GRAS status based on a published ``GRAS panel'' opinion.
    (Comment 12) One comment states that all available relevant data, 
including unpublished data, should be used in evaluating GRAS status, 
as long as any unpublished data are generated by appropriate and valid 
scientific methods as judged and reviewed by an external qualified GRAS 
panel and are accessible to FDA for review.
    (Response 12) We agree that all available relevant data should be 
used in evaluating whether a use of a substance in food is GRAS through 
scientific procedures. By ``all relevant data,'' we mean data that 
support a conclusion of GRAS status as well as data that are 
inconsistent with a conclusion of GRAS status, not just whether the 
data are published. (See Sec. Sec.  170.225(c)(9) and 170.250(c) and 
the discussion in Response 58, Response 69, and Response 78.) We also 
agree that it is appropriate for unpublished data to be generated by 
valid scientific methods and to be accessible to FDA for review (e.g., 
when such data are cited in a submission to FDA). In addition, we have 
acknowledged the practice of convening an external ``GRAS panel'' to 
evaluate whether the available scientific data, information, and 
methods demonstrate that a substance is safe under the conditions of 
its intended use in food (see section III.A.1 of CFSAN's 2010 
experience document) (Ref. 18). However, we disagree that information 
that is not generally available to qualified experts could be used as 
evidence for a GRAS conclusion merely because a GRAS panel has reviewed 
it. Such information would need to be considered, but generally would 
only be

[[Page 54975]]

corroborative of safety. (See Response 9 and Response 11.)
    (Comment 13) One comment asserts that the proposed rule treats the 
findings of GRAS panels as equivalent to determinations by 
authoritative bodies and peer reviewed published articles.
    (Response 13) We disagree. In the proposed rule, we noted that the 
basis for concluding there is expert consensus about the safety of a 
substance under the conditions of its intended use may be quite varied, 
and described common mechanisms that have been used to do so. We stated 
that these common mechanisms included publication in the primary, peer-
reviewed scientific literature; publication in the secondary scientific 
literature; documentation of the opinion of an ``expert panel'' that is 
specifically convened for this purpose; and the opinion or 
recommendation of an authoritative body such as the National Academy of 
Sciences or the Committee on Nutrition of the American Academy of 
Pediatrics on a broad or specific issue that is related to a conclusion 
of GRAS status (62 FR 18938 at 18940-18941). We also stated that there 
could be a basis to conclude that there is expert consensus that the 
published results of a particular safety study (i.e., the primary 
scientific literature) establish the safety of a substance for its 
intended use if the study raises no safety questions that experts would 
need to interpret and resolve (62 FR 18938 at 18943). In addition, 
technical literature from JECFA can provide evidence that generally 
available safety data and information are generally accepted (see 
section III.A.1 of CFSAN's 2010 experience document (Ref. 18)).
    However, acknowledging that the opinion of an ``expert panel'' 
(which we now refer to as a ``GRAS panel'') has been used to provide 
evidence that safety data and information are generally accepted does 
not mean that these mechanisms are ``equivalent.'' Whether the findings 
of a GRAS panel, a determination by an authoritative body, or a peer-
reviewed scientific study provide sufficient evidence that safety data 
and information are generally accepted would depend on the specific 
findings of the GRAS panel, the specific determination by the 
authoritative body, and the data and information in the peer-reviewed 
scientific study rather than on the classification of the mechanism for 
providing evidence that safety data and information are generally 
accepted.
    (Comment 14) One comment asks us to develop and publish guidelines 
regarding specific duties that would be expected of any GRAS panel. 
This comment suggests that such guidelines could include 
recommendations for: (1) Number of panel members; (2) measures of 
``general acceptance,'' such as a majority (rather than unanimous) 
opinion and the impact of a dissenting opinion; and (3) the content of 
a letter from a GRAS panel.
    (Response 14) See Response 125. We intend to issue for public 
comment a draft guidance to address GRAS panels.
    (Comment 15) Some comments assert it can be difficult to publish 
data and information that do not raise an issue of concern.
    (Response 15) We infer this comment to refer primarily to 
toxicology studies. Toxicology studies are designed to provide 
information about potential adverse effects from exposure to a 
substance and any dose-response relationship. Although studies that 
fail to identity any adverse effects may be difficult to publish, some 
scientific journals report the findings of such studies. (See section 
III.A.1 of CFSAN's 2010 experience document (Ref. 18)).
    (Comment 16) One comment asks us to require that both toxicology 
and exposure data be published because a safety assessment for the use 
of a substance in food requires consideration of both.
    (Response 16) We agree that a safety assessment for the use of a 
substance in food requires consideration of both safety information 
(such as toxicology studies) and dietary exposure (i.e., the amount of 
the substance that consumers are likely to eat or drink). Toxicology 
data are ordinarily published.
    A premarket exposure assessment typically would be calculated by 
applying generally available and accepted methods to two types of data 
and information: (1) Generally available and accepted data about food 
consumption; and (2) specific food categories, and levels of use in 
those food categories, projected by the sponsor of a food additive 
petition or by the proponent of GRAS status (Ref. 24 and Ref. 25). 
Using generally available and accepted data about food consumption, a 
qualified expert who has access to the specific food categories and 
associated levels of use intended by the proponent of GRAS status can 
calculate an estimated dietary exposure. When the proponent of GRAS 
status submits a GRAS notice, the proponent must: (1) Provide data and 
information about dietary exposure (see Sec.  170.235); and (2) include 
a narrative that addresses the safety of the notified substance, 
considering all dietary sources (see Sec.  170.250). Those calculations 
and discussions included in the GRAS notice are subject to the public 
disclosure provisions of this rule (see Sec.  170.275) and, thus, would 
be available to the expert scientific community. However, when the 
proponent of GRAS status does not submit a GRAS notice, the expert 
scientific community that does not have access to the specific food 
categories and associated levels of use would not be able to calculate 
an estimated dietary exposure. When the available data and information 
suggest that the specific food categories and associated levels of use 
must be carefully chosen to keep consumption of the substance in a safe 
range (e.g., when fortifying food with certain vitamins), the expert 
scientific community that does not have access to the specific food 
categories and associated levels of use would not be able to reach a 
conclusion about whether the substance is safe under the conditions of 
its intended use, and GRAS criteria would not be satisfied.
    After market entry of the substance, it may be appropriate to re-
assess dietary exposure. For example, dietary exposure may need to be 
reassessed when a key assumption in the methodology is changed; as 
dietary consumption patterns change; when there is an unresolved 
question about consumer intake; when there is a small margin of 
exposure; or when other new information becomes available. As with a 
premarket exposure assessment, a postmarket exposure assessment 
typically would be calculated by applying generally available and 
accepted methods to two types of data and information: (1) Generally 
available and accepted data about food consumption; and (2) specific 
food categories, and levels of use in those food categories. In some 
cases, postmarket exposure assessments have been published so that the 
expert scientific community has access to them. For example, exposure 
assessments have been published for some sweeteners using relative 
sweetness as the basis of the estimate (Ref. 26). As another example, 
estimates of dietary exposure to caffeine have been published to 
address consumer intake and patterns of use (Ref. 27 through Ref. 29). 
However, as with a premarket exposure assessment, when a postmarket 
exposure assessment is not publicly available, the expert scientific 
community that does not have access to the specific food categories and 
associated levels of use would not be able to reach a conclusion about 
whether the substance is safe under the conditions of its intended use 
when the available data and information suggest

[[Page 54976]]

that the specific food categories and associated levels of use must be 
carefully chosen to keep consumption of the substance in a safe range.
    (Comment 17) One comment asks us to recognize that published 
literature does not need to address a specific substance, but could 
involve publications on a class of substances or a related substance to 
support a conclusion that the use of a substance is GRAS through 
scientific procedures.
    (Response 17) We agree that published information for a specific 
substance is not always necessary to support a conclusion that the use 
of a substance is GRAS through scientific procedures. For example, 
there may be situations where the safety of the use of the substance in 
food can be demonstrated by relevant published information on a 
closely, structurally related compound. In such cases, the analysis 
leading to the conclusion of GRAS status should explain how the 
information on the closely, structurally related compound is relevant 
to the safety assessment of the substance being evaluated. In other 
cases, there may a body of information published in the primary or 
secondary literature about a class of substances, which reflect 
generally available and accepted data and information that can be 
called to bear on the safety assessment of a specific substance. For 
example, generally available metabolism information about commonly 
consumed components of food, such as carbohydrates, lipids, and 
proteins, could support a conclusion that a specific substance is GRAS 
under the conditions of its intended use.
    To help ensure that the data are, in fact, relevant to the safety 
assessment of the substance being evaluated, we strongly encourage any 
person who intends to rely on data and information regarding a class of 
substances, or a specific substance related to the substance that would 
be added to food, to submit any conclusion of GRAS status to FDA via 
the GRAS notification procedure.
    (Comment 18) One comment states that the use of an approved food 
additive can, through the passage of time, become GRAS as the substance 
becomes widely used and as information about the substance becomes 
publicly available.
    (Response 18) We disagree that widespread use of an approved food 
additive as time passes has any bearing on the eligibility of this use 
for classification as GRAS. Eligibility for classification as GRAS 
through scientific procedures would depend on the status of the 
information--as generally available and generally accepted--rather than 
on the amount of time that a food additive has been used in food. 
However, in general, much of the data submitted for our review of a 
food additive contains unpublished data and trade secret or 
confidential information that is neither published nor otherwise 
generally available. Although the safety data are available for public 
disclosure under 21 CFR 171.1(h)(1), they typically are based on 
unpublished studies sponsored by the petitioner.
    See also the discussion in Response 19 regarding the impact of the 
passage of time and the discussion in Response 79 that the qualified 
experts who evaluate the basis for a conclusion that the notified 
substance is safe under the conditions of its intended use must not 
exclusively be ``FDA's experts.''
    (Comment 19) One comment asks us to exclude uses of ``novel'' 
substances from consideration for eligibility for classification as 
GRAS. The comment asserts that novel or newly discovered uses of 
substances that are the subject of a conclusion of GRAS status are in 
conflict with the original intent of the 1958 amendment and the plain 
meaning of ``generally recognized,'' because there is no history of 
safe use for these substances. The comment also states that similar 
``general recognition'' provisions for new drugs are not interpreted to 
allow industry-made safety determinations for new or novel drugs.
    (Response 19) We do not have a regulatory definition for a 
``novel'' substance. As a general matter, section 201(s) of the FD&C 
Act provides two alternatives for general recognition of safety--
through scientific procedures, or through experience based on common 
use in food. Section 201(s) does not limit eligibility, or otherwise 
exclude, the use of a substance from classification as GRAS through 
scientific procedures if there is no history of use. Likewise, section 
201(s) does not limit eligibility, or otherwise exclude, the use of a 
substance from classification as GRAS through scientific procedures 
based on other criteria, such as whether a substance or its use in food 
is ``novel'' or ``newly discovered.'' Unlike the definition of a ``new 
drug'' in section 201(p) of the FD&C Act, section 201(s) does not 
require that a food ingredient be used ``to a material extent or for a 
material time under such conditions'' before it can become GRAS. 
Rather, the criteria for eligibility for classification as GRAS depend 
on whether generally available and accepted data and information 
establish that the substance is safe under the conditions of its 
intended use.
    However, a conclusion of GRAS status must be based on common 
knowledge throughout the scientific community knowledgeable about the 
safety of substances added to food that there is reasonable certainty 
that the substance is not harmful under the conditions of its intended 
use (Sec.  170.30(a)), and a substance cannot be considered GRAS when 
its characteristics are known to only a few experts (Final rule 
establishing GRAS criteria, 41 FR 53600, December 7, 1976). In 
addition, the passage of time is relevant in an evaluation of whether a 
substance is GRAS under the conditions of its intended use. In our 1974 
proposed rule on general recognition of safety and prior sanctions for 
food ingredients, we acknowledged that there would be at least some gap 
between the gathering of the scientific knowledge necessary to provide 
the toxicological underpinning for general recognition of safety and 
the dissemination to and assimilation by the scientific community of 
this material that is necessary for general recognition of safety to 
exist.'' (39 FR 34194 at 34194, September 23, 1974). More recently, the 
discussions in sections III.A.4 and IV.K of CFSAN's 2010 experience 
document (Ref. 18) show our approach to the time gap between the 
publication of safety data and the use of the published safety data to 
support a conclusion of GRAS status during the Interim Pilot program. 
See also Response 67 regarding nanotechnology applications in food 
substances.
    (Comment 20) One comment asserts that we must define the extent of 
agreement needed to establish a consensus among qualified experts, and 
that we must exclude from eligibility for classification as GRAS any 
substance whose safety has been called into question by expert 
authorities or authoritative entities within the scientific community.
    (Response 20) The proponent of a GRAS conclusion for a food 
substance must demonstrate that the conditions of use of the substance 
satisfy the definition of ``safe'' in our regulations (i.e., that there 
is reasonable certainty that the substance is not harmful under the 
conditions of its intended use (see Sec.  170.3(i)). The proponent of 
GRAS status also must demonstrate that there is common knowledge about 
this safety throughout the knowledgeable scientific community (Sec.  
170.30(a)). Although courts have established that general recognition 
of safety requires a consensus of expert opinion regarding the safety 
of the use of the substance, (see, e.g., United States v. Western

[[Page 54977]]

Serum Co., Inc., 666 F.2d 335, 338 (9th Cir. 1982) (citing Weinberger 
v. Hynson, Westcott & Dunning, 412 U.S. 609, 629-32 (1973)), we 
disagree that we must define the extent of agreement needed to 
establish such a consensus. Courts have established that general 
recognition of safety does not require unanimous agreement. See, e.g., 
United States v. Articles of Drug * * * 5,906 Boxes, 745 F.2d 105, 119 
n. 22 (1st Cir. 1984); United States v. Articles of Food and Drug 
(Coli-Trol 80), 518 F.2d 743, 746 (5th Cir. 1975) (``What is required 
is not unanimous recognition but general recognition''). Importantly, 
general recognition of safety does not exist if there is a genuine 
dispute among qualified experts that the use of a substance is safe. 
See, e.g., Premo Pharmaceutical Laboratories v. United States, 629 F.2d 
795, 803-4 (2nd Cir. 1980) (``genuine dispute among qualified experts'' 
precludes finding of general recognition, and no general recognition 
existed as a matter of law where there was a ``sharp difference'' of 
expert opinion); United States v. Article of Food * * * Coco Rico, 752 
F.2d 11, 15 n 6 (1st Cir. 1985) (substance was not GRAS as a matter of 
law based on existence of ``genuine dispute among qualified experts'' 
regarding safety of use). For discussions of additional judicial 
decisions bearing on the criteria for eligibility for classification as 
GRAS, see the notice of declaratory order providing our final 
determination regarding partially hydrogenated oils (80 FR 34650).
    A conclusion of GRAS status must be based on the totality of the 
publicly available and corroborative evidence about the safety of the 
substance under the conditions of its intended use, including both 
favorable and potentially unfavorable information. Thus, reports of 
expert authorities or authoritative entities within the scientific 
community may indicate that there is no general recognition of safety 
when the reports call into question the safety of a substance for use 
in food. However, we disagree that the outcome of an evaluation of such 
information can be predetermined as suggested by the comments. 
Regardless of whether particular scientific data and information lead 
experts to conclude that a substance is safe under the conditions of 
its intended use, or raise questions about the safety of the substance 
under the conditions of its intended use, the evaluation of whether a 
use of a substance in food is safe, and whether safety is generally 
recognized, is a case-by-case evaluation. For example, data and 
information that lead expert authorities or authoritative entities 
within the scientific community to raise a concern about the safety of 
the substance under the conditions of its intended use in food would 
have reduced significance if the concern was related to a contaminant 
in the substance and scientifically valid data and information supplied 
by the proponent of GRAS status provide evidence that an improved 
method of manufacture eliminates that contaminant.
    See also Response 77, in which we explain that we proposed to 
provide the judicial interpretation of section 201(s) of the FD&C Act 
in the requirement for the comprehensive discussion of the notifier's 
basis for a conclusion of GRAS status to provide more context to 
notifiers than merely repeating the statutory language. However, as 
discussed in Response 77, we have decided to use the statutory language 
(i.e., ``generally recognized'') rather than the proposed term 
``consensus'' in the submission requirements for a GRAS notice to 
mirror the GRAS criteria in Sec.  170.30, which continue to use the 
statutory language rather than the consensus standard applied by the 
courts in applying the statutory language to specific situations.
    (Comment 21) In the proposed rule, we asked for comment on the 
potential for a conclusion of GRAS status through scientific procedures 
to be based in part on the ``substantial equivalence'' of the 
applicable substance to a substance that is GRAS through experience 
based on common use in food. One comment agrees with the view, 
expressed in a 1996 JECFA Report (Ref. 30) and reported in the proposed 
rule (62 FR 18938 at 18944), that ``substantial equivalence'' embodies 
the concept that if a new food component is found to be substantially 
equivalent to an existing food component, the food component could be 
considered to be as safe as the existing food component, after taking 
into account any processing that the food component may undergo as well 
as the intended use and the intake by the population. Several comments 
assert that the concept of substantial equivalence, although useful, is 
nonetheless ambiguous. One comment asks us to clearly state our 
interpretation of this concept in the final rule.
    (Response 21) We have decided not to include the term ``substantial 
equivalence'' in the regulatory text of this rule, because whether, and 
to what extent, similarity between two substances could support a 
conclusion of GRAS status depends on too many situation-specific 
variables. As discussed in section IV.N of CFSAN's 2010 experience 
document, GRAS notices filed during the Interim Pilot program that 
relied on the concept of ``substantial equivalence'' generally 
addressed alternative sources of enzymes already used in food (Ref. 
18). Most of these notices both emphasized the similarities of the new 
enzyme preparations to existing enzyme preparations and explained the 
differences between the new enzyme preparation and currently used 
enzyme preparations. However, none of these GRAS notices relied solely 
on the concept of ``substantial equivalence.'' Instead, these notices 
also described other applicable data and information, such as data and 
information about the biological source of the enzyme preparation; the 
method of manufacture of the enzyme preparation; constituents of the 
enzyme preparation that derive from the source organism or the 
manufacturing process; the technical effect of the enzyme preparation; 
dietary exposure to the enzyme preparation; specifications for the 
enzyme preparation; and applicable safety studies.

C. Criteria for Eligibility for Classification as GRAS Through 
Experience Based on Common Use in Food

    We proposed to amend the criteria for eligibility for 
classification as GRAS through experience based on common use in food 
(Sec.  170.30(c)(2)) to state that persons who claim that use of a 
substance is GRAS through experience based on its common use in food 
outside of the United States should notify FDA of that claim in 
accordance with the GRAS notification procedure. We received no 
comments that disagreed with this proposed amendment and are finalizing 
it as proposed, with conforming changes as shown in table 29.
    See section XXV.B regarding revisions to the criteria for 
eligibility for classification as GRAS through experience based on 
common use in food for a substance used in animal food.

D. Other Comments on the Criteria for Eligibility for Classification as 
GRAS

    (Comment 22) One comment asserts that the proposed rule would add 
unnecessary complexity to continued use of substances currently 
presumed to be GRAS. This comment also asserts that the proposed rule 
would remove the ``pre-1958 exemption'' and, as a result, would place 
an unnecessary burden on food producers and processors with respect to 
substances

[[Page 54978]]

that are the subject of previous conclusions of GRAS status.
    (Response 22) These comments are unclear. By ``pre-1958 exemption'' 
these comments could mean a conclusion of GRAS status through 
experience based on common use in food, which requires common use in 
food before January 1, 1958. Alternatively, these comments could be 
referring to the statutory exception from the definition of ``food 
additive'' for a substance that is the subject of a prior sanction 
within the meaning of section 201(s)(4) of the FD&C Act and part 181 
(21 CFR part 181). Either way, nothing in this rule would affect a 
lawful use of a food substance that is GRAS based on common use in food 
prior to January 1, 1958 or that is the subject of a prior sanction. 
This rule does not remove GRAS status based on common use in food prior 
to January 1, 1958. Likewise, the lawful use of a substance listed in 
part 181 as being the subject of a prior sanction is not affected by 
this rule.
    However, any person who relies on a conclusion of GRAS status 
through experience based on common use in food prior to 1958 or on a 
prior sanction within the meaning of section 201(s)(4) of the FD&C Act 
needs to consider whether the conditions of use associated with the 
applicable substance, such as the foods in which the substance would be 
used and the levels of use of the substance, are within the scope of 
these statutory provisions. As discussed in section I.D, in 2010 we 
issued warning letters informing four companies marketing caffeinated 
alcoholic beverages that caffeine, as used in the companies' products, 
is an unsafe food additive, and therefore the products are adulterated 
under section 402(a)(2)(C) of the FD&C Act, and the companies 
subsequently ceased distribution of these products. Thus, we advise any 
manufacturer or distributor to carefully consider whether there is 
adequate support for concluding that a substance is GRAS under the 
conditions of its intended use and to submit a GRAS notice to us if it 
intends to manufacture or distribute a food product containing a 
substance that has been used in food as a GRAS substance under 
conditions of use different from those in the manufacturer's or 
distributor's product.
    In addition, new data and information may call into question the 
safety of a substance used in food as a GRAS substance, whether the 
basis for a conclusion of GRAS status is through experience based on 
common use in food or through scientific procedures. As discussed in 
section I.A, in 1969 we deleted various cyclamate salts from the GRAS 
list because they were implicated in the formation of bladder tumors in 
rats; as discussed in section I.D, we recently issued a declaratory 
order making a final determination that there is no longer a consensus 
among qualified experts that PHOs are GRAS for any use in human food 
(80 FR 34650).
    (Comment 23) One comment asks us to require minimum safety or 
short-term toxicology studies for all conclusions of GRAS status, 
regardless of whether the conclusion is through scientific procedures 
or through experience based on common use in food before 1958. This 
comment explains that such studies could corroborate safety when GRAS 
status is based on common use on food, e.g., by taking into account any 
impact of the manufacturing process on food safety.
    (Response 23) We decline this request. We agree that the method of 
manufacture can impact safety, regardless of whether GRAS status is 
through experience based on common use on food or through scientific 
procedures. See, e.g., our guidance entitled ``Assessing the Effects of 
Significant Manufacturing Process Changes, Including Emerging 
Technologies, on the Safety and Regulatory Status of Food Ingredients 
and Food Contact Substances, Including Food Ingredients that Are Color 
Additives'' (Ref. 6). The rule requires submission of a description of 
the method of manufacture in sufficient detail to evaluate the safety 
of the notified substance as manufactured, regardless of whether the 
basis for the conclusion of GRAS status is through scientific 
procedures or through experience based on common use in food (see Sec.  
170.230(b)). If the method of manufacture has changed over time, a new 
evaluation of GRAS status based on scientific procedures may be 
warranted. We advise any manufacturer of a substance that is used in 
food based on a conclusion of GRAS status to carefully consider the 
impact of its method of manufacture on the safety of the substance 
before introducing the substance into commerce.
    We disagree that the rule must require minimum safety or short-term 
toxicology studies for all conclusions of GRAS status because the kinds 
of data and information needed to demonstrate safety (or that could be 
used to corroborate safety) will vary based on the substance and its 
intended use. A conclusion of GRAS status based on scientific 
procedures must be based on the same quantity and quality of scientific 
evidence as is required to obtain approval of a food additive (Sec.  
170.30(b)). We have issued guidance on the types of data and 
information in support of a food additive petition, and these types of 
data and information would be useful in the evaluation of the safety of 
a substance when the proponent of the substance seeks to demonstrate 
that the substance is GRAS under the conditions of its intended use 
(see Response 37 and Response 66).
    For a safety assessment of a chemical, the specific types of data 
and information generally follow from the chemical structure and 
estimated dietary exposure of the substance. For example, chemistry 
data, including manufacturing information, as well as information 
sufficient to estimate exposure, are necessary to consider in arriving 
at a conclusion of GRAS status. Whether toxicological studies are 
necessary to demonstrate safety depends on the properties of the 
substance such as the presence or absence of chemical alerts, physical 
properties, and physiological fate of the substance. For example, well 
understood and accepted metabolism information about a substance that 
is a component of commonly consumed foods (such as vegetables or 
fruits) may provide sufficient safety information to arrive at a 
conclusion of GRAS status at a specified level of the use of that 
substance in food. As discussed in section III.A.2 of CFSAN's 2010 
experience document, during the Interim Pilot program it was CFSAN's 
view that toxicological studies were not necessary to evaluate the 
safety of substances such as carrot fiber and dried orange pulp (Ref. 
18). Likewise, for simple substances (such as minerals and their salts) 
that are readily dissociated to components that have long been viewed 
as GRAS (e.g., by a listing in part 182 or by a GRAS affirmation 
regulation in part 184), toxicological studies would likely not be 
necessary. As discussed in section III.A.2 of CFSAN's 2010 experience 
document, during the Interim Pilot program it was CFSAN's view that 
toxicological studies were not necessary to evaluate the safety of 
substances such as potassium bisulfate and seaweed-derived calcium 
(with calcium carbonate as the major component) (Ref. 18).
    For a safety assessment of a substance produced from a 
microorganism, the specific types of data and information generally 
follow from the identity of the microorganism and how the substance is 
produced from that microorganism in addition to the substance itself. 
For example, the safety of a substance produced from a microorganism 
generally considers generally available microbiological data and 
information about the potential toxigenicity and

[[Page 54979]]

pathogenicity of the microorganism. Whether toxicological studies would 
be necessary to demonstrate the safety of the substance as manufactured 
would depend on what the substance is and its intended use in food.

E. GRAS Status of Certain Food Substances

    We proposed to remove Sec.  170.30(f), which expresses our intent 
to review the GRAS status of certain food substances. We received no 
comments that disagreed with our proposal to remove Sec.  170.30(f) and 
are removing it as proposed.

VII. Comments on the Substitution of a GRAS Notification Procedure for 
the GRAS Affirmation

Petition Process
    Our regulations specify procedures for us to affirm the GRAS status 
of the use of a food substance, whether on our own initiative (Sec.  
170.35(a) and (b)) or on the petition of an interested person (Sec.  
170.35(c)). We proposed to eliminate the GRAS affirmation petition 
process in Sec.  170.35(c) and replace it with a GRAS notification 
procedure (proposed Sec.  170.36) in which any person may notify us of 
a claim that a particular use of a substance is exempt from the 
statutory premarket approval requirements based on the notifier's 
determination that such use is GRAS. Under the proposed notification 
procedure, we would evaluate whether the submitted notice provides a 
sufficient basis for a GRAS determination and whether information in 
the notice or otherwise available to us raises issues that lead us to 
question whether use of the substance is GRAS. We also proposed to 
presumptively convert any filed GRAS affirmation petition that is 
pending on the date that the petition process is replaced with a 
notification procedure (``pending petition'') to a GRAS notice and 
provide an opportunity for the person who had submitted a pending 
petition (``affected petitioner'') to amend the petition to meet the 
requirements for a GRAS notice.
    In the 2010 notice, we discussed several issues broadly applicable 
to the proposed substitution of a GRAS notification procedure for the 
GRAS affirmation petition process (see table 3).

  Table 3--Issues in the 2010 Notice Broadly Applicable to the Proposed
 Substitution of a GRAS Notification Procedure for the GRAS Affirmation
                            Petition Process
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
N/A.......  Our intent to use  75 FR 81536 at 81537.
             ``Plain
             Language'' tools
             such as pronouns
             in the final
             rule.
2.........  Our reasons for    75 FR 81536 at 81538.
             tentatively
             concluding that
             the terms
             ``conclude'' and
             ``conclusion''
             would be more
             appropriate in
             lieu of
             ``determine''
             and
             ``determination'
             '.
17........  Alternative        75 FR 81536 at 81542-81543.
             approach to
             administering
             pending GRAS
             affirmation
             petitions.
------------------------------------------------------------------------

    Several comments support the proposed replacement of the GRAS 
affirmation petition process with a GRAS notification procedure. For 
example, several comments support the expectation we expressed in the 
proposed rule (62 FR 18938 at 18941) that the substitution of a GRAS 
notification procedure for the GRAS affirmation petition process would 
result in our increased awareness of the composition of the nation's 
food supply and the cumulative dietary exposure to GRAS substances. 
Most of these comments agree that such increased awareness could be an 
advantage of the notification procedure if manufacturers view our 
response to a GRAS notice as an incentive to participate in the 
program. Many comments that support the proposed replacement of the 
GRAS affirmation petition process with a GRAS notification procedure 
nonetheless raise questions about how we would administer the pending 
GRAS affirmation petitions. We discuss those comments in section XXIII.
    In the following sections, we discuss comments that disagree with 
one or more aspects of our proposal to replace the GRAS affirmation 
petition process with a GRAS notification procedure (see, e.g., Comment 
24, Comment 25, and Comment 32); ask us to clarify how we generally 
will administer the proposed GRAS notification procedure (see, e.g., 
Comment 31); or suggest one or more general changes to the proposed 
GRAS notification procedure (see, e.g., Comment 27, Comment 28, Comment 
30, Comment 31, and Comment 36). After considering these comments, we 
are replacing the GRAS affirmation petition process with a GRAS 
notification procedure, using the terms ``conclude'' and ``conclusion'' 
as described in the 2010 notice. As noted in the 2010 notice, the final 
rule uses Plain Language tools such as pronouns.
    To improve clarity and readability we used another Plain Language 
tool, i.e., the use of short regulatory sections that have limited 
subparagraph designations. To do so we redesignated the single proposed 
section (i.e., proposed Sec.  170.36) into several distinct, short 
sections of regulatory text in a newly established subpart E (GRAS 
Notice), with editorial changes associated with the new structure of 
the redesignated regulations. See table 4 for the section numbers and 
titles of the regulatory text in subpart E. Many provisions of the 
regulatory text in subpart E use singular nouns when discussing the 
intended use of the notified substance, e.g., the definition of ``GRAS 
notice'' means a submission that informs us of your view that a 
specified use of a substance is not subject to the premarket approval 
requirements of the FD&C Act based on your conclusion that such use is 
GRAS. The singular term ``use'' is employed for a simple and consistent 
presentation in the regulatory text and does not mean, for example, 
that you are limited to notifying us about a single use of the notified 
substance.
    We also are establishing in new subpart E the process we described 
in the 2010 notice for administering pending GRAS affirmation 
petitions. Finally, we made editorial, clarifying, and conforming 
changes as shown in table 29. Because the editorial changes associated 
with the redesignation of the notification procedure in subpart E are 
extensive, we do not list them in table 29.

A. Affirmation on the Initiative of the Commissioner

    We proposed to amend current Sec.  170.35(a) to clarify that the 
Commissioner would affirm the GRAS status of a use of a substance, 
rather than the substance itself, and to include a grammatical change 
to place Sec.  170.35(a) in the singular. The single

[[Page 54980]]

comment that expressly addressed this proposed amendment concurred with 
us on this point and we are finalizing it as proposed.
    We also proposed to amend current Sec.  170.35(a) to remove the 
provision that we may review the GRAS status of a substance added to 
food in response to a petition from an interested party. Under current 
Sec.  170.35, such a petition would be submitted in accordance with the 
provisions of the GRAS affirmation petition process established in 
current Sec.  170.35(c). We are deleting this provision as proposed. 
The comments we received relevant to our proposed deletion of the 
petition-related provision in Sec.  170.35(a) are directed to our 
proposed deletion of the GRAS affirmation petition process in current 
Sec.  170.35(c), and we discuss those comments in section VII.B.

B. Deletion of the GRAS Affirmation Petition Process

    We proposed to eliminate the GRAS affirmation petition process in 
current Sec.  170.35(c).
    (Comment 24) Several comments oppose our proposal to eliminate the 
GRAS affirmation petition process. In general, these comments assert 
that we should provide manufacturers the option of seeking GRAS 
affirmation even though we would be establishing a new notification 
procedure. The comments assert that such an option is essential to 
support the marketing of a product in certain situations, such as when 
recognition of GRAS status is needed by international standard-setting 
bodies.
    (Response 24) We acknowledge that a regulation listing the use of a 
substance in food could provide some support for marketing a product in 
certain situations, but disagree that we should retain the GRAS 
affirmation petition process. We note that CFSAN filed more than 600 
GRAS notices during the time period 1998 through 2015 (Ref. 19), for an 
average of approximately 34 GRAS notices per year, including 69 GRAS 
notices filed during 2014 and 51 GRAS notices filed during 2015. By 
contrast, during that time CFSAN finalized six GRAS affirmation 
regulations. We believe that the ongoing submission of GRAS notices is 
evidence that our response to a GRAS notice can support the marketing 
of a food substance.
    (Comment 25) Some comments assert that the proposed GRAS 
notification procedure would be less protective of food safety than the 
GRAS affirmation petition process it would replace. Some comments 
assert that our role in ensuring the safety of food ingredients is best 
carried out by a review of the data supporting the safety of the 
ingredient and that the public should also have access to these data. 
These comments also assert that the GRAS affirmation petition process, 
in which we conduct a review of supporting data, provides an incentive 
to manufacturers to fully research each substance and that removing 
this incentive would compromise safety. Other comments assert that the 
GRAS notification procedure would be less thorough than the GRAS 
affirmation petition process. One comment states that consumers are 
concerned about the safety and wholesomeness of substances added to 
food and criticizes the proposed rule as not being ``rigorous enough'' 
and as not creating a ``meaningful process for adequately reviewing the 
safety of substances used in human and animal food.''
    (Response 25) We disagree that the notification procedure is less 
protective of food safety than the affirmation petition process. In the 
proposed rule, we stated that our response to a GRAS notice would not 
be equivalent to an agency affirmation of GRAS status because we would 
neither receive nor review the detailed data and information that 
support the GRAS determination (62 FR 18938 at 18951). These comments 
may have misinterpreted that statement to mean that we would not 
conduct a substantive evaluation of the summary information that we 
receive in a GRAS notice. This is not the case. CFSAN's 2010 experience 
document (Ref. 18) demonstrates that we have conducted a substantive 
evaluation of the GRAS notices that we received during the Interim 
Pilot program. For example, section III.C.1 of CFSAN's 2010 experience 
document describes examples of situations in which we contacted a 
notifier to request clarification about data and information in the 
notice. CFSAN's 2010 experience document also demonstrates that during 
the period 1998-2009 CFSAN had questions about 21 percent of GRAS 
notices, such that CFSAN either responded to the notifier that the 
submitted GRAS notice did not provide a basis for a conclusion of GRAS 
status or the notifier asked us to cease to evaluate the GRAS notice 
(see section III.B of CFSAN's 2010 experience document). Furthermore, 
we believe that the GRAS notification procedure provides us with 
greater flexibility to respond to safety concerns that may arise about 
a substance that is the subject of a GRAS notice, compared to a 
substance that is the subject of a GRAS affirmation regulation, which 
would require rulemaking to revoke.
    We acknowledge that the term (i.e., ``evaluate'') we use to 
describe our actions when we receive a GRAS notice is different from 
the term (i.e., ``review'') we use to describe our actions when we 
receive a petition (whether a food or color additive petition or a GRAS 
affirmation petition). We decided to use a different term because, as 
already noted, the data and information we will receive in a GRAS 
notice (i.e., summary data and discussions) are different from the data 
and information we receive in a petition (which generally includes the 
underlying data from studies described in the petition).
    As discussed in Response 120, we currently make a hyperlink to an 
electronic copy of each GRAS notice accessible from our Internet site 
and, thus, the public has access to each GRAS notice. We also make our 
response to each GRAS notice accessible from our Internet site (see 
Sec.  170.275(b), Response 115, and Response 116). We acknowledge that 
supporting data and information that are provided to us in the form of 
a petition can provide the public with ready access to such data and 
information (e.g., through a FOIA request), but disagree that 
substitution of the GRAS notification procedure for the GRAS 
affirmation petition process has a fundamental impact on the public's 
access to supporting data and information, because a conclusion of GRAS 
status must be based on generally available data and information. Under 
the notification procedure, the publicly accessible GRAS notice both 
summarizes the available data and information and provides a list of 
publicly available data and information (see Sec. Sec.  170.250 and 
170.255). Under the GRAS affirmation petition process, we placed a copy 
of each publication provided by the petitioner to support a conclusion 
of GRAS status in the public docket for that petition, but our current 
practice with respect to copyrighted publications is to refer the 
public to the primary records (see Sec.  20.51, Referral to primary 
source of records).
    We cannot say whether a petition process would provide an incentive 
for a manufacturer to more fully research the safety of a substance 
before sending a GRAS notice to us. However, we advise a manufacturer 
who intends to submit a GRAS notice to expect a substantive evaluation 
of that GRAS notice by us. Likewise, we advise a manufacturer who 
reaches a conclusion that a substance is GRAS under the conditions of 
its intended use, but does not submit a GRAS notice to us, that when a 
substance is not GRAS under

[[Page 54981]]

the conditions of its intended use (or is not otherwise excepted from 
the definition of ``food additive'' in section 201(s) of the FD&C Act), 
that use of the substance is a food additive use subject to our 
premarket review as mandated by the FD&C Act. In such circumstances, we 
can take various actions, including issuing a warning letter (which we 
make public on our Web site) to companies that manufacture or 
distribute the food additive and/or food containing the food additive; 
issuing a public alert; taking enforcement action to stop distribution 
of the food substance and foods containing it on the grounds that such 
foods are or contain an unlawful food additive; and issuing a 
declaratory order determining that the substance is not GRAS under the 
conditions of its intended use and is a food additive subject to 
section 409 of the FD&C Act. For example, as already discussed in 
section I.D, we recently issued a declaratory order making a final 
determination that there is no longer a consensus among qualified 
experts that PHOs are GRAS for any use in human food (80 FR 34650). As 
another example discussed in section I.D, we have issued warning 
letters informing four companies marketing caffeinated alcoholic 
beverages that caffeine, as used in the companies' products, is an 
unsafe food additive, and therefore the products are adulterated under 
section 402(a)(2)(C) of the FD&C Act (Ref. 10 through Ref. 13), and the 
companies subsequently ceased distribution of these products. Thus, we 
advise any manufacturer or distributor to carefully consider whether 
there is adequate support for concluding that a substance is GRAS under 
the conditions of its intended use and to submit its conclusion of GRAS 
status to us in the form of a GRAS notice.
    (Comment 26) A few comments express skepticism that the 
substitution of a GRAS notification procedure for the GRAS affirmation 
petition process would result in our increased awareness of the 
composition of the nation's food supply and the cumulative dietary 
exposure to GRAS substances. These comments assert that the proposed 
notification procedure offered a risk (i.e., the risk of a publicly 
available ``insufficient basis letter'') without the potential benefit 
that was available under the petition process (i.e., a regulation 
affirming GRAS status). These comments predict that, unless we modify 
the proposed rule substantially, we likely would have less awareness of 
GRAS substances under the notification procedure than we currently have 
under the GRAS affirmation petition process.
    One comment asserts that the notification procedure would in no 
manner be equivalent to the GRAS affirmation petition process, and the 
substitution of a notification procedure for a petition process would 
be anything but neutral. This comment asserts that the proposed 
substitution of a notification process for the affirmation process 
would actually reduce the incentive for producers to notify FDA, 
because notification would invite regulatory scrutiny without requiring 
FDA to attest to a conclusion of GRAS status.
    (Response 26) We disagree that the notification procedure we are 
establishing in this rule will reduce the incentive for producers to 
notify us. As already noted in Response 24, CFSAN has filed more than 
600 GRAS notices between 1998 and 2015, for an average of approximately 
34 GRAS notices per year. In contrast, as discussed in section IV.L of 
CFSAN's 2010 experience document (Ref. 18), between 1987 and 1996 CFSAN 
received a total of fewer than 100 GRAS affirmation petitions, with an 
average of approximately 8 GRAS affirmation petitions per year. These 
data support the expectation we expressed in the proposed rule that the 
substitution of a GRAS notification procedure for the GRAS affirmation 
petition process would result in our increased awareness of the 
composition of the nation's food supply and the cumulative dietary 
exposure to GRAS substances.
    The comments that predict that we would need to modify the final 
rule substantially to achieve increased awareness of the nation's food 
supply did not suggest specific modifications for this purpose. 
However, this document discusses the changes we have made to the 
proposed notification procedure as a result of comments, described in 
this document and the 2010 notice, that raised specific issues and 
concerns regarding the proposed notification procedure. For example, 
the final rule defines the term ``amendment'' (Sec.  170.203) and 
expressly provides that a notifier may submit a timely amendment to 
address our questions (Sec.  170.260(a)). As another example, the final 
rule expressly provides that a notifier may ask us to cease to evaluate 
a GRAS notice (Sec.  170.260(b)). In addition, see Response 80 
regarding our willingness to engage with a notifier to clarify 
particular aspects of the notice and Response 96 and Response 97 
regarding comments that raise concerns about a publicly available 
insufficient basis letter. For a summary of the principal changes to 
the notification procedure in this final rule relative to the proposed 
rule, see table 2.
    (Comment 27) One comment asks us to require the submission of a 
GRAS affirmation petition on a random basis for 20 percent of the GRAS 
notices we receive. This comment states that such a requirement would 
be essential in light of our concurrent proposal to broaden the types 
of safety information that could support GRAS status in the criteria 
for eligibility for classification as GRAS through scientific 
procedures. The comment refers to this procedure as a ``verification 
audit'' and describes a ``verification audit'' as a detailed evaluation 
of the scientific data and other technical information. The comment 
asks that the final rule give FDA such ``verification authority'' and 
asserts that such a verification system would give consumers greater 
confidence that the new notification system was not just a system of 
deregulation.
    (Response 27) We decline this request. Both the GRAS notification 
procedure and the GRAS affirmation petition process that it is 
replacing are voluntary procedures and, thus, the comment's position 
that we could require a GRAS affirmation petition--on a random or any 
other basis--is incorrect. Moreover, we disagree that the revised 
criteria for eligibility for GRAS status through scientific procedures 
have any bearing on whether we should evaluate a conclusion of GRAS 
status through a notification procedure or a petition process. The 
revised criteria reflect the nature of substances being added to food, 
and the fact that the quantity and quality of scientific evidence 
required to demonstrate safety vary considerably depending upon the 
estimated dietary exposure to the substance and the chemical, physical, 
and physiological properties of the substance. See Response 23.

C. General Comments on the Proposed GRAS Notification Procedure

    (Comment 28) Some comments ask us to require that companies notify 
us of a conclusion of GRAS status and assert that we have implied legal 
authority to require such notification. These comments express concern 
that potentially dangerous substances could enter the food supply 
without our knowledge or supervision. Other comments emphasize that the 
GRAS notification procedure should remain voluntary and assert that we 
lack express statutory authority to require companies to submit GRAS 
notices.
    (Response 28) We agree that we lack express statutory authority to 
require

[[Page 54982]]

companies to submit GRAS notices. In creating the premarket approval 
requirement for food additives in the 1958 amendment, Congress excluded 
a substance that is GRAS under the conditions of its intended use from 
the definition of food additive. The creation of this GRAS provision 
reflected Congress' determination that many substances intentionally 
added to food for a specific use do not need premarket review by FDA to 
ensure their safety, either because their safety has been established 
by a long history of use in food, or because their safety has been 
established by information that is generally available to and accepted 
by qualified experts, regarding the intended conditions of use of a 
substance in food. Subsequently, in 1997, the Food and Drug 
Administration Modernization Act (FDAMA) amended section 409 of the 
FD&C Act to require the establishment of a mandatory food contact 
notification program for human food. By contrast, Congress has not 
amended section 409 of the FD&C Act to require the establishment of a 
premarket GRAS notification procedure--either voluntary or mandatory.
    We did not propose to require the submission to FDA of notices 
concerning all conclusions of GRAS status. We recognize that some 
comments suggest that such a requirement might be within our legal 
authority, even if not expressly required by the FD&C Act. We will 
consider these comments and our experience under this final rule in 
evaluating what, if any, further action is needed with respect to 
ensuring the safety of the food supply. However, mandating submission 
of GRAS notices would need to be done in a separate rulemaking to 
ensure adequate notice and comment.
    (Comment 29) One comment notes that the proposed rule did not 
specifically ask members of the food industry to notify us of all 
conclusions of GRAS status. This comment suggests that the final rule 
include such a request, explaining that such a provision would help us 
to achieve our goal of increasing our awareness of substances added to 
food.
    (Response 29) We view our establishment of the GRAS notification 
procedure in this final rule, as well as our announcement of the 
Interim Pilot program in the proposed rule, as an invitation to 
industry to submit GRAS notices to us for evaluation. See also Sec.  
170.205, entitled ``Opportunity to submit a GRAS notice.'' The ongoing 
submission of GRAS notices during the Interim Pilot program 
demonstrates that the food industry is actively submitting GRAS 
notices. As already noted in Response 26, we believe that our filing of 
more than 600 GRAS notices for substances used in human food is 
evidence that we have increased our awareness of the composition of the 
nation's food supply and the dietary exposure to GRAS substances.
    (Comment 30) Some comments ask us to require certain postmarket 
submissions of exposure and safety data related to all GRAS substances, 
to require submissions for conclusions of GRAS status that predate the 
final rule, and to require any notifier who ``withdraws'' a GRAS notice 
or receives an ``insufficient basis letter'' to notify us about any use 
of that substance.
    (Response 30) We decline this request for the same reasons that we 
discuss in Response 28. See also the discussions in Response 25 and 
Response 35 regarding the responsibility of a manufacturer to ensure 
that a substance added to food complies with the FD&C Act, and the 
potential that we may disagree with a conclusion of GRAS status and 
take regulatory action against use of the food substance when we do so.
    (Comment 31) Some comments ask us to clarify all the information we 
expect to be submitted in a GRAS notice. One comment states its 
opposition for the proposed GRAS notification procedure, but also 
states that if we implement such a program we should establish the 
framework and criteria for the voluntary submission of GRAS notices. 
Another comment asks us to include core requirements in the final rule. 
Another comment asks us to provide more explicit instructions 
concerning the level of detail necessary within the required elements 
of a GRAS notice.
    (Response 31) Subpart E of part 170 (subpart E) establishes a 
comprehensive framework for the submission of GRAS notices, describing 
in detail ``core requirements'' such as the seven distinct parts of a 
GRAS notice. Subpart E also includes provisions that will govern what 
we will do when we receive a GRAS notice, as well as provisions that 
will govern disclosure of a GRAS notice. Section 170.30 establishes the 
revised criteria for eligibility for classification of the food use of 
a substance as GRAS.
    (Comment 32) One comment expresses concern that the proposed GRAS 
notification procedure would be viewed as a ``fast-track'' option that 
would tempt a company that should submit a food additive petition to 
submit a GRAS notice instead.
    (Response 32) We recognize that there is a possibility that some 
manufacturers of food ingredients may decide that they do not need to 
submit a food additive petition because they have concluded that the 
substance is GRAS under the conditions of its intended use; this 
possibility exists regardless of how we structure the GRAS notification 
procedure. However, a manufacturer's decision that a food additive 
petition is not required must be based on the extent to which the 
manufacturer has information both that the intended conditions of use 
of a substance in food are ``safe,'' and that there is ``general 
recognition'' of that safety. In this rule, we clarify the criteria 
(Sec.  170.30) that govern when the intended conditions of use of a 
substance in food are more properly the subject of a food additive 
petition than a GRAS notice.
    The record of our actions during the Interim Pilot program 
demonstrates that we will, when appropriate, issue an ``insufficient 
basis letter'' or a ``cease to evaluate letter'' signaling that a 
petition to obtain a regulation is more appropriate than a GRAS notice. 
As described in sections III.A.4 and III.N.2 of CFSAN's 2010 experience 
document (Ref. 18), in several cases during the Interim Pilot program 
the outcome of CFSAN's review of a GRAS notice was the notifier's 
subsequent submission of a food additive petition.
    (Comment 33) One comment expresses the opinion that a GRAS notice 
could be an appropriate mechanism to inform us of a view that an 
additional use of an approved food additive is GRAS.
    (Response 33) We agree, provided that the available data and 
information demonstrate that the criteria for GRAS status are 
satisfied. Whether an additional use of a food additive is GRAS depends 
on both whether that additional use is safe and on whether the safety 
of that additional use is generally recognized by qualified experts. To 
support a conclusion of GRAS status for the additional use of the 
substance, there must be evidence that qualified experts generally (not 
solely FDA experts who conducted a premarket review of a food additive 
petition) have evaluated generally available data and information about 
the intended conditions of use of the substance, and reached agreement 
that those generally available data and information establish the 
safety of the additional use of the substance. During the Interim Pilot 
program, CFSAN received several GRAS notices informing CFSAN of a 
conclusion that an additional use of an approved food additive is GRAS. 
As discussed in section III.A.4 of CFSAN's 2010 experience document 
(Ref. 18), CFSAN's response to these GRAS notices has been a case-by-
case response

[[Page 54983]]

that depends on the circumstances. In several cases, CFSAN had no 
questions about the notifier's conclusion of GRAS status for an 
additional use of a food additive; in one case, the GRAS notice did not 
support GRAS status for the additional use of the food additive, and 
the notifier subsequently submitted a food additive petition for the 
additional use of the substance.
    (Comment 34) One comment suggests that the GRAS notification 
procedure would shift the burden of proof to FDA to demonstrate that a 
use of a substance is not safe or not GRAS after the substance is 
already on the market.
    (Response 34) We disagree. Under the FD&C Act, the burden of 
supporting a conclusion that a substance is GRAS under the conditions 
of its intended use is on the proponent of this conclusion. United 
States v. An Article of Food, 752 F.2d 11, 15 (1st Cir. P.R. 1985). 
This burden of proof remains after the substance is on the market 
regardless of whether the proponent asks FDA to evaluate that GRAS 
conclusion, and our rule does not change this. By establishing a 
process for the submission of GRAS notices for FDA to review, our rule 
encourages firms to seek our evaluation of their conclusions, before 
they introduce the substance into the market.
    (Comment 35) A few comments note that a notifier who markets a food 
substance before we issue our letter responding to the notice runs the 
risk that we may disagree with the conclusion of GRAS status. One 
comment expresses concern that we would take regulatory action to 
remove the substance from the food supply rather than discuss our 
concerns with the notifier.
    (Response 35) The comments are correct that a notifier who markets 
a food substance before we issue our letter based on our evaluation of 
the notice runs the risk that we may disagree with the conclusion of 
GRAS status. (We note that a manufacturer who markets a food substance 
without submitting a GRAS notice runs a similar risk.) However, we make 
every effort to evaluate the data and information submitted on a timely 
basis, and in this rule we commit to responding to a GRAS notice within 
180 days after filing the notice, with the option to extend an 
additional 90 days as needed. Because a substance that is GRAS under 
the conditions of its intended use is not subject to premarket review 
as a food additive under the FD&C Act, a notifier could decide to 
introduce the substance into the market without waiting for the letter; 
we could subsequently determine that the substance is an unapproved 
food additive, and we may take action to remove the substance from the 
food supply.
    See also the discussion in Response 80. Our experience during the 
Interim Pilot program demonstrates that we are willing to contact a 
notifier to clarify particular aspects of a GRAS notice. As also 
discussed in Response 80, under the final rule, we intend to contact a 
notifier when we identify a safety concern. However, whether the 
purpose of the contact is to provide an opportunity to address that 
concern (e.g., in an amendment or in a newly submitted GRAS notice), or 
to alert the notifier to our concerns while we prepare an 
``insufficient basis letter,'' has been, and will continue to be, a 
matter committed to our discretion depending on the totality of the 
circumstances.
    (Comment 36) One comment suggests that we ask notifiers who 
previously received a ``no questions letter'' under the Interim Pilot 
program to review their prior submissions and align them with the 
requirements of the final rule.
    (Response 36) We decline this suggestion. The final rule does not 
pose any substantially different data requirements than did the Interim 
Pilot program in terms of data quality and quantity to support the 
conclusion of GRAS status. We do not anticipate, as a general matter, 
the need to ask previous notifiers who received a ``no questions 
letter'' to provide any supplemental information. However, if we become 
aware of data or information that questions the GRAS status of the use 
of a substance that has been the subject of a ``no questions letter,'' 
we may send the notifier a subsequent letter advising the notifier of 
those questions (see Sec.  170.265(c)). Because we would make the 
subsequent letter readily accessible to the public (see Sec.  
170.275(b)(2)), other stakeholders would have ready access to those 
questions.
    (Comment 37) One comment states that GRAS ``determinations'' must 
be evaluated based on adequate science and recommends that GRAS 
``determinations'' comply with our guidance on food additive testing.
    (Response 37) We agree that safe use(s) of a substance must be 
supported by adequate science. We do have extensive guidance on food 
additive testing (Ref. 31 through Ref. 35), and we agree that this 
guidance on food additive testing can be useful in the evaluation of 
the safety of a substance when the proponent of the substance seeks to 
demonstrate that the substance is GRAS under the conditions of its 
intended use. As discussed in Response 128, as resources allow we 
intend to re-visit these scientific guidance documents to determine 
whether and how to modify them to clarify that our guidance on 
evaluating the safety of a food substance generally applies regardless 
of whether the substance would be used in food as a food additive or as 
a GRAS substance.
    Recently, we issued a notice (79 FR 64603, October 30, 2014) 
announcing a public meeting, and requesting comments, on our intent to 
update our guidance entitled ``Guidance for Industry and Other 
Stakeholders: Toxicological Principles for the Safety Assessment of 
Food Ingredients'' (Ref. 35; commonly referred to as our ``Redbook''). 
In that notice, we reiterated that general recognition of safety based 
upon scientific procedures requires the same quantity and quality of 
evidence as is required to approve a food additive. We also asked for 
comment on how we should balance the desire for transparency and 
consistency in risk assessment, as described in the Redbook, with the 
goal of flexibility in applying the most appropriate analysis for 
specific contexts.
    (Comment 38) One comment states that the resource-intensive 
petition process would be reserved for ingredients not eligible to meet 
GRAS criteria, or those which pose questions necessitating indepth 
review by FDA scientists, even though the safety standard for GRAS 
ingredients and food additives is the same.
    (Response 38) The comment is correct that a food additive petition 
would be required for an ingredient that is not eligible for 
classification as GRAS and is not otherwise excepted from the statutory 
definition of a food additive. We agree that indepth review of the 
safety of a substance under the conditions of its intended use in food 
by FDA scientists is necessary when there is no basis for a conclusion 
that the intended conditions of use have GRAS status. However, see 
Response 25. Our evaluation of a GRAS notice is a substantive 
evaluation even though we respond to a GRAS notice by letter rather 
than by establishing a regulation.
    (Comment 39) One comment asserts that we tentatively concluded that 
the proposed notification procedure would allow us to direct our 
resources to the more significant questions about GRAS status, without 
further explaining what these ``more significant questions'' are. This 
comment further asserts that the obvious conclusion is that we will 
simply reduce the Federal layer of oversight in the interests of 
efficiency and in doing so ignore the history of food law, which has 
repeatedly shown

[[Page 54984]]

that the public suffers when FDA declines to regulate.
    (Response 39) See the actions we describe in section I.D, on PHOs 
and caffeinated alcoholic beverages, for examples of what we mean by 
``more significant questions.'' We disagree that directing our 
resources in such a manner reduces our oversight; on the contrary, such 
actions demonstrate that we will take appropriate steps to address 
concerns about the safety of substances marketed under the GRAS 
provision of the FD&C Act. The comment provides no basis for its 
assertion that the notification procedure ignores the history of food 
law or that the public will suffer.
    (Comment 40) One comment points out that our response to a GRAS 
notice addresses the question of whether a particular use of a notified 
substance is GRAS, without limiting that question to production of that 
food substance by a specific manufacturer (e.g., the notifier who 
submitted the GRAS notice). This comment asks us to require that any 
other food producer who uses the substance in food on the basis of a 
GRAS conclusion submitted to FDA in a GRAS notice meet all requirements 
and specifications in the submitted GRAS notice, including use of the 
same source for the production of the food substance.
    (Response 40) The comment is correct that our response to a GRAS 
notice would not limit a food producer other than the notifier from 
relying on the submitted GRAS notice, and our response to that GRAS 
notice, when that food producer concludes that a substance is GRAS 
under the conditions of its intended use in food. The method of 
manufacture (including any source specified for the production of the 
notified substance) and specifications identified in a GRAS notice are 
relevant to both the identity of the substance and its safety for use 
in food. We advise any food producer who relies on a GRAS notice 
submitted by another person to carefully consider whether its 
production process, and/or the intended conditions of use of the 
notified substance, fall within the parameters, such as method of 
manufacture (including a specified source) and specifications, 
addressed by the submitted GRAS notice. We recently issued guidance to 
help food producers to do so. See our guidance entitled ``Assessing the 
Effects of Significant Manufacturing Process Changes, Including 
Emerging Technologies, on the Safety and Regulatory Status of Food 
Ingredients and Food Contact Substances, Including Food Ingredients 
that Are Color Additives'' (Ref. 6).

D. Comments on Certain Terms Used in the Proposed Regulatory Text

1. Replacing the Terms ``Determine'' and ``Determination'' With the 
Terms ``Conclude'' and ``Conclusion''
    In the 2010 notice, we explained our reasons for tentatively 
concluding that the terms ``conclude'' and ``conclusion'' would be more 
appropriate in lieu of ``determine'' and ``determination'' and 
requested comment on these terms (see Issue 2, 75 FR 81536 at 81538).
    (Comment 41) Many comments support replacing the terms 
``determine'' and ``determination'' with the terms ``conclude'' and 
``conclusion.'' One comment disagrees with changing the terms 
``determine'' and ``determination.'' This comment asserts that the 
terms ``determine'' and ``determination'' are more appropriate because 
a determination is made based on the sum of the total assembled data 
and conclusions. This comment also disagrees with changing the terms 
because individuals who already are involved in the GRAS notification 
procedure as a result of the Interim Pilot program are already familiar 
with the terms and meanings of ``determine'' and ``determination.''
    One comment observes that the terms ``determined'' and 
``determination'' are used in Sec.  170.30 of our regulations within 
the context of establishing GRAS status. This comment asks us to 
clarify how we would apply the terms ``determined,'' ``determination,'' 
``conclude,'' and ``conclusion'' and whether we would limit how some 
terms apply depending on whether a substance is the subject of a GRAS 
notice. This comment expresses concern that such a distinction in terms 
could lead to a misperception that a substance that is the subject of a 
GRAS notice has a more authoritative and/or superior legal standing 
than a substance that does not.
    (Response 41) We are replacing the term ``determination'' with 
``conclusion,'' and referring to a ``conclusion of GRAS status'' rather 
than to a ``GRAS determination,'' throughout the regulatory text for 
the GRAS notification procedure. We recognize that notifiers involved 
with the GRAS notification procedure may be more familiar with the 
terms ``determine'' and ``determination.'' Nevertheless, we believe 
that as notifiers gain more experience with the GRAS notification 
procedure set forth in this final rule, notifiers will adjust to using 
``concludes'' and ``conclusion.''
    We are making conforming changes to current regulations regarding 
the use of GRAS substances in food to no longer use the terms 
``determine'' and ``determination'' (see the changes to Sec. Sec.  
170.3(k), 170.30(c)(1), and 170.30(e) in table 29). We are making these 
conforming changes to clarify that there would be no distinction 
between a conclusion of GRAS status submitted to us as a GRAS notice 
and a conclusion of GRAS status that remains with its proponent as an 
independent conclusion (formerly referred to as a ``self-
determination'') of GRAS status.
2. The Terms ``Exempt,'' ``Exemption,'' and ``Claim''
    Several provisions in the proposed rule would use terms such as 
``exempt,'' ``exemption,'' and ``claim.''
    (Comment 42) Several comments object to some terms used in the 
proposed procedure for submitting a GRAS notice. Some comments object 
to proposed title for the GRAS notification procedure, i.e., ``Notice 
of a claim for exemption based on a GRAS determination.'' Most of these 
comments also object to our characterization of one of the proposed 
provisions (proposed Sec.  170.36(c)(1)) as a ``GRAS exemption claim.'' 
In general, these comments assert that nothing in the FD&C Act or in 
the legislative history of the FD&C Act supports designation of GRAS 
status as an ``exemption.'' In addition, several comments object to our 
use of the term ``claim'' in various proposed provisions because our 
use of this term implies that we have legal authority to deny a claim 
or that GRAS status is not operative unless a claim is filed.
    (Response 42) We have made the following editorial changes 
throughout the regulatory text to no longer use terms such as 
``exempt,'' ``exemption,'' and ``claim.'' First, we replaced the term 
``exempt'' with the phrase ``not subject to.'' Section 201(s) of the 
FD&C Act provides that a substance that is GRAS under the conditions of 
its intended use is not within the definition of food additive. Whether 
the statutory GRAS provision in section 201(s) is an ``exemption,'' or, 
is an ``exclusion,'' is not essential to this rulemaking and, thus, we 
need not include any variations of the term ``exempt'' in the final 
rule. Second, we replaced the term ``claim'' (when used as a noun) with 
the term ``view.'' In the past, we have used the term ``view'' when 
describing a statement or assertion that a use of a substance is GRAS 
(see, e.g., 62 FR 36749, July 9, 1997). Finally, we simplified the 
title of the regulatory text to ``Generally Recognized as Safe (GRAS) 
Notice.''

[[Page 54985]]

E. Comments on the Use of ``Plain Language'' in the Regulatory Text

    In the 2010 notice, we noted our intent to use ``Plain Language'' 
tools such as pronouns in the final rule (75 FR 81536 at 81537). The 
use of ``Plain Language'' tools in government writing, now called 
``plain writing,'' is consistent with the government-wide initiative to 
promote transparency, public participation, and collaboration 
throughout the Federal Government's programs and activities as set out 
in ``Improving Electronic Dockets on Regulations.gov and the Federal 
Docket Management System: Best Practices for Federal Agencies'' (Ref. 
22).
    (Comment 43) One comment recommends that we use Plain Language 
throughout the regulatory text to foster greater understanding about 
the regulatory requirements and expectations for the notification 
procedure, leading to a more effective program.
    (Response 43) We have used ``Plain Language'' tools (such as short 
sections and the use of pronouns) throughout the regulatory text of 
subpart E, which establishes the requirements for the GRAS notification 
procedure. See table 4 for the section numbers and titles of the 
redesignated regulatory text in subpart E.

 Table 4--Redesignation of the GRAS Notification Procedure in Subpart E
------------------------------------------------------------------------
         Section                               Title
------------------------------------------------------------------------
170.203..................  Definitions.
170.205..................  Opportunity to submit a GRAS notice.
170.210..................  How to send your GRAS notice to FDA.
170.215..................  Incorporation into a GRAS notice.
170.220..................  General requirements applicable to a GRAS
                            notice.
170.225..................  Part 1 of a GRAS notice: Signed statements
                            and certification.
170.230..................  Part 2 of a GRAS notice: Identity, method of
                            manufacture, specifications, and physical or
                            technical effect.
170.235..................  Part 3 of a GRAS notice: Dietary exposure.
170.240..................  Part 4 of a GRAS notice: Self-limiting levels
                            of use.
170.245..................  Part 5 of a GRAS notice: Experience based on
                            common use in food before 1958.
170.250..................  Part 6 of a GRAS notice: Narrative.
170.255..................  Part 7 of a GRAS notice: List of supporting
                            data and information in your GRAS notice.
170.260..................  Steps you may take before FDA responds to
                            your GRAS notice.
170.265..................  What FDA will do with a GRAS notice.
170.270..................  Procedures that apply when the intended
                            conditions of use of a notified substance
                            include use in a product or products subject
                            to regulation by FSIS.
170.275..................  Public disclosure of a GRAS notice.
170.280..................  Submission of a supplement.
170.285..................  Disposition of pending GRAS affirmation
                            petitions.
------------------------------------------------------------------------

VIII. Definitions Applicable to a GRAS Notice

A. Definitions We Described in the 2010 Notice

    In the 2010 notice, we requested comment on definitions for the 
terms ``amendment,'' ``notified substance,'' ``notifier,'' ``qualified 
expert,'' and ``supplement'' (see Issue 3, 75 FR 81536 at 81538). We 
received several comments that generally support adding definitions for 
these terms, and we are establishing a section in the regulatory text 
of subpart E to define these and other terms (see Sec.  170.203).

B. Definition of ``GRAS Notice''

    (Comment 44) Some comments express concern about the potential for 
confusion between the proposed GRAS notification procedure and another 
FDA ``notification program'', i.e., the premarket notification program 
for food contact substances (in part 170, subpart D) that we 
established under FDAMA. These comments assert that this confusion can 
lead to uncertainty about the nature of the proposed GRAS notification 
procedure, such as with respect to market ``exclusivity'' for the 
notified substance. One comment states that the terms ``GRAS notice'' 
and ``GRAS notification'' appear to be used interchangeably in the 2010 
notice and asks whether it is our intention to use ``notice,'' 
``notification,'' or both terms with regard to the proposed procedure 
for submission of a conclusion of GRAS status for a use of a food 
substance.
    Another comment notes that the proposed rule to establish a GRAS 
notification procedure was followed soon thereafter by the rulemaking 
to establish the premarket notification program for food contact 
substances as authorized by FDAMA (the FCN program; proposed rule 65 FR 
43269, July 13, 2000; final rule 67 FR 35724, May 21, 2002). This 
comment asserts that although the proposed GRAS notification procedure 
and the established FCN program are distinct, industry reasonably 
relied on the close temporal proximity of the 1997 proposed rule to 
establish a GRAS ``notification'' procedure, and the rulemaking to 
establish the FCN program, as contemporaneous guidance for the meaning 
of the term ``notification'' under FDAMA. Because the FCN program 
provides market ``exclusivity'' for the food contact substance, the 
comment asserts that it is understandable why regulated industry would 
think that submitting a GRAS notice likewise implies ``exclusivity'' 
for the substance. The comment notes that FDA is not responsible for 
misinterpretations made by industry, but asks us to recognize this lack 
of transparency and clarity and remedy it in a fair and equitable 
manner.
    (Response 44) In the proposed rule and in this final rule, we use 
the term ``notice'' as a noun to refer to the submission that you send 
to us and we use the term ``notification'' as an adjective, e.g., to 
modify the noun ``procedure.'' In contrast, the FCN program uses the 
term ``notification'' as a noun in addition to using the term as an 
adjective, consistent with FDAMA's use of the term as a noun. We 
continue to use the term ``notification'' as an adjective (e.g., GRAS 
notification procedure) in this preamble discussion of the requirements 
for submitting a GRAS notice. However, in the regulatory text we only 
use the term ``notice,'' and we have added a definition of the term 
``GRAS notice'' to the regulatory text (see Sec.  170.203).
    The ``exclusivity'' within the FCN program is provided by section 
409(h)(2)(C) of the FD&C Act. See also our implementing regulation at

[[Page 54986]]

Sec.  170.100(a), which provides that a FCN is effective for the food 
contact substance manufactured or prepared by the manufacturer or 
supplier identified in the FCN submission. There is no similar 
provision in the FD&C Act or our regulations providing exclusivity for 
a substance that is used in food based on a conclusion that the 
substance is GRAS under the conditions of its intended use.
C. Other Terms We Are Defining in the Rule
    We are defining the abbreviation ``GRAS'' to mean ``generally 
recognized as safe'' so that we can use that abbreviation throughout 
the regulatory text without defining it in each section where it 
appears. To clarify how pronouns apply in the regulatory text, we also 
are specifying in the definition section that ``you'' and ``your'' 
refer to a notifier, and that ``we,'' ``our,'' and ``us'' refer to FDA.

IX. Opportunity To Submit a GRAS Notice

    We proposed to provide that any person may notify FDA of a claim 
that a particular use of a substance is exempt from the statutory 
premarket approval requirements based on the notifier's determination 
that such use is generally recognized as safe (GRAS) (proposed Sec.  
170.36(a)). We are establishing this statement of an opportunity to 
submit a GRAS notice in Sec.  170.205, with the editorial changes 
described in Response 41 and Response 42.

X. Comments on Administrative Procedures for Submission of a GRAS 
Notice

    We proposed that a notice of a ``GRAS exemption claim'' be 
submitted in triplicate to a specified address (proposed Sec.  
170.36(b)). We also asked for comment on whether it would be 
appropriate to require or recommend that the submission include an 
electronic copy in addition to the three paper copies (62 FR 18938 at 
18946) or, at a minimum, an electronic copy of the proposed ``GRAS 
exemption claim'' (proposed Sec.  170.36(c)(1); final Sec.  170.225 
(part 1 of a GRAS notice).
    In the 2010 notice, we described comments asking us to permit a 
notifier to reference a previously submitted GRAS notice to support a 
view that an additional use of the applicable substance is GRAS. We 
also discussed a coordinated evaluation process with FSIS when the use 
of a notified substance includes use in products subject to regulation 
by FSIS. (Note that the discussion in the 2010 notice referred to a 
``coordinated review process.'' As discussed in Response 25, we are 
using the term ``evaluation'' rather than ``review'' in connection with 
GRAS notices. In addition, in a Memorandum of Understanding (MOU) 
between FDA and FSIS (Ref. 36), we specify that we will inform the 
notifier in writing that the notice will also be ``evaluated'' by FSIS 
to determine the suitability of the use of the substance in the 
production of meat, poultry, or egg products. Given the discussion in 
Response 25 and the terms of the MOU with FSIS, in this document, we 
use the term ``coordinated evaluation'' rather than ``coordinated 
review.'') We asked for comment relevant to these administrative 
procedures (see table 5).

      Table 5--Issues in the 2010 Notice Relevant to Procedures for
                       Administering a GRAS Notice
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
4.........  Whether the final  75 FR 81536 at 81538.
             rule should
             include a
             provision to
             expressly permit
             a notifier to
             incorporate into
             a GRAS notice
             data and
             information that
             were previously
             submitted by the
             notifier, or
             public data and
             information
             submitted by
             another party,
             when such data
             and information
             remain in our
             files.
13........  Whether a          75 FR 81536 at 81541-81542.
             notifier who
             submits a GRAS
             notice for such
             a substance
             should provide
             an additional
             paper copy or an
             electronic copy
             of the GRAS
             notice that we
             could send to
             FSIS.
------------------------------------------------------------------------

    Several comments support the administrative procedures that we 
proposed or described in the 2010 notice. For example, several comments 
support adding a provision to allow a notifier to incorporate 
information into a GRAS notice, including data and information 
previously submitted by the notifier and public data and information 
submitted by another party, because such a provision would be 
practical, promote administrative efficiency, or reduce paper. In the 
following sections, we discuss comments that disagree with one or more 
aspects of the administrative procedures that we proposed or described 
as potential modifications in the 2010 notice (see, e.g., Comment 45); 
ask us to clarify these administrative procedures (see, e.g., Comment 
48 and Comment 49); or suggest one or more changes to these 
administrative procedures (see, e.g., Comment 47). After considering 
these comments, we are providing that you may submit a GRAS notice 
either in electronic format that is accessible for our evaluation or on 
paper; for paper submissions, a single paper copy of a GRAS notice is 
sufficient.
    We also are finalizing a provision to allow for incorporation into 
a GRAS notice of data and information as described in the 2010 notice, 
with clarification that the referenced data and information must be 
specifically identified. As discussed in the 2010 notice, the provision 
specifies that incorporation into a GRAS notice applies only when data 
and information remain in our files. We do not retain records 
indefinitely; rather, records may be retired to a Federal Records 
Center and subsequently disposed of in accordance with our Records 
Control Schedule.

A. How To Send a GRAS Notice to FDA

    We proposed to specify in the regulatory text the address where you 
would send a GRAS notice. We are finalizing this administrative 
provision with updates to reflect the current mailing address and the 
editorial changes described in Response 42. See the regulatory text in 
Sec.  170.210(a).
    (Comment 45) One comment asserts that a single GRAS notice to 
either CFSAN or CVM should suffice to inform both Centers of a 
conclusion of GRAS status.
    (Response 45) We disagree. Our regulations directed to human food 
are established in subchapter B of 21 CFR (i.e., Food For Human 
Consumption, parts 100-199), whereas our regulations directed to animal 
food are established in subchapter E of 21 CFR (i.e., Animal Drugs, 
Feeds, And Related Products, parts 500-599). We have separately 
established requirements applicable to GRAS substances for use in human 
food in subchapter B of 21 CFR (e.g., in parts 170, 182, 184, and 186) 
and requirements applicable to GRAS substances for use in animal food 
in subchapter E of 21 CFR (e.g., in parts 570, 582, and 584). We also 
had separately established requirements for the GRAS affirmation 
petition process

[[Page 54987]]

(which the GRAS notification procedure is replacing) for substances for 
use in human food in subchapter B of 21 CFR (i.e., in Sec.  170.35(c)) 
and requirements applicable to the GRAS affirmation petition process 
for substances for use in animal food in subchapter E of 21 CFR (i.e., 
in Sec.  570.35(c)). We address food substances separately for human 
use and for animal use because the safety evaluation of a food 
substance relates to the conditions of its intended use, and the 
conditions of use of a substance in human food can raise different 
safety questions than the conditions of use of that same substance in 
animal food. For example, a substance containing copper can be safely 
used in human food and in food for many animal species, but even small 
amounts of copper can be toxic to sheep. As another example, FDA has 
affirmed that several uses of propylene glycol in human food are GRAS 
(Sec.  184.1666), but propylene glycol is known to be toxic to cats and 
FDA has prohibited its use in cat food (see Sec.  589.1001). Therefore, 
the final rule establishes separate (albeit parallel) requirements for 
submission of a GRAS notice to CFSAN for the use of a substance in 
human food and for submission of a GRAS notice to CVM for the use of a 
substance in animal food.

B. Option for Submission of Electronic or Paper Copies of a GRAS Notice

    (Comment 46) Most of the comments that responded to our request for 
comment on the submission of an electronic copy of a GRAS notice 
encourage us to recommend, but not require, submission of an electronic 
copy, explaining that an electronic copy would make our administration 
of the notification procedure more efficient. However, one comment 
notes that electronic technology may not be universally available. As 
discussed in Comment 47, another comment expresses concern about 
protection for confidential information in an electronic copy. One 
comment suggests that if we use an electronic means to make GRAS 
notices readily accessible to the public, then we should require that 
the submission include an electronic copy. Comments that address Issue 
13 support requiring the notifier to provide an additional paper copy 
that we would send to FSIS as part of this procedure.
    (Response 46) We agree that an electronic copy will make our 
administration of the GRAS notification procedure more efficient. For 
example, an electronic copy generated from a word processing format 
generally is searchable without the need for Optical Character 
Recognition techniques, but an electronic copy generated by scanning a 
paper document into ``Portable Document Format'' (``pdf'') requires 
Optical Character Recognition before it can be searched electronically. 
Furthermore, the Government Paperwork Elimination Act of 1998 (Pub. L. 
105-277, Title XVII) requires Federal agencies to give persons who 
correspond with these agencies the option of doing so electronically 
when practicable as a substitute for paper, and to use electronic 
authentication (electronic signature) methods to verify the identity of 
the sender and the integrity of the electronic content. We acknowledge 
that technology may not be available to every notifier and, thus, the 
final rule does not require the submission of an electronic copy. 
Instead, the final rule provides that when you submit your GRAS notice, 
you may do so either in electronic format that is accessible for our 
evaluation or on paper (see Sec.  170.210(b)). Because you have an 
option to submit a GRAS notice either electronically or on paper, an 
electronic copy will essentially replace the need for a paper copy. In 
2010, CFSAN issued draft guidance for how to transmit a submission, 
including a GRAS notice, in electronic format (Ref. 37).
    We used electronic means to make submitted GRAS notices accessible 
to the public during the Interim Pilot program, and intend to continue 
to do so under the final rule. However, we decline the request to 
require that the submission include an electronic copy solely because 
we are doing so. We acknowledge that an electronic copy will improve 
the efficiency with which we make GRAS notices available to the public 
(see the public disclosure provisions of this rule in Sec.  170.275). 
However, during the Interim Pilot program we made an electronic copy of 
a submitted GRAS notice available on the Internet by scanning the paper 
GRAS notice to create an electronic pdf document, and we intend to 
continue to do so when you submit a GRAS notice on paper under the 
final rule.
    We have decided that a single copy of a GRAS notice that is 
submitted on paper is acceptable (rather than the three copies that we 
proposed to require) and have specified that a single paper copy is 
sufficient in the regulatory text (Sec.  170.210(b)). We proposed to 
require three copies of a submitted GRAS notice to make it easier to 
provide a paper copy of the GRAS notice to all members of our staff who 
will evaluate the GRAS notice. However, in practice during the Interim 
Pilot program we developed internal procedures in which we scan a GRAS 
notice submitted on paper to create an electronic pdf version of the 
GRAS notice, and we make the electronic pdf document available to all 
staff who will evaluate the GRAS notice. This procedure has reduced the 
resources needed to distribute the GRAS notice to our staff, and we 
intend to continue to use this procedure when we receive a GRAS notice 
on paper. When we coordinate our evaluation of a GRAS notice with FSIS, 
we send an electronic copy to FSIS and, thus, an additional paper copy 
for use by FSIS is not necessary.
    (Comment 47) One comment expresses concern about the security of 
confidential information in an electronic submission. This comment asks 
us to allow a notifier to edit an electronic copy to remove 
confidential information and present that information only in the paper 
copy. Another comment asks us to provide the same protections that 
would apply to confidential information in written records to 
confidential information in electronic records.
    (Response 47) We decline the request to allow you to edit an 
electronic copy of your GRAS notice such that the electronic copy would 
differ from the paper copy. If you have concerns about the security of 
confidential information in an electronic submission, you have the 
option to send the GRAS notice on paper (see Response 46). The 
protections applicable to confidential information are the same 
regardless of whether the information is in written or electronic form 
(see part 20, ``Public Information''). In particular, under Sec.  
20.20(e), ``Policy on disclosure of Food and Drug Administration 
records,'' the term ``record'' (as well as any other term used in Sec.  
20.20 in reference to information) includes any information that would 
be an agency record maintained by the Agency in any format, including 
an electronic format.
    In addition, the final rule requires you to state in writing your 
view as to whether any of the data and information in your GRAS notice 
are exempt from disclosure under FOIA (e.g., as trade secret or as 
commercial or financial information that is privileged or confidential) 
(see Sec.  170.225(c)(8)). The final rule also requires that if you 
view any of the data and information in your GRAS notice as exempt from 
disclosure under FOIA, you must identify the specific data and 
information (Sec.  170.250(d)). Together, these provisions will give us 
notice as to whether we will need to evaluate specific data and 
information under the FOIA and take steps to protect applicable data 
and information from public disclosure.

[[Page 54988]]

C. Incorporation Into a GRAS Notice

    (Comment 48) One comment supports adding a provision to allow a 
notifier to incorporate data and information into a GRAS notice as long 
as the notifier has explicit first-hand knowledge of the referenced 
files. Other comments address the limitation, discussed in the 2010 
notice, that data and information that are submitted by a person other 
than the notifier must be public, noting that it would be difficult to 
prevent the use of public information by others or that incorporating 
such data and information into a GRAS notice would be consistent with 
the criteria for general recognition of safety.
    (Response 48) A notifier must have sufficient knowledge of data and 
information submitted by another party to be able to identify the 
specific data and information that would be incorporated into a GRAS 
notice. To make this clear, the provision we are adding to the rule to 
allow for incorporation of data and information into a GRAS notice 
requires that such data and information be specifically identified. For 
example, we expect you to provide a specific file number (e.g., for a 
GRAS notice or a food additive petition) that contains the referenced 
data and information, and to identify the specific data and information 
in that file (rather than to broadly incorporate into a GRAS notice the 
entire file without explaining which data and information to 
incorporate). Although you may also incorporate into a GRAS notice a 
``food master file'' (provided that you specifically identify both the 
file number and the data and information in that file that you are 
asking us to incorporate into a GRAS notice), the regulatory text does 
not include ``food master file'' as an example of the type of file that 
you may reference because we do not have a regulatory definition for 
``food master file.'' See the discussion of ``food master file'' in 
Response 49.
    A notifier also must have sufficient knowledge of data and 
information submitted by another party to be able to discuss these data 
and information in the narrative that is required in part 6 of a GRAS 
notice (see Sec.  170.250). This narrative must explain the basis for 
the notifier's view that the notified substance is safe under the 
conditions of its intended use and that GRAS criteria--for both general 
availability and general acceptance--are satisfied. In other words, a 
GRAS notice must present the independent conclusions of the notifier 
regarding the basis for GRAS status, even if the data and information 
on which the notifier relies were submitted by another person.
    Consistent with the discussion in the 2010 notice, the provision we 
are adding to allow for incorporation of data and information into a 
GRAS notice specifies that data and information submitted by another 
party must be ``public.'' By ``public,'' we mean data and information 
that we have provided (or would provide) in response to a request under 
the FOIA, or that are otherwise publicly available (e.g., in a docket). 
Consistent with the views expressed in the comments, we see no reason 
to preclude you from referring us to such public information when we 
already have such information in our files, provided that you identify 
the specific data and information and the file(s) containing these data 
and information. We would not, for example, search our files to look 
for the referenced data and information. However, if you intend to 
incorporate into a GRAS notice data and information that were submitted 
by another party, and that you believe to be public information, we 
recommend that you explain the basis for your view that the data and 
information are public. If we need to evaluate the status of the data 
and information under the FOIA (e.g., because the data and information 
have not previously been disclosed to the public), we may decline to 
file the GRAS notice until we have evaluated the status of the 
referenced data and information under the FOIA. Doing so would be 
appropriate in light of the perspective of the comments, as discussed 
in the 2010 notice, that the process of incorporation would be 
administratively efficient (75 FR 81536 at 81538) and the limited time 
(i.e., 180 days) that we have to respond after we file a submission as 
a GRAS notice (see Sec.  170.265(b)). A notifier who intends to 
incorporate data and information that we must evaluate under the FOIA 
before we determine whether the data and information can be disclosed 
under the FOIA may find it advantageous to request those data and 
information under our public information procedures (see part 20), and 
then either include the data and information we disclose in response to 
that request in the submitted GRAS notice, or refer us to 
administrative information identifying the completed FOIA request when 
asking us to incorporate the data and information into a GRAS notice.
    (Comment 49) One comment states its presumption that a ``food 
master file'' is not available for public viewing, referring to a 
``long-standing center policy'' that such files are confidential. This 
comment asks us to continue to provide that a ``food master file'' be a 
confidential repository for proprietary data, such as utility and 
manufacturing information.
    (Response 49) We establish a ``food master file'' for a variety of 
reasons. For example, a person who submits a food additive petition may 
need us to evaluate data and information regarding a substance that the 
petitioner purchases from another party for use in the manufacture of 
the food additive. The petitioner may ask the manufacturer of that 
substance to provide the applicable data and information to us, and we 
then place the submitted data and information in a food master file. 
Although some or all of the data in such a food master file may be 
exempt from public disclosure (e.g., as trade secret information or 
confidential commercial information), a determination of whether 
specific data and information in a food master file is exempt from 
public disclosure is based on the status of the data and information 
under FOIA rather than on the type of file in which we place the data 
and information. We do not limit the type of data and information that 
may be included in a food master file to proprietary data and 
information.
    See also Sec.  170.215 and Response 48. Data and information 
submitted by a party other than a notifier must be public information. 
If you previously submitted a food master file to us, and you view the 
data and information in your food master file as proprietary, you must 
explain in part 6 of your GRAS notice how GRAS criteria are satisfied 
(see Sec.  170.250(e)).

XI. General Requirements Applicable to a GRAS Notice

    The final rule specifies two general provisions applicable to a 
GRAS notice (see Sec.  170.220). As discussed in Response 43, we have 
redesignated the single proposed section (i.e., proposed Sec.  170.36) 
into several distinct, short sections of regulatory text in a newly 
established subpart E (GRAS Notice). The first general provision 
specifies that a GRAS notice has seven parts, refers the user to the 
regulatory text for each of these parts, and specifies that you must 
submit the information specified in each of these parts on separate 
pages or sets of pages (Sec.  170.220 (a)). Submitting the information 
on separate pages or sets of pages is consistent both with the guidance 
we developed for preparation of a GRAS notice in electronic format 
(Ref. 37) and with long-standing requirements for other regulatory 
submissions, such as a food additive petition (see Sec.  171.1(f)) and 
a health claim petition (see Sec.  101.70(g)).

[[Page 54989]]

    The second general provision specifies that you must include each 
of the seven parts; if a part is not included, you must include an 
explanation of why that part does not apply to your GRAS notice (Sec.  
170.220 (b)). We added this provision because some parts of a GRAS 
notice (e.g., Part 4 (self-limiting levels of use) and Part 5 
(experience based on common use in food before 1958)) would not apply 
to most GRAS notices. Specifying that Parts 4 and 5 do not apply to a 
particular GRAS notice will make it clear that a notifier is aware of 
the requirements of those parts and has acknowledged that they do not 
apply.

XII. Comments on Part 1 of a GRAS Notice: Signed Statements and 
Certification

    We proposed that a GRAS notice must include a dated and signed 
claim that a particular use of a substance is exempt from the premarket 
approval requirements of the FD&C Act because the notifier has 
determined that such use is GRAS. The proposed ``GRAS exemption claim'' 
would include: (1) The name and address of the notifier; (2) the common 
or usual name of the notified substance; (3) the applicable conditions 
of use of the notified substance, including the foods in which the 
substance is to be used, levels of use in such foods, and the purposes 
for which the substance is used, including, when appropriate, a 
description of the population expected to consume the substance; (4) 
the basis for the GRAS determination (i.e., through scientific 
procedures or through experience based on common use in food); and (5) 
a statement that the data and information that are the basis for the 
notifier's GRAS determination are available for our review and copying 
at reasonable times at a specific address set out in the notice or will 
be sent to us upon request (proposed Sec.  170.36(c)(1)). In the 2010 
notice, we requested comment on several issues relevant to the proposed 
``GRAS exemption claim'' (see table 6).
    As discussed in Response 42, we have made editorial changes 
throughout the rule to replace the term ``exempt'' with the phrase 
``not subject to'' and to replace the term ``claim'' (when used as a 
noun) with the term ``view.'' In light of these editorial changes, in 
the remainder of this section we generally use the term ``proposed 
signed statements'' (rather than ``GRAS exemption claim'') when 
referring to the provisions that we had proposed to include in proposed 
Sec.  170.36(c)(1)).

    Table 6--Issues in the 2010 Notice Regarding the Proposed Signed
                       Statements in a GRAS Notice
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
6a........  How to best        75 FR 81536 at 81539.
             ensure that the
             identity and
             authority of the
             person who is
             signing the GRAS
             notice is made
             clear.
6b........  Whether to         75 FR 81536 at 81539.
             require that a
             notifier submit
             a statement that
             to the best of
             his knowledge,
             the GRAS notice
             is a
             representative
             and balanced
             submission that
             includes
             unfavorable
             information, as
             well as
             favorable
             information,
             known to him and
             pertinent to the
             evaluation of
             the safety of
             the substance.
6b........  Whether to         75 FR 81536 at 81539.
             require a
             notifier to
             certify to the
             statement
             (described in
             Issue 6a)
             regarding the
             representative
             and balanced
             nature of the
             GRAS notice.
7.........  Whether to         75 FR 81536 at 81539.
             require that the
             GRAS notice
             include the name
             of the notified
             substance, using
             an appropriately
             descriptive
             term, instead of
             the ``common or
             usual name'' of
             the notified
             substance.
8.........  Whether to         75 FR 81536 at 81539.
             explicitly
             require that the
             information
             submitted in the
             ``GRAS exemption
             claim'' exclude
             non-public
             information.
9b *......  Whether to         75 FR 81536 at 81540.
             require that a
             notifier who
             identifies one
             or more trade
             secret(s) in the
             GRAS notice
             explain why it
             is trade secret
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to the
             trade secret(s).
9c *......  Whether to         75 FR 81536 at 81540.
             require that a
             notifier who
             identifies
             confidential
             commercial or
             financial
             information in
             the GRAS notice
             explain why it
             is confidential
             commercial or
             financial
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to such
             information.
13........  Whether to make    75 FR 81536 at 81541-81542.
             our coordinated
             evaluation
             process with
             FSIS explicit in
             the final rule.
------------------------------------------------------------------------
* In the 2010 notice, Issues 9b and 9c asked how qualified experts could
  conclude that the intended use of the notified substance is ``GRAS''
  rather than ``safe.'' However, the qualified experts evaluate safety
  rather than GRAS status; the person who is responsible for the
  conclusion of GRAS status considers the view of the qualified experts
  on safety in reaching the conclusion that GRAS criteria are satisfied.
  In the remainder of this document, we describe Issues 9b and 9c with
  respect to whether qualified experts could conclude that the intended
  use of the substance is ``safe'' rather than ``GRAS.''

    In general, comments directed to the proposed signed statements 
agree that we should modify the provisions as discussed in Issues 6a, 
6b, 7, 8, 9a, 9b, 9c, and 13 in the 2010 notice. In the following 
sections, we discuss comments that address the issues discussed in the 
2010 notice (see, e.g., Comment 50, Comment 51, Comment 57, Comment 58, 
and Comment 59); address provisions of the proposed signed statements 
that we did not discuss in the 2010 notice (see, e.g., Comment 53); ask 
us to clarify how we will interpret the provisions of the proposed 
signed statements and potential modifications (see, e.g., Comment 54 
and Comment 55); or suggest one or more changes to the proposed signed 
statements and potential modifications (see, e.g., Comment 52, Comment 
56, and Comment 59). After considering these comments, we are 
establishing requirements for Part 1 of a GRAS notice to include 
certain signed statements and a certification as shown in table 7, with 
editorial, clarifying, and conforming changes as shown in table 29. 
(See Sec.  170.225.) Table 7 identifies changes we made relative to the 
proposed rule or the description in the 2010 notice other than the 
editorial, clarifying, and conforming changes shown in table 29 and the 
additional editorial changes associated with the redesignation of 
proposed Sec.  170.36(c)(1) as Sec.  170.225.
    We did not receive comments disagreeing with the proposed 
requirement for a GRAS notice to: (1) Be dated and signed by a 
responsible official of your organization, or by your attorney or 
agent; (2) provide your name and address; and (3) provide the 
applicable conditions of use of the notified substance. Therefore, we 
are establishing those requirements in the rule (see Sec.  
170.225(c)(1), (2), and (4)).

[[Page 54990]]

See Comment 42 for our discussion of comments on the terms used in 
final Sec.  170.225(c)(6), in which you inform us of your view that the 
notified substance is not subject to the premarket approval 
requirements of the FD&C Act based on your conclusion that the 
substance is GRAS under the conditions of its intended use; see 
Response 42 for the editorial changes we made in response to those 
comments.

        Table 7--Final Requirements for Signed Statements and a Certification in Part 1 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No.  in  Description. Part 1    clarifying, and
    Final designation in  the       designation in the     the 2010        of your  GRAS     conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice            notice:           relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                               the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.225(a).......................  170.36(c)(1).......             N/A  Must be dated and    N/A.
                                                                         signed by a
                                                                         responsible
                                                                         official of your
                                                                         organization, or
                                                                         by your attorney
                                                                         or agent.
170.225(b).......................  N/A................               8  Must not include     Makes an exception
                                                                         any information      for Sec.
                                                                         that is trade        170.225(c)(8),
                                                                         secret or            which requires you
                                                                         confidential         to state your view
                                                                         commercial           as to whether any
                                                                         information.         of the data and
                                                                                              information in
                                                                                              Parts 2 through 7
                                                                                              of your GRAS
                                                                                              notice are exempt
                                                                                              from disclosure
                                                                                              under the FOIA.
170.225(c)(1)....................  N/A................             N/A  Informs us that you  N/A.
                                                                         are submitting a
                                                                         GRAS notice in
                                                                         accordance with
                                                                         subpart E.
170.225(c)(2)....................  170.36(c)(1)(i)....             N/A  Provides the name    N/A.
                                                                         and address of
                                                                         your organization.
170.225(c)(3)....................  170.36(c)(1)(ii)...               7  Provides the name    N/A.
                                                                         of the notified
                                                                         substance, using
                                                                         an appropriately
                                                                         descriptive term.
170.225(c)(4)....................  170.36(c)(1)(iii)..             N/A  Describes the        Uses the term
                                                                         intended             ``subpopulation''
                                                                         conditions of use    rather than
                                                                         of the notified      ``population''.
                                                                         substance,
                                                                         including the
                                                                         foods in which the
                                                                         substance will be
                                                                         used, the levels
                                                                         of use in such
                                                                         foods, and the
                                                                         purposes for which
                                                                         the substance will
                                                                         be used,
                                                                         including, when
                                                                         appropriate, a
                                                                         description of a
                                                                         subpopulation
                                                                         expected to
                                                                         consume the
                                                                         substance.
170.225(c)(5)....................  170.36(c)(1)(iv)...             N/A  Informs us of the     Specifies
                                                                         statutory basis      that a conclusion
                                                                         for your             of GRAS status
                                                                         conclusion of GRAS   through scientific
                                                                         status (i.e.,        procedures is in
                                                                         through scientific   accordance with
                                                                         procedures or        both Sec.
                                                                         through experience   170.30(a) and (b).
                                                                         based on common      Specifies
                                                                         use in food).        that a conclusion
                                                                                              of GRAS status
                                                                                              through experience
                                                                                              based on common
                                                                                              use in food is in
                                                                                              accordance with
                                                                                              both Sec.
                                                                                              170.30(a) and (c).
170.225(c)(6)....................  170.36(c)(1).......               2  States your view     See Response 42.
                                                                         that the notified
                                                                         substance is not
                                                                         subject to the
                                                                         premarket approval
                                                                         requirements of
                                                                         the FD&C Act based
                                                                         on your conclusion
                                                                         that the substance
                                                                         is GRAS under the
                                                                         conditions of its
                                                                         intended use.
170.225(c)(7)....................  170.36(c)(1)(v)....             N/A  States your          You agree to a
                                                                         agreements           procedure in which
                                                                         regarding making     we can access data
                                                                         data and             and information
                                                                         information          ``during customary
                                                                         available to us      business hours''
                                                                         upon our request.    rather than ``at
                                                                                              reasonable
                                                                                              times''.
170.225(c)(8)....................  N/A................               9  States your view as  N/A.
                                                                         to whether any of
                                                                         the data and
                                                                         information in
                                                                         Parts 2 through 7
                                                                         of your GRAS
                                                                         notice are exempt
                                                                         from disclosure
                                                                         under the FOIA.
170.225(c)(9)....................  170.36(c)(4).......              6b  Certifies that, to   Specifies that your
                                                                         the best of your     GRAS notice is
                                                                         knowledge, your      ``complete'' in
                                                                         GRAS notice is a     addition to
                                                                         complete,            ``representative''
                                                                         representative,      and ``balanced''.
                                                                         and balanced
                                                                         submission that
                                                                         includes
                                                                         unfavorable
                                                                         information, as
                                                                         well as favorable
                                                                         information, known
                                                                         to you and
                                                                         pertinent to the
                                                                         evaluation of the
                                                                         safety and GRAS
                                                                         status of the use
                                                                         of the substance.
170.225(c)(10)...................  170.36(c)(1).......              6a  States both the      N/A.
                                                                         name and position
                                                                         or title of the
                                                                         person who signs
                                                                         the GRAS notice.

[[Page 54991]]

 
170.225(c)(11)...................  N/A................              13  When applicable,     We added a
                                                                         states whether       statement
                                                                         you: (1) Authorize   communicating how
                                                                         us to send any       you want us to
                                                                         trade secrets to     handle trade
                                                                         FSIS; or (2) ask     secret information
                                                                         us to exclude any    in a copy of a
                                                                         trade secrets from   GRAS notice that
                                                                         the copy of the      we send to FSIS.
                                                                         GRAS notice that
                                                                         we will send to
                                                                         FSIS.
----------------------------------------------------------------------------------------------------------------

A. Exclusion of Trade Secret and Confidential Commercial Information 
From the Signed Statements

    (Comment 50) Several comments support a provision specifying that 
information submitted in the signed statements exclude non-public 
information. One of these comments states that the information in the 
signed statements should be publicly disclosed because public 
disclosure is critical to the continued success of the GRAS program, 
and that for the use of a substance to be ``generally recognized as 
safe'' the data and research supporting a conclusion of GRAS status 
must be available for public view. Other comments disagree that non-
public information should be excluded from the signed statements and 
assert that the final rule should allow for the submission of limited 
amounts of non-public information at the discretion of the notifier or 
when necessary to clarify the safety of the notified substance for the 
purposes of our evaluation. These comments emphasize we should take 
care to remove such non-public information from any public disclosure 
or, or at a minimum, discuss or clear our intent to disclose non-public 
information with the notifier before disclosing it.
    (Response 50) Some of these comments appear to misinterpret the 
reach of our request for comment in Issue 8 in the 2010 notice. We 
narrowly directed Issue 8 to the signed statements that would provide 
the name and address of the notifier; the name of the notified 
substance; the applicable conditions of use of the notified substance; 
the statutory basis for the conclusion of GRAS status; and agreement to 
make the data and information that are the basis for the notifier's 
conclusion of GRAS status available for our review and copying. The 
signed statements provide administrative information rather than safety 
information and, as discussed in the 2010 notice, we extract notice-
specific information from the signed statements for the purpose of 
informing the public about GRAS notices that we are evaluating. 
However, some comments seem to be addressing the issue of whether other 
sections of a GRAS notice (e.g., Part 2 of a GRAS notice (in which a 
notifier describes the method of manufacture of the notified substance) 
and Part 6 of a GRAS notice (in which a notifier discusses the safety 
of the notified substance)) can include non-public information.
    Consistent with our request for comment in Issue 8, the final rule 
specifies that a notifier must not include any information that is 
trade secret or confidential commercial information in Part 1 of a GRAS 
notice, except in the statement in Sec.  170.225(c)(8) (see Sec.  
170.225(b) and the discussion of Sec.  170.225(c)(8) in Response 57). 
This provision does not preclude a notifier from including non-public 
information in other parts of a GRAS notice. However, if a notifier 
views any submitted data and information as exempt from disclosure 
under the FOIA then that notifier must identify the specific data and 
information, and explain how there could be a basis for a conclusion of 
GRAS status if qualified experts generally do not have access to those 
data and information (see Sec.  170.250(d) and (e)). Section 170.250(d) 
and (e) is consistent with the criteria for eligibility for 
classification as GRAS, because: (1) The criteria provide that general 
recognition of safety may be corroborated by unpublished information; 
and (2) the notifier has a burden to explain how GRAS criteria are 
satisfied given that certain data and information in the GRAS notice 
are trade secret or confidential commercial information.
    See section XIII.B for a discussion of comments regarding including 
non-public information in part 2 of a GRAS notice (particularly with 
respect to the method of manufacture). Regarding whether we would 
``clear our intent'' to disclose non-public information with the 
notifier before disclosing it, see Response 70. Regarding how we treat 
non-public information in a GRAS notice, see section XXI regarding the 
provisions of the final rule regarding public disclosure of information 
in a GRAS notice. Under Sec.  170.275(c), we will disclose information 
that is not exempt from public disclosure in accordance with part 20.

B. Name of the Notified Substance, Using an Appropriately Descriptive 
Term

    (Comment 51) Some comments agree that the signed statements should 
identify the name of the notified substance using an ``appropriately 
descriptive term'' instead of the ``common or usual name,'' and also 
agree with our statement in the 2010 notice that the ``appropriately 
descriptive term'' may be the same as the common or usual name of the 
substance in some circumstances (75 FR 81536 at 81539). One comment 
disagrees and asks us to continue to specify that the signed statements 
in a GRAS notice identify the name of the notified substance using the 
common or usual name of the notified substance. This comment recommends 
that a notifier work with us to establish the common or usual name of 
the notified substance if the common or usual name is not known or well 
defined. This comment also asks us to include the common or usual name 
of the notified substance in any ``no questions letter'' from us to 
make the common our usual name clear to the public. A few comments 
support requiring that the signed statements include both the common or 
usual name of the notified substance, as well as an appropriately 
descriptive term for the notified substance. One comment asks us to 
continue the practice, described in the 2010 notice (75 FR 81536 at 
81539), of reminding notifiers that our response to a GRAS notice 
should not be considered an endorsement for any given term for the 
purpose of complying with the labeling provisions of the FD&C Act.

[[Page 54992]]

    (Response 51) The final rule requires that you provide the name of 
the notified substance, using an appropriately descriptive term, in 
Part 1 of your GRAS notice (Sec.  170.225(c)(3)). The appropriately 
descriptive term may be the same as the common or usual name of the 
substance under our labeling regulations (see 21 CFR 102.5). We decline 
the request to use resources that we are directing to the evaluation of 
the safety and regulatory status of food substances under sections 201 
and 409 of the FD&C Act to also address the labeling requirements of 
the FD&C Act given the limited time (i.e., 180 days) that we have to 
respond (see Sec.  170.265(b)). You may consult with our staff in 
operating divisions that address the labeling requirements of the FD&C 
Act, currently CFSAN's Office of Nutrition and Food Labeling (for human 
food); however, doing so would be a separate process from the GRAS 
notification procedure. (See section XXV.C for contact information for 
CVM.)

C. Intended Conditions of Use of the Notified Substance

    We did not receive comments disagreeing with the proposed 
requirement for the signed statements in a GRAS notice to include the 
applicable conditions of use of the notified substance, including the 
foods in which the substance is to be used, levels of use in such 
foods, and the purposes for which the substance is used, including, 
when appropriate, a description of the population expected to consume 
the substance, and we are establishing this requirement in the final 
rule (see Sec.  170.225(c)(4)). As noted in table 29, the final rule 
refers to the ``intended conditions of use'' rather than the 
``applicable conditions of use'' for consistency with other provisions 
in the rule. The final rule also uses the term ``subpopulation'' rather 
than ``population'' to provide more context about when it would be 
appropriate to specify the expected consumers of a food. Most foods are 
broadly available to all consumers; a few are more specifically 
targeted to particular subpopulations, such as persons with specific 
dietary needs (such as persons on liquid diets or persons with 
conditions like phenylketonuria), infants consuming infant formula, and 
persons seeking alternatives to commonly used food ingredients (such as 
persons on a gluten-free diet).

D. Statutory Basis for the Conclusion of GRAS Status

    (Comment 52) Some comments ask us to modify the rule to provide 
that the statutory basis for a conclusion of GRAS status may be through 
scientific procedures, through experience based on common use in food, 
or through both scientific procedures and experience based on common 
use in food. These comments assert that many conclusions of GRAS status 
are based on both statutory criteria.
    (Response 52) We disagree that this modification is needed. The 
final rule does not prevent you from basing your conclusion of GRAS 
status on both statutory criteria. Importantly, if you assert that your 
conclusion of GRAS status is based on both statutory criteria, you must 
fully support each conclusion and address all requirements of the rule 
regarding each conclusion; partial support for each of the two 
statutory criteria for a conclusion of GRAS status is not adequate. You 
could not, for example, assert that a substance is GRAS under the 
conditions of its intended use through scientific procedures, but 
``fill in data gaps'' by also asserting that the substance was commonly 
used in food before 1958. Likewise, you could not assert that a 
substance is GRAS under the conditions of its intended use through 
experience based on common use in food if you cannot provide evidence 
of a substantial history of consumption of the notified substance for 
food use by a significant number of consumers prior to January 1, 1958.
    These comments highlight the importance of fully supporting a 
conclusion of GRAS status through each of the statutory criteria. 
Because the general criteria in Sec.  170.30(a), as well as the 
specific criteria in Sec.  170.30(b) or (c), must be satisfied to 
support a conclusion of GRAS status, the final rule specifies that a 
conclusion of GRAS status through scientific procedures is in 
accordance with both Sec.  170.30(a) and (b) and that a conclusion of 
GRAS status through experience based on common use in food is in 
accordance with both Sec.  170.30(a) and (c).

E. Agreement To Make Data and Information Available Upon Request

    (Comment 53) Some comments recommend that there be a means for us 
to request non-public information if we deem it necessary for our 
evaluation of the intended conditions of use of the notified substance, 
provided that the information can be considered as confidential and 
protected from disclosure.
    (Response 53) These comments appear to misinterpret the reach of 
the proposed requirement to agree to provide us access to data and 
information that a notifier relies on to support a conclusion of GRAS 
status. Some of the data and information that we may ask to see during 
our evaluation of a GRAS notice may be ``public'' data and information 
in that it would be data and information that we would provide in 
response to a request under the FOIA (see Response 48), even though it 
may not have been disseminated to the public (e.g., in the scientific 
literature or on the Internet (e.g., when a science-based organization 
uses the Internet to disseminate scientific or technical information or 
recommendations)). If we receive data and information that are non-
public, such data and information would be protected from public 
disclosure in accordance with part 20.
    (Comment 54) One comment states that the phrase ``at reasonable 
times'' refers not only to hours of a day, but also to a reasonable 
amount of time following the submission of a GRAS notice. This comment 
recommends that ``several years (for example, five years)'' after 
submission of a GRAS notice would be a reasonable time for notifiers to 
retain such data and information in their active files.
    (Response 54) By ``at reasonable times,'' we meant the time of day 
that we would have access to data and information you retained but did 
not include in your GRAS notice. To clarify that the requirement 
relates to the time of day rather than to the timeframe for retaining 
the data and information, the final rule specifies that you agree to a 
procedure in which we can access data and information ``during 
customary business hours'' rather than ``at reasonable times.''
    As previously discussed (62 FR 18938 at 18951), we may, at some 
point after our response to a GRAS notice, receive additional 
information about a notified substance that raises questions about the 
safety of that substance. To address this possibility, the rule 
specifies that we will send you a subsequent letter about your GRAS 
notice if circumstances warrant (see Sec.  170.265(c)). Although the 
rule does not specify any timeframe to retain the data and information 
that support your conclusion of GRAS status, preservation of the data 
and information that are the basis for the conclusion of GRAS status 
represents prudent practice for those who claim an exclusion from a 
statutory requirement regardless of whether the person subsequently 
notifies us (62 FR 18938 at 18947).
    (Comment 55) One comment asks us to clarify that electronic records 
are acceptable for documenting the data and information that support a 
conclusion of GRAS status.

[[Page 54993]]

    (Response 55) Electronic records are acceptable for documenting the 
data and information that support a conclusion of GRAS status. If we 
ask you to send us such data and information for a notified substance 
that would be used in human food, we recommend that you do so by 
following the instructions in CFSAN's guidance entitled ``Guidance for 
Industry: Providing Regulatory Submissions in Electronic or Paper 
Format to the Office of Food Additive Safety'' (Ref. 37), which 
includes instructions for making an electronic submission through our 
Electronic Submission Gateway, as well as on media that we can access 
on our network computers. CFSAN's procedures for making an electronic 
submission through our Electronic Submission Gateway use a form that 
CFSAN developed for a GRAS notice when a substance would be used in 
human food (i.e., Form FDA 3667) (Ref. 38). Form FDA 3667 prompts a 
notifier to include certain elements of a GRAS notice in a standard 
format. The form, and elements that would be prepared as attachments to 
the form, may be submitted in electronic format via the Electronic 
Submissions Gateway, as electronic files on physical media, or in paper 
format. At this time, we cannot accept media such as thumb drives, 
which can present a security risk.
    (Comment 56) One comment asks us to develop criteria for the 
required documentation underlying industry conclusions of GRAS status.
    (Response 56) We are not establishing criteria in the rule for the 
documentation a notifier would have regarding a conclusion of GRAS 
status. Regardless of whether a person who concludes that a use of a 
food substance is GRAS notifies us, the applicable documentation would 
address the safety of the substance as described in the definition of 
``safe'' or ``safety'' (see Sec.  170.3(i)); as applicable, the 
definition of ``common use in food'' (see Sec.  170.3(f) and/or the 
definition of ``scientific procedures'' (Sec.  170.3(h)); and the 
criteria for general recognition of safety (see Sec.  170.30)).

F. Statements and Any Applicable Explanation Regarding Data and 
Information That a Notifier Views as Exempt From Disclosure Under FOIA

    In Issue 9 in the 2010 notice (75 FR 81536 at 81539-81540), we 
discussed three issues regarding confidential data and information that 
are included in a GRAS notice. See table 8. Most of the comments that 
address Issue 9 address Issue 9a, particularly with respect to how we 
would protect trade secret or confidential commercial information from 
public disclosure. See sections XIII.B and XXI.C for a discussion of 
those comments, and our response to those comments. In the following 
paragraphs, we discuss comments on Issues 9b and 9c, and respond to 
those comments.

   Table 8--Issues in the 2010 Notice Regarding Confidential Data and
                      Information in a GRAS Notice
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
9a........  Whether the final  75 FR 81536 at 81539-81540.
             rule should
             stipulate that
             the method of
             manufacture
             exclude any
             trade secrets,
             as we proposed.
9b........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies one
             or more trade
             secret(s), as
             defined in Sec.
              20.61(a), in
             the GRAS notice
             explain why it
             is trade secret
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to the
             trade secret(s).
9c........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies
             confidential
             commercial or
             financial
             information, as
             defined in Sec.
              20.61(b), in
             the GRAS notice
             explain why it
             is confidential
             commercial or
             financial
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to such
             information.
------------------------------------------------------------------------

    (Comment 57) One comment supports the recommendation we made in the 
proposed rule for a notifier who considers that certain information in 
a submission should not be available for public disclosure to identify 
as confidential the relevant portions of the submission for our 
consideration (62 FR 18938 at 18952). Those comments that address 
Issues 9b and 9c agree with the outcome of our discussion, in the 2010 
notice, that we should require that a notifier who identifies a trade 
secret or confidential commercial information explain why it is a trade 
secret or confidential commercial information and how qualified experts 
can conclude that the use of a substance is safe without access to the 
trade secret or confidential commercial information.
    (Response 57) The final rule requires a notifier to state his view 
as to whether any of the data and information in Parts 2 through 7 of a 
GRAS notice are exempt from disclosure under the FOIA (e.g., as trade 
secret or as commercial or financial information that is privileged or 
confidential) (Sec.  170.225(c)(8)). Requiring this statement in Part 1 
of a GRAS notice will give us notice as to whether we will need to 
evaluate specific data and information under the FOIA and take steps to 
protect applicable data and information from public disclosure. See 
also Sec.  170.250(d), which requires that Part 6 of a GRAS notice (a 
narrative) identify specific data and information that a notifier views 
as exempt from disclosure under the FOIA. Whereas Part 1 of a GRAS 
notice only requires that the signed statements in a GRAS notice state 
the notifier's view as to whether any of the data and information in 
Parts 2 through 7 of a GRAS notice are exempt from disclosure under the 
FOIA, in Part 6 of a GRAS notice the notifier would specifically 
identify the applicable data and information.
    During the Interim Pilot program, we sometimes received a 
curriculum vitae (e.g., of a GRAS panel member) containing personal 
privacy information that we needed to redact before we could make the 
GRAS notice available to the public. The rule does not require that a 
notifier submit such information, and redaction of unnecessary privacy 
information takes resources that we would otherwise use to evaluate the 
GRAS notice. We ask that notifiers exclude personal privacy information 
from a GRAS notice whenever possible. If a notifier does include such 
information, in Part 1 of a GRAS notice the notifier should state his 
view that the GRAS notice contains personal privacy information. In 
Part 6 of a GRAS notice, the notifier should identify the personal 
privacy information.

G. Certification Statement

    (Comment 58) Several comments support a requirement for a GRAS 
notice to include a certification statement similar to the 
certification statement that had been required in a GRAS affirmation 
petition. One

[[Page 54994]]

comment agrees that the notifier should submit a statement that the 
notice is a representative and balanced submission, but does not agree 
that the notifier needs to certify the statement.
    (Response 58) The final rule requires a certification statement as 
described in the 2010 notice, with one modification (see Sec.  
170.225(c)(9)). We added that the statement certify that the GRAS 
notices is ``complete'' in addition to ``representative'' and 
``balanced,'' to emphasize your responsibility to identify, discuss, 
and place in context, data and information that are, or may appear to 
be, inconsistent with a conclusion of GRAS status, regardless of 
whether those data and information are generally available (see the 
requirements of the narrative in Part 6 of a GRAS notice (Sec.  
170.250, in particular Sec.  170.250(c))). The certification is 
appropriate and necessary to underscore your legal responsibility for 
the conclusion of GRAS status. As discussed in the 2010 notice, the 
specific text of the certification statement that you must include in a 
GRAS notice is consistent with the specific text of the certification 
statement in the GRAS affirmation petition process that the 
notification procedure is replacing. The use of certification 
statements has become routine in other submissions to FDA for food 
programs (see, e.g., the certification statement in Part V of Form FDA 
3480 (for a food contact notification submission) (Ref. 39); and the 
certification statement in Section 13 of Form FDA 3537 (for 
registration of a food facility) (Ref. 40)).
    By ``complete,'' we also mean that your GRAS notice identifies, and 
places in context, unpublished data and information that you believe 
corroborate GRAS status. For example, if you conduct six toxicology 
studies, but only publish three of the studies, it may be that you 
consider the remaining three studies to be corroborative of safety. As 
an example, it may be that you were dissatisfied with the study design 
of one study, repeated that study with an improved study design, and 
published the study with the improved study design. If you consider 
that the findings of the unpublished studies corroborate safety, even 
if they do not establish it, a ``complete, representative, and 
balanced'' submission would briefly describe the unpublished studies. 
In addition, we expect that you would describe, and place in context, 
unpublished data and information if you consider that the findings of 
the unpublished data and information warrant sharing with any ``GRAS 
panel'' that you convene. See also the discussion in Response 69 and 
Response 78.
    (Comment 59) One comment asks us to specify that the statement 
include the date the statement was certified.
    (Response 59) The rule requires that Part 1 of a GRAS notice be 
dated and signed by a responsible official of your organization, or by 
your attorney or agent (see Sec.  170.225(a)). The certification 
statement is included in Part 1 of the GRAS notice; it is not necessary 
to date each statement included in Part 1.

H. Person Signing Part 1 of the GRAS Notice

    (Comment 60) Several comments support a provision to require a GRAS 
notice to clearly identify the person signing the GRAS notice, such as 
by printing or stating the name and the title of the person signing the 
GRAS notice.
    (Response 60) The final rule requires you to state both the name 
and position or title of the person who signs the GRAS notice (see 
Sec.  170.225(c)(10)).

I. Authorization for FDA To Send Trade Secret Information to FSIS

    In the 2010 notice, we described some of the terms of a MOU, 
between FDA and USDA's FSIS, that provides for a coordinated evaluation 
process with FSIS when the intended conditions of use of a notified 
substance include use in a product or products subject to regulation by 
USDA under statutes that it administers (75 FR 81536 at 81541-81542); 
in 2015 we amended that MOU to include more details about the 
procedures FDA and FSIS will follow to do so (Ref. 36). We also asked 
for comment on whether to make our coordinated evaluation process with 
FSIS explicit in the final rule (see Issue 13, 75 FR 81536 at 81541-
81542).
    In accordance with our public information regulations in Sec.  
20.85 (Disclosure to other Federal government departments and 
agencies), we can share confidential commercial information with 
another Federal agency pursuant to a written agreement that the record 
will not be further disclosed. The amended MOU between FDA and USDA's 
FSIS now provides for FDA to share with FSIS confidential commercial 
information in a submission such as a GRAS notice (Ref. 36). We 
generally cannot share trade secret information with other Federal 
agencies under section 301(j) of the FD&C Act (21 U.S.C. 331(j)), and 
therefore we would need your authorization to share this information 
with FSIS. For efficiency in administering the coordinated evaluation 
of a GRAS notice with FSIS, we have added a requirement for a notifier 
who submits a GRAS notice that we would send to FSIS to include in part 
1 of the GRAS notice a statement as to whether the notifier: (1) 
Authorizes us to send any trade secrets to FSIS; or (2) asks us to 
exclude any trade secrets from the copy of the GRAS notice that we will 
send to FSIS (see Sec.  170.225(c)(11)). Under the provisions that make 
the coordinated evaluation of a GRAS notice with FSIS explicit, we will 
exclude any trade secrets unless you have authorized us to send trade 
secret information to FSIS (see Sec.  170.270). These provisions will 
enable us, with your authorization, to share a GRAS notice that 
includes trade secret information with FSIS without first redacting the 
GRAS notice to remove the trade secret information and, thus, will 
reduce the time it takes for us to provide FSIS with a copy of the GRAS 
notice. These provisions also will clarify your expectations regarding 
whether we should share trade secret information with FSIS and, thus, 
require us to redact the trade secret information from the copy we send 
to FSIS when consistent with your express wishes.
    Note that our rule establishing the requirements of the GRAS 
notification procedure does not specify the data and information that 
FSIS will need to evaluate whether the intended use of the notified 
substance complies with applicable statutes and regulations, or, if 
not, whether the use of the substance would be permitted in products 
under FSIS jurisdiction under specified conditions or restrictions. We 
recommend that you contact the appropriate staff at FSIS regarding the 
data and information that FSIS will need you to provide. FSIS provides 
contact information for its programs on its Web site (Ref. 41).

XIII. Comments on Part 2 of a GRAS Notice: Identity, Method of 
Manufacture, Specifications, and Physical or Technical Effect

    We proposed to require that a GRAS notice include detailed 
information about the identity of the notified substance, including, as 
applicable, its chemical name, Chemical Abstracts Service (CAS) 
Registry Number, Enzyme Commission number, empirical formula, 
structural formula, quantitative composition, method of manufacture 
(excluding any trade secrets and including, for a substance of natural 
biological origin, source information such as genus and species), 
characteristic properties, any content of potential human toxicants, 
and specifications for food-grade material (proposed Sec.  
170.36(c)(2)). In the 2010 notice, we requested comment on

[[Page 54995]]

several issues relevant to the proposed requirements for detailed 
information about the identity of the notified substance (see table 9).

 Table 9--Issues in the 2010 Notice Regarding the Proposed Requirements
  for Detailed Information About the Identity of the Notified Substance
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
9a........  Whether the final  75 FR 81536 at 81539-81540.
             rule should
             continue to
             stipulate that
             the method of
             manufacture
             exclude any
             trade secrets,
             as proposed.
10a.......  What scientific    75 FR 81536 at 81540.
             information
             would be
             sufficient to
             identify the
             biological
             source.
10b.......  Whether to         75 FR 81536 at 81540.
             require that
             information
             about the
             identity of the
             notified
             substance
             specify any
             known toxicants
             that could be in
             the source.
10c.......  Whether the final  75 FR 81536 at 81540.
             rule should
             address, as part
             of identity,
             particle size
             and other
             chemical and
             physical
             properties that
             may be used to
             characterize
             engineered
             materials.
------------------------------------------------------------------------

    Some comments support the proposed requirements, with the potential 
modifications described in the 2010 notice, without change. For 
example, most of the comments that address the issue of scientific 
information sufficient to identify a biological source support 
requiring both taxonomic information and the part of any animal or 
plant used as a source. As another example, several comments that 
address the issue of scientific information sufficient to identify a 
biological source support requiring that this information specify 
toxicants that could be in the source.
    Most of the comments regarding our proposal to require that a GRAS 
notice include detailed information about the identity of the notified 
substance address the issues discussed in 2010 notice. In the following 
sections, we discuss these and other comments. After considering these 
comments, we are establishing requirements for Part 2 of a GRAS notice 
to include information about the identity, method of manufacture, 
specifications, and physical or technical effect of the notified 
substance as shown in table 10, with editorial, clarifying, and 
conforming changes as shown in table 29. (See Sec.  170.230). Table 10 
identifies changes we made relative to the proposed rule or the 
description in the 2010 notice other than the editorial, clarifying, 
and conforming changes shown in table 29 and the additional editorial 
changes associated with the redesignation of proposed Sec.  
170.36(c)(2) as Sec.  170.230.

    Table 10--Final Requirements for Detailed Information in Part 2 of a GRAS Notice About the Identity of a
                                               Notified Substance
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No.  in  Description. Part 2    clarifying, and
    Final designation in  the       designation in the     the 2010        of your  GRAS     conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice            notice:           relative to the
                                        (Sec.   )                                             proposed rule  or
                                                                                               the 2010 notice
----------------------------------------------------------------------------------------------------------------
170.230(a)(1)....................  170.36(c)(2).......             N/A  Must include         N/A.
                                                                         scientific data
                                                                         and information
                                                                         that identifies
                                                                         the notified
                                                                         substance.
170.230(a)(1)....................  170.36(c)(2).......             10a  Must include data     Must
                                                                         and information      provide taxonomic
                                                                         sufficient to        information at the
                                                                         identify a           sub-species level
                                                                         biological source    (e.g., variety,
                                                                         of a notified        strain) in
                                                                         substance.           addition to genus
                                                                                              and species.
                                                                                              Must
                                                                                              specify the part
                                                                                              of any plant or
                                                                                              animal used as the
                                                                                              source.
170.230(a)(2)....................  170.36(c)(2).......             10b  Must include data    N/A.
                                                                         and information
                                                                         sufficient to
                                                                         identify any known
                                                                         toxicants that
                                                                         could be in the
                                                                         source.
170.230(b).......................  170.36(c)(2).......              9a  Must include the      No longer
                                                                         method of            requires that the
                                                                         manufacture of the   method of
                                                                         notified substance   manufacture
                                                                         in sufficient        exclude any trade
                                                                         detail to evaluate   secrets.
                                                                         the safety of the    Requires
                                                                         notified substance   ``sufficient
                                                                         as manufactured.     detail to evaluate
                                                                                              the safety of the
                                                                                              notified substance
                                                                                              as manufactured''
                                                                                              rather than
                                                                                              ``detailed
                                                                                              information.''
170.230(c).......................  170.36(c)(2).......             N/A  Must include         N/A.
                                                                         specifications for
                                                                         food-grade
                                                                         material.
170.230(d).......................  N/A................             N/A  When necessary to    New requirement
                                                                         demonstrate          based on comments
                                                                         safety, must         that addressed
                                                                         include relevant     experience during
                                                                         data and             CVM's Interim
                                                                         information          Pilot program (see
                                                                         bearing on the       section XXV.E).
                                                                         physical or other
                                                                         technical effect
                                                                         the notified
                                                                         substance is
                                                                         intended to
                                                                         produce, including
                                                                         the quantity of
                                                                         the notified
                                                                         substance required
                                                                         to produce such
                                                                         effect.
----------------------------------------------------------------------------------------------------------------


[[Page 54996]]

A. Scientific Information About the Identity of a Notified Substance

1. Scientific Information Sufficient To Identify a Biological Source
    (Comment 61) One comment asserts that the scientific information, 
beyond the standard taxonomic information, that is sufficient to 
identify a biological source for a notified substance should be 
determined on a case-by-case basis consistent with established practice 
and publicly available guidance. Another comment asserts that 
identifying the source organism by the genus and species (without 
additional information such as strain or variety) is sufficient when 
the notified substance is an enzyme preparation produced by a 
microorganism. However, this comment also asserts that if safety 
concerns for a specific genus and species have been addressed (i.e., by 
genetic modification to remove a characteristic of concern) for a 
specific strain within that species then information about the strain 
would be appropriate. This comment emphasizes that the description of 
the source of a biological material should be based on the safety of 
that source and consider all relevant information related to safety.
    (Response 61) The information, beyond the standard taxonomic 
information, that we discussed in the 2010 notice is consistent with 
established practice (see section III.J.1 of CFSAN's 2010 experience 
document (Ref. 18)) and the final rule specifies that when the source 
of a notified substance is a biological material, your GRAS notice must 
include both taxonomic information (e.g., genus, species), including as 
applicable data and information at the sub-species level (e.g., 
variety, strain) and the part of any plant or animal used as the source 
(see Sec.  170.230(a)(2)). We agree that the specific scientific 
information, beyond the standard taxonomic information, that is 
sufficient to identify a biological source is determined on a case-by-
case basis, and section III.J.1 of CFSAN's 2010 experience document 
demonstrates that the specific scientific information included in a 
GRAS notice to describe a biological source varied on a case-by-case 
basis. For example, when the notified substance was derived from a 
microorganism, the notifier specified a particular strain or subspecies 
or stated the strain was a nontoxigenic and nonpathogenic strain; when 
the notified substance was derived from a plant, the notifier 
identified the specific part(s) of the plant used as the starting 
material, such as fruit, seeds or seed husks, expressed oil, flowers, 
roots, leaves, pulp, wood, or bark. However, we disagree that we should 
use guidance, rather than the regulatory text of this rule, to describe 
the types of data and information that are necessary to sufficiently 
identify the biological source because the types of information we are 
specifying are necessary--rather than merely recommended--information. 
For example, data and information at the sub-species level (e.g., 
variety, strain) is necessary for source microorganisms because so many 
microorganisms (e.g., Escherichia coli and Saccharomyces cerevisiae) 
have multiple strains, and although some strains are both non-toxigenic 
and non-pathogenic, others are not. For example, there are several 
pathogenic strains of Saccharomyces cerevisiae, even though 
nonpathogenic strains are commonly used in food and in the production 
of enzyme preparations. As another example, both Aspergillus oryzae and 
Aspergillus niger naturally produce mycotoxins, but strains that do not 
produce mycotoxins have been developed and are used for production of 
enzyme preparations. In addition, for phage production some host 
strains have been pathogens (e.g., Listeria monocytogenes) and produce 
toxins. Likewise, data and information about the part of a plant used 
as a source is necessary because some plants that have edible parts 
also secrete toxins in non-edible parts. For example, the leaf stalks 
(petioles) of rhubarb (Rheum rhaponticum) are edible, but the leaves 
contain notable quantities of oxalic acid. As another example, the 
leaves and stems of tomato (Solanum lycopersicum) contain solanine.
    We agree that the description of a biological source should be 
based on the safety of that source and consider all relevant 
information related to safety. The regulatory text requires taxonomic 
information beyond genus and species, such as variety or strain, ``when 
applicable'' for a source microorganism such as those used to produce 
enzyme preparations. Examples of when information such as variety or 
strain would be applicable are those microbial sources, such as some 
fungi, for which there are multiple strains or subspecies that have 
different properties with respect to the ability to produce toxins, 
antibiotics, or other substances that are not suitable for use in food.
    (Comment 62) One comment asks us to specify that information 
identifying a substance derived from a biological source must include 
the breed of animal or plant.
    (Response 62) During the Interim Pilot program we did not evaluate 
any GRAS notices in which the breed of an animal or plant source was a 
taxonomic descriptor necessary to sufficiently identify that animal or 
plant source. Therefore, although breed may be an appropriate taxonomic 
descriptor in some circumstances, the circumstances are rare enough 
that we have not seen it as necessary information in more than 15 
years. Therefore, we are not specifying it as an example of applicable 
taxonomic information in the rule. In a specific circumstance where 
breed is necessary to adequately identify a particular animal or plant 
source, and you do not specify the breed, we intend to ask you to amend 
your GRAS notice to identify the breed.
    (Comment 63) One comment asks us to address substances produced 
from microorganisms, particularly bioengineered microorganisms. This 
comment explains that the development of a production microorganism 
through bioengineering is, for the most part, highly confidential and 
cannot be disclosed publicly. In addition, the production microorganism 
often is modified on an ongoing basis, e.g., to improve yield. This 
comment asks us to specify the point at which subsequent modification 
of a production microorganism would trigger submission of a new GRAS 
notice and notes that in some cases subsequent modification of a 
production organism could be incorporated into the original GRAS notice 
by ``amendment'' or by reference. This comment also asserts that 
submission of a new GRAS notice should not be needed in the case of 
safe strain lineage as described in the scientific literature (Ref. 
42).
    Another comment asks us to specify that information identifying a 
substance derived from a biological source must specify whether the 
plant or animal is genetically engineered or cloned.
    (Response 63) We recommend that notifiers consult our guidance 
entitled ``Assessing the Effects of Significant Manufacturing Process 
Changes, Including Emerging Technologies, on the Safety and Regulatory 
Status of Food Ingredients and Food Contact Substances, Including Food 
Ingredients that Are Color Additives'' (Ref. 6). That guidance lists a 
change in the source microorganism (including a change in strain) used 
for a food substance derived from fermentation of a microorganism as an 
example of a significant manufacturing process change. Whenever there 
has been a significant manufacturing process change for a food 
substance that is the subject of a previous conclusion of GRAS status, 
the guidance recommends that the manufacturer consider whether the GRAS 
status of the use of the food substance would be affected; consult

[[Page 54997]]

with us regarding the conclusions about the impact of the significant 
manufacturing change on the safety and regulatory status of the use of 
the food substance; and make an appropriate regulatory submission to us 
as circumstances warrant. In the specific circumstance of a production 
microorganism that is modified on an ongoing basis, a modification that 
results in a new strain would no longer fall within the description of 
the source, which must include information at the sub-species level 
(see Sec.  170.230(a)(2)(i)). If a notifier concludes that a 
modification that results in a new strain has no impact on the 
conclusion of GRAS status, one approach could be to submit a supplement 
to the GRAS notice. Doing so would be consistent with CFSAN's 2010 
experience during the Interim Pilot program. See section IV.J of 
CFSAN's 2010 experience document (Ref. 18), in which CFSAN discusses a 
GRAS notice in which a notifier consulted with CFSAN about mechanisms 
to inform CFSAN about its conclusion that additional uses of the 
notified substance are also GRAS. The notifier supplemented its 
original GRAS notice with a letter informing CFSAN of the additional 
conclusion of GRAS status and CFSAN issued a second ``no questions 
letter'' to the notifier as additional correspondence.
    We decline the request to require that information identifying a 
substance derived from a biological source specify whether the plant or 
animal is ``genetically engineered'' or ``cloned.'' We consider that 
the more general requirement to identify a biological source at the 
sub-species level is adequate to identify the source. In practice 
during the Interim Pilot program, notifiers routinely informed us about 
the use of such techniques in describing production microorganisms, 
particularly for GRAS notices about the intended conditions of use of 
enzyme preparations. (See, e.g., the list of enzyme preparations in 
section IV.N of CFSAN's 2010 experience document (Ref. 18).) The source 
microorganisms for several of the listed enzyme preparations were 
developed using bioengineering techniques.
    When confidential data and information about the development of a 
production microorganism through bioengineering are necessary to 
provide evidence that a notified substance produced from that 
production organism is safe under the conditions of its intended use, 
the use of the notified substance would not satisfy GRAS criteria. See 
the discussion in Response 69, where we explain that it may be possible 
to explain that confidential information (whether included in a GRAS 
notice, or provided privately to a GRAS panel) is corroborative of 
safety, rather than necessary to demonstrate safety, if, for example, 
the method of manufacture included in a GRAS notice meets the 
requirements of the rule to provide sufficient detail to evaluate the 
safety of the notified substance as manufactured. Alternatively, the 
notifier could describe the development of the production microorganism 
in sufficient detail to address any safety issues associated with use 
of that production microorganism. For enzyme preparations that would be 
used in human food, we recommend that notifiers consult our guidance 
entitled ``Guidance for Industry: Enzyme Preparations: Recommendations 
for Submission of Chemical and Technological Data for Food Additive 
Petitions and GRAS Notices'' (Ref. 33), and ``Food-Processing Enzymes 
From Recombinant Microorganisms--A Review'' (Ref. 43), for details 
about our recommendations for safety information regarding enzyme 
preparations derived from bioengineered microorganisms.
2. Potential Toxicants in the Source of the Notified Substance
    (Comment 64) One comment agrees that a review of known toxicants 
that could be produced by the biological source of a notified substance 
should be part of the safety review, but recommends that the depth of 
the review be addressed on a case-by-case basis and be tailored to the 
substance and the source of the substance. This comment asserts that it 
would be difficult and impractical to define a method for this review 
or to define the specific toxicants that are required to be reviewed 
for each particular substance.
    (Response 64) We agree that the safety review should be tailored to 
the substance and its source because of the diversity of toxicants that 
could be in the biological source. It is your responsibility to 
determine how to conduct the safety review; the rule does not prescribe 
any method for this review or any specific toxicants that must be 
reviewed for a particular substance or source. In some cases (e.g., 
when it is well established in the scientific community that a source 
is non-toxigenic), citations to publicly available information about a 
biological source may be sufficient to address the safety of the 
notified substance with respect to potential toxicants in the source. 
In other cases (e.g., when a source is known to be toxigenic), the 
information about the toxigenic source would lead you to a discussion, 
in the narrative required in Part 6 of a GRAS notice, of how the method 
of manufacture and specifications for the notified substance lead you 
to conclude that the notified substance as manufactured is safe and 
that the criteria for general recognition are satisfied.
    (Comment 65) One comment refers to a statement we made, in the 2010 
notice, that we have found that information about substances known to 
be toxicants is relevant regardless of the state of the science 
regarding the specific toxicity of the substance to humans (75 FR 81536 
at 81540). This comment asserts that specifying that the identity of 
the notified substance include any known toxicants that could be in the 
source does not fully address whether the toxicants cause a safety 
concern. Another comment states that the ``GRAS process'' should 
contain a safety/risk assessment for known toxicants, not just identify 
the toxicants.
    (Response 65) We agree that a GRAS notice must address the safety 
concerns associated with toxicants known to be in a biological source, 
not just identify the toxicants. See the requirements for a GRAS notice 
to include the method of manufacture of the notified substance (Sec.  
170.230(b)), specifications for food-grade material (Sec.  170.230(c)), 
and a narrative explaining why the data and information in a GRAS 
notice provide a basis for the notifier's view that the notified 
substance is safe under the conditions of its intended use (Sec.  
170.250).
    (Comment 66) One comment recommends using our guidance entitled 
``Recommendations for Submission of Chemical and Technological Data for 
Direct Food Additive Petitions'' (Ref. 31) as a more ``holistic'' 
approach to addressing potential safety concerns regarding known 
toxicants in a biological source, because the guidance describes how to 
use the manufacturing process to control, reduce, or concentrate 
toxicant levels and explains the importance of establishing limits for 
any known natural toxicants in or on food additives derived from a 
natural source. The comment asserts that this guidance should apply to 
GRAS substances as well as food additives because general recognition 
of safety through scientific procedures requires the same quantity and 
quality of evidence as is required to establish a food additive 
regulation for the use of the substance, and therefore the information 
about the identity of the substance should be consistent with the 
requirements for food additives. This comment notes that section III.A 
of ``Recommendations for Submission of Chemical and Technological Data 
for

[[Page 54998]]

Direct Food Additive Petitions'' clearly outlines the information 
needed for ``allowing the unequivocal identification and 
characterization of the food additive'' and that the principles in 
specific sections in section III.A of the guidance apply to GRAS 
substances even though they are written to specifically address food 
additives.
    (Response 66) We agree that many of the recommendations in our 
guidance entitled ``Recommendations for Submission of Chemical and 
Technological Data for Direct Food Additive Petitions'' (Ref. 31) could 
be useful to a person who assesses whether a substance is GRAS under 
the conditions of its intended use. As the comment points out, the 
guidance currently is structured to address the specific requirements 
in Sec.  171.1 (particularly Sec.  171.1(c)) for food additive 
petitions. Consistent with available resources, we will consider 
revising that guidance to clarify how its recommendations apply to an 
evaluation of whether a substance is GRAS under the conditions of its 
intended use.

3. Particle Size

    In the 2010 notice, we noted that substances that have a small 
particle size often have chemical, physical, or biological properties 
that are different from those of their larger counterparts (75 FR 81536 
at 81540). We requested comment on whether the final rule should 
address, as part of identity, particle size and other chemical and 
physical properties that may be used to characterize engineered 
materials (see table 9).
    (Comment 67) Some comments recommend that a GRAS notice discuss 
particle size only if it is relevant to the safety or effectiveness of 
the notified substance. One comment recommends that the rule not 
address particle size, at least until this area is better understood. 
Another comment asks us to clarify what we mean by the term ``small 
particle size'' if we include that term in the rule.
    One comment asks us to require information about particle size and 
other physical/chemical properties that may be used to characterize 
engineered materials. This comment asserts that nanoparticles are not 
simply smaller versions of materials; instead nanoparticles are 
specifically engineered to create new properties and behaviors that 
give products certain attributes and highly reactive nanoparticles can 
exhibit a toxic reaction with their environments, including the cells 
of living organisms. This comment also notes that the U.S. 
Environmental Protection Agency (EPA) has already made case-by-case 
rulings on the safety of certain nanoparticles.
    Several comments assert that any requirement for a GRAS notice to 
address particle size and other chemical or physical properties should 
apply only to engineered nanomaterials, and that it is not typically 
necessary to address such properties for non-engineered materials. One 
comment asserts that engineered nanomaterials could never be eligible 
for classification as GRAS because they either are new materials with 
unfamiliar properties or represent a significant new use of a material.
    (Response 67) The final rule requires that a GRAS notice include 
scientific information that identifies the notified substance, and 
includes ``characteristic properties'' in a list of examples of 
appropriate information that a notifier would include. We agree that 
data and information about particle size, and any chemical and physical 
properties attributable to small particle size, are appropriate for 
engineered nanomaterials; a GRAS notice about an engineered 
nanomaterial likely would not provide an adequate basis for a 
conclusion of GRAS status without such information. We also agree that 
data and information about particle size may not be relevant for non-
engineered materials and, thus, we are including the broad example of 
``characteristic properties'' in the final rule without adding the 
narrow example of ``particle size'' (see Sec.  170.230(a)(1)).
    We note that we have several guidances applicable to significant 
manufacturing changes in food, including nanotechnology (Ref. 6; Ref. 
8; and Ref. 44). Our guidance entitled ``Guidance for Industry: 
Assessing the Effects of Significant Manufacturing Process Changes, 
Including Emerging Technologies, on the Safety and Regulatory Status of 
Food Ingredients and Food Contact Substances, Including Food 
Ingredients that are Color Additives'' (Ref. 6) states: ``At present, 
for nanotechnology applications in food substances, there are questions 
related to the technical evidence of safety as well as the general 
recognition of that safety, that are likely to be sufficient to warrant 
formal premarket review and approval by FDA, rather than to satisfy 
criteria for GRAS status.'' However, that guidance reflects the 
generally available data and information at present, and we disagree 
that data and information supporting the safety of engineered 
nanomaterials could never satisfy GRAS criteria. Whether the generally 
available data and information supporting the safety of the intended 
conditions of use of any substance--including an engineered 
nanomaterial--satisfy GRAS criteria is a case-by-case conclusion that 
depends on whether the generally available data and information support 
a conclusion that the substance is generally recognized, among 
qualified experts, to be safe under the conditions of its intended use. 
Section 201(s) of the FD&C Act does not limit the eligibility of a 
substance for classification as GRAS based on factors such as its 
characteristic properties.
4. Other Comments About the Identity of the Notified Substance
    (Comment 68) One comment asserts that the criteria used to conclude 
that a particular substance is GRAS, including details regarding 
biological source, known toxicants, particle size, etc., should be 
based on what qualified experts determine to be necessary.
    (Response 68) We disagree that the role of qualified experts in a 
conclusion of GRAS status means that the requirements for a GRAS notice 
should be silent on the types of data and information that generally 
apply to any conclusion of GRAS status--in this case, data and 
information regarding the identity of the substance. In the narrative 
required by part 6 of a GRAS notice, a notifier must explain why the 
data and information in the notice provide a basis for the notifier's 
view that the notified substance is safe under the conditions of its 
intended use (Sec.  170.250(a)(1)); identify what specific data and 
information that the notifier discusses to support his view that the 
notified substance is safe under the conditions of its intended use are 
generally available, and what specific data and information that the 
notifier discusses are not generally available (Sec.  170.250(a)(2)); 
and explain how the generally available data and information that a 
notifier relies on to establish safety provide a basis for the 
notifier's conclusion that the notified substance is generally 
recognized, among qualified experts, to be safe under the conditions of 
its intended use (Sec.  170.250(b)). The narrative is the appropriate 
mechanism for a notifier to explain how the view of qualified experts 
supports his view that the notified substance is GRAS under the 
conditions of its intended use.

B. Method of Manufacture

    (Comment 69) Several comments address Issue 9a, i.e., whether the 
final rule should continue to stipulate that the method of manufacture 
exclude any trade secrets, as proposed. Some of these comments support 
stipulating that the method of manufacture exclude any trade secrets. 
The stated reasons varied.

[[Page 54999]]

For example, some comments state that in the past experience of 
notifiers, it is generally possible to include sufficient information 
on the manufacturing process without disclosing trade secrets. One 
comment states that transparency, by both FDA and industry, and the use 
of publicly available information is critical to the continued success 
of the GRAS notification procedure. One comment states that the common 
knowledge element of the GRAS standard inherently limits the submission 
of confidential information and/or trade secrets by the notifier to 
substantiate a conclusion of GRAS status.
    Other comments point to the proposed requirement that a GRAS notice 
include ``detailed information about the . . . method of manufacture 
(excluding any trade secrets . . .)'' and question whether a method of 
manufacture that excludes trade secrets can be sufficiently detailed to 
meet the requirements of a GRAS notice. One comment recommends that we 
clarify the rule by requiring that the notice include appropriate 
information on the method of manufacture, sufficient to conduct an 
adequate safety review, so that confidential information would not be 
submitted when a very general and non-confidential description 
suffices.
    Several comments acknowledge that there may be situations where 
trade secret information is necessary to complete the description of 
the method of manufacture and recommend that the final rule provide 
flexibility for a notifier to provide trade secret information when 
appropriate (e.g., to help us evaluate the GRAS notice), and for FDA to 
protect trade secrets or other confidential information in a GRAS 
notice from public disclosure, just as we would in the case of 
submissions such as food additive petitions. To promote clarity and 
transparency, some of these comments recommend revising the rule to 
require that a notifier who includes trade secret information explain 
why the information is trade secret and why the trade secret 
information has a corroborative role in the safety assessment. Some 
comments emphasize that a notifier who submits trade secret information 
must mark the information as non-public. Other comments assert that 
information identified as trade secret or confidential information 
should only be allowed if the information is not critical to a 
conclusion of GRAS status.
    One comment suggests that a notifier could provide trade secret 
information to a GRAS panel for review on a confidential basis because 
deliberations of the panel would not necessarily be subject to public 
disclosure. One comment notes that supporting information can be 
valuable to a GRAS panel and allowing submission of confidential 
information in a GRAS notice could inform FDA of the full range of 
information taken into consideration by a GRAS panel.
    Some comments cite our regulations for new drugs, premarket 
notification for medical devices, and premarket approval of medical 
devices as evidence that our regulations implementing FOIA specifically 
regard methods of manufacture as confidential and urge us to adopt a 
similar approach for GRAS notices.
    See also Comment 57.
    (Response 69) See table 11, and the regulatory text in Sec. Sec.  
170.230(b), 170.225(c)(8), 170.250(d), and 170.250(e), for a series of 
changes we made to the rule to address these comments about the method 
of manufacture included in a GRAS notice, including comments about 
trade secret information associated with the method of manufacture. 
Although the changes in Parts 1 and 6 of a GRAS notice broadly apply to 
any non-public information, in this response we focus on how these 
provisions apply to trade secret information that you may include in 
the description of the method of manufacture. Collectively, these 
changes: (1) Emphasize that the description of the method of 
manufacture must be in sufficient detail to evaluate the safety of the 
notified substance as manufactured, without stipulating that the method 
of manufacture exclude any trade secrets (Sec.  170.230(b)); (2) 
require the notifier to include a signed statement with his view as to 
whether the method of manufacture includes trade secret information 
(Sec.  170.225(c)(8)); (3) require the notifier to identify any trade 
secret information in the method of manufacture (Sec.  170.250(d)); and 
(4) require the notifier to explain how there could be a basis for a 
conclusion of GRAS status if qualified experts do not have access to 
trade secret information that the notifier considered in concluding 
that the substance is safe under the conditions of its intended use 
(Sec.  170.250(e)). See also Response 57, Response 78, and section 
XVII.

  Table 11--Requirements That Apply When a Notifier Includes Trade Secret or Other Non-Public Information in a
                                                   GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                     Proposed designation
     Final designation in the         in the regulatory            Description                  Revision
    regulatory text  (Sec.   )         text  (Sec.   )
----------------------------------------------------------------------------------------------------------------
170.230(b)........................  170.36(c)(2).........  In Part 2 of your GRAS       We replaced
                                                            notice, you must include    ``detailed'' with
                                                            a description of the        ``sufficient detail to
                                                            method of manufacture in    evaluate the safety of
                                                            sufficient detail to        the notified substance
                                                            evaluate the safety of      as manufactured''.
                                                            the notified substance as   We no longer
                                                            manufactured.               stipulate that the
                                                                                        description of the
                                                                                        method of manufacture
                                                                                        must exclude trade
                                                                                        secret information.
170.225(c)(8).....................  N/A..................  In Part 1 of your GRAS      Requires a notifier who
                                                            notice, you must state      includes information
                                                            your view as to whether     that the notifier views
                                                            any of the data and         as non-public
                                                            information in Parts 2      information to make FDA
                                                            through 7 of your GRAS      aware of that view. See
                                                            notice are exempt from      Response 57.
                                                            disclosure under the FOIA
                                                            (e.g., as trade secret or
                                                            as commercial or
                                                            financial information
                                                            that is privileged or
                                                            confidential).
170.250(d)........................  N/A..................  In Part 6 of your GRAS      Requires a notifier who
                                                            notice (the narrative),     includes information
                                                            if you view any of the      that the notifier views
                                                            data and information in     as non-public
                                                            your notice as exempt       information to identify
                                                            from disclosure under the   the non-public
                                                            FOIA, you must identify     information. See section
                                                            the specific data and       XVII.
                                                            information.

[[Page 55000]]

 
170.250(e)........................                         In Part 6 of your GRAS      Requires a notifier to
                                                            notice (the narrative),     place non-public
                                                            you must explain how        information in the
                                                            there could be a basis      context of a conclusion
                                                            for a conclusion of GRAS    of GRAS status. See
                                                            status if qualified         section XVII.
                                                            experts generally do not
                                                            have access to non-
                                                            public, safety-related
                                                            data and information.
170.275(c)........................  170.36(f)(1).........  We will disclose all        Uses active voice to
                                                            remaining data and          emphasize that we will
                                                            information that are not    apply the protections
                                                            exempt from public          from public disclosure
                                                            disclosure in accordance    under the FOIA to non-
                                                            with part 20.               public information
                                                                                        included in a GRAS
                                                                                        notice.
----------------------------------------------------------------------------------------------------------------

    This rule establishes requirements for the information that a 
notifier submits to FDA in a GRAS notice. GRAS criteria require that 
any conclusion of GRAS status be based on common knowledge (see Sec.  
170.30(a)) and, thus, there could be no basis for a conclusion of GRAS 
status if trade secret information (or other non-public information) is 
necessary for qualified experts to reach a conclusion that the notified 
substance is safe under the conditions of its intended use. In the 
particular case of a conclusion of GRAS status through scientific 
procedures, GRAS criteria require that the conclusion of GRAS status be 
based on data, information, and methods that are generally available 
(see Sec.  170.30(b)). Non-public information may be used to 
corroborate safety but cannot be used to establish safety; as discussed 
in Response 9, qualified experts must be able to conclude that the 
substance is not harmful under the conditions of its intended use 
without access to ``corroborative'' information (see Sec.  170.30(a)).
    We believe that it will be rare for a GRAS notice to include trade 
secret information. Likewise, we expect it will be rare that trade 
secret information would warrant sharing with members of a GRAS panel, 
because a notifier must write a non-confidential description of the 
method of manufacture to include in the GRAS notice and could share 
this non-confidential description, rather than trade secret 
information, with the GRAS panel. If the GRAS panel had questions about 
that description of the method of manufacture, we expect that the 
notifier would revise the description to address those questions rather 
than provide the GRAS panel with trade secret information to address 
those questions. If, however, a notifier does provide the GRAS panel 
with trade secret information, we agree that the notifier should inform 
us of the full range of information taken into consideration by the 
GRAS panel, consistent with the signed statement that the GRAS notice 
is a complete, representative, and balanced submission (see Response 58 
and Sec.  170.225(c)(9)). The notifier could do so either by including 
in his GRAS notice a non-confidential description of the trade secret 
information that was shared, or by providing the trade secret 
information shared with a GRAS panel. Importantly, the notifier would 
be required to explain how there could be a basis for a conclusion of 
GRAS status if qualified experts generally do not have access to non-
public, safety related data and information (see Response 78 and Sec.  
170.250(e)). If the public description of the method of manufacture 
that a notifier includes in a GRAS notice cannot provide sufficient 
detail to evaluate the safety of the notified substance as 
manufactured, there could be no basis to support a conclusion of GRAS 
status. However, if that public description meets the requirements of 
the rule to provide sufficient detail to evaluate the safety of the 
notified substance as manufactured (see Sec.  170.230(b)), it may be 
possible to explain that trade secret information that a GRAS panel 
evaluated is corroborative of safety rather than necessary to 
demonstrate safety.
    Under Sec.  20.61, trade secrets and commercial or financial 
information which is privileged or confidential are exempt from public 
disclosure. Under Sec. Sec.  20.100(c)(7) and 171.1(h)(2)(i), 
manufacturing methods or processes, including quality control 
procedures, are exempt from public disclosure unless they have been 
previously disclosed to the public (as defined in Sec.  20.81) or they 
relate to a product or ingredient that has been abandoned. If a 
notifier believes that all information about the method of manufacture 
should be non-public, it is unlikely that the notifier has a basis to 
conclude that the notified substance is GRAS under the conditions of 
its intended use. The use of the substance would be a food additive use 
and, if the notifier submits a food additive petition for that use, our 
regulations governing a food additive petition would protect the 
information from public disclosure, as do our regulations for new 
drugs, premarket notification for medical devices, and premarket 
approval of medical devices.
    (Comment 70) Several comments express concern about the possibility 
that we would determine that information a notifier identifies as a 
trade secret or as confidential commercial information is available for 
public disclosure. One comment asserts that if we choose to allow the 
submission of confidential information in a GRAS notice, we should not 
be the party who determines whether information should be publicly 
disclosed. Another comment asks us to provide an opportunity for a 
notifier to make a ``cease to evaluate'' request before we disclose 
confidential information.
    One comment asks us to allow the submission of limited confidential 
information to supplement (or corroborate) the publicly available 
information in a GRAS notice, such as by providing sufficient 
information in a GRAS notice to support a conclusion of GRAS status but 
also including additional, corroborating information in a food master 
file. The comment explains that the public GRAS notice would be 
complete and sufficient to form a conclusion of GRAS status, but we 
would have access to additional, confidential information that would 
ensure that we are informed of new manufacturing or technological 
developments. This comment points out that we have for many years 
employed food, drug, and medical device master files for the submission 
of confidential information.

[[Page 55001]]

    (Response 70) We disagree that we should not be the party who 
determines whether information should be publicly disclosed. Under our 
public information regulations in part 20, we have the responsibility 
to determine whether information should be publicly disclosed, 
regardless of whether a person who submits the information has marked 
it as non-public. Marking records submitted to us as confidential, or 
with any other similar term, raises no obligation by FDA to regard such 
records as confidential, to return them to the person who has submitted 
them, to withhold them from disclosure to the public, or to advise the 
person submitting them when a request for their public disclosure is 
received or when they are in fact disclosed (see Sec.  20.27). We also 
disagree that providing an opportunity for a notifier to ask us to 
cease to evaluate a GRAS notice would impact the public disclosure of 
data and information that do not satisfy the criteria in part 20 for 
exemption from disclosure; under Sec.  20.29 a GRAS notice is available 
for public disclosure in accordance with part 20.
    Data and information submitted to us are available for public 
disclosure based on the nature of the data and information, not the 
name of the file where we store the data and information. Thus, asking 
us to store data and information that you view as confidential in a 
specific type of file, such as a ``food master file,'' would not 
automatically protect the information from public disclosure. 
Furthermore, in Part 6 of your GRAS notice you would be required to 
explain how there could be a basis for a conclusion of GRAS status if 
qualified experts generally do not have access to the confidential data 
and information in the separate file. We also would expect that you 
provide a statement in Part 1 of your GRAS notice with your view that 
the additional data and information in the separate file are exempt 
from disclosure under the FOIA (see Sec.  170.225(c)(8)). Because part 
20 already provides protection of non-public information from 
disclosure, and because your GRAS notice would need to both acknowledge 
the data and information in the separate file and explain how there 
could be a basis for a conclusion of GRAS status if qualified experts 
generally do not have access to these data and information, we consider 
it administratively inefficient to maintain the data and information 
submitted in support of a conclusion of GRAS status in two separate 
files, and we may decide to decline to file a GRAS notice that is 
accompanied by a separate file containing data and information that you 
view as non-public.
    (Comment 71) Some comments assert that many manufacturers will 
choose not to notify us of a conclusion of GRAS status because they 
expect that we will determine that all information submitted in a GRAS 
notice is available for public disclosure in most circumstances.
    (Response 71) Our experience during the Interim Pilot program does 
not support the assertions in these comments. As noted in Response 24 
and Response 26, CFSAN has filed more than 600 GRAS notices between 
1998 and 2015, for an average of approximately 34 GRAS notices per 
year.
    (Comment 72) One comment states that commercial and financial 
information are not relevant to the determination of safety of a 
notified substance.
    (Response 72) Confidential commercial information may on occasion 
be used to corroborate safety. One example is an article that has been 
accepted for publication, but has not yet been published. This article 
would likely be considered confidential until it is published, but it 
could be used to corroborate other published information.

C. Specifications for the Notified Substance

    We received no comments that disagreed with our proposed 
requirement for a GRAS notice to include specifications for food-grade 
material and we are finalizing it as proposed for a substance used in 
human food. See table 29 for an editorial change we made to the 
regulatory text for specifications for a substance used in animal food.

D. Data and Information Bearing on the Physical or Other Technical 
Effect of the Notified Substance

    As discussed in section XXV.E, several comments discuss their 
experience with CVM's practice, during the Interim Pilot program, of 
asking a notifier to provide data or information demonstrating the 
effectiveness, or utility, of the notified substance. After considering 
these comments, we have added a requirement for Part 2 of a GRAS notice 
to include relevant data and information bearing on the physical or 
other technical effect the notified substance is intended to produce, 
including the quantity of the notified substance required to produce 
such effect, when necessary to demonstrate safety (see Sec.  170.230(d) 
and Response 144). Data and information bearing on the physical or 
other technical effect the notified substance is intended to produce 
are only necessary when they bear on safety. This relationship to 
safety is consistent with the requirements of the FD&C Act for a 
petition to establish the safety of a food additive (see section 
409(b)(2)(C) of the FD&C Act). An example of when such data and 
information would be relevant to safety is when the intended use of the 
notified substance is as an antimicrobial agent. For example, an 
antimicrobial agent may change the microbiological profile of food such 
that it suppresses one group of pathogenic microorganisms while 
allowing others to proliferate, thereby creating a potential health 
problem (Ref. 32).

XIV. Comments on Part 3 of a GRAS Notice: Dietary Exposure

    We proposed that a notice regarding a conclusion of GRAS status 
through scientific procedures include a comprehensive discussion of, 
and citations to, generally available and accepted scientific data, 
information, methods, or principles that the notifier relies on to 
establish safety, including a consideration of the probable consumption 
of the substance and the probable consumption of any substance formed 
in or on food because of its use and the cumulative effect of the 
substance in the diet, taking into account any chemically or 
pharmacologically related substances in such diet (proposed Sec.  
170.36(c)(4)(i)(A)). In the 2010 notice, we requested comment on 
several issues relevant to the proposed requirements for a 
comprehensive discussion that considers the probable consumption of the 
substance and the probable consumption of any substance formed in or on 
food because of its use and the cumulative effect of the substance in 
the diet, and noted that the simple term ``dietary exposure'' could be 
used in place of the statutory language (i.e., derived from section 
409(c)(5) of the FD&C Act) we used in the proposed rule (see table 12). 
See table 27 for issues in the 2010 notice regarding dietary exposure 
when a notified substance would be added to animal food.

[[Page 55002]]



  Table 12--Issues in the 2010 Notice Regarding Dietary Exposure When a
             Notified Substance Would Be Added to Human Food
------------------------------------------------------------------------
                  Description of our request for
   Issue No.                 comment                     Reference
------------------------------------------------------------------------
11a............  Whether the final rule should    75 FR 81536 at 81540-
                  continue to restate the          81541.
                  statutory language of section
                  409(c)(5) of the FD&C Act or
                  whether this provision should
                  be stated more clearly, for
                  example, by requiring
                  information about dietary
                  exposure (i.e., the amount of
                  the notified substance that
                  consumers are likely to eat or
                  drink as part of a total diet).
11b............  Whether a GRAS notice should be  75 FR 81536 at 81540-
                  required to include              81541.
                  information about dietary
                  exposure to contemporary
                  consumers regardless of
                  whether the determination of
                  GRAS status is through
                  scientific procedures or
                  through experience based on
                  common use in food.
------------------------------------------------------------------------

    In the following sections, we discuss comments on the proposed 
requirements applicable to dietary exposure and the issues discussed in 
the 2010 notice. After considering these comments, we are establishing 
requirements for Part 3 of a GRAS notice as shown in table 13, with 
editorial, clarifying, and conforming changes as shown in table 29. 
(See Sec.  170.235). Table 13 identifies changes we made relative to 
the proposed rule or the description in the 2010 notice other than the 
editorial, clarifying, and conforming changes shown in table 29 and the 
additional editorial changes associated with the redesignation of some 
of the regulatory text of proposed Sec.  170.36(c)(4)(i)(A) as Sec.  
170.235.

     Table 13--Final Requirements for Data and Information About Dietary Exposure in Part 3 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No. in                          clarifying, and
    Final designation in  the       designation in the     the 2010         Description      conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice                              relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                               the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.235..........................  170.36(c)(4)(i)(A).             11a  In Part 3 of your     Uses the
                                                                   11b   GRAS Notice, you     term ``dietary
                                                                         must provide data    exposure'' and
                                                                         and information      describes it as
                                                                         about dietary        meaning ``the
                                                                         exposure (i.e.,      amount of relevant
                                                                         the amount of        substances that
                                                                         relevant             consumers are
                                                                         substances that      likely to eat or
                                                                         consumers are        drink as part of a
                                                                         likely to eat or     total diet.''
                                                                         drink as part of a   Requires
                                                                         total diet),         data and
                                                                         regardless of        information about
                                                                         whether your         dietary exposure
                                                                         conclusion of GRAS   regardless of
                                                                         status is through    whether your
                                                                         scientific           conclusion of GRAS
                                                                         procedures or        status is through
                                                                         through experience   scientific
                                                                         based on common      procedures or
                                                                         use in food.         through experience
                                                                                              based on common
                                                                                              use in food.
170.235(a).......................  170.36(c)(4)(i)(A).             11a  In Part 3 of your    Uses the term
                                                                         GRAS Notice, you     ``dietary
                                                                         must provide data    exposure.''
                                                                         and information
                                                                         about dietary
                                                                         exposure to the
                                                                         notified substance
                                                                         that includes
                                                                         exposure from its
                                                                         intended use and
                                                                         all sources in the
                                                                         diet.
170.235(b).......................  170.36(c)(4)(i)(A).             11a  When applicable, in   Uses the
                                                                         Part 3 of your       term ``dietary
                                                                         GRAS Notice you      exposure.''
                                                                         must provide data    Gives
                                                                         and information      examples of
                                                                         about dietary        substances that
                                                                         exposure to any      could be formed in
                                                                         other substance      or on food because
                                                                         that is expected     of the use of the
                                                                         to be formed in or   notified
                                                                         on food because of   substance.
                                                                         the use of the
                                                                         notified substance
                                                                         (e.g., hydrolytic
                                                                         products or
                                                                         reaction products).
170.235(c).......................  170.36(c)(4)(i)(A),             11a  When applicable, in  Requires an
                                    170.36(c)(2).                        Part 3 of your       estimate of
                                                                         GRAS Notice you      dietary exposure
                                                                         must provide data    to substances such
                                                                         and information      as contaminants
                                                                         about dietary        and by-products as
                                                                         exposure to any      a means to
                                                                         other substance      establish
                                                                         that is present      specifications for
                                                                         with the notified    applicable
                                                                         substance either     contaminants and
                                                                         naturally or due     by-products.
                                                                         to its manufacture
                                                                         (e.g.,
                                                                         contaminants or by-
                                                                         products).
170.235(d).......................  170.36(c)(4)(i)(A).             11a  In Part 3 of your    Specifies a
                                                                         GRAS notice, you     necessary aspect
                                                                         must describe the    of the proposed
                                                                         source of any food   ``comprehensive
                                                                         consumption data     discussion'' of
                                                                         that you use to      scientific data,
                                                                         estimate dietary     information, and
                                                                         exposure.            methods.
170.235(e).......................  170.36(c)(4)(i)(A).             11a  In Part 3 of your    Specifies a
                                                                         GRAS notice, you     necessary aspect
                                                                         must explain any     of the proposed
                                                                         assumptions you      ``comprehensive
                                                                         made to estimate     discussion'' of
                                                                         dietary exposure.    scientific data,
                                                                                              information, and
                                                                                              methods.

[[Page 55003]]

 
170.250(a)(1)....................  170.36(c)(4)(i)(A).             N/A  In Part 6 of your    N/A.
                                                                         GRAS notice, you
                                                                         must explain why
                                                                         the data and
                                                                         information in
                                                                         your notice
                                                                         provide a basis
                                                                         for your view that
                                                                         the notified
                                                                         substance is safe
                                                                         under the
                                                                         conditions of its
                                                                         intended use,
                                                                         considering all
                                                                         dietary sources
                                                                         and taking into
                                                                         account any
                                                                         chemically or
                                                                         pharmacologically
                                                                         related substances
                                                                         in such diet.
----------------------------------------------------------------------------------------------------------------

    See section XXV.F for a discussion of comments on the issues listed 
in table 27 regarding dietary exposure when a notified substance would 
be added to animal food and for changes we made to the regulatory text 
regarding dietary exposure when a notified substance would be added to 
animal food.
    (Comment 73) Some comments support retaining the statutory language 
derived from section 409(c)(5) of the FD&C Act when stating the 
requirement for a comprehensive discussion in a GRAS notice that 
considers dietary exposure. One of these comments states that the 
proposed statutory language regarding dietary exposure is consistent 
with the criteria for general recognition of safety through scientific 
procedures, which requires the same quantity and quality of scientific 
evidence necessary for a food additive petition. Other comments support 
revising the proposed requirement as a means of clarifying that the 
comprehensive discussion in a GRAS notice must consider dietary 
exposure.
    (Response 73) We agree that: (1) The requirements of the rule 
regarding what a notifier must include in a GRAS notice regarding 
dietary exposure must be clear; and (2) the statutory language of 
section 409(c)(5)(A) of the FD&C Act is consistent with the criteria 
for general recognition of safety through scientific procedures, which 
requires the same quantity and quality of scientific evidence necessary 
for a food additive petition. To meet both of these goals, the final 
rule requires information about dietary exposure (i.e., the amount of 
relevant substances that consumers are likely to eat or drink as part 
of a total diet), as we suggested in the 2010 notice, but also retains 
the detailed statutory direction as proposed (see Sec.  170.235(a) 
through (c), Sec.  170.250(a)(1), and table 13). In addition to 
requiring an estimate of dietary exposure to the notified substance 
(Sec.  170.235(a)), the rule requires, when applicable, that a notifier 
provide data and information about dietary exposure to any other 
substance that is expected to be formed in or on food because of the 
use of the notified substance (e.g., hydrolytic products or reaction 
products) (Sec.  170.235(b)). Example of such substances are benzoates 
(which react with ascorbic acid (such as in beverages) to form benzene) 
and sulfur dioxide (which reacts irreversibly with thiamine, such that 
we have prescribed limitations on the use of sulfur dioxide in some 
food products (see Sec.  182.3862)). The rule also requires, when 
applicable, that a notifier provide data and information about dietary 
exposure to any other substance that is present with the notified 
substance either naturally or due to its manufacture (e.g., 
contaminants or by-products). An estimate of dietary exposure to 
substances such as contaminants and by-products is necessary to 
establish specifications for applicable contaminants and by-products 
(see Sec.  170.230(c), which requires that a GRAS notice include 
specifications for food-grade material). See also Response 75.
    (Comment 74) One comment asks us to allow for a reasonable 
methodology that does not overestimate dietary exposure in the extreme.
    (Response 74) The rule neither prescribes the methodology you would 
use to estimate dietary exposure nor requires that you overestimate 
dietary exposure. Consistent with the proposed requirement for the 
consideration of dietary exposure to be a ``comprehensive discussion,'' 
the rule requires you to describe the source of any food consumption 
data that you use to estimate dietary exposure and any assumptions you 
made to estimate dietary exposure; such information is necessary for 
the estimates of dietary exposure to be scientifically sound and 
provides an opportunity for you to explain why the methodology you used 
is reasonable (see Sec.  170.235(d) and (e) and table 13). Our guidance 
entitled ``Estimating Dietary Intake of Substances in Food'' provides 
general recommendations for calculating and submitting estimates of 
dietary intake to support the documentation of the safety of substances 
introduced into food either intentionally to accomplish a technical 
effect, adventitiously as a component of an added substance, or 
inadvertently through contamination resulting from processing (Ref. 
25).
    (Comment 75) One comment emphasizes that the requirement for 
consideration of dietary exposure must discuss the potential cumulative 
effect of the notified substance.
    (Response 75) We agree. We are specifying that the narrative 
included in Part 6 of a GRAS notice must address the safety of the 
notified substance, considering all dietary sources and taking into 
account any chemically or pharmacologically related substances in such 
diet (see Sec.  170.250(a)(1)).
    (Comment 76) Some comments support requiring that a GRAS notice 
include information about dietary exposure to contemporary consumers 
when the conclusion of GRAS status is through experience based on 
common use in food prior to 1958, e.g., because dietary exposure to 
contemporary consumers serves as a baseline for future studies/
assessment. Other comments do not support such a requirement and assert 
that it is not critical to update the exposure data if consumption of 
the GRAS substance was already widespread before 1958, or that 
information about dietary exposure to contemporary consumers would only 
be necessary if the exposure has significantly changed since 1958.
    One comment questions the value of requiring information about 
contemporary dietary intake of an ingredient that is GRAS through 
experience based on common use in foods. This comment asserts that the

[[Page 55004]]

FD&C Act deems an ingredient to be GRAS if it was commonly used in 
foods prior to January 1, 1958, and that FDA has long recognized that a 
conclusion of GRAS status through experience based on common use in 
food may be made without the quantity or quality of scientific 
procedures required for establishment of a food additive regulation. 
This comment asserts that there is no requirement for a GRAS ingredient 
to be consumed at the same use level as in 1958 and that imposition of 
such a new requirement may be impracticable, e.g., because there may 
not be any databases that would allow for the calculation of dietary 
exposures prior to 1958. This comment also asserts that in many 
instances there may be insufficient information to establish an 
acceptable daily intake (ADI) for the ingredient because studies that 
can be used to calculate ADIs may not be available for many of these 
ingredients, and that without information about the ADI it would be 
difficult to imagine the relevance of the estimated daily intake, which 
would be calculated through dietary exposure.
    Another comment asserts that Sec. Sec.  170.30(c) and 170.3(f) 
clearly provide that for a substance to be GRAS through experience 
based on common use in food there must be a substantial history of 
consumption of the substance in food by a significant number of people 
prior to 1958 and that the requirements for information about 
consumption data in a GRAS notice should be consistent with those 
regulatory provisions. This comment also asserts that requiring 
information about dietary exposure to contemporary consumers would 
represent an additional regulatory burden that would not impact the 
original conclusion of GRAS status through experience based on common 
use in food if there are no safety concerns when the notified substance 
is used in accordance with the intended conditions of use.
    (Response 76) We are requiring that a notifier provide data and 
information about dietary exposure, regardless of whether the 
conclusion of GRAS status is through scientific procedures or through 
experience based on common use in food (see Sec.  170.235). The FD&C 
Act and our regulations do not provide that a substance is necessarily 
GRAS under the conditions of its intended use merely because it was 
commonly used in food prior to 1958. Rather, the FD&C Act provides that 
such a substance must be generally recognized, among experts qualified 
by scientific training and experience to evaluate its safety, through 
experience based on common use in food, to be safe under the conditions 
of its intended use. Under both the FD&C Act and the definition of 
``safe'' in our regulations, relevant factors must be considered, 
including the ``probable consumption of the substance and of any 
substance formed in or on food because of its use'' (see section 
409(c)(5)(A) of the FD&C Act and Sec.  170.3(i)(1)). We recognize that 
a conclusion of GRAS status through experience based on common use in 
food does not require the same quantity or quality of scientific 
information required for establishment of a food additive regulation; 
however, this means that a conclusion of GRAS status through experience 
based on common use in food is not necessarily supported by the same 
testing data as would be required to support establishment of a food 
additive regulation. See, for example, the 1976 final rule establishing 
GRAS criteria, which provides, ``for those substances that were widely 
used before 1958, under the terms of the statute FDA must consider 
available data and may not prohibit use of a substance merely because 
tests that would be required for new food additives have not been 
performed.'' (41 FR 53600, December 7, 1976). Like a conclusion of GRAS 
status based on scientific procedures, a conclusion of GRAS status 
through experience based on common use in food requires that the 
substance be ``safe,'' as defined in 21 CFR 170.3(i), under the 
conditions of its intended use.
    The rule requires that a notifier provide evidence of substantial 
history of consumption of the substance for food use by a significant 
number of consumers prior to January 1, 1958, but does not require an 
estimate of dietary exposure prior to 1958 (see Sec.  170.245). The 
rule requires that the narrative in Part 6 of a GRAS notice explain why 
the data and information in the notice provide a basis for the 
notifier's view that the notified substance is safe under the 
conditions of its intended use, considering all dietary sources and 
taking into account any chemically or pharmacologically related 
substances in such diet (Sec.  170.250(a)); to do so, the notifier must 
consider the estimated dietary exposure (which this comment refers to 
as ``estimated daily intake''). However, the rule does not specify that 
a notifier must determine an ``acceptable daily intake'' as part of the 
narrative.

XV. Comments on Part 4 of a GRAS Notice: Self-Limiting Levels of Use

    We proposed that a GRAS notice must include information on any 
self-limiting levels of use (proposed Sec.  170.36(c)(3)). We did not 
receive comments disagreeing with this proposed requirement. Therefore, 
we are establishing a requirement for you to include in Part 4 of your 
GRAS notice data and information on self-limiting levels of use in 
circumstances where the amount of the notified substance that can be 
added to food is limited because food containing levels of the notified 
substance above a particular level would become unpalatable or 
technologically impractical (see Sec.  170.240). We included an 
explanation of the circumstances in which the level of use is self-
limiting for clarity.

XVI. Comments on Part 5 of a GRAS Notice: Common Use in Food Before 
1958

    We proposed that a GRAS notice include a comprehensive discussion 
of, and citations to, generally available data and information that the 
notifier relies on to establish safety, including evidence of a 
substantial history of consumption of the substance by a significant 
number of consumers, for a conclusion of GRAS status through experience 
based on common use in food (proposed Sec.  170.36(c)(4)(ii)(A)). 
During the Interim Pilot program, we received fewer than a dozen GRAS 
notices where the statutory basis was through experience based on 
common use in food (Ref. 45).
    We did not receive comments disagreeing with this proposed 
requirement and we are establishing a requirement for you to include in 
Part 5 of your GRAS notice evidence of a substantial history of 
consumption of the notified substance for food use by a significant 
number of consumers prior to January 1, 1958 if the statutory basis for 
your conclusion of GRAS status is through experience based on common 
use in food (see Sec.  170.245). See table 29 for conforming changes 
for a substance used in animal food.

XVII. Comments on Parts 6 and 7 of a GRAS Notice: Narrative and List of 
Supporting Data and Information

    We proposed that a GRAS notice must include a detailed summary of 
the basis for the notifier's determination that a particular use of the 
notified substance is exempt from the premarket approval requirements 
of the FD&C Act because such use is GRAS (proposed Sec.  170.36(c)(4)). 
Regardless of whether the conclusion of GRAS status was based on 
scientific procedures or through experience based on common use in 
food, we proposed to require: (1) A comprehensive discussion of, and 
citations to, generally available and accepted scientific data and 
information that the notifier relies on to establish

[[Page 55005]]

safety (proposed Sec.  170.36(c)(4)(i)(A) and 170.36(c)(4)(ii)(A)); (2) 
a comprehensive discussion of any reports of investigations or other 
information that may appear to be inconsistent with the GRAS 
determination (proposed Sec.  170.36(c)(4)(i)(B) and (c)(4)(ii)(B)); 
and (3) the basis for concluding, in light of the data and information 
in the GRAS notice, that there is consensus among experts qualified by 
scientific training and experience to evaluate the safety of substances 
added to food that there is reasonable certainty that the substance is 
not harmful under the intended conditions of use (proposed Sec.  
170.36(c)(4)(i)(C) and (c)(4)(ii)(C)). When the conclusion of GRAS 
status is based on scientific procedures, we also proposed that the 
discussion of generally available and accepted information that the 
notifier relies on to establish safety include methods and principles, 
and include a consideration of the probable consumption of the 
substance and the probable consumption of any substance formed in or on 
food because of its use and the cumulative effect of the substance in 
the diet, taking into account any chemically or pharmacologically 
related substances in such diet (proposed Sec.  170.36(c)(4)(i)(A)).
    In the 2010 notice, we requested comment on issues relevant to the 
applicability of confidential data and information to a conclusion that 
a substance is GRAS under the conditions of its intended use (see table 
14).

   Table 14--Issues in the 2010 Notice Regarding the Applicability of
    Confidential Data and Information to a Conclusion of GRAS Status
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
9b........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies one
             or more trade
             secret(s), as
             defined in Sec.
              20.61(a), in
             the GRAS notice
             explain why it
             is trade secret
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to the
             trade secret(s).
9c........  Whether to         75 FR 81536 at 81539-81540.
             require that a
             notifier who
             identifies
             confidential
             commercial or
             financial
             information, as
             defined in Sec.
              20.61(b), in
             the GRAS notice
             explain why it
             is confidential
             commercial or
             financial
             information and
             how qualified
             experts could
             conclude that
             the intended use
             of the notified
             substance is
             safe without
             access to such
             information.
------------------------------------------------------------------------

    In the following paragraphs, we discuss comments on the proposed 
requirements applicable to a detailed summary of the basis for the 
notifier's conclusion of GRAS status and the issues discussed in the 
2010 notice. After considering these comments, we are establishing 
requirements for Part 6 of a GRAS notice to include a narrative as 
shown in table 15, and for Part 7 of a GRAS notice to include a list of 
supporting data and information as shown in table 16, with editorial, 
clarifying, and conforming changes as shown in table 29. (See 
Sec. Sec.  170.250 and 170.255.)
    Table 15 and table 16 identify changes we made relative to the 
proposed rule or the description in the 2010 notice other than the 
editorial, clarifying, and conforming changes shown in table 29 and the 
additional editorial changes associated with the redesignation of 
proposed Sec.  170.36(c)(4) as Sec. Sec.  170.250 and 170.255.

                     Table 15--Final Requirements for a Narrative in Part 6 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No. in   Description. Part 6    clarifying, and
     Final designation in the       designation in the     the 2010        of your  GRAS     conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice            notice:           relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                               the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.250..........................  170.36(c)(4).......             N/A  You must include a   N/A.
                                                                         narrative that
                                                                         provides the basis
                                                                         for your
                                                                         conclusion of GRAS
                                                                         status.
170.250(a)(1)....................  170.36(c)(4).......             N/A  You must explain     N/A.
                                                                         why the data and
                                                                         information in
                                                                         your notice
                                                                         provide a basis
                                                                         for your view that
                                                                         the notified
                                                                         substance is safe
                                                                         under the
                                                                         conditions of its
                                                                         intended use,
                                                                         considering all
                                                                         dietary sources
                                                                         and taking into
                                                                         account any
                                                                         chemically or
                                                                         pharmacologically
                                                                         related substances
                                                                         in such diet.
170.250(a)(2)....................  170.36(c)(4).......  9a, 9b, and 9c  You must identify    Requires that your
                                                                         what specific data   narrative clarify
                                                                         and information      the status of all
                                                                         are generally        data and
                                                                         available, and       information that
                                                                         what specific data   you rely on to
                                                                         and information      establish safety.
                                                                         are not generally
                                                                         available, by
                                                                         providing
                                                                         citations to the
                                                                         list of data and
                                                                         information that
                                                                         you include in
                                                                         Part 7 of your
                                                                         GRAS notice.

[[Page 55006]]

 
170.250(b).......................  170.36(c)(4).......             N/A  You must explain     Uses the term
                                                                         how the generally    ``generally
                                                                         available data and   recognized''
                                                                         information that     rather than the
                                                                         you rely on to       term
                                                                         establish safety     ``consensus.''
                                                                         provide a basis
                                                                         for your
                                                                         conclusion that
                                                                         the notified
                                                                         substance is
                                                                         generally
                                                                         recognized, among
                                                                         qualified experts,
                                                                         to be safe under
                                                                         the conditions of
                                                                         its intended use.
170.250(c).......................  170.36(c)(4).......              6b  You must either:     When applicable,
                                                                         (1) Identify,        requires an
                                                                         discuss, and place   affirmative
                                                                         in context, data     statement that you
                                                                         and information      have reviewed the
                                                                         that are, or may     available data and
                                                                         appear to be,        information and
                                                                         inconsistent with    are not aware of
                                                                         your conclusion of   any data and
                                                                         GRAS status,         information that
                                                                         regardless of        are, or may appear
                                                                         whether those data   to be,
                                                                         and information      inconsistent with
                                                                         are generally        your conclusion of
                                                                         available; or        GRAS status.
                                                                        (2) State that you
                                                                         have reviewed the
                                                                         available data and
                                                                         information and
                                                                         are not aware of
                                                                         any data and
                                                                         information that
                                                                         are, or may appear
                                                                         to be,
                                                                         inconsistent with
                                                                         your conclusion of
                                                                         GRAS status..
170.250(d).......................  N/A................       9b and 9c  In Part 6 of your    N/A.
                                                                         GRAS notice (the
                                                                         narrative), if you
                                                                         view any of the
                                                                         data and
                                                                         information in
                                                                         your notice as
                                                                         exempt from
                                                                         disclosure under
                                                                         the FOIA, you must
                                                                         identify the
                                                                         specific data and
                                                                         information.
170.250(e).......................  N/A................       9b and 9c  In Part 6 of your    Your explanation
                                                                         GRAS notice (the     must address all
                                                                         narrative), you      non-public safety-
                                                                         must explain how     related data and
                                                                         there could be a     information, not
                                                                         basis for a          just confidential
                                                                         conclusion of GRAS   data and
                                                                         status if            information
                                                                         qualified experts    included in your
                                                                         generally do not     GRAS notice.
                                                                         have access non-
                                                                         public, safety-
                                                                         related data and
                                                                         information.
----------------------------------------------------------------------------------------------------------------


      Table 16--Final Requirements for a List of Supporting Data and Information in Part 7 of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No. in   Description. Part 7    clarifying, and
     Final designation in the       designation in the     the 2010        of your  GRAS     conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice            notice:           relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                               the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.255(a).......................               9a, 9b, and 9c  You must include a   Clarifies that the
                                    170.36(c)(4)(i)(A).                  list of all of the   list includes all
                                                                 data and             data and
                                    170.36(c)(4)(ii)(A                   information that     information, not
                                    ).                                   you discuss in       just generally
                                                                         part 6 of your       available data and
                                                                         GRAS notice to       information.
                                                                         provide a basis
                                                                         for your view that
                                                                         the notified
                                                                         substance is safe
                                                                         under the
                                                                         conditions of its
                                                                         intended use.
170.255(b).......................               9a, 9b, and 9c  The data and         Requires that you
                                    170.36(c)(4)(i)(A).                  information that     characterize each
                                                                 you list must        item in your list
                                    170.36(c)(4)(ii)(A                   specify which data   as to whether it
                                    ).                                   and information      is generally
                                                                         are generally        available.
                                                                         available, and
                                                                         which data and
                                                                         information are
                                                                         not generally
                                                                         available.
----------------------------------------------------------------------------------------------------------------

    In the requirements for Parts 6 and 7 of the final rule, we made 
changes to require that the narrative in Part 6 of your GRAS notice, 
and the accompanying list of supporting data and information in Part 7 
of your GRAS notice, clarify the status of all data and information 
that you rely on to establish safety as to whether it is generally 
available (see Sec. Sec.  170.250(a)(2) and 170.255, table 15, and 
table 16). We made these changes relative to the proposed requirements 
for a detailed summary and comprehensive discussion for consistency 
with: (1) The criteria for eligibility for classification as GRAS 
through scientific procedures (which provide that a conclusion of GRAS 
status may be corroborated by the application of unpublished scientific 
data, information, or methods (see Sec.  170.30(b), Response 8, and 
Response 12)); and (2) the provisions of the rule that allow you to 
include data and information that are not generally available (see 
Sec.  170.230(b) (which no longer stipulates that the method of 
manufacture must exclude trade secret), Sec.  170.225(c)(8), Response 
57 and Response 69).
    In the requirements for Part 6 of a GRAS notice, we also made a 
change to require that your narrative either: (1) Identify, discuss, 
and place in context, data and information that are, or may appear to 
be, inconsistent with your

[[Page 55007]]

conclusion of GRAS status, regardless of whether those data and 
information are generally available; or (2) state that you have 
reviewed the available data and information and are not aware of any 
data and information that are, or may appear to be, inconsistent with 
your conclusion of GRAS status. See Sec.  170.250(c) and table 15. We 
made this change relative to the proposed requirement for a 
comprehensive discussion of any reports of investigations or other 
information that may appear to be inconsistent with a conclusion of 
GRAS status to emphasize your responsibility to seek out such reports 
and information, as we do during our evaluation of a GRAS notice. See 
also Sec.  170.225(c)(9) and Response 58, in which we discuss the 
requirements for a statement certifying that the GRAS notice is 
``complete'' in addition to ``representative'' and ``balanced,'' to 
emphasize your responsibility to identify, discuss, and place in 
context, data and information that are, or may appear to be, 
inconsistent with a conclusion of GRAS status. Under Sec. Sec.  
170.225(c)(9) and 170.250(c), we expect you to describe unpublished 
reports of investigations or other information that may appear to be 
inconsistent with a conclusion of GRAS status, not just published 
reports. If we identify relevant information that was not discussed in 
the GRAS notice, we may question the credibility of the certification 
statements in the GRAS notice and respond with an ``insufficient basis 
letter.'' As noted in Response 58, the use of certification statements 
has become routine in other submissions to FDA for food programs, and 
the certification statements in Form FDA 3480 (for a food contact 
notification submission) (Ref. 39) and in Form FDA 3537 (for 
registration of a food facility) (Ref. 40) remind the submitter of 
criminal penalties under 18 U.S.C. 1001 for a materially false, 
fictitious, or fraudulent statement to the U.S. Government. Now that 
certification statements will be required in a GRAS notice, we intend 
to modify the form that we make available for the submission of a GRAS 
notice (i.e., Form FDA 3667 (Ref. 38)) to likewise remind any person 
who submits a GRAS notice of the applicability of criminal penalties 
for a materially false, fictitious, or fraudulent statement to the U.S. 
Government.
    See also Response 78. We also expect you to describe unpublished 
data and information that you consider to be corroborative of safety 
(e.g., if you consider that the unpublished data and information 
warrant sharing with any ``GRAS panel'' that you convene).
    (Comment 77) One comment asserts that the proposed requirement for 
a GRAS notice to include the basis for concluding that there is 
consensus among qualified experts about the safety of the substance 
misstates the statutory standard for general recognition in section 
201(s) of the FD&C Act. This comment asserts that the term 
``consensus'' denotes complete or near unanimity, whereas the standard 
of general recognition requires that qualified experts predominantly, 
but not unanimously, accept the safety of the substance. Although the 
comment acknowledges that the proposed rule stated that the term 
``consensus'' does not imply unanimity (62 FR 18938 at 18941), the 
comment argues that the example used in our explanation, about whether 
a single published report questioning the safety of use of a substance 
in food would preclude general recognition, wrongly implied that 
general recognition requires near unanimity (62 FR 18938 at 18941). The 
comment asks us to revise the rule by replacing the term ``consensus,'' 
which does not appear in the statute, with the phrase ``general 
recognition,'' which derives from the statute itself.
    (Response 77) As discussed in the proposed rule (62 FR 18938 at 
18939), our interpretation that general recognition requires consensus 
is consistent with the case law on the general recognition standard. 
See United States v. Western Serum Co., Inc., 666 F.2d 335, 338 (9th 
Cir. 1982); United States v. Articles of Drug...Promise Toothpaste, 624 
F.Supp. 776, 778 (N.D. Ill. 1985), aff'd 826 F.2d 564 (7th Cir. 1987); 
United States v. Articles of Drug...Hormonin, 498 F.Supp.2d 424, 435 
(D.N.J. 1980). See also the discussion of the consensus standard in 
Response 20.
    We proposed to provide our interpretation of section 201(s) of the 
FD&C Act in the requirement for Part 6 of a GRAS notice to provide more 
context to notifiers than merely repeating the statutory language. We 
disagree with the comment's assertion that the example we described in 
the proposed rule requires ``near unanimity''; CFSAN's experience 
during the Interim Pilot program demonstrates that CFSAN's 
``insufficient basis letters'' did not apply a standard of ``near 
unanimity'' when evaluating the notifier's basis for a conclusion of 
GRAS status (see section III.A.3 of CFSAN's 2010 experience document 
(Ref. 18)).
    However, we have decided to use the statutory language (i.e., 
``generally recognized'') rather than the proposed term ``consensus'' 
because the revised GRAS criteria that we are establishing in Sec.  
170.30 continue to use the statutory language rather than the consensus 
standard applied by the courts in applying the statutory language to 
specific situations. Using the statutory language in both the GRAS 
criteria and the requirement for the submission of a narrative in a 
GRAS notice will emphasize your burden to explain how the data and 
information in the notice regarding the safety of the notified 
substance under the conditions of its intended use satisfy the GRAS 
criteria.
    See also Response 128, in which we respond to comments recommending 
that we clarify that the same standards apply to a conclusion of GRAS 
status regardless of whether the conclusion is submitted to us as a 
GRAS notice or is not submitted to us. As noted in Response 128, we 
believe that the provisions of the GRAS notification procedure will be 
a useful resource to any person who intends to use a substance in food 
based on a conclusion of GRAS status, regardless of whether the 
conclusion of GRAS status is submitted to us in a GRAS notice. In 
developing any recommendations (e.g., in guidance) that would broadly 
apply to any conclusion of GRAS status, it is simpler to consistently 
use the same regulatory text in both the GRAS criteria and the 
submission requirements for a GRAS notice.
    (Comment 78) One comment notes that industry has various options 
for handling confidential information. For example, confidential 
agreements are commonly used instruments to help maintain the 
confidentiality of proprietary trade secret information, and therefore 
qualified experts on GRAS panels can have access to such information if 
it is necessary for a conclusion of GRAS status. The comment asks us to 
require that notifiers indicate whether qualified experts (such as on 
the notifier's GRAS panel) had access to trade secrets when they 
concluded that the substance is safe under the conditions of its 
intended use.
    (Response 78) The rule establishes no requirements specific to a 
GRAS panel. However, we agree that it is appropriate for a notifier to 
indicate whether qualified experts (such as on the notifier's GRAS 
panel) who reviewed the data and information supporting safety had 
access to safety-related trade secrets in reaching a conclusion that 
the notified substance is safe under the conditions of its intended 
use. Therefore, we are requiring that a notifier explain how there 
could be a basis for a conclusion of GRAS status if

[[Page 55008]]

qualified experts generally do not have access to non-public safety-
related data and information (see Sec.  170.250(e)). This requirement 
applies to all non-public safety-related data and information, not just 
trade secret information, and is not limited to non-public safety-
related data and information that are included in the notice. As 
requested by the comment, this requirement would apply if the notifier 
provided non-public safety-related information to outside experts (such 
as on a GRAS panel). As already discussed, if a GRAS panel considers 
non-public safety-related information that a notifier does not include 
in a GRAS notice, we also expect the notifier to inform us that the 
GRAS panel had access to such information, consistent with the 
notifier's signed statement that the GRAS notice is a complete, 
representative, and balanced submission (see Sec.  170.225(c)(9)) (see 
Response 58 and Response 69).
    See also table 11 and table 15. The rule also requires that a 
notifier state his view as to whether any of the data and information 
in Parts 2 through 7 of a GRAS notice are exempt from disclosure under 
the FOIA (see Sec.  170.225(c)(8)) and identify what specific data and 
information in the notice are generally available, and what specific 
data and information in the notice are not generally available (see 
Sec.  170.250(a)(2) and (d)). Collectively, the requirements in 
Sec. Sec.  170.225(c)(8) and (9) and 170.250(a)(2), (d), and (e) 
address the underlying issue in the comment's request, i.e., that there 
must be a basis for a conclusion of GRAS status if some safety-related 
data and information that a notifier assesses in his deliberations are 
non-public (e.g., trade secret information or otherwise are 
confidential information), regardless of whether the notifier shares 
such information with a GRAS panel. If a GRAS notice does not provide a 
basis for a conclusion that the notified substance is safe under the 
conditions of its intended use without access to such information, we 
would respond to the notice with an ``insufficient basis letter.'' If 
we respond with a ``no questions letter,'' and later determine that the 
GRAS notice was not ``complete'' (e.g., because it did not describe 
unpublished reports of investigations that are, or may appear to be, 
inconsistent with the conclusion of GRAS status), we may send the 
notifier a subsequent letter regarding the omission; such a letter 
would be readily accessible to the public (Sec. Sec.  170.265(c) and 
170.275(b)(2)).
    (Comment 79) One comment suggests that if the qualified experts are 
FDA reviewers, an option might be for the notifier to submit a 
``sanitized'' version of the GRAS notice, excluding non-public 
information, together with a separate appendix to the GRAS notice where 
the notifier would include relevant trade secrets or confidential 
information needed to support the conclusion of GRAS status. 
Alternatively, we could require that a notifier submit two versions of 
the submission: (1) A sanitized version that excludes non-public 
information; and (2) a more detailed version including the confidential 
information. The comment states that these options would both allow our 
reviewers access to the information and facilitate the process of 
promptly making GRAS notices available for public disclosure.
    (Response 79) In enacting the GRAS provision, Congress clearly 
contemplated a process of concluding that a food substance is GRAS 
under the conditions of its intended use as an alternative to 
submission of a food additive petition to FDA and establishment of a 
regulation prescribing the conditions under which the substance may be 
safely used. It follows that the qualified experts who evaluate the 
basis for a conclusion that the notified substance is safe under the 
conditions of its intended use must not exclusively be ``FDA's 
experts'' (such as our scientific staff who evaluate GRAS notices). The 
suggestion of this comment that a notifier could rely exclusively on 
evaluation by FDA experts to support his view that there is a basis for 
concluding that there is consensus among ``qualified experts'' is 
inconsistent with the GRAS provision in section 201(s) of the FD&C Act, 
which requires general recognition among qualified experts. See also 
the discussion in Response 70, in which we explain our reasons for why 
we may decide to decline to file a GRAS notice that is accompanied by a 
separate file containing data and information that you view as non-
public.

XVIII. Comments on Steps a Notifier May Take Before We Respond to a 
GRAS Notice

    In the 2010 notice, we described comments regarding steps you may 
take before we respond to your GRAS notice (see table 17). As noted in 
section VIII.A, we are establishing a definition for ``amendment'' in 
the rule (see Sec.  170.203). In the following paragraphs, we discuss 
additional comments regarding the issues in table 17. Some of these 
comments agree that the rule should have such a provision. Other 
comments ask us to clarify how such a provision would operate in 
practice (see, e.g., Comment 82) or suggest one or more changes to the 
provision as we described it in the 2010 notice (see, e.g., Comment 80, 
Comment 81, and Comment 83). After considering these comments, we are 
establishing two provisions regarding steps you may take before we 
complete our evaluation of a GRAS notice. The first provision specifies 
that you may submit a timely amendment to your filed GRAS notice, to 
update your GRAS notice or in response to a question from us, before we 
respond to your notice by letter (see the regulatory text of Sec.  
170.260(a)). The second provision specifies that you may ask us to 
cease to evaluate your GRAS notice as described in the 2010 notice, 
with clarifications as a result of comments (see the regulatory text of 
Sec.  170.260(b)). One clarification is that such a request does not 
preclude you from submitting a future GRAS notice with respect to the 
notified substance. A second clarification is that we will send you a 
letter informing you of our decision regarding your request (see the 
regulatory text of Sec.  170.265(b)(3)).

 Table 17--Issues in the 2010 Notice Regarding Steps You May Take Before
                     We Respond to Your GRAS Notice
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
3a........  Whether to define  75 FR 81536 at 81538.
             ``amendment'' to
             mean any data or
             other
             information that
             you submit
             regarding a
             filed GRAS
             notice before we
             respond to the
             notice.
5.........  Whether the final  75 FR 81536 at 81538-81539.
             rule should
             explicitly
             provide that you
             may request in
             writing that we
             cease to
             evaluate your
             GRAS notice at
             any time during
             our evaluation
             of that GRAS
             notice.
------------------------------------------------------------------------


[[Page 55009]]

    See section XXV.I for a discussion of comments regarding steps you 
may take before we respond to your GRAS notice for a substance used in 
animal food, and for our response to those comments.

A. Communicating With a Notifier Before We Respond to a GRAS Notice

    (Comment 80) Several comments note that the proposed rule did not 
say that we would contact a notifier, before we issue our publicly 
available response, to provide preliminary feedback regarding our 
evaluation of a GRAS notice. One of these comments asks us to include a 
provision specifying that we may communicate with the notifier about 
any aspect of a notice while the notice is pending. Some comments 
express concern that a letter listing answerable and nonsubstantive 
questions about a GRAS notice could cause confusion and 
misunderstanding in the marketplace, particularly if additional 
information, clarification, or amendment would address our concerns.
    (Response 80) We decline the request to include a provision 
specifying that we may communicate with you about any aspect of a 
notice while your notice is pending. As discussed in section III.C.1 of 
CFSAN's 2010 experience document (Ref. 18), during the Interim Pilot 
program CFSAN contacted several notifiers to request clarification 
about data and information in the notice under the framework of 
existing regulations governing meetings and correspondence (Sec.  
10.65(g)). It is not necessary to duplicate the existing procedures in 
Sec.  10.65(g) in the requirements for the GRAS notification procedure.
    We infer that this comment is specifically asking us to require 
that we contact you to provide preliminary feedback before we respond 
to your GRAS notice with an ``insufficient basis letter.'' As discussed 
in section III.C.1 of CFSAN's 2010 experience document (Ref. 18), our 
experience during the Interim Pilot program demonstrates that we are 
willing to engage in a dialog with a notifier to clarify particular 
aspects of a GRAS notice. As discussed in section IV.H.4 of CFSAN's 
2010 experience document (Ref. 18), our experience during the Interim 
Pilot program also demonstrates that we do not issue an ``insufficient 
basis letter'' with ``nonsubstantive questions.'' Although we have 
issued ``insufficient basis letters'' due to an overall poor quality of 
a submission, to conserve resources our practices have evolved so that 
we generally do not file such submissions as GRAS notices (see section 
XIX.A regarding filing decisions and section III.K of CFSAN's 2010 
experience document (Ref. 18)). Although we expect to contact you when 
we have questions, whether we intend to provide you with an opportunity 
to submit an amendment to a GRAS notice before responding to the notice 
has been, and will continue to be, a matter committed to our 
discretion.
    In the following paragraphs, we discuss some key factors we intend 
to consider regarding the purpose of our contact with you regarding 
your GRAS notice, particularly with respect to whether we intend to 
provide you with an opportunity to submit an amendment to a GRAS 
notice. These factors are: (1) Whether our questions can be addressed 
by a timely, clarifying amendment; (2) whether our evaluation 
identifies a safety concern; and (3) whether we question whether GRAS 
criteria are satisfied, even if our evaluation does not identify a 
safety concern. See also the discussion in Response 85 regarding 
factors that could lead us to decline to file a submission as a GRAS 
notice, rather than to file it for our evaluation of your view that the 
notified substance is GRAS under the conditions of its intended use and 
issue an ``insufficient basis letter.''
    We agree that an ``insufficient basis letter'' listing answerable 
questions about a GRAS notice could cause confusion and 
misunderstanding in the marketplace, particularly if additional 
information, clarification, or amendment would address our concerns. 
Section III.C.1 of CFSAN's 2010 experience document provides examples 
of circumstances where CFSAN contacted a notifier and expected that the 
information exchanged between CFSAN and the notifier would clarify, 
rather than substantively amend, the original notice. We intend to 
continue contacting notifiers in such circumstances. By ``clarify, 
rather than substantively amend,'' we mean that the amendment would add 
or modify specific sections in the notice, not that the clarifying 
information would necessarily be nonsubstantive in nature. For example, 
as discussed in Response 96 during the Interim Pilot program we 
contacted notifiers when the notice contained insufficient information 
about dietary exposure and when the notice contained insufficient 
information to adequately identify the substance. We did so because it 
is efficient, for us as well as the notifier, to bring a GRAS notice to 
closure with a ``no questions letter'' when it is likely that a timely, 
clarifying amendment would resolve our questions. For example, it is 
more efficient for us to bring a GRAS notice to closure while our 
reviewers are already immersed in the substantive evaluation of the 
notice, rather than to issue an ``insufficient basis letter'' and begin 
the evaluation process anew when the notifier addresses the questions 
in a new GRAS notice. See section XVIII.B for a discussion of what we 
mean by a ``timely'' amendment.
    If we file your submission as a GRAS notice and our evaluation of 
the available data and information identifies a safety concern, the 
purpose of our contact with you would depend on whether the safety 
concern could be addressed by a timely, clarifying amendment. For 
example, in some cases the available data and information may support 
safety only under modified conditions of use relative to the conditions 
of use described in your GRAS notice, and our contact with you would 
focus on your opportunity to address the safety concern through a 
timely amendment specifying modified conditions of use. However, if we 
believe that the safety concern could not be addressed through a 
timely, clarifying amendment or by re-submission of a new GRAS notice 
(e.g., after studies are conducted to address the safety concern), we 
likely would contact you to make you aware of our concerns and then 
issue an ``insufficient basis letter'' that clearly and fully 
articulates our reasons for that safety concern, including the full 
context of the risk to human or animal health.
    If we file your submission as a GRAS notice and find that your 
narrative does not support a conclusion of GRAS status, even if the 
available data and information support your view that the notified 
substance is safe under the conditions of its intended use (e.g., 
because data and information that are necessary to establish safety are 
not generally available), the purpose of our contact with you would 
focus on your opportunity to address the regulatory status of the 
notified substance. For example, it may be possible for you to submit a 
new GRAS notice after publishing applicable data and information and 
allowing sufficient time to allow the expert scientific community to 
access the published information. Alternatively, it may be more 
appropriate for you to consider the notified substance as a food 
additive under the conditions of its intended use, and to make a 
premarket submission such as a food additive petition. For examples of 
circumstances leading to the options for addressing questions about the 
regulatory status of the substance when we have not identified a safety 
concern, see section III.A.4 of CFSAN's 2010 experience document (Ref. 
18). Any letter we issue would

[[Page 55010]]

include our view of the regulatory status of the substance at the time 
that we issued the letter, based on the generally available data and 
information at that time.

B. Submitting an Amendment

    Comments support adding a provision to clarify that you may submit 
an amendment to your GRAS notice and, thus, we are establishing a 
provision specifying that you may submit a timely amendment to your 
filed GRAS notice (Sec.  170.260(a)). In some cases, you would submit 
such an amendment after we contact you to discuss our questions about 
your GRAS notice. (See the discussion in Response 80 regarding 
contacting a notifier.) In other cases, you may conclude that it is 
appropriate to submit an amendment to update your GRAS notice on your 
own initiative, e.g., if new data and information about the notified 
substance under the conditions of its intended use become available 
after we file your submission as a GRAS notice. Depending on the 
circumstances, you could then decide to explain your view that the new 
data and information do not alter the basis for your conclusion of GRAS 
status; alternatively, you could decide to ask us to cease to evaluate 
your GRAS notice while you evaluate the impact of the new data and 
information on the GRAS status of the notified substance under the 
conditions of its intended use (see Sec.  170.260(b)).
    By timely, we mean that you submit your amendment in a timeframe 
that provides us with sufficient time to evaluate it before we respond 
to your GRAS notice. Given that the rule requires us to end our 
evaluation and respond to your GRAS notice within 180 days, with an 
extension of up to an additional 90 days on an as needed basis Sec.  
170.265(b)(1)), we reserve the right to not consider your amendment if 
you submit it so late in our evaluation that it would impact our 
ability to respond within our established timeframes. Therefore, as a 
companion provision, the rule also provides that we will consider any 
timely amendment that you submit to a filed GRAS notice, to update your 
GRAS notice or in response to a question from us, before we respond to 
you by letter based on our evaluation of your notice if we deem that 
doing so is feasible within the established timeframes (see Sec.  
170.265(a)(4)). If we deem that considering your amendment is not 
feasible within the established timeframes, we will inform you that we 
are not considering your amendment.
    See also the discussion in Response 101, which emphasizes that the 
role of an amendment is to clarify questions that we have about your 
conclusion of GRAS status rather than to substantively amend the GRAS 
notice.

C. Notifier's Request That We Cease To Evaluate a GRAS Notice

    (Comment 81) Some comments ask us to make public the reason for a 
notifier's request that we cease to evaluate a notice. One comment asks 
that any new information, or questions about the scientific consensus 
about whether a substance is safe, be made clear to the public as well 
as FDA. Another comment expresses concern that companies ask FDA to 
cease evaluations of their GRAS notices with ``alarming frequency.''
    (Response 81) We are establishing a provision specifying that a 
notifier may ask us to cease to evaluate his GRAS notice (see Sec.  
170.260(b)). As a companion provision, we are specifying that if a 
notifier asks us to cease to evaluate a GRAS notice, we will send the 
notifier a letter informing the notifier of our decision regarding that 
request (see Sec.  170.265(b)(3)). As discussed in section III.E of 
CFSAN's 2010 experience document (Ref. 18), during the Interim Pilot 
program CFSAN's ``cease to evaluate letters'' generally repeated any 
reason specified in a request letter, but may not have otherwise 
described the reasons underlying the request. If a notified substance 
is marketed even though we issue a ``cease to evaluate letter,'' there 
could be confusion about the GRAS status of the notified substance even 
when the conditions of use in the marketplace differ from the notified 
use that was the subject of the ``cease to evaluate letter.'' For 
example, a notifier could ask us to cease to evaluate a GRAS notice 
because we identified a safety concern about the specified use level of 
the notified substance in food products, and then decide to market the 
substance at a lower use level than the level specified in the GRAS 
notice, where we would no longer have that concern. In addition, as 
discussed in the proposed rule we proposed to make all response letters 
readily accessible to the public because such a system will properly 
underscore a notifier's acceptance of responsibility for the conclusion 
of GRAS status, and a GRAS notice that is submitted to us is a public 
notice (62 FR 18938 at 18953). A ``cease to evaluate letter'' signals 
that a submitted GRAS notice does not provide an adequate basis for a 
conclusion that the notified substance is GRAS under the conditions of 
its intended use, even though we do not issue an ``insufficient basis 
letter.'' Given the public nature of a GRAS notice, it is appropriate 
for the reasons leading to a ``cease to evaluate letter'' to also be 
public. Therefore, as of October 17, 2016, we intend to change this 
practice and increase transparency by describing the reasons leading to 
any ``cease to evaluate letter.''
    Table 1 in CFSAN's 2010 experience document (Ref. 18) shows that 
approximately 16 percent of GRAS notices that CFSAN responded to during 
the 12-year period spanning 1998 through 2009 came to closure when the 
notifier asked us to cease to evaluate a GRAS notice. Table 1 in 
CFSAN's 2010 experience document also shows that CFSAN issued equal 
numbers of ``cease to evaluate letters'' and ``insufficient basis 
letters'' during the years 1998 through 2002 (i.e., 16 ``cease to 
evaluate letters'' and 16 ``insufficient basis letters''). However, 
during the years 2003 through 2009 CFSAN issued 31 ``cease to evaluate 
letters,'' but no ``insufficient basis letters.'' In addition, table 1 
in CFSAN's 2016 experience document (Ref. 19) shows that during the 
years 2010 through 2015 CFSAN issued 48 ``cease to evaluate letters'' 
but only one ``insufficient basis letter.'' We acknowledge that there 
has been a distinct shift between the ratio of the number of ``cease to 
evaluate letters'' compared to the number of ``insufficient basis 
letters'' issued during the years 1998 through 2002 and the 
corresponding ratio for letters issued during the years 2003 through 
2015. We consider that the data in the experience document demonstrate 
an evolving practice in which CFSAN has declined to file some 
submissions as GRAS notices when the notice lacks much of the required 
data and information necessary for us to evaluate a notifier's view 
that the notified substance is GRAS under the conditions of its 
intended use (see Response 85). In addition, such a frequency 
demonstrates that CFSAN has been willing to contact notifiers with 
questions about a conclusion that the notified substance is GRAS under 
the conditions of its intended use. As discussed in Response 80, when 
our questions cannot be addressed by a timely amendment, contacting the 
notifier provides the notifier an opportunity to re-submit a new GRAS 
notice or other regulatory submission (such as a food additive 
petition) that addresses our questions.
    As discussed in section III.E of CFSAN's 2010 experience document 
(Ref. 18), in many cases a notifier who received a ``cease to evaluate 
letter'' resubmitted a new GRAS notice, and CFSAN responded with a ``no 
questions letter.'' For many GRAS notices, the

[[Page 55011]]

questions we raised and discussed with the notifier clearly addressed 
issues other than a fundamental safety concern. For example, some of 
the letters that CFSAN lists in section III.E of its 2010 experience 
document provide reasons such as preparing a new notice that will not 
contain any confidential business information and that will clarify 
that the statutory basis for the conclusion of GRAS status is through 
scientific procedures; needing to revise an estimate of dietary 
exposure; and clarifying and providing additional information for a new 
notice. However, CFSAN only made these reasons transparent to the 
public because the notifier chose to provide these reasons in his 
request that we cease to evaluate the GRAS notice. In other 
circumstances, the public had no way to know what the issue was until 
we responded to the resubmitted notice. We intend to continue to 
contact a notifier to discuss our questions, and provide an opportunity 
for the notifier to ask us to cease to evaluate the GRAS notice (e.g., 
so that the notifier can submit a new GRAS notice that addresses the 
issues). However, we also intend to briefly describe these issues in a 
``cease to evaluate letter'' that follows that contact. As CFSAN did 
during the Interim Pilot program, we intend to consider any reasons a 
notifier provides for the request, and to include those reasons in our 
``cease to evaluate letter.'' If, however, we conclude that a 
notifier's explanation does not adequately describe the reasons leading 
to a ``cease to evaluate'' request, we intend to explain the reasons 
for ceasing to evaluate the notice from our point of view. Doing so 
will both ensure clear communication about the reasons and make the 
reasons transparent to the public.
    As discussed in Response 80, if we identify a safety concern and 
believe that the safety concern could not be addressed through a 
timely, clarifying amendment, by re-submitting a new GRAS notice, or by 
submitting another premarket submission (such as a food additive 
petition), we likely would issue an ``insufficient basis letter'' even 
though we would have contacted the notifier to discuss our concerns.
    Asking us to cease to evaluate a GRAS notice does not guarantee 
that we will honor that request. Depending on the circumstances, we may 
decide to decline the request and instead respond with an 
``insufficient basis letter''; depending on the time remaining between 
when we receive the request and the timeframes by which we must respond 
to the GRAS notice, we may either send the notifier a separate letter 
declining the request, or note in the ``insufficient basis letter'' 
that we had declined the request. See the discussion in section III.C.1 
of CFSAN's 2010 experience document (Ref. 18) for an example of a 
situation in which CFSAN responded with an ``insufficient basis 
letter'' after a notifier asked CFSAN to cease to evaluate its GRAS 
notice, submitted a new GRAS notice, and asked CFSAN to cease to 
evaluate the second submitted GRAS notice.
    (Comment 82) One comment asks us to clarify that a notifier's 
request that we cease to evaluate a GRAS notice would be without 
prejudice for future submissions.
    (Response 82) The final provision specifies that your request that 
we cease to evaluate a GRAS notice does not preclude you from 
submitting a future GRAS notice with respect to the notified substance.
    (Comment 83) One comment asks us to specify that, if feasible, the 
files could be returned to the notifier at the notifier's expense.
    (Response 83) We decline this request. As discussed in the 2010 
notice (75 FR 81536 at 81538-81539), our current regulations regarding 
public information stipulate that no person may withdraw records 
submitted to FDA (see Sec.  20.29), and those regulations will apply to 
any GRAS notice that we receive. To make this clear, the provision we 
are establishing in the final rule provides an opportunity for you to 
ask us to ``cease to evaluate'' a GRAS notice rather than ``withdraw'' 
a GRAS notice.
    (Comment 84) Some comments ask us to specify that if a notifier 
requests that we cease to evaluate a submitted GRAS notice, such 
notices will remain in our files and will be available for public 
disclosure.
    (Response 84) See Sec.  20.29 and the discussion of Issue 5 in the 
2010 notice (75 FR 81536 at 81538-81539). If a notifier asks us to 
cease to evaluate a submitted GRAS notice, the notice will remain in 
our files and will be available for public disclosure in accordance 
with part 20. It is not necessary to repeat the provisions of Sec.  
20.29 in the GRAS notification procedure.

XIX. Comments on What We Will Do With a GRAS Notice

    We proposed that: (1) We would acknowledge receipt of a notice, 
within 30 days of receipt, by informing the notifier in writing of the 
date on which the notice was received (proposed Sec.  170.36(d)); (2) 
we would respond to the notifier in writing within 90 days of receipt 
of the notice (proposed Sec.  170.36(e)); and (3) a copy of any 
subsequent letter that we issued regarding a GRAS notice would be 
readily accessible for public review and copying (proposed Sec.  
170.36(f)(2)(iii)). In the 2010 notice, we asked for comment on issues 
relating to what we will do with a GRAS notice as shown in table 18.

  Table 18--Issues in the 2010 Notice Regarding What We Will Do With a
                               GRAS Notice
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
12........  Whether we should  75 FR 81536 at 81541.
             make explicit
             the process by
             which we make a
             filing decision,
             including the
             factors we would
             use to determine
             whether to file
             a submission as
             a GRAS notice.
14........  Whether we should  75 FR 81536 at 81542.
             retain a set
             timeframe for us
             to respond to a
             GRAS notice,
             and, if so,
             whether it
             should be 90
             days or another
             timeframe.
------------------------------------------------------------------------

    In the following sections, we discuss comments on what we will do 
when we receive a GRAS notice. After considering these comments, we are 
establishing requirements in Sec.  170.265 for what we will do when we 
receive a GRAS notice as shown in table 19, with editorial, clarifying, 
and conforming changes as shown in table 29. Table 19 identifies 
changes we made relative to the proposed rule or the description in the 
2010 notice other than the editorial, clarifying, and conforming 
changes shown in table 29 and the additional editorial changes 
associated with the redesignation of proposed Sec.  170.36(d), (e), and 
(f)(2)(iii) as Sec.  170.265. See section XXV.I for a discussion of 
comments specific to a filing decision for a substance used in animal 
food.

[[Page 55012]]



                      Table 19--Final Requirements for What FDA Will Do With a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No. in                          clarifying, and
    Final designation in  the       designation in the     the  2010        Description      conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice                              relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                               the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.265(a)(1)....................  N/A................              12  We will conduct an   N/A.
                                                                         initial evaluation
                                                                         of your submission
                                                                         to determine
                                                                         whether to file it
                                                                         as a GRAS notice
                                                                         for evaluation of
                                                                         your view that the
                                                                         notified substance
                                                                         is GRAS under the
                                                                         conditions of its
                                                                         intended use.
170.265(a)(2)....................  170.36(d)..........              12  If we file your      N/A.
                                                                         submission as a
                                                                         GRAS notice, we
                                                                         will send you a
                                                                         letter that
                                                                         informs you of the
                                                                         date of filing.
170.265(a)(3)....................  N/A................              12  If we do not file    Clarifies that we
                                                                         your submission as   would inform you
                                                                         a GRAS notice, we    by letter if we do
                                                                         will send you a      not file your
                                                                         letter that          submission as a
                                                                         informs you of       GRAS notice.
                                                                         that fact and
                                                                         provides our
                                                                         reasons.
170.265(a)(4)....................  N/A................              3a  We will consider     Clarifies that we
                                                                         any timely           will only consider
                                                                         amendment that you   an amendment if we
                                                                         submit to a filed    deem that doing so
                                                                         GRAS notice, to      is feasible within
                                                                         update your GRAS     the established
                                                                         notice or in         timeframes.
                                                                         response to a
                                                                         question from us,
                                                                         before we respond
                                                                         to you by letter
                                                                         based on our
                                                                         evaluation of your
                                                                         notice if we deem
                                                                         that doing so is
                                                                         feasible within
                                                                         the established
                                                                         timeframes. If we
                                                                         deem that
                                                                         considering your
                                                                         amendment is not
                                                                         feasible within
                                                                         the established
                                                                         timeframes, or if
                                                                         we have granted
                                                                         your request to
                                                                         cease to evaluate
                                                                         your notice, we
                                                                         will inform you
                                                                         that we are not
                                                                         considering your
                                                                         amendment.
170.265(b)(1)....................  170.36(e)..........              14  Within 180 days of    Specifies
                                                                         filing, we will      that the timeframe
                                                                         respond to you by    for our response
                                                                         letter based on      is 180 days,
                                                                         our evaluation of    rather than 90
                                                                         your notice. We      days.
                                                                         may extend the 180   Provides
                                                                         day timeframe by     for an extension
                                                                         90 days on an as     of our evaluation
                                                                         needed basis.        by 90 days on an
                                                                                              as needed basis.
170.265(b)(2)....................  N/A................              14  If we extend the     Provides that we
                                                                         timeframe, we will   will inform you if
                                                                         inform you of the    we extend the
                                                                         change in writing    timeframe for our
                                                                         as soon as           response.
                                                                         practicable but no
                                                                         later than within
                                                                         180 days of filing.
170.265(b)(3)....................  N/A................               5  If you ask us to     Companion change in
                                                                         cease to evaluate    light of new
                                                                         your GRAS notice,    regulatory text
                                                                         we will send you a   (in Sec.
                                                                         letter informing     170.260(b))
                                                                         you of our           expressly
                                                                         decision regarding   providing that you
                                                                         your request.        may ask us to
                                                                                              cease to evaluate
                                                                                              your GRAS notice.
170.265(c).......................  170.36(f)(2)(iii)..             N/A  If circumstances     Clarifies that we
                                                                         warrant, we will     may send a
                                                                         send you a           subsequent letter,
                                                                         subsequent letter    in addition to
                                                                         about the notice.    specifying under
                                                                                              the public
                                                                                              disclosure
                                                                                              provisions of the
                                                                                              rule that such a
                                                                                              letter would be
                                                                                              readily available
                                                                                              to the public (see
                                                                                              Sec.
                                                                                              170.275(b)(2)).
----------------------------------------------------------------------------------------------------------------

A. Filing Decision

    (Comment 85) One comment asks for greater refinement, clarity, and 
transparency when we decline to file a GRAS notice. Some comments ask 
us to communicate any questions or concerns that could be quickly 
addressed upon submission of a GRAS notice. Another comment asks us to 
use specific criteria for a ``decline to file'' determination when 
format and general categories are adequate. Another comment states that 
an explicit process for how we will make a filing decision need not be 
detailed ``in the public domain'' even though it would be beneficial to 
the notifier.
    Another comment asks us to specify the criteria that we use to 
decide to provide verbal feedback to a notifier (e.g., by telephone) 
rather than send the notifier a letter informing the notifier that we 
have declined to file a submission as a GRAS notice. This comment 
expresses concern that our refusal to explain the problem in a letter 
could be interpreted to mean that we have safety concerns. This comment 
asserts that a process in which we neither provide specific guidance, 
nor provide written feedback, when we decline to file a submission as a 
GRAS notice would both discourage voluntary submissions of GRAS 
conclusions from industry and conflict with GAO's recommendations (in 
their 2010 report) that we should take steps to increase our awareness 
of independent conclusions of GRAS status.
    (Response 85) These comments raise a number of issues regarding the 
importance of a written communication from us to a notifier when we 
decline to file a submission as a GRAS notice, including transparency 
and the potential that lack of a written explanation for why we 
declined to file

[[Page 55013]]

a submission as a GRAS notice could lead to suppositions, such as 
whether we have safety concerns. To address these issues, the final 
rule provides that if we do not file a submission as a GRAS notice, we 
will send the notifier a letter that informs the notifier of that fact 
and provides our reasons for not filing the submission as a GRAS notice 
(see Sec.  170.265(a)(3)). We would not place that letter ``in the 
public domain'' by including it in our publicly available Inventory of 
GRAS Notices, because the submission had not been filed as a GRAS 
notice and, thus, there would be no entry where we would place the 
letter. However, whether the letter would be releasable in response to 
a FOIA request would be a case-by-case determination based on the 
contents of the letter and the provisions of part 20.
    We are not specifying in the regulatory text the factors that could 
lead us to decline to file a submission as a GRAS notice, because the 
factors that apply to a particular GRAS notice may be very specific to 
that notice. Importantly, a GRAS notice presents an opportunity for a 
notifier to inform us about a conclusion of GRAS status rather than an 
opportunity for a notifier to test a hypothesis that there is a 
sufficient basis to reach a conclusion of GRAS status. If our initial 
evaluation of a submission demonstrates that it lacks much of the 
required data and information necessary for us to evaluate the 
notifier's view that the notified substance is GRAS under the 
conditions of its intended use, our current practice is to decline to 
file it as a GRAS notice (see Sec.  170.265(a)(3)). By declining to 
file a submission as a GRAS notice, we would both conserve our own 
resources and provide the notifier an opportunity to submit a new GRAS 
notice, that contains appropriate data and information and an adequate 
narrative, rather than move forward knowing that an amendment necessary 
for us to evaluate the notifier's view that the notified substance is 
GRAS under the conditions of its intended use would be so substantive 
as to make the original submission largely irrelevant. For additional 
examples of factors we have considered in determining whether to file a 
submission as a GRAS notice, see the examples we provided in the 2010 
notice (75 FR 81536 at 81541), the discussion of filing decisions in 
section III.K of CFSAN's 2010 experience document (Ref. 18), Response 
48, and Response 70. As discussed in Response 152, CVM intends to 
consider the same factors that CFSAN considers regarding whether to 
file a submission as a GRAS notice.
    (Comment 86) In the 2010 notice, we explained that we may decide to 
respond to a submission as general correspondence, rather than file it 
as a GRAS notice, if the subject of the submission is: (1) Already 
authorized for use under our regulations; or (2) a mixture of 
substances that are already authorized for use under our regulations. 
One comment asks us to clarify how we would determine that the use of a 
substance is authorized for use under our regulations, with respect to 
the similarity of factors such as: (1) The substance; (2) the intended 
conditions of use of the substance, including food categories and use 
levels; and (3) the manufacturing process.
    (Response 86) We decline this request because it is overly broad. 
We do not have a ``formula'' that would apply in all circumstances. 
Just as the factors that apply to a particular GRAS notice may be very 
specific to that notice, the factors that would apply in determining 
whether the intended conditions of use of a notified substance are 
already authorized by our regulations may be very specific to that 
substance. However, with regard to similarities in the manufacturing 
process, we likely would apply the same factors that we have advised 
industry to apply when assessing the effects of significant 
manufacturing process changes on the safety and regulatory status of 
food ingredients (Ref. 6).
    We note that we also may decide to respond to a submission as 
general correspondence, after communicating with the submitter as 
appropriate, rather than file it for evaluation as a GRAS notice, if 
the subject of the submission is: (1) Already the subject of a GRAS 
notice, and we have responded to that GRAS notice with a ``no questions 
letter''; or (2) a mixture of substances that already are the subject 
of GRAS notices, and we have responded to those GRAS notices with ``no 
questions letters.'' In contrast to the statutory provisions for the 
FCN program (section 409(h) of the FD&C Act), there is no provision in 
the FD&C Act providing exclusivity for a notifier for the use of a 
substance on the basis that it is GRAS under the conditions of its 
intended use.
    (Comment 87) One comment asks us to conduct a preliminary 
evaluation of a GRAS notice to determine whether the notice appears to 
be inadequate because the intended conditions of use of the notified 
substance raise ``general policy'' issues.
    (Response 87) It is not clear what the comment means by ``general 
policy'' issues. However, we note that we would not file a submission 
as a GRAS notice if the intended conditions of use of the notified 
substance are not eligible for classification as GRAS because, for 
example, the intended conditions of use are excepted from the 
definition of ``food additive'' in section 201(s) of the FD&C Act (and 
thus, from the GRAS provision included in that definition of ``food 
additive''). See, for example, the exception for a color additive in 
section 201(s)(3) of the FD&C Act, for a dietary ingredient intended 
for use in a dietary supplement in section 201(s)(6) of the FD&C Act, 
and for a new animal drug in section 201(s)(5) of the FD&C Act.
    (Comment 88) Some comments ask us to contact the notifier when our 
initial evaluation of a GRAS notice raises questions, and provide the 
notifier with an opportunity to withdraw the notice without prejudice 
before we begin a substantive evaluation of the notice.
    (Response 88) We agree that our decision to not file a submission 
as a GRAS notice would be without prejudice to a future submission of a 
GRAS notice for the notified substance. However, see Response 70, 
Response 112, and the discussion in the 2010 notice at 75 FR 81536 at 
81539. Just as a filed GRAS notice is available for public disclosure 
subject to the procedures established in part 20, a submission that you 
send to us is a record that is available for public disclosure subject 
to the procedures established in part 20, regardless of whether we file 
that submission as a GRAS notice. Thus, you cannot ``withdraw'' a 
submission from our files after you send it to us.
    (Comment 89) One comment asks whether ``substantial equivalence'' 
considerations are linked to ``decline to file'' decisions or play a 
dominant role in ``decline to file'' decisions. This comment also asks 
us to issue a letter to the notifier explaining the basis for a 
``decline to file'' decision if ``substantial equivalence'' is the 
reason.
    (Response 89) As discussed in section IV.N of CFSAN's 2010 
experience document (Ref. 18), several GRAS notices filed during the 
Interim Pilot program relied, in part, on the concept of ``substantial 
equivalence''; in each of the listed examples CFSAN had no questions 
about the notifier's conclusion of GRAS status. As discussed in 
Response 21, whether, and to what extent, similarity between two 
substances could support a conclusion of GRAS status depends on many 
situation-specific variables. Thus, it would be the complete evaluation 
process, rather than the initial evaluation that we conduct as part of 
a filing decision, that would determine whether a GRAS notice that 
relies on the concept of ``substantial equivalence''

[[Page 55014]]

provides a basis for a conclusion of GRAS status. As discussed in 
Response 85, the final rule provides that if we do not file a 
submission as a GRAS notice, we will send the notifier a letter that 
informs the notifier of that fact and provide our reasons for not 
filing the submission as a GRAS notice (see Sec.  170.265(a)(3)); if 
problems with a notifier's use of the concept of ``substantial 
equivalence'' play a role in our decision to not file a submission as a 
GRAS notice, we intend to say so.

B. Our Response to a GRAS Notice

1. Administrative Content of Our Response to a GRAS Notice
    (Comment 90) Several comments address the administrative content of 
a letter that responds to a GRAS notice. In general, these comments ask 
us to include the following items in the response letter: (1) Name and 
address of the notifier; (2) the date of our receipt of the notice; (3) 
the common or usual name of the notified substance; and (4) the 
applicable conditions of use of the notified substance. One comment 
states that use of a standard format and language in our letters would 
be administratively efficient.
    (Response 90) We agree that a standard format and language in our 
letters would be administratively efficient and that the administrative 
features suggested by these comments are appropriate to include in our 
response letter. During the Interim Pilot program, we both developed a 
standard format and language for our response letters and included the 
administrative features suggested by these comments (see section 
III.H.1 of CFSAN's 2010 experience document (Ref. 18)). We intend to 
continue incorporating these features in letters issued under the final 
rule. However, as discussed in Response 51, the final rule requires 
that you provide the name of the notified substance, using an 
appropriately descriptive term, rather than the ``common or usual 
name'' of the notified substance (see Sec.  170.225(c)(3)). Therefore, 
CFSAN's response letters will include an appropriately descriptive term 
for the notified substance provided in a GRAS notice submitted to 
CFSAN. See section XXV.C regarding the name of the notified substance 
provided in a GRAS notice submitted to CVM.
2. Substantive Content of Our Response to a GRAS Notice
    (Comment 91) Several comments note that the proposed rule did not 
specify what we would say in a letter responding to a GRAS notice and 
ask us to include in the final rule the specific language for the 
response letter, particularly when we do not raise any questions about 
the notifier's conclusion of GRAS status. Some comments assert that a 
notifier who invests resources in a GRAS notice deserves a response 
that is standardized and predictable and will not change as personnel 
changes occur.
    (Response 91) See table 1. During the Interim Pilot program we 
developed three categories of response letter: (1) ``No questions 
letter''; (2) ``insufficient basis letter''; and (3) ``cease to 
evaluate letter.'' As discussed in sections IV.H.1 through IV.H.7 of 
CFSAN's 2010 experience document (Ref. 18), these letters include some 
standard information that is consistent across those letters, such as 
opening and closing paragraphs using a standard format, and 
administrative information (e.g., the date of our receipt of the GRAS 
notice). They also include unique features that depend upon the 
circumstances, such as labeling issues and whether the use of the 
substance could require a color additive listing. The content of the 
three categories of response letter has evolved over time, and may 
continue to evolve. In addition, it is possible that in the future a 
response to a GRAS notice may not fit squarely within one of the 
current categories of response letter. Therefore, the final rule 
continues to specify that we will respond to a GRAS notice but does not 
specify any detail about the nature of the response.
    (Comment 92) Several comments address the content of a ``no 
questions letter.'' These comments ask that a ``no questions letter'' 
be clear and definitive, provide clear assurance that we recognize the 
GRAS status of the substance under the conditions of its intended use, 
have some regulatory significance, and be as affirmative as possible. 
Some of these comments note that our statements in the proposed rule 
(62 FR 18938 at 18950) indicated that we would evaluate a GRAS notice 
to determine whether there is a sufficient basis for the notifier's 
conclusion of GRAS status and suggest that our response to a GRAS 
notice could reflect those statements. Comments also suggest the 
following specific statements that could be included in a ``no 
questions letter'':
     ``FDA at this time does not question your determination 
that the notified use(s) of this substance is (are) Generally 
Recognized as Safe.''
     ``The Agency finds that there is substantial evidence 
supporting both the safety of the intended uses of the substance and 
the fact that this safety is generally known and accepted by qualified 
experts.''
     ``The notice provides a sufficient basis for the 
notifier's determination that the substance is GRAS for its intended 
use.''
    (Response 92) See table 1 for the typical text of a ``no questions 
letter'' that we issued during the Interim Pilot program. At this time, 
we intend to continue including such text in our ``no questions 
letters.'' We agree that the regulatory significance of a ``no 
questions letter'' should be clear. As shown in table 1, during the 
Interim Pilot program a typical ``no questions letter'' made clear 
that: (1) It is the information that is provided by the notifier that 
forms the basis for our response, and that the notifier (rather than 
FDA) is responsible for the conclusion of GRAS status; and (2) our 
response must be considered in context based on the knowledge and 
information available to us at a point in time, because scientific 
knowledge and information about a particular ingredient can evolve and 
sometimes change over time.
    The typical text of a ``no questions letter'' issued during the 
Interim Pilot program is similar to the specific suggestion of one 
comment (i.e., FDA at this time does not question your determination 
that the notified use of this substance is GRAS), except that under the 
final rule we will use the term ``conclusion'' rather than 
``determination.'' We disagree that a ``no questions letter'' should 
state that we ``find'' that there is substantial evidence supporting 
both the safety of the intended conditions of use of the notified 
substance and the fact that this safety is generally known and accepted 
by qualified experts; a GRAS notice reflects the conclusion of the 
notifier, not a finding by FDA. Likewise, we disagree that a ``no 
questions letter'' should state that a notice ``provides a sufficient 
basis'' for the notifier's conclusion that the notified substance is 
GRAS under the conditions of its intended use; the phrase ``providing a 
sufficient basis'' would imply that we are taking responsibility for 
the notifier's conclusion of GRAS status.
    As discussed in Response 41, we are replacing the term 
``determination'' with ``conclusion,'' and referring to a ``conclusion 
of GRAS status'' rather than to a ``GRAS determination,'' throughout 
the regulatory text for the GRAS notification procedure. We intend to 
modify the typical text of our response letters to refer to the 
``notifier's conclusion'' (rather than the ``notifier's 
determination'') in letters issued under the final rule (see table 20). 
We also

[[Page 55015]]

intend to specify that we have not affirmed the GRAS status of the 
notified substance under the conditions of its intended use, rather 
than to specify that we have not made our own determination. However, 
as noted in section II.B, we intend to adapt our practices, consistent 
with the provisions of this rule, as circumstances warrant and as 
necessary to administer the GRAS notification program consistent with 
appropriate public health policy, current scientific information, our 
available resources, and the scientific and regulatory issues raised by 
specific GRAS notices. Thus, the text shown in table 20 is for 
illustrative purposes only and could evolve over time.

  Table 20--Categories of Letters Responding to a GRAS Notice Under the
                               Final Rule
------------------------------------------------------------------------
                                      Typical text of for a response as
    Category of response letter      modified to incorporate terms used
                                                 in the rule
------------------------------------------------------------------------
``No questions letter''...........  Based on the information provided by
                                     the notifier, as well as other
                                     information available to FDA, the
                                     Agency has no questions at this
                                     time regarding the notifier's
                                     conclusion that the notified
                                     substance is GRAS under the
                                     conditions of its intended use. By
                                     this letter, however, the Agency
                                     has not affirmed the GRAS status of
                                     the notified substance under the
                                     conditions of its intended use in
                                     accordance with 21 CFR 170.35. As
                                     always, it is the continuing
                                     responsibility of the notifier to
                                     ensure that food ingredients that
                                     the firm markets are safe, and are
                                     otherwise in compliance with all
                                     applicable legal and regulatory
                                     requirements.
``Insufficient basis letter''.....  FDA has evaluated the data and
                                     information in the GRAS notice as
                                     well as other available
                                     information. The notice does not
                                     provide a sufficient basis for a
                                     conclusion that the notified
                                     substance is GRAS under the
                                     conditions of its intended use.
``Cease to evaluate letter''......  In correspondence dated [month, day,
                                     year], you asked that we cease to
                                     evaluate your GRAS notice. We
                                     ceased to evaluate your GRAS
                                     notice, effective the date we
                                     received your correspondence.
------------------------------------------------------------------------

    (Comment 93) One comment suggests that a written response need not 
assess the quality of the submission but rather could acknowledge 
whether the notice was complete in addressing all key issues.
    (Response 93) We disagree that we could acknowledge whether a 
notice is ``complete'' without assessing the quality of the submission. 
Providing a basis for whether the data and information regarding the 
safety of a substance under the conditions of its intended use satisfy 
GRAS criteria is not a matter of whether there is ``something behind 
each tab.'' It would not be appropriate, for example, for us to 
acknowledge that a GRAS notice is ``complete'' because it included the 
narrative required by Part 6 of a GRAS notice without assessing the 
adequacy of the narrative. Whether a notice is ``complete'' in 
addressing all key issues depends on the nature and quality of the 
submitted data and information.
    (Comment 94) Some comments ask that a ``no questions letter'' 
qualify that we have not affirmed that the intended conditions of use 
of the notified substance are GRAS. Other comments ask that a ``no 
questions letter'' qualify that we have not conducted a substantive 
review.
    (Response 94) We agree that a ``no questions letter'' should be 
clear that we have not affirmed that the substance is GRAS under the 
conditions of its intended use. See table 20.
    However, we disagree that a ``no questions letter'' should state 
that we did not conduct a substantive review of the GRAS notice. See 
Response 25. Our evaluation of a GRAS notice is a substantive 
evaluation of the notifier's basis for concluding that the intended 
conditions of use of the notified substance are safe and the criteria 
for GRAS status are satisfied. In addition, as circumstances warrant, 
we evaluate information that is not included in the notice but is 
otherwise available to us (see section IV.G of CFSAN's 2010 experience 
document (Ref. 18)).
    (Comment 95) Some comments ask that a ``no questions letter'' 
include a positive statement that we have not identified a problem with 
the notice because finished food producers have been reluctant to use a 
substance without such documentation. These comments both assert that 
the only alternative available to manufacturers whose customers require 
such a positive statement would be to seek food additive approval for 
an ingredient and maintain that such approval is unnecessary from a 
legal perspective.
    (Response 95) Consistent with the request of these comments, we 
intend to continue including a statement that we ``have no questions at 
this time'' (see table 1 and table 20). Whether a manufacturer's 
customer requires a regulation prescribing the conditions under which a 
substance may be safely used in food, when there is a basis for 
concluding that the substance is GRAS under the conditions of its 
intended use, is a business matter between the manufacturer and the 
customer. If the manufacturer submits a food additive petition and we 
find, based on the data and information submitted in the petition, that 
the intended conditions of use of the substance are safe, we would 
issue a regulation prescribing the conditions under which the food 
additive may be safely used.
    (Comment 96) Several comments address the specific content of an 
``insufficient basis letter'' and ask us to be specific about any 
deficiencies that we identify in the notice. Some comments assert that 
an ``insufficient basis letter'' must clearly distinguish between 
deficiencies that relate to safety and those that relate to a technical 
matter, such as the level of the substance that is needed to accomplish 
the intended technical effect. One comment asks us to include in the 
final rule guidelines that articulate clear standards for issues that 
are of sufficient magnitude to result in an ``insufficient basis 
letter.''
    (Response 96) We agree that we should be specific about identified 
problems and distinguish between circumstances that lead to an 
insufficient basis letter. Our experience during the Interim Pilot 
program demonstrates that we have done so, and we intend to continue 
this practice under the final rule. For example, as discussed in 
sections IV.H.4 and IV.H.7 of CFSAN's 2010 experience document (Ref. 
18), we have issued an insufficient basis letter in cases where health 
effects seen in toxicological or clinical studies were not adequately 
explained or because the notice did not describe adequate toxicological 
studies; when the notice contained insufficient information about 
dietary exposure; when the notice contained insufficient information to 
adequately identify the substance; when the notice contained 
insufficient information to satisfy the standard for demonstration of 
GRAS status through experience based on common use in food; and as a 
result of the regulatory framework associated with the substance. To 
date, we have not issued an insufficient basis letter solely as a 
result of insufficient

[[Page 55016]]

evidence regarding the level of the substance that is needed to 
accomplish the intended technical effect. However, CVM's experience 
document demonstrates that CVM has included lack of information 
regarding the intended technical effect as one of several reasons 
leading to an insufficient basis letter (Ref. 20). Some ``no questions 
letters'' issued by CFSAN have discussed the level of the substance 
that is needed to accomplish the intended technical effect, e.g., when 
CFSAN informed a notifier who received a ``no questions letter'' that 
FSIS needed information regarding the lowest level necessary for the 
substance to achieve its intended effect in meat, meat food product, or 
poultry product (see section III.L of CFSAN's 2010 experience document 
(Ref. 18)).
    Our experience during the Interim Pilot program demonstrates that 
whether a notice provides a sufficient basis for a conclusion of GRAS 
status is a case-by-case evaluation and that the circumstances vary. 
Therefore, we decline the request to specify standards for issues that 
are of sufficient magnitude to result in an ``insufficient basis 
letter.'' See sections IV.H.4 and IV.H.7 of CFSAN's 2010 experience 
document (Ref. 18) for information on specific GRAS notices that 
received an ``insufficient basis letter'' from CFSAN, and table 1 in 
CVM's experience document (Ref. 20) for information on GRAS notices 
that received an ``insufficient basis letter'' from CVM. Our letters 
responding to each of these GRAS notices describe the problems in more 
detail and are available on CFSAN's Web site (Ref. 46) and CVM's Web 
site (Ref. 47).
    (Comment 97) Some comments ask that an ``insufficient basis 
letter'' include a qualifying statement that we have not conducted a 
substantive review and have not concluded that the intended conditions 
of use of the notified substance are not GRAS. These comments assert 
that a response that does not include such a statement could have the 
practical effect of challenging the use of a substance in the absence 
of a threshold determination that the notified use is not GRAS.
    (Response 97) We disagree that an ``insufficient basis letter'' 
should state that we did not conduct a substantive review of the GRAS 
notice. See Response 25 and Response 94. Our evaluation of a GRAS 
notice is a substantive evaluation.
    The typical text of an ``insufficient basis letter'' specified that 
``the notice does not provide a sufficient basis'' for a determination 
that the notified substance is GRAS under the conditions of its 
intended use (see table 1), and we intend to continue including such 
text in letters issued under the final rule, modified to refer to a 
``conclusion'' of GRAS status rather than a ``determination'' of GRAS 
status (see table 20). This typical text addresses the adequacy of the 
notice rather than the regulatory status of the substance; consistent 
with the request of these comments, this text does not specify that we 
have concluded that the intended conditions of use of the notified 
substance are ``not GRAS.'' In several cases during the Interim Pilot 
program, a notifier who received an ``insufficient basis letter'' 
submitted a second GRAS notice and received a ``no questions letter'' 
in response to the second GRAS notice (see sections III.D and IV.K of 
the experience document (Ref. 18)). In these examples, CFSAN's response 
to the notifier's first GRAS notice made clear that the submitted 
notice did not provide a basis for a conclusion of GRAS status, but 
CFSAN had no questions about the basis for GRAS status provided by the 
second notice.
3. Our Consideration of a Timely Amendment
    As discussed in section XVIII.B, the rule provides that you may 
submit a timely amendment to your filed GRAS notice to update your GRAS 
notice or in response to a question from us (Sec.  170.260(a)). As a 
companion provision, the rule also provides that we will consider any 
timely amendment that you submit to a filed GRAS notice, to update your 
GRAS notice or in response to a question from us, before we respond to 
your notice based on our evaluation of your notice if we deem that 
doing so is feasible within the established timeframes (see Sec.  
170.265(a)(4)). If we deem that considering your amendment is not 
feasible within the established timeframes, we will inform you that we 
are not considering your amendment (see Sec.  170.265(a)(4)). We also 
will inform you that we are not considering your amendment if we have 
granted your request to cease to evaluate your notice (i.e., if we send 
you a ``cease to evaluate letter''). See Sec.  170.265(b)) and Response 
98 for the timeframe established in this rule for our response to your 
GRAS notice.
4. Timeframe for Our Response to a GRAS Notice
    (Comment 98) Several comments support retaining the proposed 90-day 
timeframe. According to these comments, a 90-day timeframe would 
provide an incentive for a manufacturer to submit a GRAS notice. One 
comment asserts that we should be held accountable to the proposed 90-
day timeframe, whereas another comment suggests that the proposed 90-
day timeframe provide a benchmark at which we should make the notifier 
aware of the current status of our evaluation of the notice even if we 
have not had sufficient time to completely review the safety of the 
notified substance.
    One comment that asks us to retain the proposed 90-day timeframe 
stresses that we should have flexibility to take additional time as 
needed. Another comment agrees that it would be appropriate for us to 
extend the evaluation period, provided we do so only in limited 
instances.
    One comment asserts that the requirements of the GRAS notification 
procedure are similar to the requirements of the GRAS affirmation 
petition process and questions whether we could respond to a GRAS 
notice within 90 days because we did not respond to a GRAS petition in 
such a short timeframe. One comment that stresses the importance of 
retaining a set evaluation timeframe suggests that the timeframe be 90-
180 days based on CFSAN's experience during the Interim Pilot program, 
and opposes a timeframe greater than 180 days. Other comments support a 
180-day timeframe because it would be realistic and reasonable, would 
be sufficient to resolve all of the issues raised by a GRAS notice with 
procedural fairness, and could be consistent and fair across both CFSAN 
and CVM.
    (Response 98) We are establishing a timeframe of 180 days from the 
date of filing for our response to a GRAS notice. We also are providing 
that we may extend the 180-day response timeframe by 90 days on an as 
needed basis; if we do so, we will inform you of the extension in 
writing as soon as practicable but no later than within 180 days of 
filing. (See the regulatory text of Sec.  170.265(b)(1) and (2)). We 
agree that the 180-day timeframe is realistic and reasonable, would be 
sufficient to resolve all of the issues raised by a GRAS notice with 
procedural fairness in most cases, and could be consistent and fair 
across both CFSAN and CVM.
    We disagree that we should establish a 90-day timeframe merely 
because we had proposed this timeframe before we gained experience with 
evaluating GRAS notices. As shown in section III.M of CFSAN's 2010 
experience document, less than 12 percent of the response letters CFSAN 
issued as of December 31, 2009, were sent within the proposed 90-day 
timeframe (Ref.

[[Page 55017]]

18). Importantly, section III.M of CFSAN's 2010 experience document 
also shows that in many cases a dialog between FDA and a notifier about 
scientific issues associated with a GRAS notice, with an ensuing 
amendment from the notifier, played a role in the timeframe for CFSAN's 
response to a GRAS notice. As discussed in the 2010 notice, several 
comments ask us to allow a notifier to address questions we have about 
a GRAS notice by submitting an amendment to the notice (see Issue 3a, 
75 FR 81536 at 81538), and the final rule expressly provides that you 
may submit an amendment to a filed GRAS notice before we respond to the 
notice (see Sec.  170.260(a)). Although we are including flexibility to 
take additional time as needed, our goal is to do so in only limited 
instances, such as when the intended conditions of use of the notified 
substance raise complex scientific issues.
    We have no basis to judge whether a 90-day timeframe, but not a 
180-day timeframe, would provide an incentive to a manufacturer to 
submit a GRAS notice. However, as noted in Response 24 CFSAN filed more 
than 600 GRAS notices during the time period 1998 through 2015, 
including 69 GRAS notices filed during 2014 and 51 GRAS notices filed 
during 2015, even though CFSAN rarely responded to a GRAS notice within 
90 days. We believe that the ongoing submission of GRAS notices is 
evidence that the 180-day timeframe that is consistent with our 
experience during the Interim Pilot program is not a disincentive to a 
manufacturer.
    We note that the procedural requirements of the GRAS notification 
procedure are very different from the procedural requirements of the 
GRAS affirmation petition process in that we respond to a GRAS notice 
by letter whereas we respond to a GRAS affirmation petition through 
rulemaking. As previously discussed (62 FR 18938 at 18941), the 
resource-intensive rulemaking process includes: (1) Publishing a filing 
notice in the Federal Register; (2) requesting comment on the 
petitioned request; (3) conducting a comprehensive review of the 
petition's data and information and comments received to the filing 
notice to determine whether the evidence establishes that the 
petitioned use of the substance is GRAS; (4) drafting a detailed 
explanation of why the use is GRAS (as opposed to simply being safe); 
and (5) publishing that explanation in the Federal Register. Therefore, 
we disagree with the perspective of one comment that our experience in 
responding to a GRAS affirmation petition should have any bearing on 
the determination of an appropriate timeframe for our response to a 
GRAS notice.
    (Comment 99) One comment expresses concern that a 90-day timeframe 
would be unrealistic unless we allocate additional resources to the 
program. This comment asks us to consider a process similar to the 
process for the FCN program, where there is a fixed review period 
during which we can ``object to'' a submitted notification. If we do 
not object within the review period or do not request an extension to 
the review period, a notification submitted to the FCN program is 
considered effective.
    (Response 99) We decline this request. We disagree that the GRAS 
notification procedure should be modeled after the FCN program. Unlike 
the GRAS notification procedure, the FCN program is a mandatory process 
for food contact substances under section 409(h) of the FD&C Act. 
Furthermore, the statute provides that the FCN program shall not 
operate unless it has certain appropriated funds. See section 
409(h)(5)(A)(i) of the FD&C Act and Sec.  170.104(c)(3). There are no 
similar statutory requirements applicable to our evaluation of the 
basis for a conclusion of GRAS status.
    (Comment 100) One comment asserts that we should respond to a GRAS 
notice within 90 days unless we identify a problem that warrants dialog 
with the notifier and an ensuing amendment.
    (Response 100) We disagree. The suggestion of this comment could 
lead to the unintended consequence of seeking unnecessary amendments 
merely to stay within an established timeframe. We believe it is more 
appropriate to establish a single timeframe that would broadly apply to 
all GRAS notices, with the potential to extend the timeframe on an as 
needed basis.
    (Comment 101) One comment asks us to stop the ``review clock'' when 
we inform a notifier that we have questions about a notice and then 
restart the ``review clock'' upon receipt of an amendment that answers 
our questions.
    (Response 101) We decline this request. We acknowledge that there 
could be an advantage to such a process, because stopping the review 
clock would reduce the time pressures on our staff. However, the role 
of an amendment is to clarify questions that we have about your 
conclusion of GRAS status rather than to substantively amend the GRAS 
notice. A process in which we stop and start a review clock implies 
that the timeframe for you to submit an amendment could be so long as 
to significantly impact our ability to respond within an established 
timeframe. Rather than a process in which we stop and start a review 
clock on a particular GRAS notice, we have provided that you may ask us 
to cease to evaluate a GRAS notice when your preparation of an 
amendment would impact our ability to respond within 180 days.
5. Responding to a GRAS Notice in All Circumstances
    In the proposed rule, we noted that the GRAS notification procedure 
could be structured so that we respond only when we question the GRAS 
status of the intended use of the substance and requested comment on 
whether we should, in all cases, provide a notifier with a letter at 
the conclusion of our evaluation of a notice (62 FR 18938 at 18951).
    (Comment 102) Several comments agree with our discussion in the 
proposed rule that a written response from us would give manufacturers 
an incentive to notify us of their conclusions of GRAS status; these 
comments recommend that we respond in writing in all circumstances. 
Other comments suggest that we limit our response to circumstances in 
which we identify a problem with a notice because such a limitation 
would make it easier for us to respond within the proposed 90-day 
timeframe. One comment expresses concern that a written response could 
create a misperception that we had undertaken an independent review of 
the data described in the GRAS notice; to prevent this misperception, 
this comment suggests that we respond in writing only if we find a 
problem with the notice.
    (Response 102) We acknowledge that limiting our response to 
circumstances in which we identify a problem with a notice would reduce 
the number of letters that we write. However, we believe that it is 
important to publicly document our evaluation of the GRAS notice in 
light of all the comments submitted to this rulemaking. (See, e.g., 
Comment 25 and the comments we discuss in section VII.C). In addition, 
in our experience it is the process of evaluating a submission and 
reaching a decision about whether the notice provides a basis for a 
conclusion of GRAS status, rather than the process of drafting and 
issuing a letter, that requires the most time.
    We acknowledge the potential that a ``no questions letter'' could 
be misinterpreted, e.g., to mean that FDA, rather than the notifier, 
had reached a conclusion of GRAS status. To mitigate the potential for 
such misinterpretation, the typical text of our response letters

[[Page 55018]]

issued during the Interim Pilot program referred to the notifier's 
determination and stated that we have not made our own determination 
regarding the GRAS status of the subject use of the notified substance 
(see table 1). We intend to continue including such typical text in 
letters issued under the final rule, modified as shown in table 20.
    (Comment 103) One comment suggests that we respond in writing only 
at the notifier's request.
    (Response 103) We decline this suggestion, which is contrary to 
emphasis that the rule places on the notifier's acceptance of 
responsibility for a conclusion of GRAS status (see the discussion at 
62 FR 18938 at 18953).
    (Comment 104) One comment asserts that a letter acknowledging 
receipt of a GRAS notice would constitute a form of response. Another 
comment suggests that a letter acknowledging receipt of a GRAS notice 
state whether the notice meets the listed requirements for a GRAS 
notice, eliminating the need for a second letter responding to the 
notice when we complete our evaluation. This comment asserts that a 
second letter would be unnecessary for two reasons. First, the notifier 
has accepted full responsibility for the conclusion of GRAS status and 
does not require premarket approval from us. Second, under the terms of 
the rule a notifier must agree to make all data and information 
available to us.
    (Response 104) The final rule provides that we will inform you of 
the date on which we filed your notice rather than the date on which we 
received it, as we had proposed. We disagree that a letter informing 
you of the date of filing in any way responds to a GRAS notice or 
should state whether the notice meets the listed requirements for a 
GRAS notice. As discussed in Response 93, we cannot acknowledge whether 
a notice ``meets the listed requirements'' without assessing the 
quality of the submission, which we do during the evaluation that 
follows filing the submission as a GRAS notice.
    We acknowledge that submitting a GRAS notice means that a notifier 
has accepted full responsibility for the conclusion of GRAS status. We 
also acknowledge that the use of a GRAS substance is not subject to our 
premarket review. However, we disagree that a relevant factor in 
determining whether we should respond to a notifier is the notifier's 
agreement to make all data and information available to us if we 
question whether the notice provides an adequate basis for a conclusion 
of GRAS status. A GRAS notice presents an opportunity for you to inform 
us about your conclusion of GRAS status rather than an opportunity for 
you to test a hypothesis that there is a sufficient basis to reach a 
conclusion of GRAS status.
    (Comment 105) One comment suggests that we issue a written response 
only when we have reached a conclusion regarding safety.
    (Response 105) This comment may have misunderstood the proposed 
notification procedure. Under the notification procedure, you analyze 
the available data and information and reach a conclusion about whether 
the notified substance is safe under the conditions of its intended use 
and whether there is a basis to conclude that the criteria for GRAS 
status are satisfied. We evaluate your conclusions regarding the 
available data and information. During the Interim Pilot program, the 
typical text of a ``no questions letter'' stated that we had not 
reached our own determination regarding the GRAS status of the notified 
substance under the conditions of its intended use (see table 1).
    To the extent that the comment is suggesting that we issue an 
``insufficient basis letter'' when the problem with the notice relates 
to safety, but not to general recognition, we disagree. It would be 
inconsistent with the legal basis of the GRAS standard for us to only 
focus on safety, and we did not do so during the Interim Pilot program. 
(See section III.A.3 of CFSAN's 2010 experience document (Ref. 18), 
where CFSAN identifies ``insufficient basis letters'' in which CFSAN 
had questions about whether there was general recognition of safety.)

C. Additional Correspondence as Circumstances Warrant

    (Comment 106) One comment expresses the view that a ``no questions 
letter'' should not affect our ability to change our position if 
additional information indicates that the use of the substance raises 
any safety concerns.
    (Response 106) We agree, and the final rule expressly provides that 
we will send the notifier a subsequent letter about the notice if 
circumstances warrant (see Sec.  170.265(c)). The circumstances may not 
relate to safety. As discussed in section IV.J of CFSAN's 2010 
experience document (Ref. 18), as of December 31, 2009, none of the 
subsequent letters CFSAN issued during the Interim Pilot program 
reflected a change in CFSAN's position and several addressed issues 
other than the safety of the use of the substance. For example, CFSAN 
issued subsequent letters that: (1) Clarified the intended conditions 
of use; (2) clarified that the term CFSAN used to refer to the notified 
substance for the purpose of the letter should not be considered an 
endorsement of that term for the purpose of declaring the substance in 
the ingredient statement of food products; (3) clarified FSIS' position 
regarding the use of the notified substance in meat, meat food product 
or poultry product; and (4) corrected a mistake in the original 
response. CFSAN also sent a subsequent letter as an administratively 
efficient mechanism of responding to a notifier who provided CFSAN with 
information supporting a conclusion that an additional use of the 
notified substance satisfied GRAS criteria.
    In addition, CFSAN has issued a subsequent letter when CFSAN's 
first letter was an ``insufficient basis letter'' rather than a ``no 
questions letter.'' For example, CFSAN did so when a notifier who 
received an ``insufficient basis letter'' submitted a new GRAS notice 
that did not address the questions CFSAN raised in the ``insufficient 
basis letter.'' CFSAN also did so when a notifier who received an 
``insufficient basis letter'' submitted a supplement to its original 
GRAS notice rather than submit a new GRAS notice. See section IV.J of 
CFSAN's 2010 experience document (Ref. 18).

D. Procedures if a Notifier Disagrees With Our Response

    In the proposed rule, we explained that there are existing 
processes that we considered would be appropriate for a notifier to use 
to engage us if the notifier disagreed with our response (see 62 FR 
18938 at 18952 and table 21). We also noted that any person with 
concerns about our response to a GRAS notice may contact our Office of 
the Chief Mediator and Ombudsman; that office works on resolving issues 
and conflicts that arise in any FDA component.

  Table 21--Existing Procedures in Our Regulations That Can Apply if a
          Notifier Disagrees With Our Response to a GRAS Notice
------------------------------------------------------------------------
   Regulatory section  (Sec.   )                 Description
------------------------------------------------------------------------
10.25.............................  Initiation of administrative
                                     proceedings.
10.33.............................  Administrative reconsideration of
                                     action.
10.65.............................  Meetings and correspondence.
10.75.............................  Internal agency review of decisions.
------------------------------------------------------------------------

    (Comment 107) Several comments express concern that the processes 
discussed in the proposed rule would be

[[Page 55019]]

available only after we sent, and made readily accessible to the 
public, an ``insufficient basis letter.'' Other comments express 
concern about the practical effect of an ``insufficient basis letter'' 
on the notifier's ability to market a notified substance while the 
notifier is seeking review of our evaluation. Some comments ask that 
our letter be ``stayed'' until any problems that we identified in our 
response to the notice are resolved under such a process.
    (Response 107) We acknowledge the concerns expressed in these 
comments but are making no changes to the rule to address these 
concerns. One of the underpinnings of the GRAS notification procedure 
is that making our response readily accessible to the public will 
properly underscore your responsibility for the conclusion of GRAS 
status (62 FR 18938 at 18953). As discussed in Response 104, a GRAS 
notice presents an opportunity for you to inform us about your 
conclusion of GRAS status rather than for you to test a hypothesis that 
there is a sufficient basis to reach a conclusion of GRAS status. If we 
send you an ``insufficient basis letter,'' we advise you to carefully 
consider whether marketing the notified substance would be lawful. 
``Staying'' an ``insufficient basis letter'' informing you that there 
may not be a legal basis to market the notified substance, e.g., so 
that you could market the substance while you are working to resolve 
the issues that led us to send you an ``insufficient basis letter'', 
would not change the legal status of the notified substance.
    (Comment 108) Several comments assert that the processes we had 
identified in the proposed rule are cumbersome and do not provide 
manufacturers with a clear framework or timeline for responding to our 
questions or concerns. In general, these comments ask us to include in 
the final rule a prompt, fair, and effective process that would be 
specific to the GRAS notification procedure. A few comments suggest 
that such an appeal mechanism also apply to subsequent correspondence 
from us about a GRAS notice.
    Some comments provide specific suggestions for how an appeals 
mechanism specific to the GRAS notification procedure could work, e.g., 
by specifying that a notifier may submit additional data and 
information for our evaluation, or by providing for an independent 
advisory committee or an FDA-certified third-party review organization 
to review the matter and issue an opinion. Some comments suggest that 
an appeals mechanism specify appeal steps and stressed the importance 
of timeframes for decisions by our officials.
    (Response 108) We decline the request to include in the final rule 
an appeals process that would be specific to the GRAS notification 
procedure. We agree that the process to contact us about a response to 
a GRAS notice should be clear. However, we disagree that the existing 
procedures are unclear, because our regulations fully describe these 
procedures (Sec. Sec.  10.25, 10.33, 10.65, and 10.75). We acknowledge 
that the listed procedures do not provide a clear timeline and that 
some of the listed procedures (e.g., Sec. Sec.  10.25 and 10.33) are 
more cumbersome than others (such as requesting a meeting under Sec.  
10.65 or requesting internal Agency review of a decision under Sec.  
10.75). In practice during the Interim Pilot program, several notifiers 
who received an ``insufficient basis letter'' took steps to resolve our 
questions and subsequently submitted a new GRAS notice or a food 
additive petition (see the discussion in section III.K of CFSAN's 2010 
experience document (Ref. 18)). Given the variety of circumstances that 
could lead to an ``insufficient basis letter,'' we believe that taking 
steps to resolve our questions, and submitting a new GRAS notice or a 
food additive petition, can be an efficient mechanism for you to use in 
lieu of the procedures we discussed in the proposed rule. Doing so 
would be consistent with the suggestion of some comments that an 
appeals mechanism specific to the GRAS notification procedure could 
include submission of additional data and information for our 
evaluation, except that the data and information would be submitted in 
a new GRAS notice rather than be an ``appeal'' to the GRAS notice that 
received an ``insufficient basis letter.''
    We do not have an FDA-certified third-party review organization 
that could review the matter and issue an opinion. We disagree that 
convening an independent advisory committee would be appropriate as an 
additional, routine mechanism to appeal an ``insufficient basis 
letter.'' Under our regulations in part 14 governing advisory 
committees, it would be FDA--not a notifier--who decided to convene a 
meeting of our Food Advisory Committee about the use of a substance in 
food. We would have little basis to convene a meeting of our Food 
Advisory Committee as part of an appeal to an ``insufficient basis 
letter'' unless the notifier had first used one or more of the 
procedures listed in table 21.

XX. Coordinating Our Evaluation of a GRAS Notice With FSIS

    In the 2010 notice, we described some of the terms of a MOU, 
between FDA and USDA's FSIS, that provides for a coordinated evaluation 
process with FSIS when the intended conditions of use of a notified 
substance include use in a product or products subject to regulation by 
USDA under statutes that it administers (75 FR 81536 at 81541-81542). 
We also asked for comment on whether to make our coordinated evaluation 
process with FSIS explicit in the final rule (see Issue 13, 75 FR 81536 
at 81541-81542). In 2015, we amended that MOU to include more details 
about the procedures FDA and FSIS will follow to do so (Ref. 36).
    (Comment 109) Comments support coordinating our evaluation of GRAS 
notices with FSIS and including the procedure for this coordination in 
the final rule. Comments also support requiring the notifier to provide 
an additional paper copy that we would send to FSIS as part of this 
procedure.
    (Response 109) The final rule includes procedures for coordinating 
our evaluation of a GRAS notice with FSIS when the use of the notified 
substance includes use in a product or products subject to regulation 
by FSIS under statutes that it administers. (See Sec.  170.270). If you 
send your GRAS notice on paper, a single paper copy is sufficient; we 
would send FSIS an electronic copy. (See Sec.  170.210(b) and Response 
46). Under Sec.  170.270(d), we will inform you of the advice we 
receive from FSIS in the letter we send you in accordance with Sec.  
170.265(b)(1), as appropriate. By ``as appropriate,'' we mean that in 
most circumstances we do not intend to provide advice from FSIS about 
the use of the notified substance when we respond with an 
``insufficient basis letter,'' because doing so has the potential to 
create confusion about the regulatory status of a use of the notified 
substance in products subject to regulation by FSIS. Likewise, we do 
not intend to provide advice from FSIS about the use of the notified 
substance when we respond with a ``cease to evaluate letter'' and, 
thus, the procedure described in Sec.  170.270(d) does not specify that 
we will inform you of the advice we receive from FSIS in a letter we 
send you in accordance with Sec.  170.265(b)(3).
    As we noted in section XII.I, this rule does not specify the data 
and information that FSIS will need to evaluate whether the intended 
use of the notified substance complies with applicable statutes and 
regulations, or, if not, whether the use of the substance

[[Page 55020]]

would be permitted in products under FSIS jurisdiction under specified 
conditions or restrictions. We recommend that you contact the 
appropriate staff at FSIS regarding the data and information that FSIS 
will need you to provide. FSIS provides contact information for its 
programs on its Web site (Ref. 41).
    (Comment 110) One comment agrees that the evaluation of a GRAS 
notice should be coordinated between FDA and FSIS when ``animal 
products'' are involved. This comment notes that FSIS does not 
currently review the use of a substance intended for use in animal food 
and recommends that CVM be involved in the safety review process of the 
notice if the notice involves a substance to be used in animal food.
    (Response 110) This comment appears to have misunderstood the 
purpose of the coordinated evaluation process that we discussed in the 
2010 notice. That process applies to the use of a substance in human 
food products, such as meat and poultry products, that are subject to 
regulation by USDA and would be evaluated by CFSAN; it does not apply 
to the use of a substance in animal food. FSIS, under the statutes it 
administers, does not evaluate a substance intended for use in animal 
food and, thus, the process would not apply to a GRAS notice received 
by CVM. See also Response 45.

XXI. Comments on Public Disclosure of a GRAS Notice

    We proposed that a ``GRAS exemption claim'' would be immediately 
available for public disclosure on the date the notice is received. All 
remaining data and information in the notice would be available for 
public disclosure, in accordance with part 20, on the date the notice 
is received (proposed Sec.  170.36(f)(1)). We also proposed that the 
following information would be readily accessible for public review and 
copying: (1) A copy of the ``GRAS exemption claim'' (proposed Sec.  
170.36(f)(2)(i)); (2) a copy of our response letter (proposed Sec.  
170.36(f)(2)(ii)); and (3) a copy of any subsequent letter we issued 
regarding the notice (proposed Sec.  170.36(f)(2)(iii)). In the 2010 
notice, we noted that although the decision to submit a GRAS notice 
would be voluntary, the provisions governing the GRAS notification 
procedure, including the information to be submitted, would be 
mandatory (75 FR 81536 at 81540).
    In the final rule, you include the signed statements that we 
proposed be in a ``GRAS exemption claim'' in Part 1 of your GRAS 
notice, and we no longer use the term ``GRAS exemption claim'' (see 
Response 42). As discussed in Response 50, the final rule stipulates 
that you must not include any information that is trade secret or 
confidential commercial information in Part 1 of your GRAS notice (see 
Sec.  170.225(b)).
    In the following sections, we discuss comments on the proposed 
requirements for public disclosure of a GRAS notice. After considering 
these comments, we are establishing requirements applicable to the 
public disclosure of a GRAS notice as shown in table 22, with 
editorial, clarifying, and conforming changes as shown in table 29. 
(See Sec.  170.275.) Table 22 identifies changes we made relative to 
the proposed rule or the description in the 2010 notice other than the 
editorial, clarifying, and conforming changes shown in table 29 and the 
additional editorial changes associated with the redesignation of 
proposed Sec.  170.36(f) as Sec.  170.275.

                  Table 22--Final Requirements Applicable to Public Disclosure of a GRAS Notice
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No. in                          clarifying, and
    Final designation in  the       designation in the     the 2010         Description      conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice                              relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                               the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.275(a)(1)....................  N/A................             N/A  The data and         Clarify that a
                                                                         information in a     notice is
                                                                         GRAS notice          considered a
                                                                         (including data      mandatory, rather
                                                                         and information      than voluntary,
                                                                         submitted in any     submission for
                                                                         amendment or         purposes of their
                                                                         supplement to your   status under the
                                                                         GRAS notice or       FOIA and part 20.
                                                                         incorporated into
                                                                         your GRAS notice)
                                                                         are considered a
                                                                         mandatory, rather
                                                                         than voluntary,
                                                                         submission for
                                                                         purposes of its
                                                                         status under the
                                                                         FOIA and part 20.
170.275(a)(2)....................  170.36(f)(1).......             N/A  The data and         Clarify that part
                                                                         information in a     20 applies to
                                                                         GRAS notice          amendments and
                                                                         (including data      supplements as
                                                                         and information      well as to the
                                                                         submitted in any     GRAS notice as
                                                                         amendment or         originally
                                                                         supplement to your   submitted.
                                                                         GRAS notice or
                                                                         incorporated into
                                                                         your GRAS notice)
                                                                         are available for
                                                                         public disclosure
                                                                         in accordance with
                                                                         part 20 as of the
                                                                         date that we
                                                                         receive your GRAS
                                                                         notice.
170.275(b)(1)....................  170.36(f)(2)(i)....             N/A  We will make         Clarifies that the
                                                                         readily accessible   list of
                                                                         to the public a      submissions that
                                                                         list of filed GRAS   we make publicly
                                                                         notices, including   available are
                                                                         the information      those that we have
                                                                         described in the     ``filed'' as GRAS
                                                                         signed statements    notices.
                                                                         you include in
                                                                         Sec.
                                                                         170.225(c)(2)
                                                                         through (c)(5).
170.275(b)(2)....................  170.36(f)(2)(ii)...             N/A  We will make         N/A.
                                                                         readily accessible
                                                                         to the public the
                                                                         text of any letter
                                                                         that we issue
                                                                         under Sec.
                                                                         170.265(b)(1) or
                                                                         (3) (e.g., a ``no
                                                                         questions letter''
                                                                         or an
                                                                         ``insufficient
                                                                         basis letter'');
                                                                         or under Sec.
                                                                         170.265(c) (a
                                                                         ``subsequent
                                                                         letter'').
170.275(b)(3)....................  170.36(f)(2)(ii)...             N/A  We will make         Clarify that the
                                                                         readily accessible   provisions in
                                                                         to the public the    which we make
                                                                         text of any letter   certain letters
                                                                         that we issue        readily accessible
                                                                         under Sec.           to the public
                                                                         170.265(b)(3)        apply to a ``cease
                                                                         (e.g., a ``cease     to evaluate
                                                                         to evaluate          letter''.
                                                                         letter'').

[[Page 55021]]

 
170.275(c).......................  170.36(f)(2)(iii)..             N/A  We will disclose     N/A.
                                                                         public information
                                                                         in accordance with
                                                                         part 20.
----------------------------------------------------------------------------------------------------------------

A. Data and Information in a GRAS Notice Are Available for Public 
Disclosure on the Date That We Receive It

    (Comment 111) One comment asserts that the releasability of the 
contents of a GRAS notice should be governed by Sec.  20.111 (data and 
information submitted voluntarily to us) because the FD&C Act does not 
require submission of a GRAS notice. The comment asserts that Sec.  
20.111 would affect the releasability of the content of a GRAS notice 
in three ways. First, while a GRAS notice is pending, Sec.  20.111 
would protect from disclosure safety data or information about an 
ingredient under development. Second, Sec.  20.111 would permanently 
protect from disclosure any data or information relating to 
manufacturing, production or sales, or formulas. Third, Sec.  20.111 
would establish that a notifier has the right to request that we 
evaluate the notifier's position that specific data or information in a 
GRAS notice are protected from disclosure because these data or 
information fall within the exemption in Sec.  20.61 for trade secrets 
and commercial or financial information, which is privileged or 
confidential.
    (Response 111) We disagree that the provisions of Sec.  20.111 
apply to a GRAS notice. Although your decision to submit a GRAS notice 
is voluntary, the information included in your GRAS notice is required. 
To make that clear, the final rule stipulates that the data and 
information in a GRAS notice (including data and information submitted 
in any amendment or supplement to your GRAS notice or incorporated into 
your GRAS notice) are considered a mandatory, rather than voluntary, 
submission for purposes of its status under the FOIA and part 20 (see 
Sec.  170.275(a)(1)).
    We agree that a notifier has a right to request that we evaluate 
the notifier's position that specific data or information in a GRAS 
notice are protected from disclosure because these data or information 
fall within the exemption in Sec.  20.61 for trade secrets and 
confidential commercial information. See Sec.  170.225(c)(8), which 
requires that you state your view as to whether any of the data and 
information in Parts 2 through 7 of your GRAS notice are exempt from 
disclosure under the FOIA.
    (Comment 112) Several comments assert that a GRAS notice should not 
be publicly available until after we have completed our evaluation. 
These comments also assert that a delay in disclosure, coupled with an 
opportunity for a notifier to amend the notice, would: (1) Avoid the 
release of information that we deemed to be inadequate or incomplete; 
and (2) avoid release of a notice that was withdrawn if coupled with an 
opportunity for a notifier to withdraw a notice.
    (Response 112) We disagree that we should refrain from disclosing 
the existence of a GRAS notice, or the contents of a GRAS notice, until 
after we have completed our evaluation. As previously discussed, 
immediate disclosure of a GRAS notice underscores a notifier's 
responsibility for a conclusion of GRAS status (62 FR 18938 at 18953). 
As discussed in Response 2, immediate disclosure of a GRAS notice also 
provides an opportunity for outside parties to make us aware of 
dissenting views about whether the available data and information 
support a conclusion that the notified substance is safe under the 
conditions of its intended use, and we did receive information from 
outside parties during the Interim Pilot program. Continuing to provide 
an opportunity for public participation is consistent with our 
substitution of the GRAS notification procedure for the former GRAS 
affirmation petition process, in which there was a public comment 
period.
    As discussed in Response 83, our current regulations regarding 
public information stipulate that no person may withdraw records 
submitted to FDA (see Sec.  20.29), and those regulations will apply to 
a GRAS notice that you to ask us to ``cease to evaluate.''
    (Comment 113) One comment asks us to make a GRAS notice available 
for public disclosure only after we accept the submission for review. 
Some comments contrast our proposal for immediate disclosure of a GRAS 
notice with the provisions of: (1) The GRAS affirmation petition 
process, in which a GRAS affirmation petition is disclosed only after 
the petition has been accepted for filing (former Sec.  170.35(c)(2)); 
and (2) the health claim petition process, in which a health claim 
petition becomes available for public disclosure only after it is filed 
and a health claim petition that is denied without filing is not 
available for disclosure (21 CFR 101.70(j)).
    (Response 113) The final rule continues to specify that the data 
and information in a GRAS notice are available for public disclosure as 
of the date of receipt (see Sec.  170.275(a)(2)). The former GRAS 
affirmation petition process did not specify when a submitted GRAS 
affirmation petition would be available for public disclosure. Instead, 
the former GRAS affirmation petition process merely specified that we 
would place the petition on public file in the office of the Division 
of Dockets Management and publish a notice of filing in the Federal 
Register within 30 days after the date of filing. In addition, we 
disagree that the public disclosure provisions in Sec.  101.70(j) 
applicable to the health claim petition process should apply to the 
GRAS notification procedure. Those provisions derive directly from the 
statutory provisions that direct the health claim program (section 
403(r)(4)(A)(i) of the FD&C Act (21 U.S.C. 343(r)(4)(A)(i))).
    Under Sec.  20.103, with few exceptions all correspondence from 
members of the public, organization or company officials, or other 
persons, is available for public disclosure at the time that we receive 
it unless a different time for such disclosure is specified in other 
rules established or cross-referenced in part 20. As noted in Comment 
86 and Response 86, we may decide to file and respond to a submission 
as general correspondence, rather than as a GRAS notice, in certain 
circumstances; if we do so, the data and information in the submission 
would be available as of the date of receipt. Retaining date of receipt 
as the timeframe for when a submission you transmit as a GRAS notice is 
available for public disclosure is both consistent with Sec.  20.103 
and a practical approach to a situation in which we receive a FOIA 
request for a GRAS

[[Page 55022]]

submission before we have determined whether to file the submission as 
a GRAS notice. As a practical matter, we believe that such situations 
will be rare, and that in most cases a GRAS submission will be 
disclosed after we have determined whether to file it and evaluate it 
as a GRAS notice, or to file it and respond to it as general 
correspondence.
    (Comment 114) Some comments disagree with the assumption we stated 
in the proposed rule (62 FR 18938 at 18952) that submission of a GRAS 
notice would not reflect the notifier's plans about the timing or the 
use of the substance in a marketed product, because a GRAS substance 
may be marketed without prior approval.
    (Response 114) We acknowledge that immediate disclosure of a GRAS 
notice could, in certain circumstances, provide information about the 
timing of market entry. However, when the data and information 
regarding the safety of the substance under the conditions of its 
intended use satisfy GRAS criteria, neither the law nor this rulemaking 
would prevent you from marketing a substance before submitting a GRAS 
notice or during our evaluation of that notice.

B. We Will Make a List of Filed GRAS Notices and Our Responses to GRAS 
Notices Readily Accessible

    (Comment 115) Several comments address our stated intention to 
maintain an inventory of GRAS notices that we receive, our response, 
and any subsequent relevant correspondence. (See the discussion at 68 
FR 18938 at 18953.) Some of these comments agree with the discussion in 
the proposed rule that an inventory of GRAS notices should be an 
adjunct to the proposed rule rather than be included in the regulatory 
text. Other comments disagree and ask us to include the creation and 
availability of the inventory in the regulatory text. These comments 
assert that a provision that merely states that the inventory exists 
and is available for public review would address the concern that we 
identified in the proposed rule about the need to maintain flexibility 
regarding our administration of the inventory.
    (Response 115) The final rule specifies that we will make the 
following readily accessible to the public: (1) A list of filed GRAS 
notices, including the information described in certain of the signed 
statements that are included in Part 1 of a GRAS notice (i.e., Sec.  
170.225(c)(2) through (c)(5)); and (2) The text of any letter that we 
issue under Sec.  170.265(b)(1) (our response to a GRAS notice based on 
our evaluation of the notice), Sec.  170.265(b)(3) (a letter if we 
grant a request that we cease to evaluate a GRAS notice), or Sec.  
170.265(c) (a subsequent letter that we send about a GRAS notice). (See 
Sec.  170.275(b).) We are not specifying that the mechanism for us to 
do so is through an ``Inventory'' because the procedure we used to make 
this information readily accessible to the public evolved over time 
during the Interim Pilot program, and may continue to evolve (see 
section III.I.1 in CFSAN's 2010 experience document (Ref. 18)).
    (Comment 116) In the proposed rule, we stated our intention to 
initially maintain a paper version of an inventory at our Dockets 
Management Branch (now Division of Dockets Management) and asked for 
comment on making an inventory available through electronic means such 
as the Internet (62 FR 18938 at 18953). Comments support maintaining an 
inventory in paper format, electronic format, or both formats so that 
all members of the public could have ready access to such information 
regarding GRAS notices. Some comments point out that electronic access 
would be particularly important to the international food industry. 
Some comments support the Division of Dockets Management as the best 
location for an inventory maintained in paper format.
    (Response 116) As discussed in section III.I.1 in CFSAN's 2010 
experience document (Ref. 18), the procedure we used to make this 
information readily accessible to the public evolved over time during 
the Interim Pilot program. It began as a paper file (first maintained 
at the Division of Dockets Management, and then maintained in the 
public reading room of our Freedom of Information Staff), and evolved 
into its current electronic format on our Internet site (Ref. 46). We 
intend to continue using the Internet as the principal means to make 
the inventory readily accessible because doing so is an efficient and 
effective mechanism to disseminate information to anyone who has access 
to the Internet. The inventory on the Internet can be accessed and 
printed from computers in the public reading room at Division of 
Dockets Management, as well as from computers located at businesses, at 
homes, and at public locations such as libraries and Internet cafes. If 
a person either does not have access to the Internet or chooses not to 
access the inventory through the Internet, that person can request each 
GRAS notice, and each letter listed in Sec.  170.265(b)(1) or (3) or 
(c), under the FOIA. It is no longer practical for us to maintain a 
paper file at the Division of Dockets Management, because all new 
information sent to the Division of Dockets Management is maintained 
electronically; paper submissions are scanned to electronic form.
    (Comment 117) One comment that addresses the discussion in the 2010 
notice about the reasons that may lead us to decline to file a 
submission as a GRAS notice, such as when the use is covered by an 
existing regulation, asks us to include those submissions in the GRAS 
inventory so there will be no confusion as to the status of the 
ingredient.
    (Response 117) We decline this request. The purpose of the 
inventory of GRAS notices is to provide a list of all the GRAS notices 
that we have filed and evaluated, not to interpret the uses listed in 
our regulations or, as discussed in Response 86, covered by an existing 
GRAS notice.
    (Comment 118) A few comments suggest that a publicly available 
inventory of GRAS notices could suffice to document that certain 
notices raised no significant issues.
    (Response 118) We agree that a publicly available inventory of GRAS 
notices can document which notices result in a ``no questions letter, 
e.g., by prominently listing the category of our response. The 
Inventory of GRAS Notices developed during the Interim Pilot program 
prominently classifies each response letter as ``no questions,'' 
``insufficient basis,'' and ``cease to evaluate'' (Ref. 46). However, 
we disagree that merely displaying the category of our response, 
without providing the full text of a letter that places that category 
of response in context, is appropriate, regardless of whether the 
response to the GRAS notice is ``no questions,'' ``insufficient 
basis,'' or ``cease to evaluate.'' For example, even when we answer 
``FDA has no questions,'' our response letter highlights key safety 
considerations, such as the importance of ensuring that the method of 
manufacture removes potential contaminants.
    (Comment 119) One comment asks us to provide ``public notice'' of 
all GRAS notices and the information provided therein. Another comment 
asks us to make the ``GRAS exemption claim'' readily accessible to the 
public by publishing information that would be in the publicly 
accessible file in the Federal Register in addition to placing the 
``GRAS exemption claim'' in a readily accessible file. This comment 
states that doing so would provide the public with access to as much 
information as possible about what substances would be used in food on 
the basis of the GRAS provision if FDA is

[[Page 55023]]

going to ``forgo its role'' in the evaluation of the safety of GRAS 
substances. This comment also asks us to publish the receipt of the 
notice and all of our subsequent responses to the notice in the Federal 
Register.
    Another comment asks us to publish semi-annually, either in a 
Federal Register notice or by regulation, a list of GRAS notices that 
receive a ``no questions letter'' in addition to posting the Inventory 
of GRAS notices on our Web site. This comment explains that questions 
are sometimes raised--especially from outside the United States--about 
the regulatory status of a substance used in food on the basis of the 
GRAS provision unless that use of the substance is either incorporated 
into the CFR or otherwise officially published. This comment asserts 
that periodic publications in the Federal Register would assist in 
addressing this concern.
    (Response 119) By specifying that we will make a list of filed GRAS 
notices readily accessible (currently, through the inventory on the 
Internet), the rule requires us to actively disclose those GRAS 
notices. There is a gap between the date on which we receive a GRAS 
notice and the date on which we add it to the inventory, e.g., CFSAN 
currently updates its inventory on an approximately monthly basis. 
However, in practice during the Interim Pilot program there was ample 
public notice of the receipt of the GRAS notice before CFSAN responded 
to it (see the discussion of the timeframe for CFSAN's response in 
section III.M of CFSAN's 2010 experience document (Ref. 18)). In 
addition, the rule provides that we may send a subsequent letter about 
the GRAS notice if circumstances warrant; such circumstances could 
include data and information, received from a member of the public, 
after we responded to the GRAS notice.
    We decline the requests to provide public notice through an 
announcement in the Federal Register. Publishing an announcement in the 
Federal Register requires an expenditure of our resources (including 
time and cost of publication) that would be inconsistent with our goal 
of using our resources efficiently and effectively. Even if we 
conserved resources by publishing such a notice only on a semi-annual 
basis, we disagree that ``officially publishing'' a list of GRAS 
notices that receive a ``no questions letter'' in the Federal Register 
would address concerns, in the domestic or international community, 
about the regulatory status of the use of a substance when that use is 
not listed in our regulations. It is the Code of Federal Regulations, 
not the Federal Register, that is the official repository of our 
regulations listing authorized uses of food substances.
    We disagree that we are forgoing our role in the evaluation of the 
safety of substances used in food on the basis of the GRAS provision. 
See Response 25.
    (Comment 120) One comment asks us to place the entire GRAS notice, 
rather than only the proposed ``GRAS exemption claim,'' in a readily 
accessible paper file, e.g., at the Division of Dockets Management. In 
the comment's view, a simple provision that a notifier submit one 
additional paper copy would mitigate our concerns about the 
administrative inefficiency of maintaining duplicate files at both the 
center and Agency levels. Another comment asks us to make the entire 
notice readily accessible in electronic form.
    (Response 120) We currently make a hyperlink to an electronic copy 
of each GRAS notice accessible from within the entry for that GRAS 
notice in the inventory, after appropriate redaction (e.g., of privacy 
information, copyrighted material, and any data and information that 
are exempt from public disclosure) (Ref. 18, footnote 3). As a 
practical matter, placing paper files on public display requires space, 
which is finite, and our Division of Dockets Management scans paper 
submissions into electronic format.

C. Public Disclosure of a GRAS Notice Is in Accordance With Our Public 
Information Regulations in Part 20

    (Comment 121) One comment agrees that information submitted under 
the proposed ``GRAS exemption claim'' should exclude from public 
disclosure the non-public confidential information with the exception 
of safety data.
    (Response 121) This comment appears to have misinterpreted the 
proposed provisions regarding submission of non-public information and 
how the public disclosure provisions of this rule apply to non-public 
information. The proposed ``GRAS exemption claim'' is the precursor of 
Part 1 of a GRAS notice (which we are establishing in Sec.  170.225). 
The rule specifies that you must not include any information that is 
trade secret or confidential commercial information in Part 1 of your 
GRAS notice, except in the statement of your view as to whether any of 
the data and information in Parts 2 through 7 of your GRAS notice are 
exempt from disclosure under the FOIA. Part 1 of a GRAS notice includes 
signed statements and a certification, not ``safety data.'' The 
``safety data'' would be included in Parts 2 through 7 of the GRAS 
notice. Consistent with the view of this comment, the rule provides 
that those data and information are available for public disclosure 
upon receipt (see Sec.  170.275(a)(2)). See also Response 50.
    (Comment 122) Some comments ask us to alert the notifier, and grant 
the notifier an option to withdraw the notice, in order to protect 
information designated as confidential from disclosure.
    (Response 122) We decline this request. A person who submits a 
record to us may not withdraw that record from our files (Sec.  20.29). 
Rather, the procedures that govern the release of information that a 
notifier identifies as confidential in a GRAS notice are established in 
Sec. Sec.  20.61 and 20.27. Under Sec.  20.61(d), a person who submits 
records to us may designate part or all of the information in such 
records as exempt from disclosure under exemption 4 of FOIA. However, 
under Sec.  20.27 marking records submitted to us as confidential, or 
with any other similar term, raises no obligation by FDA to regard such 
records as confidential, to return them to the person who has submitted 
them, to withhold them from disclosure to the public, or to advise the 
person submitting them when a request for their public disclosure is 
received or when they are in fact disclosed.

XXII. Submission of a Supplement

    The rule provides that you may submit a supplement to a GRAS notice 
after we respond to your notice based on our evaluation of your notice 
or cease to evaluate your notice (Sec.  170.280). However, if our 
response to your GRAS notice raises questions about your conclusion 
that the notified substance is GRAS under the conditions of its 
intended use, the appropriate mechanism for you to address those 
questions would be to submit a new GRAS notice or other regulatory 
submission (such as a food additive petition) rather than to submit a 
supplement. See section III.C.2 of CFSAN's 2010 experience document for 
examples of supplements that CFSAN received during the Interim Pilot 
program (Ref. 18).

XXIII. Comments on the Administrative Process for Pending GRAS 
Affirmation Petitions

    We proposed that any pending petitions would be presumptively 
converted to a GRAS notice on the date the final rule becomes effective 
(proposed Sec.  170.36(g)(1)). An affected petitioner would have an 
opportunity to amend the converted petition to meet the requirements of 
the GRAS notification procedure by submitting a

[[Page 55024]]

``GRAS exemption claim'' (proposed Sec.  170.36(g)(2)). A GRAS 
affirmation petition that is converted to a notice and that the 
affected petitioner amends would be reviewed and administered according 
to the provisions of the GRAS notification procedure; the date of 
receipt of the amendment would be the date of receipt of the notice 
(proposed Sec.  170.36(g)(3)(i)). After 90 days from the date of 
publication of the final rule, we would inform any affected petitioner 
who had not amended an applicable petition that the converted petition 
is inadequate as a GRAS notice.
    In the 2010 notice, we requested comments on three issues related 
to the pending petitions as shown in table 23. Although the 2010 notice 
classified all of these issues as ``Issue 17,'' for presentation 
purposes in this document we classify the three issues as 17a, 17b, and 
17c.

 Table 23--Issues in the 2010 Notice Regarding Pending GRAS Affirmation
                                Petitions
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
17a.......  How to reduce the  75 FR 81536 at 81542-81543.
             impact on
             affected
             petitioners
             while retaining
             the principle
             that we will not
             devote resources
             to pending
             petitions.
17b.......  Whether an         75 FR 81536 at 81542-81543.
             outcome of
             ``withdrawal
             without
             prejudice''
             instead of
             ``insufficient
             basis'' would be
             more appropriate
             when an affected
             petitioner
             simply chooses
             not to have the
             pending petition
             considered under
             the GRAS
             notification
             procedure.
17c.......  Whether an         75 FR 81536 at 81542-81543.
             affected
             petitioner could
             request that we
             incorporate into
             a GRAS notice a
             withdrawn GRAS
             affirmation
             petition into a
             GRAS notice, and
             if so, if any
             requirements of
             the GRAS
             notification
             procedure should
             be waived.
------------------------------------------------------------------------

    In the following paragraphs, we discuss comments regarding the 
disposition of pending petitions in light of the deletion of the GRAS 
affirmation petition process. After considering these comments, we are 
establishing provisions for the pending petitions as shown in table 24, 
with editorial, clarifying, and conforming changes as shown in table 
29. (See Sec.  170.285.) Table 24 identifies changes we made relative 
to the proposed rule or the description in the 2010 notice other than 
the editorial, clarifying, and conforming changes shown in table 29 and 
the additional editorial changes associated with the redesignation of 
proposed Sec.  170.36(g) as Sec.  170.285.

               Table 24--Final Requirements for Disposition of Pending GRAS Affirmation Petitions
----------------------------------------------------------------------------------------------------------------
                                                                                               Revisions (other
                                                                                               than editorial,
                                         Proposed        Issue No. in                          clarifying, and
     Final designation in the       designation in the     the 2010         Description      conforming changes)
    regulatory text  (Sec.   )       regulatory text        notice                              relative to the
                                        (Sec.   )                                              proposed rule or
                                                                                               the  2010 notice
----------------------------------------------------------------------------------------------------------------
170.285(a).......................  170.36(g)(1).......     17a and 17b  On the effective     We administratively
                                                                         date of the rule,    close the docket
                                                                         we will close the    for the GRAS
                                                                         docket for any       affirmation
                                                                         GRAS affirmation     petition
                                                                         petition that is     rulemaking rather
                                                                         still pending as     than convert the
                                                                         of that date.        pending petition
                                                                                              to a GRAS notice.
170.285(b).......................  170.36(g)(2).......             17c  Any person who       The affected
                                                                         submitted a GRAS     petitioner submits
                                                                         affirmation          a GRAS notice
                                                                         petition that is     rather than an
                                                                         pending as of the    amendment to a
                                                                         date of the final    ``converted
                                                                         rule may submit a    petition''.
                                                                         GRAS notice and
                                                                         request that we
                                                                         incorporate the
                                                                         GRAS affirmation
                                                                         petition.
N/A..............................  170.36(g)(3)(i)....             N/A  N/A................  No longer specifies
                                                                                              the procedures for
                                                                                              FDA's evaluation
                                                                                              of a former
                                                                                              pending petition.
N/A..............................  170.36(g)(3)(ii)...     17a and 17b  N/A................  No longer treats a
                                                                                              pending petition
                                                                                              that is not
                                                                                              evaluated as a
                                                                                              GRAS notice as
                                                                                              having an
                                                                                              insufficient basis
                                                                                              to support GRAS
                                                                                              status.
----------------------------------------------------------------------------------------------------------------

    (Comment 123) Some comments to the proposed rule support our 
proposal to convert pending GRAS affirmation petitions to GRAS notices 
on the effective date of the rule. However, as discussed in the 2010 
notice, many comments to the proposed rule object to our proposal for 
administering the pending petitions as being fundamentally unfair, 
because an affected petitioner had invested considerable time and 
resources in the petition process and should not be penalized by our 
adoption of a new GRAS notification procedure. Some of these comments 
state that, in most cases, FDA also had dedicated significant resources 
to the review of these petitions and, in some cases, had even arranged 
for an additional third party to review the substance that was the 
subject of the petition. These comments suggest options such as 
``grandfathering'' pending petitions, i.e., completing the rulemaking 
process for them, particularly if we had completed our scientific 
review with no outstanding questions. Some comments ask us to provide 
an affected petitioner 180 days, rather than 90 days, to amend the 
converted petition to satisfy the requirements of the GRAS notification 
procedure. One of these comments argues that there need not be any 
urgency in closing the applicable files because many of these petitions 
had been pending for years, and the subjects of the petitions had been 
marketed during those years.
    Some comments to the proposed rule assert that more resources would 
be needed to review a petition that is converted to a GRAS notice than 
would be needed to complete the review of each pending petition and 
issue a

[[Page 55025]]

regulation. One comment suggests that it would be simpler and more 
efficient administratively to allow an affected petitioner an option to 
update a GRAS affirmation petition to include additional conditions of 
use or new specifications than to require separate GRAS notices for 
such changes.
    Other comments ask us to clarify the procedures we would use to 
convert a GRAS affirmation petition to a GRAS notice as well as 
procedures for amending a petition that was converted to a GRAS notice 
through an additional submission. Some comments assert that we should 
not require an affected petitioner to submit such an amendment because 
all of the pertinent information would already be included in the 
petition and argue that technical adherence to the format of a GRAS 
notice should not take precedence over administrative efficiency and 
common sense. Other comments express concern that it was not clear that 
the proposed additional submission (proposed Sec.  170.36(g)(2)) was in 
fact a skeleton notice that primarily would cross-reference the 
original GRAS affirmation petition.
    Some comments to the 2010 notice suggest that a pending petition 
could be ``withdrawn without prejudice'' or ``suspended'' so that it 
would no longer require FDA resources to review it. Other comments to 
the 2010 notice express the view that a simple letter of conversion 
should be adequate, but that if an affected petitioner chose not do so 
then the outcome of the converted petition would more appropriately be 
described as ``withdrawn without prejudice'' rather than 
``insufficient'' as a GRAS notice. Other comments to the 2010 notice 
continue to express the view that we should ``grandfather'' a pending 
petition. One of these comments asserts that failure to grandfather 
those affirmation petitions where FDA had completed its review and no 
outstanding scientific issues exist would be unfair because the GRAS 
notification procedure results in a lower level of authoritativeness 
than the GRAS affirmation petition process, and the affected 
petitioners had invested considerable time and resources in the 
petition process. This comment also notes that after we published the 
proposed rule we continued to review GRAS affirmation petitions and 
completed the process for six GRAS affirmation petitions before 
discontinuing further activity in 1999. Comments that address Issue 17c 
recommend that an affected petitioner be allowed to incorporate 
information from a ``withdrawn'' GRAS affirmation petition into a GRAS 
notice.
    We received no comments asking us to waive any of the requirements 
of the notification procedure.
    (Response 123) We have revised the proposed provisions regarding 
the disposition of pending petitions in light of the concern of the 
comments that the proposed process was unfair to affected petitioners. 
The final rule provides that on the effective date of the rule, we will 
close the docket for any GRAS affirmation petition that is still 
pending as of that date (Sec.  170.285(a)). Any person who submitted a 
GRAS affirmation petition that is pending as of the date of the final 
rule may submit a GRAS notice and request that we incorporate the GRAS 
affirmation petition (Sec.  170.285(b)). We are closing the docket for 
the petition by operation of law because the process that would be 
necessary to bring a petition to closure (i.e., Sec.  170.35(c)) no 
longer exists. We decided to close the docket for the petition, rather 
than classify the petition as withdrawn without prejudice, for two 
reasons. First, closing the docket is an administrative option that is 
open to us, whereas in our petition processes withdrawing a petition is 
an option that falls to the petitioner (see, e.g., Sec.  171.1(j) for 
withdrawal of a food additive petition without prejudice). Second, 
``withdrawal without prejudice'' generally means ``without prejudice to 
a future filing,'' and ``future filing'' refers to the same type of 
filing; however, we have eliminated the GRAS affirmation petition 
process and, thus, an affected petitioner could not submit another GRAS 
affirmation petition.
    Closing the docket is neutral with respect to a conclusion by an 
affected petitioner that the petitioned substance is GRAS under the 
conditions of its intended use, because closing the docket does not 
result in a publicly available ``insufficient basis letter.'' To 
clarify that closing the petition is without prejudice to eligibility 
for classification of the use of the substance as GRAS, the final rule 
specifically provides that an affected petitioner may incorporate the 
former GRAS affirmation petition into a GRAS notice. Given the passage 
of time since the pending petitions were submitted, it is likely that 
some of the data and information in the petition would need to be 
updated. In addition, the affected petitioner would need to follow all 
format requirements for a GRAS notice, including the narrative required 
in Part 6 of a GRAS notice.
    We acknowledge that our response to a GRAS notice does not have the 
same level of ``authoritativeness'' as a listing in our regulations. 
However, some of the comments that objected to the proposal to convert 
a pending petition to a GRAS notice assert that the substances that are 
the subject of the pending petitions have been marketed for years; 
clearly, these affected petitioners are able to market the substance 
without a listing in our regulations.
    We agree that it is appropriate to extend the timeframe for an 
affected petitioner to take action with respect to a pending petition. 
Under final Sec.  170.285(b), there is no limit on the timeframe for an 
affected petitioner to submit a GRAS notice that incorporates a GRAS 
affirmation petition.
    We decline the request to ``grandfather'' any pending petitions. We 
simply do not have sufficient resources to devote to the rulemaking 
process that is required for GRAS affirmation, regardless of whether we 
already have completed our scientific review. For example, even if we 
have completed our scientific review, the Administrative Procedures Act 
(5 U.S.C. 553) requires that we consider relevant data, views, or 
arguments submitted to us by interested persons and that we publish a 
concise general statement of the basis and purpose of the regulation. 
In addition, Executive Order 12866 requires that we assess the costs 
and benefits of available regulatory alternatives when we conduct 
rulemaking, and the Regulatory Flexibility Act (5 U.S.C. 601-612) 
requires that we consider alternatives that would minimize the economic 
impact of our regulations on small entities. Thus, to complete the 
rulemaking associated with the GRAS affirmation petition process, we 
require significant resources beyond those associated with scientific 
review. Even if we did ``grandfather'' a pending petition, it is highly 
unlikely that we would be able to devote resources to this voluntary 
process in light of competing programs that are required by statute. 
For example, the resources that could be directed to the GRAS 
affirmation petition process must be considered together with the 
resources that are required to administer the food and color additive 
petition processes and the premarket notification process for food 
contact substances, which are required programs under sections 409 and 
721 of the FD&C Act.
    For the reasons discussed in the previous paragraph, we disagree 
that we would have needed more resources to review a petition that is 
converted to a GRAS notice than to complete the review of each pending 
petition and issue a regulation. We also disagree that it would be 
simpler and more efficient administratively to allow an affected

[[Page 55026]]

petitioner an option to update a GRAS affirmation petition. As 
discussed in CFSAN's 2016 experience document (Ref. 19), during the 10-
year period extending from 1990 through 1999, CFSAN completed the 
rulemaking process for 24 GRAS affirmation petitions, with an average 
elapsed time of approximately 7.9 years (median elapsed time 
approximately 6.9 years). In contrast, under the final rule we will 
respond to a GRAS notice in 180 days, with an option to extend the 
timeframe by an additional 90 days (see Response 98).
    As of August 17, 2016 there are 45 pending GRAS affirmation 
petitions. We intend to contact each affected petitioner to inform the 
petitioner that: (1) We are closing the affected docket as of October 
17, 2016; and (2) the petitioner may submit a GRAS notice that 
incorporates the former GRAS affirmation petition.
    (Comment 124) One comment asks us to issue a regulation, to be 
included in part 184, that lists the pending petitions. The comment 
also asks us to include a statement that the lack of an affirmation 
regulation does not indicate that FDA disagrees with the affected 
petitioner's GRAS determination.
    (Response 124) We decline this request. Our regulations in part 184 
represent our own conclusions regarding the GRAS status of a listed 
substance under the conditions of its intended use. It is inappropriate 
for our regulations to become a catalog of circumstances where we have 
not reached our own conclusion regarding GRAS status.
    However, under final Sec.  170.275(b), we will make a list of filed 
GRAS notices readily accessible to the public. The inventory of GRAS 
notices that currently makes this list available includes a link to 
information about each listed GRAS notice. When the GRAS notice was 
originally submitted as a GRAS affirmation petition, we have included 
the petition number. We intend to continue this practice under the 
final rule.
    We also have placed a list of the pending petitions that we are 
closing in the docket for this rule (Ref. 48).

XXIV. Other Comments

A. GRAS Panels and Conflict of Interest

    In the 2010 notice, we explained that the GAO report noted that we 
have not issued any conflict of interest guidance that companies can 
use to help ensure that the members of their expert panels are 
independent (75 FR 81536 at 81542). The GAO report recommended that we 
develop a strategy to minimize the potential for conflicts of interest, 
including taking steps such as issuing guidance for companies on 
conflict of interest and requiring information in GRAS notices 
regarding expert panelists' independence. In the 2010 notice, we 
requested comments on three issues related to GAO's recommendation 
regarding conflict of interest as shown in table 25. Although the 2010 
notice classified all of these issues as ``Issue 15,'' for presentation 
purposes in this document we classify the three issues as 15a, 15b, and 
15c.

  Table 25--Issues in the 2010 Notice Regarding Guidance on Conflict of
                                Interest
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
15a.......  Whether companies  75 FR 81536 at 81542.
             would find it
             useful to have
             guidance on
             potential
             conflicts of
             interest of GRAS
             expert panelists.
15b.......  If guidance on     75 FR 81536 at 81542.
             potential
             conflicts of
             interest of GRAS
             expert panelists
             would be useful,
             what companies
             currently do to
             mitigate such a
             conflict.
15c.......  Whether to         75 FR 81536 at 81542.
             require that
             GRAS notices
             include
             information
             regarding expert
             panelists'
             independence.
------------------------------------------------------------------------

    (Comment 125) Most of the comments that addressed Issues 15a and 
15b ask us to provide guidance regarding potential conflicts of 
interest of GRAS panel members. One of these comments provided an 
example of a draft guidance for our consideration. Other comments 
provide criteria that they ask us to consider in the guidance. One 
comment asks us to provide an opportunity for industry, academia, and 
the public to comment on our proposed course of action for the topic of 
conflict of interest.
    One comment asserts that there is no need for guidance regarding 
potential conflicts of interest of GRAS panel members because industry 
is aware of the importance of disclosing and addressing potential 
conflicts of interest and often has Standard Operating Procedures 
delineating rules for disclosure.
    (Response 125) We have decided to issue guidance regarding conflict 
of interest. We will do so as Level 1 guidance within the framework of 
our good guidance practices regulation (see Sec.  10.115(c) and (g)). 
Under that framework, we prepare a draft of Level 1 guidance and then: 
(1) Publish a notice in the Federal Register announcing that the draft 
guidance document is available; (2) post the draft guidance document on 
the Internet and make it available in hard copy; and (3) invite public 
comment on the draft guidance document. After providing an opportunity 
for public comment on a Level 1 guidance document, FDA will: (1) Review 
any comments received and prepare the final version of the guidance 
document that incorporates suggested changes, when appropriate; (2) 
publish a notice in the Federal Register announcing that the guidance 
document is available; (3) post the guidance document on the Internet 
and make it available in hard copy; and (4) implement the guidance 
document. We will consider the recommendations and draft guidance 
submitted in the comments to this rule in developing our draft guidance 
for public comment.
    We acknowledge that some members of industry are aware of the 
importance of disclosing and addressing potential conflicts of 
interest. However, we disagree that this awareness means that we should 
not issue a guidance regarding conflict of interest. A guidance from us 
on conflict of interest could promote consistency in addressing 
conflict of interest by different companies.
    (Comment 126) One comment notes that an external GRAS panel is not 
required for a conclusion of GRAS status when the conclusion is 
supported by peer-reviewed literature or a ``long history of safe 
use.'' (By ``long history of safe use,'' we assume that the comment is 
referring to the provision that GRAS criteria may be satisfied through 
experience based on common use in food prior to January 1, 1958. See 
Sec.  170.30(a) and (c)).
    (Response 126) We agree that an external GRAS panel is not required 
for a conclusion of GRAS status. As we previously noted, convening a 
GRAS panel has historically been a way to provide evidence that 
generally available data and information are

[[Page 55027]]

generally accepted by the expert scientific community, but convening a 
GRAS panel is not the only way to provide such evidence (62 FR 18938 at 
18943).
    (Comment 127) Some comments address Issue 15c and recommend that a 
notifier include information on independence of the panel members in a 
submitted GRAS notice.
    (Response 127) The rule neither requires that a notifier convene a 
GRAS panel nor establishes any other requirements applicable to a GRAS 
panel. Therefore, we are addressing issues regarding a GRAS panel in 
guidance rather than in the regulation. See also Comment 14 and 
Response 14.

B. Guidance on Documenting Conclusions of GRAS Status

    In the 2010 notice, we explained that the GAO report recommended 
that we issue guidance on how to document a conclusion of GRAS status 
(75 FR 81536 at 81542). We noted that there is guidance in the preamble 
to the proposed rule and in our guidance for industry entitled 
``Frequently Asked Questions About GRAS'' (Ref. 49). We requested 
comments on two issues related to guidance on documenting a conclusion 
of GRAS status as shown in table 26. Although the 2010 notice 
classified both of these issues as ``Issue 16,'' for presentation 
purposes in this document we classify the two issues as 16a and 16b.

  Table 26--Issues in the 2010 Notice Regarding Guidance on Documenting
                            GRAS Conclusions
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
16a.......  Whether there is   75 FR 81536 at 81542.
             a need to
             clarify that our
             guidance
             applying to GRAS
             submissions also
             applies to a
             GRAS conclusion
             that is not
             submitted to us
             in the form of a
             GRAS notice.
16b.......  Whether there is   75 FR 81536 at 81542.
             a need for us to
             develop further
             guidance on
             documenting a
             GRAS conclusion
             when the GRAS
             conclusion is
             not submitted to
             us as a GRAS
             notice.
------------------------------------------------------------------------

    (Comment 128) Most of the comments that addressed Issue 16a 
recommend that we clarify that the same standards apply to a conclusion 
of GRAS status regardless of whether the conclusion is submitted to us 
as a GRAS notice or is not submitted to us.
    (Response 128) To reach a conclusion of GRAS status, the proponent 
of GRAS status must: (1) Establish that the substance is safe under the 
conditions of its intended use within the meaning of section 409(c)(5) 
of the FD&C Act and our implementing regulation in Sec.  170.3(i); and 
(2) establish that the safety of the substance under the conditions of 
its intended use is generally recognized within the meaning of section 
201(s) of the FD&C Act and our regulations in Sec.  170.30 governing 
the eligibility for classification as GRAS. See the discussion in 
section I.C of the proposed rule of the elements of the GRAS standard, 
where we described the evaluation of safety as the ``technical 
element'' of the GRAS standard and the evaluation of general 
recognition as the ``common knowledge element'' of the GRAS standard. 
In considering whether GRAS criteria are satisfied because the 
available data and information demonstrate that the use of a substance 
is safe and the safety is generally recognized, we do not distinguish 
between a conclusion of GRAS status submitted to us as a GRAS notice 
and an independent conclusion of GRAS status that remains with the 
proponent. As discussed in Response 41, in this rulemaking we made 
conforming changes to current regulations regarding the use of GRAS 
substances in food, and our affirmation of GRAS status on our own 
initiative, to emphasize that point (see the changes to Sec. Sec.  
170.3(i) and (k), 170.30(c), 170.30(e), and 170.35(a) and (b) in table 
29). As already noted in section I.E of this document, we advise any 
company that intends to market a food substance on the basis of an 
independent conclusion of GRAS status to carefully consider whether 
this use fully satisfies the criteria for eligibility for 
classification as GRAS and to carefully review the discussions in this 
document relevant to those criteria, such as the discussion in Response 
9 regarding the role of corroborative data and information, the 
discussions in Response 10 and Response 11 regarding the limitations of 
a published report of a GRAS panel, and the discussion in Response 69 
regarding the ramifications of providing trade secret information (or 
other non-public information) to a GRAS panel.
    Our 2004 guidance entitled ``Frequently Asked Questions About 
GRAS'' generally applies to a conclusion of GRAS status regardless of 
whether that conclusion of GRAS status is submitted to us as a GRAS 
notice. Exceptions include current questions specific to the 
notification procedure as it operated during the Interim Pilot program, 
such as ``Where do I send my GRAS notice? '' We are modifying that 
guidance to update it in light of the publication of this rule.
    We believe that the provisions of the GRAS notification procedure 
in part 170, subpart E will be a useful resource to any person who 
intends to use a substance in food based on a conclusion of GRAS 
status, regardless of whether the conclusion of GRAS status is 
submitted to us in a GRAS notice or is an independent GRAS conclusion 
that is not submitted to us. For example, the requirements in Part 3 of 
a GRAS notice make clear that a conclusion of GRAS status requires 
consideration of dietary exposure. Likewise, the requirements in Part 6 
of a GRAS notice demonstrate the importance of a complete and balanced 
evaluation of all applicable data and information, including data and 
information that are, or may appear to be, inconsistent with a 
conclusion of GRAS status. Therefore, we recommend that any person who 
intends to use a substance in food based on a conclusion of GRAS 
status, but does not intend to submit a GRAS notice to us, use the 
provisions of part 170, subpart E as guidance. We also recommend that 
such persons organize the data and information that support an 
independent conclusion of GRAS status according to the organization 
presented by Parts 1 through 7 of a GRAS notice. Doing so would 
facilitate our evaluation of that independent conclusion of GRAS status 
if circumstances warrant, e.g., if we have cause to question the 
independent conclusion of GRAS status. Because we make information 
about GRAS notices readily accessible to the public, we also recommend 
that you make the basis for your independent GRAS conclusion publicly 
available (e.g., by making publicly available a document analogous to 
the narrative of a GRAS notice, a report of a GRAS panel (if you 
convene a GRAS panel), or both a narrative and a report of a GRAS 
panel).
    General recognition of safety based upon scientific procedures 
requires the same quantity and quality of scientific evidence as is 
required to obtain

[[Page 55028]]

approval of a food additive regulation for the ingredient (Sec.  
170.30(b)). We address scientific issues associated with demonstrating 
the safety of a food substance in a series of guidance documents on our 
Internet (Ref. 6, Ref. 25, and Ref. 32 through Ref. 35). Currently, 
some of these scientific guidance documents are expressly directed to 
evaluation of the safety of food additives. For example, in Response 66 
we noted that our guidance entitled ``Recommendations for Submission of 
Chemical and Technological Data for Direct Food Additive Petitions'' 
(Ref. 31) currently is structured to address the specific requirements 
of a food additive petition, even though many of the recommendations in 
that guidance could nonetheless be useful to any person who evaluates 
whether a substance is GRAS under the conditions of its intended use. 
As resources allow, we intend to re-visit these scientific guidance 
documents to determine whether and how to modify them to clarify that 
our guidance on evaluating the safety of a food substance generally 
applies regardless of whether the substance would be used in food as a 
food additive or as a GRAS substance. Regardless of any implication, in 
the title or text of these guidance documents, that the subject of the 
document applies to a food additive, we recommend that you consider 
that the scientific recommendations in these guidance documents may 
also apply to substances that would be used in food on the basis of a 
GRAS conclusion.
    Some scientific guidance documents already do make clear that they 
apply regardless of the regulatory status of a substance (e.g., as a 
food additive, color additive, food contact substance, or GRAS 
substance) (Ref. 6). In addition, as discussed in Response 37, we 
recently issued a notice announcing a public meeting, and requesting 
comments, on our intent to update our guidance entitled ``Guidance for 
Industry and Other Stakeholders: Toxicological Principles for the 
Safety Assessment of Food Ingredients'' (79 FR 64603), and reiterated 
that general recognition of safety based upon scientific procedures 
requires the same quantity and quality of evidence as is required to 
approve a food additive.
    (Comment 129) Some comments support issuing additional guidance on 
documenting a conclusion of GRAS status, particularly for a GRAS 
conclusion that is not submitted to us. One comment asserts that there 
is no need for us to develop additional guidance on documenting a 
conclusion of GRAS status that is not submitted to us. One comment 
agrees with the recommendation in the GAO report that we take steps to 
ensure that companies maintain proper documentation to support a 
conclusion of GRAS status.
    (Response 129) We agree that companies should maintain proper 
documentation to support a conclusion of GRAS status. As we discussed 
in the proposed rule (62 FR 18938 at 18947), any person who concludes 
that a substance is GRAS under the conditions of its intended use 
should have assembled and evaluated the evidence that forms the basis 
of that conclusion, regardless of whether the person subsequently 
notifies us. Preserving the applicable data and information represents 
prudent practice for those who assert that the statutory premarket 
review requirements do not apply to the use of a substance in food.
    To emphasize the importance of maintaining the data and information 
that support an independent conclusion of GRAS status, we are issuing a 
guidance directed to any person who evaluates whether the available 
data and information regarding the safety of a substance under the 
conditions of its intended use satisfy GRAS criteria. The purpose of 
the guidance is to: (1) Remind such persons of their responsibilities 
under the FD&C Act regarding a conclusion of GRAS status, regardless of 
whether the conclusion of GRAS status is submitted to us as a GRAS 
notice; and (2) refer such persons to key resources, such as those 
discussed in Response 128, for evaluating the safety of the substance 
under the conditions of its intended use and for evaluating whether the 
available data and information regarding safety satisfy the criteria 
for eligibility for classification as GRAS in Sec.  170.30. We believe 
that such guidance is appropriate in light of the recommendations of 
the GAO report.

C. Compliance With Other FDA Regulations

    We proposed that a GRAS notice would not constitute compliance with 
the requirements for a health claim petition in Sec.  101.14(b)(3)(ii) 
or for a new infant formula submission in Sec.  106.120(b)(6)(ii). We 
specified that any person who submits a health claim petition, or who 
submits a new infant formula submission, must comply in full with the 
requirements of the applicable program (proposed Sec.  170.36(a)(2)).
    (Comment 130) Several comments object to the perceived implication 
that a GRAS notice could never be used to support a health claim 
petition or a new infant formula submission. In general, the comments 
maintain we should consider, on a case-by-case basis, whether a 
particular GRAS notice is sufficient to comply with the requirements of 
the applicable program rather than categorically disallow a GRAS notice 
as a means for satisfying the requirements of the applicable program.
    (Response 130) We are not including this proposed provision in the 
final rule because it is not necessary to do so. Any person who submits 
a health claim petition, or who submits a new infant formula 
submission, must comply in full with the requirements of the applicable 
program whether this rule says so or not. An FDA office that evaluates 
a health claim petition or a new infant formula submission will take 
into account our response to a GRAS notice when evaluating the health 
claim petition or new infant formula submission. In practice during the 
Interim Pilot program, an FDA office evaluated a health claim petition 
or a new infant formula submission for several substances that were the 
subject of a previously submitted GRAS notice. In each case, FDA's 
evaluation of the health claim petition or new infant formula 
submission had an outcome that was consistent with our response to that 
GRAS notice (see section IV.A of CFSAN's 2010 experience document (Ref. 
18)).

D. Impact on Other Federal Agencies

    In our discussion in the proposed rule of the proposed procedures 
for making information about GRAS notices readily accessible to the 
public, we stated our belief that there would be considerable interest, 
from a broad segment of the public, including other Federal agencies, 
in notices received under the proposed notification procedure (62 FR 
18938 at 18952). We also stated our expectation that such groups will 
likely want to know whether we are aware that a substance is being used 
in food on the basis of the GRAS provision and whether we have advised 
a notifier that we have identified a problem with the notice.
    (Comment 131) The Bureau of Alcohol, Tobacco and Firearms (BATF) 
(in the U.S. Department of the Treasury (now TTB) submitted a comment 
stating that it has no major problem with our proposal to replace the 
GRAS affirmation petition process with a notification procedure, but 
that there are two ways in which the proposed rule would impact TTB. 
First, TTB's wine regulations in 27 CFR 24.250 (Application for use of 
new treating material or process) require that a proprietor who wishes 
to use a new

[[Page 55029]]

wine treating material submit to TTB an application that includes 
documentary evidence of FDA's approval of the material under the 
conditions of its intended use. If we issue a final rule to establish a 
GRAS notification procedure, TTB would need to amend this requirement 
to state that TTB needs either evidence of FDA approval or evidence 
that FDA has been notified of a conclusion of GRAS status and has no 
questions about that conclusion.
    Second, certain alcoholic beverage products require formula 
approval by TTB due to the ingredients (such as colors, flavors, herbs, 
and spices) in the products. Currently, TTB requires that these 
ingredients be approved by FDA before TTB approves the formula. If we 
issue a final rule to establish a GRAS notification procedure, TTB 
would still check the ingredients in these formulas before approving 
the formula, but could accept evidence that FDA has been notified of a 
conclusion of GRAS status and has no questions about that conclusion.
    TTB asks us to include the conditions of use in our response to a 
GRAS notice so that TTB would know the parameters that FDA evaluated in 
considering the GRAS notice (i.e., the foods and beverages and the 
amounts in those foods and beverages). TTB also asks us to publish and 
update a list of GRAS notices on a frequent basis, and to include the 
conditions of use that FDA evaluated in this list.
    (Response 131) The provisions of this rule are consistent with 
TTB's requests. The rule specifies that we will make a list of filed 
GRAS notices, including the information described in Sec.  
170.225(c)(2) through (c)(5), readily accessible to the public (see 
Sec.  170.275(b)(1)). The information the rule specifies will be 
readily accessible includes the intended conditions of use of the 
notified substance, including the foods in which the substance will be 
used, the levels of use in such foods, and the purpose(s) for which the 
substance will be used (see Sec.  170.225(c)(4)). The response letters 
that we issued during the Interim Pilot program described the 
conditions of use of the notified substance, and we intend to continue 
describing the conditions of use of the notified substance in letters 
issued under the final rule.
    (Comment 132) Some comments assert that our affirmation of GRAS 
status established a clear standard that was needed by other Federal 
agencies to carry out their own regulatory responsibilities. The 
comments cite BATF (now TTB), FSIS (in USDA), and EPA as examples of 
such Federal agencies. In general, these comments maintain that the 
applicable Federal agency must be able to accept our response to a GRAS 
notice in lieu of a regulation affirming GRAS status. One comment notes 
that the proposed rule did not explicitly address the impact of the 
proposed rule on other Federal agencies and urges us to consult with 
the cited Federal agencies prior to issuing the final rule.
    (Response 132) None of the Federal agencies cited by these comments 
have advised us that the absence of a regulation affirming GRAS status 
for the use of a food substance would preclude the applicable Agency 
from carrying out its statutory responsibilities. As discussed in the 
following paragraphs, we have interacted with each of these agencies as 
requested.
    TTB. As discussed in section IV.B of CFSAN's 2010 experience 
document (Ref. 18), during the Interim Pilot program CFSAN received and 
filed several GRAS notices for substances intended for use in alcoholic 
beverage products. These notices demonstrate that manufacturers of 
alcoholic beverage products are aware of the GRAS notification 
procedure and are using GRAS notices as a means to satisfy TTB's 
regulations. As also discussed in section IV.B of CFSAN's 2010 
experience document (Ref. 18), on September 29, 2005, representatives 
of TTB met with representatives of CFSAN in the offices of CFSAN's 
Office of Food Additive Safety. At that meeting, representatives of 
CFSAN described the GRAS notification procedure that was operating 
under the framework of the proposed rule. CFSAN provided a copy of 
TTB's comments to these representatives, and none of TTB's 
representatives expressed any concern about the operation of the 
program.
    FSIS. As discussed in section III.L of CFSAN's 2010 experience 
document (Ref. 18), during the period 1998 through 2009 more than 25 
percent of GRAS notices filed by CFSAN described use of the notified 
substance in meat, meat food products, or poultry products. During 
CFSAN's review of these GRAS notices, CFSAN consulted with FSIS 
regarding the use of the applicable substance. FSIS provided feedback 
to CFSAN about the use of the notified substance in products regulated 
by FSIS and requested that CFSAN provide this feedback to the notifier. 
In 2000, FDA and FSIS formalized this process of inter-agency 
consultation in a MOU (65 FR 33330, May 23, 2000). Subsequently, FDA 
and FSIS have amended the MOU to include simultaneous evaluation of 
substances subject to regulation by USDA under the Egg Products 
Inspection Act (21 U.S.C. 1033(a)(2)) (Ref. 36). The final rule 
includes the procedures CFSAN will use when coordinating its evaluation 
of a GRAS notice with FSIS (see Sec.  170.270).
    EPA. CFSAN has discussed the concerns raised by these comments with 
representatives from EPA (Ref. 50). The representatives from EPA 
deferred to CFSAN regarding the appropriate process for voluntary 
interaction between us and the regulated industry with respect to GRAS 
substances.

E. Impact on International Trade

    In the proposed rule, we requested comment on whether the proposed 
substitution of a GRAS notification procedure for the GRAS affirmation 
petition process would have any impact on international trade (62 FR 
18938 at 18955).
    (Comment 133) Comments that responded to this request for comment 
express the view that whether the proposed substitution of a GRAS 
notification procedure for the GRAS affirmation petition process would 
have a positive, neutral, or negative impact on international trade 
would depend on the nature of our response to a GRAS notice, 
particularly when we do not question the notifier's basis for a 
conclusion of GRAS status. The comments explain that the proposed rule 
could have a positive or neutral impact on international trade if our 
response is clear and definitive, provides regulatory significance, and 
is as affirmative as possible, but could have a negative impact on 
international trade if our response is neutral or vague. One comment 
expresses the opinion that any impact on international trade would be 
minimal because JECFA frequently assesses uses of a food ingredient, 
and foreign regulatory agencies frequently reach a decision to allow 
uses of a food ingredient, before we complete our rulemaking under the 
GRAS affirmation petition process.
    (Response 133) The ``no questions letters'' we issued during the 
Interim Pilot program make clear that the notifier (rather than FDA) is 
responsible for the conclusion of GRAS status, and place our statement 
that we have no questions about the notifier's conclusion of GRAS 
status in the contexts of both time and the available data and 
information (see table 1). These features of the ``no questions 
letters'' make the letters clear and definitive and provide regulatory 
significance (i.e., regulatory status), and we intend to retain these 
features in letters we issue under the final rule. Moreover, the fact 
that many GRAS notices were submitted by foreign firms demonstrates 
that foreign firms see value in submitting GRAS notices to us (Ref. 
51).

[[Page 55030]]

    Under the final rule, we will respond to a GRAS notice within 180 
days after we file a submission as a GRAS notice, with an option to 
extend the timeframe by an additional 90 days as needed (see Sec.  
170.265(b)(1)). As discussed in Response 123, during the ten year 
period extending from 1990 through 1999, we completed the rulemaking 
process for 24 GRAS affirmation petitions, with an average elapsed time 
of approximately 7.9 years (median elapsed time approximately 6.9 
years). Thus, we believe that the GRAS notification procedure will come 
to closure more quickly than the GRAS affirmation petition process.

F. Audits

    In the proposed rule, we stated that it would be prudent for us 
monitor compliance with the essence of the statutory requirements for 
GRAS status (i.e., that there is common knowledge among qualified 
experts that there is reasonable certainty that the substance is not 
harmful under the conditions of its intended use) and announced that we 
intended to conduct random audits of data and information maintained by 
the notifier (62 FR 18938 at 18947). In addition, because the proposed 
substitution of a GRAS notification procedure for the GRAS affirmation 
petition process would allow us to direct our resources to priority 
questions about GRAS status, we might conduct an audit on a broad issue 
or class of products if the issue or use of a class of products raises 
important public health issues.
    (Comment 134) One comment asks us to renew our commitment to random 
auditing to ensure that companies maintain proper recordkeeping 
practices.
    (Response 134) As discussed in section IV.C of CFSAN's 2010 
experience document (Ref. 18), during the Interim Pilot program, CFSAN 
did not conduct any random audits of data and information maintained by 
the notifier. However, CFSAN did not hesitate to ask a notifier to 
provide certain data or information as an amendment to a GRAS notice. 
(See also the discussion in section III.C.1 of CFSAN's 2010 experience 
document regarding amendments to GRAS notices.) In essence, CFSAN used 
its resources to seek access to data and information on a priority, 
rather than a random, basis. At this time, we intend to continue 
directing our resources on a priority basis under the final rule.
    (Comment 135) One comment asks us to provide a notifier with the 
option of converting a GRAS notice to a GRAS affirmation petition if we 
audit the data supporting a GRAS notice.
    (Response 135) As discussed in Response 24 and Response 123, we 
have eliminated the former GRAS affirmation petition process. 
Therefore, the administrative process requested by these comments is no 
longer operative.
    (Comment 136) One comment asks us to incorporate two procedures to 
avoid any uncertainty regarding the results of the audit. First, the 
comment asks us to provide the notifier with a letter confirming that 
the audit is completed and we have no basis to question the conclusion 
of GRAS status if that is the outcome of our audit. Second, the comment 
asks us to apply any appeal mechanism specified by the rule to 
circumstances in which we question a conclusion of GRAS status based on 
an audit.
    (Response 136) We decline these requests. If we have no questions 
about the notifier's conclusion of GRAS status, we would respond with a 
``no questions letter'' based on our evaluation of the entire GRAS 
notice, not based solely on the results of an audit of the data and 
information maintained by the notifier to support the notifier's GRAS 
notice. As discussed in Response 108, the rule does not include an 
appeals process that would be specific to the GRAS notification 
procedure.
    (Comment 137) One comment suggests that our audit examine the same 
``quantum of evidence'' as we would review to affirm GRAS status, and 
asserts that a strong statement of confidence, if not outright 
affirmation, would be appropriate after successful completion of this 
type of an indepth review.
    (Response 137) The purpose of the audit would be to verify that a 
notifier maintains the data and information specified in the notice, 
not to conduct a full scientific evaluation of those data and 
information (62 FR 18938 at 18947). Therefore, we decline the request 
to examine the same ``quantum of evidence'' as we would review to 
affirm GRAS status. Because the purpose of an audit would be to verify 
compliance with the statutory requirements for GRAS criteria, we 
disagree our response to a GRAS notice following a favorable audit 
should result in a ``strong statement of confidence'' rather than a 
``no questions letter.'' However, we intend that our response letter 
would mention any audit that we conduct before responding to a GRAS 
notice.

G. Lack of an Environmental Assessment

    (Comment 138) One comment suggests that a GRAS notice is ideal in 
circumstances where our evaluation of an environmental assessment, 
which is required for a food additive petition, precludes timely action 
by us on a petition.
    (Response 138) We advise potential notifiers that the lack of a 
requirement to submit an environmental component (e.g., an 
environmental assessment) with a GRAS notice does not eliminate a 
notifier's responsibility to comply with applicable Federal, State, 
tribal, and local law or requirements regarding protection of the 
environment.

H. Substances Affirmed as GRAS With Specific Limitations

    (Comment 139) One comment asks us to ``modernize the standard'' in 
Sec.  184.1(b)(2) to allow expedited review under the notification 
program of new uses of substances affirmed as GRAS under Sec.  
184.1(b)(2). (Section 184.1(b)(2) specifies that if an ingredient is 
affirmed as GRAS with specific limitation(s), it shall be used in food 
only within such limitation(s), including the category of food(s), the 
functional use(s) of the ingredient, and the level(s) of use, and any 
use of such an ingredient not in full compliance with each such 
established limitation shall require a food additive regulation.)
    (Response 139) We decline the request to amend Sec.  184.1(b) 
beyond the editorial, clarifying, and conforming changes listed in 
table 29. The comment provides no basis for us to do so. As discussed 
during the rulemaking to establish Sec.  184.1(b)(2) (41 CFR 53600 at 
53601, December 7, 1976), that regulation does not require that a 
subsequent use be covered by a food additive regulation even though it 
may be GRAS. As an alternative to a food additive regulation, the 
regulation affirming a substance as GRAS with specific limitations on 
the conditions of use may be amended to cover additional uses that have 
become GRAS. Importantly, both mechanisms (i.e., food additive 
regulation and GRAS affirmation regulation) require rulemaking, and the 
appropriate mechanism for a manufacturer to lawfully use a substance 
outside the limitations established in a regulation affirming specific 
uses of the substance as GRAS with specific limitations is to submit a 
petition to us. A manufacturer may submit a food additive petition 
asking us to conduct rulemaking that results in a food additive 
regulation; alternatively, now that the GRAS affirmation petition 
process is no longer operative, the manufacturer may submit a citizen 
petition in accordance with Sec.  10.30 asking us to conduct rulemaking 
that amends the regulation affirming a

[[Page 55031]]

substance as GRAS with specific limitations on the conditions of use. 
(See also Ref. 4.58 to CFSAN's 2010 experience document).
    See section III.N.2 of CFSAN's 2010 experience document (Ref. 18) 
for a discussion of a GRAS affirmation petition to amend a specific 
regulation that affirmed a substance as GRAS with specific limitations 
on the conditions of use; we converted that GRAS affirmation petition 
to a food additive petition and authorized the additional conditions of 
use in a food additive regulation. We advise persons who wish to 
petition us to provide for additional uses of substances that have been 
affirmed as GRAS with specific limitations that under Sec.  10.30(e) we 
may advise that we are denying the request to initiate rulemaking to 
amend the GRAS affirmation regulation, but note that we could 
accommodate the request to conduct rulemaking through the food additive 
petition process.

XXV. Comments on Substances Intended for Use in Animal Food

A. Issues in the 2010 Notice Specific to Animal Food

    In the 2010 notice, we discussed several issues associated with the 
requirements for a GRAS notice for an intended use in animal food to 
consider dietary exposure (see table 27). Although we discussed these 
issues in a section entitled ``Dietary exposure,'' these issues broadly 
applied to several provisions of the rule (see, e.g., Sec. Sec.  
570.30, 570.225(c)(4), 570.235, 570.245, and 570.250). In the following 
sections, we discuss how comments on these issues, and associated 
conforming changes, lead to specific revisions to the regulatory text. 
See table 28 for the principal changes specific to the proposed animal 
food rule other than the editorial, clarifying, and conforming changes 
shown in table 29 and the additional editorial changes associated with 
the redesignation of the proposed notification procedure (proposed 
Sec.  570.36) as part 570, subpart E. Table 28 does not include those 
changes that we made to the proposed requirements when we made an 
analogous change to the human food regulations in part 170.

       Table 27--Issues in the 2010 Notice Specific to Animal Food
------------------------------------------------------------------------
              Description of
 Issue No.   our request for                   Reference
                 comment
------------------------------------------------------------------------
11c.......  Whether it is      75 FR 81536 at 81541.
             necessary to
             clarify that the
             GRAS
             notification
             procedure is
             applicable to
             substances used
             in both food and
             drinking water
             of animals and,
             if so, whether
             it would be
             necessary to
             clarify this in
             the provisions
             of the proposed
             notification
             procedure.
11d.......  Whether it is      75 FR 81536 at 81541.
             necessary to
             clarify proposed
             Sec.
             570.36(c)(1)(iii
             ) to explicitly
             require
             submission of
             information
             about the animal
             species expected
             to consume the
             substance.
11e.......  Whether it is      75 FR 81536 at 81541.
             necessary to
             clarify
             applicable
             sections of the
             proposed rule to
             explicitly
             require, for
             substances
             intended for use
             in the food of
             an animal used
             to produce human
             food, the
             submission of
             information
             about both
             target animal
             and human safety.
------------------------------------------------------------------------


 Table 28--Summary of Principal Changes Specific to the Proposed Animal
                                Food Rule
------------------------------------------------------------------------
  Regulatory section in the final
               rule                                Change
------------------------------------------------------------------------
Sec.   570.30(a), (b), and (c)....  Specify that general recognition of
                                     safety is based on data and
                                     information that addresses safety
                                     for both the target animal and for
                                     humans consuming human food derived
                                     from food-producing animals.
Sec.   570.225(c)(4)..............  Requires you to describe the
                                     intended conditions of use of a
                                     notified substance in animal food
                                     by specifying the levels of use in
                                     foods or drinking water.
Sec.   570.235....................  In part 3 of your GRAS notice, you
                                     must provide data and information
                                     about exposure to the target animal
                                     and to humans consuming human food
                                     derived from food-producing
                                     animals.
Sec.   570.250(a) and (b).........  You must explain how the generally
                                     available data and information in
                                     your notice provide a basis for
                                     your view that the notified
                                     substance is generally recognized
                                     as safe, among qualified experts,
                                     under the conditions of its
                                     intended use for both the target
                                     animal and for humans consuming
                                     human food derived from food-
                                     producing animals.
------------------------------------------------------------------------

B. Criteria for Eligibility for Classification as GRAS for a Substance 
Intended for Use in Animal Food (Sec.  570.30)

    (Comment 140) Comments that address Issue 11e agree that data and 
information in a GRAS notice must be sufficient to address safety for 
both the target animal and for humans consuming human food derived from 
food-producing animals (see Comment 150 and Comment 151).
    (Response 140) We have modified several provisions of the GRAS 
notification procedure to specify how the notifier must provide data 
and information to address the safety of the notified substance under 
the conditions of its intended use for both the target animal and for 
humans consuming human food derived from food-producing animals (see 
Sec. Sec.  570.225(c)(4), 570.235, 570.245, and 570.250). To clarify 
that the submission requirements reflect the GRAS criteria for the use 
of a substance in animal food, we also have modified Sec.  570.30(a), 
(b), and (c) to specify that general recognition of safety is based on 
data and information that addresses safety for both the target animal 
and for humans consuming human food derived from food-producing 
animals. See the regulatory text of Sec.  570.30. See also Response 141 
regarding the definition of common use in food in Sec.  570.3(f).
    (Comment 141) One comment notes that the proposed human food 
regulations, but not the proposed animal food regulations, include 
specific criteria for eligibility for classification as GRAS through 
experience based on common use in food prior to 1958 when that use 
occurred exclusively or primarily outside the United States (see Sec.  
170.30(c)(2)). This comment asks us to maintain parallel criteria for 
eligibility for classification as GRAS through experience based on 
common use in food in the human food regulations and the animal food 
regulations by amending Sec.  570.30(c) of the animal food regulations 
to include a provision analogous to Sec.  170.30(c)(2).
    (Response 141) We are amending Sec.  570.30(c) to include a 
provision analogous to Sec.  170.30(c)(2). See the regulatory text of 
Sec.  570.30(c)(1) and (2). For consistency with the clarifying

[[Page 55032]]

amendment to the general criteria in Sec.  570.30(a), we also are 
revising Sec.  570.30(c) to clarify that general recognition of safety 
through experience based on common use in food shall address safety for 
both the target animal and for humans consuming human food derived from 
food-producing animals. For consistency with the clarifying amendment 
to the general criteria in Sec.  570.30(a), we also are revising the 
definition of common use in food to mean a substantial history of 
consumption of a substance by a significant number of animals of the 
species to which the substance is intended to be fed (and, for food-
producing animals fed with such substance, also means a substantial 
history of consumption by humans consuming human foods derived from 
those food-producing animals), prior to January 1, 1958 (see Sec.  
570.3(f) and table 29).

C. Part 1 of a GRAS Notice for a Substance Intended for Use in Animal 
Food: Name of the Notified Substance (Sec.  570.225(c)(3))

    As shown in table 6, in the 2010 notice we asked for comment on 
whether to require that the GRAS notice include the name of the 
notified substance, using an appropriately descriptive term, instead of 
the ``common or usual name'' of the notified substance (Issue 7). The 
final rule requires that Part 1 of a GRAS notice for an intended use of 
a notified substance in animal food include the name of the notified 
substance, using an appropriately descriptive term (Sec.  
570.225(c)(3)). The appropriately descriptive term may be the same as 
the common or usual name of the substance. You may consult with CVM's 
staff in operating divisions that address the labeling requirements of 
the FD&C Act, currently CVM's Division of Animal Feeds, regarding any 
common or usual name for a substance used in animal food. In addition, 
for substances used in animal food, the Association of American Feed 
Control Officials (AAFCO) annually publishes its Official Publication, 
a handbook which contains, among other things, Official Feed Terms, 
which define many of the terms commonly used in the animal food 
manufacturing industry. It also contains Official and Tentative 
Definitions of Feed Ingredients, a set of definitions for ingredients 
commonly used in animal food. Under CVM's Compliance Policy Guide CPG 
665.100 (Common or Usual Names for Animal Feed Ingredients), the 
definitions, as they appear in the AAFCO Official Publication, are 
generally regarded as constituting the common or usual name for animal 
food ingredients, including pet food (Ref. 52).

D. Part 1 of a GRAS Notice for a Substance Intended for Use in Animal 
Food: Intended Conditions of Use (Sec.  570.225(c)(4))

    (Comment 142) One comment asks us to require that a notifier 
specify whether the intended use of the notified substance is in food 
or in drinking water. Another comment asks CVM to accept the 
anticipated consumption levels by animals that are based upon general 
formulation principles that consider the availability of contemporary 
feedstuffs.
    (Response 142) The final requirements for Part 1 of a GRAS notice 
require you to describe the intended conditions of use of a notified 
substance in animal food by stating whether the substance will be added 
to food (including drinking water) for animals in which the substance 
will be used, and by identifying the foods to which it will be added 
and the levels of use in such foods (see Sec.  570.225(c)(4)). In 
describing the levels of use of the notified substance, you may base 
the levels of use upon general formulation principles that consider the 
availability of contemporary feedstuffs. See also Response 148 
regarding the calculation of target animal exposure.
    (Comment 143) Some comments ask us to specifically require 
submission of information about the animal species expected to consume 
the substance. One comment states that specifying the target animal is 
as important as specifying whether the substance would be consumed by 
humans in human food derived from the animal. Another comment suggests 
that requiring submission of information about the animal that would 
consume the substance would avoid the unnecessary delays associated 
with CVM's questions that result in an amendment to the notice with 
information about the animal species expected to consume the substance.
    (Response 143) The final requirements for Part 1 of a GRAS notice 
require you to describe the intended conditions of use of a notified 
substance in animal food, including the animal species for which the 
foods are intended. In addition, the final requirements for Part 1 of a 
GRAS notice specify that in describing the intended conditions of use 
of a notified substance in animal food, you must, when appropriate, 
describe any ``subpopulation'' expected to consume the notified 
substance; the life stage of an animal is an example of what we mean by 
``subpopulation.'' The physical, physiologic, and absorption/
distribution/metabolism/elimination characteristics of a given animal 
species may vary based on life stages within the same animal species. A 
substance that is safe for use in an animal species at one stage of 
life may not be safe for use in the same animal species at a different 
stage of life. See also Response 51.

E. Part 2 of a GRAS Notice for a Substance Intended for Use in Animal 
Food: Data and Information Bearing on the Physical or Other Technical 
Effect of the Notified Substance (Sec.  570.230(d))

    (Comment 144) Several comments discuss CVM's practice, during the 
Interim Pilot program, of asking a notifier to provide data or 
information demonstrating the effectiveness, or utility, of the 
substance. Some comments ask us to limit the notification procedure to 
the information necessary to conduct an appropriate safety assessment, 
without submission of additional data and information to demonstrate 
the technical effect of the substance within animal food in cases where 
the technical effect has no impact on safety. Some comments agree that 
the intended conditions of use of the notified substance in animal food 
must be described and supported in the notice, but assert that the need 
for utility data generated from target animal feeding studies is 
inappropriate and unnecessary because the pivotal issue is whether the 
ingredient is safe to feed to animals.
    (Response 144) We have added a requirement for Part 2 of a GRAS 
notice to include relevant data and information bearing on the physical 
or other technical effect the notified substance is intended to 
produce, including the quantity of the notified substance required to 
produce such effect, when necessary to demonstrate safety (see Sec.  
570.230(d)). We agree that data and information bearing on the physical 
or other technical effect the notified substance is intended to produce 
are only necessary when they bear on safety. This relationship to 
safety is consistent with the requirements of the FD&C Act for a 
petition to establish the safety of a food additive (see section 
409(b)(2)(C) of the FD&C Act).
    The physical or other technical effects of substances added to 
animal food fall into two main categories: (1) Substances fed for a 
nutritive effect in the animal (e.g., providing one or more nutrients 
or other nutritive effect); and (2) substances that have technical 
effects in the food (e.g., anti-caking agents, binders, emulsifiers, 
enzymes, mixing

[[Page 55033]]

aids, preservatives, processing aids, stabilizers, and substances added 
for aroma, flavor, or other technical effects) rather than nutritive 
effects in the animal. As discussed in the following paragraphs, a 
substance added for either a nutritive effect or for a technical effect 
in animal food can have an impact on safety for the target animal.
    Nutritive effect in the animal. Data and information bearing on the 
nutritive effect of a substance may be necessary to demonstrate safety 
because animals (e.g., food-producing animals, companion animals) 
typically are fed the same diet formula for long periods of their life. 
These diets are formulated to supply all of the animal's daily nutrient 
needs for a specific life stage (e.g., growth, reproduction, adult 
maintenance). The diet must provide appropriate amounts of all 
nutrients the animal requires in a form that the animal can use and 
consume daily; otherwise, a nutrient deficiency or toxicity can result, 
causing adverse effects to animal health, including poor growth, 
excessive weight loss, organ system failures, and death. Under these 
constraints of how animals are fed, a substance intended to provide one 
or more nutrients becomes unsafe if the nutrients are, in fact, not 
provided in a form usable by the animals consuming the diet.
    The typical approach to support the nutritive effect of a substance 
intended for use in animal food is to combine generally available and 
accepted data and information about the general function of the 
substance with animal feeding studies demonstrating that the substance 
acts as intended. When an appropriate animal feeding study (i.e., an 
animal feeding study that is relevant, properly designed, and well-
controlled) is already generally available (e.g., in the peer-reviewed 
scientific literature), it can be possible to support the nutritive 
effect of a substance without conducting a new study. If an appropriate 
animal feeding study is not already generally available, an animal 
feeding study specifically conducted to support the nutritive effect 
would ordinarily be published and, as discussed in Response 19, there 
would be a time gap between the publication of the study and the use of 
the published study to support a conclusion of GRAS status. (As 
discussed in Response 9, unpublished studies can be used to 
corroboratively support the intended nutritive effect of the substance 
under the conditions of its intended use.) In addition, for any animal 
feeding study a factor to be considered is whether data and information 
obtained from a feeding study conducted in one animal species (or in 
one stage of life of an animal species) can be used to support safety 
in another animal species (or in a different stage of life in the same 
animal species). See Response 145 for a discussion of when data and 
information that are obtained from an animal study and bear on the 
nutritive effect of a substance could be extrapolated from one animal 
species to another animal species, or to a different stage of life of 
the same animal species. In the following paragraphs, we provide 
examples of when data and information bearing on the nutritive effect 
of a substance intended for use in animal food could be established 
through the use of generally available and accepted data and 
information, or likely would need to be established through an animal 
feeding study that specifically supports the nutritive effect of the 
substance under the conditions of its intended use.
    For some types of substances, generally available and accepted data 
and information about the function of a substance may be adequate to 
support the nutritive effect of the substance without also relying on 
an animal feeding study. For example, generally available and accepted 
data and information about the function of fat and carbohydrates as 
sources of dietary energy often can be used for substances providing 
fat intended as a source of dietary energy (rather than as a source of 
essential fatty acids) and for substances providing carbohydrates 
intended as a source of dietary energy. Likewise, generally available 
and accepted data and information about the nutritive content of human 
food can provide support for the nutritive effect of unsalable human 
food products (such as bruised produce) being collected for animal food 
use for their nutritional content rather than entering landfills or 
being incinerated.
    For other types of substances, an animal feeding study (whether 
previously published or newly conducted) is the norm to support the 
nutritive effect of the substance. For example, for an ingredient that 
is intended to supply an essential mineral (such as phosphorus or 
zinc), generally available data and information can provide support 
that the mineral is an essential nutrient for the animal, but the 
bioavailability of the mineral in the ingredient that would be added to 
animal food generally needs to be determined in an animal feeding study 
conducted with that specific ingredient, because data regarding the 
amount of the mineral that is added to the feed in the ingredient (or 
that can be detected analytically in the feed or in the ingredient) 
would not provide evidence that the mineral is in a form that is 
available to the animal. However, for an ingredient that is intended to 
provide an essential amino acid, the need for an animal feeding study 
can depend on the form and composition of the ingredient. For example, 
it can be possible to rely on published literature to establish that a 
crystalline amino acid will be bioavailable to an animal (and, thus, 
functional). However, if a complex matrix, such as a biomass composed 
of microbial cells or a processed oilseed meal, is intended to be a 
source of amino acids, an animal feeding study generally would be 
needed to provide evidence that the bioavailability of the amino acids 
has not been adversely impacted by the other substances present in the 
complex matrix.
    Technical effect in the food (rather than nutritive effect in the 
animal). As with a substance intended to provide a nutritive effect in 
the animal, data and information bearing on a substance's technical 
effect in the food (e.g., substances such as anti-caking agents, 
binders, emulsifiers, enzymes, mixing aids, preservatives, processing 
aids, stabilizers, and substances added for aroma, flavor or other 
technical effects) may be necessary to demonstrate safety because of 
the physical form and properties of animal diets. Although generally 
available and accepted data and information can provide evidence of a 
technical effect in the food, it is common for studies to be conducted 
with the animal food to demonstrate the intended technical effect. 
Depending on the intended technical effect, an animal feeding study 
(whether previously published or newly conducted) may be also needed to 
demonstrate the intended technical effect of the substance. In the 
following paragraphs, we provide examples of when animal feeding 
studies may be needed to support the intended technical effect of the 
substance. We also provide examples of when an intended technical 
effect in animal food could be established through the use of generally 
available and accepted data and information about the technical effect 
and the studies conducted with the intended animal food matrix. As with 
a substance intended to provide a nutritive effect in the animal, when 
an appropriate study, which may be an animal feeding study, is already 
generally available (e.g., in the peer-reviewed scientific literature), 
it can be possible to support the technical effect of a substance in 
the food without conducting a new study. If an appropriate study is not 
already generally available, a study conducted

[[Page 55034]]

to support the technical effect in the food would ordinarily be 
published and, as discussed in Response 19, there would be a time gap 
between the publication of the study and the use of the published study 
to support a conclusion of GRAS status.
    Enzymes are often added to animal food to alter the bioavailability 
of nutrients already in the food. For example, it is well known that 
the enzyme phytase increases the bioavailability to animals of the 
phosphorus present in grain (Ref. 53), and substances that provide 
phytase activity are often added to diets for poultry and swine. 
Poultry and swine diets are typically formulated with the minimal 
amount of phosphorus. If the phytase enzyme does not carry out the 
effect of improving phosphorus availability to the animal as intended, 
the consequence will be a diet that is deficient in phosphorus and 
therefore results in adverse impacts on animal health in the form of 
decreased growth, increased orthopedic disease (e.g., rickets), and 
suffering animals (Ref. 54). As another example, protease enzymes can 
be added to an animal food to affect the digestibility of proteins in 
the food (Ref. 55). Both animal feeding studies and stability studies 
(to assess the stability of the enzyme in the food and, thus, its 
ability to perform its intended technical effect) are the norm when 
enzymes are added to animal food. However, when the function of an 
enzyme in animal food is well known, it is also common to use generally 
available and accepted data and information about the function of the 
enzyme in combination with animal feeding studies and stability studies 
to support the function of the enzyme (see section IV in CVM's 
experience document (Ref. 20)).
    Substances such as binders, lubricants, and pelleting agents are 
added to animal food that will be fed as pellets. In some cases, such 
substances are added to ensure that the pellet retains its desired form 
and that the individual ingredients remain agglomerated, making it more 
difficult for an animal to select only those ingredients it prefers. In 
aquaculture foods, such substances are added to prevent the pellet from 
dissolving or prevent the nutrients from leaching out of the pellet. 
Depending on the circumstances, either technical effect studies 
conducted with the animal food, or generally available and accepted 
data and information about the function of the substance, can be used 
to support the intended technical effect, such as that of a binder, 
lubricant, or pelleting agent, etc., when added to animal food.
    Flavors are added to animal food for certain species, generally for 
specific life stages of that species. For example, flavors can be added 
to animal food intended for consumption by piglets being transitioned 
from a milk-based diet to a commercial growth diet to increase 
consumption of the commercial growth diet. Flavors also are added to 
commercial animal food intended for aquaculture to attract newly 
hatched fish (fish fry) to the commercial food when the commercial food 
does not resemble the food that fish fry would consume in nature. If 
the fish fry are not attracted to the commercial food, the fish fry can 
starve to death. Animal feeding studies are the norm to support the 
function of the substance as a flavor when added to animal food.
    Substances such as emulsifiers and stabilizers are added to animal 
food to ensure that an animal consumes all of the ingredients in the 
correct proportions in order to meet its nutritional needs. 
Inconsistent nutrient content and delivery of a diet to the animal can 
cause either nutrient deficiency diseases, or toxicities. For example, 
liquid cattle foods are often available to the animal at all times and 
cattle simply lick the feeding device to obtain the food. If the 
minerals present in the liquid fall out of suspension and settle to the 
bottom, the first animals to access the feeder will consume lower 
nutrient levels than expected, while those animals that access the 
feeder later and consume the bottommost material may be at risk of 
toxicity due to higher nutrient levels. For dry ingredients, the 
ingredients in the formulated diet must be uniformly dispersed and 
mixed, remain mixed during handling, and be physically stable as a 
formulated animal diet is moved through augers and conveyors, and 
transported in bulk in trucks, which can result in the loss of 
nutrients through sifting or ``unmixing.'' These effects are assessed 
on the diet itself through appropriate studies.
    (Comment 145) One comment asks us to accept reasonable arguments as 
to the worst-case exposures (inclusion levels) if the substance or 
class of substances has well-established use patterns rather than 
require utility data to support the intended nutritional effect. This 
comment also asks us to be flexible when utility data are warranted to 
support an entirely new use in animal feeds when utility data from one 
representative species would be sufficient to address utility in the 
target animal.
    (Response 145) When animal feeding studies are necessary to provide 
data and information bearing on the nutritive effects of a substance 
intended for use in animal food, the potential to extrapolate from the 
conclusions of a feeding study conducted in one animal species to 
another animal species depends on the similarities of their digestive 
systems, physiology, and diets. For example, when a bioavailability 
study for selenium present in selenium yeast is conducted in cattle 
(which have a fermentative digestive tract), it can be possible to 
extrapolate the conclusions of that bioavailability study to other 
animal species that have fermentative digestive tracts. However, when a 
bioavailability study for copper is conducted in a ruminant animal 
species, it may not be appropriate to extrapolate the conclusions of 
that bioavailability study to sheep, even though sheep are ruminants, 
because sheep physiology is such that sheep are much more sensitive to 
copper toxicity than other ruminant species. In addition, when a 
bioavailability study for a nutrient is conducted in animals other than 
fish, it may not be possible to extrapolate the conclusions of that 
bioavailability study to aquaculture-fed fish, because aquaculture 
diets that are consumed in the water present special challenges, 
particularly for slow-feeding or bottom-feeding aquaculture species, 
where the diet pellet must retain its form and nutrient content until 
the pellet is consumed. For example, it is possible for nutrients that 
are soluble in water to dissolve out of the pellet before consumption, 
preventing the aquaculture animal from accessing all the required 
nutrients.
    See Response 144 for a discussion of circumstances where generally 
available and accepted data and information can be used to provide 
evidence bearing on the nutritive effects of a substance intended for 
use in animal food (e.g., for substances providing fat intended as a 
source of dietary energy, for substances providing carbohydrates 
intended as a source of dietary energy, for unsalable human food 
products, and when a crystalline amino acid is added to animal food). 
See also Response 150 for additional discussion of limitations on the 
use of generally available and accepted data and information, such as a 
weight of evidence approach, for the extrapolation of available data 
and information from an animal species other than the target animal.
    Regardless of whether the intended use of the notified substance is 
to provide nutritive value or technical effect, any person who 
concludes that the available data and information regarding the safety 
of a notified substance under the conditions of its intended use 
satisfy GRAS criteria must

[[Page 55035]]

have a basis for the conclusion of GRAS status, irrespective of whether 
that person notifies us of that conclusion in a GRAS notice. If you 
submit your conclusion of GRAS status to FDA, you must explain how the 
data and information in your GRAS notice provide the basis for your 
conclusion, e.g., in Part 2 of the GRAS notice (where you would 
describe the applicable data and information), in the narrative in Part 
6 of your GRAS notice, or in both Parts 2 and 6 of your GRAS notice. We 
would then evaluate whether the data, information, and narrative in 
your GRAS notice support your conclusion. When data and information 
bearing on the physical or other technical effect of the notified 
substance are necessary to support safety, we could conclude that a 
GRAS notice that does not discuss such data and information is 
incomplete, and either contact a notifier to request an amendment 
discussing such data and information, or issue an insufficient basis 
letter.
    (Comment 146) One comment asserts that a requirement for proof of 
utility, with subsequent publication of utility data, is unnecessary, 
and that a requirement for utility data to be documented by means of a 
peer-reviewed publication would burden the industry with additional 
cost, not only to conduct the studies but also to prepare the 
manuscript and have it accepted for publication. This comment also 
asserts that finding a journal willing to publish such germane studies 
may be challenging because the manuscript may be viewed as serving the 
manufacturer's interest rather than providing any new scientific 
information. As alternatives to publication of a target animal feeding 
study, this comment suggests means such as documenting the chemical 
nature of the substance in relation to same (or similar) substance with 
ample public information, and placing unpublished studies conducted by 
the notifier in the context of published literature about the use of 
the substance or related substances. This comment also asserts that CVM 
and industry resources could be better utilized to demonstrate the 
safety of the intended use of the substance with a focus on 
establishing the worst-case exposure and relating it to available 
safety information to establish a margin of safety.
    (Response 146) See Response 15, in which we respond to comments 
asserting it can be difficult to publish data and information that do 
not raise an issue of concern. Consistent with CFSAN's experience 
during the Interim Pilot program, we believe that some journals 
directed to food safety would be willing to publish data and 
information bearing on the physical or other technical effect the 
notified substance is intended to produce when those data and 
information are necessary to demonstrate safety (see section III.A.1 of 
CFSAN's 2010 experience document (Ref. 18)).
    See also Response 144 for a discussion of circumstances where 
generally available and accepted data and information can be used to 
provide evidence bearing on the nutritive effects of a substance 
intended for use in animal food. There may be situations where 
sufficient generally available and accepted data and information on 
exposure to the substance or class of substances can satisfy GRAS 
criteria without publication of specific data and information bearing 
on the physical or other technical effect the notified substance is 
intended to produce. For example, as discussed in section IV of CVM's 
experience document during the Interim Pilot program CVM responded with 
a ``no questions letter'' when the use of published information for 
technical effects such as nutrient, enzyme, and component of a defoamer 
was used, in whole or in part, to support such technical effects (Ref. 
20). As discussed in Response 12, GRAS status may be corroborated by 
unpublished scientific data, information, or methods, and there may be 
some unpublished scientific data, information, or methods regarding the 
safety of a use of a food substance. As discussed in Response 8, the 
criteria for GRAS status through scientific procedures provide for the 
application of ``generally available and accepted'' scientific data, 
information, or methods, which ``ordinarily'' are published and, thus, 
provide flexibility for supporting a conclusion of GRAS status through 
the application of scientific data, information, or methods that are 
generally available through a mechanism other than publication in a 
peer-reviewed scientific journal.
    See the discussion in Response 150 regarding the evaluation of 
safety studies, including the applicability of worst-case exposure on a 
case-by-case basis.

F. Part 3 of a GRAS Notice for a Substance Intended for Use in Animal 
Food: Target Animal and Human Exposures (Sec.  570.235)

1. Substances Intended for Use in Food or Drinking Water for Animals
    (Comment 147) Comments that address Issue 11c support clarifying 
that the GRAS notification procedure is applicable to substances used 
in both food and drinking water of animals.
    (Response 147) The final requirements for Part 3 of a GRAS notice 
specify that ``animal food'' includes ``drinking water.'' See also 
Response 142.
2. Data and Information About the Dietary Exposure for the Target 
Animal
    (Comment 148) One comment states that exposure information can 
usually be obtained from published data sources and that if a worst-
case exposure cannot be established without new data, then data for one 
representative animal species are sufficient, especially if the 
selected species represents a worst-case scenario. As an example, the 
comment suggests that data from one representative poultry species 
would be sufficient to address the conditions of use of a notified 
substance intended for poultry. As noted in Comment 142, another 
comment asks CVM to accept the anticipated consumption levels by 
animals that are based upon general formulation principles that 
consider the availability of contemporary feedstuffs.
    (Response 148) See the regulatory text of Sec.  570.235(a) for the 
requirements for what you must provide in Part 3 of a GRAS notice 
regarding exposure to the target animal. The regulatory text addressing 
the types of exposure to the target animal parallels the regulatory 
text for dietary exposure to a notified substance in the human food 
regulations (see Sec.  170.235). As noted in Response 142, you may base 
the levels of use upon general formulation principles that consider the 
availability of contemporary feedstuffs. We agree that exposure 
information may be available from published data sources. If exposure 
cannot be established without new data, then data for one 
representative animal species may be sufficient if the selected species 
represents a worst-case scenario.
    (Comment 149) One comment asks that any restatement of the 
regulatory text regarding dietary exposure consider how to use the word 
``consumer,'' because ``consumers'' are humans for the purpose of part 
170 but are ``animals'' for the purpose of part 570.
    (Response 149) To reduce the potential for confusion, the final 
requirements for part 3 of a GRAS notice for a substance intended for 
use in animal food do not use the term ``consumer.''

G. Data and Information in a GRAS Notice About Safety for the Target 
Animal (Sec.  570.250)

    (Comment 150) Comments that address Issue 11e agree that data and 
information in a GRAS notice must be

[[Page 55036]]

sufficient to address safety for the target animal. However, most of 
these comments express concern about the standard for demonstrating 
safety to the target animal, specifically whether safety must be 
established through feeding studies specific to the target animal or 
could be extrapolated from data and information regarding species other 
than the target animal. Although one comment asserts that a notifier 
must submit evidence that the substance is safe for all the species in 
question if a substance is expected to be consumed by different animal 
species, other comments emphasize that safety could be established 
through either feeding studies in the target animal or through 
extrapolation of data obtained from species other than the target 
animal. Some comments suggest that the rule require a clear and concise 
written explanation of how studies in non-target species relate to the 
target animal rather than require safety data in the target animal 
species.
    One comment disagrees that the GRAS notification procedure should 
establish any absolute requirement for data addressing safety for the 
target species. This comment asserts that CVM should not require 
species-specific data for all substances and species covered by the 
intended use of the notified substance because recognized scientific 
procedures, such as a weight of evidence approach, allow for the 
extrapolation of data and that these types of scientific procedures can 
be applied to notified substances. This comment also asserts that a CVM 
requirement for safety data in the target animal, rather than a written 
explanation of how studies in non-target species relate to the target 
animal, cannot be scientifically justified and will put the animal feed 
industry at a disadvantage for obtaining recognition of new GRAS 
substances, and that the additional cost and time will stifle 
innovation and reduce growth in the U.S. feed industry and animal 
agriculture.
    (Response 150) Whether species-specific data and information (such 
as feeding studies) are necessary to satisfy GRAS criteria depends on 
the intended use of the notified substance. We recognize that there may 
be situations where scientific procedures, such as a weight of evidence 
approach, allow for the extrapolation of available data and information 
from an animal species other than the target animal. For example, CVM 
had no questions regarding an enzyme preparation intended for use in 
food for turkeys, broiler chickens, and laying hens, when the feeding 
studies used to support target animal safety were conducted only on 
broiler chickens (Ref. 20). In such cases, you would explain the 
relevance of the available data to the target species in the narrative 
required in Part 6 of a GRAS notice rather than describe species-
specific data and information.
    However, extrapolating data from one animal species to another is 
not always appropriate because a substance that is safe for use in one 
animal species may not be safe for use in another species or in the 
same species at a different stage of life. For example, a substance 
that is safe for use in a species that is a ruminant animal (e.g., 
cattle) may not be safe for use in a species considered a monogastric 
animal (e.g., swine) because of the difference in their digestive 
systems and different nutrient requirements. For example, in ruminant 
animals, non-protein nitrogen compounds (e.g., urea and biuret) release 
ammonia, which is then metabolized by rumen microorganisms into 
microbial proteins. These microbial proteins are a useful source of 
protein to ruminant animals. However, in monogastric animals, the 
liberated ammonia from non-protein nitrogen compounds is absorbed 
directly by the animal, resulting in adverse toxicological events, and 
possibly death. Even within the same species of animal, or for 
different species in the same class of animals (e.g., chicken, duck, 
turkey), extrapolating safety data may not be appropriate. For example, 
a substance that is safe for laying hens may not be safe for use in 
broilers because of the different nutrient requirements, such as the 
higher calcium level in a laying hen diet (which is intended to meet 
the nutrient demand for egg production). If that high level of calcium 
is consumed by broiler chickens, the potential calcification of soft 
tissue such as that of kidneys could become detrimental to the broiler 
chickens. Likewise, a substance that is safe for chickens may not be 
safe for ducks or turkeys because the nutrient requirements for 
different species of poultry vary widely. Feeding a diet intended for 
one species of poultry to another species could cause nutrient 
imbalances, deficiencies, or excesses, which could have adverse 
consequences ranging from loss of production to damages to tissues and 
organs and even to death. When extrapolating data and information from 
another animal species is not appropriate, in Part 6 of your GRAS 
notice you would discuss data and information developed specifically 
for the target animal, or for the stage of life in the same animal 
species, rather than explain how you extrapolated available data and 
information from an animal species other than the target animal, or how 
you extrapolated available data and information from the same animal 
species to a different life stage of that animal species.
    Any person who concludes that the available data and information 
regarding the safety of a notified substance under the conditions of 
its intended use satisfy GRAS criteria must have a basis for the 
conclusion of GRAS status, regardless of whether that person notifies 
us of that conclusion in a GRAS notice. A resource that may help 
determine when it could be appropriate to extrapolate species-specific 
data and information from one animal species to another animal species 
is our guidance entitled ``Guidance for Industry: Recommendations for 
Preparation and Submission of Animal Food Additive Petitions'' (# 221) 
(June 2015) (Ref. 56). Section G.2 of that guidance (on target animal 
safety) recommends that target animal safety studies be conducted using 
the life stage and animal species for which the food additive will be 
marketed. In cases where the food additive is intended for multiple 
animal species or life stages, the food additive should be tested in 
the most sensitive life stage and/or species. The guidance recommends 
using current scientific literature to identify the most sensitive life 
stage and/or species. As with guidance documents prepared by CFSAN, 
CVM's scientific recommendations in a guidance directed to food 
additives can be applied to the evaluation of whether a substance is 
GRAS under the conditions of its intended use (see Response 66).
    Another resource is a book entitled ``Safety of Dietary Supplements 
for Horses, Dogs, and Cats'' by the National Research Council (Ref. 
57), which identifies five factors to consider when selecting 
appropriate surrogates for horses, dogs and cats. In addition, it 
advises considering nutritional, metabolic, pharmacokinetic, and 
natural dietary patterns when selecting appropriate animal model 
species. Although the material is directed to only three target 
animals, some aspects of its approach can be generalized.
    If you submit your conclusion of GRAS status to FDA, you must 
explain how the data and information in your GRAS notice provide the 
basis for your conclusion; we would then evaluate whether the data, 
information, and narrative in your GRAS notice support your conclusion.

[[Page 55037]]

H. Data and Information in a GRAS Notice About the Safety for Humans 
Consuming Human Food Derived From a Food-Producing Animal (Sec. Sec.  
570.235 and 570.250)

    (Comment 151) Some comments support clarifying the rule to 
explicitly require the submission of information about safety for both 
the target animal and for humans consuming human food derived from 
food-producing animals. One comment states that the safety and 
wholesomeness of food given to animals that eventually end up in human 
food must be held to the same standard as for a substance intended for 
use in human food. Another comment asks us to specify that the 
submission of data and information about both target animal and human 
safety is required when such data and information are developed for 
food-producing animals.
    One comment states that it is the responsibility of the notifier to 
determine the extent of the safety assessment of a substance intended 
for use in the food of a food-producing animal. This comment asserts 
that there is no need to set explicit standards for addressing both 
target animal and human food safety in applicable sections of the rule, 
because whether new data, such as tissue residue data, would be 
warranted would be determined through application of general scientific 
principles from the fields of animal nutrition and metabolism.
    Another comment asserts that neither human feeding studies nor 
tissue residue accumulation data should be required when available 
scientific information can be used to draw conclusions using a weight 
of the evidence approach, as CFSAN does for human food substances. This 
comment asserts that CVM must clarify what data need to be provided 
regarding safety for humans consuming human food derived from food-
producing animals before industry could agree to the requirement.
    (Response 151) We are clarifying the requirement to address safety 
for humans consuming human food derived from food-producing animals in 
Parts 3 and 6 of a GRAS notice.
    In the requirements for Part 3 of a GRAS notice for a substance 
intended for use in animal food, we have modified the title of the 
regulatory text to specify that Part 3 addresses exposures to both the 
target animal and to humans consuming human food derived from food-
producing animals (see Sec.  570.235). When the intended use of the 
notified substance is in food for food-producing animals, you must 
provide: (1) The potential quantities of any residues that humans may 
be exposed to in edible animal tissues; and (2) the data and 
information you rely on to establish the potential quantities of such 
residues (see Sec.  570.235(b)). These requirements parallel the 
requirements for target animal exposure, but are directed to the 
quantity of potential residues of the notified substance, and of any 
other substance that is expected to be formed in or on the animal food 
because of the use of the notified substance, and those residues from 
any other substances present with the notified substance, whether 
naturally, due to its manufacture (e.g., contaminants or by-products), 
or produced as a metabolite in edible animal tissues when the notified 
substance is consumed by a food-producing animal. It is well 
established that substances consumed by food-producing animals, and 
substances such as metabolites produced by a food-producing animal, can 
accumulate in edible animal tissues and have an adverse impact on 
public health. For example, aflatoxin M1 is a metabolite of aflatoxin 
B1 that is produced during normal biological processes of animals 
ingesting the toxin (e.g., from food contaminated with aflatoxin B1) 
and has been shown to cause liver cancer in certain animals (Ref. 58). 
As another example, there can be human food safety concerns about the 
level of selenium in animal tissues when food-producing animals consume 
large amounts of a substance that contains selenium in their diets.
    We agree that the specific data and information that are necessary 
to determine the safety for humans consuming human food derived from a 
food-producing animal would be determined through the application of 
general scientific principles from the fields of animal nutrition and 
metabolism and that it is the notifier's responsibility to determine 
what those specific data and information are. Therefore, we have 
modified the requirements for the narrative in Part 6 of a GRAS notice 
to clarify that the narrative must address the safety for both the 
target animal and for humans consuming human food derived from food-
producing animals (see Sec.  570.250(a)(1) and (b)).

I. Filing Decision, Opportunity for a Notifier To Submit an Amendment, 
and Asking Us To Cease To Evaluate a GRAS Notice for a Substance 
Intended for Use in Animal Food (Sec. Sec.  570.260 and 570.265)

    (Comment 152) Some comments express concern about differences in 
how CFSAN and CVM administered GRAS notices during the Interim Pilot 
program. Some comments describe CFSAN's practice of using conference 
calls to obtain a clarification or additional information, with a 
reasonable period of time for the notifier to provide the clarification 
or additional information. These comments assert that CVM's practice is 
different from CFSAN's practice because CVM does not contact a notifier 
to discuss CVM's questions after a submission has been accepted for 
filing. One comment asserts that CVM has informally indicated that once 
a GRAS notice is accepted for filing, there will be no further 
communication with the notifier and the GRAS notice will be judged 
solely on what was accepted for filing. This comment further asserts 
that such a process is unreasonable because the error or omission may 
be trivial and/or easily remedied. This comment also asserts that 
allowing informal contacts (including telephone, email, and fax) to 
address minor issues would be consistent with how FDA has handled a 
wide range of submissions that require review. Another comment asserts 
that CVM's practice of not contacting the notifier is a major concern 
for the industry and that CVM's reviewers may have questions that could 
be easily answered by the notifier, if contacted.
    Some comments ask CVM to engage in the same informal practice as 
CFSAN, with respect to contacting the notifier and allowing remedial 
action, if such action may be completed in a reasonable period of time. 
Some comments ask the Centers to establish a uniform system of contact 
and communication after a submission (and/or agreeing to evaluate an 
amendment to a GRAS notice) to prevent delays or other inefficiencies 
over issues that could easily be clarified and resolved. Some comments 
note that uniformity between CFSAN and CVM in the submission and 
handling of requests to cease to evaluate a GRAS notice is of great 
importance in maintaining transparency and efficiency in the GRAS 
notification procedure.
    (Response 152) The regulatory text governing what CVM will do with 
a GRAS notice (Sec.  570.265) is the same as the regulatory text 
governing what CFSAN will do with a GRAS notice (Sec.  170.265). In 
addition, the regulatory text that provides for a notifier who submits 
a GRAS notice to CVM to submit a timely amendment to a filed GRAS 
notice, and to ask us to cease to evaluate a GRAS notice (Sec.  
570.260), is the same as the regulatory text that provides for a 
notifier who submits a GRAS notice to CFSAN to submit a timely 
amendment to a filed GRAS

[[Page 55038]]

notice, and to ask us to cease to evaluate a GRAS notice (Sec.  
170.260).
    We disagree that CVM did not contact notifiers during the Interim 
Pilot program. As shown in table 1 in CVM's experience document (Ref. 
20), CVM contacted the notifier regarding 9 of 18 GRAS notices during 
its evaluation process. CVM issued ``no questions letters'' to seven of 
these nine notices after the notifiers provided clarifying amendments.
    Moving forward under the final rule, CVM intends to consider the 
same factors that CFSAN considers regarding whether to file a 
submission as a GRAS notice (see Response 85), the purpose of 
contacting a notifier (including whether to provide an opportunity for 
a notifier to ask us to cease to evaluate a GRAS notice) (see Response 
80), and the transparency of the reasons for a ``cease to evaluate 
letter'' (see Response 81). Because our factors regarding the purpose 
of contacting a notifier, and the provisions that provide an 
opportunity for a notifier to submit an amendment, consider whether an 
amendment is (or could be) timely, the final rule does, as requested by 
the comments, consider whether an amendment could be prepared and 
submitted in a reasonable period of time. Importantly, as discussed in 
Response 101, the role of an amendment is to clarify questions that we 
have about your conclusion of GRAS status, rather than to substantively 
amend the notice. Whether we will evaluate an amendment to a GRAS 
notice before responding to the notice is a matter that we will 
consider on a case-by-case basis.

J. Opportunity for a Notifier To Submit a Supplement to a GRAS Notice 
for a Substance Intended for Use in Animal Food (Sec.  570.280)

    (Comment 153) One comment asks CVM to adopt CFSAN's approach of 
allowing a notifier to submit information to a GRAS notice after FDA 
responds to the notice.
    (Response 153) The rule provides that, if circumstances warrant, a 
notifier who submits a GRAS notice to CVM may submit a supplement to a 
filed GRAS notice after we respond to your notice by letter or cease to 
evaluate your notice (Sec.  570.280). As discussed in section VI of 
CVM's experience document (Ref. 20), as of December 31, 2015, CVM had 
not received any supplements to a GRAS notice.

K. GRAS Affirmation Petitions for Substances Used in Animal Food

    CVM has no pending GRAS affirmation petitions and, thus, the final 
animal food regulations do not include provisions for the disposition 
of pending GRAS affirmation petitions for substances used in animal 
food.

XXVI. Editorial, Clarifying, and Conforming Amendments

    The revised regulatory text includes several changes that we have 
made to make the requirements more clear and improve readability. The 
revised regulatory text also includes several conforming changes that 
we have made when a change to one provision affects other provisions. 
We summarize the principal editorial and conforming changes in table 
29.

    Table 29--Principal Editorial, Clarifying, and Conforming Changes
------------------------------------------------------------------------
     Designation in the
 regulatory text  (Sec.   )         Revision             Explanation
------------------------------------------------------------------------
Sec.   20.100(c)(46)........  Add new paragraph     Conforming change in
                               (c)(46) to clarify    light of the new
                               applicability of      GRAS notification
                               Sec.   20.100 (the    procedures
                               handling of FDA       established in Sec.
                               records upon a         Sec.   170.36 and
                               request for public    570.36.
                               disclosure) to GRAS
                               notices in Sec.
                               Sec.   170.36(h)
                               and 570.36(h).
Sec.   25.20(k).............   Replace       Conforming
                               ``Affirmation of a    change in light of
                               food substance as     the deletion of the
                               GRAS for humans or    GRAS affirmation
                               animals, on FDA's     petition process.
                               initiative or in      Correct the
                               response to a         list of applicable
                               petition, under       categorical
                               parts 182, 184,       exclusions that
                               186, or 582 of this   apply to include
                               chapter'' with        the categorical
                               ``Establishment or    exclusions listed
                               amendment of a        in Sec.   25.32(i)
                               regulation for a      and (j).
                               food substance as
                               GRAS under the
                               conditions of its
                               intended use for
                               humans or animals
                               under parts 182,
                               184, 186, 582, or
                               584 of this
                               chapter''.
                               Replace
                               ``unless
                               categorically
                               excluded in Sec.
                               25.32(f), (k), or
                               (r)'' with ``unless
                               categorically
                               excluded in Sec.
                               25.32(f), (i), (j),
                               (k), or (r)''.
Sec.   25.32(f).............  Replace                Clarify
                               ``Affirmation of a    that GRAS
                               food substance as     affirmation applies
                               GRAS for humans or    to the intended
                               animals on FDA's      conditions of use
                               initiative or in      of a substance, not
                               response to a         the substance
                               petition, under       itself.
                               parts 182, 184,       Conforming
                               186, or 582 of this   change in light of
                               chapter'' with        the deletion of the
                               ``Establishment or    GRAS affirmation
                               amendment of a        petition process.
                               regulation for a
                               food substance as
                               GRAS under the
                               conditions of its
                               intended use for
                               humans or animals
                               under parts 182,
                               184, 186, 582, or
                               584 of this
                               chapter''.
Sec.   25.32 (i), (j), (k),   Replace ``or GRAS      Clarify
 and (r).                      affirmation           that GRAS
                               petition'' with       affirmation applies
                               ``establishment or    to the intended
                               amendment of a        conditions of use
                               regulation for a      of a substance, not
                               food substance as     the substance
                               GRAS under the        itself.
                               conditions of its     Conforming
                               intended use for      change in light of
                               humans or animals     the deletion of the
                               under parts 182,      GRAS affirmation
                               184, 186, 582, or     petition process.
                               584 of this
                               chapter''.
Sec.   170.3(h), Sec.          Specify       Clarify
 570.3(h).                     ``data from human,    that the four
                               animal, analytical,   listed types of
                               or other scientific   studies (human,
                               studies'' rather      animal, analytical,
                               than ``data from      and other) do not
                               human, animal,        necessarily apply
                               analytical, and       in all
                               other scientific      circumstances.
                               studies''.
                               Replace       Include
                               ``appropriate to      statutory language
                               establish the         from section 201(s)
                               safety of a           of the FD&C Act to
                               substance'' with      clarify that GRAS
                               ``appropriate to      status applies to
                               establish the         the intended
                               safety of a           conditions of use
                               substance under the   of a substance, not
                               conditions of its     the substance
                               intended use''.       itself.

[[Page 55039]]

 
170.3(i)....................  In the definition of  Conforming change to
                               ``safe'' or           consistently use
                               ``safety,'' replace   the exact statutory
                               ``under the           language in section
                               intended conditions   201(s) ``under the
                               of use'' with         conditions of its
                               ``under the           intended use''
                               conditions of its     rather than
                               intended use''.       variations (such as
                                                     under the intended
                                                     conditions of use).
Sec.   170.3(k).............  Replace ``General     Conforming change.
                               recognition of        See Response 41.
                               safety shall be
                               determined in
                               accordance with
                               170.30'' with
                               ``General
                               recognition of
                               safety shall be in
                               accordance with
                               Sec.   170.30''.
Throughout Sec.   170.30....  Replace ``Sec.        Correction to
                               186.1'' with ``part   clarify that the
                               186''.                provision applies
                                                     to all of part 186,
                                                     not just Sec.
                                                     186.1.
Sec.   170.30(a)............  Replace the proposed  Conforming change to
                               regulatory text       consistently use
                               ``there is            the exact statutory
                               reasonable            language in section
                               certainty that the    201(s) ``under the
                               substance is not      conditions of its
                               harmful under the     intended use''
                               intended conditions   rather than
                               of use'' with         variations (such as
                               ``there is            under the intended
                               reasonable            conditions of use).
                               certainty that the
                               substance is not
                               harmful under the
                               conditions of its
                               intended use''.
Sec.   170.30(b), Sec.        Replace ``General      Clarify
 570.30(b).                    recognition of        that FDA approves a
                               safety based upon     food additive, not
                               scientific            a ``food additive
                               procedures shall      regulation''.
                               require the same      Clarify
                               quantity and          that the same
                               quality of            quantity and
                               scientific evidence   quality of
                               as is required to     scientific evidence
                               obtain approval of    is required
                               a food additive       regardless of
                               regulation for the    whether the
                               ingredient'' with     substance is
                               ``General             intended for use as
                               recognition of        an ``ingredient''.
                               safety based upon
                               scientific
                               procedures shall
                               require the same
                               quantity and
                               quality of
                               scientific evidence
                               as is required to
                               obtain approval of
                               a food additive''.
Sec.   170.30(c)(1), Sec.     Replace ``General      Conforming
 570.30(c)(1).                 recognition of        change. See
                               safety through        Response 41.
                               experience based on   Clarify
                               common use in food    that FDA approves a
                               prior to January 1,   food additive, not
                               1958, may be          a ``food additive
                               determined without    regulation''.
                               the quantity or
                               quality of
                               scientific
                               procedures required
                               for approval of a
                               food additive
                               regulation'' with
                               ``General
                               recognition of
                               safety through
                               experience based on
                               common use in food
                               prior to January 1,
                               1958, may be
                               achieved without
                               the quantity or
                               quality of
                               scientific
                               procedures required
                               for approval of a
                               food additive''.
Sec.   170.30(c)(2).........   Replace       Conforming
                               ``if the              change to
                               information about     consistently use
                               the experience        the exact statutory
                               establishes that      language in section
                               the use of the        201(s) ``under the
                               substance is safe     conditions of its
                               within the meaning    intended use''
                               of the act (see       rather than
                               Sec.   170.3(i))''    variations (such as
                               with ``if the         ``the use of the
                               information about     substance'').
                               the experience        Clarify
                               establishes that      that the applicable
                               the substance is      section of the FD&C
                               safe under the        Act is section
                               conditions of its     201(u). Section
                               intended use within   170.3(i) is in our
                               the meaning of        regulations, not in
                               section 201(u) of     the FD&C Act.
                               the Federal Food,     Editorial
                               Drug, and Cosmetic    change to include
                               Act (see also Sec.    the full name of
                                170.3(i))''.         the statute.
                               Replace       Editorial
                               ``in this country''   change to be
                               with ``in the         specific that
                               United States''.      ``this country''
                                                     means ``the United
                                                     States''.
170.30(c)(2), 170.38(a),      Replace ``the act''   Editorial. It is now
 570.38(a).                    with ``the Federal    our practice to
                               Food, Drug, and       include the full
                               Cosmetic Act'' in     name of this
                               any provision that    statute when we
                               we otherwise          refer to it.
                               revised.
Sec.   170.30(e)............   Replace       See
                               ``Beginning in        Response 41.
                               1969, the Food and    Include
                               Drug Administration   statutory language
                               has undertaken a      from section 201(s)
                               systematic review     of the FD&C Act to
                               of the status of      clarify that GRAS
                               all ingredients       status applies to
                               used in food on the   the intended
                               determination that    conditions of use
                               they are GRAS or      of a substance, not
                               subject to a prior    the substance
                               sanction'' with       itself.
                               ``Beginning in        Clarify
                               1969, the Food and    that GRAS status
                               Drug Administration   pursuant to parts
                               has undertaken a      184 and 186 is
                               systematic review     affirmed by FDA.
                               of the status of
                               all ingredients
                               used in food based
                               on the view that
                               they are GRAS under
                               the conditions of
                               their intended use
                               or subject to a
                               prior sanction''.
                               Replace
                               ``All
                               determinations of
                               GRAS status or food
                               additive status or
                               prior sanction
                               status pursuant to
                               this review shall
                               be handled pursuant
                               to Sec.  Sec.
                               170.35, 170.38, and
                               180.1 of this
                               chapter.
                               Affirmation of GRAS
                               status shall be
                               announced in part
                               184 or Sec.   186.1
                               of this chapter''
                               with ``All
                               affirmations of
                               GRAS status or
                               determinations of
                               food additive
                               status or prior
                               sanction status
                               pursuant to this
                               review shall be
                               handled pursuant to
                               Sec.  Sec.
                               170.35, 170.38, and
                               180.1 of this
                               chapter.
                               Affirmation of GRAS
                               status shall be
                               announced in part
                               184 or part 186 of
                               this chapter''.

[[Page 55040]]

 
Sec.   170.30(l)............  Replace ``Any change  Clarify the
                               in part 182, part     applicability of
                               184, or Sec.          the requirement.
                               186.1 of this
                               chapter shall be
                               accomplished
                               pursuant to Sec.
                               170.38'' with ``Any
                               change to the GRAS
                               status of a food
                               ingredient in part
                               182, part 184, or
                               part 186 of this
                               chapter shall be
                               accomplished
                               pursuant to Sec.
                               170.38''.
Sec.   170.35(a), Sec.        Replace ``may affirm   Editorial
 570.35(a).                    the GRAS status of    change to use the
                               substances'' with     singular.
                               ``may affirm that a   Include
                               substance that        statutory language
                               directly or           from section 201(s)
                               indirectly becomes    of the FD&C Act to
                               a component of food   clarify that GRAS
                               is GRAS under the     affirmation applies
                               conditions of its     to the intended
                               intended use''.       conditions of use
                                                     of a substance, not
                                                     the substance
                                                     itself.
Sec.   170.35(b)(1), Sec.     Replace ``If the      Include statutory
 570.35(b)(1).                 Commissioner          language from
                               proposes on his own   section 201(s) of
                               initiative that a     the FD&C Act to
                               substance is          clarify that GRAS
                               entitled to           affirmation applies
                               affirmation as        to the intended
                               GRAS'' with ``If      conditions of use
                               the Commissioner      of a substance, not
                               proposes on his own   the substance
                               initiative that a     itself.
                               substance is
                               entitled to
                               affirmation as GRAS
                               under the
                               conditions of its
                               intended use''.
Sec.   170.35(b)(3), Sec.      Replace       Include
 570.35(b)(3).                 ``convincing          statutory language
                               evidence that the     from section 201(s)
                               substance is GRAS''   of the FD&C Act to
                               with ``convincing     clarify that GRAS
                               evidence that the     affirmation applies
                               substance is GRAS     to the intended
                               under the             conditions of use
                               conditions of its     of a substance, not
                               intended use''.       the substance
                               Replace       itself.
                               ``listing the         Deleted
                               substance as GRAS     reference to parts
                               in part 182, part     182 and 582. If FDA
                               184, or part 186 of   affirms GRAS
                               this chapter'' with   status, the
                               ``listing the GRAS    affirmation
                               conditions of use     regulation would
                               of the substance in   appear in part 184
                               part 184 or part      or 186.
                               186 of this
                               chapter''.
Sec.   170.35(b)(4), Sec.     Replace ``there is a  Include statutory
 570.35(b)(4).                 lack of convincing    language from
                               evidence that the     section 201(s) of
                               substance is GRAS''   the FD&C Act to
                               with ``there is a     clarify that GRAS
                               lack of convincing    affirmation applies
                               evidence that the     to the intended
                               substance is GRAS     conditions of use
                               under the             of a substance, not
                               conditions of its     the substance
                               intended use''.       itself.
Sec.   170.38(a), Sec.         Replace       See
 570.38(a).                    ``may, in             Response 41.
                               accordance with       Conforming
                               Sec.   170.35(b)(4)   change in light of
                               or (c)(5), publish    the deletion of the
                               a notice in the       GRAS affirmation
                               Federal Register      petition process.
                               determining that a    Include
                               substance is not      statutory language
                               GRAS'' with ``may,    from section 201(s)
                               in accordance with    of the FD&C Act to
                               Sec.                  clarify that GRAS
                               170.35(b)(4),         affirmation applies
                               publish a notice in   to the intended
                               the Federal           conditions of use
                               Register              of a substance, not
                               determining that a    the substance
                               substance is not      itself.
                               GRAS under the
                               conditions of its
                               intended use''.
                               Replace
                               ``may, in
                               accordance with
                               Sec.   570.35(b)(4)
                               or (c)(5), publish
                               a notice in the
                               Federal Register
                               determining that a
                               substance is not
                               GRAS'' with ``may,
                               in accordance with
                               Sec.
                               570.35(b)(4),
                               publish a notice in
                               the Federal
                               Register
                               determining that a
                               substance is not
                               GRAS under the
                               conditions of its
                               intended use''.
 Throughout part      Replace variations    Editorial change.
 170, subpart E.               of ``data or other    Although data is a
 Throughout part       information'' with    type of
 570, subpart E.               ``data and            ``information,'' it
                               information''.        is simpler and
                                                     clearer to say
                                                     ``data and
                                                     information.''
 Throughout part      Replace variations    See Response 41.
 170, subpart E.               of ``determine''
 Throughout part       and
 570, subpart E.               ``determination''
                               with ``conclude''
                               and ``conclusion''.
 Throughout part       Replace      See Response 42.
 170, subpart E.               ``exempt'' with
 Throughout part       ``not subject to:.
 570, subpart E.               Replace
                               ``claim'' with
                               ``view''.
Sec.   170.203, Sec.          In the definition of  Clarification by
 570.203.                      ``notifier,'' add a   including text from
                               parenthetical with    the definition of
                               examples of what we   ``person'' in Sec.
                               mean by ``person''     10.3.
                               (e.g., an
                               individual,
                               partnership,
                               corporation,
                               association, or
                               other legal entity).
Sec.   170.225(c)(4)........  Replace the proposed  Clarifying change to
                               phrase ``applicable   use the statutory
                               conditions of use''   term ``intended''
                               with ``intended       in place of
                               conditions of use''.  ``applicable''.
Sec.   184.1(a).............  Replace ``The direct  Clarify that the
                               human food            GRAS status of the
                               ingredients listed    uses of substances
                               in this part have     listed in part 184
                               been reviewed by      has been affirmed
                               the Food and Drug     by FDA, either on
                               Administration and    FDA's initiative or
                               determined to be      in response to a
                               generally             GRAS affirmation
                               recognized as safe    petition.
                               (GRAS) for the
                               purposes and
                               conditions
                               prescribed'' with
                               ``The direct human
                               food ingredients
                               listed in this part
                               have been reviewed
                               by the Food and
                               Drug Administration
                               and affirmed to be
                               generally
                               recognized as safe
                               (GRAS) for the
                               purposes and under
                               the conditions
                               prescribed''.

[[Page 55041]]

 
Sec.   184.1(b)(1)..........   Replace       Conforming
                               ``shall               change to reflect
                               independently         ``conclusions'' of
                               establish'' with      GRAS status.
                               ``shall have a        Conforming
                               basis to conclude''.  change in light of
                               Remove the    the deletion of the
                               last sentence,        GRAS affirmation
                               i.e., ``Persons       petition process.
                               seeking FDA
                               approval of an
                               independent
                               determination that
                               a use of an
                               ingredient is GRAS
                               may submit a GRAS
                               petition in
                               accordance with
                               170.35 of this
                               chapter.''.
Sec.   186.1(a).............  Replace ``The         Clarify that the
                               indirect human food   GRAS status of the
                               ingredients listed    uses of substances
                               in this part have     listed in part 186
                               been reviewed by      has been affirmed
                               the Food and Drug     by FDA, either on
                               Administration and    FDA's initiative or
                               determined to be      in response to a
                               generally             GRAS affirmation
                               recognized as safe    petition.
                               (GRAS)'' with ``The
                               indirect human food
                               ingredients listed
                               in this part have
                               been reviewed by
                               the Food and Drug
                               Administration and
                               affirmed to be
                               generally
                               recognized as safe
                               (GRAS)''.
Sec.   186.1(b)(1)..........   Replace      Conforming change in
                               ``shall               light of the
                               independently         deletion of the
                               establish'' with      GRAS affirmation
                               ``shall have a        petition process.
                               basis to conclude''.
                               Remove the
                               last sentence,
                               i.e., ``Persons
                               seeking FDA
                               approval of an
                               independent
                               determination that
                               a use of an
                               ingredient is GRAS
                               may submit a GRAS
                               petition in
                               accordance with
                               170.35 of this
                               chapter.''.
Sec.   570.3(f).............   Add ``of     Changes to
                               the species to        Conform
                               which the substance   with revisions to
                               is intended to be     Sec.   570.30(a)
                               fed'' in describing   and (c)
                               the animals           Conform
                               consuming the         with the
                               substance.            corresponding
                               Delete ``in   definition for
                               the United States''.  human food in Sec.
                               Add ``(and,    170.3(f), which
                               for food-producing    does not specify
                               animals fed with      ``in the United
                               such substance,       States.''
                               also means a          Clarify
                               substantial history   that substantial
                               of consumption by     history of
                               humans consuming      consumption should
                               human foods derived   be demonstrated by
                               from those food-      the same animal
                               producing animals)    species as the
                               prior to January 1,   species intended to
                               1958.                 be fed to conform
                                                     with the submission
                                                     requirements in
                                                     part 5 of a GRAS
                                                     notice when the
                                                     basis for the
                                                     conclusion of GRAS
                                                     status is through
                                                     experience based on
                                                     common use in food
                                                     (Sec.   570.245).
                                                     Clarify
                                                     that substantial
                                                     history of
                                                     consumption for
                                                     food-producing
                                                     animals also should
                                                     be demonstrated by
                                                     a substantial
                                                     history of
                                                     consumption by
                                                     humans consuming
                                                     human foods derived
                                                     from those food-
                                                     producing animals
                                                     prior to January 1,
                                                     1958 to conform
                                                     with the submission
                                                     requirements in
                                                     part 5 of a GRAS
                                                     notice.
Sec.   570.3(k).............  Replace ``General     Conforming change.
                               recognition of        The GRAS
                               safety shall be       notification
                               determined in         procedure does not
                               accordance with       use the term
                               Sec.   570.30''       ``determine.''
                               with ``General
                               recognition of
                               safety shall be in
                               accordance with
                               Sec.   570.30''.
Sec.   570.3................  Define ``food-        Clarify the meaning
                               producing animal''    of this term for
                               to mean an animal     the purpose of part
                               used to produce       570, subpart E in
                               human food.           light of provisions
                                                     that address the
                                                     safety of a
                                                     substance for
                                                     humans consuming
                                                     human food derived
                                                     from an animal used
                                                     to produce human
                                                     food.
Sec.   570.30(c)............  Replace ``General      Conforming
                               recognition of        change. The GRAS
                               safety through        notification
                               experience based on   procedure does not
                               common use in food    use the term
                               prior to January 1,   ``determine.''
                               1958, may be          Clarify
                               determined without    that FDA approves a
                               the quantity or       food additive, not
                               quality of            a ``food additive
                               scientific            regulation''.
                               procedures required
                               for approval of a
                               food additive
                               regulation'' with
                               ``General
                               recognition of
                               safety through
                               experience based on
                               common use in food
                               prior to January 1,
                               1958, may be
                               achieved without
                               the quantity or
                               quality of
                               scientific
                               procedures required
                               for approval of a
                               food additive''.
Sec.   570.30(d)............   Replace      Clarify that the
                               ``ingredients         provisions apply
                               listed as GRAS in     regardless of
                               part 582 of this      whether an
                               chapter'' with        ingredient is
                               ``ingredients         listed as GRAS in
                               listed as GRAS in     part 582 or
                               part 582 of this      affirmed as GRAS in
                               chapter or affirmed   part 584.
                               as GRAS in part 584
                               of this chapter''.
                               Replace
                               ``without specific
                               inclusion in part
                               582 of this
                               chapter'' with
                               ``without specific
                               inclusion in part
                               582 or part 584 of
                               this chapter''.
Sec.   570.30(i)............  Replace ``Any use of  Editorial correction
                               such and              of ``and'' to
                               ingredient'' with     ``an''.
                               ``Any use of such
                               an ingredient''.
570.225(c)(4),                Replace ``food''      Clarification for
 570.225(c)(5), 570.230(c),    with ``animal         part 570.
 570.235, 570.240, 570.245.    food''.
------------------------------------------------------------------------


[[Page 55042]]

XXVII. Economic Analysis of Impacts

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). We 
have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the final rule. We believe that this final rule 
is not a significant regulatory action as defined by Executive Order 
12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. The final rule replaces the voluntary GRAS affirmation 
petition process with a voluntary GRAS notification procedure. Similar 
to the petition process, we expect that profit-maximizing firms will 
only submit the GRAS notice when the private benefits equal or exceed 
the costs of the GRAS notice, regardless of the size of the firm. 
Because small firms face the same voluntary business decision as large 
firms, we certify that the final rule will not have a significant 
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before issuing ``any rule that includes 
any Federal mandate that may result in the expenditure by State, local, 
and tribal governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one 
year.'' The current threshold after adjustment for inflation is $146 
million, using the most current (2015) Implicit Price Deflator for the 
Gross Domestic Product. This final rule will not result in an 
expenditure in any year that meets or exceeds this amount.
    The final rule will eliminate the petition process to affirm a 
substance is GRAS and replace the petition process with a GRAS 
notification procedure. The level of effort required by a firm to reach 
a conclusion that a substance is GRAS for its intended use remains 
unchanged by the final rule. However, the rule will require that firms 
submit some additional information to support their conclusion with 
their notices. Although uncertain, we estimate that notifiers will 
spend between 5 more hours and 20 more hours to prepare and submit each 
notice. We estimate that this will cost notifiers less than $0.1 
million each year.
    For all affected notifiers, we expect that they will spend time 
reading and understanding the requirements of the final rule and 
revising standard operating procedures for preparing and submitting 
GRAS notices. We estimate that it will take from 20 hours to 80 hours 
for notifiers to perform this action. Firms with outstanding GRAS 
affirmation petitions may choose to submit GRAS notices and incorporate 
the information included in their petition. To account for the 
additional effort by these firms, we include the one-time cost to 
prepare and submit a GRAS notice for all outstanding petitions. We 
estimate that notifiers will spend between 170 and 190 hours to submit 
GRAS notices for each outstanding petition. The total one-time costs of 
the final rule range from $0.8 million to $2.7 million.
    We estimate that over 10 years with a 7 percent discount rate, the 
present value of the total costs of the final rule range from $0.9 
million to $3.3 million; with a 3 percent discount rate, the present 
value of the total costs range from $0.9 million to $3.4 million. The 
annualized costs of the rule range from $0.1 million to $0.4 million 
with a 7 percent discount rate and range from $0.1 million to $0.5 
million with a 3 percent discount rate.
    We do not quantify the benefits of the final rule. However, based 
on the differences in review time between the GRAS petition process and 
the GRAS notification procedure, we anticipate that industry will 
benefit from the more speedy notification procedure. For example, we 
have filed more than 600 GRAS notices for human food substances since 
1998. During this time, it took an average of 200 days for us to 
respond to 588 GRAS notices; it took an average of 7.9 years to 
complete 24 previous GRAS affirmation petitions. We began to accept 
GRAS notices for animal food substances in 2010 and we have filed 18 
GRAS notices for animal food substances since that time. It took an 
average of 294 days for us to respond to 12 GRAS notices with a ``no 
questions letter'' or ``insufficient basis letter''; it took an average 
of 4.9 years to respond to the three previous GRAS affirmation 
petitions. With the GRAS notification procedure, we can complete our 
evaluation within the timelines specified in the final rule.
    The Economic Analysis of Impacts of the final rule performed in 
accordance with Executive Order 12866, Executive Order 13563, the 
Regulatory Flexibility Act, and the Unfunded Mandates Reform Act (Ref. 
51) is available at http://www.regulations.gov under the docket number 
for this final rule and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

XXVIII. Analysis of Environmental Impact

    We have carefully considered the potential environmental effects of 
this action. We have concluded under 21 CFR 25.30(h) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

XXIX. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by OMB under the PRA (44 U.S.C. 3501-3520). The 
title, description, and respondent description of the information 
collection provisions are shown in the following paragraphs with an 
estimate of the one-time and annual reporting burdens. Included in the 
estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing each collection of information.
    Title: Substances Generally Recognized as Safe Notification 
Procedure (21 CFR parts 170 and 570) (OMB Control No. 0910-0342)--
Revision.
    Description: The FD&C Act requires that all food additives (as 
defined by section 201(s)) be approved by FDA before they are marketed 
(sections 402(a)(2)(C) and 409 of the FD&C Act). Section 201(s) of the 
FD&C Act excludes from the definition of a food additive a substance 
``generally recognized, among experts qualified by scientific training 
and experience to evaluate its safety, as having been adequately shown 
through scientific procedures (or, in the case of a substance used in 
food prior to January 1, 1958, through either scientific procedures or 
experience based on common use in food) to be safe under the conditions 
of its intended use.'' This final rule amends our regulations in parts 
170 and 570 and revises the information collection provisions regarding 
the notification procedures for GRAS substances. The

[[Page 55043]]

regulations implement the GRAS provision of section 201(s) of the FD&C 
Act in part 170 and part 570 for human food and animal food, 
respectively.
    Description of Respondents: Respondents to the collection of 
information are manufacturers of substances used in human food and 
animal food. We estimate there are 480 such respondents. As estimated 
in the Final Regulatory Impact Analysis (Ref. 51), approximately 340 to 
460 notifiers (for human food) and approximately 10 to 20 notifiers 
(for animal food) will be affected by the final rule. The Final 
Regulatory Impact Analysis reflects an overall increase in respondents 
to the program and we have therefore adjusted our respondent numbers 
accordingly.
    As discussed in section II.B of the preamble to this final rule, 
previously manufacturers were invited to submit notices of their 
independent GRAS determinations for review under the framework of the 
proposed rule during the period between issuance of the proposed rule 
and any final rule based on the proposed rule. The proposed regulations 
provided a standard format for the voluntary submission of a notice. To 
date, the GRAS program has been administered under these proposed 
procedures. Comments regarding the information collection topics 
solicited in the proposed rule and subsequent 2010 notice are discussed 
in the preamble in sections IV, VII, and X through XVIII. While none of 
the comments suggested we modify the estimated annual burden associated 
with the information collection, we have revised the underlying 
notification procedures and, consequently, have revised the underlying 
information collection provisions consistent with the final rule.
    Specifically the final rule establishes a voluntary administrative 
procedure for notifying FDA about a conclusion that a substance is GRAS 
under the conditions of its intended use in human food or animal food. 
The final rule explains that a GRAS notice must include the following 
seven parts:

   Table 30--Information To Be Included in Each Part of a GRAS Notice
------------------------------------------------------------------------
             Part No.                    Information to be included
------------------------------------------------------------------------
Part 1............................  Signed statements and a
                                     certification.
Part 2............................  The identity, method of manufacture,
                                     specifications, and physical or
                                     technical effect of the notified
                                     substance.
Part 3............................  Dietary exposure to the notified
                                     substance.
Part 4............................  Self-limiting levels of use in
                                     circumstances where the amount of
                                     the notified substance that can be
                                     added to human food or animal food
                                     is limited because the food
                                     containing levels of the notified
                                     substance above a particular level
                                     would become unpalatable or
                                     technologically impractical.
Part 5............................  The history of consumption of the
                                     substance for food use by a
                                     significant number of consumers (or
                                     animals in the case of animal food)
                                     prior to January 1, 1958, if a
                                     conclusion of GRAS status is based
                                     on common use of the substance in
                                     food prior to 1958.
Part 6............................  A narrative that provides the basis
                                     for the notifier's conclusion of
                                     GRAS status, including why the
                                     scientific data, information,
                                     methods, and principles described
                                     in the notice provide a basis for
                                     the conclusion that the notified
                                     substance is generally recognized,
                                     among qualified experts, to be safe
                                     under the conditions of its
                                     intended use.
Part 7............................  A list of the generally available
                                     data, information, and methods the
                                     notifier cites in the GRAS notice.
------------------------------------------------------------------------

    The information submitted to us in a GRAS notice is necessary to 
allow us to administer efficiently the FD&C Act's various provisions 
that apply to the use of substances added to food, specifically with 
regard to whether a substance is GRAS under the conditions of its 
intended use or is a food additive subject to premarket review. We will 
use the information collected through the GRAS notification procedure 
to complete our evaluation within the timelines specified in the final 
rule.
One-Time Reporting Burden
    Table 31 shows the estimated one-time reporting burden associated 
with the final rule. We expect that all respondents to the information 
collection will spend time reading and understanding the requirements 
of the final rule and revising standard operating procedures for 
preparing and submitting GRAS notices. As noted, we estimate that 
approximately 340 to 460 notifiers (for human food) and approximately 
10 to 20 notifiers (for animal food) will be affected by the final 
rule. We use the upper-bound estimates of 460 and 20 respondents as 
shown in rows 1 and 2. We estimate that it will take from 20 to 80 
hours for respondents to perform this action. We use the upper-bound 
estimate of 80 hours as shown in rows 1 and 2. Of the 480 affected 
respondents, some will have outstanding GRAS petitions. Firms with 
outstanding GRAS petitions regarding substances intended for use in 
human food may choose to submit GRAS notices and incorporate the 
information included in their petition. As estimated in the Final 
Regulatory Impact Analysis (Ref. 51), up to 45 petitions (for human 
food) will be submitted as GRAS notices and incorporated. We use the 
upper-bound estimate of 45 as shown in row 3. To account for the 
additional effort by these firms, we include the one-time burden to 
prepare and submit a GRAS notice for all outstanding petitions. Because 
there are no outstanding GRAS petitions regarding substances intended 
for use in animal food, we do not account for any burden for the 
submission of a GRAS notice that incorporates a GRAS petition regarding 
a substance intended for use in animal food. We estimate that 
respondents will spend between 170 and 190 hours to submit GRAS notices 
for each outstanding petition and have used, therefore, an average 
estimate of 185 hours as shown in row 3.

[[Page 55044]]



                                Table 31--Estimated One-Time Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
     Activity/21 CFR section         Number of     responses per   Total annual   Average burden    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
Notifier's review of final rule              460               1             460              80          36,800
 and revision of procedures for
 preparing and submitting GRAS
 notices for human food, 170.210
 through 170.270................
Notifier's review of final rule               20               1              20              80           1,600
 and revision of procedures for
 preparing and submitting GRAS
 notices for animal food,
 570.210 through 570.270........
Prepare and submit GRAS notice                45               1              45             185           8,325
 for an outstanding GRAS
 petition, 170.285..............
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............          46,725
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

Recurring Reporting Burden

    Table 32 shows the estimated recurring annual reporting burden 
associated with the final rule. As previously discussed, the final rule 
replaces the petition process with a GRAS notification procedure. The 
level of effort required by a firm to reach a conclusion that a 
substance is GRAS for its intended use remains unchanged by the final 
rule. However, the final rule requires that firms submit some 
additional information to support the conclusions found within their 
notices. The additional information might include an amendment 
(Sec. Sec.  170.260 and 570.260); a supplement (Sec. Sec.  170.280 and 
570.280); a request for FDA to cease to evaluate a GRAS notice 
(Sec. Sec.  170.260 and 570.260); an incorporation into a GRAS notice 
(Sec. Sec.  170.215 and 570.215); and, information required when the 
intended conditions of use of a notified substance includes use in a 
product subject to regulation by FSIS, including authorization to us to 
share any trade secrets with FSIS (Sec.  170.270). Because the amount 
of additional information may vary, we estimate that respondents will 
spend between 155 and 170 hours to prepare and submit each notice. 
Using the upper-bound figure of 170 hours, we therefore estimate that 
the 50 notifiers for human food and 25 notifiers for animal food will 
expend 12,750 hours annually as shown, respectively, in rows 1 and 2.

                                 Table 32--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
     Activity/21 CFR section         Number of     responses per   Total annual   Average burden    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
GRAS notification procedure for               50               1              50             170           8,500
 human food, 170.210 through
 170.270........................
GRAS notification procedure for               25               1              25             170           4,250
 animal food, 570.210 through
 570.270........................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............          12,750
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

Recordkeeping
    The final rule does not contain recordkeeping requirements. We 
believe that documentation used by respondents in support of a 
conclusion of GRAS status is information that is collected and retained 
as a part of usual and customary business practices for a firm engaged 
in the manufacture of substances used in human food and animal food. We 
have, therefore, not provided an estimate for these activities (5 CFR 
1320.3(b)(2)).
    This final rule also refers to other currently approved collections 
of information found in our regulations. These collections of 
information are subject to review by OMB under the PRA. The collections 
of information in 21 CFR 25.32(i) are approved under OMB control number 
0910-0541. The collections of information in 21 CFR 10.33 are approved 
under OMB control number 0910-0191.
    The information collection provisions of this final rule have been 
submitted to OMB for review as required by section 3507(d) of the PRA. 
Before the effective date of this final rule, FDA will publish a notice 
in the Federal Register announcing OMB's decision to approve, modify, 
or disapprove the information collection provisions in this final rule. 
An Agency may not conduct or sponsor, and a person is not required to 
respond to, a collection of information unless it displays a currently 
valid OMB control number.

XXX. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we have concluded that the 
rule does not contain policies that have federalism implications as 
defined in the Executive order and, consequently, a federalism summary 
impact statement is not required.

XXXI. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, and are available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they also are available electronically at http://

[[Page 55045]]

www.regulations.gov. FDA has verified the Web site addresses, as of the 
date this document publishes in the Federal Register, but Web sites are 
subject to change over time.

1. House Report No. 2284, July 28, 1958. See Reference 1 to the 
proposed rule.
2. Price, J.M., C.G. Biava, B.L. Oser, et al., ``Bladder Tumors in 
Rats Fed Cyclohexylamine or High Doses of a Mixture of Cyclamate and 
Saccharin,'' Science, 167:1131-1132, 1970. See Reference 2 to the 
proposed rule.
3. New York Times, p. 22, October 31, 1969. See Reference 3 to the 
proposed rule.
4. United States Government Accountability Office, ``Report to 
Congressional Requestors on Food Safety: FDA Should Strengthen Its 
Oversight of Food Ingredients Determined to Be Generally Recognized 
as Safe (GRAS),'' Report No. GAO-10-246, (http://www.gao.gov/new.items/d10246.pdf), February 2010. Accessed and printed on May 3, 
2010. See Reference 2 to the 2010 notice.
5. FDA, ``Draft Guidance for Industry: Assessing the Effects of 
Significant Manufacturing Process Changes, Including Emerging 
Technologies, on the Safety and Regulatory Status of Food 
Ingredients and Food Contact Substances, Including Food Ingredients 
that Are Color Additives,'' (http://www.regulations.gov in Docket 
No. FDA-2011-D-0490), 2012. Accessed and printed on February 19, 
2016.
6. FDA, ``Guidance for Industry: Assessing the Effects of 
Significant Manufacturing Process Changes, Including Emerging 
Technologies, on the Safety and Regulatory Status of Food 
Ingredients and Food Contact Substances, Including Food Ingredients 
that Are Color Additives,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm300661.htm), 2014. Accessed and printed on January 15, 2016.
7. FDA, ``Draft Guidance for Industry: Considering Whether an FDA-
Regulated Product Involves the Application of Nanotechnology,'' 
(http://www.regulations.gov in Docket No. FDA-2010-D-0530), 2011. 
Accessed and printed on February 19, 2016.
8. FDA, ``Guidance for Industry: Considering Whether an FDA-
Regulated Product Involves the Application of Nanotechnology,'' 
(http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm), 
2014. Accessed and printed on January 15, 2016.
9. The Pew Charitable Trusts, ``Fixing the Oversight of Chemicals 
Added to Our Food,'' (http://www.pewtrusts.org/~/media/legacy/
uploadedfiles/phg/content_level_pages/reports/
foodadditivescapstonereportpdf.pdf), 2013. Accessed and printed on 
February 19, 2016.
10. Letter dated November 17, 2010, from Joann M. Givens of FDA to 
Mr. Tim Baggs, Charge Beverages Corporation, (http://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm233990.htm). 
Accessed and printed on January 31, 2016.
11. Letter dated November 17, 2010, from Joann M. Givens of FDA to 
Rhonda Kallman of New Century Brewing Company, (http://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm234028.htm). 
Accessed and printed on January 31, 2016.
12. Letter dated November 17, 2010, from Joann M. Givens of FDA to 
Jaisen Freeman, Chris Hunter, and Jeff Wright of Phusion Projects, 
(http://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm234023.htm). Accessed and printed on January 31, 2016.
13. Letter dated November 17, 2010, from Joann M. Givens of FDA to 
Michael Michail of United Brands Company, (http://www.fda.gov/iceci/enforcementactions/warningletters/2010/ucm234002.htm). Accessed and 
printed on January 31, 2016.
14. TTB, Industry Circular 2010-8, (http://www.ttb.gov/industry_circulars/archives/2010/10-08.html), 2010. Accessed and 
printed on January 21, 2016.
15. The National Academies of Sciences, Health and Medicine 
Division, ``Caffeine in Food and Dietary Supplements: Examining 
Safety--Workshop Summary,'' (http://www.nationalacademies.org/hmd/Reports/2014/Caffeine-in-Food-and-Dietary-Supplements-Examining-Safety.aspx), 2014. Accessed and printed on May 27, 2016.
16. Memorandum of Meeting Held on December 11, 2014, between 
Representatives of FDA and Representatives of the Caffeine Technical 
Working Group on the American Beverage Association (ABA) Caffeine 
Technical Working Group (CTWG) Research Plans.
17. International Life Sciences Institute (ILSI North America), 
``Caffeine Working Group,'' (http://ilsina.org/our-work/food-safety/caffeine/), 2015. Accessed and printed on June 8, 2016.
18. Experience With GRAS Notices Under the 1997 Proposed Rule, 
Memorandum Dated November 4, 2010, from Linda S. Kahl of FDA to 
Docket No. FDA-1997-N-0020. See Reference 1 to the 2010 notice.
19. ``Substances that Are Generally Recognized as Safe (GRAS); 
Updated Experience With GRAS Notices,'' Memorandum Dated June 1, 
2016, from Paulette M. Gaynor of FDA to Docket No. FDA-1997-N-0020.
20. ``Experience With GRAS Notices Under CVM's Interim Pilot 
Program,'' Memorandum Dated June 10, 2016, from David Edwards of FDA 
to Docket No. FDA-1997-N-0020.
21. Memorandum for the Heads of Executive Departments and Agencies, 
Dated June 1, 1998, Signed by President William J. Clinton, (http://www.plainlanguage.gov/whatisPL/govmandates/memo.cfm). Accessed and 
printed on July 14, 2008. See Reference 3 to the 2010 notice.
22. eRulemaking Program, ``Improving Electronic Dockets on 
Regulations.gov and the Federal Docket Management System: Best 
Practices for Federal Agencies,'' (http://www.regulations.gov/docs/FactSheet_eRulemaking_Best_Practices.pdf), 2010. Accessed and 
printed on January 15, 2016.
23. Dictionary.com. Dictionary.com Unabridged. Random House, Inc. 
(http://dictionary.reference.com/browse/corroborate), 2016. Accessed 
and printed on February 23, 2016.
24. Food and Agriculture Organization of the United Nations and the 
World Health Organization, ``Chapter 6, Dietary Exposure Assessment 
of Chemicals in Food'' in Environmental Health Criteria 240. 
Principles and Methods for the Risk Assessment of Chemicals in Food, 
(http://apps.who.int/iris/bitstream/10665/44065/9/WHO_EHC_240_9_eng_Chapter6.pdf), 2009. Accessed and printed on 
February 13, 2006.
25. FDA, ``Guidance for Industry: Estimating Dietary Intake of 
Substances in Food,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm074725.htm), 2006. 
Accessed and printed on January 15, 2016.
26. Renwick, A.G., ``The Use of a Sweetener Substitution Method to 
Predict Dietary Exposures for the Intense Sweetener Rebaudioside 
A.,'' Food and Chemical Toxicology, 46:S61-S69, 2008.
27. Mitchell, D.C., C.A. Knight, J. Hockenberry, et al., ``Beverage 
Caffeine Intakes in the U.S.,'' Food and Chemical Toxicology, 
63:136-142, 2014.
28. Fulgoni, V.L., D.R. Keast, and H.R. Lieberman, ``Trends in 
Intake and Sources of Caffeine in the Diets of US Adults: 2001-
2010,'' The American Journal of Clinical Nutrition, 101:1081-1087, 
2015.
29. Branum, A.M., L.M. Rossen, and K.C. Schoendorf, ``Trends in 
Caffeine Intake Among U.S. Children and Adolescents,'' Pediatrics, 
133(3):386-393, 2014.
30. Food and Agriculture Organization and World Health Organization, 
``Joint FAO/WHO Expert Consultation on Biotechnology and Food 
Safety,'' (ftp://ftp.fao.org/es/esn/food/biotechnology.pdf), 1996. 
See Reference 6 to the proposed rule.
31. FDA, ``Guidance for Industry: Recommendations for Submission of 
Chemical and Technological Data for Direct Food Additive 
Petitions,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm124917.htm), 2009. 
Accessed and printed on January 15, 2016.
32. FDA, ``Guidance for Industry: Microbiological Considerations for 
Antimicrobial Food Additive Submissions,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm230417.htm), 2008. Accessed and printed on January 15, 2016.
33. FDA, ``Guidance for Industry: Enzyme Preparations: 
Recommendations for Submission of Chemical and Technological Data 
for Food Additive

[[Page 55046]]

Petitions and GRAS Notices,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm217685.htm), 2010. Accessed and 
printed on January 15, 2016.
34. FDA, ``Guidance for Industry: Summary Table of Recommended 
Toxicological Testing for Additives Used in Food,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm054658.htm), 2006. 
Accessed and printed on January 15, 2016.
35. FDA, ``Guidance for Industry and Other Stakeholders: 
Toxicological Principles for the Safety Assessment of Food 
Ingredients. Redbook 2000,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm2006826.htm), 2007. Accessed 
and printed on January 15, 2016.
36. 225-00-2000 ``Amendment 1: Memorandum of Understanding Between 
the United States Department of Agriculture Food Safety Inspection 
Service and the United States Department of Health and Human 
Services Food and Drug Administration, (http://www.fda.gov/AboutFDA/PartnershipsCollaborations/MemorandaofUnderstandingMOUs/DomesticMOUs/ucm441552.htm), 2000. Accessed and printed on November 
25, 2015.
37. FDA, ``Guidance for Industry: Providing Regulatory Submissions 
in Electronic or Paper Format to the Office of Food Additive Safety; 
Draft Guidance,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm2021277.htm), 2010. Accessed 
and printed on January 15, 2016.
38. Form FDA 3667. ``Generally Recognized As Safe (GRAS) Notice,'' 
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM350015.pdf), 2016. Accessed and printed on June 1, 2016.
39. Form FDA 3480. ``Food Contact Substance: Notification for New 
Use, Pre-Notification Consultation, Food Master File'', (http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM076880.pdf), 2016. Accessed and printed on June 1, 2016.
40. Form FDA 3537. ``DHHS/FDA Food Facility Registration,'' (http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm071977.pdf), 2014. Accessed and printed on January 15, 2016.
41. FSIS, ``Contact Us,'' (http://www.fsis.usda.gov/wps/portal/informational/contactus). Accessed and printed on January 28, 2016.
42. Pariza, M.W. and M. Cook, ``Determining the Safety of Enzymes 
Used in Animal Feed,'' Regulatory Toxicology and Pharmacology, 
56:332-342, 2010.
43. Olempska-Beer Z.S., R.I Merker, M.D. Ditto, and M.J. DiNovi, 
``Food-Processing Enzymes From Recombinant Microorganisms--A 
Review,'' Regulatory Toxicology and Pharmacology, 45(2):144-158, 
2006.
44. ``Guidance for Industry: Use of Nanomaterials in Food for 
Animals (# 220),'' (http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM401508.pdf), 
2015. Accessed and printed on January 15, 2016.
45. ``GRAS Notices, Search Results, Common Use in Food,'' 2016.
46. GRAS Notice Inventory, (http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm), 
2016. Accessed and printed on January 15, 2016.
47. Current Animal Food GRAS Notices Inventory, (http://www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/GenerallyRecognizedasSafeGRASNotifications/ucm243845.htm), 2016. 
Accessed and printed on February 23, 2016.
48. FDA, List of Pending GRAS Affirmation Petitions as of December 
31, 2015.
49. FDA, ``Guidance for Industry: Frequently Asked Questions About 
GRAS,'' (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRASPackaging/ucm061846.htm), 2004. Accessed and 
printed on October 13, 2010. See Reference 6 to the 2010 notice.
50. FDA, Memorandum of Telephone Conference Held on May 19, 1998, 
between Linda S. Kahl and Gloria Overholser of FDA and Carlton 
Kempter and Jonathan Fleuchaus, U.S. Environmental Protection 
Agency.
51. FDA, ``Substances Generally Recognized as Safe Final Rule: Final 
Regulatory Impact Analysis, Final Regulatory Flexibility Analysis, 
Final Unfunded Mandates Reform Act Analysis,'' 2016.
52. FDA, ``Compliance Policy Guide CPG Sec. 665.100 Common or Usual 
Names for Animal Feed Ingredients,'' (http://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm074687.htm), 
1995. Accessed and printed on January 7, 2016.
53. Selle, P.H. and V. Ravindran, ``Microbial Phytase in Poultry 
Nutrition,'' Animal Feed Science and Technology, 135:1-41, 2007.
54. Hatten., L.F., D.R. Ingram., and S.T. Pittman, ``Effect of 
Phytase on Production Parameters and Nutrient Availability in 
Broilers and Laying Hens: A Review,'' The Journal of Applied Poultry 
Research, 10(3):274-278, 2001.
55. Angel, C.R., W. Saylor, S.L. Vieira, and N. Ward, ``Effects of a 
Monocomponent Protease on Performance and Protein Utilization in 7- 
to 22-Day-Old Broiler Chickens,'' Poultry Science, 90:2281-2286, 
2011.
56. FDA, ``Guidance for Industry: Recommendations for Preparation 
and Submission of Animal Food Additive Petitions (# 221),'' (http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM367746.pdf), 
2015. Accessed and printed on January 15, 2016.
57. National Research Council, ``General Considerations in 
Determining Safety of Animal Dietary Supplements,'' in Safety of 
Dietary Supplements for Horses, Dogs, and Cats, Washington, DC, 
Chapter 9, pp. 169-175, The National Academies Press, 2009.
58. FDA, ``Compliance Policy Guide CPG Sec. 527.400. Whole Milk, 
Lowfat Milk, Skim Milk--Aflatoxin M1,'' (http://www.fda.gov/iceci/compliancemanuals/compliancepolicyguidancemanual/ucm074482.htm), 
2005. Accessed and printed on January 15, 2016.

List of Subjects

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 25

    Environmental impact statements, Foreign relations, Reporting and 
recordkeeping requirements.

21 CFR Part 170

    Administrative practice and procedure, Food additives, Reporting 
and recordkeeping requirements.

21 CFR Part 184

    Food additives.

21 CFR Part 186

    Food additives, Food packaging.

21 CFR Part 570

    Animal feeds, Animal foods, Food additives.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR 
chapter I is amended as follows:

PART 20--PUBLIC INFORMATION

0
1. The authority citation for part 20 continues to read as follows:

    Authority:  5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 
21 U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.


0
2. In Sec.  20.100, add paragraph (c)(46) to read as follows:


Sec.  20.100   Applicability; cross-reference to other regulations.

* * * * *
    (c) * * *
    (46) Generally recognized as safe (GRAS) notices, in part 170, 
subpart E and part 570, subpart E of this chapter.

[[Page 55047]]

PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS

0
3. The authority citation for part 25 continues to read as follows:

    Authority:  21 U.S.C. 321-393; 42 U.S.C. 262, 263b-264; 42 
U.S.C. 4321, 4332; 40 CFR parts 1500-1508; E.O. 11514, 35 FR 4247, 3 
CFR, 1971 Comp., p. 531-533 as amended by E.O. 11991, 42 FR 26967, 3 
CFR, 1978 Comp., p. 123-124 and E.O. 12114, 44 FR 1957, 3 CFR, 1980 
Comp., p. 356-360.


0
4. In Sec.  25.20, revise paragraph (k) to read as follows:


Sec.  25.20  Actions requiring preparation of an environmental 
assessment.

* * * * *
    (k) Establishment or amendment of a regulation for a food substance 
as GRAS under the conditions of its intended use for humans or animals 
under parts 182, 184, 186, 582, or 584 of this chapter, or 
establishment or amendment of a regulation for a prior-sanctioned food 
ingredient, as defined in Sec. Sec.  170.3(l) and 181.5(a) of this 
chapter, unless categorically excluded in Sec.  25.32(f), (i), (j), 
(k), or (r).
* * * * *

0
5. In Sec.  25.32, revise paragraphs (f), (i), (j), (k), and (r) to 
read as follows:


Sec.  25.32  Foods, food additives, and color additives.

* * * * *
    (f) Establishment or amendment of a regulation for a food substance 
as GRAS under the conditions of its intended use for humans or animals 
under parts 182, 184, 186, 582, or 584 of this chapter, and 
establishment or amendment of a regulation for a prior-sanctioned food 
ingredient, as defined in Sec. Sec.  170.3(l) and 181.5(a) of this 
chapter, if the substance or food ingredient is already marketed in the 
United States for the proposed use.
* * * * *
    (i) Approval of a food additive petition, establishment or 
amendment of a regulation for a food substance as GRAS under the 
conditions of its intended use for humans or animals under parts 182, 
184, 186, 582, or 584 of this chapter, the granting of a request for 
exemption from regulation as a food additive under Sec.  170.39 of this 
chapter, or allowing a notification submitted under 21 U.S.C. 348(h) to 
become effective, when the substance is present in finished food-
packaging material at not greater than 5 percent-by-weight and is 
expected to remain with finished food-packaging material through use by 
consumers or when the substance is a component of a coating of a 
finished food-packaging material.
    (j) Approval of a food additive petition, establishment or 
amendment of a regulation for a food substance as GRAS under the 
conditions of its intended use for humans or animals under parts 182, 
184, 186, 582, or 584 of this chapter, the granting of a request for 
exemption from regulation as a food additive under Sec.  170.39 of this 
chapter, or allowing a notification submitted under 21 U.S.C. 348(h) to 
become effective, when the substance is to be used as a component of a 
food-contact surface of permanent or semipermanent equipment or of 
another food-contact article intended for repeated use.
    (k) Approval of a food additive petition or color additive 
petition, establishment or amendment of a regulation for a food 
substance as GRAS under the conditions of its intended use for humans 
or animals under parts 182, 184, 186, 582, or 584 of this chapter, or 
allowing a notification submitted under 21 U.S.C. 348(h) to become 
effective, for substances added directly to food that are intended to 
remain in food through ingestion by consumers and that are not intended 
to replace macronutrients in food.
* * * * *
    (r) Approval of a food additive petition or color additive 
petition, establishment or amendment of a regulation for a food 
substance as GRAS under the conditions of its intended use for humans 
or animals under parts 182, 184, 186, 582, or 584 of this chapter, or 
allowing a notification submitted under 21 U.S.C. 348(h) to become 
effective for a substance that occurs naturally in the environment, 
when the action does not alter significantly the concentration or 
distribution of the substance, its metabolites, or degradation products 
in the environment.

PART 170--FOOD ADDITIVES

0
6. The authority citation for part 170 continues to read as follows:

    Authority:  21 U.S.C. 321, 341, 342, 346a, 348, 371.


0
7. In Sec.  170.3, revise paragraph (h), the first sentence of 
paragraph (i), and paragraph (k), to read as follows:


Sec.  170.3  Definitions.

* * * * *
    (h) Scientific procedures include the application of scientific 
data (including, as appropriate, data from human, animal, analytical, 
or other scientific studies), information, and methods, whether 
published or unpublished, as well as the application of scientific 
principles, appropriate to establish the safety of a substance under 
the conditions of its intended use.
    (i) Safe or safety means that there is a reasonable certainty in 
the minds of competent scientists that the substance is not harmful 
under the conditions of its intended use. * * *
* * * * *
    (k) General recognition of safety shall be in accordance with Sec.  
170.30.
* * * * *

0
8. Amend Sec.  170.30 as follows:
0
a. Revise the last sentence of paragraph (a);
0
b. Revise paragraph (b).
0
c. Revise the the first sentence of paragraph (c)(1) and revise 
paragraph (c)(2);
0
d. Remove ``Sec.  186.1'' and add in its place ``part 186'' wherever it 
appears in paragraph (d);
0
e. Revise paragraph (e);
0
f. Remove and reserve paragraph (f);
0
g. Remove ``Sec.  186.1'' and add in its place ``part 186'' in 
paragraphs (h) introductory text, (h)(1), (i), (j), and (k); and
0
h. Revise the last sentence of paragraph (l).
    The revisions read as follows:


Sec.  170.30   Eligibility for classification as generally recognized 
as safe (GRAS).

    (a) * * * General recognition of safety requires common knowledge 
throughout the scientific community knowledgeable about the safety of 
substances directly or indirectly added to food that there is 
reasonable certainty that the substance is not harmful under the 
conditions of its intended use (see Sec.  170.3(i)).
    (b) General recognition of safety based upon scientific procedures 
shall require the same quantity and quality of scientific evidence as 
is required to obtain approval of a food additive. General recognition 
of safety through scientific procedures shall be based upon the 
application of generally available and accepted scientific data, 
information, or methods, which ordinarily are published, as well as the 
application of scientific principles, and may be corroborated by the 
application of unpublished scientific data, information, or methods.
    (c)(1) General recognition of safety through experience based on 
common use in food prior to January 1, 1958, may be achieved without 
the quantity or quality of scientific procedures required for approval 
of a food additive. * * *
    (2) A substance used in food prior to January 1, 1958, may be 
generally recognized as safe through experience based on its common use 
in food when that use occurred exclusively or primarily outside of the 
United States if

[[Page 55048]]

the information about the experience establishes that the substance is 
safe under the conditions of its intended use within the meaning of 
section 201(u) of the Federal Food, Drug, and Cosmetic Act (see also 
Sec.  170.3(i)). Common use in food prior to January 1, 1958, that 
occurred outside of the United States shall be documented by published 
or other information and shall be corroborated by information from a 
second, independent source that confirms the history and circumstances 
of use of the substance. The information used to document and to 
corroborate the history and circumstances of use of the substance must 
be generally available; that is, it must be widely available in the 
country in which the history of use has occurred and readily available 
to interested qualified experts in the United States. A person who 
concludes that a use of a substance is GRAS through experience based on 
its common use in food outside of the United States should notify FDA 
of that view in accordance with subpart E of this part.
* * * * *
    (e) Food ingredients were listed as GRAS in part 182 of this 
chapter during 1958-1962 without a detailed scientific review of all 
available data and information relating to their safety. Beginning in 
1969, the Food and Drug Administration has undertaken a systematic 
review of the status of all ingredients used in food based on the view 
that they are GRAS under the conditions of their intended use or 
subject to a prior sanction. All affirmations of GRAS status or 
determinations of food additive status or prior sanction status 
pursuant to this review shall be handled pursuant to Sec. Sec.  170.35, 
170.38, and 180.1 of this chapter. Affirmation of GRAS status shall be 
announced in part 184 or part 186 of this chapter.
* * * * *
    (l) * * * Any change to the GRAS status of a food ingredient in 
parts 182, 184, or 186 of this chapter shall be accomplished pursuant 
to Sec.  170.38.

0
9. In Sec.  170.35, revise paragraphs (a), (b)(1), (3), and (4), and 
remove paragraph (c) to read as follows:


Sec.  170.35  Affirmation of generally recognized as safe (GRAS) 
status.

    (a) The Commissioner, on his own initiative, may affirm that a 
substance that directly or indirectly becomes a component of food is 
GRAS under the conditions of its intended use.
    (b)(1) If the Commissioner proposes on his own initiative that a 
substance is entitled to affirmation as GRAS under the conditions of 
its intended use, he will place all of the data and information on 
which he relies on public file in the office of the Division of Dockets 
Management and will publish in the Federal Register a notice giving the 
name of the substance, its proposed uses, and any limitations proposed 
for purposes other than safety.
* * * * *
    (3) The Commissioner will evaluate all comments received. If he 
concludes that there is convincing evidence that the substance is GRAS 
under the conditions of its intended use as described in Sec.  170.30, 
he will publish a notice in the Federal Register listing the GRAS 
conditions of use of the substance in part 184 or part 186 of this 
chapter, as appropriate.
    (4) If, after evaluation of the comments, the Commissioner 
concludes that there is a lack of convincing evidence that a substance 
is GRAS under the conditions of its intended use and that it should be 
considered a food additive subject to section 409 of the Federal Food, 
Drug, and Cosmetic Act, he shall publish a notice thereof in the 
Federal Register in accordance with Sec.  170.38.

0
10. In Sec.  170.38, revise paragraph (a) to read as follows:


Sec.  170.38   Determination of food additive status.

    (a) The Commissioner may, in accordance with Sec.  170.35(b)(4), 
publish a notice in the Federal Register determining that a substance 
is not GRAS under the conditions of its intended use and is a food 
additive subject to section 409 of the Federal Food, Drug, and Cosmetic 
Act.
* * * * *

0
11. Add subpart E, consisting of Sec. Sec.  170.203 through 170.285, to 
read as follows:

Subpart E--Generally Recognized as Safe (GRAS) Notice

Sec.
170.203 Definitions.
170.205 Opportunity to submit a GRAS notice.
170.210 How to send your GRAS notice to FDA.
170.215 Incorporation into a GRAS notice.
170.220 General requirements applicable to a GRAS notice.
170.225 Part 1 of a GRAS notice: Signed statements and 
certification.
170.230 Part 2 of a GRAS notice: Identity, method of manufacture, 
specifications, and physical or technical effect.
170.235 Part 3 of a GRAS notice: Dietary exposure.
170.240 Part 4 of a GRAS notice: Self-limiting levels of use.
170.245 Part 5 of a GRAS notice: Experience based on common use in 
food before 1958.
170.250 Part 6 of a GRAS notice: Narrative.
170.255 Part 7 of a GRAS notice: List of supporting data and 
information in your GRAS notice.
170.260 Steps you may take before FDA responds to your GRAS notice.
170.265 What FDA will do with a GRAS notice.
170.270 Procedures that apply when the intended conditions of use of 
a notified substance include use in a product or products subject to 
regulation by the Food Safety and Inspection Service (FSIS) of the 
United States Department of Agriculture.
170.275 Public disclosure of a GRAS notice.
170.280 Submission of a supplement.
170.285 Disposition of pending GRAS affirmation petitions.

Subpart E--Generally Recognized as Safe (GRAS) Notice


Sec.  170.203  Definitions.

    The definitions and interpretations of terms in Sec.  170.3 apply 
to such terms when used in this subpart. The following definitions also 
apply:
    Amendment means any data and information that you submit regarding 
a filed GRAS notice before we respond to your notice by letter in 
accordance with Sec.  170.265(b)(1) or cease to evaluate your notice in 
accordance with Sec.  170.265(b)(3).
    GRAS means generally recognized as safe.
    GRAS notice means a submission that informs us of your view that a 
substance is not subject to the premarket approval requirements of the 
Federal Food, Drug, and Cosmetic Act based on your conclusion that the 
substance is GRAS under the conditions of its intended use in 
accordance with Sec.  170.30.
    Notified substance means the substance that is the subject of your 
GRAS notice.
    Notifier means the person (e.g., an individual, partnership, 
corporation, association, or other legal entity) who is responsible for 
the GRAS notice, even if another person (such as an attorney, agent, or 
qualified expert) prepares or submits the notice or provides an opinion 
about the basis for a conclusion of GRAS status.
    Qualified expert means an individual who is qualified by scientific 
training and experience to evaluate the safety of substances under the 
conditions of their intended use in food.
    Supplement means any data and information that you submit regarding 
a filed GRAS notice after we respond to your notice by letter in 
accordance with Sec.  170.265(b)(1) or cease to evaluate your

[[Page 55049]]

notice in accordance with Sec.  170.265(b)(3).
    We, our, and us refer to the United States Food and Drug 
Administration (FDA).
    You and your refer to a notifier.


Sec.  170.205  Opportunity to submit a GRAS notice.

    Any person may notify FDA of a view that a substance is not subject 
to the premarket approval requirements of section 409 of the Federal 
Food, Drug, and Cosmetic Act based on that person's conclusion that the 
substance is GRAS under the conditions of its intended use.


Sec.  170.210  How to send your GRAS notice to FDA.

    (a) Send your GRAS notice to the Office of Food Additive Safety 
(HFS-200), Center for Food Safety and Applied Nutrition, Food and Drug 
Administration, 5001 Campus Drive, College Park, MD 20740.
    (b) When you submit your GRAS notice, you may do so either in an 
electronic format that is accessible for our evaluation or on paper. If 
you send your GRAS notice on paper, a single paper copy is sufficient.


Sec.  170.215  Incorporation into a GRAS notice.

    You may incorporate into your GRAS notice either specifically 
identified data and information that you previously submitted to the 
Center for Food Safety and Applied Nutrition (CFSAN), or specifically 
identified publicly available data and information submitted by another 
party, when such data and information remain in CFSAN's records, such 
as data and information contained in a previous GRAS notice or a food 
additive petition.


Sec.  170.220  General requirements applicable to a GRAS notice.

    (a) A GRAS notice has seven parts as required by Sec. Sec.  170.225 
through 170.255. You must submit the data and information specified in 
each of these parts on separate pages or sets of pages.
    (b) You must include each of the seven parts in your GRAS notice. 
If you do not include a part, you must include with your GRAS notice an 
explanation of why that part does not apply to your GRAS notice.


Sec.  170.225  Part 1 of a GRAS notice: Signed statements and 
certification.

    (a) Part 1 of your GRAS notice must be dated and signed by a 
responsible official of your organization, or by your attorney or 
agent.
    (b) Except as required by paragraph (c)(8) of this section, you 
must not include any information that is trade secret or confidential 
commercial information in Part 1 of your GRAS notice.
    (c) In Part 1 of your GRAS notice, you must:
    (1) Inform us that you are submitting a GRAS notice in accordance 
with this subpart;
    (2) Provide the name and address of your organization;
    (3) Provide the name of the notified substance, using an 
appropriately descriptive term;
    (4) Describe the intended conditions of use of the notified 
substance, including the foods in which the substance will be used, the 
levels of use in such foods, and the purposes for which the substance 
will be used, including, when appropriate, a description of a 
subpopulation expected to consume the notified substance;
    (5) Inform us of the statutory basis for your conclusion of GRAS 
status (i.e., through scientific procedures in accordance with Sec.  
170.30(a) and (b) or through experience based on common use in food in 
accordance with Sec.  170.30(a) and (c));
    (6) State your view that the notified substance is not subject to 
the premarket approval requirements of the Federal Food, Drug, and 
Cosmetic Act based on your conclusion that the notified substance is 
GRAS under the conditions of its intended use;
    (7) State that, if we ask to see the data and information that are 
the basis for your conclusion of GRAS status, either during or after 
our evaluation of your notice, you will:
    (i) Agree to make the data and information available to us; and
    (ii) Agree to both of the following procedures for making the data 
and information available to us:
    (A) Upon our request, you will allow us to review and copy the data 
and information during customary business hours at the address you 
specify for where these data and information will be available to us; 
and
    (B) Upon our request, you will provide us with a complete copy of 
the data and information either in an electronic format that is 
accessible for our evaluation or on paper;
    (8) State your view as to whether any of the data and information 
in Parts 2 through 7 of your GRAS notice are exempt from disclosure 
under the Freedom of Information Act, 5 U.S.C. 552 (e.g., as trade 
secret or as commercial or financial information that is privileged or 
confidential).
    (9) Certify that, to the best of your knowledge, your GRAS notice 
is a complete, representative, and balanced submission that includes 
unfavorable information, as well as favorable information, known to you 
and pertinent to the evaluation of the safety and GRAS status of the 
use of the substance;
    (10) State both the name and position or title of the person who 
signs the GRAS notice; and
    (11) When applicable, state as required by Sec.  170.270 whether 
you:
    (i) Authorize us to send any trade secrets to the Food Safety and 
Inspection Service (FSIS) of the U.S. Department of Agriculture; or
    (ii) Ask us to exclude any trade secrets from the copy of the GRAS 
notice that we will send to FSIS.


Sec.  170.230  Part 2 of a GRAS notice: Identity, method of 
manufacture, specifications, and physical or technical effect.

    In Part 2 of your GRAS notice, you must include:
    (a) Scientific data and information that identifies the notified 
substance.
    (1) Examples of appropriate data and information include the 
chemical name, applicable registry numbers (such as a Chemical 
Abstracts Service (CAS) registry number or an Enzyme Commission (EC) 
number), empirical formula, structural formula, quantitative 
composition, and characteristic properties.
    (2) When the source of a notified substance is a biological 
material, you must include data and information sufficient to identify:
    (i) The taxonomic source (e.g., genus, species) including, as 
applicable, data and information at the sub-species level (e.g., 
variety, strain);
    (ii) The part of any plant or animal used as the source; and
    (iii) Any known toxicants that could be in the source;
    (b) A description of the method of manufacture of the notified 
substance in sufficient detail to evaluate the safety of the notified 
substance as manufactured;
    (c) Specifications for food-grade material; and
    (d) When necessary to demonstrate safety, relevant data and 
information bearing on the physical or other technical effect the 
notified substance is intended to produce, including the quantity of 
the notified substance required to produce such effect.


Sec.  170.235   Part 3 of a GRAS notice: Dietary exposure.

    In part 3 of your GRAS notice, you must provide data and 
information about dietary exposure (i.e., the amount of relevant 
substances that consumers are likely to eat or drink as part of a total 
diet), regardless of whether your conclusion of GRAS status is through

[[Page 55050]]

scientific procedures or through experience based on common use in 
food, as follows:
    (a) You must provide an estimate of dietary exposure to the 
notified substance that includes exposure from its intended use and all 
sources in the diet; and
    (b) When applicable, you must provide an estimate of dietary 
exposure to any other substance that is expected to be formed in or on 
food because of the use of the notified substance (e.g., hydrolytic 
products or reaction products);
    (c) When applicable, you must provide an estimate of dietary 
exposure to any other substance that is present with the notified 
substance either naturally or due to its manufacture (e.g., 
contaminants or by-products);
    (d) You must describe the source of any food consumption data that 
you use to estimate dietary exposure in accordance with paragraphs (a) 
through (c) of this section; and
    (e) You must explain any assumptions you made to estimate dietary 
exposure in accordance with paragraphs (a) through (c) of this section.


Sec.  170.240  Part 4 of a GRAS notice: Self-limiting levels of use.

    In circumstances where the amount of the notified substance that 
can be added to food is limited because food containing levels of the 
notified substance above a particular level would become unpalatable or 
technologically impractical, in Part 4 of your GRAS notice you must 
include data and information on such self-limiting levels of use.


Sec.  170.245  Part 5 of a GRAS notice: Experience based on common use 
in food before 1958.

    If the statutory basis for your conclusion of GRAS status is 
through experience based on common use in food, in Part 5 of your GRAS 
notice you must include evidence of a substantial history of 
consumption of the notified substance for food use by a significant 
number of consumers prior to January 1, 1958.


Sec.  170.250   Part 6 of a GRAS notice: Narrative.

    In Part 6 of your GRAS notice, you must include a narrative that 
provides the basis for your conclusion of GRAS status, in which:
    (a)(1) You must explain why the data and information in your notice 
provide a basis for your view that the notified substance is safe under 
the conditions of its intended use. In your explanation, you must 
address the safety of the notified substance, considering all dietary 
sources and taking into account any chemically or pharmacologically 
related substances in such diet;
    (2) In your explanation, you must identify what specific data and 
information that you discuss in accordance with paragraph (a)(1) of 
this section are generally available, and what specific data and 
information that you discuss in accordance with paragraph (a)(1) of 
this section are not generally available, by providing citations to the 
list of data and information that you include in Part 7 of your GRAS 
notice in accordance with Sec.  170.255;
    (b) You must explain how the generally available data and 
information that you rely on to establish safety in accordance with 
paragraph (a) of this section provide a basis for your conclusion that 
the notified substance is generally recognized, among qualified 
experts, to be safe under the conditions of its intended use;
    (c) You must either:
    (1) Identify, discuss, and place in context, data and information 
that are, or may appear to be, inconsistent with your conclusion of 
GRAS status, regardless of whether those data and information are 
generally available; or
    (2) State that you have reviewed the available data and information 
and are not aware of any data and information that are, or may appear 
to be, inconsistent with your conclusion of GRAS status;
    (d) If you view any of the data and information in your notice as 
exempt from disclosure under the Freedom of Information Act, you must 
identify the specific data and information; and
    (e) For non-public, safety-related data and information considered 
in reaching a conclusion of GRAS status, you must explain how there 
could be a basis for a conclusion of GRAS status if qualified experts 
do not have access to such data and information.


Sec.  170.255  Part 7 of a GRAS notice: List of supporting data and 
information in your GRAS notice.

    (a) In part 7 of your GRAS notice, you must include a list of all 
of the data and information that you discuss in Part 6 of your GRAS 
notice to provide a basis for your view that the notified substance is 
safe under the conditions of its intended use as described in 
accordance with Sec.  170.250(a)(1).
    (b) You must specify which data and information that you list in 
accordance with paragraph (a) of this section are generally available, 
and which data and information are not generally available.


Sec.  170.260  Steps you may take before FDA responds to your GRAS 
notice.

    (a) You may submit a timely amendment to your filed GRAS notice, to 
update your GRAS notice or in response to a question from us, before we 
respond to your notice by letter in accordance with Sec.  170.265(b)(1) 
or cease to evaluate your notice in accordance with Sec.  
170.265(b)(3).
    (b) At any time before we respond to your GRAS notice in accordance 
with Sec.  170.265(b)(1), you may request in writing that we cease to 
evaluate your GRAS notice. Your request does not preclude you from 
submitting a future GRAS notice in accordance with this subpart with 
respect to the notified substance.


Sec.  170.265  What FDA will do with a GRAS notice.

    (a)(1) We will conduct an initial evaluation of your submission to 
determine whether to file it as a GRAS notice for evaluation of your 
view that the notified substance is GRAS under the conditions of its 
intended use.
    (2) If we file your submission as a GRAS notice, we will send you a 
letter that informs you of the date of filing.
    (3) If we do not file your submission as a GRAS notice, we will 
send you a letter that informs you of that fact and provides our 
reasons for not filing the submission as a GRAS notice.
    (4) We will consider any timely amendment that you submit to a 
filed GRAS notice, to update your GRAS notice or in response to a 
question from us, before we respond to you by letter in accordance with 
paragraph (b)(1) of this section, if we deem that doing so is feasible 
within the timeframes established in paragraph (b) of this section. If 
we deem that considering your amendment is not feasible within the 
timeframes established in paragraph (b) of this section or if we have 
granted your request to cease to evaluate your notice, we will inform 
you that we are not considering your amendment.
    (b)(1) Within 180 days of filing, we will respond to you by letter 
based on our evaluation of your notice. We may extend the 180 day 
timeframe by 90 days on an as needed basis.
    (2) If we extend the timeframe, we will inform you in writing of 
the extension as soon as practicable but no later than within 180 days 
of filing.
    (3) If you ask us to cease to evaluate your GRAS notice in 
accordance with Sec.  170.260(b), we will send you a letter informing 
you of our decision regarding your request.
    (c) If circumstances warrant, we will send you a subsequent letter 
about the notice.

[[Page 55051]]

Sec.  170.270  Procedures that apply when the intended conditions of 
use of a notified substance include use in a product or products 
subject to regulation by the Food Safety and Inspection Service (FSIS) 
of the United States Department of Agriculture.

    If the intended conditions of use of the notified substance include 
use in a product or products subject to regulation by FSIS under 
statutes that it administers:
    (a) When applicable, you must include in your GRAS notice a 
statement as to whether you:
    (1) Authorize us to send any trade secrets to FSIS; or
    (2) Ask us to exclude any trade secrets from the copy of the GRAS 
notice that we will send to FSIS.
    (b)(1) We will forward a copy of a GRAS notice or relevant portions 
thereof to FSIS;
    (2) We will exclude any trade secrets unless you have authorized us 
to do so in accordance with paragraph (a)(1) of this section; and
    (c) We will ask FSIS to advise whether the intended conditions of 
use comply with applicable statutes and regulations, or, if not, 
whether the use of the substance would be permitted in products under 
FSIS' jurisdiction under specified conditions or restrictions.
    (d) As appropriate, we will inform you of the advice we receive 
from FSIS in the letter we send you in accordance with Sec.  
170.265(b)(1).


Sec.  170.275  Public disclosure of a GRAS notice.

    (a) The data and information in a GRAS notice (including data and 
information submitted in any amendment or supplement to your GRAS 
notice or incorporated into your GRAS notice) are:
    (1) Considered a mandatory, rather than voluntary, submission for 
purposes of their status under the Freedom of Information Act and our 
public information requirements in part 20 of this chapter; and
    (2) Available for public disclosure in accordance with part 20 of 
this chapter as of the date that we receive your GRAS notice.
    (b) We will make the following readily accessible to the public:
    (1) A list of filed GRAS notices, including the information 
described in Sec.  170.225(c)(2) through (c)(5);
    (2) The text of any letter that we issue under Sec.  170.265(b)(1) 
or (c); and
    (3) The text of any letter that we issue under Sec.  170.265(b)(3) 
if we grant your request that we cease to evaluate your notice.
    (c) We will disclose all remaining data and information that are 
not exempt from public disclosure in accordance with part 20 of this 
chapter.


Sec.  170.280   Submission of a supplement.

    If circumstances warrant, you may submit a supplement to a filed 
GRAS notice after we respond to your notice by letter in accordance 
with Sec.  170.265(b)(1) or cease to evaluate your notice in accordance 
with Sec.  170.265(b)(3).


Sec.  170.285  Disposition of pending GRAS affirmation petitions.

    Because the procedure to submit a GRAS notice is replacing the 
former process to submit a GRAS affirmation petition, the following 
will happen to a filed GRAS affirmation petition that is pending on 
October 17, 2016.
    (a) On October 17, 2016, we will close the docket for any GRAS 
affirmation petition that is still pending as of October 17, 2016.
    (b) Any person who submitted a GRAS affirmation petition described 
in this section may submit a GRAS notice as described in this subpart 
and request that we incorporate the GRAS affirmation petition as 
described in Sec.  170.215.

PART 184--DIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED 
AS SAFE

0
12. The authority citation for part 184 continues to read as follows:

    Authority: 21 U.S.C. 321, 342, 348, 371.


0
13. In Sec.  184.1, revise the first sentence of paragraph (a), and 
revise the fifth sentence and remove the last sentence of paragraph 
(b)(1) to read as follows.


Sec.  184.1  Substances added directly to human food affirmed as 
generally recognized as safe (GRAS).

    (a) The direct human food ingredients listed in this part have been 
reviewed by the Food and Drug Administration and affirmed to be 
generally recognized as safe (GRAS) for the purposes and under the 
conditions prescribed. * * *
    (b) * * *
    (1) * * * In such a case, a manufacturer may not rely on the 
regulation as authorizing that use but shall have a basis to conclude 
that that use is GRAS or shall use the ingredient in accordance with a 
food additive regulation. * * *
* * * * *

PART 186--INDIRECT FOOD SUBSTANCES AFFIRMED AS GENERALLY RECOGNIZED 
AS SAFE

0
14. The authority citation for part 186 continues to read as follows:

    Authority:  21 U.S.C. 321, 342, 348, 371.


0
15. In Sec.  186.1, revise the first sentence of paragraph (a), and 
revise the fifth sentence and remove the last sentence of paragraph 
(b)(1) to read as follows.


Sec.  186.1  Substances added indirectly to human food affirmed as 
generally recognized as safe (GRAS).

    (a) The indirect human food ingredients listed in this part have 
been reviewed by the Food and Drug Administration and affirmed to be 
generally recognized as safe (GRAS) for the purposes and under the 
conditions prescribed, providing they comply with the purity 
specifications listed in this part or, in the absence of purity 
specifications, are of a purity suitable for their intended use in 
accordance with Sec.  170.30(h)(1) of this chapter. * * *
    (b) * * *
    (1) * * * In such a case, a manufacturer may not rely on the 
regulation as authorizing that use but shall have a basis to conclude 
that the use is GRAS or shall use the ingredient in accordance with a 
food additive regulation. * * *
* * * * *

PART 570--FOOD ADDITIVES

0
16. The authority citation for part 570 continues to read as follows:

    Authority: 21 U.S.C. 321, 341, 342, 346a, 348, 371.


0
17. In Sec.  570.3, revise paragraphs (f), (h), the first sentence of 
(i), and (k), and add paragraph (n) to read as follows:


Sec.  570.3  Definitions.

* * * * *
    (f) Common use in food means a substantial history of consumption 
of a substance by a significant number of animals of the species to 
which the substance is intended to be fed (and, for food-producing 
animals fed with such substance, also means a substantial history of 
consumption by humans consuming human foods derived from those food-
producing animals), prior to January 1, 1958.
* * * * *
    (h) Scientific procedures include the application of scientific 
data (including, as appropriate, data from human, animal, analytical, 
or other scientific studies), information, and methods, whether 
published or unpublished, as well as the application of scientific 
principles, appropriate to establish the safety of a substance under 
the conditions of its intended use.
    (i) Safe or safety means that there is a reasonable certainty in 
the minds of

[[Page 55052]]

competent scientists that the substance is not harmful under the 
conditions of its intended use. * * *
* * * * *
    (k) General recognition of safety shall be in accordance with Sec.  
570.30.
* * * * *
    (n) Food-producing animal means an animal used to produce human 
food.
0
18. In Sec.  570.30, revise the last sentence of paragraph; (a); revise 
paragraphs (b) through (d); and revise the last sentence in paragraph 
(i) to read as follows:


Sec.  570.30   Eligibility for classification as generally recognized 
as safe (GRAS).

    (a) * * * General recognition of safety requires common knowledge 
throughout the scientific community knowledgeable about the safety of 
substances directly or indirectly added to food that there is 
reasonable certainty that the substance is not harmful to either the 
target animal or to humans consuming human food derived from food-
producing animals under the conditions of its intended use (see Sec.  
570.3(i)).
    (b) General recognition of safety based upon scientific procedures 
shall require the same quantity and quality of scientific evidence as 
is required to obtain approval of a food additive. General recognition 
of safety through scientific procedures shall address safety for both 
the target animal and for humans consuming human food derived from 
food-producing animals and shall be based upon the application of 
generally available and accepted scientific data, information, or 
methods, which ordinarily are published, as well as the application of 
scientific principles, and may be corroborated by the application of 
unpublished scientific data, information, or methods.
    (c)(1) General recognition of safety through experience based on 
common use in food prior to January 1, 1958, shall address safety for 
both the target animal and for humans consuming human food derived from 
food-producing animals and may be achieved without the quantity or 
quality of scientific procedures required for approval of a food 
additive. General recognition of safety through experience based on 
common use in food prior to January 1, 1958, shall be based solely on 
food use of the substance in the same animal species prior to January 
1, 1958, and shall ordinarily be based upon generally available data 
and information. An ingredient not in common use in food prior to 
January 1, 1958, may achieve general recognition of safety only through 
scientific procedures.
    (2) A substance used in food prior to January 1, 1958, may be 
generally recognized as safe through experience based on its common use 
in food when that use occurred exclusively or primarily outside of the 
United States if the information about the experience establishes that 
the substance is safe under the conditions of its intended use within 
the meaning of section 201(u) of the Federal Food, Drug, and Cosmetic 
Act (see also Sec.  570.3(i)) for both the target animal and for humans 
consuming human food derived from food-producing animals. Common use in 
food prior to January 1, 1958, that occurred outside of the United 
States shall be documented by published or other information and shall 
be corroborated by information from a second, independent source that 
confirms the history and circumstances of use of the substance. The 
information used to document and to corroborate the history and 
circumstances of use of the substance must be generally available; that 
is, it must be widely available in the country in which the history of 
use has occurred and readily available to interested qualified experts 
in the United States. A person who concludes that a use of a substance 
is GRAS through experience based on its common use in food outside of 
the United States should notify FDA of that view in accordance with 
subpart E of this part.
    (d) The food ingredients listed as GRAS in part 582 of this chapter 
or affirmed as GRAS in part 584 of this chapter do not include all 
substances that are generally recognized as safe for their intended use 
in food. Because of the large number of substances the intended use of 
which results or may reasonably be expected to result, directly or 
indirectly, in their becoming a component or otherwise affecting the 
characteristics of food, it is impracticable to list all such 
substances that are GRAS. A food ingredient of natural biological 
origin that has been widely consumed for its nutrient properties in the 
United States prior to January 1, 1958, without known detrimental 
effects, which is subject only to conventional processing as practiced 
prior to January 1, 1958, and for which no known safety hazard exists, 
will ordinarily be regarded as GRAS without specific inclusion in part 
582 or part 584 of this chapter.
* * * * *
    (i) * * * Any use of such an ingredient not in full compliance with 
each such established limitation shall require a food additive 
regulation.
* * * * *

0
19. In Sec.  570.35, revise paragraphs (a), (b)(1), (3), and (4), and 
remove paragraph (c) to read as follows:


Sec.  570.35  Affirmation of generally recognized as safe (GRAS) 
status.

    (a) The Commissioner, on his own initiative, may affirm that a 
substance that directly or indirectly becomes a component of food is 
GRAS under the conditions of its intended use.
    (b)(1) If the Commissioner proposes on his own initiative that a 
substance is entitled to affirmation as GRAS under the conditions of 
its intended use, he will place all of the data and information on 
which he relies on public file in the office of the Division of Dockets 
Management and will publish in the Federal Register a notice giving the 
name of the substance, its proposed uses, and any limitations proposed 
for purposes other than safety.
* * * * *
    (3) The Commissioner will evaluate all comments received. If he 
concludes that there is convincing evidence that the substance is GRAS 
under the conditions of its intended use as described in Sec.  570.30, 
he will publish a notice in the Federal Register listing the GRAS 
conditions of use in this subchapter E.
    (4) If, after evaluation of the comments, the Commissioner 
concludes that there is a lack of convincing evidence that the 
substance is GRAS under the conditions of its intended use and that it 
should be considered a food additive subject to section 409 of the 
Federal Food, Drug, and Cosmetic Act, he shall publish a notice thereof 
in the Federal Register in accordance with Sec.  570.38.

0
20. In Sec.  570.38, revise paragraph (a) to read as follows:


Sec.  570.38  Determination of food additive status.

    (a) The Commissioner may, in accordance with Sec.  570.35(b)(4), 
publish a notice in the Federal Register determining that a substance 
is not GRAS under the conditions of its intended use and is a food 
additive subject to section 409 of the Federal Food, Drug, and Cosmetic 
Act.
* * * * *

0
21. Add and reserve subparts C and D.

0
22. Add subpart E, consisting of Sec. Sec.  570.203 through 570.280, to 
read as follows:

Subpart E--Generally Recognized as Safe (GRAS) Notice

Sec.
570.203 Definitions.
570.205 Opportunity to submit a GRAS notice.

[[Page 55053]]

570.210 How to send your GRAS notice to FDA.
570.215 Incorporation into a GRAS notice.
570.220 General requirements applicable to a GRAS notice.
570.225 Part 1 of a GRAS notice: Signed statements and 
certification.
570.230 Part 2 of a GRAS notice: Identity, method of manufacture, 
specifications, and physical or technical effect.
570.235 Part 3 of a GRAS notice: Target animal and human exposures.
570.240 Part 4 of a GRAS notice: Self-limiting levels of use.
570.245 Part 5 of a GRAS notice: Experience based on common use in 
food before 1958.
570.250 Part 6 of a GRAS notice: Narrative.
570.255 Part 7 of a GRAS notice: List of supporting data and 
information in your GRAS notice.
570.260 Steps you may take before FDA responds to your GRAS notice.
570.265 What FDA will do with a GRAS notice.
570.275 Public disclosure of a GRAS notice.
570.280 Submission of a supplement.

Subpart E--Generally Recognized as Safe (GRAS) Notice


Sec.  570.203  Definitions.

    The definitions and interpretations of terms in Sec.  570.3 apply 
to such terms when used in this subpart. The following definitions also 
apply:
    Amendment means any data and information that you submit regarding 
a filed GRAS notice before we respond to your notice by letter in 
accordance with Sec.  570.265(b)(1) or cease to evaluate your notice in 
accordance with Sec.  570.265(b)(3).
    GRAS means generally recognized as safe.
    GRAS notice means a submission that informs us of your view that a 
substance is not subject to the premarket approval requirements of the 
Federal Food, Drug, and Cosmetic Act based on your conclusion that the 
substance is GRAS under the conditions of its intended use in 
accordance with Sec.  570.30.
    Notified substance means the substance that is the subject of your 
GRAS notice.
    Notifier means the person (e.g., an individual, partnership, 
corporation, association, or other legal entity) who is responsible for 
the GRAS notice, even if another person (such as an attorney, agent, or 
qualified expert) prepares or submits the notice or provides an opinion 
about the basis for a conclusion of GRAS status.
    Qualified expert means an individual who is qualified by scientific 
training and experience to evaluate the safety of substances under the 
conditions of their intended use in animal food.
    Supplement means any data and information that you submit regarding 
a filed GRAS notice after we respond to your notice by letter in 
accordance with Sec.  570.265(b)(1) or cease to evaluate your notice in 
accordance with Sec.  570.265(b)(3).
    We, our, and us refer to the United States Food and Drug 
Administration (FDA).
    You and your refer to a notifier.


Sec.  570.205  Opportunity to submit a GRAS notice.

    Any person may notify FDA of a view that a substance is not subject 
to the premarket approval requirements of section 409 of the Federal 
Food, Drug, and Cosmetic Act based on that person's conclusion that the 
substance is GRAS under the conditions of its intended use.


Sec.  570.210   How to send your GRAS notice to FDA.

    (a) Send your GRAS notice to the Division of Animal Feeds (HFV-
220), Center for Veterinary Medicine, Food and Drug Administration, 
7519 Standish Pl., Rockville, MD 20855.
    (b) When you submit your GRAS notice, you may do so either in an 
electronic format that is accessible for our evaluation or on paper. If 
you send your GRAS notice on paper, a single paper copy is sufficient.


Sec.  570.215  Incorporation into a GRAS notice.

    You may incorporate into your GRAS notice either specifically 
identified data and information that you previously submitted to the 
Center for Veterinary Medicine (CVM), or specifically identified 
publicly available data and information submitted by another party, 
when such data and information remain in CVM's records, such as data 
and information contained in a previous GRAS notice or a food additive 
petition.


Sec.  570.220  General requirements applicable to a GRAS notice.

    (a) A GRAS notice has seven parts as required by Sec. Sec.  570.225 
through 570.255. You must submit the data and information specified in 
each of these parts on separate pages or sets of pages.
    (b) You must include each of the seven parts in your GRAS notice. 
If you do not include a part, you must include with your GRAS notice an 
explanation of why that part does not apply to your GRAS notice.


Sec.  570.225  Part 1 of a GRAS notice: Signed statements and 
certification.

    (a) Part 1 of your GRAS notice must be dated and signed by a 
responsible official of your organization, or by your attorney or 
agent.
    (b) Except as required by paragraph (c)(8) of this section, you 
must not include any information that is trade secret or confidential 
commercial information in Part 1 of your GRAS notice.
    (c) In Part 1 of your GRAS notice, you must:
    (1) Inform us that you are submitting a GRAS notice in accordance 
with this subpart;
    (2) Provide the name and address of your organization;
    (3) Provide the name of the notified substance, using an 
appropriately descriptive term;
    (4) Describe the intended conditions of use of the notified 
substance, including stating whether the substance will be added to 
food (including drinking water) for animals in which the substance will 
be used; identifying the foods to which it will be added, the levels of 
use in such foods, and the animal species for which these foods are 
intended (including, when appropriate, a description of a subpopulation 
expected to consume the notified substance); and the purposes for which 
the substance will be used;
    (5) Inform us of the statutory basis for your conclusion of GRAS 
status (i.e., through scientific procedures in accordance with Sec.  
570.30(a) and (b) or through experience based on common use in animal 
food in accordance with Sec.  570.30(a) and (c));
    (6) State your view that the notified substance is not subject to 
the premarket approval requirements of the Federal Food, Drug, and 
Cosmetic Act based on your conclusion that the notified substance is 
GRAS under the conditions of its intended use;
    (7) State that, if we ask to see the data and information that are 
the basis for your conclusion of GRAS status, either during or after 
our evaluation of your notice, you will:
    (i) Agree to make the data and information available to us; and
    (ii) Agree to both of the following procedures for making the data 
and information available to us:
    (A) Upon our request, you will allow us to review and copy the data 
and information during customary business hours at the address you 
specify for where these data and information will be available to us; 
and
    (B) Upon our request, you will provide us with a complete copy of 
the data and information either in an electronic format that is 
accessible for our evaluation or on paper;
    (8) State your view as to whether any of the data and information 
in Parts 2 through 7 of your GRAS notice are exempt from disclosure 
under the

[[Page 55054]]

Freedom of Information Act, 5 U.S.C. 552 (e.g., as trade secret or as 
commercial or financial information that is privileged or 
confidential);
    (9) Certify that, to the best of your knowledge, the GRAS notice is 
a complete, representative, and balanced submission that includes 
unfavorable information, as well as favorable information, known to you 
and pertinent to the evaluation of the safety and GRAS status of the 
use of the substance; and
    (10) State both the name and the position or title of the person 
who signs the GRAS notice.


Sec.  570.230  Part 2 of a GRAS notice: Identity, method of 
manufacture, specifications, and physical or technical effect.

    In Part 2 of your GRAS notice, you must include:
    (a) Scientific data and information that identifies the notified 
substance.
    (1) Examples of appropriate data and information include the 
chemical name, applicable registry numbers (such as a Chemical 
Abstracts Service (CAS) registry number or an Enzyme Commission (EC) 
number), empirical formula, structural formula, quantitative 
composition, and characteristic properties.
    (2) When the source of a notified substance is a biological 
material, you must include data and information sufficient to identify:
    (i) The taxonomic source (e.g., genus, species), including as 
applicable data and information at the sub-species level (e.g., 
variety, strain);
    (ii) The part of any plant or animal used as the source; and
    (iii) Any known toxicants that could be in the source;
    (b) A description of the method of manufacture of the notified 
substance in sufficient detail to evaluate the safety of the notified 
substance as manufactured;
    (c) Specifications for material that is of appropriate grade for 
use in animal food; and
    (d) When necessary to demonstrate safety, relevant data and 
information bearing on the physical or other technical effect the 
notified substance is intended to produce, including the quantity of 
the notified substance required to produce such effect.


Sec.  570.235  Part 3 of a GRAS notice: Target animal and human 
exposures.

    In part 3 of your GRAS notice, you must provide data and 
information about exposure to the target animal and to humans consuming 
human food derived from food-producing animals, regardless of whether 
your conclusion of GRAS status is through scientific procedures or 
through experience based on common use in food, as follows:
    (a) For exposure to the target animal, you must provide:
    (1) The amount of the notified substance that different target 
animal species are likely to consume in the animal food (including 
drinking water) as part of the animal's total diet, including the 
intended use and all other sources in the total diet; and
    (2) When applicable, the amount of any other substance that is 
expected to be formed in or on food because of the use of the notified 
substance (e.g., hydrolytic products or reaction products);
    (3) When applicable, the amount of any other substance that is 
present with the notified substance either naturally or due to its 
manufacture (e.g., contaminants or by-products);
    (4) The data and information you rely on to establish the amount of 
the notified substance and the amounts of any other substance in 
accordance with paragraphs (a)(1) through (a)(3) of this section that 
different target animal species are likely to consume in the animal 
food (including drinking water) as part of the animal's total diet; and
    (b) When the intended use is in food for food-producing animals, 
you must provide:
    (1) The potential quantities of any residues that humans may be 
exposed to in edible animal tissues, including:
    (i) Residues of the notified substance;
    (ii) Residues of any other substance that is expected to be formed 
in or on the animal food because of the use of the notified substance; 
and
    (iii) Residues from any other substance that is present with the 
notified substance whether naturally, due to its manufacture (e.g., 
contaminants or by-products), or produced as a metabolite in edible 
animal tissues when the notified substance is consumed by a food-
producing animal; and
    (2) The data and information you rely on to establish, in 
accordance with paragraph (b)(1) of this section, the potential 
quantities of any residues that humans may be exposed to in edible 
animal tissues.


Sec.  570.240  Part 4 of a GRAS notice: Self-limiting levels of use.

    In circumstances where the amount of the notified substance that 
can be added to animal food is limited because animal food containing 
levels of the notified substance above a particular level would become 
unpalatable or technologically impractical, in Part 4 of your GRAS 
notice you must include data and information on such self-limiting 
levels of use.


Sec.  570.245  Part 5 of a GRAS notice: Experience based on common use 
in food before 1958.

    If the statutory basis for your conclusion of GRAS status is 
through experience based on common use in animal food, in Part 5 of 
your GRAS notice you must include evidence of a substantial history of 
consumption of the notified substance for food use by a significant 
number of animals of the species to which the substance is intended to 
be fed prior to January 1, 1958, and evidence of a substantial history 
of consumption by humans consuming human foods derived from food-
producing animals prior to January 1, 1958.


Sec.  570.250  Part 6 of a GRAS notice: Narrative.

    In Part 6 of your GRAS notice, you must include a narrative that 
provides the basis for your conclusion of GRAS status, in which:
    (a)(1) You must explain why the data and information in your notice 
provide a basis for your view that the notified substance is safe under 
the conditions of its intended use for both the target animal and for 
humans consuming human food derived from food-producing animals. In 
your explanation, you must address the safety of the notified 
substance, considering all animal food (including drinking water) as 
part of the animal's total diet, taking into account any chemically or 
pharmacologically related substances in such diet. In your explanation, 
you must also address the safety of the notified substance in regard to 
human exposure, considering all dietary sources and taking into account 
any chemically or pharmacologically related substances;
    (2) In your explanation, you must identify what specific data and 
information that you discuss in accordance with paragraph (a)(1) of 
this section are generally available, and what specific data and 
information that you discuss in accordance with paragraph (a)(1) of 
this section are not generally available, by providing citations to the 
list of data and information that you include in Part 7 of your GRAS 
notice in accordance with Sec.  570.255;
    (b) You must explain how the generally available data and 
information that you rely on to establish safety in accordance with 
paragraph (a) of this section provide a basis for your conclusion that 
the notified substance is generally recognized, among qualified 
experts, to be safe under the conditions of its intended use for both 
the target animal and for humans consuming human food derived from 
food-producing animals;

[[Page 55055]]

    (c) You must either:
    (1) Identify, discuss, and place in context, data and information 
that are, or may appear to be, inconsistent with your conclusion of 
GRAS status, regardless of whether those data and information are 
generally available; or
    (2) State that you have reviewed the available data and information 
and are not aware of any data and information that are, or may appear 
to be, inconsistent with your conclusion of GRAS status;
    (d) If you view any of the data and information in your notice as 
exempt from disclosure under the Freedom of Information Act, you must 
identify the specific data and information; and
    (e) For non-public, safety-related data and information considered 
in reaching a conclusion of GRAS status, you must explain how there 
could be a basis for a conclusion of GRAS status if qualified experts 
do not have access to such data and information.


Sec.  570.255  Part 7 of a GRAS notice: List of supporting data and 
information in your GRAS notice.

    (a) In part 7 of your GRAS notice, you must include a list of all 
of the data and information that you discuss in Part 6 of your GRAS 
notice to provide a basis for your view that the notified substance is 
safe under the conditions of its intended use as described in 
accordance with Sec.  570.250(a)(1).
    (b) You must specify which data and information that you list in 
accordance with paragraph (a) of this section are generally available, 
and which data and information are not generally available.


Sec.  570.260  Steps you may take before FDA responds to your GRAS 
notice.

    (a) You may submit a timely amendment to your filed GRAS notice, to 
update your GRAS notice or in response to a question from us, before we 
respond to your notice by letter in accordance with Sec.  570.265(b)(1) 
or cease to evaluate your notice in accordance with Sec.  
570.265(b)(3).
    (b) At any time before we respond to your notice by letter in 
accordance with Sec.  570.265(b)(1), you may request in writing that we 
cease to evaluate your GRAS notice. Your request does not preclude you 
from submitting a future GRAS notice in accordance with this subpart 
with respect to the notified substance.


Sec.  570.265  What FDA will do with a GRAS notice.

    (a)(1) We will conduct an initial evaluation of your submission to 
determine whether to file it as a GRAS notice for evaluation of your 
view that the notified substance is GRAS under the conditions of its 
intended use.
    (2) If we file your submission as a GRAS notice, we will send you a 
letter that informs you of the date of filing.
    (3) If we do not file your submission as a GRAS notice, we will 
send you a letter that informs you of that fact and provide our reasons 
for not filing the submission as a GRAS notice.
    (4) We will consider any timely amendment that you submit to a 
filed GRAS notice, to update your GRAS notice or in response to a 
question from us, before we respond to you by letter in accordance with 
paragraph (b)(1) of this section, if we deem that doing so is feasible 
within the timeframes established in paragraph (b) of this section. If 
we deem that considering your amendment is not feasible within the 
timeframes established in paragraph (b) of this section or if we have 
granted your request to cease to evaluate your notice, we will inform 
you that we are not considering your amendment.
    (b)(1) Within 180 days of filing, we will respond to you by letter 
based on our evaluation of your notice. We may extend the 180 day 
timeframe by 90 days on an as needed basis.
    (2) If we extend the timeframe, we will inform you in writing of 
the extension as soon as practicable but no later than within 180 days 
of filing.
    (3) If you ask us to cease to evaluate your GRAS notice in 
accordance with Sec.  570.260(b), we will send you a letter informing 
you of our decision regarding your request.
    (c) If circumstances warrant, we will send you a subsequent letter 
about the notice.


Sec.  570.275   Public disclosure of a GRAS notice.

    (a) The data and information in a GRAS notice (including data and 
information submitted in any amendment or supplement to your GRAS 
notice, or incorporated into your GRAS notice) are:
    (1) Considered a mandatory, rather than voluntary, submission for 
purposes of their status under the Freedom of Information Act and our 
public information requirements in part 20 of this chapter; and
    (2) Available for public disclosure in accordance with part 20 of 
this chapter as of the date that we receive your GRAS notice.
    (b) We will make the following readily accessible to the public:
    (1) A list of filed GRAS notices, including the information 
described in Sec.  570.225(c)(2) through (c)(5);
    (2) The text of any letter that we issue under Sec.  570.265(b)(1) 
or (c); and
    (3) The text of any letter that we issue under Sec.  570.265(b)(3) 
if we grant your request that we cease to evaluate your notice.
    (c) We will disclose all remaining data and information that are 
not exempt from public disclosure in accordance with part 20 of this 
chapter.


Sec.  570.280  Submission of a supplement.

    If circumstances warrant, you may submit a supplement to a filed 
GRAS notice after we respond to your notice by letter in accordance 
with Sec.  570.265(b)(1) or cease to evaluate your notice in accordance 
with Sec.  570.265(b)(3).

    Dated: August 8, 2016.
Jeremy Sharp,
Deputy Commissioner for Policy, Planning, Legislation and Analysis.
[FR Doc. 2016-19164 Filed 8-12-16; 11:15 am]
 BILLING CODE 4164-01-P