[Federal Register Volume 75, Number 107 (Friday, June 4, 2010)]
[Notices]
[Pages 31800-31803]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-13464]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-N-0215]


Substances Generally Recognized as Safe Added to Food for 
Animals; Notice of Pilot Program

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is seeking participants 
for a voluntary pilot program whereby persons submit to FDA notices of 
claims that a particular use of a substance in food for animals is 
exempt from the statutory premarket approval requirements based on the 
notifier's determination that such use is generally recognized as safe 
(GRAS). FDA intends to evaluate these notices and will inform each 
participant (notifier) in writing either that the notice provides a 
sufficient basis for the GRAS determination or that FDA has identified 
questions as to whether the intended use of the substance is GRAS.

DATES: Submit written requests to participate in the pilot program 
beginning June 4, 2010.

ADDRESSES: Submit written requests to participate in the pilot program 
to the Division of Animal Feeds (HFV-224), Center for Veterinary 
Medicine, Food and Drug Administration, 7519 Standish Pl., Rockville, 
MD 20855.

FOR FURTHER INFORMATION CONTACT: Geoffrey K. Wong, Center for 
Veterinary Medicine (HFV-224), Food and Drug Administration, 7519 
Standish Pl., Rockville, MD 20855, 240-453-6879, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

A. The 1958 Amendment

    In 1958, in response to public concern about the increased use of 
chemicals in foods and food processing, Congress enacted the Food 
Additives Amendment (the 1958 amendment) to the Federal Food, Drug, and 
Cosmetic Act (the act). The 1958 amendment required that, before a new 
additive could be used in food, its producer must demonstrate the 
safety of the additive to FDA. The 1958 amendment defined the terms 
``food additive'' (section 201(s) of the act (21 U.S.C. 321(s))) and 
``unsafe food additive'' (section 409(a) of the act (21 U.S.C. 
348(a))), established a premarket approval process for food additives 
(section 409(b) through (h)), and amended the food adulteration 
provisions of the act to deem adulterated any food that is, or bears or 
contains, any food additive that is unsafe within the meaning of 
section 409 (section 402(a)(2)(C) of the act (21 U.S.C. 342(a)(2)(C))).
    In enacting the 1958 amendment, Congress recognized that many 
substances intentionally added to food would not require formal 
premarket review by FDA to assure their safety. Congress thus adopted, 
in section 201(s) of the act, 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

[[Page 31801]]

experience based on common use in food) to be safe under the conditions 
of their intended use.

B. Elements of the GRAS Standard

    Importantly, under section 201(s) of the act, it is the use of a 
substance, rather than the substance itself, that is eligible for the 
GRAS exemption. FDA has defined ``safe'' as a reasonable certainty in 
the minds of competent scientists that the substance is not harmful 
under its intended conditions of use (21 CFR 570.3(i)). Current Sec.  
570.30(b) (21 CFR 570.30(b)) provides that general recognition of 
safety based on scientific procedures requires the same quantity and 
quality of scientific evidence as is required to obtain approval of a 
food additive regulation for the substance. The requirement for 
scientific evidence of safety is referred to in this document as the 
``technical element'' of safety. While a determination that a food 
additive is safe requires technical evidence of safety, a determination 
that a particular use of a substance is GRAS requires both technical 
evidence of safety and a basis to conclude that this technical element 
of safety is generally recognized. Such general recognition of safety 
requires common knowledge about the substance throughout the scientific 
community, so it is referred to in this document as the ``common 
knowledge element'' of the GRAS standard.
    The common knowledge element of the GRAS standard includes two 
facets: (1) The data and information relied on to establish the 
technical element, which must be of the same kind and quality as is 
required to obtain FDA approval of the use of the substance, must be 
generally available and (2) there must be a basis to conclude that 
there is consensus among qualified experts about the safety of the 
substance for its intended use. (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)). None of the 
facets by themselves are sufficient to satisfy the common knowledge 
element of the GRAS standard.
    The usual mechanism to establish that scientific information is 
generally available is to show that the information is published in a 
peer-reviewed scientific journal. However, mechanisms to establish the 
basis for concluding that there is expert consensus about the safety of 
a substance are more varied. In some cases, publication in a peer-
reviewed scientific journal of data (such as toxicity studies) on a 
substance has been used to establish expert consensus in addition to 
general availability. In other cases, such publication of data and 
information in the primary scientific literature has been supplemented 
by: (1) Publication of data and information in the secondary scientific 
literature, such as scientific review articles, textbooks, and 
compendia; (2) documentation of the opinion of an ``expert panel'' that 
is specifically convened for this purpose; or (3) the opinion or 
recommendation of an authoritative body such as the National Research 
Council of the National Academy of Sciences on a broad or specific 
issue that is related to a GRAS determination.
    In this document, FDA is using the term ``consensus'' in discussing 
the common knowledge element of the GRAS standard. Such consensus does 
not require unanimity among qualified experts. (See United States v. 
Articles of Drug * * * 5,906 Boxes, 745 F.2d 105, 119 n. 22 (1st Cir. 
1984); United States v. An Article of Drug * * * 4,680 Pails, 725 F.2d 
976, 990 (5th Cir. 1984); Coli-Trol 80, supra, 518 F.2d at 746; Promise 
Toothpaste, supra, 624 F.Supp. at 782).
    A substance used in food prior to January 1, 1958, may be shown to 
be GRAS for an intended use through scientific procedures or through 
experience based on common use in food. Current Sec.  570.30(c) (21 CFR 
570.30(c)) provides that general recognition of safety through 
experience based on common use in food prior to January 1, 1958, may be 
determined without the quantity or quality of scientific procedures 
required for approval of a food additive regulation. Current Sec.  
570.3(f) defines ``common use in food'' as a substantial history of 
consumption for food use by a significant number of animals in the 
United States.

C. History of FDA's Approach to the GRAS Exemption

    Shortly after passage of the 1958 amendment, FDA clarified the 
regulatory status of a multitude of food substances that were used in 
food prior to 1958 and amended its regulations to include a list of 
food substances that, when used for the purposes indicated and in 
accordance with current good manufacturing practices, are GRAS. This 
GRAS list was incorporated into the agency's regulations as Sec.  
121.101(d) (now parts 182 and 582 (21 CFR parts 182 and 582)) (24 FR 
9368, November 20, 1959). As part of that rulemaking, however, FDA 
acknowledged that it would be impracticable to list all substances that 
are GRAS for their intended use.
    In 1970, FDA announced that it was undertaking a comprehensive 
agency review of substances listed as GRAS (35 FR 18623, December 8, 
1970). In the notice announcing this review, FDA proposed criteria that 
could be used to establish whether these substances should continue to 
be listed as GRAS, become the subject of a food additive regulation, or 
become the subject of an interim food additive regulation pending 
completion of additional studies. These criteria were incorporated into 
the agency's regulations in 21 CFR 121.3 (precursor of current 21 CFR 
570.30) (36 FR 12093, June 25, 1971). FDA subsequently codified 
procedures for the agency to affirm, on its own, the GRAS status of 
substances found to satisfy these criteria (Sec.  570.35(a) and (b) (21 
CFR 570.35(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 GRAS determination), that 
rulemaking included a mechanism (the GRAS petition process currently 
codified in Sec.  570.35(c)) whereby an individual could petition FDA 
to review the GRAS status of substances (37 FR 25705, December 2, 
1972).

D. The 1997 Proposed Rule

    In the Federal Register of April 17, 1997 (62 FR 18938) (the 1997 
proposed rule), FDA published a proposed rule that would replace this 
voluntary GRAS affirmation petition process in Sec. Sec.  170.35(c) (21 
CFR 170.35(c)) and 570.35(c) with a voluntary notification procedure 
whereby any person may notify FDA of a determination that a particular 
use of a substance in human food (proposed Sec.  170.36) or in animal 
food (proposed Sec.  570.36) is GRAS.
    FDA tentatively concluded in the 1997 proposed rule that the 
proposed notification procedure has advantages over the current 
petition process because the resource-intensive rulemaking that is 
associated with a petition would be eliminated. This streamlining would 
allow FDA to redirect its resources to questions about GRAS status that 
are a priority with respect to public health protection. In addition, 
the proposed notice is simpler than a GRAS affirmation petition and 
therefore conceivably would provide an incentive for manufacturers to 
inform FDA of their GRAS determinations. This would result in increased 
agency awareness of the composition of the nation's food supply and the 
cumulative

[[Page 31802]]

dietary exposure to GRAS substances. FDA also tentatively concluded in 
the 1997 proposed rule that the public health would be better served if 
some resources that are currently directed to the GRAS petition process 
were redirected to the preparation of documents that would provide the 
industry with guidance on certain food safety issues for complex 
substances (e.g., macroingredients or biological polymers, such as 
proteins, carbohydrates, and fats and oils). Finally, FDA tentatively 
concluded that the reduction in resources devoted to the evaluation of 
GRAS substances would allow FDA to shift resources to its statutorily 
mandated task of reviewing food and color additive petitions (62 FR 
18938 at 18941).
    As part of the 1997 proposed rule, FDA announced an ``interim 
policy'' whereby interested persons could begin immediately to submit 
notifications of GRAS determinations (GRAS exemption claims) as 
described in proposed Sec.  170.36(b) and (c) for substances used in 
human food. FDA stated that, in general, FDA would administer the 
notices as described in proposed Sec.  170.36(d) through (f) (i.e., FDA 
would acknowledge receipt of the notice, respond in writing to the 
notifier, and make publicly accessible a copy of all GRAS determination 
claims and the agency's response). However, although FDA would make a 
good faith effort to respond within the proposed 90-day timeframe, the 
agency would not be bound by such a timeframe (62 FR 18938 at 18954).
    As with the human food pilot program, the animal food pilot 
program, which will be administered by FDA's Center for Veterinary 
Medicine (CVM), will be based on the notification procedures announced 
in the 1997 proposed rule. Additionally, CVM has consulted with the 
Center for Food Safety and Applied Nutrition (CFSAN) and, where 
applicable, made its administrative procedures consistent with CFSAN's. 
Information about the CFSAN/GRAS notification program, including links 
to the 1997 proposed rule and relevant guidance documents, may be found 
at CFSAN's GRAS Web page: http://www.fda.gov/Food/FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm.

II. Description of the CVM Pilot Program

    FDA is implementing a voluntary pilot program to accept submission 
of notices of claims that a particular use of a substance in food for 
animals is exempt from the statutory premarket approval requirements 
based on the notifier's determination that such use is GRAS (notices of 
GRAS determination). FDA will accept notices of GRAS determination from 
all interested persons beginning immediately. However, FDA strongly 
encourages potential participants in the animal food pilot program to 
contact the Division of Animal Feeds (see ADDRESSES) prior to 
submitting notices to discuss their submission plans.
    In general, the agency will implement the pilot program for 
substances added to animal food in the same manner as the interim 
policy for substances added to human food and as described in section 
VIII of the 1997 proposed rule (62 FR 18938 at 18954 through 18955). 
FDA invites interested persons who determine that a particular use of a 
substance in animal food is GRAS to notify FDA of such GRAS 
determination as described in section III of this document (see also 
proposed Sec.  570.36(b) and (c) of the 1997 proposed rule.)

III. How to Participate in the Pilot

    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 GRAS. Notifiers 
should submit triplicate copies of their notices of GRAS determination 
to the Division of Animal Feeds (HFV-224), Office of Surveillance and 
Compliance, Center for Veterinary Medicine, Food and Drug 
Administration, 7519 Standish Pl., Rockville, MD 20855. Notifiers 
should submit the following information:
     A claim, dated and signed by the notifier, or by the 
notifier's attorney or agent, or (if the notifier is a corporation) by 
an authorized official, that a particular use of a substance is exempt 
from the premarket approval requirements of the act because the 
notifier has determined that such use is GRAS. Such a claim should 
include:
    [cir] The name and address of the notifier;
    [cir] The common or usual name of the substance that is the subject 
of the GRAS determination claim (i.e., the ``notified substance'');
    [cir] 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 (including 
the specific animal species) expected to consume the substance;
    [cir] The basis for the GRAS determination (i.e., through 
scientific procedures or through experience based on common use in 
food); and
    [cir] A statement that the data and information that are the basis 
for the notifier's GRAS determination are available for FDA's review 
and copying at reasonable times at a specific address set out in the 
notice and will be sent to FDA upon request.
     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 
substances of natural biological origin, source information such as 
genus and species), characteristic properties, any content of potential 
human or animal toxicants, and specifications for feed-grade material;
     Information on any self-limiting levels of use; and
     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 act because such use is 
GRAS. Such determination may be based either on scientific procedures 
or on common use in food.
    [cir] For a GRAS determination through scientific procedures, such 
summary should 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. Where a substance is intended for use in the food of an 
animal used to produce human food, this should include a comprehensive 
discussion of, and citations to, generally accepted scientific data, 
information, methods, or principles about both safety to the target 
animal and human food safety. The scientific data, information, 
methods, or principles provided should be sufficient to show that the 
substance is generally recognized among qualified experts to be safe 
for animals consuming food containing the substance as well as to 
humans consuming food derived from such animals (i.e., under its 
intended conditions of use);
    --A comprehensive discussion of any reports of investigations or 
other information that may appear to be

[[Page 31803]]

inconsistent with the GRAS determination; and
    --The basis for concluding, in light of the data and information 
submitted, 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.
    [cir] For a GRAS determination through experience based on common 
use in food, such summary should include:
    --A comprehensive discussion of, and citations to, generally 
available data and information that the notifier relies on to establish 
safety, including documented evidence of a substantial history of 
consumption of the substance by a significant number of animals. Where 
a substance is intended for use in the food of an animal used to 
produce human food, this should include a comprehensive discussion of, 
and citations to, generally accepted scientific data, information, 
methods, or principles about both safety to the target animal and human 
food safety. The scientific data, information, methods, or principles 
provided should be sufficient to show that the substance is generally 
recognized among qualified experts to be safe for animals consuming 
food containing the substance as well as to humans consuming food 
derived from such animals (i.e., under its intended conditions of use);
    --A comprehensive discussion of any reports of investigations or 
other information that may appear to be inconsistent with the GRAS 
determination;
    --The basis for concluding, in light of the data and information 
submitted, 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.

IV. How FDA Will Administer Notices Under the Pilot Program

    In general, the agency will administer the notices under the pilot 
program as described in proposed Sec.  570.36(d) through (f) of the 
1997 proposed rule, as follows:
    1. Within 30 days of receipt of the notice, FDA intends to 
acknowledge receipt of the notice by informing the notifier in writing.
    2. Under the 1997 proposed rule, FDA would respond to the notifier 
in writing within 90 days of receipt of the notice either that the 
notice provides a sufficient basis for the GRAS determination or that 
FDA has identified questions as to whether the intended use of the 
substance is GRAS. Due to resource limitations in the animal food 
program, it is unlikely that CVM will be able to evaluate and respond 
to notices within the 90-day timeframe contained in the 1997 proposed 
rule. CVM will therefore respond to notifications of GRAS 
determinations in its pilot program as quickly as resources permit.
     Any GRAS determination claim submitted as part of the 
pilot program shall be immediately available for public disclosure on 
the date the notice is received. All remaining data and information in 
the notice shall be available for public disclosure, in accordance with 
21 CFR part 20, on the date the notice is received.
     For each notice of GRAS determination submitted under the 
pilot program, the following information shall be readily accessible 
for public review and copying:
    [cir] A copy of the submitted GRAS determination claim,
    [cir] A copy of any letter issued by the agency, as described in 
paragraph 2 of this section.
    [cir] A copy of any subsequent letter issued by the agency 
regarding such notice.

V. Paperwork Reduction Act of 1995

    The collections of information in this notice are subject to review 
by the Office of Management and Budget (OMB) under the Paperwork 
Reduction Act of 1995 (44 U.S.C. 3501-3520), and have been previously 
approved by OMB. OMB originally approved Paperwork Reduction Act (PRA) 
burdens for GRAS notification under the 1997 proposed rule under OMB 
control number 0910-0342. The original OMB approval covered the 
collections of information in both proposed 21 CFR 170.36 and 570.36; 
however, only CFSAN operated a GRAS notification program for human food 
under the original OMB PRA approval. Extension of the original OMB PRA 
approval for GRAS notification was granted by OMB on August 24, 2009, 
under OMB control number 0910-0342.
    As with the human food GRAS notification program administered by 
CFSAN, which has operated for several years, the animal food pilot 
program, which will be administered by CVM, will be based on the 
notification procedures announced in the 1997 proposed rule. The 
provisions for GRAS notification under proposed Sec. Sec.  170.36 and 
570.36 for human and animal food, respectively, are virtually identical 
and therefore the same number of hours per response were estimated for 
reporting (150 hours) and recordkeeping (15 hours per record) burdens 
for both proposed sections under the original and extended OMB PRA 
approvals. Because CFSAN's GRAS program has successfully operated under 
these PRA estimates for several years, FDA believes these burden 
estimates remain accurate for CVM's GRAS pilot program.
    FDA's estimate of the annual number of GRAS determination notices 
that will be received by CVM in the extended OMB PRA approval (5) was 
revised downward from the original PRA approval (10). This revision was 
based on the actual number of GRAS notices received by CFSAN from 1998 
to 2008, which was lower than anticipated and caused CFSAN to also 
revise downward its estimate in the extended PRA approval. The revised 
estimate in the extended PRA approval reflects FDA's best judgment at 
this time as to the number of notices CVM will receive annually through 
this pilot program.
    CVM believes that the PRA estimates in the extended PRA approval 
cover CVM's GRAS notice program.

    Dated: May 26, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-13464 Filed 6-3-10; 8:45 am]
BILLING CODE 4160-01-S