[Federal Register Volume 75, Number 243 (Monday, December 20, 2010)]
[Proposed Rules]
[Pages 79320-79323]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-31887]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 500

[Docket No. FDA-2010-N-0612]


Animal Drugs, Feeds, and Related Products; Regulation of 
Carcinogenic Compounds in Food-Producing Animals

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its regulations regarding compounds of carcinogenic concern used in 
food-producing animals. Specifically, the Agency is clarifying the 
definition of ``So'' and revising the definition of 
``Sm'' so that it conforms to the clarified definition of 
So. Other clarifying and conforming changes are also being 
made.

DATES: Submit either electronic or written comments on the proposed 
rule by March 7, 2011. Submit comments on information collection issues 
under the Paperwork Reduction Act of 1995 by January 19, 2011 (see the 
``Paperwork Reduction Act of 1995'' section of this document).

ADDRESSES: You may submit comments, identified by Docket No. FDA-2010-
N-0612, by any of the following methods, except that comments on 
information collection issues under the Paperwork Reduction Act of 1995 
must be submitted to the Office of Regulatory Affairs, Office of 
Management and Budget (OMB) (see the ``Paperwork Reduction Act of 
1995'' section of this document).

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Fax: 301-827-6870.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. and Regulatory Information Number (RIN) (if a RIN number 
has been assigned) for this rulemaking. All comments received may be 
posted without change to http://www.regulations.gov, including any 
personal information provided. For additional information on submitting 
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kevin Greenlees, Center for Veterinary 
Medicine (HFV-100), Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855, 301-827-6975. e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act) contains 
three anticancer, or Delaney, clauses: Sections 409(c)(3)(A), 
512(d)(1)(I), and 721(b)(5)(B)(i) (21 U.S.C. 348(c)(3)(A), 
360b(d)(1)(I), and 379e(b)(5)(B)(i)), pertaining to food additives, new 
animal drugs, and color additives, respectively.

[[Page 79321]]

These clauses prohibit approval of substances that have been shown to 
induce cancer in man or animals. However, each clause contains an 
exception, termed the ``Diethylstilbestrol (DES) Proviso,'' that 
permits administration of such substances to food-producing animals 
where: (1) The food additive, color additive, or new animal drug will 
not adversely affect the animal; and (2) no residue of the food 
additive, color additive, or new animal drug will be found in any 
edible portion of that animal by a method of examination prescribed or 
approved by the Secretary of Health and Human Services by regulation. 
The regulations under part 500 (21 CFR part 500), subpart E entitled 
``Regulation of Carcinogenic Compounds Used in Food-Producing 
Animals,'' implement the DES Proviso. To elaborate on how to determine 
that there is no residue, and thus demonstrate that the second prong of 
the DES Proviso has been satisfied, the regulations define several 
terms, including So and Sm.
    So is currently defined as the concentration of the 
compound of carcinogenic concern in the total diet of test animals that 
corresponds to a maximum lifetime risk of cancer to the test animals of 
1 in 1 million, and is calculated from tumor data of the cancer 
bioassays using a statistical extrapolation procedure. The definition 
of So also provides that FDA will assume that the 
So corresponds to the concentration of residue of 
carcinogenic concern in the total human diet that represents no 
significant increase in the risk of cancer to people. The 
concentration, derived from the So, of residues of 
carcinogenic concern in a specific edible tissue is termed the 
Sm. Sponsors are required to submit to FDA a regulatory 
analytical method that is an aggregate of all experimental procedures 
for measuring and confirming the presence of the marker residue of the 
sponsored compound in the target tissue of the target animal. FDA can 
be assured that there is no residue of carcinogenic concern when no 
residue of the compound is detectable (that is, the marker residue is 
below the limit of detection) using the approved regulatory analytical 
method.\1\ A marker residue is selected whose concentration is in a 
known relationship to the concentration of the residue of carcinogenic 
concern in the last tissue to deplete to its Sm. This tissue 
is known as the target tissue and the concentration of the marker 
residues is known as the Rm. The limit of detection of the 
approved regulatory analytical method must be capable of measuring the 
selected marker residue at the Rm in the selected target 
tissue. When residues of carcinogenic concern are below the 
Rm in the target tissue as measured by the approved 
regulatory analytical method, the residues of carcinogenic concern in 
target tissue and all other edible tissues are below their respective 
Sm and therefore consumption of tissues containing these 
residues would not exceed the So. The detection of the 
marker residue in the target tissue below the Rm by the 
approved regulatory analytical method can be taken as confirmation that 
the residue of carcinogenic concern does not exceed Sm in 
each of the edible tissues and, therefore, that the residue of 
carcinogenic concern in the diet of people does not exceed 
So. However, any detectable concentration of the marker 
residue by the approved regulatory analytical method, even if below the 
Rm, fails to satisfy the statutory requirements of the DES 
Proviso. The detection of any concentration would mean that the second 
prong of the DES Proviso has not been satisfied because it has not been 
shown that no residue of the substance is present in any edible portion 
of the animal at issue.
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    \1\ The submission of such a method is approved as a collection 
of information under Office of Management and Budget (OMB) Control 
No. 0910-0032.
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    As described previously, the approach for evaluating compounds of 
carcinogenic concern currently set forth in Sec.  500.84 utilizes a 
statistical extrapolation procedure that calculates a concentration of 
residue of carcinogenic concern that corresponds to a maximum lifetime 
risk to the test animal of 1 in 1 million. In addition, to provide 
flexibility, Sec.  500.90 permits the use of alternative procedures to 
satisfy the DES Proviso, when the person requesting the use of 
alternative procedures clearly sets forth the reasons why the 
alternative procedures will provide a basis for concluding that 
approval of the compound satisfies the requirements of the Delaney 
Clause provisions of the FD&C Act, including the DES Proviso.
    In recent years, FDA has, at times, been asked to consider allowing 
the use of alternative procedures to satisfy the DES Proviso. Some of 
these proposed alternative procedures did not rely on a statistical 
extrapolation of the data to a 1 in 1 million risk of cancer to test 
animals, but nevertheless the So, Sm, 
Rm, and regulatory analytical method resulting from these 
alternative approaches would be expected to ensure that consumption of 
food derived from animals treated with the carcinogenic new animal drug 
would result in no significant increase in the risk of cancer to 
people. In the course of considering these proposed alternative 
procedures, FDA has also considered whether the term So, as 
currently defined, adequately addresses concentrations of residues of 
carcinogenic concern in the total human diet that are found to 
represent no significant increase in the risk of cancer to people, but 
which are not derived from a statistical extrapolation of data to a 1 
in 1 million risk of cancer to test animals.
    The current definition in Sec.  500.82 primarily defines 
So as the concentration of the compound of carcinogenic 
concern that corresponds to the 1 in 1 million lifetime risk of cancer 
to the test animals and secondarily as corresponding to the 
concentration of residue of carcinogenic concern in the total human 
diet that represents no significant increase in a risk of cancer to 
people. Therefore, as presently constructed, the definition of 
So is not primarily defined as the concentration of residues 
of carcinogenic concern in the total human diet derived from procedures 
not involving the extrapolation of data to a 1 in 1 million risk of 
cancer to the test animals. Thus, were FDA to allow the use of 
alternative procedures that do not rely on a statistical extrapolation 
of the data to a 1 in 1 million risk of cancer to test animals to 
satisfy the DES Proviso, it would have to develop a new set of 
terminology to describe the Center for Veterinary Medicine's (CVM's) 
approach for evaluating these compounds of carcinogenic concern. The 
proposed changes to the definitions of So and Sm 
are intended to enable CVM to consider allowing the use of alternative 
procedures to satisfy the DES Proviso without requiring the development 
of a second, alternative, set of terminology.
    FDA believes that a careful reading of the December 31, 1987, final 
rule (52 FR 49572 at 49586), suggests that an emphasis on no 
significant increase in the risk of cancer to the human consumer, 
rather than on the specific 1 in 1 million risk of cancer to the test 
animals approach, reflects the original intent of the regulation. (See, 
e.g., 52 FR 49572 at 49575 and 49582.) FDA has concluded that the 
proposed redefinition of So is consistent with this original 
intent of the regulation.
    For clarification purposes, FDA is also proposing a redefinition of 
Sm in Sec.  500.82 to conform this definition with the 
redefinition of So as described previously. Specifically, 
Sm would mean the concentration of a residue of carcinogenic 
concern in a specific edible tissue corresponding to no

[[Page 79322]]

significant increase in the risk of cancer to the human consumer. 
However, the definition of Sm would also retain the existing 
reference to a maximum lifetime risk of cancer in the test animals of 1 
in 1 million.
    Finally, FDA is proposing to amend Sec.  500.84(c) to clarify that 
for each compound that is regulated as a carcinogen, FDA will analyze 
the data submitted using either a statistical extrapolation procedure 
as provided in Sec.  500.84(c)(1) or an alternate approach as provided 
in Sec.  500.90.
    FDA's goal in these changes is to clarify that the terms 
So and Sm apply even when the alternative 
procedures provided for in Sec.  500.90 are used to satisfy the DES 
Proviso, not to alter the usual process for approving compounds of 
carcinogenic concern. As such, in the absence of a waiver of the 
requirements of Sec.  500.84(c)(1), FDA maintains that sponsors must 
meet the conditions for approval set for in Sec.  500.84, including the 
default approach of a 1 in 1 million lifetime risk to the test animal.

II. Legal Authority

    This rule, if finalized, would amend part 500, subpart E in a 
manner consistent with the Agency's current understanding and 
application of these provisions. FDA was given authority in 21 U.S.C. 
348, 360b, and 379e to establish methods of examination to determine 
that no residue of a food additive, new animal drug, or color additive 
of carcinogenic concern would be found in any edible portion of animals 
after slaughter or in any food yielded by or derived from living 
animals. Furthermore, FDA has the authority to take the actions 
proposed in this rule under various statutory provisions. These 
provisions include 21 U.S.C. 321, 331, 348, 360b, 371, and 379e.

III. Environmental Impact

    The Agency has determined 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.

IV. Analysis of Economic Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive 
Order 12866 directs Agencies 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). The Agency believes that 
this proposed rule is not a significant regulatory action as defined by 
the Executive order.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the proposed rule would not impose any 
direct or indirect costs on industry or government through the changes 
to the definitions of So and Sm and to Sec.  
500.84(c), but rather would clarify these definitions to enable FDA to 
consider using alternative procedures to satisfy the DES Proviso 
without requiring the development of a second, alternative, set of 
terminology, the Agency proposes to certify that the final rule will 
not have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``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 $135 million, using the most current (2009) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.

V. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized, would not contain policies that would 
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, the Agency tentatively concludes that the proposed 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.

VI. Paperwork Reduction Act of 1995

    This proposed rule refers to previously approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520). The collections of information in Sec.  500.84 
have been approved under OMB Control No. 0910-0032.

VII. Request for Comments

    FDA requests comments to the proposed revisions to the definitions 
of Sm and So currently found in Sec.  500.82(b) 
and to the proposed conforming changes to Sec.  500.84(c). 
Specifically, the Agency requests that comments focus on the proposal 
to emphasize ``no significant increase in the risk of cancer to the 
human consumer,'' rather than the more specific ``1 in 1 million risk 
of cancer to the test animals'' approach currently found in the 
definitions of Sm and So.
    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

VIII. Proposed Effective Date

    The Agency is proposing that any final rule that may issue based 
upon this proposed rule become effective upon publication in the 
Federal Register.

List of Subjects in 21 CFR Part 500

    Animal drugs, Animal feeds, Cancer, Labeling, Packaging and 
containers, Polychlorinated biphenyls (PCB's).

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 500 be amended as follows:

PART 500--GENERAL

    1. The authority citation for 21 CFR part 500 is revised to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353, 
360b, 371, 379e.

    2. Revise the definitions of ``Sm'' and 
``So'' in paragraph (b) of Sec.  500.82 to read as follows:


Sec.  500.82  Definitions.

* * * * *
    (b) * * *
    Sm means the concentration of a residue of carcinogenic concern in 
a specific edible tissue corresponding to no significant increase in 
the risk of

[[Page 79323]]

cancer to the human consumer. For the purpose of Sec.  500.84(c)(1), 
FDA will assume that this Sm will correspond to the 
concentration of residue in a specific edible tissue that corresponds 
to a maximum lifetime risk of cancer in the test animals of 1 in 1 
million.
    So means the concentration of a residue of carcinogenic concern in 
the total human diet that represents no significant increase in the 
risk of cancer to the human consumer. For the purpose of Sec.  
500.84(c)(1), FDA will assume that this So will correspond 
to the concentration of test compound in the total diet of test animals 
that corresponds to a maximum lifetime risk of cancer in the test 
animals of 1 in 1 million.
* * * * *
    3. Revise the introductory text of paragraph (c) of Sec.  500.84 to 
read as follows:


Sec.  500.84  Conditions for approval of the sponsored compound.

* * * * *
    (c) For each sponsored compound that FDA decides should be 
regulated as a carcinogen, FDA will either analyze the data from the 
bioassays using a statistical extrapolation procedure as outlined in 
paragraph (c)(1) of this section or evaluate an alternate procedure 
proposed by the sponsor as provided in Sec.  500.90. In either case, 
paragraphs (c)(2) and (c)(3) of this section apply.
* * * * *

    Dated: December 15, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-31887 Filed 12-17-10; 8:45 am]
BILLING CODE 4160-01-P