
[Federal Register Volume 77, Number 163 (Wednesday, August 22, 2012)]
[Rules and Regulations]
[Pages 50591-50593]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-20609]


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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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending 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: This rule is effective September 21, 2012.

FOR FURTHER INFORMATION CONTACT: Kevin Greenlees, Center for Veterinary 
Medicine (HFV-100), Food and Drug Administration, 7520 Standish Pl., 
Rockville, MD 20855, 240-276-8214, email: kevin.greenlees@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: 

I. Background

    On December 20, 2010, FDA issued a proposed rule (75 FR 79320) to 
amend its regulations regarding compounds of carcinogenic concern used 
in food-producing animals. Specifically, the Agency clarified the 
definition of ``So'' and revised the definition of 
``Sm'' so that it would conform to the clarified definition 
of So. The Agency also proposed a number of clarifying and 
conforming changes.
    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. 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'' (Sec. Sec.  500.80 through 500.92), 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.
    This rule changes the definition of So so that it is 
primarily defined as ``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 * * *'' and secondarily as 
``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.'' The change in this rule to the definition 
of So is intended to enable the Center for Veterinary 
Medicine to consider allowing the use of alternative procedures to 
satisfy the DES Proviso (See 75 FR 79320 at 79321) without requiring 
the development of a second, alternative, set of terminology. FDA 
believes that the original intent of 21 CFR part 500, Subpart E, as 
reflected in the preamble to the final rule establishing that 
regulation, was to place 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 (See e.g., 52 FR 
49572 at 49575 and 49582). Therefore, FDA has concluded that the 
redefinition of So is consistent with this original intent 
of the regulation.

[[Page 50592]]

    For clarification purposes, FDA is also redefining Sm in 
Sec.  500.82 to conform this definition with the redefinition of 
So as described previously. Specifically, Sm will 
mean the concentration of a residue of carcinogenic concern in a 
specific edible tissue corresponding to no significant increase in the 
risk of cancer to the human consumer. However, the definition of 
Sm will also retain the existing reference to a maximum 
lifetime risk of cancer in the test animals of 1 in 1 million.
    Finally, FDA is amending 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. Comments

    FDA received six comments in response to the proposed rule. Two of 
these comments were outside the scope of the rule as they advocated in 
one case that FDA hold a public hearing regarding the drug 
Avastin[supreg], and the other comment concerned veterinary 
compounding.
    (Comment 1) Of the remaining comments, one generally supported the 
rule, but mistakenly believed that the rule ``will limit carcinogenic 
compounds in food producing animals to 1 in 1 million.''
    In fact, the rule clarifies the definition of So in 21 
CFR 500.82 to mean primarily ``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 * * 
*'' and secondarily, ``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.'' The rule also clarifies the definition of 
Sm to mean primarily ``the concentration of a residue of 
carcinogenic concern in a specific edible tissue corresponding to no 
significant increase in the risk of cancer to the human consumer * * 
*'' and secondarily ``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.''
    (Comment 2) A comment from a veterinary association generally 
supported the rule and its goal to allow the use of alternative 
procedures to satisfy the DES Proviso without requiring the development 
of a second, alternative, set of terminology. The comment advocated the 
use of ``statistically valid risk assessment procedures in its 
evaluation and consideration of the compounds of carcinogenic 
concern.'' The comment continued, ``That if alternative procedures are 
allowed, they should be also definable and data driven.'' FDA generally 
agrees with the comment that an alternative procedure should be 
definable and data driven in order to be acceptable. However, the 
recommendation is also outside the current scope of the current rule as 
it clarifies the definition of So and Sm and will 
not address alternative procedures.
    (Comments 3 and 4) Another commenter opposed the rule, advocating a 
ban on all carcinogens in animal food, even in minute quantities. A 
second comment mistakenly stated that the rule ``is a proposal to 
remove any carcinogen from any drugs or feed that are given to animals 
that are generally eaten by humans.''
    As previously stated, 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), pertaining to food additives, new animal drugs, and 
color additives, respectively. These clauses prohibit approval of 
substances that have been shown to induce cancer in man or animals, 
with the following exceptions termed the ``DES Proviso.'' The DES 
Proviso permits FDA to approve carcinogenic compounds for use in food-
producing animals if it concludes that, when used in accordance with 
its label directions: (1) The compound will not adversely affect the 
animal; and (2) ``no residue'' of the compound will be found in any 
edible portion of the animals using a method of detection prescribed by 
FDA. FDA's approach to implement the Delaney clause and the DES Proviso 
is described in part 500, subpart E, entitled ``Regulation of 
Carcinogenic Compounds Used in Food-Producing Animals,'' Sec. Sec.  
500.80 through 500.92. As described earlier, the current rule clarifies 
the definitions within this set of regulations.

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 Impacts

    FDA has 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 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 final rule is not a significant 
regulatory action under Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. FDA concluded that 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. FDA did not receive any public comments that challenged 
this conclusion. As such, FDA certifies 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 $139 million, using the most current (2011) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

[[Page 50593]]

V. Federalism

    FDA has 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, the Agency has 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.

VI. Paperwork Reduction Act of 1995

    This final rule refers to previously approved collections of 
information found in FDA regulations. These collections of information 
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). The 
collections of information in Sec.  500.84 have been approved under OMB 
control number 0910-0032.

List of Subjects in 21 CFR Part 500

    Animal drugs, animal feeds, Cancer, Labeling, Packaging and 
containers, Polychlorinated biphenyls (PCBs).

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

PART 500--GENERAL

0
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.


0
2. In Sec.  500.82(b), revise the definitions of ``Sm'' and 
``So'' 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 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.
* * * * *


0
3. In Sec.  500.84, revise paragraph (c) introductory text 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 (3) of this section apply.
* * * * *

    Dated: August 17, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-20609 Filed 8-21-12; 8:45 am]
BILLING CODE 4160-01-P


