[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]
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