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###### Department of Health and Human Services

###### Food and Drug Administration

          - 21 CFR Part 500
          - [Docket No. FDA-2010-N-0612]

# AGENCY:

Food and Drug Administration, HHS.

# ACTION:

Proposed rule.

# 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:                         *kevin.greenlees@fda.hhs.gov.*

# 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.                           ( print 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.                

As described previously, the approach for evaluating compounds of carcinogenic concern currently set forth in § 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, § 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 § 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 § 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                           ( print 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 § 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 § 500.84(c)(1) or an alternate approach as provided in § 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 § 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 § 500.84(c)(1), FDA maintains that sponsors must meet the conditions for approval set for in § 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 § 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 § 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 § 500.82(b) and to the proposed conforming changes to § 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 § 500.82 to read as follows:                    

§ 500.82

* * * * *

(b) * * *

*S**m*                             means the concentration of a residue of carcinogenic concern in a specific edible tissue corresponding to no significant increase in the risk of                                   ( print page 79323)                                cancer to the human consumer. For the purpose of § 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.                        

*S**o*                             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 § 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 § 500.84 to read as follows:

§ 500.84

* * * * *

(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 § 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.

# Footnotes

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.                    
        Back to Citation      

[FR Doc. 2010-31887 Filed 12-17-10; 8:45 am]

BILLING CODE 4160-01-P