[Federal Register Volume 67, Number 246 (Monday, December 23, 2002)]
[Rules and Regulations]
[Pages 78172-78174]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-32216]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 500

[Docket No. 01N-0401]
RIN 0910-AC45


Revision of the Definition of the Term ``No Residue'' in the New 
Animal Drug Regulations

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 carcinogenic compounds used in food-producing 
animals. Specifically, FDA is deleting the operational definition of 
the term ``no residue'' and is making conforming amendments to other 
parts of these regulations. FDA is making these amendments in response 
to a legal opinion issued by the Department of Justice (DOJ), Office of 
Legal Counsel, which concluded that the operational definition of ``no 
residue'' is not legally supportable.

DATES: This rule is effective January 22, 2003.

FOR FURTHER INFORMATION CONTACT: Steven D. Brynes, Center for 
Veterinary Medicine (HFV-151), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-827-6975.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of January 17, 2002 (67 FR 2384), FDA 
proposed a rule amending its regulations regarding carcinogenic 
compounds used in food-producing animals. Specifically, the agency 
proposed to delete the operational definition of the term ``no 
residue'' and proposed to make conforming amendments to other parts of 
these regulations. FDA proposed these amendments in response to a 1995 
legal opinion issued by the DOJ, Office of Legal Counsel, which 
concluded that the operational definition of ``no residue'' is not 
legally supportable. We provided 90 days for comment on the proposed 
rule.
    FDA proposed the original regulations regarding carcinogenic 
compounds used in food-producing animals in the Federal Register of 
October 31, 1985 (50 FR 45530), in order to implement the 
diethylstilbestrol (DES) proviso of the Delaney Clause in sections 409, 
512, and 721 of the Federal Food, Drug, and Cosmetic Act (the act) (21 
U.S.C. 348, 360b, and 379e). The DES proviso provides that FDA can 
approve an animal feed additive or a new animal drug that induces 
cancer if we find that ``no residue'' of such additive or drug ``* * * 
will be found (by methods of examination prescribed or approved by the 
Secretary by regulations * * *), in any edible portion of such animals 
after slaughter * * *'' (see, e.g., excerpts from 21 U.S.C. 
360b(d)(1)(I)). We issued final regulations based on this proposal in 
the Federal Register of December 31, 1987 (52 FR 49572).
    The final rule, which was codified in part 500 (21 CFR part 500) at 
Sec. Sec.  500.80 through 500.92, included an operational definition of 
``no residue'' (Sec.  500.84). That definition provides FDA will 
consider that ``no residue'' of a carcinogenic compound remains in the 
edible tissue of treated animals when the ``* * * concentration of the 
residue of carcinogenic concern in the total diet of people will not 
exceed So * * *.'' Section 500.82 defines So as 
``the concentration of the 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 * * *.'' Section 500.82 further provides 
that FDA will assume that this ``So will correspond 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.'' Therefore, under these regulations, it is possible for a 
residue detected by the method approved by FDA to be considered ``no 
residue,'' if the detectable residue is below the level that 
corresponds to a maximum lifetime risk of cancer in the test animals of 
1 in 1 million (``insignificant risk'' or ``no significant risk'' 
level).
    In the final rule of December 31, 1987, we explained the rationale 
for this operational definition of ``no residue.'' The preamble to the 
final rule stated:
    Application of * * * the ``DES Proviso,'' hinges therefore on 
the finding of ``no residue'' of the substance in edible products.
    As a practical matter, however, FDA has been unable to conclude 
that no trace of any given substance will remain in edible products. 
The new procedures, therefore, provide an operational definition of 
``no residue.'' That is, the procedures are designed to permit the 
determination of the concentration of residue of a carcinogenic 
compound that presents an insignificant risk of cancer to the 
consuming public. That concentration corresponds to a maximum 
lifetime risk of cancer to the test animal on the order of 1 in 1 
million. Thus, the procedures provide for a quantitative estimation 
of the risk of cancer presented by the residues of a carcinogenic 
compound proposed for use in food-producing animals. ``No residue'' 
remains in food products when conditions of use, including any 
required preslaughter withdrawal period or milk discard time, ensure 
that the concentration of the residue of carcinogenic concern in the 
total diet of people will not exceed the concentration that has been 
determined to present an insignificant risk.
(52 FR 49572, December 31, 1987.)
    On October 13, 1995, the DOJ, Office of Legal Counsel, responding 
to questions posed by the Environmental Protection Agency and FDA, 
issued a legal opinion entitled ``The Food and Drug Administration's 
Discretion to Approve Methods of Detection and to Define the Term ``No 
Residue'' Pursuant to the Federal Food, Drug, and Cosmetic Act'' (DOJ 
Opinion on FDA Implementation of the DES Proviso) (Ref. 1). One of the 
questions addressed by the opinion asked whether FDA has

[[Page 78173]]

the discretion to determine that an edible tissue contains ``no 
residue'' when a method of detection reveals the presence of residues 
of carcinogenic concern that is below the ``no significant risk'' 
level.
    In considering that question, the DOJ reasoned that ``[g]iving `no 
residue' its ordinary meaning, the detected presence of any residue by 
an approved method would be incompatible with a finding of `no 
residue,' and thus would preclude a finding that the [DES] proviso 
applies.'' Furthermore, the opinion stated that ``[t]here is nothing * 
* * to suggest that a finding of `no residue' could be based upon the 
detected presence of residue, however insignificant * * *.''
    This conclusion that ``FDA may not accept a finding that residue is 
present, but below the `no significant risk' level, as satisfying the 
statutory requirement of `no residue,' '' contradicts FDA's present 
operational definition of ``no residue'' issued in Sec.  500.84. This 
final rule amends the regulations to make them consistent with the DOJ 
legal opinion.
    Specifically, the agency is revising the regulations to delete the 
operational definition of ``no residue.'' Therefore, for a substance to 
be approved under the DES proviso, no residue can be detectable by the 
approved regulatory method; that is, any residue in the target tissue 
must be nondetectable or below the limit of detection (LOD) of the 
approved regulatory method. Inasmuch as: (1) The regulatory method 
currently is defined in Sec.  500.82 as the aggregate of all 
experimental procedures for measuring and confirming the presence of 
the marker residue in the target tissue and (2) FDA must, for 
regulatory and scientific reasons, be capable of identifying the 
detected residue with a high degree of certainty, FDA is defining the 
LOD, for the purposes of this rule, as the lowest concentration of 
analyte that can be confirmed by the approved regulatory method.
    Thus, the sponsor of a carcinogenic compound must satisfy the 
following conditions with respect to the sponsor's proposed regulatory 
method. First, the sponsor must provide a method that is at least 
capable of reliably quantitating residues at and above the 
Rm (the concentration of marker residue that the regulatory 
method must be capable of measuring in the target tissue), which we 
will continue to calculate in the manner provided in the current 
regulations in Sec. Sec.  500.80 through 500.92. Therefore, FDA will 
use the ``no significant risk'' level determined through appropriate 
toxicological testing as a benchmark for assessing the acceptability of 
a regulatory method. Second, under the final regulations, a sponsor 
must provide sufficient data to permit us to estimate the LOD of the 
method as defined previously and in proposed Sec.  500.82. Given the 
first requirement, the LOD will likely be below the Rm, and 
consequently, the LOD will replace the Rm as the ``no 
residue'' determinant.
    Under the final regulations, we have defined the LOD as the lowest 
concentration of analyte that can be confirmed by the approved 
regulatory method. Believing that there are several valid procedures to 
estimate the LOD, we have chosen not to specify in this final rule any 
one specific procedure or protocol as a standard requirement for 
establishing the LOD. Thus, under the final rule, we will consider and 
evaluate any reasonable, generally recognized procedure that is 
consistent with the aims and requirements of regulatory exposure 
estimation and risk assessment practices of FDA.

II. Comments on the Proposed Rule

    The agency received no comments on the proposed rule.

III. Environmental Impact

    The agency has carefully considered the potential environmental 
impacts of this final rule. 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, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). 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 Regulatory 
Flexibility Act requires agencies to examine regulatory alternatives 
for small entities, if the rule may have a significant 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 of anticipated costs and benefits before requiring any 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million in any one year (adjusted 
annually for inflation).
    We conclude that this final rule is consistent with the principles 
set forth in the Executive order and in these two statutes. We expect 
only very slight, if any, compliance costs to result from the final 
rule. As a result, the final rule is not a significant regulatory 
action as defined by the Executive order and so is not subject to 
review under the Executive order. Further, we certify that the final 
rule would not have a significant economic impact on a substantial 
number of small entities. The Unfunded Mandates Reform Act does not 
require FDA to prepare a statement of costs and benefits for the final 
rule, because the final rule is not expected to result in any 1-year 
expenditure that would exceed $100 million adjusted for inflation. The 
current inflation-adjusted statutory threshold is about $110 million.
    We are amending the regulations regarding the carcinogenic 
compounds used in food-producing animals by deleting the operational 
definition of ``no residue.'' Under the final rule, for a carcinogenic 
compound to be approved, no residue of the compound can be detectable 
using an approved regulatory method. Any residue in the target tissue 
would have to be nondetectable or below the LOD.
    As stated previously, we are making this change in response to a 
DOJ opinion that the current operational definition of ``no residue'' 
is not legally supportable. The benefit of this change would be an 
increase in the clarity of the current regulations concerning 
carcinogenic compounds used in food-producing animals.
    The deletion of the definition is not expected to impose any 
measurable compliance costs on the sponsors of compounds that are 
submitted to us for approval as new animal drugs or feed additives. The 
submission of data to meet the requirements of the final rule will be 
in place of, and nearly identical to, data that were submitted to meet 
the operational definition of ``no residue.'' We do not expect a 
noticeable increase in the level of effort expended in preparing a 
submission. To the extent that incremental compliance costs exist, we 
believe them to be inconsequential. In theory, another result of this 
final rule might be the possible increase in the withdrawal period for 
some number of compounds submitted for approval, which would represent 
some loss of value to the sponsor. We do not have the data to estimate 
this value, but believe it to be very small.

[[Page 78174]]

    The Regulatory Flexibility Act requires agencies to examine 
regulatory alternatives for small entities, if the rule may have a 
significant economic impact on a substantial number of small entities. 
Since we have determined that the possible compliance costs to any 
sponsor would be extremely small, if they occur at all, we are 
certifying that the final rule would not have a significant economic 
impact on a substantial number of small entities. No further small 
business analysis is required.

V. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the final 
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

    The information collected in Sec.  500.88 has been approved by the 
Office of Management and Budget (OMB) under OMB control number 0910-
0032. This final rule amends Sec.  500.88 but does not substantively 
modify the information collection. Therefore, clearance by OMB under 
the Paperwork Reduction Act of 1995 is not required.

VII. Reference

    The following reference has been placed on display in the Dockets 
Management Branch (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. U.S. Department of Justice, ``The Food and Drug 
Administration's Discretion to Approve Methods of Detection and to 
Define the Term `No Residue' Pursuant to the Federal Food, Drug, and 
Cosmetic Act: Memorandum Opinion for the Assistant Administrator and 
General Counsel Environmental Protection Agency and the General 
Counsel Department of Health and Human Services,'' October 13, 1995.

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 
the authority delegated to the Commissioner of Food and Drugs, 21 CFR 
part 500 is amended as follows:

PART 500--GENERAL

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

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


Sec.  500.80  [Amended]

    2. Section 500.80 Scope of this subpart is amended in paragraph (a) 
in the third sentence by removing the phrase ``provides an operational 
definition of no residue and''.


Sec.  500.82  [Amended]

    3. Section 500.82 Definitions is amended in paragraph (b) as 
follows:
    a. By alphabetically adding ``Limit of detection (LOD) means the 
lowest concentration of analyte that can be confirmed by the approved 
regulatory method.'';
    b. By removing from the definition of ``Marker residue'' the phrase 
``permitted concentration'' and by adding in its place 
``Sm'';
    c. By removing from the definition of ``Preslaughter withdrawal 
period or milk discard time'' the phrase ``for the residue of 
carcinogenic concern in the edible product to deplete to the 
concentration that will satisfy the operational definition of no 
residue'' and by adding in its place ``at which no residue is 
detectable in the edible product using the approved regulatory method 
(i.e., the marker residue is below the LOD)'';
    d. By removing from the definition of ``Rm'' the phrase 
``in the last tissue to deplete to its permitted concentration''; and
    e. By removing the definition of ``Sm '' and by adding 
in its place ``Sm means the concentration of residue in a 
specific edible tissue corresponding to a maximum lifetime risk of 
cancer in the test animals of 1 in 1 million''.

    4. Section 500.84 is amended by revising the section heading and 
paragraph (c)(2) and by adding two sentences at the end of paragraph 
(c)(1) and adding paragraph (c)(3) to read as follows:


Sec.  500.84  Conditions for approval of the sponsored compound.

* * * * *
    (c) * * *
    (1) * * * Because the total diet is not derived from food-producing 
animals, FDA will make corrections for food intake. FDA will designate 
as Sm the concentration of residue in a specific edible 
tissue corresponding to a maximum lifetime risk of cancer in test 
animals of 1 in 1 million.
    (2) From the appropriate residue chemistry data FDA will calculate 
the Rm as described in Sec.  500.86(c). The sponsor must 
provide a regulatory method in accordance with Sec.  500.88(b). FDA 
will calculate the LOD of the method from data submitted by the sponsor 
under Sec.  500.88. The LOD must be less than or equal to 
Rm.
    (3) FDA will conclude that the provisions of this subpart are 
satisfied when no residue of the compound is detectable (that is, the 
marker residue is below the LOD) using the approved regulatory method 
under the conditions of use of the sponsored compound, including any 
required preslaughter withdrawal period or milk discard time.

    5. Section 500.88 is amended by revising paragraphs (b) and (c) to 
read as follows:


Sec.  500.88  Regulatory method.

* * * * *
    (b) The regulatory method must be able to confirm the identity of 
the marker residue in the target tissue at a minimum concentration 
corresponding to the Rm. FDA will determine the LOD from the 
submitted analytical method validation data.
    (c) FDA will publish in the Federal Register the complete 
regulatory method for ascertaining the marker residue in the target 
tissue in accordance with the provisions of sections 409(c)(3)(A), 
512(d)(1)(I), and 721(b)(5)(B) of the act.

    Dated: December 17, 2002.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 02-32216 Filed 12-20-02; 8:45 am]
BILLING CODE 4160-01-S