[Federal Register Volume 67, Number 12 (Thursday, January 17, 2002)]
[Proposed Rules]
[Pages 2384-2387]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-1170]


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 Proposed Rules
                                                 Federal Register
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 This section of the FEDERAL REGISTER contains notices to the public of 
 the proposed issuance of rules and regulations. The purpose of these 
 notices is to give interested persons an opportunity to participate in 
 the rule making prior to the adoption of the final rules.
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  Federal Register / Vol. 67, No. 12 / Thursday, January 17, 2002 / 
Proposed Rules  

[[Page 2384]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 500

[Docket No. 01N-0401]


Revision of the Definition of the Term ``No Residue''

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 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 proposing 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: Submit written or electronic comments on the proposed rule by 
April 17, 2002.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

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 October 31, 1985 (50 FR 45530), FDA 
issued a proposed rule implementing 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 we (FDA) can approve an animal 
feed or color 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., 21 U.S.C. 360b(d)(1)(I). We issued final 
regulations based on the 1985 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) in 
Secs. 500.80 to 500.92, included an operational definition of ``no 
residue'' in Sec. 500.84. That definition provides that 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 the ``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.
    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). 
Specifically, the opinion addressed the following questions: (1) 
Whether the FDA has the discretion to refuse to permit the use of an 
additive in animal feed if the agency finds that there is no method 
that can ``reliably measure and confirm'' the presence of residues of 
carcinogenic concern at and above the ``no residue'' level for such 
residues, (2) whether the FDA must revise its regulations to adopt more 
sensitive methods when they become available once the agency has 
approved a method of detection, and (3) whether the FDA has 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.
    With respect to the first question, the opinion determined that FDA 
is under no obligation to approve at least one method for the detection 
of a residue of a carcinogenic animal food additive and that it has the 
discretion to refuse to permit the use of unsatisfactory detection 
methods. In so concluding, the DOJ further stated that FDA may use the 
``no significant risk'' level (defined in Sec. 500.84) as a benchmark 
for rejecting analytical methods. These conclusions are consistent with 
FDA's current interpretations of the DES proviso regarding analytical 
methods.
    The second question asks whether FDA must revise its regulations to 
adopt the ``best available'' methods for the detection of carcinogenic 
residues or

[[Page 2385]]

whether it has discretion to continue to accept results from less 
sensitive methods. The DOJ asserted that, although one interpretation 
of the proviso could allow the best available method approach, the 
statute does not compel that course of action. Thus, the opinion 
concluded that the statute does not require FDA to replace currently 
approved methods with more sensitive methods as they become available. 
Once again, this conclusion agrees with the position taken by FDA.
    In considering the third 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 * * *.''
    DOJ's 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. 
Therefore, we are proposing amendments to the regulations to make them 
consistent with the DOJ legal opinion.

II. Description of the Proposed Rule

    The agency is proposing to revise 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 [emphasis added] 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 proposing 
to define the LOD, for the purposes of this rule, as the lowest 
concentration of analyte that can be confirmed by the approved 
regulatory method.
    The agency is proposing the following conditions that a sponsor of 
a carcinogenic compound must satisfy 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 Secs. 500.80 to 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 proposed regulations, a sponsor 
must provide sufficient data to permit us to estimate the LOD of the 
method as defined above 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 proposed 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 proposed rule 
any one specific procedure or protocol as a standard requirement for 
establishing the LOD. Therefore, under the proposed rule, we would 
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.

III. Environmental Impact

    The agency has carefully considered the potential environmental 
impacts of this proposed 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 proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121)), and the Unfunded Mandates Reform Act of 
1995 (Public Law 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 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 (Public Law 104-4) 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
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).
    The agency concludes that this proposed rule is consistent with the 
principles set forth in the Executive order and in these two statutes. 
The agency expects only very slight, if any, compliance costs to result 
from the proposed rule. Companies have requested approvals for 
carcinogenic compounds under the current regulation in only a few cases 
since it was published as a final rule in 1987, probably at least in 
part because of concerns over public acceptance of such products. We 
anticipate that, for the same reasons, companies will rarely request 
approvals for carcinogenic compounds under a final version of the 
proposed rule. As a result, the proposed 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 proposed 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 proposed rule, because the proposed 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 proposing to amend the regulations regarding the 
carcinogenic compounds used in food-producing animals by deleting the 
operational definition of ``no residue.'' Under the proposed 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

[[Page 2386]]

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 or color 
additives. The submission of data to meet the requirements of the 
proposed 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 proposal 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. However, because we 
anticipate very few requests for approval of new animal drug 
applications or feed additives under the provisions of the proposed 
rule, we believe any loss of value would be insignificant.
    As stated above, 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 proposal 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 proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed 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 proposed 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. Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written or electronic comments regarding this proposal 
by April 17, 2002. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday.

VIII. Reference

    The following reference has been placed on display in the Dockets 
Management Branch (address above) 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 (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.


Sec. 500.80  [Amended]

    2. Section 500.80 Scope of this subpart is amended in paragraph (a) 
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) by 
alphabetically adding ``Limit of Detection (LOD) means the lowest 
concentration of analyte that can be confirmed by the approved 
regulatory method.''; by removing from the definition of ``Marker 
residue'' the phrase ``permitted concentration'' and by adding in its 
place ``Sm''; by removing from the definition for 
``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)''; by 
removing from the definition of ``Rm'' the phrase ``in the 
last tissue to deplete to its permitted concentration''; and by 
revising the definition of ``Sm'' to read ``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, by 
adding two sentences at the end of paragraph (c)(1), by revising 
paragraph (c)(2), and by 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 revised to read as follows:


Sec. 500.88  Regulatory method.

    (a) The sponsor shall submit for evaluation and validation a 
regulatory

[[Page 2387]]

method developed to monitor compliance with this subpart.
    (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: January 3, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-1170 Filed 1-16-02; 8:45 am]
BILLING CODE 4160-01-S