[Federal Register Volume 67, Number 246 (Monday, December 23, 2002)]
[Rules and Regulations]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 02-32216]
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'' in the New
Animal Drug Regulations
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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.
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
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''
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
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''
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
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
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.
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.
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.
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:
1. The authority citation for 21 CFR part 500 continues to read as
Authority: 21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353,
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
a. By alphabetically adding ``Limit of detection (LOD) means the
lowest concentration of analyte that can be confirmed by the approved
b. By removing from the definition of ``Marker residue'' the phrase
``permitted concentration'' and by adding in its place
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
(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]
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