[Federal Register: January 17, 2002 (Volume 67, Number 12)]
[Proposed Rules]
[Page 2384-2387]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17ja02-14]
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Proposed Rules
Federal Register
________________________________________________________________________
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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[[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
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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