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Pesticide Tolerance for Metalaxyl
Note: EPA no longer updates this information, but it may be useful as a reference or resource.
[Federal Register: November 2, 1994]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[PP 0F3893/R2084; FRL-4917-4]
RIN 2070-AB78
Pesticide Tolerance for Metalaxyl
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This rule establishes a tolerance for combined residues of the
fungicide metalaxyl [N-(2,6-dimethylphenyl)-N-(methoxyacetyl) alanine
methyl ester] and its metabolites containing the 2,6-dimethylaniline
moiety, and N-(2-hydroxymethyl-6-methyl)-N-(methoxyacetyl)-alanine
methylester, each expressed as metalaxyl, in or on the raw agricultural
commodity leafy vegetables (except Brassica) group (except spinach).
Ciba-Geigy Corp. petitioned for this regulation to establish the
maximum permissible levels for residues of the fungicide.
EFFECTIVE DATE: October 19, 1994.
ADDRESSES: Written objections and hearing requests, identified by the
document control number, [PP 0F3893/R2084], may be submitted to:
Hearing Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M
St., SW., Washington, DC 20460. A copy of any objections and hearing
requests filed with the Hearing Clerk should be identified by the
document control number and submitted to: Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, bring copy of objections and hearing
requests to Rm. 1132, CM #2, 1921 Jefferson Davis Hwy., Arlington, VA
22202. Fees accompanying objections shall be labeled ``Tolerance
Petition Fees'' and forwarded to: EPA Headquarters Accounting
Operations Branch, OPP (Tolerance Fees), P.O. Box 360277M, Pittsburgh,
PA 15251.
FOR FURTHER INFORMATION CONTACT: By mail: Leonard S. Cole, Jr., Acting
Product Manager (PM) 21, Registration Division (7505C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. Office location and telephone number: Rm. 227, CM
#2, 1921 Jefferson Davis Hwy., Arlington, VA 22202; (703)-305-6900.
SUPPLEMENTARY INFORMATION: EPA issued a notice of filing, published in
the Federal Register of December 13, 1991 (56 FR 29767), which
announced that Ciba-Geigy Corp., P.O. Box 18300, Greensboro, NC 27419,
had submitted pesticide petition PP 0F3893 to EPA requesting that the
Administrator, pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), establish a tolerance for
combined residues of the fungicide metalaxyl [N-(2,6-dimethylphenyl)-N-
(methoxyacetyl) alanine methyl ester] and its metabolites containing
the 2,6-dimethylaniline moiety, and N-(2-hydroxymethyl-6-methyl)-N-
(methoxyacetyl)-alanine methylester, each expressed as metalaxyl, in or
on the raw agricultural commodity leafy vegetables (except Brassica)
group (except spinach) at 5.0 ppm.
There were no comments or requests for referral to an advisory
committee received in response to the notice of filing. By way of
public reminder, this notice also reiterates the registrant's
responsibility under section 6 (a)(2) of FIFRA to submit additional
factual information regarding adverse effects on the environment and to
human health by the pesticide. The scientific data submitted in the
petition and other relevant material have been evaluated. The
toxicological data considered in support of the tolerance include:
1. A 3-month dietary study in rats with a no-observed-effect level
(NOEL) at 17.5 milligrams per kilogram (mg/kg) body weight (bwt)/day
(250 parts per million (ppm)).
2. A developmental toxicity study in rats with a NOEL of 50 mg/kg
bwt for developmental toxicity and maternal toxicity.
3. A developmental toxicity study in rabbits with a NOEL of 300 mg/
kg bwt, the highest dose tested (HDT). Metalaxyl did not cause
developmental toxicity, even in the presence of maternal toxicity.
4. Metalaxyl was negative in bacterial and mammalian gene mutation.
The fungicide also did not increase the frequency of reverse mutations
in yeast. Metalaxyl was negative in an in vivo cytogenetics assay
(hamsters) and a dominant-lethal assay (mice). Metalaxyl did not
increase unscheduled DNA synthesis in rat primary hepatocytes or in
human fibroblasts. These results suggest that metalaxyl is not
genotoxic.
5. A three-generation rat reproduction study with a NOEL of 63 mg/
kg bwt/day (1,250 ppm).
6. A 6-month dog feeding study with a NOEL of 6.3 mg/kg bwt/day
(250 ppm). Effects found at 25 mg/kg were increased serum alkaline
phosphatase activity and increased liver weight and liver-to-brain
weight ratios without histological changes.
7. A 2-year rat chronic feeding/carcinogenicity study with no
compound-related carcinogenic effects under the conditions of the study
at dietary levels up to 1,250 ppm. The NOEL is 13 mg/kg bwt/day (250
ppm). The lowest-observed-effect level (LOEL) is 63 mg/kg/day based
upon slight increases in liver weight to body weight ratios and
periacinar vacuolation of hepatocytes.
8. A 2-year mouse oncogenic study with no compound-related
carcinogenic effects under the conditions of the study at dietary
levels up to 190 mg/kg/day.
Because of concerns raised over some equivocal increases in tumor
incidences in the male mouse liver and the male rat adrenal medulla,
and the female rat thyroid, the two chronic feeding studies were
submitted to the Environmental Pathology Laboratories (EPL) for an
independent reading of the microscopic slides. The new pathological
evaluation by EPL and the original reports of the rat and mouse
oncogenicity studies were then both submitted for review to EPA's
Carcinogen Assessment Group (CAG). A final review of the
carcinogenicity studies and related material was performed by the Peer
Review Committee of the Toxicology Branch (TB) of the Office of
Pesticide Programs (OPP).
The four major issues evaluated by CAG and the peer review group
included: (1) Perifollicular cell adenomas in the thyroid of female
rats; (2) adrenal medullary tumors (pheochromocytomas) in male rats;
(3) liver tumors in male mice; and (4) whether the HDT (1,250 ppm) in
the rat and mouse oncogenicity studies represented a maximum-tolerated
dose (MTD).
Regarding the thyroid tumors in female rats, the peer review group
concluded that the increased incidences of thyroid tumors in females of
treated groups were not compound related. This conclusion was based on
the following: (1) There was no progression of benign tumors (adenomas)
to malignancy (carcinomas); (2) there was no increase in hyperplastic
changes; (3) there was no dose-response relationship; and (4) the two
reevaluations of the microscopic slides by the pathologists at EPL and
TB in OPP further did not confirm any apparent effects observed in the
original report.
The issue of a possible treatment-related increase of adrenal
medullary gland tumors, namely, pheochromocytomas, in the male rat was
also reassessed by both CAG and the Peer Review Committee. Both
concluded that the data, especially in view of the reevaluation of the
microscopic slides performed by EPL, did not support a compound-related
increase of adrenal medullary tumors; the incidence of
pheochromocytomas more accurately represented spontaneous variations of
a commonly occurring tumor in the aged rat.
The analysis of the significance of the equivocal increase in the
incidence of liver tumors in male mice was very similar to that
performed for the rat thyroid and adrenal gland tumors. The original
pathological reading of the tissue slides reported an elevated increase
of tumors in some treatment groups; however, these increases were not
evident after a reevaluation of the microscopic slides was performed by
an independent pathologist at EPL and by the reading of a CAG
pathologist. The Peer Review Committee concurred that the reevaluation
of the slides is reliable and does not show any compound-related
increase in the incidence of liver tumors in the mouse.
The Agency believes that the data from the rat and mouse long-term
studies are sufficient to support the conclusion that metalaxyl does
not show a carcinogenic potential in laboratory animals. This
conclusion is supported by the following: (1) The doses tested in both
the rat and mouse long-term studies approached an MTD based upon
compound-related changes in liver weight and/or liver histology; (2)
extensive available mutagenic evidence indicates no potential genotoxic
activity which correlates with the negative carcinogenic potential
demonstrated in long-term testing; (3) metalaxyl is not structurally
related to known carcinogens; and (4) under the conditions of the rat
and mouse tests, no indication of compound-related carcinogenic effects
was noted at any of the treatment doses, sexes, or species.
The chronic dietary exposure analysis used a reference dose (RfD)
of 0.08 mg/kg bwt/day, based on a NOEL of 7.8 mg/kg bwt/day and an
uncertainty factor of 100. The NOEL is taken from a 6-month dog feeding
study which demonstrated increased alkaline phosphatase activity and an
increase in relative liver weights at 30.63 mg/kg bwt/day. The RfD was
taken from actual dose values and has thus changed from 0.06 mg/kg bwt/
day to the 0.08 used in the analysis.
Food uses evaluated in the residue analysis were the published uses
of metalaxyl listed in 40 CFR 180.408 and 185.4000 and the proposed use
on leafy vegetables (except Brassica) group (except spinach). In a memo
of June 21, 1991, Chemistry Branch Tolerance Support recommended for a
tolerance reassessment for metalaxyl on leafy vegetables (except
Brassica) group (except spinach). In 40 CFR 180.408 tolerances exist
for metalaxyl on leafy vegetables (0.1 ppm), spinach (10 ppm), and head
lettuce (5 ppm). Data submitted lead to the proposed new tolerance of 5
ppm for the crop group leafy vegetables (except Brassica) group (except
spinach) for metalaxyl.
The nature of the residue is adequately understood, and adequate
analytical methods (GLC and AFID) are available for enforcement
purposes in the Pesticide Analytical Manual, Vol. II.
A chronic exposure analysis was performed using tolerance level
residues and 100-percent-crop-treated information to estimate the
Theoretical Maximum Residue Contribution (TMRC) for the general
population and 22 subgroups. Percent-crop-treated data were used to
calculate the Anticipated Residue Contribution (ARC) for the Dietary
Risk Evaluation System (DRES) population subgroups for certain
commodities.
The anticipated residue contribution (ARC) for the overall U. S.
population from published uses is 6.5 x 10<SUP>-3 mg/kg bwt/day, which
represents 812f the RfD. The proposed use on leafy vegetables (except
Brassica) group (except spinach) contributes an exposure of 4.7 x
10<SUP>-4 mg/kg bwt/day, representing less than 112f the RfD. When the
proposed exposure is added to the public exposure for metalaxyl the ARC
is 6.9 x 10<SUP>-3 mg/kg bwt/day, or 912f the RfD.
The subgroup most highly exposed, children (1 to 6 years old), has
an ARC from existing uses of 1.2 x 10<SUP>-2 mg/kg bwt/day,
representing 1612f the RfD. The proposed use contributes an additional
6.1 x 10<SUP>-4 mg/kg bwt/day and raises the overall ARC 1.3 x 10<SUP>-
2 mg/kg bwt/day, still representing 1612f the RfD.
Based on the exposure and risk estimates arrived at through this
analysis, the Agency believes that the proposed use for metalaxyl does
not pose a chronic dietary risk that is of concern.
There are presently no actions pending against the continued
registration of this chemical.
Based on the information and data considered, the Agency has
determined that the tolerance established by amending 40 CFR part 180
will protect the public health. Therefore, the tolerance is established
as set forth below.
Any person adversely affected by this regulation may, within 30
days after publication of this document in the Federal Register, file
written objections to the regulation and may also request a hearing on
those objections. Objections and hearing requests must be filed with
the Hearing Clerk, at the address given above (40 CFR 178.20). A copy
of the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40
CFR 180.33(i). If a hearing is requested, the objections must include a
statement of the factual issue(s) on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the objector (40 CFR 178.27). A request for a hearing
will be granted if the Administrator determines that the material
submitted shows the following: There is genuine and substantial issue
of fact; there is a reasonable possibility that available evidence
identified by the requestor would, if established, resolve one or more
of such issues in favor of the requestor, taking into account
uncontested claims or facts to the contrary; and resolution of the
factual issue(s) in the manner sought by the requestor would be
adequate to justify the action requested (40 CFR 178.32).
Under Executive Order 12866 (58 FR 51735, October 4, 1993), the
Agency must determine whether the regulatory action is ``significant''
and therefore subject to all the requirements of the Executive Order
(i.e., Regulatory Impact Analysis, review by the Office of Management
and Budget (OMB)). Under section 3(f), the order defines
``significant'' as those actions likely to lead to a rule (1) having an
annual effect on the economy of $100 million or more, or adversely and
materially affecting a sector of the economy, productivity,
competition, jobs, the environment, public health or safety, or State,
local or tribal governments or communities (also known as
``economically significant''); (2) creating serious inconsistency or
otherwise interfering with an action taken or planned by another
agency; (3) materially altering the budgetary impacts of entitlement,
grants, user fees, or loan programs; or (4) raising novel legal or
policy issues arising out of legal mandates, the President's
priorities, or the principles set forth in this Executive Order.
Pursuant to the terms of this Executive Order, EPA has determined
that this rule is not ``significant'' and is therefore not subject to
OMB review.
Pursuant to the requirements of the Regulatory Flexibility Act
(Pub. L. 96-354, 94 Stat. 1164, 5 U.S.C. 601-612), the Administrator
has determined that regulations establishing new tolerances or raising
tolerance levels or establishing exemptions from tolerance requirements
do not have a significant economic impact on a substantial number of
small entities. A certification statement to this effect was published
in the Federal Register of May 4, 1981 (46 FR 24950).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: October 19, 1994.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
Therefore, 40 CFR part 180 is amended as follows:
PART 180--[AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. Section 180.408 is amended in paragraph (a) in the table therein
by revising the entry for leafy vegetables (except brassica) group, to
read as follows:
Sec. 180.408 Metalaxyl; tolerances for residues.
(a) * * *
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Parts per
Commodity million
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Leafy vegetables (except Brassica) group (except spinach).. 5.0
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[FR Doc. 94-26799 Filed 11-1-94; 8:45 am]
BILLING CODE 6560-50-F