metalaxyl (Apron, Ridomil, Subdue) Pesticide Tolerances 3/93
40 CFR Parts 180, 185, and 186
[PP 6F3362, FAP 6H5493/P556; FRL-4573-4]
RIN 2070-AC18
Pesticide Tolerances for Metalaxyl
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
------------------------------------------------------------
SUMMARY: This document proposes to establish a tolerance for
residues of the fungicide metalaxyl [N-(2,6-dimethylphenyl)-
N-(methoxyacetyl) alanine methyl ester] and its metabolites
containing the 2,6-dimethyl-aniline moiety, and N-(2-hydroxymethyl-
6-methyl)-N-(methoxyacetyl) alanine methyl ester in or on grapes
at 2.0 parts per million (ppm), wet and dry grape pomace at
10.0 ppm, raisins at 6.0
ppm and raisin waste at 10.0 ppm. This
regulation to establish the maximum permissible levels for residues
of metalaxyl in or on the commodities was requested in petitions
submitted by the Ciba-Geigy Corp.
DATES: Comments, identified by the document control number,
[PP 6F3362 and FAP 6H5493/P556], must be received on or before
April 9, 1993.
ADDRESSES: By mail, submit written comments to: Public Document
and Freedom of Information Section, Field Operations Division
(H7506C), Office of Pesticide Programs, 401 M St., SW., Washington,
DC 20460. In person, bring comments to: Rm. 246, CM #2, 1921
Jefferson Davis Hwy., Arlington, VA 22202, (703)-305-6900.
Information submitted as a comment concerning this document
may be claimed confidential by marking any part or all of that
information as "Confidential Business Information" (CBI). Information
so marked will not be disclosed except in accordance with procedures
set forth in 40 CFR part 2. A copy of the comment that does
not contain CBI must be submitted for inclusion in the public
record. Information not marked confidential may be disclosed
publicly by EPA without
prior notice. All written comments will
be available for public inspection in Rm. 1128C at the address
given below, from 8 a.m. to 4 p.m., Monday through Friday, excluding
legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Susan T. Lewis, Product
Manager (PM) 21, Registration Division (H7505C), Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460, Rm.
227, CM #2, 1921 Jefferson Davis Hwy., Arlington, VA 22202,
(703)-305-7382.
SUPPLEMENTARY INFORMATION: EPA issued a notice, published in
the Federal Register of March 19, 1986 (51 FR 9513), which announced
that Ciba-Geigy Corp., P.O. Box 18300, Greensboro, NC 27419,
had submitted a pesticide tolerance petition, PP 6F3362, and
a food/feed additive petition, FAP 6H5493, to EPA requesting
that the Administrator, pursuant to section 408(d) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 346a(d)), propose the
establishment of tolerances for the fungicide metalaxyl [N-(2,6-
dimethyl-phenyl)-N-(methoxyacetyl) alanine methyl ester] and
its metabolites containing the 2,6-dimethylaniline moiety, and
N-(2-hydroxymethyl-6-methyl)-N-(methoxyacetyl) alanine methyl
ester in or on grapes at
2.0 ppm, and in or on the processed
commodities wet grape pomace at 3.0 ppm, dry grape pomace at
6.0 ppm, grape juice at 2.0 ppm, grape wine at 2.0 ppm, raisins
at 6.0 ppm, and raisin waste at 9.0 ppm. Since then Ciba-Geigy
Corp. has petitioned the Agency to amend the proposed tolerances
for use in or on grapes at 2.0 ppm, wet and dry grape pomace
at 10.0 ppm, raisins at 6.0 ppm, and raisin waste at 10.0 ppm.
There were no comments received in response to the notice
of filing.
The data submitted in support of the petition and other relevant
material have been evaluated. The pesticide is considered useful
for the purposes for which the tolerances and food additive
regulation are being sought and capable of achieving the intended
physical or technical effect.
The toxicological data considered in support of the tolerance
include the following:
1. A 3-month dietary study in rats with a no-observed-effect
level (NOEL) at 12.5 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
400 mg/kg bwt (highest dose tested [HDT]). Metalaxyl did not
cause developmental
toxicity, even in the presence of maternal
toxicity.
3. A developmental toxicity study in rabbits with a NOEL
of 300 mg/kg bwt (HDT). Metalaxyl did not cause developmental
toxicity, even in the presence of maternal toxicity.
4. Metalaxyl did not induce gene mutations in bacteria, yeast,
and lymphoma cells in vitro with or without metabolic activation.
The fungicide also caused no structural or numerical chromosomal
aberrations in yeast, hamsters (in vivo nucleus anomaly assay),
or mice (a dominant lethal assay). No DNA damage was observed
in bacteria, and no unscheduled DNA synthesis was noted in rat
primary hepatocytes or human fibroblasts in vitro as the result
of exposure to metalaxyl. These results suggest that metalaxyl
is not genotoxic.
5. A mouse dominant-lethal study that was negative for mutagenicity.
6. A three-generation rat reproduction study with a NOEL
of 62.5 mg/kg bwt/day (1,250 ppm).
7. A 6-month dog feeding study with a NOEL of 6.25 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.
8. 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
6.25 mg/kg bwt/day (250 ppm). The LOEL is 1,250 ppm based upon
slight increases in liver weight to body weight ratios and periacinar
vacuolation of hepatocytes.
9. A 2-year mouse oncogenic study with no compound-related
carcinogenic effects under the conditions of the study at dietary
levels up to 1,250 ppm. The NOEL is 1,250 ppm.
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 reference dose (RfD) based on the 6-month dog feeding
(NOEL 6.25 mg/kg bwt/day), and using a hundredfold safety factor,
is calculated to be 0.060 mg/kg bwt/day. The theoretical maximum
residue contribution from previously established tolerances
and food additive regulations and the tolerances and food additive
regulations established here are 0.011815 mg/kg bwt/day and
utilize 19.69 percent of the RfD.
The nature of the residue is adequately understood, and adequate
analytical methods (capillary N/P GLC) are available for enforcement
purposes. Because of the long lead time from establishing these
tolerances and food/feed additive regulations to publication
of the enforcement methodology in the Pesticide Analytical Manual,
Vol. II, the analytical methodology is being made available
in the interim to anyone interested in pesticide enforcement
when requested from: Calvin Furlow, Public Information Branch,
Field Operations Division (H7506C), 401 M St., SW., Washington,
DC 20460. Office location and telephone number: Rm. 1128C, CM
#2, 1921 Jefferson Davis Hwy., Arlington, VA 22202, (703)-305-
5232.
The pesticide is considered useful for the purpose for which
the tolerances and food/feed additive regulations are sought,
and the pesticide is
capable of achieving the intended physical
or technical effect. Existing meat and milk tolerances are adequate
to cover any secondary residues from the feed use of metalaxyl
in conjunction with proposed tolerances. Based on the information
and data considered, the Agency concludes that the establishment
of the tolerance for grapes, wet and dry grape pomace, raisins
and raisin waste will protect the public health, and use of
the pesticide in accordance with the terms of the prepared food
additive regulation will be safe. Therefore, the tolerance and
food/feed additive regulations are established as set forth
below.
Any person who has registered or submitted an application
for registration of a pesticide, under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA), as amended, which contains
any of the ingredients listed herein, may request within 30
days after publication of this document in the Federal Register
that the rulemaking proposal for a tolerance on grapes be referred
to an Advisory Committee in accordance with section 408(e) of
the Federal Food, Drug, and Cosmetic Act.
Interested persons are invited to submit written comments
on the proposed regulations. Comments must bear a notation indicating
the document control number, [PP 6F3362 and FAP 6H5493]. All
written comments filed in
response to this petition will be
available in the Public Docket and Freedom of Information Section,
at the address given above, from 8 a.m. to 4 p.m., Monday through
Friday, except legal holidays.
The Office of Management and Budget has exempted this rule
from the requirements of section 3 of Executive Order 12291.
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 food additive regulations or raising tolerance levels or
food additive regulations 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 (40 FR 24950).
The Office of Management and Budget has exempted this rule
from the requirement of section 3 of Executive Order 12291.
List of Subjects in 40 CFR Parts 180, 185, and 186
Administrative practice and procedures, Agriculture commodities,
Food additives, Feed additives, Pesticides and pests, Reporting
and recordkeeping
requirements
Dated: March 3, 1993.
Lawrence E. Culleen,
Acting Director, Registration Division, Office of Pesticide
Programs.
Therefore, it is proposed that chapter I of title 40 of the
Code of Federal Regulations be amended as follows:
PART 180-[AMENDED]
1. In part 180:
a. The authority citation for part 180 continues to read
as follows:
Authority: 21 U.S.C. 346a and 371.
b. Section 180.408(a) is amended in the table therein by
adding and alphabetically inserting a new entry for grapes,
to read as follows:
180.408 Metalaxyl; tolerances for residues.
(a) * * *
------------------------------------------------------------------------------
Commodity Parts per
million
------------------------------------------------------------------------------
* * * * *
Grapes......................................................... 2.0
* * * * *
------------------------------------------------------------------------------
2. In part 185:
a. The authority citation for part 185 continues to read
as follows:
Authority: 21 U.S.C. 348.
b. Section 185.4000(a) is amended in the table therein by
adding and alphabetically inserting the food additive raisins,
to read as follows:
185.4000 Metalaxyl.
(a) * * *
------------------------------------------------------------------------------
Food Parts per
million
------------------------------------------------------------------------------
* * * * *
Raisins........................................................ 6.0
* * * * *
------------------------------------------------------------------------------
* * * * *
PART 186-[AMENDED]
3. In part 186:
a. The authority citation for part 186 continues to read
as follows:
Authority: 21 U.S.C. 348.
b. Section 186.4000(a) is amended in the table therein by
adding and alphabetically inserting the feed commodities grape
pomace (dry and wet) and raisin waste, to read as follows:
186.4000 Metalaxyl.
(a) * * *
------------------------------------------------------------------------------
Food Parts per
million
------------------------------------------------------------------------------
* * * * *
Grape pomace (dry)............................................. 10.0
Grape pomace (wet)............................................. 10.0
* * * * *
Raisin waste................................................... 10.0
* * * * *
----------------------------------------------------
* * * * *
[FR Doc. 93-5498 Filed 3-9-93; 8:45 am]
BILLING CODE 6560-50-F
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