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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