[Federal Register Volume 59, Number 211 (Wednesday, November 2, 1994)]
[Rules and Regulations]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-26799]


[[Page Unknown]]

[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 10-3 mg/kg bwt/day, which 
represents 8% of the RfD. The proposed use on leafy vegetables (except 
Brassica) group (except spinach) contributes an exposure of 4.7 x 
10-4 mg/kg bwt/day, representing less than 1% of the RfD. When the 
proposed exposure is added to the public exposure for metalaxyl the ARC 
is 6.9 x 10-3 mg/kg bwt/day, or 9% of the RfD.
    The subgroup most highly exposed, children (1 to 6 years old), has 
an ARC from existing uses of 1.2 x 10-2 mg/kg bwt/day, 
representing 16% of the RfD. The proposed use contributes an additional 
6.1 x 10-4 mg/kg bwt/day and raises the overall ARC 1.3 x 10-
2 mg/kg bwt/day, still representing 16% of 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