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Fenarimol; Pesticide Tolerance

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 [Federal Register: April 26, 1995]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[PP 3E4249/P613; FRL-4949-2]
RIN 2070-AC18
 
Fenarimol; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.

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SUMMARY: EPA proposes to establish a tolerance for the combined 
residues of the fungicide fenarimol in or on the imported raw 
agricultural commodity bananas at 0.5 part per million (ppm). Not more 
than 0.25 ppm shall be present in the pulp after the peel is removed. 
DowElanco petitioned for this regulation to establish a maximum 
permissible level for combined residues of the fungicide.

DATES: Comments, identified by the document control number [PP 3E4249/
P613], must be received on or before May 26, 1995.

ADDRESSES: By mail, submit written comments 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 a copy of the comments to Rm. 
1132, CM #2, 1921 Jefferson Davis Hwy., Arlington, VA 22202.
    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. 1132 at 
the address given above, from 8 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Connie B. Welch, 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; e-mail: 
welch.connie@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA is proposing to establish an import 
tolerance for the combined residues of the fungicide fenarimol, [alpha-
(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidinemethanol] and its 
metabolites [alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-1,4-dihydro-
5-pyrimidinemethanol and 5-(2-chlorophenyl)-(4-chlorophenyl)methyl]-
3,4-dihydro-4-pyrimidinol measured as the total of fenarimol and 5-[(2-
chlorophenyl)-(4-chlorophenyl)methyl]pyrimidine (calculated as 
fenarimol)], in or on the raw agricultural commodity bananas at 0.5 
part per million (ppm). Not more than 0.25 ppm shall be present in the 
pulp after the peel is removed. The proposed regulation to establish a 
maximum permissible level of the fungicide pursuant to section 408(e) 
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a, by 
amending 40 CFR 180.421 to include this commodity was requested in a 
pesticide petition, PP 3E4249, submitted by DowElanco, 9002 Purdue Rd., 
Indianapolis, IN 46268-1189. The scientific data submitted in the 
petition and other relevant material have been evaluated. The 
toxicological data considered in support of the proposed tolerance 
include the following:

    

  1.  A 1-year dog-feeding study using doses of 0, 1.25, 12.5, and 125 
milligrams/kilogram (mg/kg) body weight (bwt)/day. The no-observedeffects 
level (NOEL) is 12.5 mg/kg bwt/day. The 125 mg/kg bwt/day dose 
level caused increased serum alkaline phosphatase, increased liver 
weights, increased p-nitroanisole o-demethylase activity, and mild 
hepatic bile stasis.

  2.  An initial 2-year chronic feeding/oncogenicity study in rats 
using dietary concentrations of 0, 50, 130, and 350 ppm (equivalent to 
doses of 0, 2.5, 6.5, and 17.5 mg/kg bwt/day). In a Federal Register 
document published in the issue of March 5, 1986 (51 FR 7567), the 
Agency indicated fenarimol to be oncogenic. In that document, the 
Agency's initial conclusion that fenarimol was oncogenic was based on a 
finding in the 2-year rat study of a statistically significant increase 
in hepatic lesions (adenomas and [[Page 20472]] hyperplastic nodules) 
at the highest dose tested (17.5 mg/kg bwt/day), when data for male and 
female rats were combined.
    Since that time, the compound has been reevaluated. The Agency now 
considers it more appropriate to separate data for males and females 
and also to separate hyperplastic nodules from tumors (adenomas and 
carcinomas). When a reevaluation of the hepatic lesions for males and 
females was performed separately with the elimination of hyperplastic 
nodules, the data did not demonstrate a statistically significant 
increased incidence in adenomas and/or carcinomas in either sex. 
Moreover, the mouse oncogenicity study did not demonstrate oncogenic 
potential at dose levels up to and including a dose level of 85.7 mg/kg 
bwt/day (the highest dose level tested).
    Because of the appearance of a low incidence of fatty change of the 
liver (nonneoplastic pathological lesions) in the low-dose groups in 
this study, it was unclear if a NOEL for fatty change of the liver was 
established in this study.

  3.  Additional 2-year chronic feeding/oncogenicity studies in rats 
using dietary concentrations of 0, 12.5, 25, and 50 ppm (equivalent to 
doses of 0, 0.63, 1.25, and 2.5 mg/kg bwt/day). The purpose of these 
additional studies was to assist in determining a NOEL for fatty liver 
changes. The first of these two studies was compromised, however, by an 
outbreak of chronic respiratory disease which reduced survival in all 
experimental groups, including controls. The study was then repeated 
with the same dose levels. In the second study, no fatty liver changes 
or oncogenic effects were observed at the doses tested under the 
conditions of the study. Using data from all three 2-year studies, a 
NOEL for fatty liver change of 6.5 mg/kg bwt/day was established.

  4.  A 2-year oncogenicity study in mice using dietary concentrations 
of 0, 50, 170, and 600 ppm (equivalent to 0, 7, 24.3, and 85.7 mg/kg 
bwt/day) that was negative for oncogenic effects at all doses tested 
under the conditions of the study. At 600 ppm, an increase in fatty 
change of the liver was demonstrated. The NOEL for this effect was 170 
ppm (24.3 mg/kg bwt/day).

  5.  A rabbit teratology study that was negative for teratogenic 
effects at all doses tested (0, 5, 10, and 35 mg/kg).

  6.  A rat teratology study that demonstrated hydronephrosis at 35 
mg/kg (doses tested were 0, 5, 13, and 35 mg/kg). A second study in 
rats (with a postpartum evaluation) again demonstrated hydronephrosis 
at 35 mg/kg, but also indicated that the dose level of 35 mg/kg was 
associated with a maternal toxic effect (decreased body weight gain 
during treatment). The Agency considers the NOEL for hydronephrosis and 
for maternal toxicity to be 13 mg/kg.

  7.  A multigeneration reproduction study in rats that demonstrated 
decreased fertility in males and delayed parturition and dystocia in 
females at 5 mg/kg bwt/day. The NOEL for reproductive effects in this 
study was 2.5 mg/kg bwt/day.

  8.  Multigeneration reproduction studies in guinea pigs and mice 
that were negative for reproductive effects at doses up to 35 mg/kg 
bwt/day (highest dose tested) and 20 mg/kg bwt/day, respectively.

  9.  An aromatase inhibition study in rats that showed fenarimol to 
be a moderately weak inhibitor of aromatase activity.
    The adverse reproductive effects observed in the rat 
multigeneration reproduction study are considered to be a speciesspecific 
effect caused by aromatase inhibition. This enzyme promotes 
normal sexual behavior in rats and mice, but not in guinea pigs, 
primates, or man. A NOEL of 35 mg/kg bwt/day for reproductive effects 
relevant to humans was established in the multigeneration reproduction 
study in guinea pigs.

  10.  A mouse lymphoma forward mutation assay, a DNA repair synthesis 
study in rat liver culture systems, gene mutation assays in Salmonella 
typhimurium (Ames test) and Escherichia coli, a dominant-lethal assay 
in Wistar rats, an assay for transformation activity in the C3H/10T 1/2 
embryonic mouse fibroblast, and an in vivo assay for chromosome 
aberration in the Chinese hamster. Fenarimol did not demonstrate 
mutagenic activity in any of these studies. Furthermore, fenarimol did 
not induce altered foci or neoplastic nodules in an initiation and 
promotion study in rat liver tissue.
    Based on the above findings, the Agency concluded that fenarimol 
was not oncogenic in long-term studies in rats and mice under the test 
conditions in which the highest dose tested for both species approached 
a maximum-tolerated dose as evidenced by increased fatty change in the 
liver.
    The acceptable daily intake (ADI) based on the 2-year rat chronic 
feeding study (NOEL of 6.5 mg/kg bwt/day) with an uncertainty factor of 
100 is calculated to be 0.065 mg/kg bwt/day. The theoretical maximum 
residue contribution (TMRC) from previously established tolerances and 
the tolerance established here is 0.000431 mg/kg/day for the general 
population and utilizes 0.6612f the ADI. The percentage of the ADI for 
the most highly exposed subgroup, non-nursing infants (less than 1 year 
old), is 2.68The TMRC was calculated based on the assumption that 
fenarimol occurs at the maximum legal limit in all of the dietary 
commodities for which tolerances are proposed. Even with this probable 
large overestimate of exposure/risk, the TMRC is well below the ADI for 
the population as a whole and for each of the 22 subgroups considered. 
Thus, the dietary risk from exposure to fenarimol appears to be 
minimal.
    The nature of the residues is adequately understood, and adequate 
analytical methodology is available for enforcement. Prior to their 
publication in the Pesticide Analytical Manual, Vol. II, the 
enforcement methodology is being made available in the interim to 
anyone who is interested in pesticide enforcement when requested from: 
Calvin Furlow, Public Information Branch, Field Operations Division 
(7505C), Office of Pesticide Programs, Environmental Protection Agency, 
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 
tolerance is sought. 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 tolerances are 
established as set forth below. 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 these pesticides.
    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 this rulemaking proposal 
be referred to an Advisory Committee in accordance with section 408(e) 
of the FFDCA.
    Interested persons are invited to submit written comments on the 
proposed regulation. Comments must bear a notation indicating the 
document control number, [PP 3E4249/P613]. All written comments filed 
in response to this petition will be available in the Public Response 
and Program Resources Branch, at the address given above from 
[[Page 20473]] 8 a.m. to 4 p.m., Monday through Friday, except legal 
holidays.
    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: April 17, 1995.

Donald R. Stubbs,
Acting Director, Registration Division, Office of Pesticide Programs.

    Therefore, it is proposed that 40 CFR part 180 be 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. In Sec. 180.421(b) by revising the table therein, to read as 
follows:

Sec. 180.421   Fenarimol; tolerances for residues.
* * * *
    (b) *  *  *  
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             Commodity                        Parts per million         
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Bananas\1\.........................  0.5 (Not more than 0.25 ppm shall  
                                      be present in the pulp after peel 
                                      is removed)                       
Cherries...........................  1.0.                               
Grapes.............................  0.2.                               
                                                                        
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\1\There are no United States registrations for bananas as of April 26, 
  1995.                                                                 

[FR Doc. 95-10252 Filed 4-21-95; 2:56 pm]
BILLING CODE 6560-50-F

 
 

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