[Federal Register Volume 59, Number 62 (Thursday, March 31, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-7848]


[[Page Unknown]]

[Federal Register: March 31, 1994]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[PP 0E3859/R2053; FRL-4772-7]

 

Proposed Pesticide Tolerance for Procymidone

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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SUMMARY: This document proposes to establish a tolerance for residues 
of the fungicide procymidone, N-(3,5-dichlorophenyl)1,2-
dimethylcyclopropane-1,2-dicarboximide, in or on the raw agricultural 
commodity (RAC) wine grapes at 5.0 parts per million (ppm). This 
regulation to establish the maximum permissible level for residues of 
procymidone in or on wine grapes was requested in a petition submitted 
by Sumitomo Chemical Co., Ltd.

DATES: Comments, identified by the document control number, [PP 0E3859/
R2053], must be received on or before April 30, 1994.

ADDRESSES: By mail, submit written comments to: Public Document and 
Freedom of Information Section, Field Operations Division (7506C), 
Office of Pesticide Programs, 401 M St., SW., Washington, DC 20460. In 
person, bring comments to: Rm. 1128, CM #2, 1921 Jefferson Davis 
Highway. 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 Room. 1128 
at the Virginia address given above, from 8 a.m. to 4 p.m., Monday 
through Friday, excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Sidney C. Jackson, Acting 
Product Manager (PM) 21, Registration Division (7505C), Environmental 
Protection Agency, 401 M St., SW., Washington DC 20460. Office location 
and telephone number: Rm. 227, CM #2, 1921 Jefferson Davis Highway., 
Arlington, VA 22202, (703) 305-6900

SUPPLEMENTARY INFORMATION: In the Federal Register of September 25, 
1990 (55 FR 39171), EPA issued an advanced notice of proposed 
rulemaking (ANPR) to solicit comment on its consideration of Sumitomo's 
petition to establish under section 408 of the Federal, Food, Drug and 
Cosmetic Act, 21 U.S.C. 346a, a tolerance of 5 ppm for residues of the 
fungicide procymidone on grapes and to establish immediately an interim 
tolerance of 7 ppm to last 1 year. The Agency issued this ANPR to (1) 
give its preliminary assessment of the risk posed by procymidone 
residues in imported wine, (2) set out its options for a decision, and 
(3) request public comment on key scientific and policy questions 
raised by this petition for tolerance. After considering the comments 
received on the ANPR and after further review of the data submitted by 
Sumitomo, EPA issued a proposed rule in the Federal Register of 
February 6, 1991 (56 FR 4772), giving notice that Sumitomo Chemical 
Co.,Ltd., had submitted a pesticide petition, PP 0E3859, under section 
408(e) of the Federal Food, Drug and Cosmetic Act (FFDCA) (21 U.S.C. 
301 et seq.). This document proposed to establish a time-limited 
tolerance for procymidone in wine grapes grown prior to January 1, 1990 
at 7 ppm. In the Federal Register of February 20, 1991 (56 FR 6821), 
EPA reissued the proposed rule in its entirety to include certain 
statements in the proposed rule document that were inadvertently 
omitted in the February 6, 1991 issuance. EPA addressed 17 comments 
received in response to the second proposed rule in its final rule that 
established a time-limited tolerance for procymidone in or on wine 
grapes at 7.0 ppm (56 FR 19518, published April 26, 1991). This 
tolerance has two conditions placed on it: (1) The tolerance will only 
be effective for 4 years, and (2) the tolerance will only apply to wine 
grapes grown in 1989 or before. Since then Sumitomo has requested that 
the Administrator, pursuant to section 408 (e) of the FFDCA, amend the 
pesticide petition to remove the restriction which allows use only on 
wine grapes grown before 1990 and to remove the expiration date (April 
1995) for the tolerance.
    This document proposes to establish a permanent tolerance for 
procymidone in or on wine grapes at 5.0 ppm.
    The data submitted in support of this petition and all other 
relevant material have been evaluated. The toxicology data considered 
in support of the tolerance include the following:
    1. A chronic feeding and carcinogenicity study in rats. A chronic 
feeding and carcinogenicity study in rats fed 0, 100, 300, 1,000, and 
2,000 ppm in the diet for 104 weeks displayed a dose-related increase 
in the incidence of testicular interstitial cell tumors and hyperplasia 
at dose levels of 1,000 and 2,000 ppm, a dose-related increase in 
pituitary adenomas in females at dose of 1,000 and 2,000 ppm, an 
increased incidence of ovarian stromal hyperplasia at 2,000 ppm, 
hepatic cytomegaly at 1,000 and 2,000 ppm (both sexes). Systemic 
toxicity was noted at 300 ppm and above in the form of increased liver 
weights and decreased body weight gains. The No observed effect level 
(NOEL) was set at 100 ppm (5 mg/kg), and the Lowest effect level (LEL) 
at 300 ppm (15 mg/kg) based on body weight/liver effects and the low 
numbers of animals at these dose levels at study termination.
    2. A carcinogenicity study in mice. A carcinogenicity study in mice 
fed 0, 30, 100, 300 and 1,000 ppm in the diet showed no significant 
compound or dose related effects for survival, body weights/body weight 
gains, food and water consumption or ophthalmological changes in either 
sex. Consistent dose related increases in liver weights were seen in 
both sexes. Liver cytomegaly was observed in both sexes at the highest 
dose tested and increases in multifocal fatty liver changes in males 
and diffuse fatty liver changes in females were displayed at the 
highest dose tested. Dose-related liver cytologic alterations were also 
noted in males at the 52-week interim sacrifice. Hepatocellular 
adenomas and combined hepatocellular adenomas/carcinomas were increased 
in female mice. Hepatoblastomas, a rare variant of hepatocellular 
carcinoma was increased in male mice.
    3. A developmental toxicity study in rats by oral gavage at dose 
levels of 0, 3.5, 12.5, 125 and 500 mg/kg/day. Maternal toxicity was 
observed at 125 mg/kg/day and above as increased clinical observations, 
lower body weight gain, decreased food consumption and efficiency. 
Developmental toxicity was noted at 12.5 mg/kg/day and above as reduced 
anogenital distance in males. Reproductive toxicity was at 12.5 mg/kg/
day and above as decreased anogenital distance in the male pups at 
postpartum day 1 and 21, an increase in the number of male rats with 
undescended testes, increased incidences of hypospadias with severity 
of the hypospadias increased with increasing dose, distended preputial 
gland, decreased testis and prostate weights. Female pups were 
relatively unaffected. Maternal NOEL = 12.5 mg/kg/day; Maternal LOEL = 
125 mg/kg/day; Developmental Toxicity NOEL = 3.5 mg/kg/day; 
Developmental LOEL = 12.5 mg/kg/day; Reproductive Toxicity NOEL = 12.5 
mg/kg/day; Reproductive LOEL = 125 mg/kg/day.
    4.  A developmental toxicity study in rabbits with dose levels at 
0, 30, 150, 750 and 1,000 mg/kg/day. No treatment related effects were 
noted on maternal or developmental toxicity up to and including the 
highest dose tested (limit dose). Maternal NOEL > 1,000 mg/kg/day; 
Developmental Toxicity NOEL > 1,000 mg/kg/day.
    5. A 12 month chronic study in dogs with dose levels at 0, 20, 100, 
and 500 mg/kg/day. There was no indication of toxicity at any dose 
level, therefore the NOEL for both sexes was 500 mg/kg/day (highest 
dose tested); a LOEL was not established.
    6. A reproductive toxicity study in rats with dose levels at 0, 50 
ppm (= 2.5 mg/kg), 250 ppm (= 12.5 mg/kg) and 750 ppm (= 37.5 mg/kg). 
Systemic toxicity was observed in adults and pups at 250 ppm and above 
in the form of decreased body weight gain and food consumption, 
increased absolute and relative liver weights in the males, testes 
weights and combined and adjusted testes volume, along with decreases 
in pup prostate and epididymal absolute and relative weights. There was 
evidence of macroscopic and microscopic changes in the liver and male 
external genitalia. The abnormalities of the external genitalia 
included reduced anogenital distance and hypospadias. Reproductive NOEL 
= 250 ppm; Reproductive LOEL = 750 ppm based on reduced fertility in 
males with developmental toxicity in the form of changes in external 
genitalia.
    7. A Mutagenic-Ames study. A Mutagenic-Ames study on Salmonella 
concluded that procymidone is non-mutagenic in these assays.
    8. A Mutagenic Chromosomal Aberration in vitro study. A Mutagenic 
Chromosomal Aberration in vitro study concluded that neither activated 
nor nonactivated doses was clastogenic.
    9. A Mutagenic Unscheduled DNA Synthesis study. A Mutagenic 
Unscheduled DNA Synthesis study in rat hepatocytes concluded that the 
test material was negative in this assay at doses from 3 to 300 
g/ml.
    10.  Metabolism study in rats. Excretion of procymidone derived 
radioactivity was relatively rapid at the single low oral dose and 
repeated low oral dose levels, with the urine as the major route of 
excretion. The rate of urinary excretion was decreased at the 250 mg/kg 
oral dose level. The percentage of unchanged procymidone found within 
feces was increased at the 250 mg/kg dose level in both sexes, 
supporting the idea of decreased adsorption at this dose. Highest 
concentrations of procymidone derived radioactivity at sacrifice were 
found within the liver, residual carcass, kidney, urogenital fat, 
epididymides, blood and lymph node of both male and female rats at the 
250 mg/kg dose only. The amount of procymidone derived radioactivity 
found in urogenital fat was approximately 4 times higher in female than 
in male rats. Repeated oral dosing or a single high dose of 250 mg/kg 
did not significantly affect the disposition or metabolic profile of 
procymidone. Identification of urinary and fecal metabolites showed 
several oxidative metabolites of procymidone as well as minor amounts 
of hydroxyprocymidone glucuronide and dichloroaniline glucuronide. In 
feces, unmetabolized procymidone accounted for most of the 
radioactivity and small amounts of 4-hydroxyprocymidone, a novel 
metabolite not found in urine, was present also. The metabolic profile 
in urine was not significantly affected by repeated oral dosing or 
single high dosing of procymidone.
    Procymidone has been classified by the HED Carcinogenicity Peer 
Review Committee (CPRC) as a B2 carcinogen. The B2 classification was 
based on the statistically significant increasing trend and pair-wise 
increase in interstitial cell adenomas in male rats, pituitary adenomas 
in female rats and liver adenomas and combined adenomas/carcinomas in 
female mice. Additionally, a rare variant of hepatocellular carcinoma, 
hepatoblastoma, had a significantly increasing trend in male mice. For 
the purpose of risk characterization, a low dose extrapolation model 
applied to the experimental animal tumor data was overwhelmingly 
recommended for quantification of human risk. The Federal Insecticide, 
Fungicide, and Rodenticide Act Scientific Advisory Panel (FIFRA SAP) 
reviewed HED's assessment of the weight of the evidence for the 
carcinogenic potential of procymidone. The SAP cited only the 
testicular tumors seen in the chronic rat study as support for a group 
C classification. CPRC considered SAP's evaluation and reaffirmed its 
original conclusion that the increased incidence of hepatocellular 
adenomas in female mice was treatment-related and quantification of 
risk was recommended again for testicular tumors in males and liver 
tumors in females.
    The developmental and reproductive toxicity data submitted in 
support of the import tolerance on procymidone was also reviewed by the 
HED Developmental Peer Review Committee. The Committee concluded that 
developmental toxicity was induced in rats via the oral route of 
administration. The NOEL for developmental toxicity by the oral route 
in rats was 3.5 mg/kg/day. The NOEL for reproductive toxicity by the 
oral route in rats was 12.5 mg/kg/day. Maternal toxicity by the oral 
route was noted at 125 mg/kg/day and above. Developmental and maternal 
toxicity was not observed in rabbits by the oral route up to and 
including the highest dose tested (1,000 mg/kg/day). The NOEL for 
maternal toxicity by the oral route in the reproduction study was 50 
ppm (2.5 mg/kg). It was recommended that the NOEL for developmental 
toxicity, 3.5 mg/kg/day, in the oral rat developmental study be used 
for assessment of acute dietary risk.
    The RfD/Peer Review Committee recommended that a reference dose 
(RfD) be established based on a NOEL of 3.5 mg/kg/day based on the 
results of the rat developmental study. An uncertainty factor of 100 
was recommended to account for the inter-species extrapolation and 
intra-species variability. Therefore, the RfD was calculated to be 
0.035 mg/kg/day.
    The nature of the residue is adequately understood and adequate 
analytical methods are available. Procymidone residues can be 
quantified by FDA multiresidue methods. These methods are available in 
the Pesticide Analytical Manual Volume I for enforcement purposes.
    The U.S. population may potentially be exposed to procymidone and 
its potentially toxic metabolite DCA as a result of residues being 
present in imported wine. The upper bound carcinogenic risk is 
estimated to be 4.0  x  10-6 for a high consumer (daily 
consumption of 8 oz wine) and 3.8  x  10-7 for an average consumer 
(consumption of 4 oz of wine every 5.3 days. This risk assessment 
assumed that use of procymidone would result in residues of 2.4 ppm of 
procymidone and DCA in wine. The risk assessment took into account that 
only imported wine could contain procymidone and DCA and that only a 
portion of imported wine was manufactured from procymidone treated 
grapes. The percent RfD utilized by high consumers would be 0.7 
percent, and 0.06 percent by low consumers. The margin of safety (MOS) 
for developmental effects, assuming high consumption only, would be 
370. A MOS of 100 is typically acceptable.
    It is expected that actual residues of procymidone and DCA in wine 
will be present at levels much lower than 2.4 ppm as used in the risk 
estimates, based on available Food and Drug Administration monitoring 
data. Therefore, the risk estimates provided here adequately consider 
the toxicity of both procymidone and DCA.
    The pesticide is considered useful for the purposes for which the 
tolerance is sought. Based on the above information considered by the 
Agency, the tolerance established by amending 40 CFR part 180 would 
protect the public health. Therefore, it is proposed that the tolerance 
be established as set forth below.
    Any person who has registered or submitted an application for 
registration of a pesticide under FIFRA, as amended, which contains any 
of the ingredients listed herein, may request within 30 calendar days 
after publication of this document in the Federal Register that this 
rulemaking proposal be referred to an Advisory Committee in accordance 
with FFDCA section 408(e).
    Interested persons are invited to submit written comments on the 
proposed regulation. Comments must bear a notation indicating the 
document control number, [PP 0E3859/R2053]. 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.
    Under Executive Order 12866 (58 FR 51735, October 4, 1993), the 
Agency must determine whether the regulatory action is ``significant'' 
and therefore subject to review by the Office of Management and Budget 
(OMB)). Under section 3(f), the order defines ``significant regulatory 
action'' as action that is likely to result in 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 referred to 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.
    The Office of Management and Budget has exempted this rule from 
review under section 3 of Executive Order 12866.
    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 
tolerances 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 pest, Reporting and 
recordkeeping requirements.

    Dated: March 28, 1994.

Stephen L. Johnson,
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. Section 180.455 is amended by revising the table therein to read 
as follows:


Sec. 180.455  Procymidone; tolerances for residues.

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                   Commodity                        Parts Per Million   
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Wine grapes....................................                     5.0 
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[FR Doc. 94-7848 Filed 3-29-94; 3:12 pm]
BILLING CODE 6560-50-F