[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
