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procymidone (Sumilex) Proposed Tolerance 3/94

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 MUg/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:   

sec180.455  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]