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Cyproconazole - Pesticide Tolerance 8/95

[Federal Register: August 9, 1995 (Volume 60, Number 153)] [Proposed Rules]
[Page 40545-40548]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]

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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[PP 0E3875/P623; FRL-4967-7]
RIN 2070-AC18
Cyproconazole; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.

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SUMMARY: EPA proposes to establish a time-limited tolerance for the residues
of the fungicide cyproconazole, (2RS,3RS)-2-(4-chlorophenyl)- 3-cyclopropyl-1-
(1H-1,2,4-triazole-1-yl)butan-2-ol, in or on the imported raw agricultural
commodity coffee beans at 0.1 part per million (ppm). Sandoz Agro, Inc.,
petitioned pursuant to the Federal Food, Drug and Cosmetic Act (FFDCA) for
this regulation to establish a maximum permissible level for residues of the
fungicide.

DATES: Comments, identified by the document control number [PP 0E3875/ P623],
must be received on or before September 8, 1995.

ADDRESSES: By mail, submit written comments to: Public Response and Program
Resource 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 notice 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 4:30 p.m., Monday through Friday,
excluding legal holidays.

Comments and data may also be submitted electronically by sending electronic
mail (e-mail) to: opp-docket@epamail.epa.gov.
Electronic comments must be submitted as an ASCII
file avoiding the use of special characters and any form of encryption.
Comments and data will also be accepted on disks in WordPerfect in 5.1 file
format or ASCII file format. All comments and data in electronic form must be
identified by the docket number, [PP 0E3875/P623]. No Confidential Business
Information (CBI) should be submitted through e-mail. Electronic comments on
this proposed rule may be filed online at many Federal Depository Libraries.
Additional information on electronic submissions can be found below in this
document.

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 residues of the fungicide cyproconazole, (2RS,3RS)-2- (4-
chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazole-1-yl)butan-2-ol, in or on the
raw agricultural commodity coffee beans at 0.1 part per million (ppm). 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 part 180 to include this commodity
was requested in a pesticide petition (PP 0E3875) submitted by Sandoz Agro,
Inc., 1300 East Touhy Ave., Des Plaines, IL 60018. 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 90-day rat study, in which the levels tested in Han Wistar strain rats
were 0, 20, 80, and 320 ppm (0, 1, 4, and 16 mg/kg). Cyproconazole inhibited
body weight gain, increased blood sodium, increased liver weights, and
produced histological changes in the liver at the high dose. Increased blood
creatinine and decreased calcium levels were observed at the high and low
dose, but not at the mid-dose. Effects were reversed after cessation of dosing
and a 4-week recovery period. Since these changes were not observed after the
recovery period they were considered treatment related. A NOEL for this study
was therefore not attained, but the NOEL would be less than 1.0 mg/kg.

2. A 13-week feeding study in dogs treated at 0, 20, 100, and 500 ppm yielded
a NOEL of 20 ppm (0.8 mg/kg/day) and an LEL of 100 ppm (4 mg/kg/day). At the
high dose, treatment-related changes included slack muscle tone, depressed
body weight gain, and decreases in bilirubin, total cholesterol, HDL-
cholesterol, triglycerides, total protein, and albumin. There were increases
in platelet counts, alkaline phosphatase, gamma glutamyl transferase, absolute
and relative liver weights, relative kidney weights, and relative brain
weights. Liver toxicity was indicated by hepatomegaly.

3. A 21-day dermal study, in which levels tested in New Zealand white rabbits
were 50, 250, and 1,250 mg/kg. The NOEL was 250 mg/kg and the LEL was 1,250
mg/kg. Effects included depressed body weight gain and food consumption and
increased levels of AST, creatinine, and cholesterol.

4. A 1-year dog study. When dogs were fed a diet containing cyproconazole at
levels of 0, 30, 100, or 350 ppm for one year, a NOEL of 30 ppm (1.0
mg/kg/day) and an LEL of 100 ppm (3.2 mg/kg/day) were attained. Several
clinical laboratory parameters indicated a difference between the control and
treated animals which was consistent with liver effects. Laminal eosinophilic
intrahepatocytic bodies were observed in all males and two females at the high
dose, and in one male at the mid- level dose. These changes were thought to
represent adaptive hypertrophy of the endoplasmic reticulum. Relative kidney
weights were increased in low- and high-dose females; cytochrome P450 was
significantly increased in males and females at 350 ppm and females at 100 ppm.

5. A mouse carcinogenicity study in which cyproconazole at levels of 0, 15,
100, or 200 ppm added to the diet of CD-1 mice for 81 weeks (males) and 88
weeks (females) resulted in a NOEL for systemic toxicity of 15 ppm (1.8 mg/kg
for males and 2.6 mg/kg for females). The LEL was 100 ppm (13.2 mg/kg for
males and 17.7 mg/kg for females) based on a significantly increased incidence
of hepatic single cell necrosis and diffuse hepatocytic hypertrophy at the two
highest levels. The effect was more severe in males than females. There was a
decreased amount of testicular germinal epithelium in males at the high dose
which corresponded to an increased incidence of flaccid testes. There was an
increased incidence of liver adenomas and carcinomas in both sexes.

6. A rat chronic/carcinogenicity study in which cyproconazole fed to KFM
Wistar (HAN Wistar origin) rats (males for 118 weeks, females for 121 weeks)
at 0, 20, 50, or 350 ppm (males: 1.0, 2.2, and 15.6 mg/ kg; females: 1.2, 2.7,
and 21.8 mg/kg) resulted in slightly decreased body weights in the high-dose
females and increased incidence of fatty infiltration of the liver in the
high-dose males. The NOEL for systemic toxicity was 50 ppm. The LEL was 350
ppm. It was determined that the dose levels were inadequate for the assessment
of the carcinogenic potential of cyproconazole in the rat. The HED
Carcinogenicity Peer Review Committee recommended that this phase of the study
be repeated. The committee classified cyproconazole as a quantitated Group
B2 carcinogen with a Q1* of 0.30 (mg/kg/day)-1 based on the absence of
an adequate carcinogenicity study in rats and the structural relationship of
cyproconazole to closely related analogues shown to have carcinogenic activity.

7. A rat developmental toxicity study in which cyproconazole (95.6% purity)
was administered as a suspension by gavage to sperm-positive Wistar/HAN female
rats at dose levels of 0, 6, 12, 24, or 48 mg/kg on days 6 through 15 of
gestation. The NOEL for maternal toxicity was 6 mg/kg, and the LEL was 12
mg/kg based on decreased body weight gain during dosing. The NOEL for
developmental toxicity was 6 mg/kg. The LEL was 12 mg/kg based on the
increased incidence of supernumerary ribs.

8. A chinchilla rabbit developmental toxicity study in which cyproconazole
(95.6% purity) was administered by gavage to 16 Chinchilla rabbits on days 6
through 18 of gestation at 0, 2, 10, or 50 mg/kg. The NOEL for maternal
toxicity was 10 mg/kg (equivocal). The LEL was 50 mg/kg based on decreased
body weight gain during dosing. Developmental effects were also evaluated.
Hydrocephalus internus was observed in 1 fetus at each treatment level.
Therefore, the NOEL for developmental toxicity was set at less than 2 mg/kg,
and the LEL was 2 mg/kg. The incidence was 0.85, 0.83, and 0.93 for the low-,
mid-, and high-dose fetuses and 0.08 for the historical control.

9. A New Zealand white rabbit developmental toxicity study in which
cyproconazole (94.8% purity) was administered by gavage to 18 inseminated New
Zealand White rabbits once daily on days 6 through 18 of gestation at dose
levels of 2, 10, or 50 mg/kg. The NOEL for maternal toxicity was 10 mg/kg, and
the LEL was 50 mg/kg based on decreased body weight gain. There was also
evidence of developmental toxicity. The NOEL for developmental toxicity was 2
mg/kg, and the LEL was 10 mg/kg based on the increased incidence of malformed
fetuses and litters with malformed fetuses.

10. A rat two-generation reproduction study in which technical cyproconazole
(95.6% purity) was administered to 26 male and 26 female F0 and
F1 KFM-Wistar rats per group for 10 and 12 weeks, respectively,
during the pre-mating period via the diet at 0, 4, 20, or 120 ppm. Treatment
of males continued for 3 weeks after termination of mating and females were
treated until necropsy (post-weaning). The systemic NOEL for parental toxicity
was set at 20 ppm (1.7 mg/kg) based on liver effects at 10.6 mg/kg/day. For
reproductive toxicity, the NOEL was set at 4 ppm (0.4 mg/kg) and the LEL at 20
ppm (1.7 mg/kg) based on increased gestation length in the F0 dams
and decreased F1 litter sizes.

11. Several mutagenicity studies. Mutagenicity potential of cyproconazole was
tested in several studies considered acceptable by the Agency. Since the
results of two chromosomal aberration assays indicated the cyproconazole is
clastogenic, additional mutagenicity data were requested to address an
identified heritable risk concern. For the potential to induce chromosome
aberrations in CHO cells, cyproconazole was positive under nonactivated and
activated conditions, thus supporting the evidence that cyproconazole is
clastogenic in this test system. Cyproconazole was negative in Salmonella,
mouse micronucleus, and SHE/cell transformation assays. A dominant-lethal
assay in rats was submitted and was negative. Based on this evidence, the
concern for a possible heritable effect was not pursued.

12. Metabolism/pharmacokinetics studies. Cyproconazole was shown to be
extensively metabolized in the rat. Unchanged cyproconazole and 13 metabolites
were isolated and identified, and 35 metabolites were detected in the excreta.
Excretion was relatively rapid with the majority of the radioactivity
appearing in the feces as a result of biliary elimination. Residues were found
in renal fat, adrenals, kidney and liver, although no significant tissue
radioactivity was observed at 168 hours post-dose.

The reference dose (RfD) used in the dietary exposure analysis was 0.01 mg/kg
bwt/day based on a NOEL of 30.0 ppm (1.00 mg/kg bwt/day) from a 1-year dog
feeding study with an uncertainty factor of 100 that demonstrated
hepatotoxicity and organ weight changes observed at 3.2 mg/kg/day. The
theoretical maximum residue contribution (TMRC) for the general population is
0.000002 mg/kg/day and for females, 20 years old and older, the TMRC is
0.000003 mg/kg/day. The anticipated residue contributions (ARC) as percentages
of the RfD are 0.018 and 0.028% for the general population and females 20
years old or older, respectively. The chronic analysis for cyproconazole is
not a worst-case estimate of dietary exposure, with all residues at
anticipated levels and 100% of the commodities assumed to be treated with
cyproconazole. Based on the risk estimates calculated in this analysis, it
appears that chronic dietary risk from the use recommended is not of concern.
The upper-bound cancer risk, based on a Q1* of 0.30 (mg/kg/day)**-1, was
calculated to be 5.3 x 10**-7, contributed
through the proposed use of cyproconazole in the production of imported coffee
beans. The carcinogenic analysis demonstrates that, using the proposed
anticipated residues and without percent crop treated information incorporated
into the analysis, the use on coffee does not result in a risk estimate
exceeding the Agency's value for negligible cancer risk of 10**-6.
The nature of the residue in coffee is not fully understood. A metabolism
study in coffee, using triazole-labeled cyproconazole, was submitted and was
acceptable. Cyproconazole per se was the primary component of the residue. A
metabolism study in wheat is being conducted to determine the fate of the
phenyl portion of cyproconazole in plants. Preliminary results of the study
have been submitted. It is the Agency's conclusion that the results of this
study will not significantly alter the risk evaluation for cyproconazole and,
therefore, establishing a time-limited tolerance for coffee beans would not
pose any significant dietary risk to the public during the timeframe involved
in completing and reviewing the wheat metabolism data on this chemical.
Adequate analytical methodology is available for enforcement. However,
additional data are required to demonstrate that residues of several other
pesticides registered for use on coffee do not interfere with the method.

Prior to 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 Response and Program Resource Branch, Field Operations Division
(7506C), Office of Pesticide Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. Office location and telephone number: Rm.
1130A, CM #2, 1921 Jefferson Davis Hwy., Arlington, VA 22202, (703)-305-5937.
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 notice 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 0E3875/P623]. 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 8 a.m. to 4:30 p.m., Monday through
Friday, except legal holidays.

A record has been established for this rulemaking under docket number
[PP0E3875/P623] (including comments and data submitted electronically as
described below). A public version of this record, including printed, paper
versions of electronic comments, which does not include any information
claimed as CBI, is available for inspection from 8 a.m. to 4:30 p.m., Monday
through Friday, excluding legal holidays. The public record is located in Room
1132 of the Public Response and Program Resources Branch, Field Operations
Division (7506C), Office of Pesticide Programs, Environmental Protection
Agency, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments can be sent directly to EPA at:
opp-Docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption.

The official record for this rulemaking, as well as the public version, as
described above will be kept in paper form. Accordingly, EPA will transfer all
comments received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which will
also include all comments submitted directly in writing. The official
rulemaking record is the paper record maintained at the address in ADDRESSES
at the beginning of this document.

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: July 27, 1995.

Stephen L. Johnson,
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. By adding new Sec. 180.485, to read as follows:

Sec. 180.485 Cyproconazole; tolerances for residues.

A time-limited tolerance is established for the residues of the fungicide
cyproconazole, (2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1- (1H-1,2,4-
triazole-1-yl)butan-2-ol, in or on the following imported raw agricultural
commodity:

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Parts per
Commodity                  million                    Expiration date
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Coffee beans 1\              0.1                       July 1, 1997

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1\ There are no U.S. registrations as of August 9, 1995 for use on coffee
beans.

[FR Doc. 95-19531 Filed 8-8-95; 8:45 am] BILLING CODE 6560-50-F