[Federal Register Volume 60, Number 153 (Wednesday, August 9, 1995)]
[Proposed Rules]
[Pages 40545-40548]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-19531]



=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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., 

[[Page 40546]]
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: [email protected]. 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: 
[email protected].
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 

[[Page 40547]]
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 [PP 

[[Page 40548]]
0E3875/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-D[email protected]


    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:

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