[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: 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
[[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-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:
----------------------------------------------------------------------------------------------------------------
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
