[Federal Register Volume 63, Number 194 (Wednesday, October 7, 1998)]
[Rules and Regulations]
[Pages 53829-53835]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-26904]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-300742; FRL-6036-9]
RIN 2070-AB78


Cyproconazole; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes a permanent tolerance for residues 
of cyproconazole, (2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-
1,2,4-triazole-1-yl)butan-2-ol in or on coffee, bean, green. Novartis 
Crop Protection, Inc. requested this tolerance under the Federal Food, 
Drug and Cosmetic Act (FFDCA), as amended by the Food Quality 
Protection Act (FQPA) of 1996 (Pub. L. 104-170).

DATES: This regulation is effective October 7, 1998. Objections and 
requests for hearings must be received by EPA on or before December 7, 
1998.

ADDRESSES: Written objections and hearing requests, identified by the 
docket control number, OPP-300742, must be submitted to: Hearing Clerk 
(1900), Environmental Protection Agency, Rm. M3708, 401 M St., SW., 
Washington, DC 20460. Fees accompanying objections and hearing requests 
shall be labeled ``Tolerance Petition Fees'' and forwarded to: EPA 
Headquarters Accounting Operations Branch, OPP (Tolerance Fees), P.O. 
Box 360277M, Pittsburgh, PA 15251. A copy of any objections and hearing 
requests filed with the Hearing Clerk identified by the docket control 
number, OPP-300742, must also be submitted to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticide Programs, Environmental Protection Agency, 
401 M St., SW., Washington, DC 20460. In person, bring a copy of 
objections and hearing requests to Rm. 119, Crystal Mall 2 (CM #2), 
1921 Jefferson Davis Hwy., Arlington, VA.
    A copy of objections and hearing requests filed with the Hearing 
Clerk may also be submitted electronically by sending electronic mail 
(e-mail) to: [email protected]. Copies of objections and 
hearing requests must be submitted as an ASCII file avoiding the use of 
special characters and any form of encryption. Copies of objections and 
hearing requests will also be accepted on disks in WordPerfect 5.1/6.1 
file format or ASCII file format. All copies of objections and hearing 
requests in electronic form must be identified by the docket control 
number [OPP-300742]. No Confidential Business Information (CBI) should 
be submitted through e-mail. Electronic copies of objections and 
hearing requests on this rule may be filed online at many Federal 
Depository Libraries.

FOR FURTHER INFORMATION CONTACT: By mail: Mary L. Waller, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St., SW., Washington, DC 20460. Office 
location, telephone number, and e-mail address: CM #2, 1921 Jefferson 
Davis Hwy., Arlington, VA, (703) 308-9354, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION: In the Federal Register of July 2, 1997 (62 
FR 35804)(FRL-5722-9), EPA, issued a notice pursuant to section 408 of 
the FFDCA, 21 U.S.C. 346a(e) announcing the filing of a pesticide 
petition (PP) 0E3875 for a tolerance by Novartis Crop Protection, Inc., 
P.O. Box 18300, Greensboro, NC 27419. This notice included a summary of 
the petition prepared by Norvartis Crop Protection, Inc., the 
registrant. There were no comments received in response to the notice 
of filing.
    The petition requested that 40 CFR 180.485 be amended by 
establishing a permanent tolerance for 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 coffee, bean, green at 0.1 part per 
million (ppm). A time-limited tolerance for cyproconazole in or on 
coffee beans was established with an expiration date of July 1, 1997 in 
the Federal Register of September 27, 1995 (60 FR 49795)(FRL-4976-5). 
This rule will establish a permanent tolerance.

I. Risk Assessment and Statutory Findings

    Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a 
tolerance (the legal limit for a pesticide chemical residue in or on a 
food) only if EPA determines that the tolerance is ``safe.'' Section 
408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable 
certainty that no harm will result from aggregate exposure to the 
pesticide chemical residue, including all anticipated dietary exposures 
and all other exposures for which there is

[[Page 53830]]

reliable information.'' This includes exposure through drinking water 
and in residential settings, but does not include occupational 
exposure. Section 408(b)(2)(C) requires EPA to give special 
consideration to exposure of infants and children to the pesticide 
chemical residue in establishing a tolerance and to ``ensure that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to the pesticide chemical residue. . . 
.''
    EPA performs a number of analyses to determine the risks from 
aggregate exposure to pesticide residues. For further discussion of the 
regulatory requirements of section 408 and a complete description of 
the risk assessment process, see the Final Rule on Bifenthrin Pesticide 
Tolerances published in the Federal Register of November 26, 1997 (62 
FR 62961)(FRL-5754-7).

II. Aggregate Risk Assessment and Determination of Safety

    Consistent with section 408(b)(2)(D), EPA has reviewed the 
available scientific data and other relevant information in support of 
this action. EPA has sufficient data to assess the hazards of 
cyproconazole and to make a determination on aggregate exposure, 
consistent with section 408(b)(2), for a tolerance for residues of 
cyproconazole, (2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-
triazole-1-yl)butan-2-ol on coffee, bean, green at 0.1 ppm. EPA's 
assessment of the dietary exposures and risks associated with 
establishing the tolerance follows.

A. Toxicological Profile

    EPA has evaluated the available toxicity data and considered its 
validity, completeness, and reliability as well as the relationship of 
the results of the studies to human risk. EPA has also considered 
available information concerning the variability of the sensitivities 
of major identifiable subgroups of consumers, including infants and 
children. The nature of the toxic effects caused by cyproconazole is 
discussed below.
    1. Acute studies. Acute studies indicate that the technical grade 
of cyproconazole is in Toxicity Category III for acute oral, acute 
dermal and acute inhalation and in Toxicity Category IV for dermal 
irritation and eye irritation. There was no dermal sensitization.
    2. Subchronic toxicity testing. i. A 90-day rat study, was 
conducted in which the levels of cyproconazole (95.7% purity) tested 
were 0, 20, 80, and 320 ppm (0, 1, 4, and 16 mg/kg/day). 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 four week recovery 
period. Since these changes were not observed after the recovery 
period, they were considered treatment related. A No Observed Adverse 
Effects Level (NOAEL) for this study was therefore not attained but the 
NOAEL would be <1.0 mg/kg/day.
    ii. A 13-week feeding study was conducted with dogs treated at 0, 
20, 100, and 500 ppm cyproconazole (95.6% purity) in which the NOAEL 
was 20 ppm (0.8 mg/kg/day) and the Lowest Observed Adverse Effect Level 
(LOAEL) was 100 ppm (4 mg/kg/day) based on adverse liver effects. 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.
    iii. A 21-day dermal study was conducted, in which levels of 
cyproconazole (95.6% purity) tested in New Zealand white rabbits were 
50, 250, and 1,250 mg/kg. The NOAEL was 250 mg/kg and the LOAEL was 
1,250 mg/kg. Effects included depressed body weight gain and food 
consumption and increased levels of AST, creatinine and cholesterol.
    3. Chronic toxicity studies. In a one-year dog study in which dogs 
were fed a diet containing cyproconazole (95% purity) at levels of 0, 
30, 100, or 350 ppm, a NOAEL of 30 ppm (1.0 mg/kg/day) and an LOAEL of 
100 ppm (3.2 mg/kg/day) was attained based on liver effects. Several 
clinical laboratory parameters indicated differences between the 
control and treated animals which were 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.
    4. Carcinogenicity i. A mouse carcinogenicity study was conducted 
in which cyproconazole (95.1% purity) at levels of 0, 5, 15, 100 or 200 
ppm added to the diet of mice for 81 weeks (males) and 88 weeks 
(females) resulted in a NOAEL for systemic toxicity of 15 ppm (1.8 mg/
kg for males and 2.6 mg/kg for females). The LOAEL 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 in both sexes. 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.
    ii. A rat chronic/carcinogenicity study in which cyproconazole 
(95.6% purity) fed to rats (males for 118 weeks, females for 121 weeks) 
at 0, 20, 50 or 350 ppm (males: 0, 1.0, 2.2 and 15.6 mg/kg; females: 0, 
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 NOAEL for systemic toxicity was 
50 ppm. The LOAEL 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.
    5. Developmental toxicity i. A rat developmental toxicity study was 
conducted in which cyproconazole (95.6% purity) was administered as a 
suspension by gavage to sperm-positive female rats at dose levels of 0, 
6, 12, 24, or 48 mg/kg on days 6 through 15 of gestation. The NOAEL for 
maternal toxicity was 6 mg/kg and the LOAEL was 12 mg/kg based on 
decreased body weight gain during dosing. The NOAEL for developmental 
toxicity was 6 mg/kg. The LOAEL was 12 mg/kg based on the increased 
incidence of supernumerary ribs.
    ii. In a rabbit developmental toxicity study, 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 NOAEL for 
maternal toxicity was 10

[[Page 53831]]

mg/kg (equivocal). The LOAEL 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 NOAEL for developmental toxicity was set at < 2 mg/kg 
and the LOAEL was 2 mg/kg. The incidence was 0.85, 0.83, and 0.93 for 
the low, mid, and high dose fetuses and 0.09 for the historical 
control.
    iii. A rabbit developmental toxicity study was conducted 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 NOAEL for 
maternal toxicity was 10 mg/kg and the LOAEL was 50 mg/kg based on 
decreased body weight gain. There was also evidence of developmental 
toxicity. The NOAEL for developmental toxicity was 2 mg/kg and the 
LOAEL was 10 mg/kg based on the increased incidence of malformed 
fetuses and litters with malformed fetuses.
    6. Reproductive toxicity. In a rat 2-generation reproduction study, 
technical cyproconazole (95.6% purity) was administered to 26 male and 
26 female F0 and F1 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 three weeks after 
termination of mating and females were treated until necropsy (post-
weaning). The systemic NOAEL for parental toxicity was set at 20 ppm 
(1.7 mg/kg) based on liver effects at 10.6 mg/kg. For reproductive 
toxicity, the NOAEL was set at 120 ppm (10.6 mg/kg). The increased 
gestation length in the F0 dams and decreased F1 
litter sizes were not considered treatment related.
    7. Mutagenicity. Several mutagenicity studies were conducted. 
Mutagenicity potential of cyproconazole was tested in several studies 
considered acceptable by the Agency. Since the results of 2 chromosomal 
aberration assays indicated that cyproconazole is clastogenic, 
additional mutagenicity data were requested to address an identified 
heritable risk concern. For the potential to induce chromosome 
aberrations in Chinese hampster ovary (CHO) cells, cyproconazole was 
positive under nonactivated and activated conditions, which supports 
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 which was negative. Based on this evidence, the concern for a 
possible heritable effect was not pursued.
    8. Metabolism. In 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.
    9. Neurotoxicity. There have been no clinical neurotoxic signs or 
other types of neurotoxicity observed in any of the evaluated 
toxicology studies. It was not recommended that a developmental 
neurotoxicity study be required for cyproconazole.
    10. Other toxicological considerations. Cyproconazole has a 
complete data base and no other toxicological concerns have been 
identified in the evaluated studies.

B. Toxicological Endpoints

    1. Acute toxicity. The Agency concluded that since developmental 
toxicity was induced in rats and rabbits by the oral route, the acute 
risk estimate should be performed using the NOAEL (2 mg/kg/day) for 
developmental toxicity in the oral rabbit study.
     2. Short - and intermediate - term toxicity. Registration of 
cyproconazole for use on coffee is not proposed for the United States 
and domestic uses on turf and roses will be discontinued so short- and 
intermediate-exposure assessments are not relevant.
     3. Chronic toxicity. EPA has established the reference dose (RfD) 
for cyproconazole at 0.01 milligrams/kilogram/day (mg/kg/day). This RfD 
is based on the chronic feeding study in dogs with a NOAEL of 1.0 mg/
kg/day and an uncertainty factor of 100. The LOAEL was 3.2 mg/kg/day, 
based on hepatotoxicity and organ weight changes.
    4. Carcinogenicity. Using its Guidelines for Carcinogen Risk 
Assessment published September 24, 1986 (51 FR 33992), EPA has 
classified cyproconazole as a Group B2 Carcinogen (Probable Human 
Carcinogen). It was recommended that for the purpose of risk 
characterization, a low-dose extrapolation methodology Q1* 3.0 x 
10-1 (mg/kg/day)-1 be used for the estimation of 
human risk.

C. Exposures and Risks

    1. From food and feed uses. A time-limited tolerance was 
established (40 CFR 180.485) for the residues of cyproconazole, 
(2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazole-1-
yl)butan-2-ol, in or on coffee beans at 0.1 ppm. The tolerance expired 
on July 1, 1997. In today's action, a permanent tolerance will be 
established for residues of cyproconazole in or on coffee, bean, green 
at 0.1 ppm. Risk assessments were conducted by EPA to assess dietary 
exposures from cyproconazole as follows:
    The RfD used in the dietary exposure analysis was 0.01 mg/kg/day 
based on a NOAEL of 30.0 ppm (1.00 mg/kg/day) from a 1-year dog feeding 
study with an uncertainty factor of 100 that demonstrated 
hepatotoxicity and organ weight changes 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, is 0.000003 mg/kg/day. The anticipated residue contributions 
(ARC) as percentage 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.
    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 used proposed 
anticipated residues without adjustment for percent crop treated 
information incorporated into the analysis.
    Section 408(b)(2)(E) authorizes EPA to use available data and 
information on the anticipated residue levels of pesticide residues in 
food and the actual levels of pesticide chemicals that have been 
measured in food. If EPA relies on such information, EPA must require 
that data be provided 5 years after the tolerance is established, 
modified, or left in effect, demonstrating that the levels in food are 
not above the levels anticipated. Following the initial data 
submission, EPA is authorized to require similar data on a time frame 
it deems appropriate. As required by section 408(b)(2)(E), EPA will 
issue a data call-in for information relating to anticipated residues 
to be submitted no later than 5 years from the date of issuance of this 
tolerance.

[[Page 53832]]

    i.  Acute exposure and risk. Acute dietary risk assessments are 
performed for a food-use pesticide if a toxicological study has 
indicated the possibility of an effect of concern occurring as a result 
of a one day or single exposure. The acute dietary exposure endpoint of 
concern for cyproconazole is developmental (increased incidence of 
malformed fetuses and litters with malformed fetuses). For the 
population subgroup of concern, females 13+ years old, the calculated 
Margin of Exposure (MOE) value is 33,000. No anticipated residues were 
used in this assessment.
    ii. Chronic exposure and risk. In conducting the chronic dietary 
(food only) risk assessment, anticipated residues were utilized. The 
proposed cyproconazole tolerance for coffee results in an ARC that is 
equivalent to <0.1% of the RfD for the U.S. population (48 states) and 
all other subgroups except non-nursing infants (<1 year old). The 
percent of RfD for non-nursing infants is 0 since coffee is not 
consumed by this subgroup.
    iii. Dietary cancer risk. Cyproconazole is classified as a Group B2 
carcinogen with a Q1* of 3.0 x 10-1 (mg/kg/
day)-1. Based on this figure, the upper bound cancer risk 
was calculated to be 5.3 x 10-7, contributed through the use 
of cyproconazole on imported coffee.
    2. From drinking water. There will be no exposure of the U.S. 
population from drinking water. Novartis Crop Protection, Inc. has 
agreed to suspend importation of cyproconazole and will suspend the 
sale of cyproconazole for all registered uses (turf and roses) in the 
United States after the current stock is depleted.
    3. From non-dietary exposure. Cyproconazole is currently registered 
for use on the following non-food sites: turf and roses. The registrant 
of products containing cyproconazole has committed to stop importation 
of this chemical for these uses at this time. Risk from non-dietary 
exposure from these uses until current stocks of products are depleted 
is considered to be minimal since stocks are already low and use is not 
wide-spread.
    4. Cumulative exposure to substances with common mechanism of 
toxicity. Section 408(b)(2)(D)(v) requires that, when considering 
whether to establish, modify, or revoke a tolerance, the Agency 
consider ``available information'' concerning the cumulative effects of 
a particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.''
    EPA does not have, at this time, available data to determine 
whether cyproconazole has a common mechanism of toxicity with other 
substances or how to include this pesticide in a cumulative risk 
assessment. Unlike other pesticides for which EPA has followed a 
cumulative risk approach based on a common mechanism of toxicity, 
cyproconazole does not appear to produce a toxic metabolite produced by 
other substances. For the purposes of this tolerance action, therefore, 
EPA has not assumed that cyproconazole has a common mechanism of 
toxicity with other substances. For information regarding EPA's efforts 
to determine which chemicals have a common mechanism of toxicity and to 
evaluate the cumulative effects of such chemicals, see the Final Rule 
for Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997).

D. Aggregate Risks and Determination of Safety for U.S. Population

    1. Acute risk. Since there are no drinking water or non-dietary 
exposures, acute risk is from dietary exposure only. For dietary risk 
to the population subgroup of concern, females 13+ years old, the 
calculated MOE is 33,000. EPA has no concerns if the MOE is greater 
than 100 when the NOAEL used in calculating the MOE is taken from an 
animal study. Since the MOE value of 33,000 is much greater than 100, 
there are no acute dietary concerns.
    2. Chronic risk. Using the ARC exposure assumptions described 
above, EPA has concluded that aggregate exposure to cyproconazole from 
food will utilize <0.1% of the RfD for the U.S. population. The major 
identifiable subgroup with the highest aggregate exposure is females 
(20+ years, not pregnant, not nursing). EPA generally has no concern 
for exposures below 100% of the RfD because the RfD represents the 
level at or below which daily aggregate dietary exposure over a 
lifetime will not pose appreciable risks to human health. Since there 
will be no potential for exposure to cyproconazole in drinking water 
and from non-dietary, non-occupational exposure, EPA does not expect 
the aggregate exposure to exceed 100% of the RfD. EPA concludes that 
there is a reasonable certainty that no harm will result from aggregate 
exposure to cyproconazole residues.
    3. Short- and intermediate-term risk. Short- and intermediate-term 
aggregate exposure takes into account chronic dietary food and water 
(considered to be a background exposure level) plus indoor and outdoor 
residential exposure. No short- or intermediate-term risk is expected 
since there is no expectation of exposure from the proposed use of 
cyproconazole on coffee.
    4. Aggregate cancer risk for U.S. population. The only risk from 
cancer is from dietary (food) exposure. The upper bound cancer risk was 
calculated to be 5.3 x 10-7, contributed through the use of 
cyproconazole on imported coffee. The Agency does not consider this 
cancer risk to be of concern. Since there will be no exposure from 
water or non-dietary exposure, aggregate cancer risk will not exceed 
the upper bound cancer risk.
    5. Determination of safety. Based on these risk assessments, EPA 
concludes that there is a reasonable certainty that no harm will result 
from aggregate exposure to cyproconazole residues.

E. Aggregate Risks and Determination of Safety for Infants and Children

    1. Safety factor for infants and children-- i. In general. In 
assessing the potential for additional sensitivity of infants and 
children to residues of cyproconazole, EPA considered data from 
developmental toxicity studies in the rat and rabbit and a 2-generation 
reproduction study in the rat. The developmental toxicity studies are 
designed to evaluate adverse effects on the developing organism 
resulting from maternal pesticide exposure gestation. Reproduction 
studies provide information relating to effects from exposure to the 
pesticide on the reproductive capability of mating animals and data on 
systemic toxicity.
    FFDCA section 408 provides that EPA shall apply an additional 
tenfold margin of safety for infants and children in the case of 
threshold effects to account for pre-and post-natal toxicity and the 
completeness of the database unless EPA determines that a different 
margin of safety will be safe for infants and children. Margins of 
safety are incorporated into EPA risk assessments either directly 
through use of a margin of exposure (MOE) analysis or through using 
uncertainty (safety) factors in calculating a dose level that poses no 
appreciable risk to humans. EPA believes that reliable data support 
using the standard uncertainty factor (usually 100 for combined inter- 
and intra-species variability)) and not the additional tenfold MOE/
uncertainty factor when EPA has a complete data base under existing 
guidelines and when the severity of the effect in infants or children 
or the potency or unusual toxic properties of a compound do not raise 
concerns regarding the adequacy of the standard MOE/safety factor.
    ii. Developmental toxicity studies.-- a. Rats. In the developmental 
study in rats, the maternal NOAEL was 6 mg/kg,

[[Page 53833]]

and the LOAEL was 12 mg/kg based on decreased body weight gain during 
dosing. The developmental NOAEL was 6 mg/kg and the LOAEL was 12 mg/kg 
based on the increased incidence of supernumerary ribs.
    b. Rabbits. In the developmental toxicity study in rabbits, the 
maternal NOAEL was 10 mg/kg/. The LOAEL was 50 mg/kg based on decreased 
body weight gain during dosing. The NOAEL for developmental toxicity 
was set at <2 mg/kg and the LOAEL was 2 mg/kg.
    c. Rabbits. In another rabbit developmental toxicity study, the 
NOAEL for maternal toxicity was 10 mg/kg and the LOAEL was 50 mg/kg 
based on decreased body weight gain. The NOAEL for developmental 
toxicity was 2 mg/kg and the LOAEL was 10 mg/kg based on the increased 
incidence of malformed fetuses and litters with malformed fetuses.
    iii. Reproductive toxicity study.-- Rats. In the 2-generation 
reproductive toxicity study in rats, the parental (systemic) NOAEL was 
1.7 mg/kg, based on liver effects at 10.6 mg/kg. For reproductive 
toxicity, the NOAEL was 10.6 mg/kg. The increased gestation length in 
the F0 dams and decreased F1 litter sizes were 
not considered treatment related.
    iv. Pre- and post-natal sensitivity.  The pre- and post-natal 
toxicology data base for cyproconazole is complete with respect to 
current toxicological data requirements. The results of these studies 
indicate that infants and children are not more sensitive to exposure, 
based on the results of the oral rat and rabbit developmental toxicity 
studies and the 2-generation reproductive toxicity study in rats.
    v. Conclusion. EPA concludes that, although the rabbit data 
indicate increased sensitivity of the fetus, no increase in sensitivity 
is implicated for infants and children and therefore, an additional 
uncertainty factor on the RfD is not required given the fact that the 
fetal NOAEL of 2, which is less than the maternal NOAEL of 10 (and 
therefore an additional factor is already considered in the risk 
assessment process), is twice the NOAEL used for the RfD. There is no 
indication that an acute MOE of 100 is not adequate. These data taken 
together suggest minimal concern for developmental or reproductive 
toxicity and do not indicate any increased pre- or post-natal 
sensitivity. No additional uncertainty factor for increased sensitivity 
in infants and children is appropriate. There is a complete toxicity 
database for cyproconazole and exposure data is complete or is 
estimated based on data that reasonably accounts for potential 
exposures.
    2. Acute risk. Since there are no drinking water or non-dietary 
exposures, acute risk is from dietary exposure only. For dietary risk, 
the MOE is calculated to be 33,000 for the most highly exposed subgroup 
, females 13+ years old. Since coffee is not generally consumed by 
infants and children, the MOE would be even greater for this group.
    3. Chronic risk. Using the exposure assumptions described above, 
EPA has concluded that aggregate exposure to cyproconazole from food 
will utilize 0% (non-nursing infants <1 year old) and <0.1% of the RfD 
from dietary exposure for children 1-6 years old and for the U.S. 
population. EPA generally has no concern for exposures below 100% of 
the RfD because the RfD represents the level at or below which daily 
aggregate dietary exposure over a lifetime will not pose appreciable 
risks to human health. Since there will be no potential for exposure to 
cyproconazole in drinking water and from non-dietary, non-occupational 
exposure, EPA does not expect the aggregate exposure to exceed 100% of 
the RfD.
    4. Short- or intermediate-term risk. No short- or intermediate-term 
risk is expected since there is no expectation of exposure from the 
proposed use of cyproconazole on coffee.
    5. Cancer risk. The only risk from cancer is from dietary (food) 
exposure. The upper bound cancer risk was calculated to be 5.3 x 
10-7, contributed through the use of cyproconazole on 
imported coffee. The Agency does not consider cancer risk to be of 
concern for estimates below approximately 1 x 10-6. Since 
there will be no exposure from water or non-dietary exposure, aggregate 
cancer risk will not exceed the upper bound cancer risk.
    6. Determination of safety. Based on these risk assessments, EPA 
concludes that there is a reasonable certainty that no harm will result 
to infants and children from aggregate exposure to cyproconazole 
residues.

III. Other Considerations

A. Metabolism In Plants and Animals

    1. Plants. The nature of the residue in coffee is fully understood. 
Cyproconazole per se was the primary component of the residue and is 
the only residue of regulatory concern. Similar results were observed 
in apples, grapes and coffee.
    2. Animals. 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 after 
treatment.

B. Analytical Enforcement Methodology

    An adequate analytical method is available for enforcement 
purposes. Residues are quantified by gas chromatography equipped with a 
nitrogen-phosphorus detector. The limit of quantification is 0.01 ppm. 
The analytical method, AM-0822-1288-0, is available in the Pesticide 
Analytical Manual, Vol. II.

C. Magnitude of Residues

    The average cyproconazole residue in green coffee beans in 
submitted studies was 0.026 ppm. The concentration of cyproconazole 
residues in roasted or instant coffee was not of sufficient magnitude 
to require separate tolerances for these commodities but concentration 
factors were used to calculate anticipated residues. The anticipated 
residues in roasted coffee beans were 0.038 ppm and 0.033 ppm for 
instant coffee. The residues in coffee will not exceed the proposed 
tolerance of 0.1 ppm.

D. International Residue Limits

    There are no Codex, Canadian or Mexican residue limits established 
for cyproconazole on coffee. Therefore, no compatibility problems exist 
for the proposed tolerance on coffee.

E. Rotational Crop Restrictions

    Rotational crop studies are not required for uses of pesticides on 
coffee.

IV. Conclusion

    Therefore, the tolerance is established for residues of 
cyproconazole, (2RS,3RS)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-
triazole-1-yl)butan-2-ol in coffee, bean, green at 0.1 ppm.

V. Objections and Hearing Requests

    The new FFDCA section 408(g) provides essentially the same process 
for persons to ``object'' to a tolerance regulation issued by EPA under 
new section 408(e) and (l)(6) as was provided in the old section 408 
and in section 4-. However, the period for filing objections is 60 
days, rather than 30 days. EPA currently has procedural regulations 
which govern the submission of objections and hearing requests. These 
regulations will require some modification to reflect the new law. 
However, until those modifications

[[Page 53834]]

can be made, EPA will continue to use those procedural regulations with 
appropriate adjustments to reflect the new law.
    Any person may, by December 7, 1998, file written objections to any 
aspect of this regulation and may also request a hearing on those 
objections. Objections and hearing requests must be filed with the 
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of 
the objections and/or hearing requests filed with the Hearing Clerk 
should be submitted to the OPP docket for this rulemaking. The 
objections submitted must specify the provisions of the regulation 
deemed objectionable and the grounds for the objections (40 CFR 
178.25). Each objection must be accompanied by the fee or a request for 
a fee waiver as prescribed by 40 CFR 180.33(i). If a hearing is 
requested, the objections must include a statement of the factual 
issues on which a hearing is requested, the requestor's contentions on 
such issues, and a summary of any evidence relied upon by the requestor 
(40 CFR 178.27). A request for a hearing will be granted if the 
Administrator determines that the material submitted shows the 
following: There is genuine and substantial issue of fact; there is a 
reasonable possibility that available evidence identified by the 
requestor would, if established, resolve one or more of such issues in 
favor of the requestor, taking into account uncontested claims or facts 
to the contrary; and resolution of the factual issues in the manner 
sought by the requestor would be adequate to justify the action 
requested (40 CFR 178.32). Information submitted in connection with an 
objection or hearing request may be claimed confidential by marking any 
part or all of that information as CBI. Information so marked will not 
be disclosed except in accordance with procedures set forth in 40 CFR 
part 2. A copy of the information 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.

VI. Public Record and Electronic Submissions

    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 any copies of objections and hearing requests 
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 
Virginia address in ``ADDRESSES'' at the beginning of this document.
    Electronic comments may be sent directly to EPA at:
[email protected].


    Electronic objections and hearing requests must be submitted as an 
ASCII file avoiding the use of special characters and any form of 
encryption. Objections and hearing requests will also be accepted on 
disks in WordPerfect 5.1/6.1 or ASCII file format. All copies of 
objections and hearing requests in electronic form must be identified 
by the docket control number OPP-300742. No CBI should be submitted 
through e-mail. Electronic copies of objections and hearing requests on 
this rule may be filed online at many Federal Depository Libraries.

VII. Regulatory Assessment Requirements

A. Certain Acts and Executive Orders

    This final rule establishes a tolerance under FFDCA section 408(d) 
in response to a petition submitted to the Agency. The Office of 
Management and Budget (OMB) has exempted these types of actions from 
review under Executive Order 12866, entitled Regulatory Planning and 
Review (58 FR 51735, October 4, 1993). This final rule does not contain 
any information collections subject to OMB approval under the Paperwork 
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable 
duty or contain any unfunded mandate as described under Title II of the 
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does 
it require any prior consultation as specified by Executive Order 
12875, entitled Enhancing the Intergovernmental Partnership (58 FR 
58093, October 28, 1993), or special considerations as required by 
Executive Order 12898, entitled Federal Actions to Address 
Environmental Justice in Minority Populations and Low-Income 
Populations (59 FR 7629, February 16, 1994), or require OMB review in 
accordance with Executive Order 13045, entitled Protection of Children 
from Environmental Health Risks and Safety Risks (62 FR 19885, April 
23, 1997).
    In addition, since tolerances and exemptions that are established 
on the basis of a petition under FFDCA section 408(d), such as the 
tolerance in this final rule, do not require the issuance of a proposed 
rule, the requirements of the Regulatory Flexibility Act (RFA) (5 
U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has 
previously assessed whether establishing tolerances, exemptions from 
tolerances, raising tolerance levels or expanding exemptions might 
adversely impact small entities and concluded, as a generic matter, 
that there is no adverse economic impact. The factual basis for the 
Agency's generic certification for tolerance actions published on May 
4, 1981 (46 FR 24950) and was provided to the Chief Counsel for 
Advocacy of the Small Business Administration.

B. Executive Order 12875

    Under Executive Order 12875, entitled Enhancing the 
Intergovernmental Partnership (58 FR 58093, October 28, 1993), EPA may 
not issue a regulation that is not required by statute and that creates 
a mandate upon a State, local, or tribal government, unless the Federal 
government provides the funds necessary to pay the direct compliance 
costs incurred by those governments. If the mandate is unfunded, EPA 
must provide to OMB a description of the extent of EPA's prior 
consultation with representatives of affected State, local, and tribal 
governments, the nature of their concerns, copies of any written 
communications from the governments, and a statement supporting the 
need to issue the regulation. In addition, Executive Order 12875 
requires EPA to develop an effective process permitting elected 
officials and other representatives of State, local, and tribal 
governments ``to provide meaningful and timely input in the development 
of regulatory proposals containing significant unfunded mandates.''
    Today's rule does not create an unfunded Federal mandate on State, 
local, or tribal governments. The rule does not impose any enforceable 
duties on these entities. Accordingly, the requirements of section 1(a) 
of Executive Order 12875 do not apply to this rule.

C. Executive Order 13084

    Under Executive Order 13084, entitled Consultation and Coordination 
with Indian Tribal Governments (63 FR 27655, May 19,1998), EPA may not 
issue a regulation that is not required by statute, that significantly 
or uniquely affects the communities of Indian tribal governments, and 
that imposes substantial direct compliance costs on those communities, 
unless the Federal government provides the funds necessary to pay the 
direct compliance costs incurred by the tribal governments. If the 
mandate is unfunded, EPA must provide to OMB, in a separately 
identified section of the preamble to the rule, a description of

[[Page 53835]]

the extent of EPA's prior consultation with representatives of affected 
tribal governments, a summary of the nature of their concerns, and a 
statement supporting the need to issue the regulation. In addition, 
Executive Order 13084 requires EPA to develop an effective process 
permitting elected officials and other representatives of Indian tribal 
governments ``to provide meaningful and timely input in the development 
of regulatory policies on matters that significantly or uniquely affect 
their communities.''
    Today's rule does not significantly or uniquely affect the 
communities of Indian tribal governments. This action does not involve 
or impose any requirements that affect Indian tribes. Accordingly, the 
requirements of section 3(b) of Executive Order 13084 do not apply to 
this rule.

VIII. Submission to Congress and the Comptroller General

    The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the 
Small Business Regulatory Enforcement Fairness Act of 1996, generally 
provides that before a rule may take effect, the agency promulgating 
the rule must submit a rule report, which includes a copy of the rule, 
to each House of the Congress and to the Comptroller General of the 
United States. EPA will submit a report containing this rule and other 
required information to the U.S. Senate, the U.S. House of 
Representatives, and the Comptroller General of the United States prior 
to publication of the rule in the Federal Register. This rule is not a 
``major rule'' as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Reporting and 
recordkeeping requirements.

    Dated: September 29, 1998.

James Jones,

Director, Registration Division, Office of Pesticide Programs.
    Therefore, 40 CFR chapter I is 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 180.485 is revised to read as follows:


Sec. 180.485  Cyproconazole; tolerances for residues.

    (a) General.  A tolerance is established for 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 agricultural 
commodity coffee, bean, green at 0.1 ppm. There are no U.S. 
registrations as of October 7, 1998, for use on coffee beans.
    (b) Section 18 emergency exemptions. [Reserved]
    (c)  Tolerances with regional registrations. [Reserved]
    (d)  Indirect or inadvertent residues. [Reserved]

[FR Doc. 98-26904 Filed 10-6-98; 8:45 am]
BILLING CODE 6560-50-F