[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: opp-docket@epamail.epa.gov. 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:
waller.mary@epamail.epa.gov.
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="">-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="">0 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="">-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="">-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="">0 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="">-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:
opp-docket@epamail.epa.gov.
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
