[Federal Register Volume 63, Number 69 (Friday, April 10, 1998)]
[Rules and Regulations]
[Pages 17699-17706]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-9679]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-300643; FRL-5785-1]
RIN 2070-AB78


Cyprodinil; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.

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SUMMARY: This regulation establishes tolerances for residues of 
cyprodinil, 4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine in or on 
the folowing commodities: almond hulls at 0.05 ppm; almond nutmeats at 
0.02 ppm; apple pomace, wet at 0.15 ppm; grapes at 2.0 ppm; pome fruit 
at 0.1 ppm; raisins at 3.0 ppm and stone fruit at 2.0 ppm. Novartis 
Crop Protection, Inc. requested these tolerances under the Federal 
Food, Drug and Cosmetic Act (FFDCA), as amended by the Food Quality 
Protection Act of 1996 (Pub. L. 104-170).
DATES: This regulation is effective April 10, 1998. Objections and 
requests for hearings must be received by EPA on or before June 9, 
1998.
ADDRESSES: Written objections and hearing requests, identified by the 
docket control number, [OPP-300643], 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-300643], 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, 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-300643]. 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, Acting 
Product Manager (PM) 21, 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: Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, 
(703) 308-9354, e-mail: [email protected].
SUPPLEMENTARY INFORMATION: In the Federal Register of April 2, 1997 (64 
FR 15690)(FRL-5593-9) EPA issued a notice pursuant to section 408 of 
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e) 
announcing the filing of pesticide petitions (PP 6F4656 and 6H5746) for 
tolerances by Novartis Crop Protection, Inc. Greensboro, NC 27419 
(formerly Ciba Crop Protection). This notice included a summary of the 
petitions prepared by Novartis Crop Protection, Inc., the registrant. 
There were no comments received in response to the notice of filing.
    The petitions requested that 40 CFR part 180 be amended by 
establishing tolerances for residues of the fungicide cyprodinil, 4-
cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine in or on the following 
commodities: almond hulls at 0.05 ppm; almond nutmeats at 0.02 ppm; 
apple pomace, wet at 0.15 ppm; grapes at 2.0 ppm; pome fruit at 0.1 
ppm; raisins at 3.0 ppm and stone fruit at 2.0 ppm.
    Note that the scientific assessments relevant to establishing these 
tolerances for cyprodinil were conducted jointly between EPA and the 
Pest Management Regulatory Agency (PMRA) of Canada as a pilot project 
under the North American Free Trade Agreement (NAFTA) and the Canadian 
United States Trade Agreement (CUSTA). Cyprodinil qualified as the 
first candidate for such a pilot program due to its classification as a 
reduced risk pesticide.

I. Risk Assessment and Statutory Findings

    New 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

[[Page 17700]]

``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 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. First, EPA determines the 
toxicity of pesticides based primarily on toxicological studies using 
laboratory animals. These studies address many adverse health effects, 
including (but not limited to) reproductive effects, developmental 
toxicity, toxicity to the nervous system, and carcinogenicity. Second, 
EPA examines exposure to the pesticide through the diet (e.g., food and 
drinking water) and through exposures that occur as a result of 
pesticide use in residential settings.

A. Toxicity

    1.  Threshold and non-threshold effects. For many animal studies, a 
dose response relationship can be determined, which provides a dose 
that causes adverse effects (threshold effects) and doses causing no 
observed effects (the ``no-observed effect level'' or ``NOEL'').
    Once a study has been evaluated and the observed effects have been 
determined to be threshold effects, EPA generally divides the NOEL from 
the study with the lowest NOEL by an uncertainty factor (usually 100 or 
more) to determine the Reference Dose (RfD). The RfD is a level at or 
below which daily aggregate exposure over a lifetime will not pose 
appreciable risks to human health. An uncertainty factor (sometimes 
called a ``safety factor'') of 100 is commonly used since it is assumed 
that people may be up to 10 times more sensitive to pesticides than the 
test animals, and that one person or subgroup of the population (such 
as infants and children) could be up to 10 times more sensitive to a 
pesticide than another. In addition, EPA assesses the potential risks 
to infants and children based on the weight of the evidence of the 
toxicology studies and determines whether an additional uncertainty 
factor is warranted. Thus, an aggregate daily exposure to a pesticide 
residue at or below the RfD (expressed as 100 percent or less of the 
RfD) is generally considered acceptable by EPA. EPA generally uses the 
RfD to evaluate the chronic risks posed by pesticide exposure. For 
shorter term risks, EPA calculates a margin of exposure (MOE) by 
dividing the estimated human exposure into the NOEL from the 
appropriate animal study. Commonly, EPA finds MOEs lower than 100 to be 
unacceptable. This hundredfold MOE is based on the same rationale as 
the hundredfold uncertainty factor.
    Lifetime feeding studies in two species of laboratory animals are 
conducted to screen pesticides for cancer effects. When evidence of 
increased cancer is noted in these studies, the Agency conducts a 
weight of the evidence review of all relevant toxicological data 
including short-term and mutagenicity studies and structure activity 
relationship. Once a pesticide has been classified as a potential human 
carcinogen, different types of risk assessments (e.g., linear low dose 
extrapolations or MOE calculation based on the appropriate NOEL) will 
be carried out based on the nature of the carcinogenic response and the 
Agency's knowledge of its mode of action.
    2. Differences in toxic effect due to exposure duration. The 
toxicological effects of a pesticide can vary with different exposure 
durations. EPA considers the entire toxicity data base, and based on 
the effects seen for different durations and routes of exposure, 
determines which risk assessments should be done to assure that the 
public is adequately protected from any pesticide exposure scenario. 
Both short and long durations of exposure are always considered. 
Typically, risk assessments include ``acute,'' ``short-term,'' 
``intermediate term,'' and ``chronic'' risks. These assessments are 
defined by the Agency as follows.
    Acute risk, by the Agency's definition, results from 1-day 
consumption of food and water, and reflects toxicity which could be 
expressed following a single oral exposure to the pesticide residues. 
High end exposure to food and water residues are typically assumed.
    Short-term risk results from exposure to the pesticide for a period 
of 1-7 days, and therefore overlaps with the acute risk assessment. 
Historically, this risk assessment was intended to address primarily 
dermal and inhalation exposure which could result, for example, from 
residential pesticide applications. However, since enaction of FQPA, 
this assessment has been expanded to include both dietary and non-
dietary sources of exposure, and will typically consider exposure from 
food, water, and residential uses when reliable data are available. In 
this assessment, risks from average food and water exposure, and high-
end residential exposure, are aggregated. High-end exposures from all 
three sources are not typically added because of the very low 
probability of this occurring in most cases, and because the other 
conservative assumptions built into the assessment assure adequate 
protection of public health. However, for cases in which high-end 
exposure can reasonably be expected from multiple sources (e.g. 
frequent and widespread homeowner use in a specific geographical area), 
multiple high-end risks will be aggregated and presented as part of the 
comprehensive risk assessment/characterization. Since the toxicological 
endpoint considered in this assessment reflects exposure over a period 
of at least 7 days, an additional degree of conservatism is built into 
the assessment; i.e., the risk assessment nominally covers 1-7 days 
exposure, and the toxicological endpoint/NOEL is selected to be 
adequate for at least 7 days of exposure. (Toxicity results at lower 
levels when the dosing duration is increased.)
    Intermediate-term risk results from exposure for 7 days to several 
months. This assessment is handled in a manner similar to the short-
term risk assessment.
    Chronic risk assessment describes risk which could result from 
several months to a lifetime of exposure. For this assessment, risks 
are aggregated considering average exposure from all sources for 
representative population subgroups including infants and children.

B. Aggregate Exposure

    In examining aggregate exposure, FFDCA section 408 requires that 
EPA take into account available and reliable information concerning 
exposure from the pesticide residue in the food in question, residues 
in other foods for which there are tolerances, residues in groundwater 
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or 
buildings (residential and other indoor uses). Dietary exposure to 
residues of a pesticide in a food commodity are estimated by 
multiplying the average daily consumption of the food forms of that 
commodity by the tolerance level or the anticipated pesticide residue 
level. The Theoretical Maximum Residue

[[Page 17701]]

Contribution (TMRC) is an estimate of the level of residues consumed 
daily if each food item contained pesticide residues equal to the 
tolerance. In evaluating food exposures, EPA takes into account varying 
consumption patterns of major identifiable subgroups of consumers, 
including infants and children. The TMRC is a ``worst case'' estimate 
since it is based on the assumptions that food contains pesticide 
residues at the tolerance level and that 100% of the crop is treated by 
pesticides that have established tolerances. If the TMRC exceeds the 
RfD or poses a lifetime cancer risk that is greater than approximately 
one in a million, EPA attempts to derive a more accurate exposure 
estimate for the pesticide by evaluating additional types of 
information (anticipated residue data and/or percent of crop treated 
data) which show, generally, that pesticide residues in most foods when 
they are eaten are well below established tolerances.
    Percent of crop treated estimates are derived from federal and 
private market survey data. Typically, a range of estimates are 
supplied and the upper end of this range is assumed for the exposure 
assessment. By using this upper end estimate of percent of crop 
treated, the Agency is reasonably certain that exposure is not 
understated for any significant subpopulation group. Further, regional 
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant subpopulations 
including several regional groups, to pesticide residues. For this 
pesticide, the most highly exposed population subgroup, non-nursing 
infants, was not regionally based.

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. Reviews of the submitted data were conducted under a joint 
review between Pest Management Regulatory Agency (PMRA), Canada and the 
EPA. EPA has sufficient data to assess the hazards of cyprodinil and to 
make a determination on aggregate exposure, consistent with section 
408(b)(2), for tolerances for residues of cyprodinil in or on these 
commodities: almond hulls at 0.05 ppm; almond nutmeats at 0.02 ppm; 
apple pomace, wet at 0.15 ppm; grapes at 2.0 ppm; pome fruit at 0.1 
ppm; raisins at 3.0 ppm and stone fruit at 2.0 ppm.
    EPA's assessment of the dietary exposures and risks associated with 
establishing these tolerances 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 cyprodinil are 
discussed below.
    1. Acute toxicity. The acute toxicity data of cyprodinil show that 
this chemical is not acutely toxic by the oral, inhalation and dermal 
routes of exposure. Technical cyprodinil, however, is a dermal 
sensitizer.
    2.  Subchronic toxicity. i. In a range-finding subchronic toxicity 
study, cyprodinil was administered in the diet to rats at 0, 100, 600, 
3,000 or 15,,000 ppm (males - 0, 10.3, 64.8, 316 or 1460 milligrams/
kilogram/day (mg/kg/day); females - 0, 10.1, 62.2, 299 or 1390 mg/kg/
day) for 28 days. In this study, the LOEL is 3,000 ppm (316 and 299 mg/
kg/day for males and females respectively) based on lower bodyweight 
gains, microcytosis, increased cholesterol and phospholipid levels and 
hepatocyte hypertrophy. The NOEL is 600 ppm (64.8 and 62.2 mg/kg/day 
for males and females respectively).
    ii. In a subchronic toxicity study, cyprodinil was administered to 
rats by gavage at dose levels of 0, 10, 100, or 1,000 mg/kg/day for 28 
days. In this study, the LOEL is 100 milligrams/kilogram body weight/
day (mg/kg bwt/day) for rats, based on increased liver weights and 
abnormalities in liver morphology. The NOEL is 10 mg/kg bwt/day.
    iii. In a subchronic toxicity study, cyprodinil was administered in 
the diet to rats at dose levels of 0 or 12,000 ppm (0 or 810 mg/kg/day, 
respectively, for males; 0 or 803 mg/kg/day, respectively, for 
females), and to rats at dose levels of 50, 300, or 2,000 ppm (3.14, 
19.0, or 134 mg/kg/day, respectively, for males; 3.24, 19.3, or 137 mg/
kg/day for females) for 90 days. In this study, the LOEL is 300 ppm (19 
mg/kg bwt/day) for rats, based on increased chronic tubular kidney 
lesions in males. The NOEL is 50 ppm (3.14 mg/kg/day).
    iv. A 3-month range-finding study was carried out in mice where 
animals were fed diets containing 0, 500, 2,000 or 6,000 ppm (actual 
doses: males - 0, 73.3, 257 or 849 mg/kg/day; females - 0, 103, 349 or 
1,121 mg/kg/day) of cyprodinil. In this study, the LOEL is 2,000 ppm 
based on histopathological changes in the liver. The NOEL is 500 ppm 
(males - 73.3; females - 103 mg/kg/day).
    v. A 3-month study was carried out in Beagle dogs where animals 
were fed diets containing 0, 200, 1,500, 7,000 or 20,000 ppm (actual 
doses: males - 0, 6.07, 45.87, 210.33 or 559.66 mg/kg/day; females - 0, 
6.79, 52.75, 231.93 or 580.95 mg/kg/day) of cyprodinil. In this study, 
the LOEL is 20,000 ppm (males - 560, females - 581 mg/kg/day) based on 
lower bodyweight gains and decreased food consumption in both sexes. 
The NOEL is 7,000 ppm (males - 210, females - 232 mg/kg/day).
    vi. Groups of rats received repeated dermal applications of 
cyprodinil at doses of 0, 5, 25, 125 or 1,000 mg/kg/day, 6 hours/day, 5 
days /week over a 28-day period. Hunched posture was observed in 
females at 125 mg/kg/day. In this study, the LOEL is 25 mg/kg/day for 
female rats and 1,000 mg/kg/day for male rats, based on alterations in 
clinical signs (piloerection). The NOEL is 5 mg/kg/day for females and 
125 mg/kg/day for males.
    3. Chronic toxicity. i. A 24-month chronic toxicity/carcinogenicity 
study was carried out in rats where animals (50 rats/sex/dose - 
carcinogenicity portion, plus 20/sex/dose laboratory investigations) 
were fed diets containing 0, 5, 75, 1,000 or 2,000 ppm cyprodinil 
(actual doses: males - 0, 0.177, 2.7, 35.6 or 73.6 mg/kg/day; females - 
0, 0.204, 3.22, 41.2 or 87.1 mg/kg/day). An additional 10/sex/dose were 
fed test diets for 12 months (interim sacrifice). In this study the 
LOEL is 1,000 ppm (35.6 mg/kg/day) based on the degenerative liver 
lesions (spongiosis hepatis) in males. The NOEL for chronic toxicity is 
set at 75 ppm (2.7 mg/kg/day).
    ii. In a chronic toxicity study, cyprodinil was administered to 
five Beagle dogs/sex/dose in the diet at dose levels of 25, 50, or 100 
ppm for females (0.7, 1.6, or 3.1 mg/kg/day, respectively) and 50, 100, 
or 200 ppm for males (1.8, 3.0, or 5.7 mg/kg/day, respectively) for 52 
weeks. An additional 1-year study was carried out in Beagle dogs where 
animals (4/sex/dose) were fed diets containing 0, 25, 250, 2,500 or 
15,000 ppm (actual doses: males - 0, 0.72, 6.87, 65.63 or 449.25; 
females - 0, 0.76, 6.80, 67.99 or 446.37 mg/kg/day) cyprodinil. In this 
study, the LOEL is 15,000 ppm (males - 449.25, females 446.37 mg/kg/
day) based on lower bodyweight gains and decreased food consumption and 
food efficiency. The NOEL is 2,500 ppm (males - 65.63, females - 67.99 
mg/kg/day).

[[Page 17702]]

    4. Carcinogenicity. i. For the discussion of the rat study, see 
Unit II.A.3.i. of this preamble. This study was tested to adequate 
levels based on signs of toxicity in males at 2,000 ppm and females at 
5,000 ppm. There was no indication of carcinogenic potential at any 
dose level.
    ii. An 18-month carcinogenicity study was carried out in mice where 
animals (50 mice/sex/dose - carcinogenicity portion, plus 10/sex/dose - 
hematology) were fed diets containing 0, 10, 150, 2,000 or 5,000 ppm 
(actual doses: males - 0, 1.15, 16.1, 212.4 or 630; females - 0, 1.08, 
14.7, 196.3 or 558.1 mg/kg/day) of cyprodinil. In this study the LOEL 
is 2,000 ppm (males - 212.4 mg/kg/day) based on a dose-related increase 
in the incidence of focal and multifocal hyperplasia of the exocrine 
pancreas in males. The NOEL is 150 ppm (males - 16.1 mg/kg/day). This 
study was tested to adequate levels based on signs of toxicity in males 
at 2,000 ppm and females at 5,000 ppm. There was no indication of 
carcinogenic potential at any dose level.
    5. Developmental toxicity. i. In a developmental toxicity study, 
cyprodinil was administered in 3% aqueous corn starch suspension by 
oral gavage to 20-23 female rats per dose of 0, 20, 200 or 1,000 mg/kg/
day or gestation days 6-15. The LOEL for maternal toxicity is 1,000 mg/
kg/day based on lower bodyweight/bodyweight gain and reduced food 
consumption. The NOEL for maternal toxicity was 200 mg/kg/day. The LOEL 
for developmental toxicity is 1,000 mg/kg/day based on lower mean fetal 
weights and an increased incidence of delayed ossification. The NOEL 
for developmental toxicity is 200 mg/kg/day.
    ii. In a developmental toxicity study, cyprodinil was administered 
in 3% aqueous corn starch suspension to 19 inseminated female rabbits, 
dosed by gavage at dose levels of 0, 5, 30, 150, or 400 mg/kg/day from 
days 7 through 19 of gestation. In this study, the maternal LOEL is 400 
mg/kg/day, based on decreased body weight gain. The maternal NOEL is 
150 mg/kg/day. The fetal developmental LOEL is 400 mg/kg/day based on a 
slight increase of litters showing extra (13th) ribs. The fetal 
developmental NOEL is 150 mg/kg/day.
    6. Reproductive toxicity. A two-generation reproduction study was 
carried out in rats, with one litter per generation. Animals (30 rats/
sex/dose) received cyprodinil in the diet at doses of 0, 10, 100, 1,000 
or 4,000 ppm (actual intake males - 0, 0.7, 6.7, 68 or 273; females - 
0, 0.8, 8.2, 81 or 326 mg/kg/day) for a 10 week pre-mating period. In 
this study, the LOEL for maternal systemic toxicity is 4,000 (about 326 
mg/kg/day) based on lower body weights in the F0 females 
during the pre-mating period. The NOEL for maternal systemic toxicity 
is 1,000 ppm (about 81 mg/kg/day). The LOEL for reproductive/
developmental toxicity is 4,000 ppm (about 326 mg/kg/day) based on 
decreased pup weights (F1 and F2). The NOEL for 
reproductive toxicity is 1,000 ppm (about 81 mg/kg/day).
    7. Neurotoxicity. Neurotoxicity studies were not required for this 
chemical.
    8. Mutagenicity. Mutagenicity studies with cyprodinil included gene 
mutation assays in bacterial and mammalian cells, a mouse micronucleus 
assay and in vivo unscheduled DNA synthesis (UDS) assays. The results 
were negative for mutagenicity in all studies.
    9. Metabolism. In a metabolism study, single oral doses (0.5 or 100 
mg/kg bwt) of phenyl or pyrimidyl-radiolabelled cyprodinil were 
administered to rats, with one low-dose group receiving unlabeled 
cyprodinil for 2 weeks prior to treatment with radiolabelled compound. 
Absorption was very rapid (tcmax= 0.3 hours) with rapid 
clearance (tcmax/2=1.2 hours). A minimum of 75% of the 
administered dose was absorbed. A biphasic first order kinetics was 
observed for radioactivity depletion, with a duration of 0.3-1.2 hours 
for the first phase, and 27-65 hours for the second phase. Excretion 
was rapid and almost complete, with urine as the principle route of 
excretion (48-68%), and > 90% of the administered dose detected in the 
urine and feces within 48 hours. Tissue residues declined rapidly, with 
the highest concentrations ( 1.8 ppm) found in kidneys, 
liver, lungs, spleen, thyroid, whole blood, and carcass. The urine, 
fecal, and bile metabolite patterns were complex, with 8 and 9 defined 
metabolite fractions, respectively. Unchanged parent compound was 
detected in feces extract only. Excretion, distribution and metabolite 
profiles were essentially independent of dose level, pretreatment, and 
type of label, although there were some sex-dependent qualitative 
differences in two urinary metabolite fractions.
    Excreta (Group D1 and D2) and bile (Group G1) from radiolabelled 
cyprodinil-treated rats were used to characterize, isolate and identify 
metabolites of cyprodinil. Eleven metabolites were isolated from urine, 
feces and bile, and the metabolic pathways in the rat were proposed. 
All urinary and biliary metabolites (with the exception of 7U) were 
conjugated with glucuronic acid or sulfonated, and excreted. Cyprodinil 
was almost completely metabolized by hydroxylation of the phenyl ring ( 
position 4) or pyrimidine ring (position 5), followed by conjugation. 
An alternative pathway involved oxidation of the phenyl ring followed 
by glucuronic acid conjugation. A quantitative sex difference was 
observed with respect to sulfonation of the major metabolite that 
formed 6U. The monosulfate metabolite (1U) was predominant in females, 
whereas equal amounts of mono- and disulfate (6U) conjugates were noted 
in males. Most of the significant metabolites in feces were exocons of 
biliary metabolites (2U, 3U, 1G). These were assumed to be deconjugated 
in the intestines, partially reabsorbed into the general circulation, 
conjugated again, and eliminated renally. The major metabolic pathways 
of cyprodinil were not significantly influenced by the dose, treatment 
regimen, or sex of the animal.

B. Toxicological Endpoints

    1. Acute toxicity. No effects that could be attributed to a single 
exposure (dose) were observed in oral toxicity studies including the 
developmental toxicity studies in rats and rabbits. Therefore, a dose 
and endpoint were not identified for acute dietary risk assessment.
     2. Short- and intermediate-term toxicity. The dose of 25 mg/kg/day 
was selected as the toxicological endpoint for short- and intermediate-
term risk calculations based on the repeated dose study in rats 
resulting in hunched postures in female rats at 125 mg/kg/day.
     3. Chronic toxicity. EPA has established the RfD for cyprodinil at 
0.03 mg/kg/day. This RfD is based on a chronic rat study with a NOEL of 
2.7 mg/kg/day and an Uncertainty Factor of 100. Effects seen at the 
LOEL, 35.6 mg/kg/day, were histopathological alternations in the liver 
(spongiosis hepatis) in males.
    4. Carcinogenicity. Based on the lack of evidence of 
carcinogenicity in mice and rats at doses that were judged to be 
adequate to assess the carcinogenic potential, cyprodinil was 
classified as ``not likely'' human carcinogen according to EPA Proposed 
Guidelines for Carcinogen Risk Assessment (April 10, 1996).

C. Exposures and Risks

    1. From food and feed uses. Currently, there are no established 
tolerances (40 CFR part 180) for the residue of cyprodinil, in or on 
any raw agricultural commodities. Risk assessments were conducted by 
EPA to assess dietary

[[Page 17703]]

exposures and risks from cyprodinil as follows:
    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. No effects that could be attributed to 
a single exposure (dose) were observed in oral toxicity studies 
including the developmental toxicity studies in rats and rabbits. 
Therefore, a dose and endpoint were not identified for acute dietary 
risk assessment.
    ii. Chronic exposure and risk. Chronic dietary (food only) exposure 
estimates were calculated by using the proposed tolerance levels for 
all pome fruit, stone fruit, almond and grape commodities. The required 
tolerances result in a Theoretical Maximum Residue Contribution (TMRC) 
that is equivalent to the following percent of the RfD: (only values 
greater than those for the U.S. population are listed below)

------------------------------------------------------------------------
                                                              Percent of
                         Subgroups                               RFD    
------------------------------------------------------------------------
U.S. population (48 states)................................          5.8
Non-Hispanic White.........................................          6.2
Nursing Infants (< 1 year old).............................         14.0
Non-Nursing Infants (< 1 year old).........................         27.0
Females (13+ years, nursing)...............................          6.5
Children (1-6 years old)...................................         15.0
Children (7-12 years old)..................................          7.5
------------------------------------------------------------------------

    EPA does not consider the chronic dietary risk to exceed the level 
of concern.
    2. From drinking water--i.  acute exposure and risk. No acute 
endpoint was identified, therefore no drinking water risk assessment is 
presented.
    ii. Chronic exposure and risk. The drinking water levels of concern 
(DWLOC) are 990 parts per billion (ppb) for U.S. population and 200 ppb 
for non-nursing infants. The estimated maximum concentration in surface 
water is 16 ppb. The estimated average concentration in surface water 
is expected to be less than 16 ppb. Chronic concentrations in 
groundwater are not expected to be higher than the acute 
concentrations. The maximum estimated concentrations of cyprodinil in 
surface water are less than OPP's levels of concern for cyprodinil in 
drinking water as a contribution to acute aggregate exposure. Also, the 
estimated average concentrations in groundwater are less than OPP's 
levels of concern for cyprodinil in drinking water as a contributor to 
chronic aggregate exposure. Therefore, taking into account the proposed 
uses in this action, EPA concludes with reasonable certainty that 
residues of cyprodinil in drinking water (when considered along with 
other sources of exposure for which EPA has reliable data) would not 
result in unacceptable levels of aggregate human health risk.
    EPA bases this determination on a comparison of estimated 
concentrations of cyprodinil in surface water and groundwaters to back-
calculated ``levels of concern'' for cyprodinil in drinking water. 
These levels of concern in drinking water were determined after EPA has 
considered all other non-occupational exposures for which it has 
reliable data, including all uses considered in this action. The 
estimates of cyprodinil in surface water are derived from water quality 
models that use conservative assumptions (health-protective) regarding 
the pesticide transport from the point of application to surface and 
ground water.
    3. From non-dietary exposure. Cyprodinil is not currently 
registered for use on residential non-food sites. Therefore residential 
risk assessments are not required.
    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.'' The Agency believes that ``available 
information'' in this context might include not only toxicity, 
chemistry, and exposure data, but also scientific policies and 
methodologies for understanding common mechanisms of toxicity and 
conducting cumulative risk assessments. For most pesticides, although 
the Agency has some information in its files that may turn out to be 
helpful in eventually determining whether a pesticide shares a common 
mechanism of toxicity with any other substances, EPA does not at this 
time have the methodologies to resolve the complex scientific issues 
concerning common mechanism of toxicity in a meaningful way. EPA has 
begun a pilot process to study this issue further through the 
examination of particular classes of pesticides. The Agency hopes that 
the results of this pilot process will increase the Agency's scientific 
understanding of this question such that EPA will be able to develop 
and apply scientific principles for better determining which chemicals 
have a common mechanism of toxicity and evaluating the cumulative 
effects of such chemicals. The Agency anticipates, however, that even 
as its understanding of the science of common mechanisms increases, 
decisions on specific classes of chemicals will be heavily dependent on 
chemical specific data, much of which may not be presently available.
    Although at present the Agency does not know how to apply the 
information in its files concerning common mechanism issues to most 
risk assessments, there are pesticides as to which the common mechanism 
issues can be resolved. These pesticides include pesticides that are 
toxicologically dissimilar to existing chemical substances (in which 
case the Agency can conclude that it is unlikely that a pesticide 
shares a common mechanism of activity with other substances) and 
pesticides that produce a common toxic metabolite (in which case common 
mechanism of activity will be assumed).
    EPA does not have, at this time, available data to determine 
whether cyprodinil 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, 
cyprodinil 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 cyprodinil has a common mechanism of toxicity 
with other substances.

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

    1. Acute risk. There was no acute dietary endpoint identified, 
since cyprodinil does not pose acute dietary risk.
    2. Chronic risk. Using the Theoretical Maximum Residue Contribution 
(TMRC) exposure assumptions described above, EPA has concluded that 
aggregate exposure to cyprodinil from food will utilize 5.8% of the RfD 
for the U.S. population. The major identifiable subgroup with the 
highest aggregate exposure is non-nursing infants (< 1 year old) 
discussed below. 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. Despite the potential for exposure to cyprodinil 
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

[[Page 17704]]

aggregate exposure to cyprodinil 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 cyprodinil, EPA considered data from 
developmental toxicity studies in the rat and rabbit and a two-
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 during 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 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. In a prenatal developmental 
toxicity study, rats received oral administration of cyprodinil in 3.0% 
aqueous corn starch suspension at dose levels of 0, 20, 200 or 1,000 
mg/kg/day during gestation days 6 through 15. For maternal toxicity, 
the NOEL was 200 mg/kg/day, and the LOEL was 1,000 mg/kg/day based on 
decreased body weight, decreased body weight gain, and decreased food 
consumption. For developmental toxicity, the NOEL was 200 mg/kg/day, 
and the LOEL was 1,000 mg/kg/day based on increased incidence of 
skeletal variations (primarily absent or reduced ossification of the 
metacarpals) and on decreased mean fetal weight.
    In a prenatal developmental toxicity study, New Zealand White 
rabbits (19/group) received oral administration of cyprodinil in 3.0% 
corn starch suspension (4 ml/kg) at dose levels of 0, 5, 30, 150 or 400 
mg/kg/day during gestation days 7 through 19. For maternal toxicity, 
the NOEL was 150 mg/kg/day and the LOEL was 400 mg/kg/day based on 
decreased body weight gain during the treatment period. For 
developmental toxicity, the NOEL was 150 mg/kg/day and the LOEL was 400 
mg/kg/day, based on an increased incidence of 13th rib.
    iii. Reproductive toxicity study. In a two-generation reproduction 
study, rats (30/sex/group) were fed diets containing cyprodinil at does 
levels of 0, 10, 100, 1,000 or 4,000 ppm (0.7, 6.7, 68 or 273 mg/kg/day 
in males and 0.8, 8.2, 81 or 326 mg/kg/day in females) For parental 
systemic toxicity, the NOEL was 1,000 ppm (81 mg/kg/day) and the LOEL 
was 4,000 ppm (326 mg/kg/day) based on decreased parental female 
premating body weight gain. In addition, significant increases in liver 
and kidney weight at 4,000 ppm were judged to be non-adverse due to 
lack of corroborative histopathological lesions. However, in light of 
the fact that the chronic study demonstrates liver toxicity, the EPA 
believes that these organ weight changes should be considered as 
supportive evidence of toxicity at the LOEL of 4,000 ppm. Organ weight 
changes at 1,000 ppm were not considered sufficient in magnitude to 
allow revision of the NOEL and LOEL for parental systemic toxicity. For 
offspring toxicity, the NOEL was 1,000 ppm (81 mg/kg/day) and the LOEL 
was 4,000 ppm (326 mg/kg/day), based on decreased F1 and 
F2 pup body weight during lactation and continuing into 
adulthood for F1 rats.
    iv. Pre- and post-natal sensitivity. The pre- and post-natal 
toxicology database is complete with respect to current toxicological 
data requirements. Based on the developmental and reproductive toxicity 
studies discussed above, there does not appear to be an extra 
sensitivity to pre- and post- natal effects.
    v. Conclusion. EPA concludes that reliable data support use of the 
hundredfold uncertainty factor and that an additional tenfold factor is 
not needed to ensure the safety of infants and children from dietary 
exposure.
    2. Chronic risk. Using the conservative exposure assumptions 
described above, EPA has concluded that aggregate exposure to 
cyprodinil from food will utilize 14% of the RfD for nursing infants (< 
1 year old), 27% of the RfD for non-nursing infants (< 1 year old), 15% 
of the RfD for children 1 to 6 years old and 7.5% of the RfD for 
children 7 to 12 years old. 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. Despite the potential for exposure 
to cyprodinil 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 to infants and children from aggregate exposure to 
cyprodinil residues.

 III. Other Considerations

A. Metabolism in Plants and Animals

    1. Nature of residue -- plants. The nature of the residue in plants 
is understood. Acceptable metabolism studies using 14C-
labeled cyprodinil have been performed in stone fruit (peaches), pome 
fruit (apples), wheat, tomatoes, and potatoes. Cyprodinil is 
metabolized primarily by hydroxylation followed by sugar conjugation. 
Cleavage of the amino bridge, opening of the pyrimidine ring, opening 
of the cyclopropyl ring and formation of thiolactic acid conjugates are 
also minor pathways. Incorporation into starch was also observed in 
potato tubers and wheat grain.
    EPA has determined that there are no cyprodinil metabolites of 
toxicological or regulatory concern in plants.
    2. Nature of residue-- animals-- i. Ruminants. The nature of the 
residue in ruminants is understood. An acceptable metabolism study 
using 14C phenyl-labeled cyprodinil has been performed in 
goats. Based on the structures characterized, the metabolism of 
cyprodinil proceeded predominantly via hydroxylation followed by 
conjugation with sulfuric and glucuronic acid. A breakdown of the 
pyrimidine ring was seen only in the liver and resulted in metabolite 
L1. Cleavage of the amino bridge between the phenyl and the pyrimidine 
ring was only a minor reaction as indicated by the small amounts of CGA 
249287 found in the liver and kidneys of goats dosed with 
14C-pyrimidine cyprodinil.
    For compounds with multiple rings, it is generally required that 
acceptable metabolism studies be performed with each ring labeled. 
However, as the acceptable metabolism study using 14C-
phenyl-labeled cyprodinil indicated that ring cleavage is a minor 
pathway and the available data from a supplementary ruminant metabolism 
study using 14C-pyrimidine-labeled cyprodinil support this 
conclusion, further ruminant

[[Page 17705]]

metabolism studies for cyprodinil will not be required.
    EPA has determined that there are no cyprodinil metabolites of 
toxicological or regulatory concern in animals based on the dietary 
burden associated with the proposed uses.
    ii. Poultry. There are no poultry feed items associated with the 
proposed uses. Therefore data on the nature of the residue in poultry 
is not required for this petition.

B. Analytical Enforcement Methodology

    An adequate enforcement methodology, AG-631B, is available to 
enforce the tolerance on stone fruits, pome fruits, almond hulls, 
almond nutmeats and grapes. Quantitation is by high performance liquid 
chromatography with column switching. Information about the analytical 
method is available to the public from: Calvin Furlow, Information 
Resources and Services Division, Public Information and Records 
Integrity Branch, 7502C, Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St., SW., Washington, DC 20460, office 
location and telephone number: Room 101FF, CM #2, 1921 Jefferson Davis 
Highway, Arlington, VA 22202 (703-305-5229).
    Because no tolerances for animal commodities are required, no 
analytical methods for animal commodities were required.

C. Magnitude of Residues

    The residues of cyprodinil resulting from the proposed uses will 
not exceed almond hulls at 0.05 ppm; almond nutmeats at 0.02 ppm; apple 
pomace, wet at 0.15 ppm; grapes at 2.0 ppm; pome fruit at 0.1 ppm; 
raisins at 3.0 ppm and stone fruit at 2.0 ppm. .

D. International Residue Limits

    There are no Codex or Mexican residue limits established for 
cyprodinil. As part of the joint review, Canada will be setting 
equivalent tolerances for pome fruits and stone fruits and equivalent 
import tolerances for almonds and grapes. Therefore no compatibility 
problems exist for the proposed tolerances.

E. Rotational Crop Restrictions

     Stone fruit, pome fruit, almonds and grapes are not rotated, 
therefore rotational crop restrictions do not apply to this petition.

IV. Conclusion

    Therefore, the following tolerances are established for residues of 
cyprodinil: almond hulls at 0.05 ppm; almond nutmeats at 0.02 ppm; 
apple pomace, wet at 0.15 ppm; grapes at 2.0 ppm; pome fruit at 0.1 
ppm; raisins at 3.0 ppm and stone fruit at 2.0 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 409. 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 can be made, EPA will continue to 
use those procedural regulations with appropriate adjustments to 
reflect the new law.
    Any person may, by June 9, 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 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 
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 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 Docket

    EPA has established a record for this rulemaking under docket 
control number [OPP-300643] (including any comments and data submitted 
electronically). 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 8:30 a.m. 
to 4 p.m., Monday through Friday, excluding legal holidays. The public 
record is located in Room 119 of the Public Information and Records 
Integrity Branch, Information Resources and Services Division (7502C), 
Office of Pesticide Programs, Environmental Protection Agency, Crystal 
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Electronic comments may be sent directly to EPA at:
    [email protected].

    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption.
    The official record for this rulemaking, as well as the public 
version, as described above will be kept in paper form. Accordingly, 
EPA will transfer 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.

VII. Regulatory Assessment Requirements

    This final rule establishes tolerances 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

[[Page 17706]]

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 these tolerances and exemptions that are 
established on the basis of a petition under FFDCA section 408(d), such 
as the tolerances set 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.

 VIII. Submission to Congress and the General Accounting Office

     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: April 6, 1998.

Stephen L. Johnson,

Acting Director, 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. By adding Sec. 180.532 to subpart C to read as follows:


Sec. 180.532  Cyprodinil, tolerances for residues.

    (a) General . Tolerances are established for residues of the 
fungicide cyprodinil, 4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine 
in or on the following food commodities:

------------------------------------------------------------------------
                                                              Parts per 
                         Commodity                             million  
------------------------------------------------------------------------
Almond hulls...............................................         0.05
Almond nutmeats............................................         0.02
Apple pomace, wet..........................................         0.15
Grapes.....................................................          2.0
Pome fruit.................................................          0.1
Raisins....................................................          3.0
Stone fruit................................................          2.0
------------------------------------------------------------------------

    (b) Section 18 emergency exemptions. [Reserved]
    (c) Tolerances with regional registrations. [Reserved]
    (d) Indirect or inadvertent residues. [Reserved]

[FR Doc. 98-9679 Filed 4-9-98; 8:45 am]
BILLING CODE 6560-50-F