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pyrimethanil Pesticide Tolerance 11/97

 

[Federal Register: December 2, 1997 (Volume 62, Number 231)]
[Rules and Regulations]               
[Page 63662-63669]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02de97-15]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Parts 180

[OPP-300589; FRL-5758-7]

 
Pyrimethanil; Pesticide Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: This regulation establishes an import tolerance for residues 
of the fungicide 4,6-dimethyl-N-phenyl-2-pyrimidinamine expressed as 
pyrimethanil in or on the raw agricultural commodity (RAC) wine grapes 
at 5.0 ppm. AgrEvo USA Company submitted a petition to EPA under the 
Federal Food, Drug, and Cosmetic Act (FFDCA) as amended by the Food 
Quality Protection Act of 1996 (Pub. L. 104-170) requesting the 
tolerance.

DATES: This regulation becomes effective December 2, 1997. Objections 
and requests for hearings must be received by EPA on or before February 
2, 1998.
ADDRESSEES: Written objections, and hearing requests identified by the 
docket control number, OPP-300589, 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-300589, must also be submitted to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person, bring a copy 
of objections and hearing requests to Rm. 1132, 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

[[Page 63663]]

of objections and hearing requests in electronic form must be 
identified by the docket control number [OPP-300589]. 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 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: Crystal Mall #2, 1921 
Jefferson Davis Hwy., Arlington, VA, (703) 308-9354, e-mail: 
waller.mary@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: In the Federal Register of August 1, 1997 
(62 FR 41379) (FRL-5732-4), 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 a pesticide tolerance petition (PP 4E4384) by 
AgrEvo USA Company, Little Falls Center One, 2711 Centerville Rd., 
Wilmington, DE 19808. The notice included a summary of the petition 
prepared by AgrEvo USA Company. There were no comments received in 
response to the notice of filing. The petition requested that 40 CFR 
part 180 be amended by establishing a tolerance for residues of the 
fungicide 4,6-dimethyl-N-phenyl-2-pyrimidinamine expressed as 
pyrimethanil in or on the raw agricultural commodity wine grapes at 5.0 
parts per million (ppm).

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 if 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 of 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 more 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% or less of the 
RfD) is generally considered acceptable by EPA to pose a reasonable 
certainty of no harm. EPA generally uses the RfD to evaluate chronic 
risks posed by pesticide exposure. For shorter term risks, which could 
occur for residential uses of a pesticide, 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 100-fold MOE is based on the same 
rationale as the 100-fold uncertainty factor. The MOE is a measure of 
how close the exposure comes to the NOEL.
    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 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,'' 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 enactment of FQPA, 
this risk 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 reassessment, 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,

[[Page 63664]]

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 risks 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 ground water 
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 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 pesticide. 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 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 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. Review of this regional data allows EPA 
to be reasonably certain that no regional population is exposed to 
residue levels higher than those estimated by the Agency.

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 
pyrimethanil and to make the determination on aggregate exposure, 
consistent with section 408(b)(2), for a tolerance for pyrimethanil on 
wine grapes at 5.0 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 pyrimethanil are 
discussed below.
    1. A battery of acute toxicity studies resulted in an acute oral 
LD50 = 4,149 milligrams/kilograms (mg/kg) (males) and 5,971 
mg/kg (females); an acute dermal LD50 >5,000 mg/kg for both 
sexes; an acute inhalation LC50 >1.98 mg/L; slight eye 
irritation; no dermal irritation; and a finding that pyrimethanil is 
not a sensitizer.
    2. A subchronic oral toxicity study in rats fed pyrimethanil at 
dose levels of 0, 80, 800, or 8,000 ppm for 13 weeks. Those doses were 
equivalent to daily intake of 0, 5.4, 54.5, 529.1 milligrams/kilograms/
day (mg/kg/day) for males and 0, 6.8, 66.7, 625.9 mg/kg/day for 
females. A supplementary control and a high dose (8,000 ppm) group were 
similarly treated for 13 weeks then maintained off-dose for 28 days to 
investigate the reversibility of any findings. Treatment of 
pyrimethanil did not affect mortality, clinical signs, water intake, 
ophthalmology, hematology, blood chemistry, or macroscopic pathology.
    Under the conditions of this study, the No Observed Effect Level 
(NOEL) was estimated to be 80 ppm (equivalent to a daily intake of 5.4 
mg/kg/day for males and 6.8 mg/kg/day for females). The Lowest Observed 
Effect Level (LOEL) was estimated to be 800 ppm (54.5 mg/kg/day for 
males and 66.7 mg/kg/day for females). The LOEL is based on decreased 
body weight gains in females, changed coloration of urine specimens, 
and increased incidence of hypertrophy of centrilobular hepatocytes in 
males.
    3. A subchronic oral toxicity in mice fed technical pyrimethanil at 
dose levels of 0, 80, 900, or 10,000 ppm for 13 weeks. Those doses were 
equivalent to 0, 12, 139, or 1,864 mg/kg/day for males and 0, 18, 203, 
or 2,545 mg/kg/day for females, respectively. There were no treatment-
related effects in mortality, clinical signs, water intake, or 
hematological parameters.
    The NOEL was estimated to be 900 ppm, equivalent to daily intake of 
139 and 203 mg/kg/day for males and females, respectively. The LOEL was 
estimated to be 10,000 ppm, equivalent to daily intake of 1,864 and 
2,545 mg/kg/day for males and females, respectively. The LOEL is based 
on decreased body weight gains, clinical chemistry data, necropsy, and 
histopathological findings.
    4. A subchronic oral toxicity study in dogs dosed with technical 
pyrimethanil by gavage at dose levels of 0, 6, 80, or 1,000/800 mg/kg/
day for 13 weeks. The highest dose was reduced from 1,000 mg/kg/day to 
800 mg/kg on day 7 due to persistent vomiting seen in all dogs 
receiving 1,000 mg/kg. Concentrations of dosing suspension (0.5% (w/v) 
methyl cellulose in distilled water) were within ranges of 82.5% to 
121.7% of nominal. There were no treatment related effects on 
mortality, organ weights, necropsy findings, histopathological, 
ophthalmoscopical, or hematological parameters.

[[Page 63665]]

    Under the conditions of this study, the NOEL was estimated to be 6 
mg/kg. The LOEL was estimated to be 80 mg/kg. The LOEL is based on the 
increased incidence of vomiting and diarrhea, salivation, cream 
coloration of feces, hypoactivity, and decreased water consumption.
    5. A chronic oral toxicity study in dogs dosed with pyrimethanil by 
gavage at doses of 0, 2, 30, or 400/250 mg/kg/day for 12 months. 
Administration of the test material at 400 mg/kg/day caused a high 
incidence of vomiting/emesis during week 1 of the study. For this 
reason, the dose regimen was decreased to 250 mg/kg/day on day 8 of the 
study. At this dose (250 mg/kg) vomiting was decreased to about 1% in 
all animals.
    Based on the results of this study, the NOEL is 30 mg/kg/day and 
the LOEL is 250 mg/kg/day, based on the decrease in body weight, food 
consumption, feed efficiency, and water consumption, reduced clotting 
times, and increases in white blood cells, (mainly neutrophils).
    6. A carcinogenicity feeding study in mice fed technical 
pyrimethanil at dose levels of 0, 16 ppm (males 2.0, females 2.5 mg/kg/
day), 160 ppm (males 20.0, females 24.9 mg/kg/day), or 1,600 ppm (males 
210.9, females 253.8 mg/kg/day) for 80 weeks resulted in a dose-related 
increase in the percentage (24%, 38%, 40%, and 67% in control, low-, 
mid-, and high-dose males, respectively) of deaths occurring prior to 
week 56 in males but there was no dose-related adverse effect on 
survival in either sex and adequate numbers of mice (both sexes) were 
available at study termination.
    Treated males displayed a higher incidence of urinary bladder 
distension at necropsy, and urogenital tract lesions were increased at 
the high-dose level compared to the control values. Since all 
urogenital tract tissues of the low-and mid-dose males were not 
examined, a dose-response cannot be determined. The NOEL for systemic 
effects can be set at 1,600 ppm (males 210.9, females 253.8 mg/kg/day), 
the highest dose tested (HDT). There was no increase in the incidence 
of any tumor type in either sex.
    7. A combined chronic toxicity/carcinogenicity study in rats fed 
pyrimethanil at dose levels of 0, 32, 400, or 5,000 ppm for 52 weeks 
(interim kill) or 104 weeks (main study). Those doses were equivalent 
to daily intake of 0, 1.3, 17, or 221 mg/kg/day for males and 0, 1.8, 
22, or 291 mg/kg/day for females.
    At the interim kill (52 weeks), relative liver/body weight ratios 
of animals given 5,000 ppm were siginificantly higher than controls. 
Necropsy revealed dark thyroids in 5,000 ppm treated animals only. 
Microscopic pathology showed minimal to moderate hypertrophy of 
centrilobular hepatocytes in animals given 5,000 ppm. In the thyroid 
gland, at 5,000 ppm, there were higher incidences of minimal to slight 
colloid depletion and hypertrophy of the follicular epithelium in males 
and females. A single focus of follicular hyperplasia was seen in males 
only. There were minimal to moderate intra-epithelial depositions of 
brown pigment (lipofuscin).
    At the terminal kill (104 weeks), at 5,000 ppm, an increase of 
absolute liver weight was observed in males only while increases of 
relative liver/body weight ratios were seen in both sexes. Non-
neoplastic findings included minimal to slight hypertrophy of 
centrilobular hepatocyes. There were higher incidences of eosinophilic 
foci in the liver of males and females compared with controls. Minimal 
to moderate focal cystic degeneration of the liver was also observed in 
males and females. In the thyroid gland, colloid depletion and 
hypertrophy of the follicular epithelium was seen in males and females 
compared to controls. Depositions of intra-cytoplasmic brown pigment 
(lipofuscin) within the thyroid follicular epithelium were seen only in 
animals given 5,000 ppm (38/50 males and 47/50 females).
    The only tissue showing a higher incidence of tumors than controls 
was the thyroid gland with benign follicular cell adenomas in both 
sexes. A pair-wise comparison for the incidence in high dose (5,000 
ppm) treated males was not statistically higher than the control. The 
incidence in both sexes was higher than the historical control range. A 
positive trend of the incidence for both sexes was noted. In addition, 
thyroid follicular cell adenocarcinomas were seen in animals treated at 
32 ppm (males) and 5,000 ppm (1 male only); however, the incidence was 
within the historical control range.
    At 400 ppm, a statistically significant increase of serum GGT level 
in males only was observed at week 102. Increased absolute liver weight 
(the relative liver/body weight ratio was comparable to control) in 
males was reported in the terminal necropsy findings. However, these 
parameters are considered to be of no toxicological significance 
because no corresponding significant histopathological finding was 
seen.
    No treatment-related significant effects were seen in animals given 
32 ppm.
    Under the condition of this study, the NOEL was estimated to be 400 
ppm. (equivalent to 17 mg/kg/day for males and 22 mg/kg/day for 
females). The LOEL was estimated to be 5,000 ppm (equivalent to 221 mg/
kg/day for males and 291 mg/kg/day for females). The LOEL was based on 
decreased body weight gains, increased serum cholesterol and GGT 
levels, increased relative liver/body weight ratios, necropsy, and 
histopathological findings.
    8. An oral development toxicity study in rats gavaged with 
pyrimethanil suspensions (1% (w/v) aqueous methyl cellulose at doses of 
0, 7, 85, or 1,000 mg/kg/day from gestation days 6 through 15. Maternal 
toxicity (hunched body posture, emaciation, and hair loss) were noted 
in high-dose animals. Treatment-related, statistically significant 
decreases in body weights and body weight gains were observed in high-
dose animals. Except for statistically significant decreased in mean 
litter weight and mean fetal weight of high-dose animals, all other 
caesarian section data were comparable to control values. The maternal 
NOEL was 85 mg/kg/day and the LOEL was 1,000 mg/kg/day (limit dose), 
based on decreases in mean body weight, mean body weight gain, mean 
litter weight, and mean fetal weight. The developmental NOEL was 1,000 
mg/kg/day (limit dose). The developmental LOEL was not established.
    9. A developmental toxicity (teratology) study in rabbits gavaged 
with pyrimethanil at doses of 0, 7, 45, or 300 mg/kg/day on gestation 
day 7 through 19. At 7 mg/kd/day, no treatment-related maternal or 
developmental effects were observed. The maternal NOEL is 7 mg/kg/day 
and the maternal LOEL is 45 mg/kg/day based on the slight increase in 
the number of females with reduced production and size of fecal 
pellets. The developmental NOEL is 45 mg/kg/day and the LOEL is 300 mg/
kg/day based on decreased fetal weight, increased incidence of fetal 
runts, increase in retarded ossification of fetal bones, increase in 
fetuses with 13 thoracic vertebrae, and 13 pairs of ribs.
    10. A reproduction toxicity study in rats fed pyrimethanil at dose 
levels of 0, 32, 400, or 5,000 ppm (males: 0, 1.9, 23.1, or 294 mg/kg/
day; females: 0, 2.2, 27.4, 343 mg/kg/day) during premating, gestation, 
and lactation periods. No treatment-related differences were noted in 
the necropsy findings of parental animals and their offspring. 
Treatment-related decreases in mean body weights were limited to high-
dose parental animals and their offspring.
    The NOEL for reproductive toxicity is 5,000 ppm (294 mg/kg/day, 
males; 343

[[Page 63666]]

mg/kg/day, females), the highest dose tested. The NOEL for 
developmental/systemic toxicity is 400 ppm (23.1 mg/kg/day, males; 343 
mg/kg/day, females); the LOEL was established at 5,000 ppm (294 mg/kg/
day, females), based on decreased pup body weights on lactation day 21.
    11. Studies on gene mutation and other genotoxic effects: A 
bacterial mutation assay with s. typhimurium; a bacterial mutation 
assay with E. Coli; a mouse micronucleus assay; an in vitro metaphase 
chromosomal aberration assay (human lymphocytes); an in vivo 
unscheduled DNA synthesis assay (rats) showed no evidence of mutagenic 
activity.
    12. A metabolism study showed that the majority (90%) of 
the administered dose of 14C-pyrimethanil following 14 days 
of repeated oral exposure to unlabeled pyrimethanil (5/sex) at a dose 
level of 10 mg/kg was eliminated within 24 hours, and the major route 
of elimination was via the urine (72%). Approximately 17-18% 
of the dose was eliminated via feces. Radiolabeled pyrimethanil was 
detected only in the liver, kidney, and blood at study termination (24 
hours post dose). The highest residue was displayed in the liver in 
both sexes. There was no significant sex difference. The overall 
recovery of radiolabeled pyrimethanil was 91%.
    13. A metabolism study showed that the majority of a radiolabeled 
dose of pyrimethanil (97% low dose; 65% high dose) 
administered following single oral exposures of rats to dose levels of 
11.89 or 800 mg/kg of pyrimethanil was eliminated within 24 hours, and 
the major route of elimination was via the urine (low dose 74%-76%; 
high dose 65%-67%). Approximately 21%-23% of the low dose and 
15%-18% of the high dose was eliminated via the feces. The 
highest residues were displayed in the liver, kidney, thyroid, and 
blood at the high dose. The overall recovery of radiolabeled 
pyrimethanil following single-dose exposure was >94% at the high dose 
and >101% at the low dose. No sex differences were observed. Since 
tissue levels were measured at only one time point, no statement 
regarding bioaccumulation can be made.
    14. A metabolism study in rats administered 14C-
pyrimethanil orally once a day over a period of 28 days (10 mg/kg), 
with periodic sacrifices at days 1, 3, 5, 8, 11, 17, 23, 28, and 32 for 
residue analysis of organs/tissues showed detectable levels of 
radiolabeled pyrimethanil in adrenals, blood, kidney, liver, spleen, 
and thyroid. Blood and liver displayed detectable levels of 
radiolabeled pyrimethanil after a single dose (24-hour sample). Four 
days after the last dose, detectable levels of radiolabeled 
pyrimethanil were found in the liver, kidney, and thyroids. It appeared 
that the levels in the blood, kidney, and thyroid continued to increase 
with increased exposure time, while the level in the adrenal appeared 
to reach a plateau, and levels in the liver appeared to decline.

B. Toxicological Endpoints

    1. Acute toxicity. To assess acute dietary exposure, the Agency 
used a NOEL of 45 mg/kg/day and a LOEL of 300 mg/kg/day from a 
developmental toxicity study in rabbits for evaluating acute risk to 
females 13+, the subpopulation of concern.
    2. Chronic toxicity. A RfD of 0.2 mg/kg was established based on a 
long-term rat toxicity study with a NOEL of 400 ppm and an uncertainty 
factor of 100.
    3. Carcinogenicity. Pyrimethanil was classified as a Group C 
chemical - possible human carcinogen. The Agency's Carcinogenicity Peer 
Review Committee (CPRC) chose a non-linear approach (MOE) based on a 
NOEL of 17 mg/kg/day for increased incidences of thyroid tumors in 
rats. The MOE methodology was selected because of thyroid tumors 
associated with administration of pyrimethanil in the rat which may be 
due to a disruption in the thyroid-pituitary status.
    4. Toxicity endpoints for non-dietary exposure. A toxicity endpoint 
for non-dietary exposure is not required as the Agency is only 
considering the import tolerance on wine grapes.

C. Exposure and Risks

    1. From food and feed uses. This is the first tolerance for 
residues of pyrimethanil in or on a raw agricultural commodity. Risk 
assessments were conducted by EPA to assess dietary exposures and risks 
from pyrimethanil as follows:
    i. Acute dietary exposure and risk. An acute dietary endpoint for 
females 13+ and the general public were assessed because of potential 
oral consumptions. For the subpopulation of concern, females 13+, the 
estimated acute Margin of Exposure (MOE) of 405 demonstrates no acute 
dietary concern.
    ii. Chronic exposure and risk. The RfD used for the chronic dietary 
analysis was 0.20 mg/kg/day. A tolerance of 5.0 ppm in or on wine 
grapes was used. Using the tolerance level residue (5.0 ppm) and 
assuming that 100% of the crop is treated, the risk assessment resulted 
in use of less than 1% of the RfD for the general population and all 22 
subgroups, including infants under 1 year and children under 13 years 
of age. No feed items are associated with wine grapes and therefore, 
secondary residues are not expected. In the best judgement of the 
Agency, the pyrimethanil chronic dietary risk does not exceed the level 
of concern.
    2. From drinking water. Since this is an import tolerance and there 
are no U.S. registrations for this chemical, there are not risks 
associated with drinking water.
    3. From non-occupational non-dietary exposure. As stated, this is 
an import tolerance and there are no U.S. registrations, therefore no 
non-occupational non-dietary exposure and risk are expected.
    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

[[Page 63667]]

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 pyrimethanil 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, 
pyrimethanil does not appear to produce a toxic metabolite produced by 
other substances. For the purposes of this tolerance action, therefore, 
EPA has assumed that pyrimethanil does not have a common mechanism of 
toxicity with other substances.

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

    1. Chronic risk. Using the TMRC exposure assumptions described 
above, EPA has concluded that aggregate exposure to pyrimethanil from 
food will utilize less than 1% of the RfD for the U.S. population and 
the 22 subgroups, including infants and children. EPA generally has no 
concern for exposures below 100% of the RfD because the RfD represents 
the level at or below which daily aggregate exposure over a lifetime 
will not pose appreciable risks to human health. EPA concludes that 
there is a reasonable certainty that no harm will result from aggregate 
exposure to pyrimethanil residues.
    2. Acute risk. Acute dietary margins of exposure greater than 100 
tend to cause no dietary concern. The estimated MOE value of 450 does 
not exceed the Agency's level of concern and therefore, EPA has a 
reasonable certainty that no harm will result from acute dietary 
exposure.

E. Aggregate Cancer Risk for the U.S. Population

    This chemical has been classified as a Group C - chemical (possible 
human carcinogen) and a non-linear methodology (MOE) was applied for 
the estimation of human cancer risk. Cancer MOEs are estimated by 
dividing the carcinogenic NOEL of 17 mg/kg/day from the rat chronic 
feeding study by the chronic exposure (TMRC). The cancer MOE was 
estimated for the U.S. population as 40,380. The estimated MOE does not 
exceed the Agency's level of concern and therefore, EPA has a 
reasonable certainty that no harm will result from exposures to 
residues of pyrimethanil.

F. 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 pyrimethanil, 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 pesticide exposure during prenatal development to one or 
both parents. 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 data base unless EPA determines that a different 
margin of safety will be safe for infants and children. The 
developmental and reproductive toxicity data base for pyrimethanil is 
considered to be complete. The data base includes an acceptable 2-
generation reproduction study in rats and acceptable pre-natal 
developmental toxicity studies in rats and rabbits. The data did not 
suggest any additional sensitivity to the embryo or neonate following 
in utero or early post-natal exposure to pyrimethanil. The maternal 
NOEL was 85 mg/kg/day and the developmental NOEL was 1,000 mg/kg/day 
(highest dose tested) in the rat developmental toxicity study. In the 
developmental toxicity study in rabbits, the maternal NOEL was 7 mg/kg/
day and the developmental NOEL was 45 mg/kg/day. Results from the 2-
generation reproduction toxicity study in rats indicated a reproductive 
toxicity NOEL of 294 mg/kg/day for males and 343 mg/kg/day for females 
(highest dose tested). The developmental toxicity NOEL was established 
at 23.l mg/kg/day for males and 27.4 mg/kg/day for females. The 
developmental and reproductive NOEL are at least 1,000 fold higher than 
the RfD (0.2 mg/kg/day), and should be protective for infants and 
children. No additional safety factors are warranted.
    2. Chronic risk. Using the conservative exposure assumptions 
described above, EPA has concluded that aggregate exposure to 
pyrimethanil from food will utilize less than 1% of the RfD for infants 
and children. 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. EPA concludes that there is a reasonable 
certainty that no harm will result to infants and children from 
aggregate exposure to pyrimethanil residues.

III. Other Considerations

A. Metabolism in Plants and Animals.

    The metabolism in plants is adequately understood for the purposes 
of this use of pyrimethanil on wine grapes. The residue of regulatory 
concern is the parent compound only, pyrimethanil. Since it has been 
determined that secondary residues in livestock commodities are not 
likely to result from this use, metabolism of pyrimethanil in animals 
is not relevant to this requested use on wine grapes.

B. Analytical Enforcement Methodology

    The method accepted by EPA for enforcement of pyrimethanil in wine 
grapes is AgrEvo USA's Method (R2/2) Analytical Method for the 
Determination of Residues of Pyrimethanil in Wine by HPLC (MRID # 
433450-10). This method is available from the Docket under docket 
control number [OPP-300589] at the address stated above.

C. Magnitude of Residues.

    Fifty-seven field trials consisting of different applications and 
concentrations of pyrimethanil were performed in Italy, Germany, South 
Africa, France, Spain, and Greece. HPLC/UV was the analytical method 
used for residue determination. Grape and wine samples were stored at -
20  deg.C and 4  deg.C, respectively, until analysis. Maximum storage 
period was 9 months and 12 months for wine and grape samples, 
respectively. The storage period, as indicated by the storage stability 
data, is considered adequate for storage samples. Residues of 
pyrimethanil for grapes ranged from 0.74 to 4.14 ppm. The maximum value 
of 4.14 ppm was obtained after a maximum total application rate of 4 kg 
ai/Ha and a PHI of 26 days. Additionally, one study showed a maximum 
residue for grapes of 6.2 ppm (PHI = 0 days, Total application rate = 
2.4 kg ai/Ha) and another maximum residue of 9.5 ppm (PHI = 26 days, 
Total application rate = 3.0 kg ai/Ha). However, most of the residue in 
wine grapes were less than 4.14 ppm. For

[[Page 63668]]

grape must, residues ranged from 0.41 to 1.3 ppm. For wine, residues 
ranged from <0.05 to 1.8 ppm.
    A processing study was conducted in Fresno, California in which one 
application of pyrimethanil (40 SC) was made at a nominal rate of 1 kg 
ai/Ha at each of the following growth stages: flowering, grape closure, 
color change, and 21 days pre-harvest. Applications were made by 
airblast ground rig sprayer and all plots were harvested at normal 
harvest time.
    Residues of pyrimethanil in whole grapes concentrated in all 
processed commodities produced from those grapes except juice. Raisins 
and juice are considered to be the only processed commodities. Raisin 
waste, wet and dry grape pomace are not considered processed 
commodities for the purposes of this petition in/on wine grapes. 
However, since this petition is for wine grapes and not for table 
grapes, a tolerance in/on raisins is not needed at this time. For 
future tolerance petitions in grapes grown for fresh consumption, a 
tolerance will be required for raisins.

D. Codex Considerations

    There are no Mexican, Canadian, or Codex listings for residues of 
pyrimethanil; therefore, there are no harmonization issues.

IV. Conclusion

    Therefore, the tolerance is established for pyrimethanil in or on 
wine grapes at 5.0 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 
the new section 408(e) and (1)(6) as was provided in the old section 
408 and in section 409. However, the period of 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 its current procedural regulations with appropriate adjustments to 
reflect the new law.
    Any person may, by February 2, 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-300589 (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 1132 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 Hwy., Arlington, VA.
    Electronic comments may be sent directly to EPA at: opp-
docket@epamail.epa.gov.
    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption.
    The official record for this rulemaking, as well as the public 
version, as described above will be kept in paper form. Accordingly, 
EPA will transfer 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 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 At (RFA) (5 
U.S.C.601 et. seq.) do not apply. Nevertheless, the Agency 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

[[Page 63669]]

to the Chief Counsel for Advocacy of the Small Business Administration.

VIII. Submission to Congress and the General Accounting Office

    Under 5 U.S.C. 801(a)(1)(A), as added by the Small Business 
Regulatory Enforcement Fairness Act of 1996, the Agency has submitted 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 General Accounting Office prior to publication of this rule in 
today's Federal Register. This is not a ``major rule'' as defined by 5 
U.S.C. 804(2).

List of Subjects in 40 CFR Parts 180

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pest, Reporting and 
recordkeeping requirements.
    Dated: November 21, 1997.
Linda A. Travers,
Acting Director, Office of Pesticide Programs.
    Therefore, 40 CFR chapter I is amended as follows:

PART 180--[AMENDED]

    a. The authority citation for part 180 continues to read as 
follows:

    Authority: 21 U.S.C. 346a and 371

    b. Section Sec. 180.518 is added to read as follows:


Sec. 180.518   Pyrimethanil; tolerances for residues.

    (a) General. [Reserved]
    (b) Section 18 emergency exemptions. [Reserved]
    (c) Tolerances with regional registrations. [Reserved]
    (d) Indirect or inadvertent residues. [Reserved]
    (e) Import. Import tolerances are established for residues of the 
fungicide 4,6-dimethyl-N-phenyl-2-pyrimidinamine expressed as 
pyrimethanil in or on the following raw agricultural commodity:

                                                                        
------------------------------------------------------------------------
                 Commodity                        Parts per million     
------------------------------------------------------------------------
Wine grapes...............................  5.0 ppm                     
------------------------------------------------------------------------


[FR Doc. 97-31552 Filed 12-1-97; 8:45 am]
BILLING CODE 6560-50-F