[Federal Register Volume 62, Number 231 (Tuesday, December 2, 1997)]
[Rules and Regulations]
[Pages 63662-63669]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-31552]
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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
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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:="">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
