Notice of Filing of Pesticide Petition 8E7353

IR-4 Project Headquarters  

EPA Registration Division contact: Susan Stanton (703) 305-5218 

EPA has received a pesticide petition (PP #8E7353) from IR-4 Project
Headquarters, 500 College Road East, Suite 201W, Princeton, NJ 08540,
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.518 by
establishing tolerances for residues of the fungicide pyrimethanil
4,6-dimethyl-N-phenyl-2-pyrimidinamine in or on the raw agricultural
commodities as follows 1) revise the existing tolerance for the fruit,
stone, group 12, except cherry at 3.0 parts per million (ppm) to fruit,
stone, group 12 at 10 ppm, 2) revise the tolerance designation for
fruit, citrus, group 10 postharvest to exclude lemons at 10 ppm to read
fruit, citrus, group 10, except lemons (postharvest) at 10 ppm  and 3)
add a separate tolerance for lemon at 11.0 ppm. EPA has determined that
the petition contains data or information regarding the elements set
forth in section 408(d)(2) of the FFDCA; however, EPA has not fully
evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petition.  Additional data may be
needed before EPA rules on the petition.

A. Residue Chemistry                                        

	1. Plant metabolism. The metabolic profile of pyrimethanil has been
investigated following application to five different crops (apple,
carrots, grapes, lettuce and tomatoes) and is well understood.  In
plants, pyrimethanil is the only significant residue ranging from
essentially all of the Total Radioactive Residues (TRR) in carrots and
tomatoes to 44% in lettuce. Limited metabolism of pyrimethanil occurs
with minor amounts (less than 10%) of the phenyl and pyrimidyl
hydroxylated metabolites (AE C614276, AE C614277, AE C614278 and AE
C621312) being released after acid hydrolysis. Analysis of the foliage
from apples and carrots confirmed that the metabolism of pyrimethanil in
plants proceeded primarily via hydroxylation of the aromatic ring
structures as well as the methyl groups.



	2. Analytical method.  The plant metabolism studies indicated that
analysis for the parent compound, pyrimethanil was sufficient to enable
the assessment of the relevant residues in crop commodities.  For the
stone fruit group, peaches, plums, and sweet cherries were analyzed as
representative crops.  For peaches, plums, and sweet cherries
pyrimethanil was extracted by homogenization with acetone, the extract
acidified and washed with hexane and basified to enable solvent
partition  (ethyl acetate and hexane).  Final clean up was by silica
SPE, with determination by gas chromatography with mass selective
detection.  The validated sensitivity of the method is 0.05 ppm for
pyrimethanil, which allows for the detection and measurement of residues
in or on stone fruits at or above the proposed tolerance level.

	3. Magnitude of residues. Magnitude of residue trials were conducted
for pyrimethanil applied postharvest to peaches, plums, and cherries by
whole fruit dip, and high volume sprays and to peaches and plums by low
volume sprays. Three (3) peach field trials were conducted during the
2004 and 2005 growing seasons, two in California (Region 10) and one in
New Jersey (Region 2).  Likewise, three (3) plum field trials were
conducted during the 2004 growing season, one each in California,
Washington (region 11) and Michigan (Region 5).  California represents
54% of the U.S. fresh (freestone) peach production and over 90% of the
US plum production.  U.S. cherry trials (3) were conducted in 2006 in
California, Michigan, and Washington.  Additional trials were conducted
in Germany with fruits originating from Chile and Argentina.  Samples
were harvested at maturity and analyzed with the validated analytical
method described above.  

In each U.S. trial, the stone fruits were dipped for approximately 30
seconds in the fungicide solution at a rate of approximately 0.881 lb ai
/100 gal mix (equivalent to 400 g ai/100 gal or 1000 ppm AI).  Two
additional treatments were examined in the California trials and
Washington cherry trials, whereby fruit were sprayed with PENBOTEC™
400SC at a rate of approximately 400 grams AI/200,000 lb fruit (400
grams AI/25,000 lbs fruit for cherries) in a high-volume or low-volume
spray, except for cherries where a low volume application was not
conducted.   A fruit wax adjuvant was added to each of the mixtures for
all treatments.  In the foreign trials, fruit were dipped for 30-60
seconds in aqueous solutions containing either 323 or 430 ppm
pyrimethanil,and sampled for residues after 0, 3, 7, 14, 28, 31, 35, and
42 days in cold or ambient storage. Following treatment, the fruits were
allowed to dry and the pits were removed prior to frozen storage until
analysis.

The results from the three peach trials show that the maximum residue in
fruit following a 30-second post-harvest dip in PENBOTEC 400SC at
approximately 0.881 lb ai/100 gal mix was 8.2 ppm.  Residues were
lower in samples treated with the low-volume spray (400 g ai/16.42 gal
oil and water mixture) of PENBOTEC 400SC at approximately 400 grams
AI/200,000 lb fruit, with a maximum residue of 3.3 ppm.  The lowest
residues were observed in samples treated with the high-volume spray
(400 g ai/~ 100 gal oil and water mixture) of PENBOTEC 400SC at
approximately 400 grams AI/200,000 lb fruit, with a maximum residue of
2.1 ppm.

On plums, the results from the three trials show that the maximum fruit
residue following a 30-second post-harvest dip in PENBOTEC 400SC at
approximately 0.881 lb ai/100 gal mix was 2.00 ppm.  Residues were
lower in samples treated with the low-volume spray (400 g ai/16.42 gal
oil and water mixture) of PENBOTEC 400SC at approximately 400 grams
AI/200,000 lb fruit, with a maximum residue of 0.347 ppm.  The lowest
residues were observed in samples treated with the high-volume spray
(400 g ai/~ 100 gal oil and water mixture) of PENBOTEC 400SC at
approximately 400 grams AI/200,000 lb fruit, with a maximum residue of
0.204 ppm.

On sweet cherries, the results from the three U.S trials show that the
maximum fruit residue following a 30-second post-harvest dip in PENBOTEC
400SC at approximately 0.881 lb ai/100 gal mix was 13.00 ppm. 
Residues were about the same in samples treated with the high-volume
spray (400 g ai/~ 100 gal oil and water mixture) of PENBOTEC 400SC at
approximately 400 grams AI/25,000 lb fruit, with a maximum residue of
12.0 ppm.  In the foreign trials, fruit dipped at 323 or 430 ppm AI had
maximum residues of 1.21 ppm and 1.47 ppm, respectively.  

Since the registrant is proposing a maximum application rate that is
half the rate tested (i.e. 500 ppm vs 1000 ppm for dip treatment), the
data were extrapolated and the MRL calculator used to project a proposed
tolerance level.  When the MRL calculator rejects lognormality, it
recommends the California Method of the mean plus three standard
deviations.  The resulting recommendation for the stone fruit crop group
is 7 ppm for postharvest use.  Since there is already an existing
tolerance of 3.0 ppm for the stone fruit crop group (except cherries), a
revised tolerance of 10.0 ppm for the entire Crop Group 12 – Stone
Fruits is proposed. 

Five lemon trials were conducted in California, representing NAFTA
growing region 10.  At each trial, one foliar airblast application of
Scala 600SC at a rate of approximately 0.70 lb ai/A was applied.  No
adjuvant was added to the spray mixtures.  Commercially mature lemons
were collected 7 days prior to harvest.  The maximum storage interval
for field-treated samples in this study was 523 days.  Storage
stability testing was performed after 542 days of frozen storage;
results demonstrated stability.  Pyrimethanil residues ranged from 0.068
to 0.31 ppm with the lowest residues (0.068 ppm and 0.095 ppm) in a
single trial, while in the remaining trials, residues ranged from 0.12
to 0.31 ppm, and the highest average field trial was 0.27 ppm.  

B. Toxicological Profile 

	1. Acute toxicity.  Pyrimethanil is of low acute toxicity placing the
active ingredient in Toxicity Category II, III and IV.  Pyrimethanil is
non-irritating to the eyes and skin and is not a skin sensitizer. 

	2. Genotoxicity. Pyrimethanil is not mutagenic or genotoxic in any
assay in either the presence or absence of metabolic activation.

	3. Reproductive and developmental toxicity. Pyrimethanil is not a
developmental or reproductive toxicant.

a.  Teratology - Rat

Thirty Sprague Dawley rats/group received doses of 0, 7, 85, 1,000 mg/kg
of pyrimethanil by gavage from gestation days (GD) 6-15.  At the highest
dose tested, reduced maternal body weight gain was observed during
GD6-15, along with a slight but statistically significant decrease in
food consumption, hair loss, hunched posture, slight emaciation, and
slightly reduced mean fetal body weight.  The maternal and developmental
NOEL was 85 mg/kg.

b.  Teratology - Rabbit

Groups of at least 18 time-mated New Zealand White rabbits received oral
gavage doses of 0, 7, 45 or 300 mg/kg/d pyrimethanil over gestation days
(GD) 7-19.  At the highest dose tested, there was a decrease in body
weight gain, production of feces and food consumption.  Three females
were euthanized due to severe emaciation.  The highest dose, 300
mg/kg/day exceeded the maternal maximum tolerated dose (MTD).  The
maternal NOAEL was 45 mg/kg/d due to reduced fecal production in 1/3 of
the animals. The high dose resulted in reduced mean fetal body weight,
increased incidence of runts, delayed skeletal ossification and
incidence of fetuses with 13 thoracic vertebrae and ribs. The maternal
NOEL was 7 mg/kg/day.  The developmental NOEL was 45 mg/kg/d.

c.  Two-Generation Reproduction - Rat

Three groups of 30 Sprague-Dawley rats per sex received dietary exposure
to pyrimethanil at levels of 0, 1.7, 20.9 or 266.7 mg/kg/d.  In the
parental generation at the highest dose tested there was a statistically
significant decrease in mean body weight gain in both sexes.  Mean pup
weights, observed on PND1 through weaning, were reduced, though were
within the range of historical controls.  In the F1 generation at the
highest dose tested, mean body weights and mean food consumption were
reduced.  Though the mean score for the combined sexes was the same as
the controls, a marginally different air-righting reflex at PND11
associated with reduced body weight was seen in high dose male pups. 
The NOEL for maternal and developmental toxicity was 20.9 mg/kg/d.  The
reproductive NOEL was 266.7 mg/kg/d.

	4. Subchronic toxicity. 

28-Day Dietary – Rat

Five Sprague-Dawley rats/sex/group received dietary exposure to
pyrimethanil for 28 days at 0, 844, 1,161, 1,500 and 2,710 mg/kg/day. 
All doses exceeded the maximum tolerated dose.  Severe emaciation was
observed at all dose levels.  Body weight gains and food consumption
were reduced.  Liver and thyroid histopathology were observed, along
with reduced hemoglobin, MCV and MCH.  Kidney, adrenal and liver weights
were altered.  No NOEL or NOAEL was achieved.



90 Day Dietary – Rat

Ten Sprague-Dawley rats/sex/group received pyrimethanil in the diet at
dose levels of 0, 5.4-6.8, 54.5-66.7, 545-667 mg/kg/d (males and
females, respectively).  High dose animals had reduced body weight gain
and food consumption, increased urinary protein in males, colored urine
(not blood or bilirubin) and minimal hepatocellular hypertrophy.  The
NOAEL in males was 54.5-66.7 (males and females, respectively) due to
colored urine and a low incidence of minimal centrilobular
hepatocellular hypertrophy.  The NOEL was 5.4 mg/kg/d (males) -6.8
mg/kg/d  (females).

28-Day Dietary-Mouse

Five CD-1 mice/sex/group received dietary doses of 0, 167-236, 567-667,
1960-2357 mg/kg/d, males and females respectively, for 28 days (all the
mice in one additional high dose group, 30,000 ppm, died within the
first week of the study).  At  1960-2357 mg/kg/day, animals experienced:
 body weight loss (females), decreased body weight gain during the 1st
two weeks (males), a statistically significant decrease in cholesterol,
statistically significant decreases in relative liver weights (females),
pigmentation of thyroid follicles, urolithiasis, moderate urothelial
hyperplasia in urinary bladder, and slight kidney tubular degeneration
(females).  The NOEL was 167-236 mg/kg/d.

90-Day Dietary-Mouse 

Twenty CD-1 mice/sex/group received pyrimethanil diet exposure at dose
levels of 0, 12-18, 139-203, 1,864-2,545 mg/kg/d males-females for 90
days.  At the high dose, animals had decreased body weight and increased
food consumption, cholesterol and total bilirubin.  High dose females
had increased relative liver weights.  Histopathology in the high dose
animals was found in the kidneys, liver, thyroid, and urinary bladder. 
High dose males had slight urinary tract tubular dilation and slight to
moderate hyperplasia of bladder epithelium.  The NOEL was determined to
be 12 mg/kg/d (males) -18 mg/kg/d (females).  Based on mild hepatic
glycogen depletion, the NOAEL was 139-203 mg/kg/d (males and females,
respectively).

90-Day Dietary-Dog

Four beagle dogs/sex/group received pyrimethanil by gavage for 90 days
at doses of 0, 6, 80, 1,000 mg/kg/d.  The high dose was lowered to 800
mg/kg/d on day 7 due to frequent and consistent vomiting.  Decreased
body weight, food and water consumption were observed.  Males had a
significant reduction in phosphate, while females experienced a slight
reduction in sodium, anion gap and total protein.  At 80 mg/kg/day,
infrequent vomiting after dosing and decreased water consumption were
observed.  After 4 weeks of dosing at 80 mg/kg/day, males had
significantly reduced phosphate.  The NOAEL was 80 mg/kg/day.  The NOEL
was 6 mg/kg/day.



f.   Dermal Toxicity Evaluation

No dermal studies have been conducted for pyrimethanil. 

	5. Chronic toxicity 

a.  Chronic Toxicity - Dog 

Four beagle dogs/sex/group received pyrimethanil by gavage at levels of
0, 2, 30, or 250 mg/kg/day for twelve months.  The high dose was reduced
from 400 to 250 mg/kg/day on day 8 of treatment due to excessive
vomiting during the first week of treatment. At the high dose, there was
a decrease in mean body weight gain and mean consumption of food and
water.  The NOEL for the study was 30 mg/kg/day, with the high dose of
250 mg/kg/day being the NOAEL.

b.  Combined Chronic Toxicity / Oncogenicity - Rat

Seventy Sprague-Dawley rats/sex/group received pyrimethanil by diet at
levels of 0, 1.3-1.8, 17-22, 221-291 mg/kg/day (males and females,
respectively) for two years.  At the highest dose tested, body weight
gain and food consumption were decreased.  Absolute liver weights were
increased.  Histopathology revealed centrilobular hepatocyte
hypertrophy, increased incidence of eosinophilic foci (males), thyroid
follicular hyperplasia, hypertrophy and colloid depletion, and the
presence of a brown pigment, identified as lipofuscin in thyroid
follicular cell epithelium.  There was a statistically significant,
dose-dependent increase in the incidence of benign thyroid follicular
cell adenomas.  There was no increased incidence in any malignant tumor
or increase in tumor multiplicity as a result of daily dietary ingestion
of pyrimethanil at any dose level.  The results of special studies,
discussed below, demonstrate that the benign thyroid tumors are likely a
secondary result of a disruption of thyroid-pituitary homeostasis, a
well-known, threshold-mediated mechanism.  The NOEL was 17 mg/kg/d
(males) and 22 mg/kg/day (females).

c.  Oncogenicity - Mouse

Fifty-one CD-1 mice/sex/group received pyrimethanil by diet at 0, 16,
160 and 1,600 ppm (corresponding to 0, 2-2.5, 20-24.9, 210.9-253.8
mg/kg/day in males and females, respectively).  There was an increase in
the number of high dose male deaths caused by urogenital tract lesions. 
Urinary bladder histopathology on those dying during the course of the
study indicates an increase in the incidence of male urinary bladder
distension, cystitis, urothelial hyperplasia and inflammation of the
penis.  These findings are consistent with the findings of both the 28-
and 90-day studies indicating that high dose administration of
pyrimethanil resulted in urolith formation leading to irritation,
distension and hyperplasia of the urinary bladder and urinary tract. 
Chronic dietary treatment with pyrimethanil produced no increased
incidence of tumor-bearing mice nor of any specific tumor type
suggestive of a carcinogenic effect. The NOEL for both sexes was 20-24.9
mg/kg/d (males and females, respectively).

d.  Special Studies

Since rodent thyroid tumors are fairly common, and since the EPA has
established that five lines of evidence are required to prove the
thyroid-pituitary disruption mode of action for rodent thyroid tumors,
special studies were undertaken

Thyroid mechanistic study (14-Day)

Sprague Dawley rats received 378.5 mg/kg/d of pyrimethanil for 14 days
to study the effects of pyrimethanil on the thyroid and liver microsomal
enzymes.  An increase in the levels of UDPGT and a corresponding
statistically significant increase in liver weight were observed. 
Thyroid hormones T4 and T3 were decreased, while TSH levels were
significantly increased.  All effects were shown to be reversible.

Dietary Thyroid Function Test Using Perchlorate Discharge (7-Day)

Sprague Dawley rats received 509 mg/kg/d pyrimethanil or 177 mg/kg/d
propylthiouracil, or 109 mg/kg/d phenobarbital in order to study the
function of the thyroid gland.  The animals fed pyrimethanil had 43%
decreased body weight gain, 21% decreased food consumption and a 150%
increase in uptake of iodine-125.  There was no significant discharge of
radioactive iodine from the thyroid after administration of perchlorate.

The required five lines of evidence to support the threshold mode of
action for thyroid pituitary disruption and rat thyroid tumors are
satisfied in the pyrimethanil studies.

The EPA’s final rule establishing a tolerance for pyrimethanil in wine
stated that “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.  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. 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.”

	6. Neurotoxicity. 

a.  Acute Neurotoxicity

Groups of 10 rats/sex/group were dosed once by oral gavage at dose
levels of  0, 30, 100, 1,000 mg of pyrimethanil/kg bodyweight.  On the
day of dosing, high dose animals experienced transient behavioral
effects attributable to receipt of a substantial bolus dose of test
substance.  No histopathological lesions accompanied these transient
behavioral changes.  The NOAEL was 100 mg/kg due to reduced body
temperature for males.  The NOEL was 30 mg/kg.

b.  Subchronic Neurotoxicity

Groups of 12 Sprague-Dawley rats per sex were treated for 13 weeks with
pyrimethanil via the diet  at 0, 4, 38.7-44.3, 391.9-429.9 mg/kg/d
(males and females, respectively).  There were no treatment-related
findings in behavioral assessments, neuropathology or brain
morphometrics.  The NOEL for this study is 38.7 – 44.3 mg/kg/day
(males and females, respectively) based upon decreased body weight and
food consumption in the high dose group.

	6. Animal metabolism. Pyrimethanil is rapidly metabolized and excreted
from lactating dairy cows.  The observed total radioactive residues in
edible tissues and milk were as follows: milk - maximum residue of 0.069
ppm; liver -0.363 ppm; kidney – 0.249 ppm and muscle – 0.017 ppm. 
The metabolic pathway is similar to that of plants involving
hydroxylation of the phenyl and pyrimidine rings as well as
hydroxylation of the methyl substituents.  Further metabolic reactions
occur including cleavage of the phenyl ring to produce substituted
pyrimidines.  The major metabolite was AE C614276 (46% of the kidney
residues, 63% of the milk residues) resulting from hydroxylation of the
phenyl ring.  Hydroxylation of the pyrimidinyl ring of pyrimethanil
resulted in formation of minor amounts of AE C614277.  Hydroxylation of
the methyl groups of pyrimethanil resulted in formation of minor amounts
of AE C614278.  Hydroxylation of the methyl groups of AE C614276
resulted in formation of minor amounts of AE C614800.	

7. Endocrine disruption. Chronic, life span, and multi-generational
bioassays in mammals and acute and subchronic studies on aquatic
organisms and wildlife did not reveal endocrine effects.  Any endocrine
related effects would have been detected in this definitive array of
required tests.  The probability of any such effect due to agricultural
uses of pyrimethanil is negligible.

C. Aggregate Exposure

effects.  Any endocrine related effects would have been detected in this
definitive array of required tests.  The probability of any such effect
due to agricultural uses of pyrimethanil is negligible.

	1. Dietary exposure.  An increase in the pyrimethanil tolerance under
40 CFR §180.518 is proposed for the stone fruit crop group 12 to allow
for post-harvest application. Tolerances are currently established for
the residues of the fungicide pyrimethanil in or on the following raw
agricultural commodities: almond (0.2 ppm), almond hulls (12 ppm), apple
wet pomace (12 ppm), banana (0.1 ppm), citrus oil (150 ppm), citrus
fruit crop group 10 – postharvest (10 ppm), pome fruit crop group 11
– preharvest and postharvest (3 ppm), stone fruit (except cherry) crop
group 12 (3 ppm), grape (5 ppm), grape, raisin (8 ppm), onion, dry bulb
(0.1 ppm), onion, green (2 ppm), pistachio (0.2 ppm), strawberry (3
ppm), tomato (0.5 ppm), and vegetable, tuberous and corm subgroup 1C
(0.05 ppm).  Tolerances are also established for the combined residues
of pyrimethanil and its metabolite 4-[4,6-dimethyl-2-pyrimidinyl) amino]
phenol in or on fat, meat, meat by-products (except kidney) of cattle,
goat, horse, and sheep (0.01 ppm) and kidney of cattle, goat, horse, and
sheep (0.3 ppm), and of the combined residues of pyrimethanil and the
metabolite 4,6-dimethyl-2-(phenylamino)-5-pyrimidinol in or on milk
(0.03 ppm).   There are no residential uses proposed for pyrimethanil. 
Therefore, potential human risk scenarios cover aggregate exposure from
food residues and drinking water.

	i. Food  and drinking water

Estimates of acute dietary exposure from potential pyrimethanil residues
with the addition of postharvest uses on stone fruits are all well under
100% of the acute reference dose at the 95th percentile.   This assumed
all commodities contained tolerance level residue concentrations, 100%
crop treated, and all consumed water at the highest EEC.  The highest
exposed subpopulation of children 1-2 years old utilizes 64.0% of the
reference dose (aRfD), while females aged 13-49 years old utilize 22% of
the acute population adjusted dose (aPAD).  These potential dietary
exposures were assessed based on the Dietary Exposure Evaluation Model
– Food Consumption Database (DEEM-FCID, ver 1.30) and Lifeline (ver.
2.00) models.  

Chronic dietary exposure estimates resulting from the proposed uses of
pyrimethanil are well within acceptable limits for all population
subgroups examined.  This assumes all commodities contained average
field trial residue concentrations, 100% crop treated, combined mean
residue concentrations as modeled, high-end pome fruit residues, and all
consumed water at the highest EEC.  The highest exposed subpopulation
was Non-nursing infants; at the chronic cRfD of 0.17 mg/kg body weight
(BW), exposure occupied 18% of the cRfD.  The U.S. Population (total)
exposure was 0.005624 mg/kg BW, with a margin of exposure (MOE) of
3,023.  

US EPA’s Standard Operating Procedure (SOP) for Drinking Water
Exposure and Risk Assessments was followed to perform the Tier One
drinking water assessment.  This SOP uses a variety of tools to conduct
drinking water assessments, including water models such as SCI-GROW,
FIRST, PRZMS/EXAMS, and monitoring data.  If monitoring data are not
available then the models are used to predict potential residues in
surface and ground water and the highest levels (whether ground or
surface) are assumed to be the drinking water residue.  In the case of
pyrimethanil, monitoring data are not available.  SCI-GROW and FIRST
were used to estimate a drinking water residue.  Calculation of the
Drinking Water Estimated Concentration (DWEC) for surface water for the
worst-case pyrimethnail use scenario results in a acute DWEC of 122 ppb
and a chronic DWEC of 37 ppb.  DWLOCs calculated based on the acute and
chronic risk assessments described above are many fold higher than these
conservative DWECs.  The adult acute and chronic DWLOCs are 9,860 ppb
and 5,936 ppb respectively.  Children’s acute and chronic DWLOCs are
2,641ppb and 1,686 ppb respectively.

	2. Non-dietary exposure. Pyrimethanil products are not labeled for
residential uses (food or non-food), thereby eliminating the potential
for residential exposure or non-occupational exposure. 

D. Cumulative Effects  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.” There are no 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 form a toxic metabolite produced by
other substances.  For the purposes of the tolerance petition and this
reduced risk rationale, therefore, it has been assumed that pyrimethanil
does not have a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. 

Using the assumptions and data described above, based on the
completeness and reliability of the toxicity data, it is concluded that
dietary risk from the proposed uses of pyrimethanil are acceptable for
all populations examined.  Chronic exposure for the US Population
utilizes 3.3% (0.005624 mg/kg bw/day) of the chronic reference dose. 
The most highly exposed population of non-nursing infants utilizes 18%
of the chronic reference dose and the most highly exposed population of
children 1-2 years old utilizes 64% of the acute reference dose.  The
actual exposures are likely to be much less as more realistic data and
models are developed.  EPA generally has no concern for exposures below
100% of the RfD (acute or chronic), because the RfD represents the level
at or below which exposure will not pose appreciable risk to human
health.  Drinking Water Levels of Comparison (DWLOC) for adults both
acute (9,860 ppb) and chronic (5,936 ppb) are several orders of
magnitude above the conservative Drinking Water Estimated Concentration
(DWEC) for acute (122 ppb) and chronic (37 ppb) worst case scenarios. 
Therefore there is a reasonable certainty that no harm will occur to the
US Population from aggregate exposure (food and drinking water) to
residues of pyrimethanil.



	2. Infants and children. 

The relevant toxicity studies as discussed in the toxicology section
above show no extra sensitivity of infants and children to pyrimethanil,
therefore, the FQPA safety factor can be removed.  Using the assumptions
and data described in the exposure section above, it is concluded that
dietary risk from the proposed uses of pyrimethanil are acceptable for
all infant and children sub-populations examined.  The most highly
exposed sub-populations were Non-nursing infants for chronic analysis,
and children 1-2 years old for acute analyses.  The sub-population
Non-nursing infants, utilizes 18% (0.030240 mg/kg bw/day) of the chronic
reference dose and the sub-population of children 1-2 years old utilizes
64% of the acute reference dose.  All other infant and children
populations have less exposure.   The chronic and acute drinking water
levels of concern for children (1,684 ppb and 2,600 ppb respectively)
are well above the conservative drinking water estimated concentrations
for chronic and acute scenarios.  The chronic DWEC is 37 ppb and the
acute DWEC is 122 ppb.  Therefore, there is a reasonable certainty that
no harm will occur to infants and children from aggregate exposure to
residues of pyrimethanil.

F. International Tolerances  Maximum Residue Limits (Codex MRLs) for
pyrimethanil have not been established by the Codex Alimentarius
Commission.

 62 Federal Register 63662-63669 (December 2, 1997)

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