Document ID: EPA-HQ-OPP-2015-0012-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-04-06T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE 

EPA Registration Division contact: Hope Johnson; (703) 305-5410

 

>

<Bayer CropScience >

< 4F8291 >

<	EPA has received a pesticide petition (4F8291) from Bayer CropScience,
2 T.W. Alexander Drive, Research Triangle Park, NC 27709 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 by establishing a
tolerance for residues of pyrimethanil
(4,6-dimethyl-N-phenyl-2-pyrimidinamine)  in or on the raw agricultural
commodities berries and small fruit: caneberry (crop subgroup 13-07A) at
15.0 parts per million (ppm) and berries and small fruit: bushberry
(crop subgroup 13-07B) at 8.0 parts per million (ppm). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of the FDDCA; 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 demonstrated that
analysis for the parent compound, pyrimethanil is sufficient to enable
the assessment of the relevant residues in crop commodities. 
Pyrimethanil was extracted from crops by homogenization with acetone. 
An aliquot of the extract was diluted with a mixture of acetonitrile and
water with subsequent residue determination by HPLC-MS/MS.  The method
allows the detection and measurement of residues in or on agricultural
commodities at or above the proposed tolerance level.

	3. Magnitude of residues. Magnitude of residue trials were conducted
for pyrimethanil on blackberry/raspberry as representative of the
caneberry (Crop Subgroup 13-07 A) and blueberry as a representative of
bushberry (Crop Subgroup 13-07B). Trials were conducted in the various
required regions across the United States in accordance with EPA
guidance for crop field trials under OPPTS 860.1500.

B. Toxicological Profile

	1. Acute toxicity.  Pyrimethanil shows low toxicity by the oral
(toxicity category III), inhalation (toxicity category III), and dermal
(toxicity category IV) routes. It is slightly irritating to the eyes and
non-irritating to the skin in rabbit studies. Pyrimethanil is not a
dermal sensitizer.  Acute neurotoxicity of pyrimethanil in the rat was
assessed, the NOAEL was 100 mg/kg due to reduced body temperature in
males, and transient behavioral effects observed at the high dose tested
(HDT).

	2. Genotoxicty. 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.  An oral developmental toxicity
study in the Sprague Dawley rat did not reveal any evidence of
teratogenic potential. The maternal and developmental NOAEL was 85
mg/kg/day.  An oral developmental toxicity study in New Zealand rabbits
did not reveal any evidence of teratogenic potential and the NOAEL was
45 mg/kg/day. The maternal and developmental LOAEL was 300 mg/kg/day due
to reduced body weights, reduced fecal production, and food consumption
in the dams and decreased mean body weight, body weight gain, food
consumption, and an increased incidence of fetuses with 13 thoracic
vertebrae and ribs. A two-generation reproduction study in the
Sprague-Dawley rats did not indicate any disruption of reproductive
function.  The NOAEL for maternal and developmental toxicity was 20.9
mg/kg/day due to reduced body weights at higher dose levels, and the
reproductive NOAEL was 266.7 mg/kg/day, the HDT.

	4. Subchronic toxicity. A 28–day dietary toxicity study was conducted
in CD- 1 mice established a NOAEL of 202 mg/kg/day.  A 90-day dietary
toxicity study in Sprague-Dawley rats showed a NOAEL of 54.5 and 66.7,
in males and females, respectively. A 90-day dietary toxicity study was
conducted in CD-1 mice and demonstrated a NOAEL of 139 and 203 mg/kg/day
in males and females, respectively, based on changes found in the
kidney, liver, thyroid, and urinary bladder at higher dose levels.  A
90-day oral toxicity study in dogs showed a NOAEL of 80 mg/kg/day due to
decreased body weight and food consumption and changes in clinical
chemistry endpoints at 800 mg/kg/day.  A subchronic neurotoxicity study
in Sprague-Dawley rats indicated no treatment-related findings in
behavioral assessments, neuropathology or brain morphometrics. The NOAEL
was 44.3 mg/kg/day in females based upon decreased mean body weight,
body weight gain and food consumption at 429.9 mg/kg/day. There were no
treatment related effects in males at any dose level up to 391.9
mg/kg/day.  A 28-day immunotoxicity study conducted in female
Sprague-Dawley rats revealed no evidence of immune suppression at dose
levels up to and including 652 mg/kg/day, the HDT.

	5. Chronic toxicity. A 12-month chronic toxicity study in the dog
demonstrated a NOAEL of 30 mg/kg/day due to a decrease in mean body
weight gain and mean consumption of food and water at higher dose
levels. Two oncogenicity studies were conducted using CD-1 mice
continually exposed to pyrimethanil by administration in the diet. These
lifetime feeding studies demonstrated no evidence of oncogenic potential
at dose levels up to, and including 984 mg/kg/day (males) and 1217
mg/kg/day (females), the HDT. A 2-year combined chronic
toxicity/oncogenicity study conducted in the Sprague-Dawley rat showed a
NOAEL of 17 mg/kg/day (males) and 22 mg/kg/day (females) due to
decreased body weight gain and food consumption, and effects on the
liver and thyroid at 221 mg/kg/day (males) and 291 mg/kg/day (females). 
The results of mechanistic studies, demonstrate that the thyroid effects
are likely secondary due to induction of enzymes in the liver involved
in metabolism of thyroid hormones, a well characterized,
threshold-mediated mechanism.

	6. Animal metabolism. Metabolism and pharmacokinetic studies in the rat
show rapid absorption and elimination within 24-hours of pyrimethanil
administration. The major routes of elimination were the urine
(approximately 72% of the administered dose), and the feces (17-18% of
the administered dose). The main pathways of metabolism involved
oxidation to phenols in either or both aromatic rings. The minor pathway
of metabolism involved oxidation of the methyl group to the
corresponding alcohol.

	7. Metabolite toxicology. Not applicable. The primary residue of
concern in both crop and animal commodities is pyrimethanil.

	8. Endocrine disruption. There is no evidence to suggest that
pyrimethanil has any potential primary endocrine disruption.  Chronic,
life span, and multi-generational bioassays in mammals and acute and
subchronic studies on aquatic organisms and wildlife did not reveal any
potential endocrine effects. Changes in the thyroid are secondary to
induction of metabolic enzymes in the liver, and not due to a direct
effect on endocrine mediated functions.

C. Aggregate Exposure

	1. Dietary exposure. For dietary analysis, an acute reference dose
(aRfD) of 0.45 mg/kg/day was derived for females 13 – 49 yrs. from an
NOAEL of 45 mg/kg/day in the rabbit developmental study, based on an
increased incidence of fetuses with 13 thoracic vertebrae and ribs, and
an uncertainty factor of 100.  For the general population including
infants and children, the acute reference dose is 1 mg/kg/day from on an
NOAEL of 100 mg/kg/day in the acute rat neurotoxicity study, based on
transient behavioral effects, and an uncertainty factor of 100.  A
chronic reference dose (cRfD) of 0.17 mg/kg/day for all populations was
derived from the chronic toxicity study in the rat,  based on decreased
body weight gain and food consumption, increased liver weights and
histopathological changes, and an uncertainty factor of 100.  EPA has
evaluated the potential for increased susceptibility of infants and
children from exposure to pyrimethanil and has determined there was no
quantitative or qualitative evidence of increased susceptibility
following prenatal exposure (in rats and rabbits), or postnatal exposure
(in rats). There were no effects on fertility or reproduction in the
two-generation reproduction study in rats. The special FQPA safety
factor has been reduced to 1X based on toxicological considerations, the
nature of the assumptions used in the dietary exposure risk assessments,
the completeness of the residue chemistry and environmental fate
databases, and the lack of the potential for residential exposures. 
Acute and chronic Population Adjusted Doses (aPAD and cPAD) are,
therefore, the same as the reference doses for the populations and
subpopulations of interest.

	i. Food. Dietary exposure to pyrimethanil was estimated from potential
residues on food using DEEM-FCID Ver. 3.16 software for dietary
analyses.  Consumption data used in this program were taken from NHANES
WWEIA 2003-2008.  The acute Tier 1 assessments used 100% crop treated
and tolerance level residue values.  The chronic Tier 2 assessment is
based on tolerances, average residue values for key crops and percent
crop treated values for key crops from the 2004 EPA assessment.  All
registered uses plus proposed uses on the caneberries and bushberries
crop subgroups were included in the assessment.  Acute exposure (95th
percentile) for food only utilizes 12.5% of the aPAD for Females 13-49
yrs. old and 9.6% and 34% of the aPAD for the US Population and Children
1-2 yrs. old respectively.  Chronic exposure utilizes 13.5% for the US
Population and 75% for Children 1-2 yrs. old, the most highly exposed
subpopulation.  These are conservative estimates and actual exposures
are likely to be much less.

	ii. Drinking Water. EPA drinking water values (2011) were used in the
assessment.  EDWCs were calculated for use on strawberries (the scenario
resulting in the highest drinking water exposure), and included
pyrimethanil and its major metabolite (2-amino-4,6-dimethylpyrimidine). 
The surface water estimated drinking water concentrations (EDWCs) were
determined using PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis
Modeling System).  Ground water EDWCs, calculated using SCI-GROW
(Screening Concentration in Ground Water), model were lower than the
surface water EDWCs.  For surface water, the maximum estimated peak
acute concentration of the combined residues is 86.5 (g/L. The maximum
estimated annual mean non-cancer chronic exposure concentration for the
combined residues (adjusted for regional percent cropped area) is 29.4
(g/L.  The addition of the acute estimated drinking water concentration
(EDWC) of 86.5 ppb resulted in 9.8% of the aPAD utilized for the US
Population, 13% of the aPAD utilized for females 13-49 yrs. old, and 38%
utilized for Children 1-2 yrs. old, the most highly exposed
subpopulation.  The addition of the chronic EDWC of 29.4 ppb utilized
13.8% of the cPAD for the US Population and 76% of the cPAD for Children
1-2 yrs. old, the most highly exposed subpopulation.  In conclusion, the
results of these conservative acute and chronic estimates (including
drinking water) are acceptable for all population subgroups examined. 
Therefore, there is a reasonable certainty that no harm will result from
exposure to potential residues of pyrimethanil in food and drinking
water. 

	2. Non-dietary exposure. Pyrimethanil is not registered for use on any
sites that would result in residential exposure.  Therefore, the
aggregate risk is the sum of the risk from food and water.

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.”   EPA has not made a common mechanism
of toxicity finding as to pyrimethanil and any other substances and
pyrimethanil does not appear to produce a toxic metabolite produced by
other substances.

E. Safety Determination

	1. U.S. population. Risk assessments for pyrimethanil are based on a
complete and reliable toxicity data package and highly conservative
assumptions. Chronic aggregate dietary (food and water) exposure will
utilize about 14% of the cPAD for the US Population.  Acute aggregate
dietary exposure (food and water) for the U.S. population, utilizes 10%
of the aPAD.  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. EPA has determined that the toxicology
database for pyrimethanil regarding potential pre- and post-natal
effects in children is complete and does not indicate any particular
developmental or reproductive concerns.  The special FQPA SF has been
reduced to 1X.  Using the conservative assumptions described in the
exposure section above, chronic dietary exposure to residues of
pyrimethanil in food and water for Children 1-2 yrs. old (the most
highly exposed sub group) is about 76% of the cPAD.  Acute aggregate
dietary exposure to residues of pyrimethanil in food and water for
Children 1-2 yrs. old (the most highly exposed sub group) is 38% of the
aPAD.  There are no non-dietary concerns for infants and children.
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

	Codex tolerances are currently not available for pyrimethanil on
caneberries or bushberries. Tolerances have been established for
caneberries and bushberries in the EU at 10 ppm and 5 ppm, respectively.

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