Document ID: EPA-HQ-OPP-2015-0775-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-02-07T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER (4/29/2016)

EPA Registration Division contact: Tony Kish, (703) 308-9443

Syngenta Crop Protection, LLC

PP# 6F8474

	EPA has received a pesticide petition (6F8474) from Syngenta Crop
Protection, LLC, P.O. Box 18300, Greensboro, NC 27419 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 180.662.

	1. by establishing a tolerance for residues of Pydiflumetofen in or on
the raw agricultural commodity [] at []  

	

	Barley, grain at 4.0 parts per million (ppm)

Barley, hay at 30.0 parts per million (ppm)

Barley, straw at 30.0 parts per million (ppm)

Corn, field, grain at 0.015 parts per million (ppm)

Corn, field, forage at 6.0 parts per million (ppm)

Corn, field, stover at 15.0 parts per million (ppm)

Corn, field, milled by products at 0.06 parts per million

Corn, pop, grain at 0.015 parts per million (ppm)

Corn, pop, forage at 6.0 parts per million (ppm)

Corn, pop, stover at 15.0 parts per million (ppm)

Corn, sweet, ear at 0.01 parts per million (ppm)

Corn, sweet, forage at 5.0 parts per million (ppm)

Corn, sweet, stover at 9.0 parts per million (ppm)

Corn, sweet, cannery waste at 2.0 parts per million (ppm)

Fruits, small vine climbing, except fuzzy kiwi subgroup 13-07F at 1.5
parts per million (ppm)

Grape, raisin at 2.0 parts per million (ppm)

Grape wet pomace at 1.5 parts per million (ppm)

Grain, aspirated fractions at 100.0 parts per million (ppm)

Grain, cereal, forage, fodder and straw, group 16 at 50 parts per
million (ppm)

Oat, grain at 2.0 parts per million (ppm)

Oat, forage at 10.0 parts per million (ppm)

Oat, hay at 40.0 parts per million (ppm)

Oat, straw at 20.0 parts per million (ppm)

Peas and bean, dried shelled, except soybean, subgroup 6C at 0.4 parts
per million (ppm)

Peas, hay at 40.0 parts per million (ppm)

Peas, vine at 6.0 parts per million (ppm)

Peanut, nutmeat at 0.02 parts per million (ppm)

Peanut, refined oil 0.05 parts per million (ppm)

Peanut, hay at 20.0 parts per million (ppm)

Potato, wet peel at 0.03 parts per million (ppm)

Potato, dried pulp at 0.05 parts per million (ppm)

Potato, processed waste at 0.03 parts per million (ppm)

Rapeseed, subgroup 20A at 0.9 parts per million (ppm)

Rye, grain at 4.0 parts per million (ppm)

Rye, hay at 50.0 parts per million (ppm)

Rye, straw at 30.0 parts per million (ppm)

Soybean, seed at 0.4 parts per million (ppm)

Soybean, forage at 30.0 parts per million (ppm)

Soybean, hay at 150 parts per million (ppm)

Tomato, dried pomace at 15.0 parts per million (ppm)

Tomato, wet pomace at 1.5 parts per million (ppm)

Tomato, sun-dried at 3.0 parts per million (ppm)

Quinoa, grain at 4.0 parts per million (ppm)

Vegetables, fruiting, crop group 8-10 at 0.6 parts per million (ppm)

Vegetables, tuberous and corm subgroup 1C at 0.015 parts per million
(ppm)

Vegetables, cucurbit, crop group 9 at 0.5 parts per million (ppm)

Wheat, grain at 0.3 parts per million (ppm)

Wheat, forage at 15.0 parts per million (ppm)

Wheat, hay at 50.0 parts per million (ppm)

Wheat, straw at 30.0 parts per million (ppm)

Additionally tolerances are proposed for the crops in the proposed Crop
Subgroup 4–15A, Leafy greens subgroup at 40.0 parts per million (ppm)
including amaranth, Chinese; amaranth, leafy; aster, Indian; blackjack;
cat’s whiskers; chervil, fresh leaves; cham-chwi; cham-namul;
chipilin; chrysanthemum, garland; cilantro, fresh leaves; corn salad;
cosmos; dandelion; dang-gwi; dillweed; dock; dol-nam-mul; ebolo; endive;
escarole; fameflower; feather cockscomb; good king henry; huauzontle;
jute, leaves; lettuce, bitter; lettuce, head; lettuce, leaf; orach;
parsley, fresh leaves; plantain, buckhorn; primrose, English; purslane,
garden; purslane, winter; radicchio; spinach; spinach, malabar; spinach,
New Zealand; spinach, tanier; swiss chard; and violet, Chinese; and
crops in the proposed Crop Subgroup 22B, Leaf petiole vegetable subgroup
at 15.0 parts per million (ppm) including Cardoon; celery; celery,
Chinese; fuki; rhubarb; udo; zuiki

2. by establishing a tolerance for residues of

	

	Pydiflumetofen and 2,4,6 trichlorophenol (free and conjugated) in or on
the animal commodity [] at []  

commodities [cattle, fat] at [0.03] ppm, [cattle, kidney] at [0.02]
ppm,[cattle, liver] at [0.04] ppm, [cattle, meat] at [0.02] ppm,
[cattle, byproducts] at [0.04] ppm; [goat, fat] at [0.03] ppm,[goat,
kidney] at [0.02] ppm, [goat, liver] at [0.04] ppm, [goat, meat] at
[0.02] ppm, [goat, meat byproducts] at [0.04] ppm; [horse, fat] at
[0.03] ppm, [horse, kidney] at [0.02] ppm, [horse, liver] at [0.04] ppm,
[horse, meat] at [0.02] ppm,[horse, meat byproducts] at [0.04] ppm;
[milk] at [0.02] ppm, [milk, cream] at [0.04] ppm; [sheep, fat] at
[0.03] ppm, [sheep, kidney] at [0.02] ppm, [sheep, liver] at [0.04],
[sheep, meat] at [0.02] ppm, [sheep, meat byproduct] at [0.04] ppm.

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of  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.  Plant Metabolism studies with pydiflumetofen
(SYN545974) were performed in wheat, oil seed rape, and tomatoes as
representative crops in order to characterize the fate of pydiflumetofen
in all crops.  Two radiocarbon labels were studied in each crop, with
14-C labels positioned in phenyl and pyrazole ring structures.
Pydiflumetofen was the predominant component of residue in crops.  The
metabolism in all plants (oil seed rape, wheat, tomatoes) was very
similar.  The principal metabolic transformations of pydiflumetofen in
all commodities occurred via reduction of the parent molecule
(N-demethoxylation of the amide nitrogen) and by demethylation of the
pyrazole ring.

2. Analytical method.i. Food  The proposed definition of the residue for
pydiflumetofen (SYN545974) in commodities of plant origin is parent
pydiflumetofen for both compliance monitoring and consumer risk
assessments. Method GRM061.03A has been developed for the determination
of SYN545974 in crops for use in pre-registration studies, with an LOQ
of 0.01 mg/kg. This method has also been validated.  Additionally,
QuEChERS multi-residue method (EN 15662:2009) has been validated and
independently validated for post-registration monitoring of SYN545974
for compliance with MRLs and import tolerances in plant commodities at
an LOQ of 0.01 mg/kg. 

 ii. Livestock  The corresponding definitions in commodities of animal
origin are parent pydiflumetofen (SYN545974) and 2,4,6-trichlorophenol
(free and conjugated) for monitoring. The residue definition for risk
assessment in commodities of animal origin are parent SYN545974 and
2,4,6-trichlorophenol (free and conjugated) in all commodities, in
addition it is proposed that SYN548263 is included for bovine kidney and
SYN547897 is included for bovine liver and kidney for risk assessment.
Method GRM061.06A for animal products has been validated for use in
pre-registration development studies and independently validated.  The
method determines parent SYN545974, with an LOQ of 0.01mg/kg. Method GRM
061.08A for milk has been validated for use in pre-registration
development studies.  The method determines metabolites SYN548264 and
SYN508272, with an LOQ of 0.01 mg/kg for each compound. This method was
also validated. Method GRM061.09A for liver and kidney has been
validated for use in pre-registration development studies.  The method
determines free and conjugated SYN547897 and free and conjugated
SYN548263, with an LOQ of 0.01 mg/kg. Method GRM061.07A for animal
products has been validated for use in pre-registration development
studies and independently validated for post-registration monitoring. 
The method employs a hydrolysis step to determine total
2,4,6-trichlorophenol (free and conjugated) with an LOQ of 0.01 mg/kg.
QuEChERS multi-residue method (EN 15662:2009) has been validated and
independently validated for post-registration monitoring of SYN545974 in
animal commodities for compliance with MRLs and import tolerances for
animal commodities at an LOQ of 0.01 mg/kg. 

3. Magnitude of residues. The number and locations of the field trials
are in accordance with OPPTS 860.1500.  Field trials were carried out
using the maximum label rates, maximum number of applications, and the
minimum pre-harvest interval (PHI) for all the crops.  Field trials were
conducted on fruiting vegetables (Crop Group 8-10), cucurbit vegetables
(Crop Group 9), leafy vegetables (proposed Crop Group 4-15A) and leaf
petiole vegetables (proposed Crop Group 22B), tuberous and corm
vegetables (Crop Group 1C), rapeseed Crop Group 20A (canola varieties),
soybeans, dried shelled pea and bean subgroup (Crop Group 6C), grapes,
peanuts, corn (field, pop, sweet), and cereals - wheat, barley, oats.
Additional trials have been conducted in Canada to obtain registration
and propose harmonized tolerances between US, Canada, and Mexico. 
Detected residues of in all crops support the proposed tolerances based
on parent only – pydiflumetofen (SYN545974).

Syngenta conducted adequate magnitude of residue trials on wheat,
barley, and oats under OPPTS 180.1500 to support the requested use on
cereals.  A tolerance on rye was requested based on the November 25,
2009 ChemSAC decision that provides an allowance for extrapolating
residue data for barley and wheat to additional small cereal grains if
the use patterns are identical.  Since the directions for use are the
same, the requested tolerances on rye are adequately supported. 
Additionally, a tolerance for quinoa was requested based on the May 27,
2015 ChemSAC decision which allows for translation to cereal grains. 

B. Toxicological Profile 

                                                                        
                                  

	1. Acute toxicity. The estimated acute oral median lethal dose (MLD)
for pydiflumetofen via the oral route was greater than 5000 mg/kg bw,
the median lethal dose following acute inhalation exposure was estimated
to be greater 5.11 mg/L.  The acute dermal median lethal dose was shown
to be greater than 5000 mg/kg bw. SYN545974 was minimally irritating to
the eye since positive scores cleared by 24 hours and a non-irritant to
the skin.  Pydiflumetofen is not a skin sensitizer. 

	2. Genotoxicity.  Pydiflumetofen has been tested in a range of in vitro
and in vivo genotoxicity assays.  In vitro assays include two in vitro
Ames tests (reverse mutation assay with Salmonella typhimurium and
Escherichia coli), an in vitro cell gene mutation test (in mouse
lymphoma L5178Y cells) and in an in vitro chromosome aberration test (in
human lymphocytes). Two in vivo mouse bone marrow micronucleus tests
were conducted.  The genotoxicity data generated demonstrates that
pydiflumetofen is not genotoxic.

	3. Reproductive and developmental toxicity.   In a prenatal
developmental study in the rat, 100 mg/kg/day group showed an initial
reduction in body weight and food intake on days 6 to 9 of gestation. 
There were no effects of pydiflumetofen on uterine, implantation or
fetal data.  The incidence and intergroup distribution of major, minor
and variant fetal abnormalities were not affected by the administration
of pydiflumetofen.  The NOAEL for maternal and developmental toxicity
was 100 mg/kg/day, which is the highest dose tested (HDT). 

In rabbits, developmental toxicity was not observed.  There were no
treatment related effects on maternal or fetal parameters. The NOEL was
500 mg/kg/day (HDT).

Pydiflumetofen was evaluated in a two-generation reproduction study in
the rat at dietary inclusion levels of 0, 150, 450 and 1500 ppm
(females) or 0, 150, 750 and 4500 ppm (males).  For the parental
generation, the pre-pairing mean daily intake of pydiflumetofen was 0,
11.9, 36.1, and 116.2 mg/kg/day for females and 0, 9.1, 46.1, and 276.6
mg/kg/day for males. 

The parental and offspring NOAEL was considered to be 4500/1500 ppm
(equivalent to 276.6/116.2 mg/kg bw/day P-generation pre-pairing) in
males and females respectively.  The NOEL for reproduction was 4500/1500
ppm (equivalent to 276.6/116.2 mg/kg bw/day P- generation pre-pairing)
in males and females respectively.  

The parental and offspring NOAEL was considered to be 276.6 and 116.2
mg/kg bw/day (P-generation pre-pairing) in males and females
respectively.  The NOEL for reproduction was also 276.6 and 116.2 mg/kg
bw/day (P- generation pre-pairing) in males and females respectively. 

 

	4. Subchronic toxicity. Pydiflumetofen is generally a low order of
toxicity in all species tested in short-term to intermediate-term
studies.  The target organ was the liver with increased liver weight and
hypertrophy in the rat and mouse.  There was also some thyroid
hypertrophy in rat and mouse.  In the 28-day rat study, the NOEL/NOAEL
was 40-43 mg/kg/day.  In the 90-day rat study the NOEL/NOAEL in males
was 18.6 mg/kg/day, with an increase in group mean covariant liver
weight compared to controls of greater than 20% at doses of 111
mg/kg/day.  In the 106 mg/kg/day female group, the only
treatment-related effect was a group mean increase in liver weight
(<20%), with no associated changes in clinical chemistry or
histopathology parameters. The NOAEL in female rats is 106 mg/kg/day.  

In the 28 day mouse study, increases in liver weight were observed in
both sexes at all doses.  In the 90 day study, which was conducted using
a similar dose range as the 28 day study, body weight gain was lower in
all male groups and in females receiving 500 ppm or 7000 ppm.  Adverse
effects were limited to changes in clinical chemistry, greater than 20%
increases in group mean covariant liver weight and hepatocyte
hypertrophy in males and females at doses of 4000 ppm (846.3 mg/kg/day)
and higher.  The NOEL was 100 ppm (17.5 mg/kg/day) for male mice, and
for females, the NOEL was 500 ppm (105.9 mg/kg/day).  

Administration of SYN545974 once daily, by capsule, for at least 90 days
to the beagle dog, was generally well tolerated at a dose level of 1000
mg/kg/day, with the exception of initial body weight losses followed by
reduced body weight gain and lower food consumption.  An adaptive
hepatic hypertrophy was also observed in these animals and was
associated with elevated plasma alkaline phosphatase and triglycerides
and increased liver weight.  At a dose level of 300 mg/kg/day, effects
of treatment were confined to initial, slight and transient body weight
losses, an increase in plasma alkaline phosphatase and increases in
liver weight, without corresponding liver histopathological changes;
these changes were considered not adverse.  The NOAEL was considered to
be 300 mg/kg/day.

	5. Chronic toxicity. In a 2 year combined chronic
toxicity/carcinogenicity study in Wistar rats, significantly lower body
weight, body weight gain and food consumption were observed in both
sexes at the mid and top dose (51 and 319 mg/kg/day in males; 31 and 102
mg/kg/day in females).  In the 51 and 319 mg/kg/day males and 102
mg/kg/day females, liver hepatocyte hypertrophy was observed at 52 and
104 weeks, with a corresponding increase in liver weight in both sexes
from the mid dose.  In addition, males in the 319 mg/kg/day group showed
grossly prominent lobular architecture of the liver at 52 and 104 weeks
and hepatocyte cytoplasmic eosinophilic inclusions in the 319 mg/kg/day
at 104 weeks.  There were no other treatment related effects on organ
weight or histopathology.  There were no treatment-related neoplastic
findings.  A NOAEL was established at 51.0 mg/kg/day in males and 31.0
mg/kg/day in females.

In a carcinogenicity study in the mouse, liver weights were increased in
both males and females at 287.9 and 306.2 mg/kg/day, respectively. There
were no treatment-related neoplastic findings in females in this study. 
In males, neoplastic and non neoplastic findings were observed in the
liver only.  Treatment related increased incidence of hepatocellular
carcinomas and adenomas were observed in males at 45.4 and 287.9
mg/kg/day, which were statistically significant at 287.9 mg/kg/day.  In
addition, centrilobular hypertrophy was observed in males only at 45.4
and 287.9 mg/kg/day.  Although there was a higher incidence of
eosinophilic foci of cellular alteration in the liver of male mice at
9.2 mg/kg/day, this difference was not statistically significant and
considered to be incidental to treatment. The NOEL for the 80-week mouse
study was established at 9.2 and 9.7 mg/kg/day in males and females,
respectively.

When administered orally for 52 weeks to the beagle dog at doses of 30,
100 or 300 mg/kg/day, pydiflumetofen was well tolerated eliciting
increases in plasma alkaline phosphatase and liver weight at 300
mg/kg/day, but no evidence of target organ pathology.  Group mean liver
weights were significantly higher than controls at 300 mg/kg/day and
attributed to particularly high liver weights for one male and two
females.  There was no evidence of hepatic hypertrophy in the 300 mg/kg
/day groups.  The NOAEL was considered to be 300 mg/kg/day. 

6. Animal metabolism. The metabolism and distribution of pydiflumetofen
have been investigated in poultry and ruminant species (hen and goat).
There was very little transfer of residues into tissues, milk or eggs
following the dosing of pydiflumetofen to the hen or the goat. 
Metabolic profiles observed in livestock commodities arise from four
principal biotransformation steps.  These transformations are summarized
in the proposed metabolism pathway.  The principal routes of metabolism
are:

i) N-pyrazole demethylation of pydiflumetofen

ii) N-demethoxylation of the amide nitrogen of pydiflumetofen

iii) cleavage at the benzylic methylene, N-alkyl and amide linkages
between the phenyl and pyrazole rings

iv) oxidation resulting in 

monohydroxylation of the benzyl methylene functionality

monohydroxylation of the trichlorophenol ring

  

Overall the biotransformation pathway of pydiflumetofen in ruminants and
poultry is well understood and consistent with that observed in the rat.

7. Metabolite toxicology. Toxicity and genotoxicity studies have been
conducted with the metabolite CSAA798670.  Synonyms for this metabolite
are CA4312 and NOA449410.  The identical metabolite has also been tested
in studies undertaken by other registrants under the test substance code
M700F001 and hence the summaries for studies conducted by refer to the
test substance as M700F001, whereas the Syngenta study summaries refer
to this metabolite using the test substance code CSAA798670. An acute
oral toxicity study has been conducted with the metabolite SYN508272 by
another registrant under test substance code M700F007. This study has
previously been reviewed by USEPA.  

8. Endocrine disruption.  Pydiflumetofen does not belong to a class of
chemicals known as suspected of having adverse effects on the endocrine
system. There is no evidence in other relevant toxicity studies (e.g.
sub-chronic and chronic toxicity, developmental toxicity and
multi-generation reproductive studies) which would suggest that has any
endocrine disruptive potential.

9. Neurotoxicity.  Examination of the toxicity database for SYN545974
demonstrates that existing studies are adequate to evaluate adverse
effects of repeated dosing on neurotoxicity.  SYN545974 did not have any
direct influence on nervous-system-related parameters in acute,
subchronic and chronic studies in rats, mice, and dogs following
repeated dosing.   

Based on the results of this study and the above-mentioned
considerations, 2000 mg/kg is considered to be the
no-observed-adverse-effect level (NOAEL) for males and 100 mg/kg is
considered to be the NOAEL for females.

10. Immunotoxicity. A thorough review of the toxicology database for
pydiflumetofen has shown sporadic effects on immunological parameters
related effects; however, these effects were observed in a
non-dose-dependent manner and were not consistent in directionality of
the change (e.g. decreased and increased white blood cell counts at
various time points). In addition, there is no immunological concern for
other chemicals of this class of fungicides. Adequate toxicological and
risk evaluations can be performed with the available studies, and
conducting a 28-day immunotoxicity study will not provide a more
conservative endpoint or otherwise significantly impact risk assessment
or hazard characterization.  

C. Aggregate Exposure

1. Dietary exposure. Tier III acute, short-term, and chronic aggregate
risk assessments were performed for pydiflumetofen using the Dietary
Exposure Evaluation Model (DEEM-FCID™ Version 4.02, Evaluation Copy);
consumption data was from the USDA NHANES “What We Eat in America”
survey, 2005-2010.  These assessments included all proposed use patterns
for fruiting vegetables (Crop Group 8-10), cucurbit vegetables (Crop
Group 9), leafy vegetables (Crop Group 4-15A), leaf petiole vegetables
(Crop Group 22B), tuberous and corm vegetables (Crop Group 1C), canola
subgroup (Crop Group 20A), soybean, dried shelled pea and bean subgroup
(Crop Group 6C), grape, peanut, corn (field, pop, sweet), wheat, barley,
oat, and forage and straw of cereal grains (Crop Group 16).  The Tier
III assessments incorporated field trial residue values where
pydiflumetofen was applied at the maximum intended use rate and samples
were harvested at the minimum pre-harvest interval (PHI) to obtain the
maximum expected residues.  Percent of crop treated values were
conservatively estimated to be 100% for all uses in the assessments. 
Drinking water estimates were incorporated directly into the acute and
chronic dietary exposure assessments using the highest estimated
drinking water concentrations (EDWCs) for surface and ground water.

i. Food.  Acute exposure.  The pydiflumetofen acute food risk
assessments were performed for all population subgroups using an acute
reference dose of 1.0 mg/kg-bw/day based upon a developmental toxicity
study in rats with a no observed adverse effect level (NOAEL) of 100
mg/kg/day and an uncertainty factor of 100X to account for intra- and
inter-species variations.  No additional FQPA safety factor was applied.
 For the purpose of the acute aggregate risk assessments, the exposure
values were expressed in terms of margin of exposure (MOE), which was
calculated by dividing the NOAEL by the exposure for each population
subgroup.  In addition, exposure was expressed as a percent of the acute
reference dose (%aRfD).  At the 99.9th percentile, acute (food only)
exposure to the U.S. population resulted in a MOE of 1,342 (7.5% of the
aRfD of 1.0 mg/kg-bw/day).  The most exposed sub-population was children
(1-2 years old) with a MOE of 744 (13.4% of the aRfD of 1.0
mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and
since the EPA generally has no concern for exposures above the Benchmark
MOE or below 100% of the aRfD, Syngenta believes that there is a
reasonable certainty that no harm will result from dietary (food only)
exposure to residues arising from all proposed uses of pydiflumetofen.

Chronic exposure.  The pydiflumetofen chronic dietary food risk
assessments were performed for all population subgroups using a chronic
reference dose of 0.09 mg/kg-bw/day based upon a 80 week study in mice
with a no observed adverse effect level (NOAEL) of 9.2 mg/kg/day and an
uncertainty factor of 100X to account for intra- and inter-species
variations.  No additional FQPA safety factor was applied.  For the
purpose of aggregate risk assessment, the exposure values were expressed
in terms of margin of exposure (MOE), which was calculated by dividing
the NOAEL by the exposure for each population subgroup.  In addition,
exposure was expressed as a percent of the chronic reference dose
(%cRfD).  Chronic (food only) exposure to the U.S. population resulted
in a MOE of 4,660 (2.1% of the cRfD of 0.09 mg/kg-bw/day).  The most
exposed sub-population was children (1-2 years old) with a MOE of 2,904
(3.4% of the cRfD of 0.09 mg/kg-bw/day).  Since the Benchmark MOE for
this assessment was 100 and since the EPA generally has no concern for
exposures above the Benchmark MOE or below 100% of the cRfD, Syngenta
believes that there is a reasonable certainty that no harm will result
from dietary (food only) exposure to residues arising from all proposed
uses of pydiflumetofen.

Cancer.  A quantitative risk assessment using a cancer endpoint was not
performed.

ii. Drinking water.  The Estimated Drinking Water Concentrations (EDWCs)
of pydiflumetofen were determined using Tier I model FIRST, which
estimates pesticide concentration in surface water; and Tier l models
SCI-GROW and PRZM-GW, which estimate pesticide concentration in ground
water. EDWCs of pydiflumetofen from proposed uses on fruiting vegetables
(Crop Group 8-10), cucurbit vegetables (Crop Group 9), leafy vegetables
(Crop Group 4-15A) and leaf petiole vegetables (proposed Crop Group
22B), tuberous and corm vegetables (Crop Group 1C), canola subgroup
(Crop Group 20A), soybeans, dried shelled pea and bean subgroup (Crop
Group 6C), grapes, peanuts, corn (field, pop, sweet), wheat, barley,
oats, quinoa, turf and ornamentals were determined. The acute and
chronic surface water EDWCs resulting from FIRST modelling were 12.5 ppb
and 4.21 ppb, respectively, based on proposed uses on leafy vegetables
(Crop Group 4-15A) and soybeans.  No Percent Cropped Area (PCA)
adjustment was made to the surface water EDWCs. The ground water EDWC
resulting from SCI-GROW modelling was 0.035 ppb (acute and chronic)
based on proposed uses on leafy vegetables (Crop Group 4-15A), soybeans,
dried shelled pea and bean subgroup (Crop Group 6C), grapes, turf and
ornamentals. PRZM-GW provided the highest acute and chronic ground water
EDWCs of 44.2 ppb and 37.0 ppb, respectively, based on the proposed use
on grapes. The ground water EDWCs derived from PRZM-GW were used for
risk assessment purposes.

Acute Exposure from Drinking Water:  The acute ground water EDWC of 44.2
ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the acute drinking water
exposures.  Exposure contributions at the 99%-ile of exposures were
determined by taking the difference between the aggregate (food +
drinking water) exposures and the food (alone) exposures for each
population subgroup.  Acute drinking water exposure U.S. population
resulted in a MOE of 130,208 (0.1% of the acute RfD of 1 mg/kg-bw/day). 
The most exposed sub-population was children (1-2 years old) with a MOE
of 70,472 (0.1% of the acute RfD of 1 mg/kg/day).  Since the benchmark
MOE for this assessment was 100 and since EPA generally has no concern
for exposures below 100% of the acute RfD, Syngenta believes that there
is a reasonable certainty that no harm will result from acute drinking
water exposure to residues arising from the proposed uses of
pydiflumetofen.

Chronic Exposure from Drinking Water:  The chronic ground water EDWC of
37.0 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the chronic drinking water
exposures.  Chronic drinking water exposure to the U.S. population
resulted in a MOE of 12,039 (0.8% of the chronic RfD of 0.092
mg/kg-bw/day).  Chronic drinking water exposure to the most exposed
sub-population (infants, <1 year old) resulted in a MOE of 3,223 (3.1%
of the chronic RfD of 0.012 mg/kg-bw/day).  Since the benchmark MOE for
this assessment was 100 and since EPA generally has no concern for
exposures below 100% of the acute RfD, Syngenta believes that there is a
reasonable certainty that no harm will result from acute drinking water
exposure to residues arising from the proposed uses of pydiflumetofen.

2. Non-dietary exposure.  Residential exposure risk assessments were
performed for use of pydiflumetofen formulated as A19649 200 SC on
ornamentals and golf course turf. A19649 200 SC Turf is labeled for use
on golf course turf; therefore, no residential handler exposure
assessments are required for this product.  Homeowner application of
A19649 200 SC on ornamentals is allowed; therefore residential handler
exposure assessments are required.  Residential exposure assessments
were performed for pydiflumetofen to evaluate exposures resulting from
off-site drift of agricultural products into residential areas. 
Incidental exposure to consumers from spray drift from non-residential
uses were not included in the aggregate consumer risk; this approach
agrees with the EPA’s current policy and practice.  The following
endpoints were used: a 9.2 mg/kg/day NOAEL for children 1-6 years old
(oral, short-term) from an 80 week mouse study; a 100 mg/kg/day NOAEL
for adults (dermal and inhalation, short-term) from a developmental
toxicity study in rats.  Residential exposure risk from pydiflumetofen
was acceptable for all population subgroups, with Margins of Exposure
above the Benchmark MOE of 100 for all scenarios assessed.  Adults 19+
years old were most-exposed via post-application exposure to treated
gardens, with a short-term MOE of 8,655.  Youth golfers 11-16 years old
were most-exposed via post-application exposures from liquid-treated
turf, with a short-term MOE of 323,750.  Youths 6-11 years old were
most-exposed via post-application exposures from activities in or near
liquid-treated gardens, with a short-term MOE of 12,644.  Children 1-6
years old were most-exposed via post-application exposures from play
activities on liquid-treated residential turf, with a short-term MOE of
10,760.    Since the MOEs for children (1-6 years), youths (6-16 years),
and adults (19+ years) were all above the Benchmark MOE of 100,
residential exposure risks for pydiflumetofen do not exceed the EPA’s
Level of Concern.

D. Cumulative Effects

Cumulative Exposure to Substances with a 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 EPA does not have, at this time,
available data to determine whether pydiflumetofen has a common
mechanism of toxicity with other substances or how to include this
pesticide in a cumulative risk assessment.  For the purposes of this
tolerance action, the EPA has not assumed that pydiflumetofen has a
common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. The acute dietary exposure analysis (food plus
water) showed that exposure from all proposed uses of pydiflumetofen
would result in a MOE of 1,328 (7.5% of the aRfD of 1.0 mg/kg-bw/day)
for the general U.S. population, which exceeds the Benchmark MOE of 100.
 For the short-term aggregate exposure analysis, the corresponding food,
water, and residential MOEs were aggregated using the inverse MOE
approach.  The short-term aggregate (food, drinking water, and
residential) MOE was 2,371 for adults (50-99 years old), which exceeds
the Benchmark MOE of 100.  The chronic dietary exposure analysis (food
plus water) showed that exposure from all proposed uses of
pydiflumetofen resulted in a MOE of 3,360 (2.9% of the cRfD of 0.09
mg/kg-bw/day) for the general U.S. population, which also exceeds the
Benchmark MOE of 100.  Based on the completeness and reliability of the
toxicity data supporting these petitions, Syngenta believes that there
is a reasonable certainty that no harm will result from aggregate
exposure to residues arising from all current, pending, and proposed
uses of pydiflumetofen, including anticipated dietary exposure from
food, water, and all other types of non-occupational exposures.

2. Infants and children. The acute dietary exposure analysis (food plus
water) showed that exposure from all proposed uses of pydiflumetofen
would result in a MOE of 736 (13.6% of the aRfD of 1.0 mg/kg-bw/day) for
the most sensitive population subgroup, children (1-2 years), which
exceeds the Benchmark MOE of 100.  For the short-term aggregate exposure
analysis, the corresponding food, water, and residential MOEs were
aggregated using the inverse MOE approach.  The short-term aggregate
(food, drinking water, and residential) MOE was 1,847 for children (1-2
years), which exceeds the Benchmark MOE of 100.  The chronic aggregate
dietary (food plus water) exposure analysis showed that exposure from
all proposed uses of pydiflumetofen would result in a MOE of 2,181 (4.5%
of the cRfD of 0.09 mg/kg-bw/day) for the most sensitive population
subgroup, children (1-2 years), which exceeds the Benchmark MOE of 100. 
Based on the completeness and reliability of the toxicity data
supporting these petitions, Syngenta believes that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to residues arising from all current, pending, and
proposed uses of pydiflumetofen, including anticipated dietary exposure
from food, water, and all other types of non-occupational exposures.

F. International Tolerances

Codex Alimentarius Commission has not yet established Maximum Residue
Limits (MRLs) for pydiflumetofen.

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