Document ID: EPA-HQ-OPP-2015-0787-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-12-23T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division Contact: Kathryn Montague (703) 305-1243 

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.

TEMPLATE:

[K-I CHEMICAL U.S.A., INC.]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from
K-I CHEMICAL U.S.A., INC. c/o Landis International, Inc., P. O. Box 5126
Valdosta, GA  31603-5126 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 180.659 by establishing  tolerances for residues of
the herbicide pyroxasulfone
(3-[(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)
pyrazole-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-oxazole) and
its metabolites in or on dried shelled peas and beans (crop subgroup 6C)
at 0.15 ppm, pea hay at 0.4 ppm, pea vines at 0.2 ppm, cowpea hay at
0.07 ppm, cowpea forage at 3.0 ppm, flax at 0.07 ppm, peanut at 0.2 ppm,
and peanut hay at 3 ppm, peanut meal at 0.40 ppm, vegetable, foliage of
legume, except soybean, subgroup 07A at 3.0 ppm.  The LC/MS/MS has been
proposed to enforce the tolerance expression for pyroxasulfone. 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.

Residue Chemistry

1. Plant Metabolism. Plant metabolism studies were conducted and
accepted by the Agency for soybean and field corn.  A potato metabolism
is being submitted at this time. The plant and animal metabolism of
pyroxasulfone is well understood. Primary metabolic processes are
cleavage between the two ring structures, side chain oxidation to
carboxylic acid and demethylation.  Pyroxasulfone and its major
metabolites M-1, M-3, M-25, and M-28 have been identified in the
metabolism studies. The metabolism of pyroxasulfone in plants and
animals is understood for the purposes of the proposed tolerances. 
Pyroxasulfone and its metabolites M-3 and M-28 are the residues of
concern for tolerance setting purposes for crop subgroup 6C.
Pyroxasulfone only contains the residues of concern for tolerance
setting purposes for flax. Pyroxasulfone and its metabolites M-1, M-3,
M-25 and M-28 are the residues of concern for tolerance setting purposes
for peanut.

	2. Analytical method. EPA has approved an analytical enforcement
methodology including liquid chromatography, mass spectrometry, and mass
spectrometry (LC/MS/MS) to enforce the tolerance expression for
pyroxasulfone. 

	3. Magnitude of residues. 

Crop Subgroup 6C

A total of 26 dry edible bean and pea residue raw agricultural commodity
(RAC) field trials were conducted representing typical plus crop growing
regions in US and Canada. Bean trials were conducted in regions 5, 7,
7A, 8, 9, 10, 11, and 14. Successful cowpea trials were conducted in
regions 5 and 7. Pea trials were conducted in regions 5, 7, 11 and 14. 
All applications were made according to the protocol.  Extraction
methods included extraction into aqueous acetonitrile followed by
clean-up steps. Analysis was conducted by LC-MS/MS. The proposed
tolerances were calculated using the OECD residue calculator. The
registrant proposes the following tolerances for pyroxasulfone
(3-[(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)
pyrazole-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-oxazole) and
its metabolites in or on dried shelled peas and beans (crop subgroup 6C)
at 0.15 ppm, pea hay at 0.4 ppm, pea vines at 0.2 ppm, cowpea hay at
0.07 ppm, cowpea forage at 3.0 ppm, and vegetable, foliage of legume,
except soybean, subgroup 07A at 3.0 ppm.  

Flax

	A total of 10 flax trials treated with pyroxasulfone were conducted
representing major commercial flax regions in the US and Canada. Flax
trials were conducted in regions 5, 7, and 14. Extraction methods
included extraction into aqueous acetonitrile followed by various
clean-up steps, depending on the analyte and matrix. Analytical methods
were validated for pyroxasulfone, M-1, M-3, M-25 and M-28 in flax seed,
meal and oil with analysis by LC-MS/MS. A tolerance for pyroxasulfone
and its metabolites on flax at 0.07 ppm is being proposed according to
the OECD MRL calculator.

Peanut

	A total of 13 peanut trials treated with pyroxasulfone were conducted
representing typical peanut growing regions in the US. Of the thirteen
trial sites, two sites included processed commodity components and three
sites included residue decline components. The trails were conducted in
regions 2, 3, 6 and 8. All applications were made according to the
protocol (one pre-ermergence or one post-emergence) by broadcast spray.
Extraction methods included extraction into aqueous acetonitrile
followed by various clean-up steps, depending on the analyte and matrix.
Analysis was by LCMS/MS. The LOQ for each analyte was 0.01 ppm.
Tolerances for pyroxasulfone and its metabolites on peanut at 0.2 ppm,
peanut hay at 3 ppm, and peanut meal at 0.40 ppm are being proposed
according to the OECD MRL calculator and the results of the processing
studies.

 Confined Rotational Crop Study

Pyrazole or isoxazoline ring labeled 14C KIH-485 was sprayed on confined
plots of bare soil prior to planting soybean, radish and wheat at 30,
120 and 365 day intervals.  There were two treated plots for each
plantback interval, one of which was wheat only and the other was
planted half with soybean and half with radish.  All plots were treated
at a target application rate of 300 g a.i./ha but the actual rate was
313 g a.i./ha.  Samples were analyzed by combustion analysis and liquid
scintillation counting.  All treated crops contained radioactive residue
>0.01 ppm and were subjected to further analysis.  The highest total
radioactive residue (TRR), 5.2 ppm was found at the 30 day rotational in
wheat straw; the residue level declined to 0.02 ppm at 485 days.  The
primary metabolites were M-1 and M-3.  

Field Rotational Crop Study

A field rotational crop study was conducted in Georgia (GA) and Texas
(TX) on a fine and coarse textured soil, respectively. The purpose of
the study was to obtain raw agricultural commodity (RAC) residue data
for pyroxasulfone and its metabolites M-1, M-3, M-25, M-28, and M-37 on
rotational crops that are planted in plots that have been treated with
Pyroxasulfone 85 WG at the proposed label rate and aged for various time
intervals prior to planting the rotational plot. Each plot was treated
at an appropriate time for growing the target crop and then allowed to
age for the specified aging interval (120, 270, 300 and 365 days,
nominal intervals).  There was no residue seen in any crop matrix at any
sampling interval above the LOQ except for one replicate 120 day potato
top sample which showed residue of M-1 at the LOQ (0.01 ppm).    As a
result, neither pyroxasulfone nor any of its metabolites are expected to
accumulate in rotational crops when Pyroxasulfone 85 WG is applied to
target crops at the labeled rates.      

   

Cow Feeding Study

	Holstein dairy cows were treated orally with gelatin capsules fortified
with pyroxasulfone.  These were administered once daily for 28
consecutive days at dose levels of 0, 1.8, 5.4, and 18 ppm per cow/day
on a dry weight basis amounting to concentrations of control, 1X, 3X and
10X dose groups, respectively.  These dose levels were equivalent to 0,
35.8 mg/cow/day, 109.9 mg/cow/day and 367.4 mg/cow/day, respectively. 
Milk samples from the high dose animals (10X) were found to contain no
residues of the parent compound or metabolites with the exception of 3
milk samples from day 7 which contained an average of 0.003 ppm parent
pyroxasulfone.  No other milk samples from the other dose levels were
found to contain residues of pyroxasulfone or metabolites.  No other
matrix (muscle, liver, kidney or fat) was found to contain residues of
pyroxasulfone or metabolites above LOQ.  The LOQs were 0.001 ppm in milk
and 0.01 ppm in all other matrices.  Therefore, no tolerances for
residues of pyroxasulfone and its metabolites are being proposed for
meat, milk, eggs or other edible tissues of livestock or poultry.

B. Toxicological Profile

1.  Acute Toxicity. Pyroxasulfone was found to be of low acute toxicity
via oral, dermal and inhalation routes of administration.  It was not
irritating to skin or eyes and was not a sensitizing agent.  The
formulated product (85WG) was also of low acute toxicity and was found
to be mildly irritating to skin, moderately irritating to eyes and was a
dermal sensitizer.  In an acute neurotoxicity study in rats, there were
no test substance-related effects on body weights, food consumption,
clinical observations, functional observational battery assessments,
motor activity measurements, or gross and microscopic neuropathology.
The NOEL was demonstrated to be >2000 mg/kg/day in adult male and female
rats.

2.  Genotoxicity. Pyroxasulfone and its metabolites and impurities do
not induce gene mutations in bacterial cells.  Pyroxasulfone does not
induce gene mutations or chromosomal aberrations in in vitro mammalian
cells or in vivo in the mouse micronucleus test.  Pyroxasulfone is
non-genotoxic.

3.  Reproductive and developmental toxicity. In a developmental toxicity
study in rats, the NOEL for maternal and developmental toxicity was
>1000 mg/kg/day, the highest dose tested.

	In a developmental toxicity study in rabbits, there were slight test
substance-related effects on fetal weight and number of implant
resorptions at 1000 mg/kg/day, the highest dose tested.  The NOEL for
maternal toxicity was 1000 mg/kg/day. The NOEL for developmental
toxicity was 500 mg/kg/day.

	In a rat one-generation reproductive study no reproductive toxicity was
observed up to and including the high dose of 5000 ppm.  The NOEL for
reproductive toxicity was >5000 ppm, the highest dose tested.  The NOEL
for P1 adult rats was 25 ppm.  The NOEL for F1 offspring was 250 ppm and
the NOEL for F1 adults was 250 ppm.

	In a rat two-generation reproduction study there were no test
substance-related effects for reproductive toxicity at 2000 ppm, the
highest concentration tested.   The NOEL for reproductive toxicity was
>2000 ppm, the highest concentration tested. Test substance-related
effects were observed at 2000 ppm in both adults and offspring.
Therefore, the NOAEL for systemic toxicity was demonstrated to be 100
ppm (6.94 – 11.76 mg/kg/day) in both parents and offspring.

	In a developmental neurotoxicity study conducted on pyroxasulfone in
mated female rats no reproductive effects were observed in the maternal
animals at 2000 ppm, the highest concentration tested. No effects were
observed on FOBs, auditory startle response habituation, pre-pulse
inhibition, learning and memory of offspring.  A slight (5%) decrease in
absolute brain weight at 900 mg/kg/day was present on PD 66, although no
effect was present when evaluated on a % body weight basis.  Based on
the effects observed in this study, the maternal and offspring systemic
NOAEL is 900 mg/kg/day. The NOEL for functional development was judged
to be 900 mg/kg/day. A NOEL for histomorphological development of the
brain of the offspring was judged to be 300 mg/kg/day.

	Two studies were performed to assess the availability of the test
substance to the pup.  These studies indicated that pyroxasulfone was
available in the milk to nursing pups.

	4.  Subchronic toxicity. Pyroxasulfone was evaluated in a 28-day
inhalation toxicity study in rats.  There were no test substance-related
effects.  The NOEL was >200 mg/m3, the highest dose tested.

	In a 28-day dermal toxicity study there was a test substance-related
increase in the incidence of minimal to mild cardiac myofiber
degeneration with inflammation observed in males and females dosed with
1000 mg/kg/day and cutaneous myofiber degeneration with inflammation
observed in the treated skin of males dosed with 1000 mg/kg/day.  The
NOEL was 100 mg/kg/day.

	Immunotoxicity was evaluated in rats and mice following dietary
exposure for 28 days.  There were no test substance related effects for
any of the immunotoxicity parameters examined.  In the rat, systemic
toxicity was limited to reductions in body weight and food consumption. 
The NOEL for immunotoxicity was 7500 ppm (529 and 570 mg/kg in males and
females) and the NOEL for systemic effects was 250 ppm (18 and 19 mg/kg
in males and females).  In the mouse, the NOEL for immunotoxicity was
4000 ppm (633 mg/kg/day males: 791 mg/kg/day females) and the NOEL for
systemic effects was 400 ppm (61 mg/kg males: 77 mg/kg females).

	Pyroxasulfone was evaluated in 13-week oral toxicity studies in rats,
mice and dogs. In the 13 week mouse study, no test substance-related
effects on in-life and clinical pathology parameters were observed at
any level tested. Test substance-related effects at 2500 ppm were
limited to an increased incidence of minimal to mild chronic progressive
nephropathy in female mice and increased liver weight in males and
females fed 2500 ppm.  The NOEL was 250 ppm for female mice (51.2
mg/kg/day).  The NOEL for male mice was 2500 ppm (394.0 mg/kg/day).

	 In the 13 week rat study, a NOEL of 250 ppm for male and female rats
corresponded to mean daily intake values of 16.4 and 20.6 mg/kg/day in
males and females, respectively.  Test substance related effects were
increased cardiac myofiber degeneration with inflammation and diffuse
mucosal hyperplasia of the urinary bladder.  Increased liver weights and
centrilobular hypertrophy were also observed in 2500 ppm males and
females. In a second study evaluating recovery, full or partial recovery
was evident in all the above effects apart from kidney weights in
females with all microscopic findings in the liver, heart, muscle and
pancreas of 5000 ppm animals comparable to control rats indicating a
complete reversal of the treatment-related findings noted at the
terminal sacrifice.

	In an oral 90 day toxicity study in beagle dogs administered
pyroxasulfone in a capsule, the NOEL was 2.0 mg/kg. The only effects
noted were degeneration of muscle fiber of the musculature portion of
the diaphragm, hyperplasia of the satellite cell of the muscle and nerve
fiber degeneration of the sciatic nerve in one 10mg/kg/day group male
only.  In a second study dosed with 0 or 15 mg/kg of pyroxasulfone, 
male dogs showed a decrease in body weight and histopathology similar to
the full study.

	Pyroxasulfone was evaluated in a subchronic 90 day neurotoxicity
dietary study in rats.  There were no effects on body weights, food
consumption, clinical observations, FOB assessments, motor activity
measurements, or gross and microscopic neuropathology. The NOEL was
>2500 ppm, the highest dose tested, for male and female rats
corresponding to mean daily intake values of 161.48 and 199.59 mg/kg/day
in males and females, respectively.

5.  Chronic toxicity. Chronic toxicity studies were conducted in the rat
and dog. In the rat one year chronic toxicity study test
substance-related effects occurred at 1000 ppm and above that included
reduced body weight parameters and microscopic findings in the liver
(centrilobular hepatocellular hypertrophy in males), heart (increased
cardiomyopathy in females) and urinary bladder (mucosal hyperplasia in
males and females) and urinary bladder hyperplasia considered to be
secondary to inflammation or irritation.  At 2000 ppm, these effects
were accompanied by increased clinical observations of red discharge
from the penis and associated red-stained cageboards as well as
increased liver and kidney weights. A slight increase in liver and
kidney weights was observed in the 2000 ppm male and female dietary
exposure groups. The NOEL is 50 ppm (2.22 and 3.12 mg/kg/day for males
and females, respectively).

	In a one-year dog study beagle dogs/sex/dose were administered capsules
containing 0.0, 0.2, 2.0 and 10.0 mg/kg/day.  Adverse test
article-related findings were limited to the 10.0 mg/kg/day group, the
highest dose tested and not all animals at the 10 mg/kg/day dosage had
clear test-article related abnormal observations.  Adverse changes in
the clinical pathology parameters were increases in creatine kinase,
aspartate aminotransferase and change in the pathology limited to the
sciatic nerve and spinal cord.  The NOAEL is 2.0 mg/kg/day.

	The carcinogenic potential of pyroxasulfone was evaluated in rats and
mice. The Agency has classified pyroxasulfone as “Not likely to be
carcinogenic to humans” at doses that do not cause crystals with
subsequent calculi formation resulting in cellular damage of the urinary
tract.

6.  Animal metabolism.  In the rat, pyroxasulfone is rapidly and
completely eliminated.  Between 80 to 90% of pyroxasulfone was
eliminated in the urine during the first 24 hours and elimination was
essentially complete after 48 to 72 hours.  Absorption was calculated
(bile and urine) at 76%.  Maximum plasma concentrations were achieved at
2 hours in the low and 11 hours in the high dose animals.  At 96 hours
only 7% of the low dose and <0.5% of the high dose was present in the
carcass demonstrating the near complete elimination of pyroxasulfone. 
Of the radioactivity present in the animals, the highest levels were
seen in the liver and kidney.  The major metabolites were a carboxylated
(pyrazole ring methyl group) and cleavage products between the
isoxazoline and pyrazole ring structure with subsequent carboxylation. 
The absorption, distribution, metabolism and elimination of
pyroxasulfone is unaffected by sex or treatment regimen.   

	In a preliminary study in the dog, pyroxasulfone is rapidly eliminated
with 76.9% of radioactivity excreted within 24 hours.  Excretion is
approximately equal in urine and feces. The terminal half life was 89.58
hr and 40.80 hr in blood and plasma, respectively.  The feces were found
to contain only unchanged pyroxasulfone while no parent molecule was
found in the urine.  At 120 hr after dosing, the levels of radioactivity
in the tissues were highest in the liver and blood. 

	In a preliminary mouse metabolism study, 73% of the applied dose of
pyroxasulfone was excreted in urine within 24 hours of dosing. 
Pyroxasulfone was rapidly absorbed and distributed through the tissues
of the mouse but by 24 hours after dosing, radioactivity concentrations
in the majority of tissues were indistinguishable from background
levels.

	Metabolism studies in livestock and poultry (Nature of Residue Studies
with Goat and Hen) with repeated dose established that pyroxasulfone was
rapidly metabolized and excreted and that there was minimal transmittal
of residues of pyroxasulfone and its metabolites to meat or milk.  For
goats fed 10 ppm of radiolabeled pyroxasulfone, the highest residues
(TRR) were seen in liver and kidney.  In the hen, fed 10 ppm, the
highest residue was seen in liver and muscle.  

7.  Metabolite toxicology. Three plant metabolites and three impurities
were evaluated in acute oral toxicity studies.  All six test substances
evaluated showed LD50’s >2000 mg/kg similar to the parent,
pyroxasulfone.  Two metabolites were further assessed in a 14 day
toxicity study in rats.  The NOEL for each of the metabolites was > 1000
mg/kg.  The same three metabolites and impurities were evaluated in a
bacterial gene mutation test with and without activation.  All test
substances were non-genotoxic.  

8.  Endocrine disruption. Pyroxasulfone does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system.  There is no evidence that pyroxasulfone has any effect on
endocrine function in developmental, reproduction or developmental
neurotoxicity studies.  Furthermore, histological investigation of
endocrine organs in chronic dog, rat and mouse studies did not indicate
that the endocrine system is targeted by pyroxasulfone.

C. Aggregate Exposure

	1. Dietary exposure. It can be concluded with reasonable certainty that
residues of pyroxasulfone in food will not result in unacceptable levels
of human health risk. Using proposed tolerances for corn, soybean and
wheat, both the acute and chronic dietary exposure MOEs for the overall
US population and 25 population subgroups are above the EPA level of
concern.

	i. Food. Acute and chronic dietary exposure assessments were conducted
using a Tier I approach.  This Tier I assessment incorporated tolerance
level residues and 100% crop-treated in the DEEMTM (Dietary Exposure
Evaluation Model; Exponent, Inc., v.4.02) software system.  The acute
reference dose (aRfD) used was 1 mg/kg/day based on the most current
risk assessments conducted by the EPA for amending the corn tolerance
dated 22 May 2015 (DP Barcode D417422). The chronic toxicological
endpoint selected for assessment of risk following chronic dietary
exposure was 2 mg/kg/day based on the one-year chronic feeding dog study
with a NOEL of 2 mg/kg/day. The chronic reference dose (cRfD) was
determined to be 0.02 mg/kg/day assuming the cRfD is 1 percent of the
NOEL. Using proposed tolerances for corn, soybean, wheat, cotton, crop
subgroup 6C, flax and peanut, the acute and chronic dietary exposure
Margin of Exposure (MOEs) for the overall US population and 25
population subgroups are above the EPA level of concern. It can be
concluded with reasonable certainty that residues of pyroxasulfone in
food will not result in unacceptable levels of human health risk. 

	ii. Drinking water. Based on the Pesticide Root Zone Model/Exposure
Analysis Modeling System (PRZM/EXAMS) and Pesticide Root Zone Model
Ground Water (PRZM GW), the estimated drinking water concentrations
(EDWCs) of pyroxasulfone for acute exposure are estimated to be 17 ppb
for surface water and 210 ppb for ground water. EDWCs of pyroxasulfone
for chronic exposures for non-cancer assessments are estimated to be 3.2
ppb for surface water and 174 ppb for ground water. It can be concluded
with reasonable certainty that residues of pyroxasulfone in drinking
water will not result in unacceptable levels of human health risk. 

	2. Non-dietary exposure. 

	i. Occupational exposure Pyroxasulfone is a wettable granule
formulation to be applied corn, cotton, flax, peanut, pulse crops,
soybeans, wheat, and fallow land using groundboom or aerial spray
equipment. The potential exposures and associated risks for handlers
mixing, loading and applying pyroxasulfone and for workers re-entering
treated areas are based on the proposed label for Pyroxasulfone 85WG
Herbicide (pyroxasulfone 85% dry flowable formulation). The maximum
application rate is 0.27 lb ai/acre (flax, peanut, pulse crops).
Pyroxasulfone 85 WG may be applied preplant surface, preplant
incorporated, preemergence, early postemergence, postemergence layby, or
in the fall. 

Short- and intermediate-term dermal and inhalation exposures are
predicted for occupational handlers mixing, loading, and applying
pyroxasulfone. Since pyroxasulfone-specific exposure data are not
available, handler scenarios were assessed using the EPA Occupational
Pesticide Handler Unit Exposure Surrogate Reference Table - Revised
September 2015. The occupational handler exposure and risk estimates for
pyroxasulfone are listed below.  The estimates are for flax as flax has
the highest application rate and is considered a high acreage crop.

Occupational Handler Exposure & Risk Estimates for Pyroxasulfone 

Short- & Intermediate-Term Exposure	Unit Exposure1 (mg/lb ai handled)
Application Rate

(lb ai/A)	Units Treated2 (A/day)	Average Daily Dose3 (mg ai/kg bw/day)
Short- & Intermediate-Term MOE4

Mixer/Loader – Liquids – Open Loading for Aerial Application

Dermal	0.0516	0.27	1200	0.21	490

Inhalation	0.00179	0.27	1200	0.0071	280

Mixer/Loader – Liquids – Open Loading for Groundboom Application

Dermal	0.0516	0.27	200	0.034	2,900

Inhalation	0.00896	0.27	200	0.0060	340

Applicator – Liquids – Aerial

Dermal	0.00208	0.27	1200	0.0083	12,000

Inhalation	0.0000049	0.27	1200	0.000020	102,000

Applicator – Liquids – Groundboom

Dermal	0.0161	0.27	200	0.011	9,400

Inhalation	0.00471	0.27	200	0.00023	8,900

1 Unit Exposure (UE) = mg ai/lb ai handled from Occupational Pesticide
Handler Unit Exposure Surrogate Reference Table - Revised September
2015.  PPE = long-sleeve shirt, long pants, socks, shoes, gloves and PF5
respirator (latter for aerial mixer/loader only).

2 Units Treated taken from Science Advisory Council for Exposure,
Standard Operating Procedure 9.1, Standard Values for Daily Acres
Treated in Agriculture, Rev. 25, September 2001.

3 Average Daily Dose (ADD) = Unit Exposure x Application Rate x Units
Treated x Absorption Factor ÷ Body Weight (80 kg).  Dermal absorption
factor = 100%, inhalation absorption factor = 100%.

4 Margin of Exposure (MOE) = NOAEL (mg/kg/day) ÷ ADD (mg/kg/day);
NOAELdermal = 100 mg/kg/day, NOAELinhalation = 2.0 mg/kg/day for all
durations.

Short- and intermediate-term dermal exposures are predicted for
post-application exposure to workers performing typical agricultural
tasks.  Since pyroxasulfone-specific exposure data are not available,
post-application scenarios were assessed using   HYPERLINK
"http://www.epa.gov/pesticides/science/exposac-policy-3-march2013.pdf" 
Science Advisory Council for Exposure (ExpoSAC) Policy 3 – Revised
March 2013 . The occupational post-application exposure and risk
estimates for pyroxasulfone are listed below. 



Occupational Post-Application Exposure & Risk Estimates for
Pyroxasulfone 

Short- & Intermediate-Term Exposure	Crop

Activity	Transfer Coefficient1 (cm2/hr)	Application Rate

(lb ai/A)	Average Daily Dose2 (mg ai/kg bw/day)	Short- &
Intermediate-Term MOE3

Dermal	Corn, Irrigation (hand set)	1900	0.21	0.11	880

Dermal	Cotton, Scouting	210	0.11	0.0066	15,000

Dermal	Flax, Scouting	1100	0.27	0.082	1,200

Dermal	Peanut, Weeding, Hand	70	0.27	0.0052	19,000

Dermal	Pulse (Dried Shelled Beans and Peas), Irrigation (hand set)	1900
0.27	0.14	700

Dermal	Soybeans, Scouting	1100	0.19	0.057	1,700

Dermal	Wheat, Scouting	1100	0.13	0.041	2,400

1 Transfer Coefficient from   HYPERLINK
"http://www.epa.gov/pesticides/science/exposac-policy-3-march2013.pdf" 
Science Advisory Council for Exposure (ExpoSAC) Policy 3 – Revised
March 2013 .  PPE = long-sleeve shirt, long pants, socks, shoes.

3 Average Daily Dose (ADD) = Transfer Coefficient (TC) x Dislodgeable
Foliar Residue (DFR) x Duration * Absorption Factor ÷ Body Weight
(80 kg).  DFR = 25% * Application Rate, Duration = 8 hrs/day, Dermal
Absorption Factor = 100%.

4 Margin of Exposure (MOE) = NOAEL (mg/kg/day) ÷ ADD (mg/kg/day);
NOAELdermal = 100 mg/kg/day for all durations.

All occupational handler and post-application exposures from
agricultural applications of pyroxasulfone result in MOEs greater than
100 and therefore do not exceed HED’s level of concern. 

	ii. Residential (Non-occupational) exposure and risk  There are no
proposed uses of pyroxasulfone which would lead to direct exposure to
residents, either through mixing, loading and application or due to post
application exposure; however, there are potential indirect
post-application exposures to adults and children due to drift onto
residential lawns from agricultural applications.  These indirect
post-application scenarios were assessed based on the proposed label for
Pyroxasulfone 85WG Herbicide (pyroxasulfone 85% dry flowable
formulation) using draft Residential Exposure Assessment Standard
Operating Procedures - Addenda 1: Consideration of Spray Drift (November
1, 2013). The greatest indirect residential exposure potential is from
aerial application to flax, peanuts, and pulse crops. The residential
post-application exposure and risk estimates for pyroxasulfone are
listed below. 



Residential Exposure & Risk Estimates for Pyroxasulfone 

Short- & Intermediate-Term Exposure	Lifestage	Drift Application Rate1
(lb ai/A)	Average Daily Dose2 (mg ai/kg bw/day)	Short- &
Intermediate-Term MOE3

High Contact Lawn

Dermal	Adult	0.050	0.019	5,400

Dermal	1 to <2 years	0.050	0.037	2,700

Hand-to Mouth

Incidental Oral	1 to <2 years	0.050	0.00076	130,000

Object-to-Mouth

Incidental Oral	1 to <2 years	0.050	0.000023	4,400,000

Soil Ingestion

Incidental Oral	1 to <2 years	0.050	0.0000017	59,000,000

1 Drift Application Rate (ARdrift)= Application Rate * Drift Factor. 
Application rate = 0.27 lb ai/A.  Drift Factor = 0.257 from Exposure
Assessment Standard Operating Procedures - Addenda 1: Consideration of
Spray Drift (November 1, 2013)

3 Average Daily Dose (ADD) for each exposure scenario was calculated
using the algorithms in the Standard Operating Procedures for
Residential Pesticide Exposure Assessment: October 2012.  ARdrift was
used in place of application rate in exposure calculations.

3 Margin of Exposure (MOE) = NOAEL (mg/kg/day) ÷ ADD (mg/kg/day);
NOAELdermal = 100 mg/kg/day, NOAELincidental oral = 100 mg/kg/day for
all durations.

All adult and children’s exposures due to drift from agricultural
applications of pyroxasulfone result in MOEs greater than 100 and
therefore do not exceed HED’s level of concern. 

D. Cumulative Effects

	Pyroxasulfone represents a new class of pyrazole herbicides.  No other
products are known to have the same mode of action as pyroxasulfone.
Therefore, a cumulative assessment is not appropriate at this time.

E. Safety Determination

	1. U.S. population. The toxicity database for pyroxasulfone is
complete. Based on the NOEL of 2 mg/kg/day from a 1-year toxicity study
in the dog, proposed uses represent 18.5% percent of the cRfD of 0.02
mg/kg/day for the total US population.  The aRfD used was 1 mg/kg/day as
referenced in EPA’s dietary assessment for amending the corn tolerance
dated 22 May 2014, DP Barcode D417422. The percent aRfD for the US
population was 2.03% for the 99th percentile. There is reasonable
certainty that no harm to the U.S. population will result from the
proposed uses of pyroxasulfone.

	2. Infants and children. The toxicity database for pyroxasulfone is
complete.  The database includes acute, subchronic, chronic,
mutagenicity, genotoxicity, developmental, reproduction, neurotoxicity
and immunotoxicity studies on pyroxasulfone and acute mutagenicity and
genotoxicity studies on several metabolites.  The weight of evidence
indicates that infants and children are not expected to be more
sensitive to pyroxasulfone than are adults.  Consequently, EPA reduced
the FQPA Safety Factor from 10x to 1x.

F. International Tolerances.

	Tolerances are approved on wheat, barley and triticale in Australia.
Tolerances are approved for corn and soybean in Canada and pending for
wheat. 

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