EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division Contact: Kathryn Montague

IR

- 4 ; Petition # 6E8454

EPA has received a pesticide petition ( 6E8454 ) from Interregional Research Project Number 4 (IR

- 4), Rutgers, The State University of NJ, 500 College Road East, Suite 201 W, 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 a mend 4 0 CFR part 180 by establishing a tolerance for residues of pyroxasulfone 3

- [[[5

- (difluoromethoxy)

- 1

- methyl

- 3

- (trifluoromethyl)

- 1 H

- pyrazol

- 4

- yl]methyl]sulfonyl]

- 4,5

- dihydro

- 5,5

- dimethylisoxazole, and its metabolites, 5

- (difluoromethoxy)

- 1

- methyl

- 3

- (tr ifluoromethyl)

- 1 H

- pyrazol

- 4

- carboxylic acid (M

- 3); [5

- (difluoromethoxy)

- 3

- (trifluoromethyl)

- 1H

- pyrazol

- 4

- yl]methanesulfonic acid (M

- 25); 3

- [1

- carboxy

- 2

- (5,5

- dimethyl

- 4,5

- dihydroisoxazol

- 3

- ylthio)ethylamino]

- 3

- oxopropanoic acid (M

- 28); and [5

- (difluorometho xy)

- 1

- methyl

- 3

- (trifluoromethyl)

- 1 H

- pyrazol

- 4

- yl]methanesulfonic acid (M

- 1) calculated as the stoichiometric equivalent of pyroxasulfone in or on the raw agricultural commodit y Sunflower subgroup 20B at 0.2 ppm (parts per million ). EPA has determined tha t 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. Add itional data may be needed before EPA rules on the petition.

A. 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. Th e 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 toler ance 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 fo r 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

.2

Crop Subgroup 20B Magnitude of residue data have been collected from 12 field trials located in NAFTA Regions. Each trial consisted of at least two treated plots. One treated plot at each trial received a pre

- emergent broadcast application while the o ther treated plot received a foliar broadcast application. The pre

- emergent application rates ranged from 0.249 to 0.278 lb ai/A per application. The foliar broadcast application rates ranged from 0.263 to 0.277 lb ai/A per application. The ND02 trial had an additional treated plot for processing samples with a pre

- emergent application of 0.801 lb ai/A (3X)

. All applications were made using appropriate spray equipment, and the spray volume was sufficient to provide adequate dispersal of the test substance. Sampling started in the untreated control plot and ended in the treated plot. At all the field trials, samples were harvested at commercial maturity after the pre

- emergent application and 57

- 64 days after the foliar broadcast application. Additionally , at the ND02 trial, additional samples for processing were collected from the untreated and 3X treated plot at commercial maturity. The samples were analyzed using a working method very similar to the reference methods, “KIH

- 485/M

- 3, M

- 1, and M

- 25 Analyt ical Method in Cotton Processed Commodities as Described in “Magnitude of the Residue of KIH

- 485 85 WG Herbicide in Cotton Processed Commodities,” Janine E. Martin, Ph.D., PTRL West Study No. 2340W, SPONSOR: Kumiai Chemical Industry Co., Ltd. A nd “The Magn itude of Residues of Pyroxasulfone Metabolite M

- 28 in/on Soybean Seed and Processed Commodities”, study conducted by PTRL West (625

- B Alfred Noble Dr., Hercules, CA 94547) and sponsored by Kumiai Chemical Industry Co., Ltd. The residues of pyroxasulfone w ere <0.010 ppm in samples treated with a pre

emergent application and ranged from <0.010 to 0.015 ppm in samples treated with a foliar broadcast application. Residues of M

- 1 were <0.010 ppm in samples treated with a
pre

- emergent application and ranged from <0.010 to 0.054 ppm in samples treated with a foliar broadcast application. There were no residues above the lowest level of method validation in any sample for M

- 3 (0.010 ppm), M

- 25 (0.010 ppm), and M

- 28 (0.050 ppm). Also, there were no residues above th e lowest level of method validation for any analyte in the meal and oil samples. The LOQ for each analyte was 0.01 ppm . Tolerances for pyroxasulfone and its metabolites M

- 1, M

- 3, M

- 25 and M

- 28 on S unflower subgroup 20B at 0. 2 ppm are being proposed accord ing to the OECD MRL calculator and the results of the processing studies.

Confined Rotational Crop Study Pyrazole or isoxazoline ring labeled 14 C KIH

- 485 was sprayed on confined plots of bare soil prior to planting soybean, radish and wheat at 30, 120 an d 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 actu al 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. The3

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 h ave 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 specifi ed 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 wit h 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, res pectively. 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 except ion 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, eg gs 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

su bstance

- 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 m ale and female rats.4

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 develo pmental toxicity study in rabbits, t here 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 n o 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 P 1 adul t rats was 25 ppm. The NOEL for F 1 offspring was 250 ppm and the NOEL for F 1 adults was 250 ppm.

In a rat two

- generation reproduction study t here were no test substance

- related effects for reproductive toxicity at 2000 ppm, the highest concentration tes ted. 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 (6.9 4

– 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 eff ects 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. Pyr oxasulfone was evaluated in a 28

- day inhalation toxicity study in rats. There were no test substance

- related effects. The NOEL was > 200 mg/m 3, the highest dose tested.

In a 28

- day dermal toxicity study there was a test substance

- related increase in the5

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. Th e 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 immunotoxi city 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 stu dy, 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 fe male 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 m icro scopic 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 admi nistered 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 n erve 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 neurotoxic ity 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.6

5. Chronic toxicity. Chronic toxicity studies were conducted in the rat and dog. In the rat one year chronic toxicity study t est sub stance

- 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 (m ucosal 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 associate d 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, r espectively).

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 animal s at the 10 mg/kg/day dosage had clear test

- article related abnormal observation s. 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 subseq uent 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 a nd <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 carboxylate d (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, resp ectively. 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 meta bolism study, 73% of the applied dose of7

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 m ajority 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 th ere 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 se en 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 metabo lites 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 subst ances 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. Aggregat e 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 ch ronic 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 DEEM TM (Dietary Exposure Evaluation Model; Exponent, Inc., v.4.02 ) software system. The acute reference dose (aRf D ) 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 (cRf D ) was determined to be 0.02 mg/kg/day assuming the cRf D is 1 percent of the NOEL. Using proposed tolerances for corn, soybean

, wheat, cotton , crop subgroup 6C, flax, peanut, and sunflower subgroup 20B the acute an d chronic dietary exposure Margin of Exposure (MOEs) for the overall US population and 258

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 unacc eptable 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 p yroxasulfone 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. I t 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 formulati on to be applied to Sunflower Crop Subgroup 20B 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 prop osed label for Pyroxasulfone 85WG Herbicide (pyroxasulfone 85% dry flowable formulation). The maximum application rate for Sunflower Crop Subgroup 20B is 0.27 lb ai/acre. Pyroxasulfone 85 WG may be applied pre

- plant incorporated, pre

- emergence after planti ng but prior to crop emergence, or post emergent up to 60 days before harvest.

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 lis te d below

.

Occupational Handler Exposure & Risk Estimates for Pyroxasulfone

Short

- & Intermediate

Term Exposure Unit Exposure 1

(mg/lb ai handled) Application

Rate (lb ai/A) Units

Treated 2 (A/day) Average

Daily Dose 3 (mg ai/kg bw/day) Short

- &

Intermedia te

Term MOE 4 Mixer/Loader

– Liquids

– Open Loading for Aerial Application Dermal 0.0516 0.27 350 0.060 1,700 Inhalation 0.00179 0.27 350 0.0021 960

Mixer/Loader

– Liquids

– Open Loading for Groundboom Application Dermal 0.0516 0.27 80 0.014 7,3009

Inh alation 0.00896 0.27 80 0.0024 840 Applicator

– Liquids

– Aerial Dermal 0.00208 0.27 350 0.0024 41,000 Inhalation 0.0000049 0.27 350 0.0000057 350,000 Applicator

– Liquids

– Groundboom Dermal 0.0161 0.27 80 0.0043 23,000 Inhalation 0.00471 0.27 80 0. 000090 22,000

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 Applicati on 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); NOAEL dermal = 100 mg/kg/day, NOAEL inhalation = 2.0 m g/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 scenari os were assessed using Science Advisory Council for Exposure (ExpoSAC) Policy 3

– Revised March 2013 . The occupational post

- application exposure and risk estimates for pyr oxasulfone are listed below.

Occupational Post

- Application Exposure & Risk Estimates for Pyroxasulfone

Short

- & Intermediate

Term Exposure Crop

Activity Transfer

Coefficient 1 (cm 2 /hr) Application

Rate (lb ai/A) Average

Daily Dose 2 (mg ai/kg bw/day) Sho rt

- &

Intermediate

Term MOE 3

Dermal Sunflower

,

Scouting 90 0.27 0.0067 15,000

1 Transfer Coefficient from Science Advisory Council for Exposure (ExpoSAC) Policy 3

– Revis ed 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); NOAEL dermal = 100 mg/kg/day for all durations.10

All occupational handler and post

- application exposures from agricultural applications of pyroxasul fone 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

m ixing, 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 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 Rate 1 (lb ai/A) Averag e

Daily Dose 2 (mg ai/kg bw/day) Short

- & Intermediate

Term MOE 3

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 (AR drift )= Application Rate * Drift Factor. Application rate = 0.27 lb ai/A. Drift Factor = 0.257 from Exposure As sessment 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 Exp osure Assessment: October 2012. AR drift was used in place of application rate in exposure calculations.
3 Margin of Exposure (MOE) = NOAEL (mg/kg/day) ÷ ADD (mg/kg/day); NOAEL dermal = 100 mg/kg/day, NOAEL incidental 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 Effects11

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 complet e. Based on the NOEL of 2 mg/kg/day from a 1

- year toxicity study in the dog, proposed uses
repr esent 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 amend ing the corn tolerance dated 22 May 2014, DP Barcode D417422. The percent aRfD for the US population was 2.03% for the 99 th 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

m utagenicity 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 1 x.

F. International Tolerances

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

.