EPA REGISTRATION DIVISION CO MPANY 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 p reparing the pesticide petition. In

cases where the outline element does not apply, please insert “NA-Remove” and

maintain the outline. Please do not chan ge 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 by establishing

tolerances for residues of pyroxasulfone (3-[(5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl) pyrazole-4-ylmethylsu lfonyl]-4,5-dihydro-5,5-di methyl-1,2-oxazole)

and its metabolites M-3 (5-difluoromethoxy-1-methyl-3-t rifluoromethyl-1H-pyrazol-4- carboxylic acid) and M-28 (3-[1-carboxy-2-(5,5-dimet hyl-4,5-dihydroisoxazol-3- ylthio)ethylamino]-3-oxopropanoic acid) calculat ed as the stoichiometric equivalent of pyroxasulfone in or on the raw agricultural commodities dried shelled peas and beans (crop subgroup 6C) at 0.09 ppm (parts per million) and pyroxasulfone (3-[(5- (difluoromethoxy)-1-methyl-3-(trifluor omethyl) pyrazole-4-ylmethylsulfonyl]-4,5- dihydro-5,5-dimethyl-1,2-oxazole) in or on the raw agricultural commodities flax at 0.01 ppm (parts per million) and pyroxasulfone (3-[(5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl) pyrazole-4-ylmethylsu lfonyl]-4,5-dihydro-5,5-di methyl-1,2-oxazole)

and its metabolites M-1 (5-difluoromethoxy-1-methyl-3-t rifluoromethyl-1H-pyrazol-4- yl) methanesulfonic acid), M-3 (5-difluoromethoxy-1-methyl-3-trifluoromethyl-1Hpyrazol-4-carboxylic acid), M-25 (5-difluoromethoxy-3-trif luoromethyl-1H-pyrazol-4- yl)methanesulfonic acid) and M-28 (3-[1-carboxy-2-(5,5-dim ethyl-4,5-dihydroisoxazol3-ylthio)ethylamino]-3-oxopropanoi c acid) calculated as the stoi chiometric equivalent of pyroxasulfone in or on the raw agricultural commodities peanut at 0.2 ppm and peanut hay at 2 ppm ppm (parts per million). EPA has determined that the petition contains data or information regarding the elements se t 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 peti tion. Additional data may be needed before2

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. The plant and animal metabolism of pyroxasulfone is well understood. Primary metabolic processes are cleavage between the two ring structures, si de chain oxidation to carboxylic acid and demethylation. Pyroxa sulfone and its major metabolites M-1, M-3, M-25, and M-28 have been id entified in the metabolism studies. The metabolism of pyroxasulfone in plants and animals is unde rstood for the purposes of the proposed tolerances. Pyroxasulfone and its metabolite s M-3 and M-28 are the residues of concern for tolerance setting purposes for crop s ubgroup 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 re sidues of concern for tolerance setting purposes for peanut.

2. Analytical method. EPA has approved an analy tical enforcement methodology including liquid chromatography, mass spectrometry, and mass spectrometry (LC/MS/MS) to enforce the tolera nce 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 typi cal 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 a nd 7. Pea trials were conducted in regions 5, 7, 11 and 14. All applications were made acco rding to the protocol. Extraction methods included extraction into aqueous acetonitrile followed by cl ean-up steps. Analysis was conducted by LC-MS/MS. The proposed tolera nces were calculated using the OECD residue calculator. The proposed toleran ce for cotton seed based on the combined residues of pyroxasulfone and its metabol ite M-3 is 0.01 ppm (LOQ). The proposed tolerance for pyroxasulfone and its metabolite s M-3 and M-28 on dried shelled peas and beans (crop subgroup 6C) is 0.09 ppm.

Flax

A total of 10 flax trials treated with pyroxasulfone were conducted representing major commercial flax regions in the US a nd Canada. Flax trials were conducted in regions 5, 7, and 14. Extraction methods incl uded 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 tole rance for pyroxasulfone on flax at 0.01 ppm is being proposed according to the OECD MRL calculator.

Peanut A total of 13 peanut trials treated w ith pyroxasulfone were conducted representing3

typical peanut growi ng regions in the US. Of the thirteen trial sites, two sites included processed commodity component s 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 a nd matrix. Analysis was by LCMS/MS. The LOQ for each analyte was 0.01 ppm. Toleranc es for pyroxasulfone and its metabolites M-1, M-3, M-25 and M-28 on peanut at 0.2 pp m and peanut hay at 2 ppm are being proposed according to the OECD MRL calcu lator 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 planti ng soybean, radish and wheat at 30, 120 and 365 day intervals. There were two treated plots for each plan tback interval, one of which was wheat only and the other was planted half with soybean a nd half with radish. All plots were treated at a target application rate of 300 g a.i./ha but the actual ra te was 313 g a.i./ha. Samples were analyzed by combustion analysis and liqui d scintillation counti ng. All treated crops contained radioactive residue >0.01 ppm and we re subjected to further analysis. The highest total radioactive re sidue (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 conducte d in Georgia (GA) and Texas (TX) on a fine and coarse textured soil, respectivel y. The purpose of the study was to obtain raw agricultural commodity (RAC) residue data fo r pyroxasulfone and its metabolites M-1, M-3, M-25, M-28, and M-37 on rotational crops that are planted in plot s that have been treated with Pyroxasulfone 85 WG at the pr oposed 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 inte rval (120, 270, 300 and 365 days, nominal intervals). Ther e 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 th e LOQ (0.01 ppm). As a result, neither pyroxasulfone nor any of its metabolites are ex pected to accumulate in rotational crops when Pyroxasulfone 85 WG is applied to targ et crops at the labele d 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/d ay, 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 metabolite s with the exception of 3 milk samples from day 7 which contained an average of 0.003 ppm parent pyroxasulfone. No other4

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 a bove LOQ. The LOQs were 0.001 ppm in milk and 0.01 ppm in all other matrices. Th erefore, 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 neur otoxicity study in rats, there were no test substance-related effects on body weights, food consumption, clinical observations, functional observational battery assessments, motor activity measurem ents, or gross and microscopic neuropathology. The NOEL was de monstrated to be >2000 mg/kg/day in

adult male and female rats.

2. Genotoxicity. Pyroxasulfone and its metabolite s and impurities do not induce gene mutations in bacterial cells. Pyr oxasulfone does not induce gene mutations or

chromosomal aberrations in in vitro mammalian cells or in vivo in the mouse micronucleus test. Pyroxa sulfone is non-genotoxic.

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

In a developmental toxicity study in ra bbits, there were sli ght test substancerelated effects on fetal weight and number of implant reso rptions at 1000 mg/kg/day, the highest dose tested. The NOEL for matern al toxicity was 1000 mg/kg/day. The NOEL for developmental toxicity was 500 mg/kg/day.

In a rat one-generation reproductive st udy no reproductive toxicity was observed up to and including the high dose of 5000 ppm. The NOEL for reprodu ctive toxicity was >5000 ppm, the highest dose tested. The NOEL for P 1 adult 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 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 st udy conducted on pyroxasulfone in mated5

female rats no reproductive effects were obs erved in the maternal animals at 2000 ppm, the highest concentration tested. No effect s 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 brai n of the offspring was judged to be 300 mg/kg/day.

Two studies were performed to assess the av ailability of the test substance to the pup. These studies indicated that pyroxasulf one was available in the milk to nursing

pups.

4. Subchronic toxicity. Pyroxasulfone was evaluate d in a 28-day inhalation toxicity study in rats. Ther e were no test substance-relate d 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 the

incidence of minimal to mild cardiac myofiber degenerati on 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 rela ted effects for any of the immunotoxicity parameters examined. In the rat, system ic 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 studie s in rats, mice and dogs. In the 13 week mouse study, no test substa nce-related effects on in-life and clinical pathology parameters were observed at any leve l tested. Test substanc e-related effects at 2500 ppm were limited to an increased incidenc e of minimal to mild chronic progressive nephropathy in female mice and increased li ver 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 mu cosal hyperplasia of th e urinary bladder. Increased liver weights and centrilobular hypertrophy were also observed in 2500 ppm6

males and females. In a second study evaluati ng recovery, full or partial recovery was evident in all the above effects apart from ki dney weights in females with all microscopic findings in the liver, heart, muscle and pa ncreas 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 b eagle dogs administered pyroxasulfone in a capsule, the NOEL was 2.0 mg/kg. The only eff ects noted were degeneration of muscle fiber of the musculature portion of the diaphrag m, 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 histop athology similar to the full study.

Pyroxasulfone was evaluated in a subc hronic 90 day neurotox icity dietary study in rats. There were no effects on body weight s, food consumption, clinical observations, FOB assessments, motor activity measur ements, or gross and microscopic neuropathology. The NOEL was >2500 ppm, the highe st 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 chroni c 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 hepato cellular hypertr ophy in males), heart (increased cardiomyopathy in females) and urinary blad der (mucosal hyperplasia in males and females) and urinary bladder hyperplasia consid ered to be secondary to inflammation or irritation. At 2000 ppm, these effects we re accompanied by increased clinical observations of red discharge from the peni s and associated red- stained cageboards as

well as increased liver and ki dney weights. A slight increas e in liver and kidney weights was observed in the 2000 ppm male and fema le dietary exposure groups. The NOEL is 50 ppm (2.22 and 3.12 mg/kg/day for ma les 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. Adve rse test article-re lated 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 re lated abnormal observations. Adverse changes in the clinical pathology parameters were increases in creatine kinase, aspartate aminotransferase and change in the pathology limited to the sc iatic 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 subs equent 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 pyroxasulf one was eliminated in the urine during the7

first 24 hours and elimination was essentially complete after 48 to 72 hours. Absorption was calculated (bile and urine) at 76%. Ma ximum 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 presen t in the carcass demonstrating the near complete elimination of pyroxasulfone. Of th e 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 betw een 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, pyroxasu lfone is rapidly eliminated with 76.9% of radioactivity excreted with in 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 uncha nged pyroxasulfone while no parent molecule was found in the urine. At 120 hr after dosing, the levels of radioac tivity in the tissues were highest in the liver and blood.

In a preliminary mouse metabolis m study, 73% of the applied dose of pyroxasulfone was excreted in urine within 24 hours of dosing. Pyroxasulfone was rapidly absorbed and distribu ted through the tissues of th e mouse but by 24 hours after dosing, radioactivity concentratio ns in the majority of tissues were indistinguishable from background levels.

Metabolism studies in livestock and poultr y (Nature of Residue Studies with Goat and Hen) with repeated dose established that pyroxasulfone was ra pidly 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 s een 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. A ll six test substances ev aluated showed LD50’s >2000 mg/kg similar to the parent, pyroxasu lfone. 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 w ithout activation. All test subs tances were non-genotoxic.

8. Endocrine disruption. Pyroxasulfone does not belong to a class of chemicals known or suspected of having adverse effect s 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 orga ns 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 reasona ble certainty that residues of8

pyroxasulfone in food will not re sult 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 populati on 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 in corporated tolerance le vel residues and 100% crop-treated in the DEEM TM (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 D41 7422). The chronic toxi cological 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 determin ed to be 0.02 mg/kg/day assuming the cRfD is 1 percent of the NOEL. Using proposed to lerances 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 popula tion and 25 population subgroups are above

the EPA level of concern. It can be conclude d with reasonable certai nty that residues of pyroxasulfone in food will not result in unacceptable levels of human health risk.

ii. Drinking water. Based on the Pesticide Root Z one Model/Exposure Analysis Modeling System (PRZM/EXAMS) and Pest icide Root Zone Model Ground Water (PRZM GW), the estimated dr inking 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 re sidues 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 cr ops, soybeans, wheat, and fallow land using groundboom or aerial spray equipment. The poten tial exposures and associated risks for handlers mixing, loading and applying pyroxasulf one and for workers re-entering treated areas are based on the proposed label for Py roxasulfone 85WG Herbicide (pyroxasulfone 85% dry flowable formulation). The maximum application rate is 0.27 lb ai/acre (flax, peanut, pulse crops). Pyroxasulfone 85 WG ma y be applied preplant surface, preplant incorporated, preemergence, early postemer gence, postemergence layby, or in the fall.

Short- and intermediate-term dermal a nd inhalation exposures are predicted for occupational handlers mixing, loadin g, and applying pyroxasulfone. Since pyroxasulfone-specific exposure data are not available, handl er scenarios were assessed using the EPA Occupational Pesticide Handler Unit Exposure Surrogate Reference Table - Revised September 2015. The occupational ha ndler exposure and risk estimates for9

pyroxasulfone are listed below. The estimates are for flax as flax has the highest application rate and is co nsidered a high acreage crop.

Occupational Handler Exposure & Ri sk Estimates for Pyroxasulfone

Short- &

IntermediateTerm 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- &

Intermediate-Term

MOE 4
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 Pe sticide Handler Unit Exposure Surr ogate Reference Table - Revised September 2015. PPE = long-sleeve shirt, long pants, socks, shoe s, gloves and PF5 respirator (l atter for aerial mixer/loader o nly).

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 Abso rption 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 mg/kg/day for all durations.

Short- and intermediate-term dermal expos ures are predicted for post-application exposure to workers performing typical agricu ltural tasks. Since pyroxasulfone-specific exposure data are not availabl e, post-application scenarios were assessed using Science Advisory Council for Exposure (ExpoSAC ) Policy 3 – Revised March 2013. The occupational post-application exposure and risk estimates for pyroxasulfone are listed

below.10

Occupational Post-Application Exposure & Risk Estimates for Pyroxasulfone

Short- &

IntermediateTerm Exposure Crop Activity Transfer

Coefficient 1

(cm 2 /hr) Application

Rate (lb ai/A) Average Daily Dose 2

(mg ai/kg bw/day) Short- &

Intermediate-Term

MOE 3

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 Science Advi sory 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 Di slodgeable 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.

All occupational handler and post- application exposures from ag ricultural 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 di rect exposure to residents, either through mixing, loading and application or due to pos t application exposure; however, there are potential indirect post-applic ation exposures to adults a nd children due to drift onto residential lawns from agricultural applications. These indirect post-application scenarios were assessed based on the proposed la bel for Pyroxasulfone 85WG Herbicide (pyroxasulfone 85% dry flowable formula tion) using draft Residential Exposure Assessment Standard Operating Procedures - Addenda 1: Considera tion of Spray Drift (November 1, 2013). The greatest indirect re sidential exposure potential is from aerial application to flax, peanuts, and pulse cr ops. The residential post-application exposure and risk estimates for pyroxa sulfone are listed below.11

Residential Exposure & Risk Estimates for Pyroxasulfone

Short- &

Intermediate-Term Exposure Lifestage Drift Application

Rate 1 (lb ai/A) Average Daily

Dose 2 (mg ai/kg bw/day) Short- & IntermediateTerm 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 Assessment Standard Operating Procedures - Adde nda 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 f or Residential Pesticide Exposure 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 fro m 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 pyroxa sulfone 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% percen t 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 Barc ode D417422. The percent aRfD for the US population was 2.03% for the 99 th percentile. There is reason able 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 immunotoxi city studies on pyroxasulfone and acute mutagenicity and genotoxicity studies on several metabolites. The weight of evidence indicates that infants and children are not expe cted 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. Tolerances12

are approved for corn and soybean in Canada and pending for wheat.