 

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

Docket ID Number: EPA-HQ-OPP-2017-0334

EPA Registration Division Contact: Shaja Joyner (703) 308-3194 

Interregional Research Project No. 4 (IR-4)

Pesticide Petition (PP) number: 7E8570

	EPA has received a pesticide petition (PP# 7E8570) from Interregional Research Project No. 4 (IR-4), Rutgers, The State University of New Jersey, 500 College Rd. East, Suite 201W, 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 amend 40 CFR part 180 by establishing general tolerances for residues of the herbicide pyroxasulfone 3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]sulfonyl]-4,5-dihydro-5,5-dimethylisoxazole and its metabolites and degradates in or on the raw agricultural commodities Peppermint, tops at 0.15 ppm (parts per million), Peppermint, oil at 0.48 ppm, Spearmint, tops at 0.15 ppm, Spearmint, oil at 0.48 ppm and Soybean, vegetable, succulent at 0.2 ppm.

Additionally, regional tolerances are proposed for Grass, forage at 0.5 ppm and Grass, hay at 1.0 ppm.

 EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

 Residue Chemistry

      1. Plant Metabolism. Plant metabolism studies were conducted and accepted by the Agency for soybean and field corn.  A potato metabolism was submitted in a previous application and is pending review. 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.  

	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. 

Grasses (Seed Crop) - A total of 4 grasses (seed crop) residue raw agricultural commodity (RAC) field trials were conducted in regions US EPA Regions 11 and 12. At each trial, one broadcast application of the test substance was made to the treated plots when the grass was in dormancy.  The application rates ranged from 0.174 to 0.192 lb ai/A per season.  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, forage samples were harvested 59-68 days after the last application and hay samples were harvested at boot to early seed head and dried.  
      
      Residues of pyroxasulfone, M-1, M-3, and M-25 are extracted from the crop with acetonitrile/water. The extract is purified with liquid/liquid partition. For some compounds, the extracts were further cleaned up by solid phase extraction. The final extracts for each compound are diluted in 1:1 acetonitrile:water (v/v), and then submitted to LC-MS/MS analysis. Residues of M-28 are extracted with acetonitrile/water. The final extracts for each compound are diluted in 1:1 acetonitrile:water (v/v), and then submitted to LC-MS/MS analysis.
      
      Flumioxazin residues are extracted using acetone:water (4/1, v/v) and cleaned up via liquid-liquid partition with dichloromethane and Solid Phase Extraction (SPE) using ENVI-Carb/NH2 cartridges. The sample is then analyzed for flumioxazin by GC-MS detection in selective ion monitoring mode.
      
      The total residues of flumioxazin ranged from <0.02 to 0.18 ppm in forage samples and <0.02 to 0.032 ppm in hay sample. The total pyroxasulfone residues ranged from 0.13 to 0.25 ppm in forage samples and 0.14 to 0.56 ppm in hay samples.
      
      The proposed tolerances were calculated using the OECD MRL calculator. The proposed tolerance for pyroxasulfone for grass forage is 0.5 ppm and the proposed tolerance for grass hay is 1.0 ppm. 
      
Mint -	A total of 5 mint residue raw agricultural commodity (RAC) field trials were conducted in US EPA Regions 5 and 11. Each trial consisted of at least one treated plot. At each trial, one treated plot received one broadcast application with rates ranging from 0.258 to 0.281 lb ai/A. The WA*05 and WI05 trials had an additional treated plot for processing samples with one broadcast application with rates ranging from 0.802 to 0.830 lb ai/A (3X).  All applications were made during dormancy. All applications were made using appropriate spray equipment, and the spray volume was sufficient to provide adequate dispersal of the test substance.   

      Residues of pyroxasulfone, M-1, M-3, and M-25 are extracted from mint tops and mint oil with acetonitrile and water. The extract is purified with liquid/liquid partition. For some compounds, the extracts were further cleaned by solid phase extraction (SPE) cartridge. The final extracts for each compound are diluted in 1:1 acetonitrile:water (v/v), and then submitted to LC-MS/MS analysis. 

	Residues of M-28 are extracted from mint tops with acetonitrile/water. Samples are cleaned up by SCX solid phase extraction. The final extracts are diluted in 1:1 acetonitrile:water (v/v), and then submitted to LC-MS/MS analysis. 

	For mint oil, residues of M-28 are solubilized with acetonitrile and cleaned up by silica solid phase extraction. The final extracts are diluted in 1:1 acetonitrile:water (v/v), and then submitted to LC-MS/MS analysis.

      The residues of total pyroxasulfone ranged from 0.064 to 0.088 ppm in mint top samples. For samples treated at the 3X rate, total pyroxasulfone residues were 0.070 ppm in mint tops and 0.225 ppm in mint oil.

      The proposed tolerances were calculated using the OECD MRL calculator. The registrant is proposing tolerances for crop peppermint tops at 0.15 ppm; peppermint oil at 0.48 ppm; spearmint tops at 0.15 ppm; and spearmint oil at 0.48 ppm.  

Crop Edamame (Vegetable Soybean) - A total of 6 edamame residue raw agricultural commodity (RAC) field trials were conducted in regions US EPA Regions 1, 2, 4, 5 and 5A.  Each trial consisted of two treated plots. One treated plot (TRT02) received a broadcast application made prior to crop and weed emergence. The application rates ranged from 0.218 to 0.248 lb ai/A (243.8 to 278.2 g ai/Ha) per application. The other treated plot (TRT03) received a broadcast application during the third trifoliate stage. The application rates ranged from 0.214 to 0.231 lb ai/A (240.2 to 258.8 g ai/Ha) per application.  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, succulent bean seeds without pods samples and pods with seeds samples were harvested when they were commercially mature. Additionally, at the OH*350 trial, duplicate pods with seeds samples were collected 66, 70, 74, 79, and 84 days after the last application.  
      Residues of pyroxasulfone, M-1, M-3, and M-25 are extracted from the crop with acetonitrile and water. The extract is purified with liquid/liquid partition. The extracts were further cleaned by solid phase extraction (SPE) cartridge. The final extracts for each compound are diluted in 1:1 acetonitrile: water (v/v), and then submitted to LC-MS/MS analysis. 
      	
      Residues of M-28 are extracted with acetonitrile/water. Samples are cleaned up by SCX and DIOL solid phase extraction. The final extracts are diluted in 1:1 acetonitrile:water (v/v), and then submitted to LC-MS/MS analysis.
      
      The total residues of pyroxasulfone ranged from 0.064 to 0.97 ppm in succulent beans seeds without pods samples and from 0.064 to 0.084 ppm in pods with seed samples.  The proposed tolerances were calculated using the OECD MRL calculator. The registrant is proposing tolerances for soybean, vegetable succulent at 0.2 ppm. 

 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 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 the approved tolerances for other crops and the proposed tolerances for grasses (seed crop), mint and edamame 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 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 dried shelled pea and bean (except soybean) Crop Subgroup 6C, flax, peanut and sunflower crop subgroup 20B dated January 31, 2017. 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 the approved tolerances for corn, cotton, crop subgroup 6C, flax, peanut, soybean, sunflower and other crop subgroup 20B crops, and wheat with the proposed tolerances for bulb vegetables, tuberous and corm vegetables, grass (seed crop), mint and edamame 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. Acute exposure to the total US population is 1.15% of the aRfD.  The most exposed population in the acute assessment is all infants at 3.89% of the aRfD at the 95th percentile. Chronic exposure to the total US population is 19.0% of the RfD. The most exposed population is all infants at 67.7% of the RfD for chronic exposure. 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 to bulb vegetables, corn, cotton, flax, peanut, pulse crops, soybeans, tuberous and corm vegetables, the sunflower subgroup (20B), wheat, and fallow land using groundboom, chemigation, or aerial spray equipment. The proposed crops are grasses (seed crop), mint and edamame. 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, sunflower and potato). The maximum application rates for the crops addressed in this Notice of Filing are 0.27 lb ai/acre for mint, 0.18 lb ai/acre for grass grown for seed, and 0.22 lb ai/acre for edamame.  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 November 2016. The occupational handler exposure and risk estimates for pyroxasulfone are listed below.  The estimates are for the crops, as noted, with the highest operator exposure for each scenario.

     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- & Intermediate-Term MOE[4]
Mixer/Loader  -  Dry Flowable  -  Open Loading for Aerial Application  -  Flax, Peanut
                                    Dermal
                                    0.0516
                                     0.27
                                     1200
                                     0.21
                                      490
                                  Inhalation
                                    0.00179
                                     0.27
                                     1200
                                    0.0071
                                      280
Mixer/Loader  -  Dry Flowable  -  Open Loading for Groundboom Application - Flax, Peanut
                                    Dermal
                                    0.0516
                                     0.27
                                      200
                                     0.034
                                     2,900
                                  Inhalation
                                    0.00896
                                     0.27
                                      200
                                    0.0060
                                      340
Mixer/Loader  -  Dry Flowable  -  Open Loading for Chemigation  -  Flax, Peanut, Pulse crops, Sunflower, Potato, Mint
                                    Dermal
                                    0.0516
                                     0.27
                                      350
                                     0.060
                                     1,700
                                  Inhalation
                                    0.00896
                                     0.27
                                      350
                                     0.010
                                      190
              Applicator  -  Liquids  -  Aerial  -  Flax, Peanut
                                    Dermal
                                    0.00208
                                     0.27
                                     1200
                                    0.0083
                                    12,000
                                  Inhalation
                                   0.0000049
                                     0.27
                                     1200
                                   0.000020
                                    102,000
             Applicator  -  Liquids  -  Groundboom - Flax, Peanut
                                    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 November 2016.  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 Science Advisory Council for Exposure (ExpoSAC) Policy 3  -  Revised January 2017. 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 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
                               Edamame, Scouting
                                     1100
                                     0.22
                                     0.068
                                     1,500
                                    Dermal
                                Flax, Scouting
                                     1100
                                     0.27
                                     0.082
                                     1,200
                                    Dermal
                 Grasses Grown for Seed, Irrigation (hand set)
                                     1,900
                                     0.18
                                     0.095
                                     1,000
                                    Dermal
                          Mint, Irrigation (hand set)
                                     1900
                                     0.27
                                     0.142
                                     1,000
                                    Dermal
                           Bulb Onion, Hand Weeding
                                     4200
                                     0.13
                                     0.20
                                      490
                                    Dermal
                             Peanut, Weeding, Hand
                                      70
                                     0.27
                                    0.0052
                                    19,000
                                    Dermal
                         Potato, Irrigation (hand set)
                                     1900
                                     0.27
                                     0.19
                                      520
                                    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
                                   Sunflower
                                      90
                                     0.27
                                     0.082
                                     1,200
                                    Dermal
                                Wheat, Scouting
                                     1100
                                     0.13
                                     0.041
                                     2,400
[1] Transfer Coefficient from Science Advisory Council for Exposure (ExpoSAC) Policy 3  -  Revised January 2017.  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 Rate[1] (lb ai/A)
                    Average 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 (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 19.0% 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 dried shelled pea and bean (except soybean) Crop Subgroup 6C, flax, peanut and sunflower crop subgroup 20B dated January 31, 2017. The percent aRfD for the US population was 3.89% for the 95[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 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, triticale and winter legume in Australia. Tolerances are approved for corn, soybean, wheat, peanut (import tolerance), pulse crops and flax in Canada. 
