**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division Contact:**  **Kathryn Montague (**  **703) 305 -**  **1243 INSTRUCTIONS:**  **Please utilize this outline in preparing the pesticide petition. In**  **cases where the outline element does not apply, please insert “NA -**  **Remove” and maintain the outline. Please do not change the margins, font, or format in your**  **pesticide petition. Simply replace the instructions that appear in green**  **, i.e., “ [**  **i nsert**  **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 b y establishing tolerances for residues of **pyroxasulfone** ( 3 - [(5 - (difluoromethoxy ) - 1 - methyl - 3 - (trifluorometh yl ) p yrazole - 4 - yl methylsulfonyl] - 4,5 - dihydro - 5,5 - dimethyl - 1,2 - oxazole ) and its metabolites **M -**  **3** ( 5 - difluoromethox y- 1 - methyl - 3 - trifluorometh yl - 1H - py razol - 4 - carbox yl ic acid), **M -**  **25** (5 - difluoromethox y- 3 - trifluoromethyl - 1H - py razol - 4 - yl )methanesulfonic acid and **M -**  **28** ( 3 - [1 - carbox y- 2 - (5,5 - dimethyl - 4,5 - dihydroisoxazol - 3 - yl thio)eth yl amino] - 3 - oxopropanoic acid) calculated as the stoichiometric equivalent of py roxasulfone in or on the raw agricultural commodities **soybean seed at 0.07** and **pyroxasulfone** ( 3 - [(5 - (difluoromethox y) - 1 - methyl - 3 - (trifluorometh yl ) p yr azole - 4 - yl methylsulfonyl] - 4,5 - dihydro - 5,5 - dimethyl - 1,2 - oxazole ) and its metabolites **M -**  **1** ( 5 - difluoromethox y- 1 - methyl - 3 - trifluoromethyl - 1H - py razol - 4 - yl methanesulfonic acid ), **M**   ** 3** ( 5 - difluoromethox y- 1 - methyl - 3 - trifluoromethyl - 1H - py razol - 4 - carbox yl ic acid), and **M -**  **25** (5 - difluoromethoxy- 3 - trifluorometh yl - 1H - py razol - 4 - yl )methanesulfonic acid) calculated as the stoichiometric equivalent of p yr oxasulfone in or on the raw agricultural commo dities **soybean forage at 1.5 and soybean hay at 2.0** ppm (parts per million). 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 full y evaluated the suffi ciency

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.2

A. Residue Chemistr

y 1. Plant Metabolism. Plant metabolism studies were conducted and accepted by the Agency

for soy bean and field corn. The plant and animal metabolism of py roxasulfone is well understood. Primary metabolic processes are cleavage between the two ring structures, side chain oxidation to carboxylic acid and demethylation. Py roxasul fone and its major metabolites M - 1 , M - 3 , and M - 25 were metabolites in corn and soy bean. The metabolism of py roxasulfone in plants and animals is understood for the purposes of the propo sed tolerances. Py roxasulfone and its metabolites M - 1 , M - 3, M 25and M - 28 are the residues of concern for tolerance setting purposes for soy bean . 2. Analytical method. EPA has approved an anal yt ical enforcement methodology including liquid chromatograph y, mass spectrometry, and mass spectrometry (L C/MS/MS) to enforce the t olerance expression for py roxasulfone. 3. Magnitude of residues. A total of 25 soy

bean residue (RAC) field trials were conducted in regions 2, 4 and 5 of the United States. S amples were collected from each plot at the appropriate time. Matrices were extracted with acetonitrile or aqueous methanol followed by v arious cleanup steps depending on the matrix and anal yte. Anal ys is was performed using LC MS/MS for py

roxasulfone and its metabolites in all matrices. The proposed tolerances were calculated using the OECD residue calculator. The proposed tolerance in or on soy bean seed for combined residues of py roxasulfone, M - 3, M - 25, and M - 28 is 0.07 ppm. The proposed tolerance in or on soy bean forage and hay

f or combined residues of py roxasulfone, M - 1, M - 3 , and M - 25 is 1.5 ppm and 2.0 ppm, respectively . The proposed tolerances on processed soy bean commodities are not necessary at this time since residues on these commodities are not expected to exceed those in the raw agricultural commodities (RAC) and thus will be covered b y the RAC tolerances. C onfined Rotational Crop Study Py razole or isoxazoline ring labeled 14 C KIH - 485 was sprayed on confined plots of bare soil prior to planting so ybean, radish and wheat at 30, 120 and 365 day intervals. There were tw o treated plots for each plantback interval, one of which was wheat onl y and the other was planted half with soy bean 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 anal yz ed b y combustion analysis and liquid scintillation counting. All treated crops contained radioactive residue >0.01 ppm and were subjected to further analy sis. The highest total radioactive residue (TRR), 5.2 ppm was found at the 30 day rotati onal in wheat straw; the residue level declined to 0.02 ppm at 485 day s. The primary metabolites were M - 1 and M - 3. Cow Feeding Study Holstein dairy

cows were treated orally with gelatin capsules fortified with py roxasulfone. These were administere d once daily for 28 consecutive day s at dose3

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 , respectivel y. 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 p yroxasulfone. 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 p yroxasulfone 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 py roxasulfone and its metabolites are being proposed for meat, milk, eggs or other edible tissues of livestock or poultry . B. Toxicological Profile 1. Acute Toxicity. Py

roxasulfone 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, moderatel y 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 obse rvations, 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. Py

roxasulfone and its metabolite s and impurities do not induce gene mutations in bacterial cells. Py roxasulfone does not induce gene mutations or chromosomal aberrations in in vitro mammalian cells or in vivo in the mouse micronucleus test. Py

roxasulfone is non - genotoxic. 3. Reproduc tive 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. Ina d evelopmental toxicity

s tudy i n 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. T he NOEL for maternal toxicity w as 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 adult rats was 25 ppm. The NOEL for F 1 offspring was 250 ppm and the NOEL f or 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. The4

NOEL for reproductive toxicity was > 2000 ppm, the highest con centration tested. Test substance - related effects were observed at 2000 ppm in both adults and offspring. Therefore, the NOAEL for sy stemic 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 py

roxasulfone 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 - p ulse 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 sy stemic 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 perf

ormed to assess the availability of the test substance to the pup. These studies indicated that py roxasulfone was available in the milk to nursing pups. 4. Subchronic toxicity. Py roxasulfone was evaluated in a 28 - day inhalation toxicity study in rats. There were no test substance - related effects. The NOELwas > 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 degeneration with inflamm ation observed in males and females dosed with 1000 mg/kg/day and cutaneous m yofiber 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 mic e following dietary exposure for 28 day s. There were no test substance related effects for any of the immunotoxicity parameters examined. In the rat, s ys temic toxicity was limited to reductions in body weight and food consumption. The NOEL for immunotox icity 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 N OEL for sy stemic effects was 400 ppm (61 mg/kg males: 77 mg/kg females). Py roxasulfone 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 nephropath y 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 NOELfor male mice was 2500 ppm (394.0 mg/kg/day).5 Inthe 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 m ales and females, respectivel y. Test substance related effects were increased cardiac myofiber degeneration with inflammation and diffuse mucosal hy perplasia of the urinary

bladder. In creased liver weights and centrilobular h ypertrophy 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 icroscopic findings in the liver, heart, muscle and pancreas of 5000 ppm ani mals 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 py roxasulfone in a capsule, the NOEL was 2.0 mg/kg. The onl y ef fects noted were degeneration of muscle fiber of the musculature portion of the diaphragm, hy perplasia 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 p yr oxasulfone, male dogs showed a decrease in body weight and histopathology similar to the full study. Py roxasulfone 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 NOELwas > 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, respectivel y. 5. Chronic toxicity. Chronic toxicity studies were conducted in the rat and dog. In the rat one ye ar chronic toxicity study t est substance - related effects occurred at 1000 ppm and above that included redu ced body weight parameters and microscopic findings in the liver (centrilobular hepatocellular hypertroph y in males), heart (increased cardiom yopath y in females) and urinary bladder (mucosal hyperplasia in males and females) and urinary

bladder hy

perplasia considered to be secondary to inflammation or irritation. At 2000 ppm, these effects were accompanied b y 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 - ye ar dog study beagle dogs/sex/dose were admini stered 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 obs ervation 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 .6 The carcinogenic pot ential of py roxasulfone 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 cry stals with subsequent calculi formation resulting in cellular damage of the urinary

tract. 6. Animal metabolism. In the rat, p yroxasulfone is rapidly and completel y eliminated. Between 80 to 90% of py roxasulfone was eliminated in the urine during the first 24 hours and elimination was essentiall y 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 py roxasulfone. Of the radioactivity present in the animals, the highest levels were seen in the liver and kidney . The major metabolites were a carbox yl ated (py

razole ring meth ylgroup) and cleavage products between the iso xazoline and py razole ring structure with subsequent carboxylation. The absorption, distribution, metabolism and elimination of py roxasulfone is unaffected by sex or treatment regimen. In a preliminary

study in the dog, py

roxasulfone is rapidly

elimi nated 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, respectivel y. The feces were found to contain only unchanged py

roxasulf one 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 py roxasulfone was excreted in urine within 24 hours of dosing. P yroxasulfone 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 p yro xasulfone was rapidl y metabolized and excreted and that there was minimal transmittal of residues of p yroxasulfone and its met abolites to meat or milk. For goats fed 10 ppm of radiolabeled py roxasulfone, the highest residues (TRR) were seen in liver and kidney . In the hen, fed 10 ppm, the highest re sidue was seen in liver and muscle . 7. Metabolite toxicology. Three plant me tabolites 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, p yr oxasulfone. Two metabolites were further assessed in a 14 day

toxicity study in rats. The NOELfor 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. Py roxasulfone does not belong to a class of chemicals7

known or suspected of having adverse effects on the endocrine s ys tem. There is no evidence that py

roxasulfone has any

effect on endocrine function in developmental, reproduction or developmental neurotoxicity studi es. Furthermore, histological investigation of endocrine organs in chronic dog, rat and mouse studies did not indicate that the endocrine s ys tem is targeted by py roxasulfone. C. Aggregate Exposure 1. Dietary exposure. It can be concluded with reasonabl e certainty that residues of py roxasulfone in food will not result in unacceptable levels of human health risk. Using proposed tolerances for corn, soy bean and wheat, both the acute and chronic dietary exposure MOEs for the overall US population and 25 pop ulation 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., 2003) software s ys tem. The acute toxicological endpoint selected for assessment of risk following acute dietary

exposure was 300 mg/kg/day based on the Developmental Neurotoxicity

Study with a NOEL 300 mg/kg/d ay for motor activity

and brain morphology . The acute reference dose (aRfd) was determined to be 3 mg/kg/day assuming the aRdf is 1 percent of the NOEL. The chronic toxicological endpoint selected for assessment of risk following chronic dietary exposure w as 2 mg/kg/day based on the one - year chronic feeding dog study with a NOE L of 2 mg/kg/day . The chronic reference dose (cRfd) was determined to be 0.02 mg/kg/day assuming the cRfd is 1 percent of the NOEL. Using proposed tolerances for corn, so ybean and whe at, the acute and chronic dietary exposure Margin of Exposure (MOEs) for the overall US population and 25 population subgroups are above the EPA level of concern. It can be concluded with reasonable certainty

that residues of py

roxasulfone 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 S ys tem (PRZM/EXAMS) and Pesticide Root Zone Model Ground Water (PRZM GW), the estimated drinking water concentrati ons (EDWCs) of py roxasulfone for acute exposure are estimated to be 17 ppb for surface water and 210 ppb for ground water. EDWCs of p yroxasulfone 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 py

roxasulfone in drinking water will not result in unacceptable levels of human health risk. 2. Non - dietary exposure . Py roxasulfone is not intended for an y specific use patter ns that would result in residential exposures. D. Cumulative Effects Py roxasulfone represents a new class of p yrazole herbicides. No other products are known to have the same mode of action as p yr oxasulfone. Therefore, a cumulative8

assessment is not a

ppropriate at this time. E. Safety Determination 1. U.S. population. The toxicity database for py

roxasulfone is complete. Based on the NOEL of 2 mg/kg/day from a 1 - ye ar toxicity

study in the dog, proposed uses represent 1 percent of the cRfD of 0.02 mg/kg/day. Based on the NOEL of 300 mg/kg/day

from a developmental neurotoxicity study , the proposed uses represent 1 percent of the RfD of 3 mg/kg/day . There is reasonable certainty that no harm to the U.S. population will result from the proposed uses of py roxasulfone. 2. Infants and children . The toxicity database for py

roxasulfone is complete. The database includes acute, subchronic, chronic, mutagenicity, genotoxicity , developmental, reproduction, neurotoxicity and immunotoxicity

studies on py

roxasul fone 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 Fact or from 1 0 x to 1 x. F. International Tolerances No international tolerances exist at this time. Tolerances are simultaneously being sought in Canada at the same levels and for the same crops as for the U.S. Tolerances are simultaneously being sought o n wheat, barely and triticale in Australia.