EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Kathryn Montague 703 - 305 - 1243 Bayer CropScience LLC PP# 9F7680 The EPA has received a pesticide petition (9F76 80) from Bay er CropScience LLC, 2 T. W. Alexander Drive, Research Triangle Park, NC 27709 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 the herbicide, p yrasulfotole including its metabolites and degradates. Compliance with the tolerance levels specified is to be determined b y measuring residues of p yr asulfotole (AE 0317309)5 - hy droxy - 1,3 - dimethyl - 1H - py razol - 4 - yl ) - [2 - (methylsulfo nyl) - 4 - (trifluoromethyl) - phen yl methanone and its metabolite (5 - Hy drox y - 3 - methyl 1H - py razol - 4 - yl ) - [2 - (methylsulfonyl) - 4 - (trifluoromethyl)phen yl ] methanone, calculated as the stoichiometric equivalent of py rasulfotole] in or on the raw agricultural commodit ies [sorghum, grain] at [0.8] parts per million (ppm); [sorghum, forage] at [1.2] ppm; [sorghum, stover] at [0.35] ppm; [grass, hay ] at [2.5] ppm; and [grass, forage] at [10] ppm. In addition, increased tolerances are proposed for residues of the herbicide py rasulfotole including its metabolites and degradate. Compliance with the tolerance levels specified is to be determined by measuring residues of py

rasulfotole (AE0317309) (5 - hy droxy - 1,3 - dimethyl - 1H - py razol - 4 - yl )[2 - (methylsulfonyl) - 4 - (trifluoromethyl)phe nyl] - methanone and its metabolite (5 - Hy drox y - 3 - methyl - 1H - py

razol - 4 - yl - 2 - (meth yl sulfony l) - 4 - (trifluoromethyl)phenyl] methanone, calculated as the stoichiometric equivalent of py rasulfotole in or on [cattle, goat, hog, sheep and horse meat] at [0.04] ppm;[c attle, goat, hog, sheep and horse fat] at [0.04] ppm; [cattle, goat, hog, sheep and horse, meat b yproducts except liver] at [2] ppm and [cattle, goat, hog, sheep and horse, liver] at [8] ppm. EPA has determined that the petition contains data or informatio n regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not full y 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 ru les on the petition. A. Residue Chemistry 1. Plant metabolism . The nature of p yr asulfotole residues in plants and livestock is adequatel y understood. The residues of concern are combined residues of pyrasulfotole and its metabolite (5 - Hy drox y - 3 - methyl - 1H - p yr azol - 4 - yl )[2 - (methylsulfonyl) - 4 - (trifluoromethyl) phenyl] methanone, calculated as py rasulfotole, calculated as the stoichiometric equivalent of py rasulfotole. 2. Analytical method . The anal yt ical method is an LC/MS/MS method which quantifies py

rasulfoto le and its metabolite (5 - Hy droxy - 3 - methyl - 1H - py razol - 4 - yl )[2 - (methylsulfonyl) - 4 - (trifluoromethyl)phenyl]methanone with an LOQ of 0.01 mg/kg. Py rasulfotole and its metabolite are solvent extracted, hy drolyzed to released conjugated residues and purified b y C18 solid phase extraction. Residues are quantified b y LC/MS/MS using isotopically

labeled internal standards. Validation of the methodology for the determination of py rasulfotole and its metabolite demonstrated that it could accuratel y determine residues at the LOQ of 0.01 ppm in all appropriate matrices. Py rasulfotole and its metabolite are stable for at least 11 months for the above matrices.3. Magnitude of residues . The appropriate number of residue trials was conducted in sorghum

and grasses in the a

ppropriate locations in the United States to support the requested tolerances on the sorghum and grass commodities. Specifically , twelve field trials were conducted to measure the magnitude of total p yr asulfotole residues in/on sorghum forage, grain, and s tover or grass hay

and forage following two foliar spray applications of HUSKIE herbicide to sorghum or grass. Residues of p yrasulfotole and its metabolite (5 - Hy droxy - 3 - methyl 1Hpy razol - 4 - yl ) - [2 - (methylsulfonyl) - 4 - (trifluoromethyl) - phenyl]methanone were q uantified in the harvested matrices (sorghum grain, forage and stover as well as grass hay and grass forage) following a postemergence application of Huskie Herbicide. The addition of sorghum and grass matrices to the cattle diets resulted in a change to the maximum theoretical dietary burden (MTDB) for cattle and therefore, a revision of the cattle commodity tolerances as given above. B. Toxicological Profile 1. Acute toxicity . P yrasulfotole has a low order of acute toxicity via the oral, dermal, and inhal ation routes (Category I II or IV). Py

rasulfotole is not a dermal sensitizer or irritant (Category I V) and has been shown to be a moderate ey e irritant (Category III). 2. Genotoxicty . P yrasulfotole is not genotoxic based on genotoxicity studies using in viv o and in vitro tests, including mammalian cell gene mutation tests, chromosomal aberration tests, unscheduled DNA sy nthesis tests, bacterial DNA repair tests and other mutagenicit y studies. 3. Reproductive and developmental toxicity . In the prenatal develo pmental toxicity study in rats, an increased incidence of skeletal variations was observed in fetal offspring at the mid dose, as was decreased fetal body weight in male offspring. However, both effects were observed in the presence of maternal toxicity at the same dose. In the DNT study in rats, an identical NOAEL was established in both dams and offspring based on ocular toxicity as well as several developmental effects observed at the mid dose. In the prenatal developmental toxicity study in rabbits, an increased incidence of skeletal variations was observed in fetal offspring at the mid dose. However, maternal toxicity (decreased body

weight gain and food consumption) was observed only

at the next highest dose tested. Therefore, increased susceptibility of offspring was observed in the rabbit developmental toxicity study but not in the developmental toxicity study in rats or DNT study

in rats. In the 2 - generation reproductive toxicity study in rats, ocular toxicity

(keratitis, corneal opacit y and/or corne al neovascularization), was observed at the mid and high doses in the adults and offspring of two generations. Thy roid (colloid alteration, pigment deposition) and kidney (tubular dilation) toxicity were observed in adult animals of each generation. Colloi d alteration and pigment deposition were also observed in adult rats following short - term dermal and chronic oral exposure of rats, although they were attributed to aging in the latter case. Colloid alteration and pigment deposition were of minimal severity in the 2 - generation reproductive toxicity study and therefore not of concern. At the highest dose tested, decreased viabilit y and decreased bod y weight were observed in offspring of both generations. At the mid and/or high doses, delay s in balanopreputia l separation (males) and vaginal patency (females) were observed in first generation offspring. 4. Subchronic toxicity . Ocular toxicity was observed in male and female rats exposed to py rasulfotole for 90 day s either in the diet or by gavage. Mortality

and multi - organ histopathology

in the kidney , urinary

bladder, thy

roid, and ureters were also observed in the dietary study . I n mice, toxicity

of the urinary

bladder was observed in males, while toxicity of the adrenal glands was observed in females treated i n the diet for 28 day s. Neither effect was reproduced in the 90 - day toxicity study in mice; however, urinary bladder toxicity

was observedin the 29 - day toxicity study in the dog, the 90 - day

toxicity study in the rat, and the mouse carcinogenicity

study . R ats treated with py rasulfotole for 28 day s by the dermal route demonstrated toxicity

of the thy

roid and pancreas. In a dermal toxicity

study in rats, the local dermal NOAEL was >1,000 mg/kg/day . The sy stemic NOAEL was 10 mg/kg/day based on histopathologica l changes in the pancreas at 100 mg/kg/day . 5. Neurotoxicity. Acute, subchronic and developmental neurotoxicity of p yr asulfotole was assessed in the rat. No neurotoxic effects were observed in the acute and subchronic neurotoxicity

studies or the developme ntal neurotoxicity study . Thus, based on the mode of action of p yrasulfotole and the available data from multiple studies, the chemical is not considered neurotoxic. 6. Chronic toxicity . Py

rasulfotole has been classified by the HED CARC as having “Suggesti ve Evidence of Carcinogenic Potential,” based on increased incidences of corneal tumors in male rats at the highest dose tested (2500 ppm) in the chronic toxicity /carcinogenicit y study in rat and urinary

bladder transitional cell tumors in male and female mice at the highest dose tested (4000 ppm) in the mouse carcinogenicity study . Quantification of carcinogenic potential is not required. The chronic RfD of 0.01 mg/kg/day , based on the rat chronic toxicity /carcinogenicit y s tudy

(NOAEL = 25 ppm [1 mg/kg/day] and LOAELof 250 ppm [10 mg/kg/day]) would be protective of both non - cancer and potential cancer precursor effects. 7. Animal metabolism . The excretion of p yrasulfotole was rapid. Following oral administration, greater than 96% of the administered dose w as excreted within 24 hours. In all experiments, the majority of the radioactivity

was excreted in the urine. Fecal excretion represented 8 to 10% of the administered dose during the intravenous experiments. No volatile residues were detected, and no miner alization was observed. Residue levels in all tissues were highest in liver and kidney . Once absorbed, py rasulfotole was not greatl y m etabolized, as 87 to 95% of the administered dose was excreted unchanged as p yrasulfotole. Hydrox ym ethyl py rasulfotole, de smethyl py rasulfotole, and py

rasulfotole benzoic acid were observed as minor metabolites in the urine and feces. Greater than 96% of the administered dose in each experiment was identified. The major metabolic pathway occurred via N - demeth yl ation of py rasu lfotole. 8 . Metabolite toxicology . Plant and animal metabolism studies showed two primary metabolites of py

rasulfotole in food and feed commodities - the desmethyl py rasulfotole (5 - hy drox y - 3 - methyl - 1H - py razol - 4 - yl )[2 - (meth yl sulfony l) - 4 - (trifluoromethyl)ph en yl ] methanone and a benzoic acid metabolite (2 - (methylsulfonyl) - 4 - (trifluoromethyl)benzoic acid). Based on the structure of the compound and its presence as a rat metabolite the desmethyl py rasulfotole is considered to have toxicity similar to parent p yr asulfotole. EPA has determined that the benzoic acid metabolite is not of toxicological relevance for human risk assessment based on a series of toxicology studies conducted with the compound. The studies have shown that it is not an inhibitor of HPPDase, is not genotoxic, and not orally toxic. A 28 - day

repeated dose rat feeding study

with the benzoic acid metabolite resulted in a NOAEL of 15,000 ppm (1118 mg/kg b.w.) in males and 15,000 ppm (1269 mg/kg b.w.) in females, making it significantl y less toxic than the parent compound. Similarly , dietary administration of the benzoic acid metabolite for 90 day s at 0, 1200, 4800, and 12000 ppm had no effects on clinical signs, food consumption, body weight or body

weight gain, ophthalmological findings, hematology or clinical chemistry , organ weights, or histopathological findings. The NOAEL was 12,000 ppm (769 mg/kg bw/day for males and 952 mg/kg bw/day for females), the highest dose tested. In a developmental toxicity study , AE B197555 was administered to pregnantfemale rats at doses of 0, 75, 250, and 750 mg/kg bw/day . Maternal body weight and food consumption were decreased at the top two doses, but there was no effect at any dose on fetal body weight or external, visceral, or skeletal findings. The maternal NO AEL was 75 mg/kg bw/day , while the fetal NOAEL was 750 mg/kg bw/day . As a result of these studies, AE B197555 is considered not of toxicological concern for risk assessment and was not included in the risk assessment. 9 . Endocrine disruption . The toxicolog y database for p yrasulfotole is current and complete. Studies in this database include evaluation of the potential effects on reproduction and development and an evaluation of the pathology of the endocrine organs following short or long - term exposure. The re is no indication of endocrine disruption in any study following administration of py

rasulfotole. C. Aggregate Exposure Assessments were conducted to evaluate potential risks due to chronic and acute dietary exposure of the U.S. population and selected p opulation subgroups to residues of py rasulfotole and its metabolite (5 - Hy drox y - 3 - methyl - 1H - py razol - 4 - yl )[2 - (meth yl sulfony l) - 4 - (trifluorometh yl )phen yl] methanone. These assessments included current and proposed uses of py rasulfotole (registered cereal grai ns, as well as proposed uses on sorghum and grass grown for seed).Exponent Inc.'s Dietary Exposure Evaluation Model (DEEM - FCID , Version 2.14), which is licensed to Bay er, was used to estimate the chronic and acute dietary exposure. This software uses the food consumption data from the 1994 - 1998 USDA Continuing Survey s of Food Intake by I ndividuals (CSFII 1994 - 1998). The aRfD for the general U.S. population, including infants and children, was established based on adverse effects observed in the development al neurotoxicity

study in the rat. Relevant toxicological effects that could be the result of a single dose to the fetus during gestation were delay ed preputial separation (males), decreased cerebrum length (PND 21 females), and decreased cerebellum height (PND 21 males). These adverse effects were observed in offspring at the lowest - observable - adverse - effect - level (LOAEL) of 37 mg/kg/day

(NOAEL = 3.8 mg/kg/day). The aRfD/aPAD is 0.038 mg/kg. This study and endpoint are the most appropriate for the populati on of concern following a single oral exposure. 3.4.2 Chronic Reference Dose (cRfD) The cRfD was established based on ocular toxicity observed in the combined chronic toxicity /carcinogenicit y s tudy

in the rat. Adverse effects included corneal opacity , neov ascularization of the cornea, inflammation of the cornea, regenerative corneal hy perplasia, corneal atroph y, and/or retinal atroph y in both sexes, and hepatocellular h ypertroph y along with increased serum cholesterol in males at the LOAEL of 10/14 mg/kg/da y (M/F) (NOAEL = 1.0 mg/kg/day). This study

provided the critical effect across three chronic toxicity studies in the rat, mouse, and dog. The 2 - generation reproduction study is a co - critical study . Altered colloid and/or pigment deposition were observed i n the thy roid of parental animals at the LOAEL of 2.5/3.1 mg/kg bw/day

(M/F). Application of a 3X uncertaint y factor for extrapolation of a LOAEL to a NOAEL, based on minimal severity of the effect at the LOAEL, would lead to a point of departure of 1 mg/k g/day . The cRfD/cPAD is 0.01 mg/kg/day . Results from the acute and chronic dietary exposure anal ys es described below demonstrate a reasonable certainty

of no harm to the overall U.S. population or any population subgroup will result from the proposed use o f p yrasulfotole on cereal grains.] i. Food . Tier 1 acute and chronic risk assessments were conducted using the results of field trials conducted at maximum label application rates and the shortest pre - harvest intervals. No adjustments were made to account for dissipation of residues during storage, transportationfrom the field to the consumer, washing or peeling. Therefore, the actual dietary exposure will be less than that presented here. The acute dietary

exposure assessment estimated the percent of the aRfD for the U.S. Population and numerous population subgroups. This anal ys is showed that the population subgroup with highest acute exposure was Children 1 - 2 with exposure equal to 12.6% of the aRfD for food and water. Exposure to U.S. Population was 3.7 % of the aRfD for food and water. Therefore, the acute dietary

exposure estimates are below EPA's level of concern for the overall U.S. population as well as the various subpopulations. The chronic dietary

exposure estimated the percent of the chronic refe rence dose (cRfD) for the overall US population and various subpopulations. In this analy sis, the population subgroup with the highest exposure was Children 1 - 2 with exposure equal to 13.7% of the cRfD while the U.S. population had exposure equal to 4.6% o f the cRfD. Therefore, the chronic exposure estimates are below EPA's level of concern for the overall U.S. population as well as all subpopulations. ii. Drinking water . EPA’s Tier 1 EDWCs for surface and ground water were generated using FI RST and SCIGROW , respectivel y. Based on the results of these simulations, EPA recommended an acute surface water EDWC of 4.0 μg/L and a chronic EDWC of 2.8 μg/Lfor use in the human - health risk assessment. These recommendations are based on the use of py rasulfotole on ce real grains (wheat, barley , oats, and triticale) at an annual application rate of 0.045 lb ai/A/y ear. The recommended EDWC for groundwater was 1.4 μg/L and is also based on the use of p yr asulfotole on cereal grains at the previously stated rate. Potential water residues are included in the dietary exposure calculated above. 2. Non - dietary exposure . There are no current residential uses for py rasulfotole. D. Cumulative Effects Py rasulfotole is an herbicide that acts b y inhibiting the breakdown of the amino a cid ty rosine in plants and animals at the 4 - hy drox yphenyp yruvic acid diox ygenase (HPPDase) enzy me; the second enzyme in the ty rosine catabolism pathway . Although there are other herbicides that are HPPDase inhibitors, it has not been established that p yr as ulfotole will have cumulative effects with other HPPDase inhibitors. E. Safety Determination 1. U.S. population . [Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that aggre gate exposure to residues of p yr asulfotole presents a reasonable certainty of no harm. The acute assessment indicated that exposure from residues in crops utilized approximately 3.4% of the acute RfD for the U. S. Population when food and water are include d. Exposure from residues in crops and water utilizes 4.6% of the cRfD for the U.S. Population. EPA generall y has no concerns for exposures below 100% of the cRfD. An aggregate assessment for the proposed uses for py rasulfotole demonstrates that there is a reasonable certaint y that no harm will result to the US Population from these uses of imidacloprid. 2. Infants and children . Developmental studies have been conducted in the rat and the rabbit and a developmental neurotoxicity study conducted in the rat. In addition, a twogeneration reproduction stud y was conducted in the rat. Based on the available data, there is no concern for pre - and/or postnatal toxicity resulting from exposure to py rasulfotole. There is no evidence of increased susceptibility followi ng pre - /post - natal exposure to rats in the developmental neurotoxicity study or the 2 - generation reproduction study . Evidence of quantitative susceptibility was noted in the rabbit developmental toxicity study based on skeletalvariants in fetuses (75 mg/k g bw/day), in the absence of overt clinical toxicity in the dams. However, based on the data available regarding sensitivity of the rabbit to ty

rosinemia, and since the skeletal variants were similar to those noted in rats and rabbits with other HPPDase inhibitors, these effects are considered secondary to elevated t yrosine in the dams and are not relevant for human health risk assessment. FFDCA section 408 provides that EPA shall apply an additional tenfold margin of safet y for infants and children in the case of threshold effects to account for pre and post natal toxicity and the completeness of the data base unless EPA determines that a different margin of safet y will be safe for infants and children. The toxicological database for pyrasulfotole is comple te for FQPA purposes and there are no residual uncertainties for pre - /post - natal toxicity for p yr asulfotole. Based on the available toxicity data the Special FQPA Safet y Factor can be reduced to 1x. Based on the exposure assessments described above and on the completeness and reliability of the toxicity data, it can be concluded that the dietary exposure from the proposed uses for py rasulfotole consumes 12.6% of the aRfD and 13.7% of the cRfD for Chil dren 1 - 2 (the most sensitive population subgroup). Thus, it can be concluded that there is a reasonable certaint y that no harm will result from aggregate expo sure to py rasulfotole residues. F. International Tolerances No CODEX Maximum Residue Levels (MRLs) have been established for residues of py rasulfotole on cereal grains, sorghum or grass grown for see