EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER ( 7 /1/200 7 ) EPA Registration Division contact: [insert name and telephone number with area code] 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 i n your pesticide petition. Simply replace the instructions that appear in green , i.e., “ [ insert company name ] ,” with the information specific to your action. TEMPLATE: [ Bayer CropScience ] [Insert petition number] EPA has received a pesticide p etition ( [insert petition number] ) from [ Bayer CropScience ] , [ P.O. Box 12014, 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 4 0 CFR part 180. ( Options (pick one) 1. by establishing a tolerance for residues of [ Prothioconazole, 2 - [2 - (1 - chlorocyclopropyl) - 3 - (2 - chlorophenyl - 2 - hydroxypropyl] - 1,2 - dihydro - 3 H - 1,2,4 - triazole - 3 - thione and its desthio metabolite ] in or on the raw or processed agricultural commodity [ rice, grain ] at [ 0.25 ] parts per million (ppm) , [ rice, hulls ] at [ 1.0 ] parts per million (ppm) , [ alfalfa , forage and alfalfa , hay ] at [ 0.02 ] parts per million (ppm) and [ potato, tuber ] at [ 0.02 ] parts per million (ppm ) . Baye r CropScience is also proposing use of the currentl y established tolerances for residues of Prothioconazole, 2 - [2 - (1 - chlorocyclopropyl) - 3 - (2 - chlorophenyl - 2 - hydrox yp rop yl ] - 1,2 - dihydro - 3 H - 1,2,4 - triazole - 3 - thione and its desthio metabolite , in or on the raw agricultural commodity [ p ea and bean, dried shelled, except so ybean, subgroup 6C ], [ s oy

bean, forage ], [ s oy

bean, hay], [soy

bean, seed] to support the use of prothioconazole as a seed treatment on these crops. Baye r CropScience is also proposing th at the above proposed tolerances on rice, based on foliar data, also support the use of prothioconazole as a seed treatment on rice.2

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 sufficiency

of the submitted d ata at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant m etabolism. [ Inplants, the metabolism of prothioconazole is adequately understood for purposes of establishing these proposed tolerances. Prothioconazole was extensively

metabolized in plants with the major residue found in all crops (wheat, peanuts and su gar beets) being JAU6476 - desthio with smaller amounts of various isomers of JAU6476 - hydroxy - desthio, and their conjugates also being found. Triazolylalanine, triazolylhydrox ypropionic acid, and triazolylacetic acid, metabolites common to the triazole - deriv ative class of fungicides, were also found. Based on the above data the residues of concern in plants are prothioconazole and its m etabolite JAU6476 - desthio. The risk assessment for the common metabolites arising from the triazole - derivative fungicides is being addressed by the US Triazole Task Force. In large animals, the nature of residues is also adequatel y understood for purposes of establishing the proposed tolerances. The residues of concern in edible tissues and milk are prothioconazole, its metabol ites JAU6476 - desthio, JAU6476 - 4 - hydrox y, and their conjugates that can be converted to these three compounds by acid hydrolysis. ] 2. Analytical method. [ The anal yt ical method for determining residues of concern in plants extracts residues of prothiocon azole and JAU6476 - desthio and converts the prothioconazole to JAU6476 - desthio and JAU6476 - sulfonic acid. Following addition of internal standards the sample extracts are anal yz ed by L C/MS/MS. Radiovalidation and independent laboratory

validation have shown that the method adequatel y quantifies prothioconazole residues in treated commodities. The validated LOQ for total prothioconazole - derived residues in rice grain was 0.02 ppm. The validated LOQs were 0.01 ppm for 1 H

- 1,2,4 - triazole and 0.05 pm for the tri azole conjugates for grain. The anal yt ical method for anal ys is of large animal tissues includes extraction of the residues of concern, followed b y addition of an internal standard to the extract. The extract is then hydrol yz ed to release conjugates, partit ioned and anal yz ed b y LC/MS/MS as prothioconazole, JAU6476 - desthio and JAU6476 - 4 - hydrox y. The method for anal ys is of milk eliminated the initial extraction step in the tissue method. ] 3. Magnitude of residues. [ A total of 16 field trials (14 harvest an d 2 decline) were conducted as part of the supervised crop field trial study for rice to measure the prothioconazole derived residues in/on rice following two foliar spray applications of JAU6476 480 SC at a target rate of 0.18 lb ai/acre/application (0.20 kg ai/ha/application), with a 13 to 16 day

spray interval. Rice grain and straw were collected from each treated plot with P HI s ranging from 40 to 67 day s . At two locations additional samples were taken to determine residue decline. The average prothioc on azole derived residue was 0.03 ppm in/on rice grain with a maximum residue of 0.22 ppm. Results of the rice processing study

indicated that prothioconazole residues concentrated in rice hulls3

(4.4X), but not in polished grain or bran. Residues of 1 H - 1,2,4 - triazole were less than the LOQ (<0.01 ppm) in/on rice grain. Maximum residues of the triazole conjugates were 0.571 ppm (rice grain) . The maximum storage interval of crop samples from harvest to anal ys is for total prothioconazole - derived residues was 124 0 day s (40.8 months). The degree of loss of prothioconazole - derived residues and prothioconazole - desthio residues is not expected to exceed 30% after 40.8 months in rice samples . For alfalfa, results from a TRR study indicate a no residue situation. The T RR in alfalfa forage from three successive cuttings from plants grown from seed treated with [triazole 3,5 - 14C] prothioconazole at a target rate of 5 g a.i./100 kg seed and 15 g a.i./100 kg seed loading was <0.005 ppm. The TRR in alfalfa hay from the secon d and third cuttings from plants grown from seed treated with [triazole - 3,5 - 14C] prothioconazole at both application rates was also <0.005 ppm. Although the TRR in alfalfa hay from the first cutting was not measured, the percent dry matter for forage from the first cutting was measured and when adjusted to reflect the t ypical percent dry matter in alfalfa hay (89%)5 the net residues in alfalfa hay at both treatment levels are <0.005 ppm . For potato, results from a TRR study indicate a no residue situation for components of the residue definition. Potato seed, treated with [triazole - UL - 14C] prothioconazole at a rate of 0.36 g ai/100 kg seed (3.7 ppm; 1.02X the target rate of 0.36 g ai/100 kg seed), was planted and potato was grown to maturity . The potato raw agricultural commodity (RAC) of tubers was collected at harvest time. The total radioactive residue (TRR) in the tubers was 0.0061 ppm. The residues in tubers were extracted and characterized. Mainly highl y polar degradation products were found in pot ato; only very small amounts (5% or <0.001 ppm) of the components of the residue definition were detected. ] B. Toxicological Profile 1. Acute toxicity. [ Prothioconazole exhibits very low acute oral, dermal and inhalation toxicity . The acute oral LD 50 for prothioconazole in rats was >6200 mg/kg/day

while the dermal LD50 was >2000 mg/kg/day and the four - hour rat inhalation LC50 >4990 mg/m 3 . Prothioconazole was not irritating to the eye or skin of rabbits and did not cause skin sensitization in guinea pigs . ] 2. Genotoxicty. [ Prothioconazole is not mutagenic. Slightly positive and equivocal responses seen in in vitro cy togenetic and UDS assay s were negative in in vivo tests . ] 3. Reproductive and developmental toxicity. [ Prothioconazole is not con sidered a primary reproductive toxicant in a two - Generation rat reproduction study . The NOAEL for parental toxicity as well as the NOAEL for reproductive and neonatal effects is 95.6 mg/kg bw/day . In the rat oral developmental toxicity study the fetal NOA EL was 500 mg/kg bw/day

and the maternal NOAEL was 80 mg/kg bw/day . A dose level of 1000 mg/kg bw/day

administered to the rat by the dermal route does not elicit developmental toxicity . In the rabbit, prothioconazole does not produce developmental toxicity at dose levels exceeding the maximum tolerated dose. Thus, prothioconazole is not teratogenic in4

either the rat or rabbit. ] 4. Subchronic toxicity. [ 90 - day feeding studies conducted in rats, mice, and dogs showed the liver and/or kidney to be the targ et organs. In these subchronic studies NOAELs were established at 100 mg/kg/day for the rat and 25 mg/kg/day for the mouse and dog. ] 5. Chronic toxicity. [ Prothioconazole is not carcinogenic in either the rat or the mouse even at dose levels in the rat exceeding the maximum tolerated dose. The liver and kidney are target organs of prothioconazole for non - neoplastic toxicity in the rat, mouse and dog. The lowest NOAELestablished on the basis of long - term toxicity studies is 5 mg/kg bw/day

in the rat chronic toxicity /carcinogenicity

study and the dog 52 - week toxicity study . ] 6. Animal metabolism. [ Metabolism and pharmacokinetic studies in the rat demonstrate that prothioconazole is rapidly absorbed, metabolized and eliminated. The primary metabolites included JAU6476 - desthio, as well as S - and O - glucuronides of prothioconazole . ] 7. Metabolite toxicology . [ The major metabolite of prothioconazole in the rat, plants and large animals is JAU6476 - desthio. Therefore, a comprehensive evaluation of the mammalian toxicity

of JAU6476 - desthio has been performed. The acute oral, dermal, and inhalation toxicity of JAU6476 - desthio in the rat is low (LD50 values: 2806 /2506mg/kg [male/female], >5000mg/kg, 4 - hour LC50: >5077mg/m 3 , respectively). Itis non - irritating to skin and only very slightly irritating to eyes and has no cutaneous sensitizing potential by topical application. The short and long - term oral toxicity of JAU6476 - desthio has been investigated b y dietary administration in the rat, mouse and dog. T he common target organ in all 3 species is the liver. Secondary effects on the th yr oid in the rat and dog were associated with increased hepatic enzy me induction. In the long term studies, 52 weeks in the rat and 30 weeks in the dog, the NOAEL for the rat and the dog were 1.1 and 10.1 mg/kg bw/day , respectivel y. JAU6476 - desthio is not carcinogenic in either the rat or the mouse. The NOAEL selected for human risk assessment is 1.1 mg/kg bw/day established in the combined chronic toxicity and carcinogenicit y study in the rat. JAU6476 - desthio was negative for mutagenicity and genotoxicity

in all in vitro and in vivo studies both with and without metabolic activation . In a two - generation reproduction study the maternal NOAEL was 2.7 mg/kg bw/day and the NOAEL for reproductive and neonatal effects 10.0 mg/kg bw/day . The main targets at the highest dose were dy stocia (probabl y secondary to hepatic toxicity), decreased pup viability , growth retardation and low incidence of cleft palates. In the developmental toxi city studies cleft palates were seen in the rat and rabbit at the highest dose levels and supernumerary ribs in the rat at lower dose levels. The oral5

NOAEL is 1 mg/kg bw/day in the rat and 2 mg/kg/day in the rabbit. A developmental neurotoxicity study (D NT) in rats was conducted with JAU6476 - desthio as the anticipated dietary exposure is mainly

to JAU6476 - desthio and not the parent. No evidence of neurotoxicity was seen in this study , including no compound - related effects involving neurobehavioral tests and neuropathology . Compound - related effects were limited to overt toxicity and developmental effects which were consistent with effects seen in other developmental toxicity studies. The overall NOAEL was 3.6 mg/kg bw/day . ] 8. Endocrine disruption . [ Th e toxicology database for prothioconazole is current and complete. Studies in this database include evaluation of the potential effects on carcinogenic, reproduction and development effects including an evaluation of the pathology of the endocrine organs following short - or long - term exposure. Prothioconazole is considered not to have primary endocrine effects. ] C. Aggregate Exposure 1. Dietary exposure. [ An aggregate risk assessment was conducted fo r all registered uses on barley ; dried beans and p eas (Crop Group 6C); canola; peanuts; wheat; triticale; soy

beans; and sugar beets; the pending petition requesting tolerances be established on the cereal grain crop group 15 and 16 (except sweet corn, sorghum, and rice) and sweet corn; and this proposed p etition requesting tolerances on rice , alfalfa and potato . In actualit y, rice and potato do not contribute to the dietary burden since the TRR studies show a no residue situation . The acute toxicity

endpoint used in the acute assessment was the NOAEL of 2.0 mg/kg/day

from the prothioconazole - desthio rabbit developmental toxicity study as described in the Agency ’s HED risk assessment memorandum on prothioconaz ole dated January 5, 2009 . No acute endpoint was identified for the general U.S. population; Femal es, 13 - 49 years of age, was the only population subgroup to be included in the acute assessment . Application of a 100 x uncertainty factor results in an acute reference dose (aRfD) of 0.0 2 mg/kg/day . The chronic reference dose (cRfD) o f 0.0 1 mg/kg/day r esul ts from application of a 1 00x uncertaint y factor to the NOAEL of 1.1 mg/kg/day from the rat chronic \ oncogenicity prothioconazole - desthio toxicity study . The acute and chronic dietary assessments for combined food and water exposure show 7.33 % utilization of the aRfD by females 13 - 49 years and 9.0% utilization of the cRfD b y the most sensitive subgroup, all infants. Results from the dietary exposure assessment s demonstrate a reasonable certainty that no harm to the overall U.S. population or an y populatio n subgroup will result from the use of prothioconazole on the above crops. ] i. Food. [ An acute, Tier 2 dietary (food onl y) risk assessment was conducted. For the population subgroup females 13 - 49 years old, the acute anal ys is indicates an exposure of 0 .57 % of the aRfD at the 95 th percentile . Results from a chronic, Tier 2 dietary (food only) risk assessment show that the most highly exposed population subgroup is children 1 to 2 years with an exposure equal to 1.4 % of the cRfD followed b y all infants at 0.9% .6

Chronic exposure to the overall U.S. population is 0.6 % of the cRfD. ] ii. Drinking water. [No monitoring data are available for residues of prothioconazole in drinking water, and EPA has established no health advisory levels or maximum contaminant levels for residues of prothioconazole in drinking water. In order to address drinking water, water was included i n the dietary anal ys is for food . DEEM anal ys es were performed using the upper bound estimates for the peanut and sugar beet crop scenarios; the EDWC for the acute assessment is 29 ppb from the peanut scenario and 13 ppb from the sugar beet scenario for the chronic assessment (the estimated drinking water concentrations for the proposed foliar use on rice were less than those used in recent ac ute and chronic exposure assessments and so do not factor into the dietary assessment). For the population subgroup females 13 - 49 years old, the acute anal ys is results in an exposure of 6. 76 % of the aRfD. Results from a chronic, Tier 2 d ietary risk assessm ent indicate that the most highly exposed population subgroup was all infants with an exposure equal to 8.1 % of the cRfD. Chronic exposure to the overall U.S. population i s 2.5 % of the cRfD. ] 2. Non - dietary exposure . [ Prothioconazole is not registered for residential uses nor are an y registrations pending for such uses. ] D. Cumulative Effects [ Prothioconazole is a member of the conazole family of fungicides. The cumulative effects of the primary common metabolites are being addressed by the US Triazole Task Force . ] E. Safety Determination 1. U.S. population. [ Inthe Agency ’s HED risk assessment memorandum on prothioconazole dated October 13, 2006, it is stated that quantification of acute risk to the general population including infants and children is not required. Based on the conservative exposure assumptions described above and on the completeness of the toxicity data, it can be concluded that total food and drinking water exposure to prothioconazole from all proposed uses will utilize 7 .33 % of the acute RfD for females 13 - 49 years old and 3.1 % of the chronic RfDs for the overall U.S. population. EPA generall y has no concerns for exposures below 100% of the RfD, because the RfD represents the level at or below which dail y aggregate exposure over a lifetime will not pose appreciable risks to human health. ] 2. Infants and children . [ In the Agency ’s HED risk assessment memorandum on prothioconazole dated January 5, 2009 , it is stated: “There are adequate data in the prothioconazole (including metabolites) database to characterize the potential for pre natal or post - natal risks to infants and children: two - generation reproduction studies in rats; developmental studies in rats and rabbits; and a developmental neurotoxicity study in rats. T he effects seen in these studies suggest that offspring are more susceptible: offspring effects were seen at levels below the LOAELs for maternal toxicity and, in7

general, were of comparable or greater severity compared to the effects observed in adults. However, the point of departure for the most sensitive of these studies (the rabbit developmental toxicity) is lower than that of the other studies (2 mg/kg/day), and is based on effects observed in the fetus, not the parent. Therefore, the offspring are considered to be protected and there is no need to retain the 10X FQPA f actor, and it is reduced to 1X.” EPA also stated “No acute endpoint was identified for the general U.S. population. Females, 13 - 49 years of age, was the only population subgroup inc luded in the acute assessment.” In addition to the adequacy of the toxicity

database, there are also no uncertainties with respect to the exposure database . Both the dietary food and water exposure assessment s are conservative in nature. Additionally , there is no potential for residential exposure. In Bayer’s chronic exposure assessment, the most high ly exposed population subgroup, all infants , utilized 9.0 % of the chronic RfD. EPA generall y has no concerns for exposures below 100% of the RfD, becaus e the RfD represents the level at or below which daily

aggregate exposure over a lifetime will not pose appreciable risks to human health. ] F. International Tolerances [ Codex MRL s are not yet published ; however, prothioconazole was evaluated at both the 2008 and 2009 JMPR , so CODEX MRL s should be established in the near future . ]