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June 30, 2015

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (7/1/2007)

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 in your pesticide petition. Simply replace the instructions that appear in green , i.e., “ [insert company name] ,” with the information specific to your action.

TEMPLATE:

[Bayer CropScience]

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from [Bayer CropScience], [P.O. Box 12014, 2 T.W. Ale xander 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:

1. 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 [cotton, undelinted seed, (Crop Subgroup 20C] at [0.4] parts per million (ppm), [cotton, gin by-products] at [4.0] parts per million (ppm),

2. amending existing 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 [sugar beet, roots] at [0.3] parts per million (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 need ed before EPA rules on the petition

A. Residue Chemistry

1. Plant metabolism. [ The metabolism of prothioconazole in plants is adequately understood for purposes of establishing these proposed tolerances. Prothioconazole was extensively metabolized in plants with pr othioconazole-desthio as the major residue found in all crops (wheat, peanuts, and sugar beets). Smaller amounts of various isomers of JAU6476-hydroxy-desthio and their conjugates and triazolylalanine, triazolylhydroxypropionic acid, and triazolylacetic acid, metabolites common to the2 triazole-derivative class of fungicides, were also found. Based on the above data the residues of concern for tolerance enforcement and for risk assessment in plant commodities are prothioconazole and its me tabolite JAU6476-desthio, calculated as prothioconazole equivalents. The risk as sessment for the common metabolites arising from the triazole-derivative fungicides is being addressed by the US Triazole Task

Force.

The nature of residues in animal commo dities is also adequately understood. For the purpose of tolerance enforcement, the residues of concern are the sum of prothioconazole, the prothioconazole-destio metabolite, and conjugates that can be converted to either of these two compounds by acid hydrolysis. For purposes of riskassessment, the residues of concern consist of prothioconazole, the prothioconazoledesthio metabolite, the 4-hydroxy prothioconazole metabolite, and conjugates that can be converted to any of these three compounds by acid hydrolysis.]

2. Analytical method. [ The analytical method for determining residues of concern in plants extracts residues of prothioconazole and JAU6476-desthio and converts the prothioconazole to JAU6476-desthio and JAU6476-sulfonic acid. Following the addition of internal standards, the sample extracts are analyzed by LC/MS/MS. Radiovalidation and independent laboratory validation have shown that the method adequately quantifies prothioconazole residues in treated commodities. The validated LOQ for total prothioconazole-derived residues was 0.04 ppm in sugar beet and cotton commodities. The validated LOQs were 0.01 ppm for 1 H -1,2,4-triazole and the triazole conjugates for cotton. The analytical method for analysis of large animal tissues includes extraction of the residues of concern, followed by addition of an internal standard to the extract. The extract is then hydrolyzed to release conjugates, partitioned and analyzed by LC/MS/MS as prothioconazole, JAU6476-desthio and JAU6476-4-hydroxy. The method for analysis of milk eliminated the initial extraction step in the tissue method. ]

3. Magnitude of residues. [Residue trials were conducted in the various required regions across the United States and Canada in accordance with the EPA and PMRA guidelines for crop field trials (OPPTS 860.1500; DACO 7.4.1; DACO 7.4.2) to support the tolerances requested above including the following:

Cotton:

A total of 12 field trials were conducted on cotton as a representative of the Cottonseedsubgroup (Crop Subgroup 20C) in the USA and Canada following seed treatment, an infurrow plus two foliar, or three foliar applica tions of Proline 480 SC. Two field trials were also conducted to measure the magnitude of prothioconazole residues in/on cotton processed commodities.

Sugar beet:

Three bridging field trials were conducted to compare the magnitude of prothioconazole

residues in/on sugar beet commodities following foliar spray applications in accordance with

currently registered use pattern with residues from the proposed seed treatment application

or seed treatment plus in-furrow and foliar applications of prothioconazole to sugar beet.

The maximum total prothioconazole residue found in the sugar beet root samples from this

bridging trial study was similar to the maximum residue (0.24 ppm) found in the sugar beet

root samples from the original field residue study and did not exceed the established MRL

(0.25 ppm) for this commodity in the US and Canada. Bayer CropScience requests an

amendment of the established MRL for prothioconazole residues in sugar beet roots from3 0.25 ppm to 0.30 ppm to minimize the likelihood of future MRL exceedance and to

harmonize the domestic US tolerance with international MRL for prothioconazole residues

in/on sugar beet roots.

B. Toxicological Profile

1. Acute toxicity. Prothioconazole exhibits very low acute oral, dermal and inhalation toxicity. The acute oral LD50 for prothioconazole in rats was >6200 mg/kg-bw/day, while the dermal LD50 was >2000 mg/kg-bw/day, and the four-hour rat inhalation LC50 was >4990 mg/m3. Prothioconazole was not irritating to the eye or skin of rabbits and did not cause skin sensitization in guinea pigs.

2. Genotoxicity. Prothioconazole is not mutagenic. Slightly positive and equivocal responses observed in in vitro cytogene tic and unscheduled D NA synthesis assays were not supported by negative in in vivo tests.

3. Immunotoxicity. Immunotoxicity potential was evaluated as part of a subchronic toxicity study in rats. Spleen cell counts and a plaque-forming assay used to determine splenic IgM antibody synthesis in response to antigen showed no evidence of treatment-related immunotoxicity at doses up to 500 mg/kg-bw/day (the highest dose tested) for 31 days. Prothioconazole is not considered to be immunotoxic based on the results of this study and additional studies conducted using mice and dogs.

4. Reproductive and developmental toxicity. Prothioconazole is not considered a primary reproductive toxicant based on a two-generation rat reproduction study. The NOAEL for parental toxicity was 9.7 mg/kg- bw/d, and the NOAEL for both reproductive and neonatal effects was 95.6 mg/kg-bw/day. In the rat oral developmental toxicity study, the fetal NOAEL 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 administer ed to the rat by the dermal route did not elicit developmental toxicity. In the rabbit, prothioconazole did not produce developmental toxicity at dose levels exceeding the maximum tolerated dose. Thus, prothioconazole is not teratogenic in the rat or rabbit.

5. Subchronic toxicity. 90-day feeding studies conducted in rats, mice, and dogs showed the liver and/or kidney to be the target organs. In these subchronic studies NOAELs were established at 100 mg/kg-bw/day for the rat and 25 mg/kg-bw/day for the mouse and dog.

6. Chronic toxicity. Prothioconazole is not carcinogenic in the rat or the mouse, even at dose levels that exceed the maximum tolerated dose for rats. The liver and kidney are target organs of prothioconazole for non-neoplastic toxicity in the rat, mouse, and dog.

The lowest NOAEL established on the basis oflong-term toxicity studies is 5 mg/kgbw/day in the rat chronic toxicity/carcinog enicity study and the dog 52-week toxicity study.

7. Animal metabolism. Metabolism and pharmacokinetic studies in the rat demonstrate that prothioconazole is rapidl y absorbed, metabolized and eliminated. The primary metabolites included JAU6476-desthi o (also referenced as SXX0665) and Sand O-glucuronides of prothioconazole.

8. Metabolite toxicology. The major metabolite of prothioconazole in the rat, large animals, and plants is JAU6476-desthio. Therefore, a comprehensive evaluation of the mammalian toxicity of JAU6476-desthio has been performed.4

The acute oral, dermal, and inhalation toxicities of JAU6476-desthio in the rat are low, with LD50 values of 2806/2506 (male/female) mg/kg, LD50 >5000mg/kg, and a 4-hour LC50 >5077mg/m3, respectively. JAU6476-desthio is non-irritating to skin, and only very slightly irritating to eyes, and has no cutaneous sensitizing potential by topical application.

JAU6476-desthio was negative for mutagenicity and genotoxicity in all in vitro and in

vivo studies both with and without metabolic activation.

The short and long-term oral toxicities of JAU6476-desthio have been investigated by dietary administration in the rat, mouse, and dog. The common target organ in all three species is the liver. Secondary effects on the thyroid in the rat and dog were associated with increased hepatic enzyme induction. In the long term studies, 52 weeks in the rat and 30 weeks in the dog, the NOAELs for the rat and the dog were 1.1 and 10.1 mg/kg-bw/day, respectively. JAU6476-desthio is not carc inogenic in 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 carcinogenicity study for JAU6476-desthio in the rat.

In a two-generation reproduction study in rats, the maternal, reproductive, and neonatal NOAEL doses were 2.7 mg/kg-bw/day, 11.0 mg/kg-bw/day and 18.6 mg/kg-bw/day. The main reproductive toxicities observed at the highest dose were an increased incidence of dystocia (likely secondary to hepatic toxicity), decreased pup viability, growth retardation, and a low incidence of cleft palate.

In the developmental toxicity studies, an increased incidence of cleft palate was observed in the rat and rabbit at the highest dose levels. Supernumerary ribs and retarded growth were observed in the rat at lower dose levels, with an NOAEL = 3 mg/kg-bw/day. The oral NOAEL selected for human health risk assessment was 2 mg/kg-bw/day, established in rabbit developmental toxicity study.

A developmental neurotoxicity study (DNT) 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 up to the highest dose tested, including no compound-related effects involving neurobehavioral tests and neuropathology. Compound-related effects were limited to overt toxicity and developmental effects that were consistent with effects seen in other developmental toxicity studies. The overall NOAEL for offspring was 3.6 mg/kg-bw/day.

9. Endocrine disruption. The 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 for all existing registered uses on barley; dried beans and peas (Crop Group 6C); canola; peanuts; wheat; triticale; soybeans; sugar beets; cereal grain crop group 15 and 16 (except sorghum) sweet corn; rice; alfalfa; potato and this proposed petition requesting tolerances on cucurbits (Crop Group 9), blueberry (Crop Group 13B), and cranberry (Crop Group 13H). A previous Tier 2 dietary risk assessment was conducted by EPA (PC Code 113961) on December 9 th , 2010. Residues for the additional crop groups were based on5 highest average field trial (HAFT) for acute assessment and the average residue for

chronic assessment.

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 prothioconazole dated January 5, 2009. No acute endpoint was identified for the general U.S. population; Females, 13-49 years of age, was the only population subgroup to be included in the acute assessment. Application of a 100x uncertainty factor results in an acute reference dose (aRfD) of 0.02 mg/kg/day. The chronic reference dose (cRfD) of 0.011 mg/kg/day results from applying a 100x uncertainty 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 25% utilization of the aRfD by females 13-49 years and 63% utilization of the cRfD by the most sensitive subgroup, all infants. Results from the dietary exposure assessments demonstrate a reasonable certainty that no harm to the overall U.S. population or any population subgroup will result from the use of prothioconazole on the above crops. ]

i. Food. [ An acute, Tier 2 dietary (food only) risk assessment was conducted. For the population subgroup females 13-49 years old, the acute analysis indicates an exposure

of 3.75% 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 9.7% of the cRfD followed by all infants at 3.9%. Chronic exposure to the overall U.S. population is 3.2% 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 in the dietary analysis for food. DEEM analyses were performed using the upper bound estimates for the cranberry crop scenario; the EDWC for the acute and chronic assessment is 94 ppb. For the population subgroup females 13-49 years old, the acute analysis results in an exposure of 21% of the aRfD. Results from a chronic, Tier 2 dietary risk assessment indicate that the most highly exposed population subgroup was all infants with an exposure equal to 59% of the cRfD. Chronic exposure to the overall U.S. population is 18% of the cRfD. ]

2. Non-dietary exposure

. [ Prothioconazole is not registered for residential uses nor are any registrations pending for such uses. ] Occupational exposures and risk will not exceed those previously evaluated by EPA and determined to be acceptable.

D. Cumulative Effects

[Prothioconazole is a member of the conazole family of fungicides. The cumulative effects of the primary common metabolites are addre ssed by the US Triazole Task Force in conjunction with the US EPA. Human health risk assessment (June 15, 2013) for exposure to common conazole metabolites 1,2,4-triazole , triazolylalanine, and triazolylacetic acid concluded that risk estimates for aggregate exposures are below the level of concern for all populations, indicating no dietary exposure co nsiderations for common triazole metabolites of prothioconazole.]6 E. Safety Determination

1. U.S. population. [ In the Agency’s HED risk assessment memorandum onprothioconazole dated June 15, 2013, 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 36% of the acute RfD for females 13-49 years old and 24% of the chronic RfDs for the overall U.S. population. EPA generally has no concerns for exposures below 100% of the RfD, because the RfD represents the level at or below which daily 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 June 15, 2013, it is stated: “There are adequate data in the prothioconazole (including metabolites) databa se to characterize the potential for prenatal or post-natal risks to infants and children: two-generation reproduction studies in rats; developmental studies in rats and rabbi ts; and a developmental neurotoxicity study

in rats. The effects seen in these studies suggest that offspring are more susceptible: offspring effects were seen at levels below the LOAELs for maternal toxicity and, in general, were of comparable or greater se verity 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 n eed to retain the 10X FQPA factor, 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

included 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 assessments are conservative in nature. Additionally, there is no potential for residential exposure.

In Bayer’s chronic exposure assessment, the most highly exposed population subgroup, all infants, utilized 85 % of the chronic RfD. EPA generally has no concerns for exposures below 100% of the RfD, because 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

[ International tolerance/MRL has been established at 0.30 ppm for prothioconazole residues in/on sugar beet roots. An amendment of the established US and Canada MRL for sugar beet roots from 0. 25 ppm to 0.30 ppm will ha rmonize the domestic North

America MRL with international MRL for th is commodity. No international MRL has

been established for cotton. ]