EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Shaja Joyner, (703) 308-3194

INSTRUCTIO

NS: 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. Simp ly replace the instructions that appear in green, i.e., “ [insert company name] ,” with the information specific to your action. TEMPLATE: ISK Biosciences Corporation [Insert petition number]
EPA has received a pesticide p etition ( [insert petition number] ) from ISK Biosciences Corporation , 7470 Auburn Road, Suite A, Concord, Ohio, 44077, 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 a tolerance for residues of the fungicide pyriofenone, (5-chloro-2 - methoxy-4 - methyl-3 - pyridinyl)(2,3,4 -trimethoxy-6- methylphenyl)methanone, in or on the raw agricultural commodity grape at 0. 2 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 o f the submitted data at this time or whether the data supports granting of the petition. Additional data may b e needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism

. The metabolism of pyriofenone as well as the nature of the residues in plants is adequately understood for the purposes of this tolerance. Metabolism studies were conducted with three diverse crops, grapes, wheat and tomatoes. All three crops showed a similar pattern of metabolism with unchanged pyriofenone remaining on the plant surfaces. The metabolism of pyriofenone in plants results in a large numb er of fragments in only trace amounts. Hence, parent pyriofenone is the only residue of concern. 2. Analytical method. A practical analytical method for Pyriofenone using Liquid Chromatography-MS/MS is available for analysis of grapes . This2
method has b een confirmed through independent laboratory validation and is available for enforcement purposes. 3. Magnitude of residues. Seventeen grape trials were conducted in Germany (4 trials), Northern France (4 trials), southern France (4 trials), Spain (3 trials) and Italy (2 trials). T hese studies cover a wide range of geographies with diverse climates and growing conditions, as well as various cultural practices. T he residue values reported gave results which lead to a proposed tolerance of 0.20 ppm. In f our trials , samples were processed into juice, wine and raisins

. There was no concentration of pyriofenone in grape juice, wine, or raisins. Residues in raisins seen during processing trials were considered to reflect water loss during the drying process used to produce them and are as expected.

B. Toxicological Profile The proposed tolerance for pyriofenone is for an imported commodity only. T he acute oral toxicity and acute neurotoxicity studies are the only studies required to evaluate acute toxicity. S ubchronic dermal and inhalation studies are not required because residential and occupational risk assessments are not necessary to set a tolerance on an imported commodity. 1. Acute toxicity. Pyriofenone exhibits low oral acute toxicity. The o ral LD 50 is greater than 2 000 mg/kg. Since this petition is for an import tolerance, oral toxicity data sufficiently assesses the risk of acute exposure for this use. In an acute neurotoxicity study, pyriofenone was administered by oral gavage to groups o f CD rats at doses up to 2000 mg/kg. The animals were observed for 14 days. A single oral administration of pyriofenone at doses up to 2000 mg/kg, the maximum dose required by the guidelines to which the study was designed, resulted in minimal, transient chan ge and there was no evidence of any neurological effect. C onsequently, 2000 mg/kg was considered to be the NOEL . 2. Genotoxicity

. The genotoxic potential of pyriofenone has been assessed as negative by several in vitro and in vivo mutagenicity studies. Pyriofenone did not elicit a genotoxic response in any of the studies conducted. 3. Reproductive and developmental toxicity. Results from a two-generation study indicate that pyriofenone is not a reproductive toxicant. The dietary concentrations f or the study were 0, 150, 1000 and 5000 ppm. The3 NOEL for systemic toxicity was 1000 ppm (equivalent to 64.1 and 79.2 mg/kg/day, respectively for P males and females and 76.8 and 84.4 mg/kg/day for F1 males and females). The NOEL for reproductive toxicity was 5000 ppm (equivalent to 334 and 395 mg/kg/day for P males and females, respectively and 393 and 434 mg/kg/day for F1 males and females) . Results from developmental studies in rats and rabbits provided no indication of teratogenic effects for fetuses of either species and no evidence of developmental effects in the absence of maternal toxicity. For the rat teratology study, doses of 0, 30, 300 or 1000 mg/kg bwt/day were administered between Days 6 and 19 of gestation . The NOEL for maternal toxicity was 30 mg/kg bwt/day. T he NOEL for developmental toxicity was 1000 mg/kg bwt/day, the highest dose tested. Pyriofenone technical was not teratogenic to rats. For the rabbit teratology study, doses of 0, 30, 100, or 300 mg/kg bwt/day were administered between Days 6 and 27 of gestation . The NOEL for maternal toxicity was 100 mg/kg bwt/day. The NOEL for developmental toxicity was 300 mg/kg bwt/day, the highest dose tested. Pyriofenone technical was not teratogenic to rabbits. 4. Subchronic toxicity. Short-term (28 -day) toxicity studies were conducted in rats and dogs . Doses evaluated in the rat study were 0, 300, 3000, 10,000, and 20,000 ppm. T he NOEL was 300 ppm (equivalent to 24.2 and 26.1 mg/kg bwt/day, respectively for males an d females). Effects observed at 3000 ppm included hyaline droplets in the kidney proximal tubular cells, changes in the blood plasma and increased liver weights for males and increased liver weights, increased kidney weights and hepatocyte hypertrophy in one animal for females . Doses evaluated in the dog study were 0, 500, 1500, 5000, and 15,000 ppm. T he NOEL was 5000 ppm for males (equivalent to 144 mg/kg bwt/day) and 1500 ppm (equivalent to 47.5 mg/kg bwt/day) for females. In addition, subchronic (90-day) feeding studies were conducted in rats, mice, and dogs. Doses evaluated in the rat study were 0, 300, 1000, 2500, and 5000 ppm. T he NOEL was 1000 ppm (equivalent to 60.5 and 69.0 mg/kg bwt/day, respectively for males an d females). Effects observed at 2500 ppm included high plasma protein, albumin, calcium, low chloride, and increased liver, kidney and cecum weights . In females at 2500 ppm, increased activated partial thromboplastin time and globulin , and increased liver, kidney and cecum weights were observed . Doses evaluated in the mouse study were 0, 300, 1000, 300, and 7000 ppm. T he NOEL was 1000 ppm (equivalent to 176 mg/kg bwt/day) for males and 300 ppm (equivalent to 61.0 mg/kg bwt/day) for females. Effects included increased liver weights and the presence of periportal hypertrophy in males at 3000 ppm and and increased liver weight observed in females at 1000 ppm. Doses evaluated in the dog study were 0, 500, 3000 and 25,000 ppm in males and 0, 500, 3000 and 15,000 ppm in females. T he NOEL was 3000 ppm (equivalent to 90.3 and 89.8 mg/kg bwt/day, respectively for males an d females). At4
the high doses, effects included decreased weight gain and food intake as well as increased kidney weights in males, and progressive increase of alkaline phosphatase in b oth sexes . 5. Chronic toxicity. An 18- month oncogenicity study was conducted in mice with dietary concentrations of 0, 600, 1800 and 5400 ppm for males and 0, 300, 1000, and 3000 ppm for females. The systemic NOEL was 600 ppm (77.6 mg/kg bwt/day) for males based on non-neoplastic changes in the kidney and liver. The systemic NOEL was 1000 ppm (167 mg/kg bwt/day) for females based on reduced body weights and food consumption. There was no evidence of carcinogenicity. A 2 -year chronic toxicity/carcinogenicity study was conducted in rats with dietary concentrations of 0, 200, 1000 and 5 000 ppm technical pyriofenone. T he systemic NOEL was 100 0 ppm (36.4 mg/kg bwt/day) for males based on reduced body weight gains and non-neoplastic changes in the kidney, liver, and mesenteric lymph nodes. The systemic NOEL was 200 ppm (9.13 mg/kg bwt/day) for females based on reduced body weight and non-neoplastic changes in the kidney. There was no evidence of carcinogenicity. A 52 -week chronic toxicity study was conducted in dogs with dietary concentrations of 0, 500, 3000 and 25,000 ppm for males and 0, 500, 3000, and 15,000 ppm for females. T he NOEL was 3000 ppm (83.5 and 86.2 mg/kg bwt/day for males and females, respectively) . The LOEL was 25,000 ppm (701 mg/kg bwt/d ay) for males and 15,000 ppm (448 mg/kg bwt/day) for females based decreased weight gain, decreased food intake, and increased kidney weights observed for the males and progressive increase of alkaline phosphatase observed in both sexes. 6. Animal metabolism. The metabolism of pyriofenone in rats and goats is adequately understood. Pyriofenone is rapidly excreted in the urine and feces and was extensively metabolized to a number of components through a number of metabolic pathways including glucuronidation. There are no significant qualitative differences between rat and ruminant metabolic pathways. 7. Metabolite toxicology

. No toxicologically significant metabolites were detected in plant or animal metabolism studies. The residue of concern for tolerance setting purposes is the parent compound. Consequently, there is no additional concern for toxicity of metabolites. 8. Endocrine disruption

. The submitted studies 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 data demonstrate no treatment-related effects on the endocrine system.5

9. Immunotoxicity

. Four-week immunotoxicity studies were conducted in female rats and mice. Dietary doses up to 20,000 ppm were evaluated in the rat study. There was no effect on the immune system at any dose tested. The NOEL was greater than 20,000 ppm(≥1690 mg/kg bwt/day). Dietary doses up to 7000 ppm were evaluated in the mouse study. T here was no effect on the immune system at any dose tested. T he NOEL was greater than 7000 ppm (≥1270 mg/kg bwt/day). C. Aggregate Exposure 1. Dietary exposure. E xposure assessments were conducted to evaluate the potential risk due to dietary exposure of the U.S. population to residues of pyriofenone . For acute dietary exposure, an Acute Reference Dose (aRfD) is not identified for Pyriofenone since there was no evidence of initial acute effects in the acute oral or short-term toxicity studies, or the developmental toxicity studies in rats and rabbits. Furthermore, effects in the acute neurotoxicity study were seen only at the limit dose level of 2000 mg/kg/day. No initial acute effects were seen in the 90-day neurotoxicity study. For chronic dietary exposure, the chronic reference dose (cRfD) is 0.106 mg/kg bwt/day, based on the NOAEL from the rat combined chronic toxicity/carcinogenicity study ( 10.6 mg/kg bwt /day) and dividing by an uncertainty factor of 100. T he chronic population adjusted dose (cPAD) is also 0.106 mg/kg bwt/day since the FQPA safety factor is anticipated to be 1 for pyriofenone . i. Food. Tier 1 chronic dietary exposure analyses were conducted for pyriofenone in/on grapes to determine the exposure contribution of this commodity to the diet and to ascertain the chronic risk potential. T he exposure estimates were based on the proposed tolerance level residues , average processing factors and a market share of 100% crop treated as a conservative assumption . The consumption data were from the USDA’s CSFII (1994 through 1996 and 1998) continuing survey of food intake using Exponent's Dietary Exposure Evaluation Module (DEEMFCID) software, version 2.16. Using all of the worst case exposure scenarios listed above, the Tier 1 chronic dietary exposure estimates resulted in an estimated exposure for the general U.S. population of 0.000130 mg/kg bwt/day. T his exp osure corresponds to 0.1 % of the cPAD of 0.106 mg/kg bwt/day. The highest exposure estimate calculated was for the subgroup children, 1 -2 years . T his exposure was determined to be 0.000753 mg/kg bwt/day (0.7 % of the cPAD) . The chronic dietary exposure analysis is summarized in the table below.6 Population Exposure Estimate % of cPAD Subgroup (mg/kg body wt/day) U.S. Population 0.00013 0 0.1 All Infants (< 1 year old) 0.000209 0 .2 Children (1 -2 years old) 0.000 753 0.7 Children (3 -5 years old) 0.000456 0.4 Children (6- 12 years old) 0.00 0 171 0.2 Youth (13 - 19 years old) 0.000062 0.1 Females (13 -49 years old) 0.000078 0.1 Adults (20-49 years old) 0.0000 92 0.1 Adults (50+ years old) 0.000083 0.1 It can be concluded that long-term dietary exposure to pyriofenone through residues on treated grapes should not be of cause for concern. ii. Drinking water

. Pyriofenone is proposed for use only on an imported commodity (grape), therefore the only anticipated exposure route for the US population is by dietary (food) exposure. With no propos ed US registration, there will be no pyriofenone residues in surface or ground water that would be used for drinking water.

2. Non

-dietary exposure . The proposed use for pyriofenone is for an imported commodity (grape) . T he only anticipated exposure route for the US population is via the diet (food only). Therefore, residential and occupational exposure risk assessments for the incidental oral, dermal, and inhalation exposure routes are not required. D. Cumulative Effects EPA has not made a co mmon mechanism of toxicity finding as to pyriofenone and any other substances, and pyriofenone does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that pyrio fenone has a common mechanism of toxicity with other substances. E. Safety Determination 1. U.S. population. Based on the completeness and reliability of the toxicity data and the conservative exposure assessments, there is a reasonable certainty that no harm will result from the aggregate exposure of residues of pyriofenone .7

2. Infants and children

. Based on the completeness and reliability of the toxicity data and the conservative exposure assessments, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure of residues of pyriofenone . F. Interna tional Tolerances Presently, there are no Codex maximum residue levels (MRLs) established for residues of pyriofenone on any crop.