EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Laura Nollen, (703) 305 - 7390

Inter r eg ional Research Project Number 4 (IR- 4) Petition Number 9E7612 EPA has received a pesticide petition ( PP# 9E7612 ) from Interr egional Research Project Number 4 (IR- 4) , 500 College Road East, Suite 201 W . , Princeton, NJ 08540, proposing, pursuant to s ection 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. 484 by establishing a tolerance for residues of flutolanil , N - (3 - (1 - methylethoxy)phenyl) - 2 - (trifluoromethyl)benzamide and its metabolites convert ed to 2 - (trifluoromethyl) benzoic acid and calculated as flutolanil in or on the raw agricultural commodities ginseng at 3. 5 parts per million (ppm) ; vegetable, Brassica, leafy, group 5 at 0.11 ppm; and turnip, greens at 0.1 1 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 needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The metabolic profile of flutolanil is well understood and has been elucidated in three dissimilar crops: peanuts, rice and cucumber. The metabolic profile is similar in all crops. The major route of degradation is 4' - 0 - dealkylation to desisopropylflutolanil (M- 4) , followed by conjugation. Other metabolites may occur at very low levels due to hydroxylation and oxidation of the side chain, hydroxylatio n of the aniline ring, and methylation of the hydroxyl groups. These minor metabolites were also subject to conjugation. The residues of concern are the parent (flutolanil) and M - 4 (desisopropyl flutolanil) . 2. Analytical method. Residues of flutolanil and M- 4 are extracted from ma cerated samples with acetone or a mixture of methanol and water. For cabbage and ginseng, an aliquot of the extract is diluted with water and analyzed using HPLC - MS/MS. For broccoli and mustard greens, the acetone extract i s diluted with water and the residues are partitioned into a mixture of ethyl acetate and dichloromethane. This solvent is dispelled and the residue is reconstituted in2

ace tone for purification through Florisil. The purified eluent is taken to dryness an d the residues are reconstituted in a mixture of acetonitrile and water. Residues of flutolanil and M - 4 are chromatographed and quantified using an HPLC

–MS/MS. The Limit of Quantitation is 0.05 ppm for each flutolanil and M - 4. 3. Magnitude of residues. Maximum residues of flutolanil and M - 4 in ginseng (dry) and mustard greens were 2.17 ppm and 0.06 ppm flutolanil, respectively, with no M- 4 residues detected in any sample. No detectable residues of either flutolanil or M- 4 (Limit of Quantitation was 0 .05 ppm for each molecule) were detected in either broccoli or cabba ge. Permanent tolerances of 3.5 ppm and 0.1 1 ppm are proposed for ginseng, Brassica leafy vegetables (Crop Group 5) and turnip greens , respectively. B. Toxicological Profile 1. Acu te toxicity. Acute toxicity data show that technical grade flutolanil has relatively low acute toxicity (Category III and IV). Flutolanil is not a dermal sensitizer, primary eye irritant, or primary skin irritant. 2. Genotoxicty. The toxicological dat abase for flutolanil is complete. The database contains no evidence of genotoxicity attributable to flutolanil. 3. Reproductive and developmental toxicity. The Agency has set the FQPA Safety Factor for flutolanil at 1X because there was no increased sensitivity to fetuses as compared to maternal animals in the developmental rat and rabbit studies and no increased sensitivity to pups as compared to adults in a multi - generation reproduction study in rats. 4. Subchronic toxicity Subchronic and chroni c toxicity studies showed that the primary effects of flutolanil are increases in liver weight combined with decreases in body weight. The available data for flutolanil do not show neurotoxic, carci nogenic, or mutagenic effects. Flutolanil is not a develop mental or reproductive toxicant. There is no evidence of increased susceptibility of rat or rabbit fetuses to in - utero exposure or rat pups to post- natal exposure to flutolanil. No toxic effects were observed in studies in which flutolanil was administered by the dermal routes of exposure. 5. Chronic toxicity. Only a chronic dietary endpoint was identified for flutolanil. The Agency has selected a chronic RfD/PAD of 0.50 mg/kg/day (NOAEL = 50 mg/kg/day; Uncertainty Factor = 100). This chronic RfD/PAD i s based on the chronic oral toxicity study in dogs in which increased incidences of clinical signs (emesis, salivation, and soft stool) occurred at LOAEL = 250 mg/kg/day following 65 weeks of exposure. 6. Animal metabolism. The metabolism of flutolanil has been extensively studied in various species of mammals. Studies in rats, ruminants, and poultry suggest that flutolanil is not well absorbed following oral administration. Once3

absorbed, however, it is rapidly metabolized, primarily to desisopropylflutolanil and it conjugates, and rapidly excreted via urine and feces. 7. Metabolite toxicology

. Flutolanil does not metabolize to a significantly toxic metabolite nor does it share a toxic metabolite with any other pesticide registered in the U.S. 8. Endocrine disruption

. No evidence of endocrine effects has been observed in the subchronic, chronic or reproductive studies. The potential for flutolanil to cause endocrine effects is not considered relevant. C. Aggregate Exposure 1. Dietary exposure. Sufficient residue data for flutolanil are available to assess tolerances and conduct a dietary risk assessment. No acute dietary risk assessment is necessary as no toxic effects from a single oral dose have been observed in toxicology studies. A T ier I chronic riskassessment was conducted based on the Agency’s cPAD of 0.5 mg/kg bw/day using DEEM - FCID v. 2.16. The maximum dietary risk for any dietary subpopulation wa s a maximum of 2% of the cPAD (non - Hispanic, non -white, non - black). i. Food. A Tier I risk analysis ( assumed tolerance - level residues with 100% crop treated) was run including all proposed tolerances. The addition of ginseng (dry) and Brassica leafy vegetables at presumed tolerance levels had a negligible effect on chronic dietary risk. ii. Drinking water

. Worst- case drinking water values were included in the chronic dietary risk assessment described above. T he drinking water residues used in the dietary risk assessment were provided by the Ageny in a memorandum (S. Abel : “Fluto lanil Tier II Estimated Environmental Concentration for Use in the Human Health Drinking WaterRisk Assessment, D260066, 12/13/99) The maximum drinking w ater re sidue of 0.00375 ppm was incorporated in the DEEM- FCID into the food categories“water, direct, all sources” and “water, indirect, all sources.” 2. Non

- dietary exposure

. Flutolanil is currently registered for use on the following residential non - dietary sites: Turf grass. The risk assessment was conducted using the following residential exposure a ssumptions: There are non occupational uses associated with flutolanil. Non - occupational handlers may mix, load, and apply flutolanil products on turf grass. These exposures were assessed for inhalation risk. Post- application inhalation exposure following turfgrass treatment is considered negligible and was not assessed. Because certain flutolanil products are registered for use on residential lawns, postapplication exposure to infants may result in their hand - to - mouth activities on treated turf. The MOE’s for these scenarios ranged from 6.7 x 10 2 to 1.4 x 10 3 . These modeled exposures do not trigger the Agency’s L evel of Concern . D. Cumulative Effects4

Flutolanil has demonstrated only minimal toxicity in animal studies and the mechanism of this toxicity is not known. Flutolanil does not share a mechanism of toxicity with another registered pesticide nor does it share a common toxic metabolite with any other registered pesticide. There are no available data to indicate that flutolanil has a common mecha nism of toxicity with other substances. E. Safety Determination 1. U.S. population. An acute dietary endpoint has not been set for flutolanil by the Agency due to a lack of observable toxic effects from a single dose at any level tested. A chronic dietary risk assessment has been conducted using the Agency’s cPAD of 0.5 mg/kg bw/day. The calculated chronic daily exposure for the general US population is 0. 0.0026 72 mg/kg/bw/day which represents 0.5% of the cPAD. 2. Infants and children

. The Age ncy has set the FQPA factor for flutolanil at 1X based on lack of neurotoxic and teratogenic effects in chronic tests on rabbits and rats. The highest chronic risk calculated for any pre - teen dietary subgroup was 1.4% of the cPAD (non - nursing infants). F. International Tolerances There are no national or transnational MRLs for flutolanil on Brassica (Cole) leafy vegetables or ginseng .