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 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 pestic ide petition ( [insert petition number] ) from Bayer CropScience, 2 T.W. Alexander Drive, P.O. Box 12014, 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. ( Options (pick one) 1. by establishing tolerances and/or changing existing tolerance s for residues of 2. to establish an exemption from the requirement of a tolerance for trifloxystrobin (b enzeneacetic acid, (E,E) - α - (met hoxyimino) - 2 - [[[[1 - [3 - (trifluoromethyl) phenyl]ethylidene]amino]oxy]methyl] - methyl ester) and the free form of its acid metabolite CGA

–321113 ( ( E,E) - methoxyimino - [2 - [1 - (3 - trifluoromethyl - phenyl) - ethylideneaminooxymethyl] - phenyl]acetic acid ) in or on the raw agricultural commodity [alfalfa, forage] at 0.0 1 parts per million (ppm) and [alfalfa, hay] at 0.01 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 F DDCA; 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 Chemistry2

1. Plant meta bolism

. The metabolism of trifloxystrobin in plants (cucumbers, apples, wheat, sugar beets and peanuts) is well understood. Identified metabolic pathways are substantially similar in plants and animals (goat, rat and hen). EPA has det ermined that trifloxystrobin parent and its metabolite CGA- 321113 are the residue of concern for tolerance setting purposes. 2. Analytical method. A practical analytical methodology for detecting and measuring levels of trifloxys trobin in or on raw agricultural commodities has been submitted. The limit of detection (LOD) for each analyte of this method is 0.08 ng injected, and the limit of quantitation (LOQ) is 0. 02 ppm. The method is based on crop specific cleanup procedures and determination by gas chromatography with nitrogen - phosphorus detection . A newer analytical method is available employing identical solvent mixtures and solvent to matrix ratio ( as the first method ) , deuterated internal standards, and liquid chromatography/mass spectrometry- mass spectrometry (LC/MS - MS) with an electrospray interface, operated in the positive ion mode . The limits of detection (LOD) for trifloxystrobin range from 0.00 2 ppm to 0.0 1 ppm , depending on the crops, and the limit of quantitation is 0.01 ppm. 3. Magnitude of residues. Alfalfa seed, treated with [benzeneacetic - phenyl - UL - 14C] trifloxystrobin at rates of 0.0039 lb. ai/100 lb. seed and 0.01 2 5 lb. ai/100 lb. seed ( 0.83X the target maximum rate of 0.015 lb. ai/100 lb. seed), was pla nted, and alfalfa was grown to maturity. The alfalfa raw agricultural commodity (RAC) of forage was collected from three cuttings at BBCH 61 to 65 (10% flowering to 50% flowering). Additionally, alfalfa hay samples were collected, following drying, from th e second and third cuttings. All RAC samples were homogenized and radioassayed. The limit of quantitation (LOQ) for detection of total radioactive residue from all RACs was 0.0028 ppm. The total radioactive residue (TRR) in both alfalfa forage and hay from seed treated at both application rates was comparable to that of control samples at all three cuttings (net residue < 0.0028 ppm). B. Toxicological Profile 1. Acute toxicity. There is a full battery of acute toxicity studies for trifloxystrobin . T rifloxystrobin is of mild acute toxicity by oral, dermal, or inhalation routes of exposure (Cat. IV) , however it is a strong dermal sensitizer. Trifloxystrobin is a mild ocular ( Cat I II ) and dermal irritant (Cat IV) . 2. Genotoxicty. No genotoxic activity is expected of trifloxystrobin under in vivo or physiological conditions. The compound has been tested for its potential to induce gene mutation and chromosomal changes in five different test systems. The only positive finding was seen in the in vitro test system (Chinese hamster V79 cells) as a slight increase in mutant frequency at a very narrow range (250

– 278  g/ mL ) of cytotoxic and precipitating concentrations (compound solubility in water was reported to be 0.61  g/mL ; precipitate was visually noted in culture medium at 150  g/mL ). The chemical was found to be non - mutagenic in the in vivo system or all other in vitro systems. Consequently, the limited gene mutation activity in the3

V79 cell line is considered a nonspecific ef fect under non - physiological in vitro conditions and not indicative of a real mutagenic hazard. 3. Reproductive and developmental toxicity. In a developmental study in rats, reductions in body weight gain and food consumption wer e observed in the dams at  100 mg/kg/day . No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for the increased incidence of enlarged thymus at 1000 mg/kg/day . The developmental NOEL was 10 0 0 mg/kg/day . In the ra bbit developmental study, body weight loss and reduced food consumption were observed in the dams at  50 mg/kg, resulting in a maternal NOEL of 50mg/kg. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for the i ncrease in skeletal anomaly of fused sternebrae - 3 and - 4 at the top dose level of 500 mg/kg. This finding is regarded as a ma rginal effect on skeletal development that could have resulted from the 40 - 65% lower food intake during treatment at this dose leve l. The developmental NOEL was 250 mg/kg. In the 2 - generation rat reproduction study, body weight gain and food consumption were decreased at 750 ppm, especially in females during lactation. Consequently, the reduced pup weight gain during lactation ( 750 ppm) and the slight delay in eye opening (1500 ppm) are judged to be a secondary effect of ma ternal toxicity. No other fetal effects or any r eproductive changes were noted. The low developmental NOEL, 50 ppm (3.8 mg/kg) seen in this study was probably due to the lack of intermediate dose levels between 50 and 750 ppm. The reproductive NOAEL was 1500 ppm (=110.6 mg/kg/day) . 4. Subchronic toxicity. In a subchronic stud y in rats a NOAEL of 500 ppm (30.6 - 32.8 mg/kg/day) was found based on decreased body weights (males), hypertrophy of hepatocytes (males), and pancreatic atrophy observed at the LOAEL of 2000 pp m (127 - 133 m g/kg/day). In mice, a NOAEL was determined at 500 ppm (76.9 - 110 mg/kg/day) based on increased liver weights and necrosis of hepatocytes observed at the LOAEL of 2000 pp m (315 - 425 mg/kg/day). A subchronic feeding study in dogs resulted in a NOAEL of 30 mg/kg/day. Increased liver weight and hepatocyte hypertrophy in males were observed at the LOAEL of 150 mg/kg/day . In a 28

–day dermal toxicity study in rat s t he NOAEL was found at 100 mg/kg/day. Increased liver and kidney weight were observed at the LOAEL of 1,000 mg/kg/day . 5. Chronic toxicity. A chronic feeding study in dogs established a no - observed adverse effect level (NOAEL) of 5 mg/kg/ day. The lowest effect level (LOAEL) for this study was found at 50 mg/kg/day, based on clinical signs, increase d liver weight and hepatocellular hypertrophy .4

In a carcinogenicity study in mice liver effects were observed at doses of and above the LOAEL of 1000 ppm (131.1 mg/kg/day). The NOAEL was determined to be 300 ppm (39.4 mg/kg/day). A chronic toxicity/carc inogenicity study in rats established a NOAEL of 250 ppm (9.81

– 11.37 mg/kg/day). Decreased mean body weight and decreased mean body weight gain (compared to control) were observed at the LOAEL of 750 ppm (29.7

– 34.5 mg/kg/day). The compound did not cause a ny treatment- related increase in general tumor incidence, any elevated incidence of rare tumors, or shortened time to the development of palpable or rapidly lethal tumors in the 18 - month mouse and the 24 - month rat studies. An ad hoc subcommittee of the Ca ncer Assessment Review Committee on May 27, 1999 determined that trifloxystrobin should be classified as a "Not Likely Human Carcinogen," based on the lack of evidence for carcinogenicity in rats and mice. 6. Animal metabolism. Trifloxystrobin is moderately absorbed from the gastrointestinal tract of rats and is rapidly distributed. Subsequent to a single oral dose, the elimination half life is about 2 days and excretion is primarily via bile. Trifloxystrobin is extensively metab olized by the rat into about 35 metabolites, but the primary actions are on the methyl ester (hydrolysis into an acid), the methoxyimino group (O - demethylation), and the methyl side chain (oxidation to a primary alcohol). Metabolism is dose dependent as it was almost complete at low doses but only about 60% complete at high doses. In the goat, elimination of orally administered trifloxystrobin is primarily via the feces. The major residues were the parent compound and the acid metabolite (CGA- 321113) plus its conjugates. In the hen, trifloxystrobin is found as the major compound in tissues and in the excreta, but hydroxylation of the trifluormethyl phenyl moiety and other transformations, including methyl ester hydrolysis and demethylation of the methoxyimi no group, are also seen. In conclusion, the major pathways of metabolism in the rat, goat, and hen are the same. 7. Metabolite toxicology

. Metabolism of trifloxystrobin has been well characterized in plants, soil, and animals. I n plants and soil, photolytically induced isomerization results in a few minor metabolites not seen in the rat; however, most of the applied material remained as parent compound as shown in the apple and cucumber studies. All quantitatively major plant and/or soil metabolites were also seen in the rat. The toxicity of the major acid metabolite, CGA- 321113 (formed by hydrolysis of the methyl ester), has been evaluated in cultured rat hepatocytes and found to be 20 - times less cytotoxic than the parent compoun d. Additional toxicity studies were conducted for several minor metabolites seen uniquely in plants and/or soil. The studies indicate that these metabolites, including CGA- 357261, CGA - 373466, and NOA - 414412, are not mutagenic to bacteria and are of low acu te toxicity (LD50 >2000 mg/kg). In conclusion, the metabolism and toxicity profiles5

support the use of an analytical enforcement method that accounts for parent trifloxystrobin . 8. Endocrine disruption

. Trifloxystrobin does not b elong to a class of chemicals known for having adverse effects on the endocrine system. Developmental toxicity studies in rats and rabbits and reproduction study in rats gave no indication that trifloxystrobin might have any effects on endocrine function r elated to development and reproduction. The subchronic and chronic studies also showed no evidence of a long - term effect related to the endocrine system. C. Aggregate Exposure 1. Dietary exposure. Assessments, using the DEEM F CID Version 2.0, 1994 - 1996, 98 CSFII software, were conducted to evaluate potential risks due to chronic and acute dietary exposure of the U.S. population and selected population subgroups to residues of trifloxystrobin. These analyses cover all register ed and pending uses including the proposed use as a seed treatment in alfalfa. The EPA has established an acute Population Adjusted Dose (aPAD) of 2.5 mg/kg/day for acute dietary risk assessments based on a NOAEL of 250 mg/kg bw/day from a rabbit develo pmental toxicity study and an uncertainty factor or 100. The FQPA SF was reduced to 1 x based on toxicological considerations by the FQPA Safety Factor Committee (HED Doc. No. 013545, B. Tarplee, 01/JUL/1999), the conservative residue assumptions used in th e dietary and residential exposure risk assessments, and the completeness of the residue chemistry and environmental fate databases (DP Num: 3 17330, B. O'Keefe,1 6/AUG/2006). For chronic dietary analyses, the EPA established a chronic Population Adjusted Dose (cPAD) of 0.038 mg/kg/day based on a NOAEL of 3.8 mg/kg bw/day from the rat reproducti on toxicity study and an uncertainty factor of 100. Results from the acute and chronic dietary exposure analyses described below demonstrate a reasonable certainty that no harm to the overall U.S. population or any population subgroup will result from the use of trifloxystrobin on currently registered uses plus the proposed changes to corn and sweet corn tolerances. i. Food. For food, a Tier 1 acute and chronic dietary exposure assessments were performed. Acute exposure, expressed at the 95 th percentile of exposure, was 1.5 % of the aPAD for F emales 13 - 49 years old (only population subgroup of concern). The chronic exposure was 36.2 % cPAD for the T otal US P opulation and 69.6 % cPAD for the most sensitive population, Children 1 - 2 year s old. ii. Drinking water

. Acute and chronic exposure estimates from water are included in the exposure values given above for food. These exposure esti ma tes for water are based on EPA’s surface water estimated environmental concentrations (EECs) of trifloxystrobin and CGA - 321113 for acute exposure and for chronic exposures at 140 ppb. These values are listed in the Federal Register (71 FR 55313) .6 2. Non

- dietary exposure

. The re is no potential for dermal or incidental oral exposure during or post application of trifloxystrobin when applied as a seed dressing to alfalfa. As such, non - dietary exposure from these new tolerances are covered by previous non - dietary risk assessments performed by EPA. As published in the Federal Register (FR Vol 68, no. 175, 10 - Sep - 03, FR Vol 73, no. 1, 02 -Jan - 08 ), the EPA considered chronic, short term and intermediate term risk from residential uses of trifloxystrobin . The EPA determined that the risk did not exceed the Agency’s level of concern . D. Cumulative Effects EPA has determined, as published in the Federal Register ( FR Vol 73, no. 1, 02 -Jan - 08) ), that unlike othe r pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, trifloxystrobin does not appear to produce a toxic metabolite produced by other substances. Therefore EPA has not assumed that trifloxystrobin has a common mechanism of toxicity with other substances. E. Safety Determination 1. U.S. population. Based on the information supplied above under Aggregate Exposure, there is reasonable certainty that exposure from trifloxystrobin will result in no harm to the adult U.S. population. 2. Infants and children

. Based on the information supplied above under Aggregate Exposure, there is reasona ble certainty that exposure from trifloxystrobin will result in no harm to the infants and children . F. International Tolerances In ternational tolerances and CODEX tolerances for trifloxystrobin are established for many crops in vari o us countries. No tolerances exist yet in Canada or Mexico for the new proposed uses.