**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (**  **7 /1/200**  **7 )**  **EPA Registration**  **Division contact: Dominic Schuler, (703) 347**  **- 0260** 

**INS TRUCTIONS:**  **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 petitio**  **n. Simply replace the instructions that appear in green**  **, i.e., “ [**  **insert company name**  **] ,” with the information specific to your action.**  **TEMPLATE: Bayer CropScience**  **1F7930** EPA has received a pesticide petition **1F7930** 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. 555 by establishing tolerances and/or chang ing existing tolerance s for residues of **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 **[ almond, hulls**  **]** at **9 .0**  parts per million (ppm)

. EPA has determined that the petition contains data or information regarding the elements s et 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 metabolism of trifloxystrobin in plants (cucumbers, apples, wheat, sugar beets and peanuts) is well understood. Identified metabolic**  **pathways are substantially similar in plants and anima ls (goat, rat and hen). EPA**  **has determined 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 detectin g and** 2

**measuring levels of trifloxystrobin 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 cr**  **op 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 s**  **tandards, 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 crop s,**  **and the limit of quantitation of each analyte**  **is 0.01 ppm.**  3. Magnitude of residues. **Five field trials were conducted to measure the magnitude of trifloxystrobin**  **residues in/on almond hulls and almond nutmeat**  **following t hree**  **airblast foliar**  **spray applications of Trifloxystrobin 500 SC**  **. The first application was made at a**  **target rate of 0.143 lb**  **ai/A/application . The second and third applications were**  **made at a target rate of 0.178 lb ai/A/application. Trifloxystrobin 500 SC is a**  **suspension concent rate formulation containing 500 g ai/L** 

. **The applications were made with a target 7**  **- day interval for all trials and a target 14**  **- day pre**  **- harvest**  **interval (PHI) for the harvest trials and target 0, 7, 14, 21, and 28 -**  **day PHIs for the decline trial.**  **At a PHI of 14**  **days, the average**  **HAFT of total trifloxystrobin residues in**  **almond hulls and almond nutmeats**  **was 1.96 ppm and <0.01 ppm, respectively.**  B. Toxicological Profile 1. Acute toxicity. **There is a full battery of acute toxicity studies for trifloxystro**  **bin . Trifloxystrobin is of mild acute toxicity**  **by oral, dermal, or inhalation routes of exposure**  **(Cat. I V** **) , 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 findi**  **ng 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 /**  **m L**  **) of cytotoxic and precipitating concentrations (compound solubility in water was**  **reported to be 0.61**  **g /m** **L ;**  **precipitate was visually noted in culture medium at 150**   **g /m** **L ). 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 the V79 cell line is considered a nonspeci**  **fic effect 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 consumpti**  **on were 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**3

**1000 mg/kg** **/day . The developmental NOEL was 10**  **0 0**  **mg/kg /day**  **. In**  **the rabbit 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 increase in skeletal anomaly of fused sternebrae**  **- 3 and**  **- 4 at the top dose level of 500 mg/kg. This fin**  **ding 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 level. The developmental NOEL was**  **250 mg/kg. In the 2**  **- generation rat reproduction study, body weight ga**  **in 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 reproductive 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 pp m (=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 ob served at the**  **LOAEL of 2000 pp m**  **(127 -**  **133 mg/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,**  **increased liver weight and hepatocellular hypertrophy**  **. 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/carcinogenicity study in rats established a NOAEL**  **of 250 ppm**  **(9.81**

**– 11.37 mg/kg/day). Decreased mean body weight and decreased mean body** 4

**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 any 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 Cancer**  **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 metabolized 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 al**  **cohol). 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 hydr olysis and**  **demethylation of the methoxyimino 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 cha**  **racterized in plants, soil, and animals. In 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 s**  **tudies. 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**  **- ti**  **mes less cytotoxic than the parent compound. 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 no**  **t mutagenic to bacteria and are of low acute toxicity (LD50 >2000 mg/kg). In conclusion, the metabolism and toxicity profiles**  **support the use of an analytical enforcement method that accounts for parent trifloxystrobin**  **.** 8. Endocrine disruption

. **Trifloxystrobin does not belong 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 migh**  **t have any effects on endocrine function related to**5

**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 FCID Version 2. 14**  **, 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 trifloxy**  **strobin. These analyses cover all registered and**  **pending uses including the proposed use as a seed treatment in alfalfa , import**  **tolerances for globe artichokes and coffee, and the proposed tolerance increase for almond hulls from 3.0 to 9.0 ppm**  **. The EP** **A 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 developmental toxicity study and an uncertainty**  **factor or 100. The FQPA SF was reduced to**  **1 x b**  **ased on toxicological considerations by the FQPA Safety Factor Committee (HED Doc. No. 013545, B. Tarplee,**  **01/JUL/1999), the conservative residue assumptions used in the 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 reprod**  **ucti 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 fro**  **m the use of trifloxystrobin on currently registered uses**  **, proposed uses and the proposed**  **increase in the tolerance on almond hulls.**  i. Food. **For food, a Tier 1 acute**  **and chronic**  **dietary exposure assessments were performed. Acut**  **e exposure, expressed at the 95 th**  **percentile of exposure, was 1.4**  **% of the aPAD for**  **F emales 13**  **- 49 years old (only population subgroup of**  **concern). The chronic exposure was**  **3 1.1**  **% cPA** **D for the T**  **otal US P**  **opulation and 62.0**  **% cPAD for the most sensitive popu**  **lation, 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 estimates for**  **water are based on EPA’s surface water estimated environmental c oncentrations**  **(EECs) of trifloxystrobin and CGA -** **321113 for acute exposure and for chronic exposures at**  **48 ppb**  **and 47 ppb respectively as given in EPA’s Human Health Risk**  **Assessment for a Section 3 Petition Proposing Increased Tolerances for Residues in/on**  **Field, Sweet, and Pop Corn (February 25, 2010 , DP Barcode 369104**  **) .**  2. Non

- dietary exposure

. **The re is no potential for dermal or incidental oral**  **exposure during or post application of trifloxystrobin when applied to**  **almonds .**  **As**6

**suc h, non**  **- dietary expo**  **sure from this new tolerance**  **is 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 te rm 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 Regis ter (**  **FR Vol 73, no. 1, 02**  **- Jan**  **- 08)**  **), that unlike other 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 tr**  **ifloxystrobin 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 reasonable certainty that exposure from**  **trifloxystrobin will result in no**  **har m to the**  **infants and children .**  F. International Tolerances **In ternational**  **and CODEX tolerances (MRLs)**  **for trifloxystrobin are established**  **for many crops in**  **vari o**  **us countries.**  **CODEX MRLs are currently established for trifloxystrobin on almond hulls.**  **Trifloxystrobin MRLs are also established on almonds in Canada, Japan, and Taiwan.**