**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 PP# 3F8180**  EPA has received a pesticide petition **( PP#3F8180**  **)** 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 changing existing tolerance s for residues of **trifloxystrobin (** **b enzeneacetic acid, (E,E)**  **- α**  **- (methoxyimino)**  **- 2**  **- [[[[1**  **- [3**  **- (trifluoromethyl) phenyl]ethylidene]amino]oxy]methyl]**  **- methyl ester)**  **and the free form of its acid metab**  **olite CGA**

**– 321113**  **( (**  **E,E )**  **- methoxyimino**  **- [2**  **- [1**  **- (3**  **- trifluoromethyl**  **- phenyl)**  **- ethylideneaminooxymethyl]**  **- phenyl]acetic acid**  **)** in or on the raw agricultural commodity **[ pea, dry, seed**  **]** at **0.06** parts per million (ppm) ; **[pea, field**  **, hay]**  at **15** parts per million (ppm); **[ pea,**  **field , vines]**  at **4.0** parts per million (ppm); **[chickpea, seed]** at **0.06** parts per million (ppm) ; and **[lentil, seed]** at **0.06** 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 d ata 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 Chem istry 1. Plant metabolism

. **The metabolism of trifloxystrobin in plants (cucumbers,**2

**apples, wheat, sugar beets and peanuts) is well understood. Identified metabolic pathways are substantially similar in plants and animals (goat, ra**  **t 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 detecting and measur** **ing 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 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, an**  **d liquid chromatography/mass spectrometry** **- mass**  **spectrometry (LC/MS -**  **MS) with an electrospray interface, operated in the positive ion mode**  **. The**  **LOD s**  **for trifloxystrobin range from 0.00**  **2 ppm to 0.0**  **1 ppm**  **, depending on the crops,**  **and the LOQ**  **of each analyte is**  **0.01 ppm.** 3. Magnitude of residues. **Nine field -**  **residue trials (eight harvest, one decline) were established across Canada (three trials in Crop Growing Region 7, five in Crop Growing Region 14) and the**  **US (1 in Crop Growing Regions 7) where dry pea s are commonly grown. The**  **treated plot received two foliar spray applications of FOX 325 SC at 0.88 L FOX 325 SC/ha/application (286 g ai/ha/application) for a total target seasonal rate of 572**  **g ai/ha. FOX 325 SC active ingredient is comprised of 150 g tr ifloxystrobin/L and**  **175 g prothioconazole/L. The corresponding target rate for trifloxystrobin was 132 g trifloxystrobin/ha/application for a total seasonal rate of 264 g trifloxystrobin/ha.**  **The residue data from this study with dry peas is intended to su pport proposed**  **tolerances for dry peas, chickpeas and lentils. Dry pea vines (forage) and hay were collected at PHIs of 6 to 8 days in the eight**  **harvest trials and at 0, 3, 7, and 13 days in the single decline trial. Dry pea seed was collected at PHIs of**  **29 to 31 days in the harvest trials and at 20, 25, 31, 34, and 40 days in the decline trial. Vines, hay, and seed samples were collected from the**  **control plots at the same time the 7 day vine and pea and the 30 -**  **day seed samples were collected from the trea**  **ted plots. All samples were placed in frozen storage within 81⁄4 hours after collection. The samples were analyzed for residue of total**  **trifloxystrobin (sum of trifloxystrobin and trifloxystrobin acid). The residue of total trifloxystrobin was quantitated**  **by high -**  **pressure liquid chromatography/triple stage quadrupole mass spectrometry (LC/MS/MS) using stable**  **- labeled internal**  **standards. The limit of quantitation (LOQ) for total trifloxystrobin residue was 0.02 ppm for dry pea vines, hay, and seed.**  **Total tr ifloxystrobin residue in dry pea seed ranged from <0.020 ppm to a**  **maximum of 0.033 ppm for individual samples collected at the desired PHI of 30 days. The HAFT residue found in/on dry pea seed was 0.032 ppm.** 3

**Total trifloxystrobin residue in dry pea hay ra nged from 2.1 ppm to a maximum of**  **8.4 ppm for individual samples collected at the desired PHI of 7 days. The HAFT residue found in/on dry pea hay was 7.1 ppm.**  **Total trifloxystrobin residue in dry pea vines ranged from 0.58 ppm to a maximum of 2.3 ppm for**  **individual samples collected at the desired PHI of 7 days. The HAFT residue found in/on dry pea vines was 2.0 ppm.**  B. Toxicological Profile 1. Acute toxicity. **There is a full battery of acute toxicity studies for trifloxystrobin**  **. 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 finding was seen in the in v** **itro 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 visual**  **ly 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 nonspecific effect under non**  **- ph**  **ysiological 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 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 1000**  **mg/kg /day**  **. The developmental NOEL was 10 0**  **0 mg/kg** **/day .**  **In the rabbit developmenta l study, body weight loss and reduced food**  **consumption were observed in the dams at**  **50 mg/kg /day**  **, resulting in a maternal NOEL of 50**  **mg/kg /day**  **. 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** **/day . This finding is regarded**  **as a marginal effect on skeletal development that could have resulted from the 40 -**  **65% lower food intake during treatment at this dose level. T he developmental**  **NOEL was 250 mg/kg /day**  **. In the 2**  **- generation rat reproduction study, body weight gain and food**  **consumption were decreased at 750 ppm (55.3 mg/kg/day)**  **, especially in females during lactation. Consequently, the reduced pup weight gain durin**  **g lactation (750 ppm) and the slight delay in eye opening (1500 ppm**  **; 110.6 mg/kg/day )**  **were judged**  **to be a secondary effect of maternal toxicity. No other fetal effects or any**4

**reproductive changes were noted. The low developmental NOEL, 50 ppm ( 3.8**  **mg/kg /d**  **ay ) 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 p pm**  **(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 mg/kg/day). In mice, a**  **NOAEL was determined at 500 ppm (76.9 -**  **110 mg/kg/day) b ased 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 obse rved 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 1000 mg/kg/day**  **.** 5. Chronic toxicity. **A chronic feeding study in dogs established a NOAEL of 5**  **mg/kg /**  **day. The 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**  **at and above**  **t he 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**  **wei ght 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 o**  **f 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**5

**methoxyimin o 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 trifloxys trobin 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 trif luormethyl**  **** **phenyl moiety and other transformations, including methyl ester hydrolysis 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 characterized 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 ap**  **plied 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 meth**  **yl ester), has been evaluated in cultured rat hepatocytes and found to be 20**  **- times 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 t**  **hat these metabolites, including CGA -**  **357261, CGA**  **- 373466, and NOA**  **- 414412, are not mutagenic to bacteria and are of low acute**  **toxicity (LD 50**  **>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 rabb its and reproduction study in rats gave no indication**  **that trifloxystrobin might have any effects on endocrine function related 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. **Dietary risk assessments, using the DEEM -**  **FCID software Version 3.14 with USDA’s National Health and Nutrition Examination**  **Survey (NHANES) from 2003 to 2008 nationw ide continuing surveys of food intake**  **by individuals, 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 re gistered and pending uses**  **including the proposed uses on dry peas,**  **chickpeas and**  **lentils. A Tier 1 dietary assessment was evaluated based on established tolerances for all**  **registered uses and 100% crop treated. For the proposed use on dry peas,**  **chickpeas and**  **lentils , the proposed tolerance of 0.06 ppm was used in this assessment.** 6

**Chickpeas and dry peas can be used as alternative feedstuff serving as a source of roughage and protein. The proposed uses are not feed to feedlot beef. Addition of**  **the propos ed uses on feed items will have minimal effect on total burden for dairy**  **cattle. The current risk assessments are based on established livestock tolerances (milk = 0.02 ppm) which are more conservative than residues estimated from**  **Maximum Reasonably Balan ced Diets (MRBD).**  **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 developmental 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 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 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 populati on subgroup will result from the use of trifloxystrobin on currently**  **registered uses and**  **proposed uses on**  **dry peas, chickpeas**  **and lentils**  **.** i. Food. **For food, a Tier 1 acute**  **and chronic**  **dietary exposure assessments were performed.**  **Acute exposure for food only, expressed at the 95th percentile of exposure, was 1.3% of the aPAD for Females 13**  **- 49 years old (only population**  **subgroup of concern). The chronic exposure for food only was 27% cPAD for the Total US Population and 59% cPAD fo**  **r the most sensitive population, Children 1 -**  **2 years 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 concentrations**  **(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 Toler ances 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**  **dry peas, c**  **hickpeas and**  **lentils .**  **As suc h, non**  **- dietary exposure 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 term and intermediate term risk from residential**  **uses of trifloxystrobin**  **. The EPA determined that the risk did not exceed the**7

**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 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 to xic 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. **Acute and chronic dietary r isk estimates associated with**  **exposure to trifloxyst r**  **obin in food and water are expected to be well below the Agency's level of concern. The Tier I acute exposure analysis performed for all**  **currently registered and proposed food uses show that exposure to trifloxystrobin**  **utilizes 2% of the aPAD for Females 13 -**  **49 years old (only population subgroup of concern). The Tier I chronic exposure analysis performed for all currently**  **registered and proposed food uses show that exposure to trifloxystrobin utilizes 3**  **0% of the cPAD for the U.S. population and 62% of the cPAD for children 1**  **- 2 years old, the subpopulation at greatest exposure. This analysis was conducted**  **assuming 100% crop treated and tolerance level residue values for all crops. The contribution of t**  **rifloxystrobin residues in drinking water to acute and chronic aggregate exposure was minimal. Therefore, Bayer CropScience concludes that**  **even when considering the potential incremental risk resulting from the proposed use on**  **dry peas, chickpeas**  **and lent** **ils, there is a reasonable certainty that no harm will result from aggregate exposure to trifloxystrobin residues.**  2. Infants and children

. **No indication of increased susceptibility of rat or rabbit fetuses to in utero and/or postnatal exposure was no**  **ted in the developmental and reproductive toxicity studies. The Agency has previously determined that no**  **additional safety factor to protect infants and children is necessary for this product. Using the conservative assumptions described in the exposure**  **section above, aggregate exposure to trifloxystrobin from currently registered food uses will utilize**  **39% of cRfD for infants, and 62% of the cRfD for children 1 -**  **2 years old, the subpopulation at greatest exposure. Even when considering the potential**  **incr emental dietary risk resulting from the proposed use on chickpeas, lentils, and**  **dry peas, the potential for exposure to residues i n drinking water and from non**  **** **dietary, non -**  **occupational exposure, the aggregate exposure to trifloxystrobin is expected to be well below the level of concern. Bayer CropScience concludes that**  **there is a reasonable certainty that no harm will result to infa nts and children from**  **aggregate exposure to trifloxystrobin residues.** F. International Tolerances **In ternational**  **and CODEX tolerances (MRLs)**  **for trifloxystrobin are**8

**established for many crops**  **in vari**  **o us**  **countries. At this time, there are no**  **internat ional tolerances established for trifloxystrobin on dry pea, chickpea, or**  **lentil.**