EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 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 pes ticide 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 pesticide petition ( [insert petition number] ) from [ Bayer CropScience ] , [ 2 T.W. Alexander Drive, 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 by establi shing a tolerance for residues of [ penflufen , ( 1 H - Py razole- 4 - carboxamide, N - [2 - (1,3 - dimethylbutyl)phenyl] - 5 - fluoro - 1,3 - dimethyl-) ] in or on the raw agricultural commodities [ alfalfa , forage and hay ] at [ 0.01 ] parts per million (ppm), [cotton, gin byproducts ] at [ 0.01 ] ppm , [ canola, borage, crambe, cuphea, echium, flax seed, gold of pleasure, hare’s ear mustard, lesquerella, lunaria. m eadowfoam, milkweed, mustard seed, oil radish, poppy seed, rapeseed, sesame, swe et rocket, calendula, castor oil plant, Chin ese tallowtree, euphorbia, evening primrose, jojoba, niger seed, rose hip, safflower, stokes aster, sunflower, tallowwood, tea oil plant, vernonia, cottonseed ] at [ 0.01 ] ppm , [ grain, cereal, group 15 ] at [ 0. 01 ] ppm, [ grain, cereal, forage, fodder and straw , group 16 ] at [ 0.01 ] ppm , [vegetable, legume, group 06 ] at [ 0.01 ] ppm , [vegetable, foliage of legume, group 07 ] at [ 0.01 ] ppm , and [vegetable, tuberous and corm, subgroup 01C ] at [ 0.01 ] ppm . EPA has determined that the petition contains data or informati on 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 rul es on the petition. A. Residue Chemistry 1. Plant metabolism. [ Plant metabolism studies with penflufen were performed2

in wheat, soybeans and potatoes after seed treatments and on rice after soil treatment in the planting hole. In addition , metaboli sm studies were performed on corn, canola, cotton, sunflowers, succ ulent peas and beans , and alfalfa to determine the total radioactive residue (TRR) uptake of penflufen. Metabolism studies with penflufen in rotational crops were performed i n wheat, soybe ans, turnips and Swiss chard. The metabolism in all plants was very similar. The main reactions involved were hydroxylation at the 3 -position and conjugation of the hydroxyl group with glucose and malonic acid; conjugation with homoglutathione or glutath ione via substitution of the fluorine atom followed by metabolic degradation of the glutathione moiety; cleavage of the N-phenyl bond and of the c arboxamide bond; and N - demethylation and oxidation of the methyl group in the pyrazole moiety. ] 2. Analytical method. [ Tolerances are being proposed in primary crops solely for p enflufen . The analytical method involves solvent extraction, filtration, and addition of an isotopically labeled internal standard followed by acid hydrolysis . Quantitation is by hi gh performance liquid chromatography- electrospray ionization/tandem mass spectrometry (LC/MS/MS). ] 3. Magnitude of residues. [ Based on the results from the TRR studies, a reduced program of ma gnitude of the residue trials were conducted in the various required regions across the United States and Canada in accordance with guidance for crop field trials under OPPTS 860.1500 and DIR2003 - 02 (Harmonization of Regulation of Pesticide Seed Treatment in Canada and the United States) to support the requested to lerances. ] B. Toxicological Profile 1. Acute toxicity. [ Penflufen has very low acute toxicity to mammals irrespective of the route of exposure (oral, percutaneous or inhalation exposure). It is not a skin sensitizer, it is non -irritating to skin (Magnusson and Kligmann assay) and causes only a minimal reversible redness of the conjunctivae in the rabbit eye. Overall, it is classified as Toxicity Classification III. The oral LD 50 in rats is greater than 2000 mg/kg. The dermal LD 50 value in rats i s greater than 2000 mg/kg. The inhalation LC 50 for a four- hour exposure (nose only) is greater than 2022.5 g/m3

. No clinical signs nor body weight changes or necropsy findings were observed in the acute oral and dermal toxicity studies conducted in rats. In the acute inhalation toxicity study, clinical signs were occasionally observed with recovery within four days after exposure. In acute neurotoxicity studies , a NOAEL of 100 mg/kg and 50 mg/kg was established for males and females, respectively based on slight effects in measures of motor and locomotor activity. ] 2. Genotoxicty. [ Genotoxicity potential was evaluated in a series of tests including in vitro and in vivo tests. There was no indication of gene mutation either in the presence or absence of metabolic activation in both the bacterial reverse mutation and mammalian gene mutation tests. The in vitro chromosome aberration test and the in vivo mouse micronucleus test were also both negative. These studies3

demonstrate that penflufen has no gen otoxic potential. ] 3. Immunotoxicity. [ Immunotoxicity potential was evaluated in a four week study in rats. Determination of cell counts in the spleen and performance of the plaque f orming assay showed no evidence for treatment- related effects at any dos e. T he high dose of 7000 ppm (755.6 mg /kg bw/day in males and of 960.5 mg /kg bw/day in females) was determined to be the NOEL for immunotoxicity for both males and females. Pen flufen is therefore, not considered to be immunotoxic ] 4

. Reproductive and developmental toxicity. [ In the rat two - generation reproduction study, the parental systemic NOAEL was 1000 ppm (64.1 mg/kg/day in males, 75.9 mg/kg/day in females) based on decreased body weight, decreased body weight gain, alterati ons in food consumption, increased liver weight with associated hepatocellular hypertrophy, and decreased thymus weight in both genders, as well as, decreased terminal body weight and spleen weights in f emales. The reproductive NOAEL wa s 1000 ppm for the f emales (73.4 mg /kg bw/day) based on a slight decrease in litter size in both the P and F 1 - generations. Fo r males the NOAEL was greater than 4000 ppm in males (>338.6 mg /kg bw/day) based on no reproductive findings observed at the highest dose tested. T he offspring NOAEL was 1000 ppm (72.5 mg /kg bw/day) based on maternal effects leading to secondarily- mediated effects on pup weight, pup weight gain, delayed vaginal patency and balanopreputial separation and organ weight changes (brain and spleen). In a rat developmental toxicity study, the maternal NOAEL was 30 mg/kg/day, based on reduced body weight gain, and liver changes. The fetal NOAEL was 300 mg/kg/day based on no findings obse rved at the highest dose tested . In a rabbit developmental toxicity s tudy, the NOAEL was 100 mg/kg/day both in the dam (decreased body weight gain and reduced food consumption ) and in terms of fetal development ( decreased fetal body weight) in the New Zealand White rabbit. ]
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. Subchronic toxicity. [ Subchronic studies s howed that the liver is the major t arget organ in rats and dogs. In addition to the liver, the kidney (males) was also a target organ in rats. In the male rat, specific nephropathy (hyaline droplet neph ropathy) was observed. In mice , n o effects were obs erved at the highest dose tested. The dog was the most sensitive species followed by the rat with the mouse being the least sensitive. Overall, the lowest NOAEL was observed in the subchronic dog study. In this study, the NOAEL for the dog was establish ed at 5.6 and 6.1 mg/kg bw/day in males and females, respectively. However, the NOAEL in the dog was based on doses which each varied by an order of magnitude. The LOAELs established in the subchronic dog and chronic dog studies were both based on the sa me endpoints of increase d liver weights and hepatocellular hypertrophy and the NOAEL of 1000 ppm established in the chronic dog toxicity study was between the do ses for establishing the NOAEL of 180 ppm and the LOAEL of 1800 ppm in the subchronic dog stu dy. Therefore, relevant subchronic NOAEL of 32 mg/kg/day was established from the chronic dog toxicity study. This NOAEL is also comparable with the maternal NOAEL of 30 mg/kg/day in the rat developmental4

toxicity study. In a 90 - day neurotoxicity study at 0, 250, 2000 and 8000 ppm, no evidence of neurotoxicity was observed at any treatment level. Treatment- related findings of general toxicity at the high - dose consisted of decreased body weight, total body weight gain and food consumption in males and fe males and decreased terminal body weight in females. Also, liver weights were increased in high - dose males and females. Treatment- related findings in mid - dose males and females included increases in liver weights (absolute and/or relative) and decreased food consumption in females, with no corresponding effect on body weight. Based on neurotoxicology endpoints, a NOAEL of 8000 ppm was established for males and females (516.0 and 608.8 mg/kg for male and female rats, respectively). In a four week dermal toxicity study in rats, a NOAEL of 300 mg/kg/day was established based on increased lymphocyte debris within the thymic cortices of the 1000 mg/kg males and females. ] 6

. Chronic toxicity. [ In the rat, at the end of the combined chronic toxicity and ca rcinogenicity study, treatment- related macroscopic findings consisted of enlarged liver and white focus in the liver in females only. At the microscopic examination, in the liver, a higher incidence of centrilobular to panlobular hepatocellular hypertrophy and of centrilobular hepatocellular macrovacuolation was observed in both sexes. In females, a higher incidence of hepatocellular brown pigments was also noted. A higher incidence of colloid alteration in the thyroid gland was observed in females only. There was no evidence of a treatment- related increased incidence of tumors of any type in any organ. Penflufen is thus considered not to be carcinogenic in the rat after a 104 week treatment period. The NOAEL over a carcinogenic (24 month) period of di etary administration of penflufen to the rat was 100 ppm in both sexes (equivalent to 4.0 mg/kg/day weight/day in males and 5.6 mg/kg body weight/day in females). In a mouse carcinogenicity study, the target organs were the liver and thyroid gland. The p rincipal changes noted in the liver were increased liver weights associated with higher incidence and/or severity of diffuse centrilobular hepatocellular hypertrophy in both sexes. In females a higher severity of hepatocellular vacuolation and higher inci dence and severity of diffuse mainly periportal hepatocellular macrovacuolation was also observed. In addition, a higher incidence and severity of follicular cell hyperplasia in the thyroid gland was noted in 38/50 females compared to 23/50 females in the control group. No treatment- related neoplastic changes were observed at any dose level tested in either sex. The NOAEL in the mouse was established at 1000 ppm in both sexes (equating approximately to 146 mg/kg body weight/day for males and 182 mg/kg bo dy weight/day). ]

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. Animal metabolism. [ In the rat, penflufen is rapidly and almost completely absorbed (>96% of the dose in a bile fistulation experiment) following oral5

administration by gavage. Penflufen was extensively metabolized with unchanged parent compound found only in low percentages of the recovered dose. The metabolism of penflufen in male and female rats was similar and included N demethylation in the pyrazole ring, hydroxylation and extensive oxidation. Some cleavage of the rings was observed as was conjugation of several hydroxylated metabolites with glucuronic acid and cysteine . In ruminants and poultry, penflufen was also extensively metabolized. P enflufen residues do not accumulate i n animal tissues, milk or eggs. ] 8

. Metabo lite toxicology

. [Not applicable as parent is the compound of concern. ]

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. Endocrine disruption

. [ There is no evidence to suggest that penflufen has any primary endocrine disruptive potential. Reproductive and developmental findings provided no evide nce of an enhanced sensitivity of the young. Bayer CropScience will conduct any studies that may be required under EPA’s Endocrine Disrupter Screening Program. ] C. Aggregate Exposure 1. Dietary exposure. [ The toxicological and exposure database for penflufen is considered complete. There was no indication of an increased sensitivity of the young in any studies including the reproductive and developmental studies in rats and rabbits. Therefore, the special FQPA can be reduced to 1X and an uncertain ty factor of 100 is adequate to account for inter- and intra- species variability. Acute and chronic Population Adjusted Doses (aPAD and cPAD) are, therefore, the same as the reference doses for the populations and subpopulations of interest. Acute dieta ry exposure was expressed as a percentage of the aPAD of 0.5 mg/kg bw/day from a NOAEL of 50 mg/kg bw/day establis hed for females, based on slight effects on measures of motor and locomotor activity in the acute neurotoxicity study in rats, with an uncertainty factor of 100. Chronic dietary exposure was expressed as a percentage of the chronic Population Adjusted Dose (cPAD) of 0.04 mg/kg bw/day based on a NOAEL of 4 mg/kg bw/day in the rat chronic/oncogenicity study in rats with an uncertainty factor of 1 00 . ] i. Food. [ Tier 1 acute and chronic dietary risk assessments were conducted to evaluate the dietary exposure of the U.S. population and selected subpopulations to penflufen residues. This assessment i ncludes all proposed primary crops and inadvert ent or rotational crop residues. Penflufen residues in tissues and milk were not included in the assessment because of negligible residues in the animal feed items. The assessment assumed 100% of the crops were treated. The Tier 1 acute and chronic asse ssments were conducted using DEEM-FCIDTM, Version 2.14 software. Consumption data used in this program were taken from USDA’s CSFII, 1994 - 1996, 1998. With these conservative assumptions, a cute exposure (9 5 th percentile) for food only utilizes 0.1 % of the aPAD for the US Population an d 0.2 % for Children 1 - 2, the most highly exposed subpopulation. Chronic exposure for6

food only utilizes 0.4 % of the cPAD for the US Population and 0.7 % of the cPAD for Children 1 -2, the most highly exposed subpopulation .] ii. Drinking water

. [ Estimate d Drinking Water Concentrations (EDWCs) from ground water and surface water sources were calculated for the residues of penflufen and the major environmental metabolites BYF 14182 -3 - hydroxybutyl and BYF 14182 -pyrazolyl-AAP, resulting from penflufen use on potatoes, wheat, corn, beans, soybeans, canola, sunflowers, cotton, alfalfa, and rice. Except for rice, PRZM (Version 3.12.2; May 2005 )/EXAMS (Version 2.98.04.06; April 2005 ) and SCI - GROW (Version 2.3, July 28, 2003 ) were used to calculate surface water a nd ground wat er concentrations, respectively . F or rice , the RICE Water Quality (RICEWQ Version 1.7.3; 2010 ) model was used to refine Tier I rice model estimate which significantly overestimate s water exposure, especially for seed treatment. The highest g round water concentration was 0.23 μg/L from the potato use (160 g a.i./ha). Concentrations resulting from seed treatment uses (< 10 g a.i./ha) were significantly lower. Overall, the highest potential drinking water concentrations were estimated from surface water with an acute concentration of 0.95 μg/L and a chronic concentration of 0.34 μg/L from the Maine potato scenario. D rinking water did not significantly increase dietary exposure. The incorporation of the EDWC of 0.95 μg/L into an acute exposure assessment resulted in the U.S. adult population utilizing 0.1% of the aPAD and Children 1 -2, the most highly exposed subpopulation , utilizing 0.2% of the aPAD . The addition of the chronic EDWC of 0.34 μg/L resulted in the U.S. adult population utilizing 0. 5 % of the cPAD and Children 1 - 2, the most highly exposed subpopulation , utilizing 0.7 % . In conclusion, the results of the very conservative acute and chronic dietary exposure analyses (including food and drinking water) demonstrates that penflufen expo sure consumes a very small percentage of the risk cup for all scenarios and population subgroups examined. Therefore, there is a reasonable certainty that no harm will result from exposure to potential residues of penflufen in food and water . ]

2. Non

- dietary exposure

. [ Based on the use patterns non - dietary exposure to penflufen is not anticipated. D. Cumulative Effects [ Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consid er “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity.” Penflufen is a novel su ccinate- dehydrogenase inhibitor (SDHI). EPA has not made a common m echanism of toxicity finding as to penflufen and any other substances and penflufen does not appear to produce a toxic metabolite produced by other substances .]7

E. Safety Determination 1. U.S. population. [ Risk assessments for penflufen are based on a complete and reliable toxicity data package and highly conservative assumptions. C hronic aggregate dietary exposure (food and water) utilize s 0.5% of the cPAD for the US Population . Acute aggregate dietary exposure (food and water) for the U.S. a dult population utilizes 0.1% of the aPAD. Non - dietary exposure of the U.S. population to penflufen is not anticipated. Therefore, there is a reasonable certainty that no harm will occur to the US Populatio n from aggregate exposure (food and drinking water) to residues of penflufen .] 2. Infants and children

. [ The toxicological and exposure database for penflufen is considered complete. There was no indication of an increased sensitivity of the young in any studies including the reproductive and developmen tal studies in rats and rabbits. Therefore, the special FQPA can be reduced to 1X and an uncertainty factor of 100 is adequate . Based on conservative assumptions, c hronic aggregate dietary exposure (food and water) utilizes 0.7 % of the cPAD for Children 1 -2, the most highly exposed subpopulation. Acute aggregate dietary exposure (food and water) utilizes 0.2% of the aPAD for Children 1 - 2, the most highly exposed subpopulation . Non - dietary exposure of children to penflufen is not anticipated. Therefore, there is a reasonable certainty that no harm will occur to infants and children f

rom aggregate exposure (food and drinking water) to residues of penflufen .] F. International Tolerances [No tolerances have been established for penflufen. Penflufen is being reviewed as an OECD Joint Review among the U.S. , Canada and Australia. In the EU , tolerances are also being applied for in potatoes. Harmonized tolerances are being proposed to minimize trade barriers between the participating regions.]