EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGIST ER

EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS: Please utilize this outline in preparing the pest icide petition. In cases where the outline element does not apply, ple ase insert “NA-Remove” and maintain the outline. Please do not change the marg ins, 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 pesticide petition ([insert petition number]) from [Bayer CropScience], [2 T.W. Alexander Drive, Research Tri angle Park, NC 27709] proposing, pursuant to section 408(d) of the Federa l Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 18 0 by establishing a tolerance for

residues of [penflufen, (1 H -Pyrazole-4-carboxamide, N -[2-(1,3- dimethylbutyl)phenyl]-5-fluoro-1,3-dimethyl-)] in or on the raw agricultural

commodities [sugar beet, root ] at [0.01] parts per million (ppm)

. EPA has determined that the petition contains data or information rega rding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully ev aluated the sufficiency of the submitted data at this time or whether the data sup ports granting of the petition. Additional data may be needed before EPA rules on t he petition.

A. Residue Chemistry

1. Plant metabolism. [Plant metabolism studies with penflufen were perf ormed in wheat, soybeans and potatoes after seed treatmen ts and on rice after soil treatment in the planting hole. In addition, metab olism studies were performed on corn, canola, cotton, sunflowers, succulent peas an d beans, alfalfa and sugar beets to determine the total radioactive residue (TRR) uptak e of penflufen after seed treatment. Metabolism studies with penflufen in ro tational crops were performed in wheat, soybeans, turnips and Swiss chard. The meta bolism in all plants was very similar. The main reactions involved were hydroxyl ation at the 3-position and conjugation of the hydroxyl group with glucose and malonic acid; conjugation with homoglutathione or glutathione via substitution of the fluorine atom followed by2

metabolic degradation of the glutathione moiety; cl eavage of the N-phenyl bond and of the carboxamide bond; and N-demethylation and ox idation of the methyl group in the pyrazole moiety.]

2. Analytical method. [Tolerances are being proposed in primary crops sol ely for penflufen. The analytical method involves solv ent extraction, filtration, and addition of an isotopically labeled internal standa rd followed by acid hydrolysis. Quantitation is by high performance liquid chromato graphy-electrospray ionization/tandem mass spectrometry (LC/MS/MS).]

3. Magnitude of residues. [Based on the results from the TRR study in sugar beets, residue field trials were not required in ac cordance with guidance for crop field trials under OPPTS 860.1500 and DIR2003-02 (H armonization of Regulation

of Pesticide Seed Treatment in Canada and the Unite d States) to support the requested tolerance.]

B. Toxicological Profile

1. Acute toxicity. [Penflufen has very low acute toxicity to mammals irrespective of the route of exposure (oral, percut aneous or inhalation exposure). It is not a skin sensitizer, it is non-irritating to s kin (Magnusson and Kligmann assay) and causes only a minimal reversible redness of the conjunctivae in the rabbit eye. Overall, it is classified as Toxicity Classificatio n III. The oral LD 50 in rats is greater than 2000 mg/kg. The dermal LD 50 value in rats is greater than 2000 mg/kg. The

inhalation LC 50 for a four-hour exposure (nose only) is greater th an 2022.5 g/m 3 . 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 ob served with recovery within four days after exposure. In acute neurotoxicity studie s, a NOAEL of 100 mg/kg and 50 mg/kg was established for males and females, respec tively based on slight effects in measures of motor and locomotor activity.]

2. Genotoxicty. [Genotoxicity potential was evaluated in a series o f tests including in vitro and in vivo tests. There was no indication of gene mutation e ither 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 studies demonstrate that penflufen has no genotoxic potenti al.]

3. Immunotoxicity. [ Immunotoxicity potential was evaluated in a four we ek study in rats. Determination of cell counts in the spleen and performance of the plaque forming assay showed no evidence for treatme nt-related effects at any dose. The high dose of 7000 ppm (755.6 mg /kg bw/day in m ales and of 960.5 mg /kg bw/day in females) was determined to be the NOEL fo r immunotoxicity for both males and females. Penflufen is therefore, not con sidered to be immunotoxic]3

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 decre ased body weight, decreased body weight gain, alterations in food consumption, increased liver weight with associated hepatocellular hypertrophy, and decrease d thymus weight in both genders, as well as, decreased terminal body weight and spleen weights in females. The reproductive NOAEL was 1000 ppm for the females (73.4 mg /kg bw/day) based on a slight decrease in litter size in both the P a nd F 1 -generations. For 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. The offspring NOAEL was 1000 ppm (72.5 mg /kg bw/day) based on maternal effects leading to secondarily-mediated effects on pup weight, pup wei ght gain, delayed vaginal patency and balanopreputial separation and organ we ight changes (brain and spleen). In a rat developmental toxicity study, th e maternal NOAEL was 30 mg/kg/day, based on reduced body weight gain, and l iver changes. The fetal NOAEL was 300 mg/kg/day based on no findings observ ed at the highest dose tested. In a rabbit developmental toxicity study, the NOAEL was 100 mg/kg/day both in the dam (decreased body weight gain and red uced food consumption) and in terms of fetal development (decreased fetal body we ight) in the New Zealand White rabbit.]

5. Subchronic toxicity. [Subchronic studies showed that the liver is the ma jor target 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 ne phropathy (hyaline droplet nephropathy) was observed. In mice, no effects wer e observed at the highest dose tested. The dog was the most sensitive species fol lowed by the rat with the mouse being the least sensitive. Overall, the lowest NOA EL was observed in the subchronic dog study. In this study, the NOAEL for the dog was established at 5.6 and 6.1 mg/kg bw/day in males and females, respecti vely. 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 chroni c dog studies were both based on the same endpoints of increased liver weights an d hepatocellular hypertrophy and the NOAEL of 1000 ppm established in the chroni c dog toxicity study was between the doses for establishing the NOAEL of 18 0 ppm and the LOAEL of 1800 ppm in the subchronic dog study. Therefore, releva nt subchronic NOAEL of 32 mg/kg/day was established from the chronic dog toxi city study. This NOAEL is also comparable with the maternal NOAEL of 30 mg/kg/day in the rat developmental 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 decr eased body weight, total body weight gain and food consumption in males and femal es and decreased terminal body weight in females. Also, liver weights were i ncreased in high-dose males and females. Treatment-related findings in mid-dose ma les and females included increases in liver weights (absolute and/or relativ e) and decreased food consumption4

in females, with no corresponding effect on body we ight. 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 NOA EL of 300 mg/kg/day was established based on increased lymphocyte debris wi thin the thymic cortices of the 1000 mg/kg males and females.]

6. Chronic toxicity. [In the rat, at the end of the combined chronic tox icity and carcinogenicity study, treatment-related macroscopi c 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 p anlobular hepatocellular hypertrophy and of centrilobular hepatocellular mac rovacuolation was observed in both sexes. In females, a higher incidence of hepa tocellular brown pigments was also noted. A higher incidence of colloid alterati on 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. Penf lufen 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 dietary administr ation 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 principal changes noted in the liver we re increased liver weights associated with higher incidence and/or severity of diffuse centrilobular hepatocellular hypertrophy in both sexes. In femal es a higher severity of hepatocellular vacuolation and higher incidence and severity of diffuse mainly periportal hepatocellular macrovacuolation was also observed. In addition, a higher incidence and severity of follicular cell hyperplas ia in the thyroid gland was noted in 38/50 females compared to 23/50 females in the cont rol 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 se xes (equating approximately to 146 mg/kg body weight/day for males and 182 mg/kg b ody weight/day).]

7. Animal metabolism. [In the rat, penflufen is rapidly and almost comple tely absorbed (>96% of the dose in a bile fistulation ex periment) following oral administration by gavage. Penflufen was extensivel y metabolized with unchanged parent compound found only in low percentages of th e recovered dose. The metabolism of penflufen in male and female rats wassimilar and included Ndemethylation in the pyrazole ring, hydroxylation a nd extensive oxidation. Some cleavage of the rings was observed as was conjugati on of several hydroxylated metabolites with glucuronic acid and cysteine. In ruminants and poultry, penflufen was also extensively metabolized. Penflufen residu es do not accumulate in animal tissues, milk or eggs. ]5

8. Metabolite toxicology

. [Not applicable as parent is the compound of

concern.]

9. Endocrine disruption

. [There is no evidence to suggest that penflufen has any primary endocrine disruptive potential. Reprod uctive and developmental findings provided no evidence of an enhanced sensit ivity of the young. Bayer CropScience will conduct any studies that may be re quired under EPA’s Endocrine Disrupter Screening Program.]

C. Aggregate Exposure

1. Dietary exposure. [The toxicological and exposure database for penflu fen 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 re duced to 1X and an uncertainty factor of 100 is adequate to account for inter- and intra- species variability. Acute and chronic Population Adjusted Doses (aPAD and cPA D) are, therefore, the same as the reference doses for the populations and subp opulations of interest. Acute dietary exposure was expressed as a percentage of t he aPAD of 0.5 mg/kg bw/day from a NOAEL of 50 mg/kg bw/day established for fem ales, 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 d ietary 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 chron ic/oncogenicity study in rats with an uncertainty factor of 100.]

i. Food. [Tier 1 acute and chronic dietary risk assessments were conducted to evaluate the dietary exposure of the U.S. populatio n and selected subpopulations to penflufen residues. This assessment includes all p roposed primary crops and inadvertent or rotational crop residues. Penflufen residues in tissues and milk were not included in the assessment because of negligibl e residues in the animal feed items. The assessment assumed 100% of the crops we re treated. The Tier 1 acute and chronic assessments were conducted using DEEM-F CIDTM, Version 4.02 software. Consumption data used in this program we re taken from NHANES 2-day food consumption data for 2005-2010. With these co nservative assumptions, acute exposure (95th percentile) for food only utilizes 0 .19% of the aPAD for the US Population and 0.69% for all infants, the most high ly exposed subpopulation. Chronic exposure for food only utilizes 0.10% of th e cPAD for the US Population and 0.36% of the cPAD for all infants, the most hig hly exposed subpopulation.]

ii. Drinking water. [Estimated Drinking Water Concentrations (EDWCs) from ground water and surface water sources were us ed as reported in the “Tier I Drinking Water Exposure Assessment for the New Chem ical Registration of Penflufen (DP # 386698)” for the residues of penflu fen 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,6

cotton, alfalfa, and rice. The screening model FIR ST (FQPA Index Reservoir Screening Tool, version 1.1, 01/01/07) was used to calculate the surface water EDWCs. Estimated groundwater EDWCs were calculated using the screening model SCI-GROW (Screening Concentrations in Ground Water, version 2.3,07/29/03). The highest EDWC (16.6 ppb) resulte d from the application of penflufen to potatoes and was used in both the acut e and chronic dietary assessments.]

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 consi dering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular p esticide’s residues and “other substances that have a common mechanism of toxicity .” Penflufen is a novel succinate-dehydrogenase inhibitor (SDHI). EPA has not made a common mechanism of toxicity finding as to penflufen and a ny other substances and penflufen does not appear to produce a toxic metabo lite produced by other substances.]

E. Safety Determination

1. U.S. population. [Risk assessments for penflufen are based on a comp lete and reliable toxicity data package and highly conse rvative assumptions. Chronic aggregate dietary exposure (food and water) utilize s 0.10% of the cPAD for the US Population. Acute aggregate dietary exposure (food and water) for the U.S. adult population utilizes 0.19% 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 Population from aggregate exposure (food and drinking water) to residues of penflufen.]

2. Infants and children

. [The toxicological and exposure database for penflu fen 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 re duced to 1X and an uncertainty factor of 100 is adequate. Based on conservative a ssumptions, chronic aggregate dietary exposure (food and water) utilizes 0.36% of the cPAD for all infants, the most highly exposed subpopulation. Acute aggregate dietary exposure (food and water) utilizes 0.64% of the aPAD for all infants, 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 from aggregate exposure (food and drinking water) to residues of penflufen.]7

F. International Tolerances

[Tolerances in alfalfa forage and hay, tuberous an d corm vegetables (CSG 1C), grain, legume vegetables (CG 6), foliage of le gume vegetables (CG7), cereal grain (CG 15), cereal grain, forage, fodder and str aw (CG 16), oilseeds(CG 20) and cotton gin by-products have been established in the US and Canada at 0.01 ppm for

all commodities. Australia has established maximum residue limits in cereal grains, cotton seed, potatoes, rape seed, milk, eggs and ed ible offal and meat of poultry and mammals at 0.01 ppm for all commodities. In the EU , tolerances have been approved in potatoes at 0.01 ppm. Tolerances in su gar beets are being proposed to minimize trade barriers between the participating r egions.]