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**EPA REGISTRATION**  **DIVISION COMPANY**  **NOTICE OF**  **FILING FOR**  **PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA**  **Registration Division contact:**  **Erin Malone, 703 -** **347 -**  **0253 TEMPLATE:**  **Cheminova, Inc. P# 4G8247**  EPA has received a pesticide petition **( P#4G8247** **)** from **Cheminova, Inc.**  **, 1600**  **Wilson Blvd.,**  **Suite 700,**  **Arlington, VA**  **22209 -** **2510** 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 e stabl ishing a temporary tolerance for residues of **Flutriafol** in or on the raw agricultural commodity **corn, sweet,**  **kernel plus**  **cob with**  **husks removed**  at **0.01** parts per million (ppm); **corn, sweet,**  **forage** at **5** parts per million (ppm) ; **corn, s** **weet, stover**  at **15** 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 o f the submitted data at this time or whether the data supports granting of the petition. Additional data may b e needed before EPA rules on the petition. A. Residue Chemistry **1.** Plant metabolism. The nature of the residue in plants is adequately understood. The major residue in apples, oilseed rape, sugar beet and cereals treated with flutriafol is the parent compound.

2. Analytical method. Adequate enforcement analytical methods for determining flutriafol in/on appropriate raw agricultural commodities and processed commodities are available for the estab lished and proposed tolerances. 3. Magnitude of residues. Crop Field Trials There are no available residue data for sweet corn . The proposed maximum use rate for flutriafol on sweet corn is the same as the currently registered use rate on field corn and p opcorn. Consequently, Cheminova believes that the field corn data are applicable to this petition and support the proposed2 temporary

tolerance for sweet corn at the same level. For example, the existing tolerance for corn, field, grain is 0.01 ppm (which corresponds to the LOQ). Field trial data have been generated for flutriafol and three triazole metabolites on field corn. Twenty trials were conducted in major field corn growing regions during the 2009 growing season. Two decline trials were conducte d, and data on field corn processed commodities were provided from one site. The LOQ and LOD for flutriafol in corn matrices were 0.01 ppm and 0.003 ppm, respectively. Results from the decline trials show that flutriafol residues were <LOQ (<0.01 ppm) in all grain samples collected at each of the five sampling intervals, up to 21 days after the last application (DALA). Field corn commodity and processed samples were also analyz ed for the three metabolites, 1,2,4

-triazole (T), triazole alanine (TA), and triazole acetic acid (TAA). The LOQ for each metabolite was 0.01 ppm. No residues of metabolites T and TAA >LOQ were found in treated grain, whereas TA residues ranged from <LOQ to 0.112 ppm. For dietary

exposure assessment, EPA has concluded that the residues of concern in field corn and popcorn consist of flutriafol (free and conjugated) and defluorinated flutriafol. T otal residues of concern are estimated by multiplying the measured parent flutriafol residue by a factor of 2.2X. B. Toxicological Profile 1. Acute toxicity. The acute oral LD50 is 1140 mg/kg bw and 1480 mg/kg bw in male and female rats, respectively. The acute dermal LD50 of flutriafol is >2000 mg/kg bw in rats. The acute inhalation LC 50 in rats is >5.20 mg/L. Flutriafol displayed mild eye irritation in rabbits. Iti s not a skin irritant to rabbits. Flutriafol is not a skin sensitizer. 2. Genotoxicty. Flutriafol was evaluated for possible mutagenic/genotoxic effects in in vitro and in vivo test systems. In these studies flutri afol was not mutagenic in either bacterial or mammalian cells at concentrations that were not highl y cy totoxic in the presence and absence of metabolic activation in vitro. No clastogenic potential in in vitro and in vivo cy togenetic studies was demonstrated, and no induction of forward mutations was observable in vitro. Furthermore, flutriafol did not induce unscheduled DNA sy nthesis in vivo, and no clastogenicity

was observable in germ cells of mice. Overall, the data indicate that flutriafol has no genotoxic/mutagenic potential in vitro and in vivo.3

Inthree genotoxicity

studies flutriafol was not mutagenic in either bacterial or mammalian cells at concentrations that were not highly c ytotoxic in the presence and absence of metabolic activation in vitro. No clastogenic potential in the in vitro chromosome aberration study w as demonstrated. These results are consistent with the conclusions of the originally submitted genotoxicity studies. 3. Reproductive and developmental toxicity. A two
- generation reproductive toxicity study in rats was conducted with flutriafol at doses of 0, 60, 240 or 1000 ppm in the diet. The parental NOAEL was 240 ppm (calculated by EPA to be 20.6 mg/kg bw/day in males and 21.9 mg/kg bw/day

in females) based on reduced body w eight gain and food consumption, and effects on the liver (increased liver weights, centrilobular hy pertrophy and fatty changes). The NOAELf or developmental and reproductive toxicity

was 240 ppm (20.6 mg/kg bw/day f or males and 21.9 mg/kg bw/day

f or females) based on reduced litter sizes and effects on the liver (fatty change/vacuolation). Ina s econd two
- generation reproduction study, flutriafol was administered to groups of rats at concentrations of 0, 30, 80, 150 and 300 ppm in the diet. In the P and F1 parental generations, dietary exposure to flutriafol resulted in centrilobular hepatocellular hy pertrophy at 300 ppm. These findings correlated with increased liver to body w eight ratios in P parental animals, which are indicative of an adaptive change to meta bolic activation by a xenobiotic and not a toxic response due to the administration of flutriafol. At 150 ppm, 80 ppm and 30 ppm, no test item

-related effects were noted. There were no treatment
-related differences in reproductive parameters between treated animals and controls. There were no treatment
-related differences in litter parameters between treated groups and controls. Based on these results, 300 ppm (15.6 mg/kg bw/day f or males and 20.7 mg/kg bw/day for females) is the NOAEL for parental toxicity and is the NOEL for effects on reproductive function. The NOEL for parental toxicity i s 150 ppm. The results of this new study c onfirm the earlier study that flutriafol is not a reproductive toxicant to rats. In the rat developmental toxicity study, flutriafol was orall y administered at doses of 0, 2, 5, 10 or 75 mg/kg bw/day

. The maternal toxicity NOAELwas 10 mg/kg bw/day

b ased on reduced body

weight gain and food consumption. The developmental toxicity NOAEL was 10 mg/kg bw/day based on increased late resorptions and specific malformations/variations, including hyoid arch absent, interrupted, and/or misshapen. Inthe rabbit developmental study, flutriafol was administered at doses of 0, 2.5, 7.5 or 15 mg/kg bw/day

. The NOAELf or maternal toxicity

w as 7.5 mg/kg bw/day

based on reduced body

weight gain and food consumption. The4
NOAEL for developmental toxicity w as 7.5 mg/kg bw/day b ased on an increase in post
- implantation losses and a reduction in the number of viable fetuses. Flutriafol is neither a reproductive nor developmental toxicant in the absence of paternal/maternal toxicity

. 4. Subchronic toxicity. The short

-term toxicity

o f flutriafol was investigated in several subchronic studies including a 90

- day f eeding study

in rats and a 90

- day

study in dogs. A 28

- day dermal toxicity

study in rats was also performed. The 90

- day

rat feeding study

w as conducted with dietary c oncentrations of 0, 20, 200 or 2000 ppm. The NOAEL of 200 ppm (14 mg/kg bw/day f or males and 22 mg/kg bw/day

f or females) was based on decreased body weight gain and food consumption and liver toxicity (increased absolute and relative liver weights, increased endoplasmic reticulum proliferation in the male rats and increased APDM activity). Inthe 90

- day

study in dogs, flutriafol was administered at concentrations of 0, 1, 5 or 15 mg/kg bw/day

via capsule. The NOAEL was 5 mg/kg bw/day based on reduced body

w eight gain in females, changes in hematology and clinical chemistry p arameters in both sexes, and effects in the livers of males and females and in the spleens of the males at the 15 mg/kg bw/day

. In the 28

- day

dermal toxicity

study in rats, there was no evidence of systemic toxicity and the NOAEL was >1000 mg/kg bw/day

. 5. Chronic toxicity. A one - ye ar oral study

in the dog was conducted at concentrations of 0, 1, 5 or 20 mg/kg bw/day

. The NOAEL was 5 mg/kg bw/day b ased on adverse liver findings (increased liver weights, increased lipid content of hepatocy tes, and increased alkaline phosphatase, albumin and triglycerides), increased adrenal cortical vacuolation of the zona fasciculate, and increased hemosiderin deposition in the spleen and liver of both sexes; decreased body weight gain, and increased adrenal weights in females. In a two
- ye ar chronic toxicity and oncogenicity

study, flutriafol was administered in the diet to rats at doses of 0, 20, 200 or 2000 ppm. The NOAEL was 200 ppm (calculated by EPA to be 10.0 mg/kg bw/day in males and 12.2 mg/kg bw/day in females) based on reduced body w eight, body weight gain, and food consumption in both sexes and adverse liver effects (increased liver weights, fatty change, bile duct proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer cells and centrilobular hy

pertrophy) and clinical chemistry f indings. There was no evidence of carcinogenicity in this study

.5
Ina two - ye ar oncogenicity

study, flutriafol was administered in the diet to mice at doses of 0, 10, 50 or 200 ppm. The NOAELw as 50 ppm (calculated by EPA to be 5.9 mg/kg bw/day in males and 7.4 mg/kg bw/day in females) based on reduced body

weight and body

w eight gain in males and females, increased liver weight, and hepatocellular hy pertrophy and centrilobular fatty change in the liver. There was no evidence of carcinogenicity in this study. 6. Neurotoxicity

. In an acute neurotoxicity study, rats were administered flutriafol by gavage at doses of 0, 125, 250 or 750 mg/kg bw. EPA concluded that the systemic NOAEL was 250 mg/kg bw based on decreased body weight gain and food consumption and clinical signs of toxicity indicative of a moribund condition. The neurotoxicity

NOAEL was >750 mg/kg bw. In a subchronic neurotoxicity study, flutriafol was administered in the diet to rats at doses of 0, 500, 1500 or 3000 ppm. The systemic NOAEL was 1500 ppm (84.3 mg/kg bw/day in males and 97.6 mg/kg bw/day in females) based on decreased body

weight gain and decreased absolute and relative food consumption. The neurotoxicity NOAEL was >3000 ppm (>172.1 mg/kg bw/day in males and >185.0 mg/kg bw/day in females). 7. Immunotoxicity
. Inan immunotoxicity

study, flutriafol was administered to 10 Crl:CD1(ICR) female mice/group in the diet at dose levels of 0, 50, 250, 500 and 1000 ppm (equivalent to 0, 9.8, 46.8, 94.0 and 208.0 mg/kg bw/day, respectively) for 28 consecutive days. Immunotoxic ity was evaluated by

assessment of the spleen IgM antibody

response to the T
- dependent antigen, sheep red blood cells (sRBCs). The NOAE L for general toxicity in female CD

- 1 mice was 50 ppm (9.8 mg/kg bw/day) based on increased absolute and relative liver weights and hematology

e ffects (decreased mean corpuscular volume). There were no significant effects on absolute and relative spleen weights, spleen cell number and spleen IgM antibody response to the T cell

- dependent antigen, sheep erythrocy tes at any dos e level. Therefore, the immunotoxic NOELi s 1000 ppm (208 mg/kg bw/day), the highest dose tested.
8. Animal Metabolism

. Based on a series of studies, flutriafol is extensively metabolized in the rat and the metabolic processes are well understood. F lutriafol was quantitatively a bsorbed after oral administration to rats and the extent of absorption was in the range of 90% to 99% of the administered dose. Flutriafol is rapidly

distributed, metabolized and eliminated in rats for all dosing regimens after oral administration. After single oral administration 78% and 91% of the dose given was excreted in urine and bile/feces within 72 hours and 47% to 79% of the dose was eliminated with bile. Only 0 .8% to 10.4% of the dose given was directly excreted with feces. After repeated oral6 administration, excretion in urine and feces 24 hours after the first and last dose was comparable. The major route of excretion was urinary accounting for approximately

5 0% to 61% of the daily dose excreted within 24 hours after dosing, while fecal excretion accounted for approximately 3 0% to 40%. Residues in carcass 168 hours after the last of 14 daily doses of flutriafol were found to be less than 3% of administered doses. Flutriafol is distributed systemically resulting in highest tissue levels in whole blood, kidneys, liver, and muscle within the range of 0.7% to 1.46 % of daily dose. The metabolites identified indicated that the 2

- fluorophenylring of flutriafol was the main site for biotransformation. The initial metabolic step probably involved epoxidation followed by e ither rearrangement to form the dihydrodiol isomers of flutriafol or to form hydroxy or dihydroxy metabolites. The hydroxylgroups on these primary m etabolites may

then be either conjugated with glucuronic ac id or methylated. A second, minor route, for the metabolism of flutriafol was via the removal of the triazole ring to form 1

- (2 fluorophenyl)

- 1

- (4

- fluorophenyl)

- ethandiol, which is then conjugated with glucuronic acid. The results demonstrated that absorption, distribution, metabolism, and excretion of flutriafol was comparable in both sexes and also similar after single low, single high, or repeated low

- dose scenario. The data indicate that flutriafol and/or its metabolites do not bioaccumulate. 9 . Metab olite Toxicology Data regarding the potential toxicity o f the three metabolites common to triazoles have been developed and submitted by the US Triazole Task Force. The Task Force has entered into a data access agreement with Cheminova A/S by which it has authorized Cheminova to rel y on all of the studies, data and information that the Task Force has submitted to EPA. This includes the comprehensive risk assessment of these three metabolites. Cheminova hereby incorporates and relies on the Task Force studie s, data and information in support of its pesticide action. This includes relyingon the T
- D metabolite risk assessment submitted to the EPA by the Task Force.
10 . Endocrine Disruption All guideline studies conducted to characterize the toxicological pro file showed no endocrine

-related toxicity or tumorigenicity

. C. Aggregate Exposure

1. Dietary exposure. Temporary

tolerances are proposed for residues of flutriafol on corn, sweet, K+CWHR; corn, sweet, forage; and corn, sweet, stover. These temporary

tolerances, which reflect direct foliar application, will replace the existing tolerances for sweet corn commodities as a rotational crop.7

For the purposes of assessing the potential dietary ( food and drinking water) exposure, an exposure assessment including sweet corn commodities in addition to all of the registered and pending crops was conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID) software, consumption data derived from the 2003

- 2008 National Health and Nutrition Ex amination Survey (NHANES), assuming tolerance

- level residues and 100% crop treated

. E stimated potential concentrations in drinking water were incorporated directly

into the dietary

exposure assessments to provide total aggregate dietary

expo sure estimates. For the purpose of dietary exposure assessment, it is assumed that the residues of concern for all commodities are parent flutriafol and the three triazole metabolites designated as T, TA and TAA. Adjustment factors to account for potenti al residues of conjugated or defluorinated flutriafol metabolites are included as appropriate in risk assessment calculations for corn, cotton, peanut, wheat and triticale commodities. 2. Non

- dietary exposure

. Flutriafol is currently

not registered for use on any residential non- food site. Therefore, residential exposure to flutriafol residues will be through dietary exposure only

. D. Cumulative Effects Flutriafol is a member of the triazole class of fungicides. Other members of this class are registered for use in the United States. Although flutriafol and other triazoles may have similar fungicidal modes of action, there are no available data to determine whether flutriafol has a common mechanism of mammalian toxicity with other triazoles or information on how to include this pesticide in a cumulative risk assessment. Therefore, for the purposes of this tolerance petition no assumption has been made with regard to cumulative exposure with other compounds having a common mode of action. E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that total food and drinking water exposure to flutriafol from all registered, pending and propo sed crop uses will be 1.08% of the aPAD and 19.4% of the cPAD for the overall US population. F or females 13

- 49 years old, the population

specific aPAD is 0.075 mg/kg bw and estimated acute dietary exposures accounted for 29.03% of the aPAD. EPA generally has no concern for exposures below 100% of the PAD because the PAD represents the level at or below which daily aggregate exposures will not pose appreciable8 risks to human health. Thus, it can be concluded that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from the proposed tolerances that are the subject of this petition and all approved and pending uses of flutriafol. 2. Infants and children

. Using the conservative exposure assumptions described above and based on the completeness of the toxicity data, it can be concluded that total food and drinking water exposure to flutriafol from all proposed crop uses will be ≤2.58% of the aPAD and ≤62.4% of the cPAD for infants and children. In assessing the potential for additional sensitivity o f infants and children to residues of flutriafol, the data from developmental toxicity studies in both the rat and rabbit and a reproduction study in rats have been considered. The developmental toxicity studies evaluate potential adverse effects on the developing animal re sulting from pesticide exposure to the mother during prenatal development. The reproduction study evaluates effects from exposure to the pesticide on the reproductive capability o f mating animals through two generations, as well as any observed systemic toxicity

. EPA has concluded that there is no increased quantitative sensitivity to infants and children based on the developmental and reproductive studies conducted with flutriafol. Therefore, infants and children are adequately protected and an additional uncertainty factor for infants and children is not warranted. F. International Tolerances Codex Maximum Residue Levels (MRLs) were established in 2012 for residues of flutriafol for the following commodities: banana (0.3 ppm); coffee beans (0.15 ppm); peanut (0.15 ppm); peanut fodder (20 ppm); peppers, sweet (including pimento or pimiento) (1 ppm); peppers chili, dried (10 ppm); pome fruits (0.3 ppm); soya bean (dry) (0.4 ppm); wheat (0.15 ppm); wheat bran, unprocessed (0.3 ppm); and wheat straw and fodder, dry

( 8 ppm). Codex MRL s are under review for grapes (0.8 ppm) and dried grapes (2 ppm). There are no established tolerances for flutriafol on any crops in Canada and Mexico.