# i

**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: [**  **Hope Johnson , 703**  **- 30**  **5 -**  **5410 ]**  **INSTRUCTIONS: Please utilize this outline in prepa**  **ring 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 i**  **n green**  **, i.e., “ [**  **insert company name**  **],” with the information specific to your action.**  **TEMPLATE: [**  **Cheminova, Inc. ]**  **[Insert petition number]** EPA has received a pesticide petition **( [insert**  **petition number] )**  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 establishing a tolerance for residues of **[ Flutriafol**  **]** in or on the raw agricultura l commodity **[ hops, dried cones**  **]** at **[ 2**  **0 ]**  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 th e 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 Chemistry **1.** Plant metabolism. The nature of the residue in plants is adequatel y understood. The major residue in apples, oilseed rape, sugar beet and cereals treated with flutriafol is the parent compound. 2. Analytical method. Adequate enforcement anal yt ical methods for determining flutriafol in/on appropriate raw agricultural commodities and proces sed commodities are available for the established and proposed tolerances. 3. Magnitude of residues. Appropriate residue field trials have been conducted to support the use of flutriafol on hops as proposed in this petition. All raw agricultural commoditie s in all fied trials were anal yz ed for flutriafol and three triazole metabolites

–2

1,2,4
- triazole (T), triazole alanine (TA), and triazole acetic acide (TAA). The flutriafol residues reported in these field trials support the proposed tolerances. B. Toxi cological Profile 1. Acute toxicity. The acute oral LD50 is 1140 mg/kg bw and 1480 mg/kg bw in male and female rats, respectivel y. The acute dermal LD50 of flutriafol is >2000 mg/kg bw in rats. The acute inhalation L C50 in rats is >5.20 mg/L. Flutriafol dis play ed mild ey e irritation in rabbits. It is 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 sy stems. In these studies flutri afol was not mutagenic in either bacterial or mammalian cells at concentrations that were not highl y cyt otoxic in the presence and absence of metabolic activation in vitro. No clastogenic potential in in vitro and in vivo cy

togenetic studies was demonstrat ed, 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 genot oxic/mutagenic potential in vitro and in vivo. In three genotoxicity

studies flutriafol was not mutagenic in either bacterial or mammalian cells at concentrations that were not highl y c yt otoxic in the presence and absence of metabolic activation in vitro. No clastogenic potential in the in vitro chromosome aberration study was demonstrated. These results are consistent with the conclusions of the originally submitted genotoxicity

studies. 3. Reproductive and developmental toxicity. A two
- generation reproduc tive toxicity study in rats was conducted with flutriafol at doses of 0, 60, 240 or 1000 ppm in the diet. The parental NOAELwas 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 weight gain and food consumption, and effects on the liver (increased liver weights, centrilobular hy pertrophy and fatt y changes). The NOAEL for developmental and reproductive toxicity was 240 ppm (20.6 mg/kg bw/day for males and 21.9 mg/kg bw/day for females) based on reduced litter sizes and effects on the liver (fatty change/vacuolation). In a second two

- generation reproduction stud y, 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 weight ratios in P parental animals, which are indicative of an adaptive change to metaboli c 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

for males and 20.7 mg/kg bw/day for females) is the NOAEL for parental toxicity an d is the NOEL for effects on reproductive function. The NOEL for parental3

toxicity is 150 ppm. The results of this new study confirm the earlier study that flutriafol is not a reproductive toxicant to rats. In the rat developmental toxicity study , flutria fol was orall y administered at doses of 0, 2, 5, 10 or 75 mg/kg bw/day . The maternal toxicity NOAEL was 10 mg/kg bw/day based on reduced bod y weight gain and food consumption. The developmental toxicity NOAEL was 10 mg/kg bw/day based on increased late res orptions and specific malformations/variations, including h yoid arch absent, interrupted, and/or misshapen. In the rabbit developmental study , flutriafol was administered at doses of 0, 2.5, 7.5 or 15 mg/kg bw/day . The NOAEL for maternal toxicity was 7.5 mg/kg bw/day

based on reduced bod y weight gain and food consumption. The NOAEL for developmental toxicity was 7.5 mg/kg bw/day

based on an increase in post

- implantation losses and a reduction in the number of viable fetuses. Flutriafol is neither a reprod uctive nor developmental toxicant in the absence of paternal/maternal toxicity. 4. Subchronic toxicity. The short

- term toxicity of flutriafol was investigated in several subchronic studies including a 90

- day feeding 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

was conducted with dietary concentrations of 0, 20, 200 or 2000 ppm. The NOAEL of 200 ppm (14 mg/kg bw/day for males and 22 mg/kg bw/day for females) was based on dec reased bod y 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). In the 90

- day

study in dogs, flutriafol was admini stered 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 weight gain in females, changes in hematology and clinical chemistry parameters in both sexes, and effects in the livers of males and fem ales 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 s ys temic 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 based on adverse liver findings (increased liver weights, increased lipid content of hepatocy tes, and increased alkaline phosphatase, albumin and trigl ycerides), 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 oncogenicit y study, flutria fol was administered in the diet to rats at doses of 0, 20, 200 or 2000 ppm. The NOAEL was 200 ppm4

(calculated b y EPA to be 10.0 mg/kg bw/day in males and 12.2 mg/kg bw/day in females) based on reduced body weight, bod y 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 h ypertrophy) and clinical chemistry findings. There was no evidence of c arcinogenicity

in this study
. In a two
- ye ar oncogenicity study , flutriafol was administered in the diet to mice at doses of 0, 10, 50 or 200 ppm. The NOAEL was 50 ppm (calculated b y EPA to be 5.9 mg/kg bw/day

in males and 7.4 mg/kg bw/day in females) base d on reduced body weight and body weight gain in males and females, increased liver weight, and hepatocellular hy pertrophy and centrilobular fatt y 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 sy stemic 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 s ys temic 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
. In an immuno toxicity study , flutriafol was administered to 10 Crl:CD1(I CR) 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 day s. Immunotoxicity was evaluated by

assessment of the spleen IgM antibody response to the T

- dependent antigen, sheep red blood cells (sRBCs). The NOAEL 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 effects (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 ery

throcy tes at any dose level. Therefore, the immunotoxic NOEL is 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. Flutriafol was quantitatively absorbed 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 adminis tration. 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 with5

feces. After r epeated oral 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

50% to 61% of the dail y dose excreted within 24 hours after dosing, while fecal excretion accounted for approximately 30% 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 sy stemically resulting in highest tissue le vels in whole blood, kidney s, liver, and muscle within the range of 0.7% to 1.46 % of dail y dose. The metabolites identified indicated that the 2

- fluorophenyl ring of flutriafol was the main site for biotransformation. The initial metabolic step probabl y involved epoxidation followed by

either rearrangement to form the dihydrodiol isomers of flutriafol or to form h ydrox y or dih ydrox y m etabolites. The hydrox yl groups on these primary metabolites may then be either conjugated with glucuronic acid or methylat ed. 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. Metabolite Toxicology

. Data regarding the potential toxicity of 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 Chem inova to rely 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 hereb y incorporates and relies on the Task Force studies, data and inf ormation in support of its pesticide action. This includes rel yi ng on 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 profile showed no end ocrine

- related toxicity or tumorigenicity
. C. Aggregate Exposure 1. Dietary exposure. A tolerance i s proposed for residues of flutriafol on hops, dried cones . For the purposes of assessing the potential dietary (food and drinking water) exposure, an expos ure assessment including hops, dried cones 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 N ational Health and Nutrition Examination Survey (NHANES), assuming tolerance

- level residues and 100% crop treated in treated commodities and calculated anticipated residues in livestock commodities . Estimated6

potential concentrations in drinking water wer e incorporated directl y into the dietary exposure assessments to provide total aggregate dietary exposure 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 potential residues of conjugated or defluorinated flutriafol metabolites are included as appropriate in risk assessment calculations for corn, cotton, peanut, whe at and triticale commodities. **Acute Dietary Exposure.** The acute population adjusted dose (aPAD) for females 13
- 49 y ears old is 0.075 mg/kg bw (NOAEL of 7.5 mg/kg/day from the rabbit developmental toxicity

study with a 100

- fold uncertainty factor). The aPAD for other subpopulations is 2.5 mg/kg bw (NOAEL of 250 mg/kg from the acute neurotoxicity screening battery

with a 100

- fold uncertainty factor). These endpoints were used to characterize the risk associated with acute dietary exposures. Cheminova has conducted an acute dietary

exposure Tier 1 anal ys is with DEEM

- FCID using the proposed temporary

tolerances that are the subject of this petition in addition to all previously registered and pending tolerances. Additional assumptions included 100% crop tr eated and default processing factors, where appropriate. To account for total residues of concern for risk assessment purposes in animal diets (i.e., free and conjugated flutriafol and defluorinated flutriafol), residues in grain sorghum, corn (field, pop and sweet), cotton, peanut, and wheat commodities were multiplied by a factor of 2.2. Maximum reasonable dietary

burdens for livestock were calculated using median or highest average field trial (HAFT) residues in feed commodities, as appropriate. Antic ipated residues in livestock commodities were calculated based on the resulting maximum total residue dietary burdens. For purposes of risk assessment, secondary residues of flutriafol in meat and milk were estimated using tissue:feed ratios from the feeding studies, and then factors derived from the goat metabolism study were used to account for all of the residues of concern in livestock tissues. Potential residues in water were included using the peak concentration in ground water modeled with PRZM

- GW (version 1.0 7 , dated May 14, 2014 ) of 1 52 ppb based on the pending use pattern on cotton (one at

- plant in

furrow application at 0.26 lb ai/A and two foliar applications at 0.114 lb ai/A). The acute dietary assessment was conducted for the overall US popul ation and select subpopulations (i.e., all infants <1 ye ar old, children aged 1

- 2 y ears old, children aged 3

- 5 y ears old, children aged 6

- 12 y ears old, youths aged 13

- 19 y ears old, adults aged 20

- 49 ye ars old, adults 50+ y ears old, and females aged 13

- 49 y ears old). The results of this Tier 1 acute anal ys is indicate that the most highl y exposed population is children 1

- 2 ye ars old, with an estimated acute exposure of 0.061 00 6 mg/kg bw at the 95th percentile, which corresponds to 2.4 4 % of the aPAD of 2.5 mg/kg bw. For the overall US population, the acute exposure at the 95th percentile is 0.026 195 mg/kg bw, which corresponds to 1.0 5 % of the aPAD. For females 13

- 49 y ears old, the acute exposure at the 95th percentile is 0.02 1614 mg/kg bw, which corresponds to 2 8.82 % of the population

- specific aPAD of 0.075 mg/kg bw. **Chronic Dietary Exposure .**  The chronic population adjusted dose (cPAD) of 0.05 mg/kg bw/day

(NOAELof 5 mg/kg/d from the one

- ye ar feeding study in the dog7

with a 100

- fold uncertainty factor) was used to characterize risk associated with chronic dietary exposures. Cheminova has conducted a dietary exposure Tier 1 analy sis with DEEM
- FCID using the proposed temporary tolerances that are the subject of this petition in addition to the previously reg istered and pending tolerances. Additional assumptions included 100% crop treated and default processing factors, where appropriate. To account for total residues of concern for risk assessment purposes in animal diets (i.e., free and conjugated flutriaf ol and defluorinated flutriafol), tolerances for grain sorghum, corn (field, pop and sweet), cotton, peanut, and wheat commodities were multiplied by a factor of 2.2. Maximum reasonable dietary burdens for livestock were calculated using median or HAFT re sidues in feed commodities, as appropriate. Anticipated residues in livestock commodities were calculated based on the resulting maximum total residue dietary burdens. For purposes of risk assessment, secondary residues of flutriafol in meat and milk wer e estimated using tissue:feed ratios from the feeding studies, and then factors derived from the goat metabolism study were used to account for all of the residues of concern in livestock tissues. In addition, potential residues in water were included usi ng the post

- breakthrough average concentration in ground water modeled with PRZM

- GW (version 1.0 7 , dated May 14, 2014 ) of 1 3 7 ppb based on the pending use pattern on cotton (one at plant in

- furrow application at 0.26 lb ai/A and two foliar applications at 0.114 lb ai/A). The chronic dietary assessment was conducted for the overall US population and select subpopulations (i.e., all infants <1 ye ar old, children aged 1

- 2 y ears old, children aged 3

- 5 y ears old, children aged 6

- 12 y ears old, youths aged 13
- 19 ye ars old, adults aged 20

- 49 y ears old, adults 50+ y ears old, and females aged 13

- 49 y ears old). The results of this Tier 1 chronic analy sis indicate that the most highly exposed population is children aged 1

- 2 y ears old, with an estimated chronic exposur e of 0.02 8747 mg/kg bw/day , which corresponds to 57 .5 % of the cPAD. For the overall US population, the chronic exposure is calculated to be 0.0095 33 mg/kg bw/day, which corresponds to 19. 1 % of the cPAD. 2. Non

- dietary exposure
. Flutriafol is currentl y not registered for use on an y 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 c lass 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 actio n. 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 total8

food and drinking water exposure to flutriafol from all registered , pending and proposed crop uses will be 1.0 5 % of the aPAD and 19. 1 % of the cPAD for the overall US population. For females 13

- 49 y ears old, the population

- specific aPAD is 0.075 mg/kg bw and estimated acute dietary exposures accounted for 2 8.82 % of the aPAD. EPA generall y has no concern for exposures below 100% of the PAD because the PAD represents the level at or below which dail y aggregate exposures will not pose appreciable risks to human health. Thus, it can be concluded that there is a reasonable c ertaint y 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 assump tions 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. 4 4 % of the aPAD and < 5 7 .5 % of the cPAD for infants and children. In assessing the potential for additional sensitivity of 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 toxi city studies evaluate potential adverse effects on the developing animal resulting from pesticide exposure to the mother during prenatal development. The reproduction study evaluates effects from exposure to the pesticide on the reproductive capability of mating animals through two generations, as well as any observed s ys temic 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 uncertaint y factor for infants and children is not warranted. F. International Tolerances Codex Maximum Residue Levels (MRLs) are established for residues of flutriafol for the following commodities: banana (0.3 ppm); coffee beans (0.15 ppm); grapes (0.8 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); raisin (2 ppm); s oya bean (dry) (0.4 ppm); wheat (0.15 ppm); wheat bran, unprocessed (0.3 ppm); and wheat straw and fodder, dry (8 ppm). Codex MRLs are under review for grapes (0.8 ppm) and dried grapes (2 ppm). There are no established tolerances for flutriafol on any cro ps in Canada and Mexico.