EPA REGISTRATIONDIVISION COMPANYNOTICE OFFILING FOR PESTICIDEPETITIONS PUBLISHED IN THEFEDERALREGISTER EPA Registration Division contact: Cynthia Giles-Parker, 703-305-7740
Cheminova A/S Petition number ("!'!'!] [ P \ has recci\cd a pesticide petition (petition number ).''!) from C'heminova A

/S, c/o Cheminova, Inc., 1600 Wilson Blvd., Suite 700, Arlington, VA 22209-2510, proposing. pursuant to section408(d) ofthe Icdcral food. Drug. and Cosmcttc Act (l·FDCA). 21 U
.S
.C. 346a(d}. to amend 40 Cl·R part 180.629 f c1rresidues ofthe fungicide flutriafol (chemical nameis (RS)-2,4'-difluoro-a-(lHl,2,4-triazol-1-ylmethyl)benzhydryl alcohol) in oron the foliO\\ing fU\\ agricultural

**commodltH;~** and processl.'d food produLts. by establishing tolerances for residues offlutriafol for Brassica, head and stem, SubgroupSA at 1.5 ppm; Brassica, leafy greens, SubgroupSB at7.0 ppm; egg at0
.01 ppm; hog, liverat0.05 ppm; hog, meat byproducts, except liverat 0.02 ppm; hog, muscle at0.01 ppm; leafpetioles, Subgroup4B at3.0 ppm; leafy greens, Subgroup4A, except head lettuce at 10 ppm; lettuce, head at 1.5ppm; poultry, meatbyproducts at0.02 ppm; radicchio at 1.5 ppm; sorghum, grain, forage at 2.0 ppm; sorghum, grain, grain at 1.5 ppm; and sorghum, grain, stover at6.0 ppm; by amending tolerances for residues offlutriafol forcotton, gin byproducts from 0.5 ppm to 5
.0 ppm; cotton, undelinted seed from 0.35 ppm to 0.5 ppm; grain, and aspirated grainfractions from 2.2 ppm to 6.0 ppm; and by deleting tolerances for residues offlutriafol for cotton, meal at0.5 ppm; cotton, refined oil at0.5 ppm; and hog, meat byproducts at0.02 ppm. EPA has detcnnined thatthe petition contains data or information regarding the clements set forth in section408 (d)(2) of i· H)( 'A: hO\\C\cr. EPA has not full) e\aluated the sutlicicnc) ofthe suhmitted data at this time or\\hetherthe data supports grantingof tht: petition. Additional data may be needed

**hefon~** EPA ruJes on thl! petition
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1 Plam metaho/i
. \J11. Thenature ofthe residue in plants is adequately understood. Themajor residue in apples, oilseed rape, sugarbeet and cereals treated with flutriafol is the parent compound. 2. Anahtita/mt?tlwcl Adequate enforcement analytical methods for2 determining flutriafol in/on appropriate ra\\ agricultural commodities and processed commodities are available for the established and proposed tolerances .

1. Hagnilllde

**t~/ re~idue'i**  **.** Appropriate residue field trials have been conducted to support the use of flutriafol on the crops proposed in this petition. Field trials were conducted on celery, head lettuce, leaflettucc, spinach, cabbage, broccoli, mustard greens, cotton and grain sorghum. All raw agricultural commodities in all field trials were analyzed for flutriafol and three triazolc metabolites: 1 ,2,4-triazole (T), triazole alanine (T A), and triazole acetic acid (T AA). The flutriafol residues reported in these field trials support the proposed tolerances. H f'orico/op,iml Prl?/ile I . lc:llle toxicity The acute oral LD!io is 1140 mglkg bw and 1480 mglkg bw in male and female rats, respectively. The acute dermal Ll>!io of nutriafol is >2000 mglkg b"" in rats. The acute inhalation LC 50 in rats is >5.20 mg!L. Flutriafol displayed mild eye irritation in rabbits. It is not a skin irritant to rabbits. Flutriafol h, not a skin sensitizer. 2. Uenotoxict; . Flutriafol was el- · aluated for possible mutagenic/genotoxic effects in in vitro and in vivo test systems. In these studies flutriafol was not mutagenic in either bacterial or mammalian cells at concentrations that were not highly cytotoxic in the presence and absence of metabolic activation ;, vitro. No clastogenic potential in in vitro and i11 vivo qtogenetic studies was demonstrated, and no induction of fonvard mutations \\3S observable bt vitro. Furthermore, flutriafol did not induce unscheduled DNA synthesis ill vivo, and no clastogenicity ''as observable in germ cells of mice. Overall, the data indicate that flutriafol has

no genoto'\ic/mutagenic potential in vitro and i11 vivo. In three new genotoxicity studies submitted with the tolerance petition and not yet reviewed by EPA, flutriafol was not mutagenic in either bacterial or mammalian cells at concentrations that were not highly cytotoxic in the presence and absence of metabolic activation ;, 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. Reproducliw and derelopmentaltoxic:ity . A t\\o-generation reproductive

toxicity study in rats was conducted n · ith flutriafol at doses of 0, 60, 240 or 1000 ppm in the diet. The parental NOAEL was 2.&0 ppm (calculated b} EPA to be 20.6 mglkg bw/day in males and 21.9 mglkg bw/day in females) based on reduced body weight gain and food consumption, and effects on the lher (increased liYer neights, centrilobular hypertrophy and fatty changes). The NOAEL for developmental and reproductive toxicity was 240 ppm (20.6 mglkg 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 study, flutriafol was administered3
to groups ofrats at concentrations of0, 30, 80, 150 and 300 ppm in the diet
. In the P and Fl parental generations, dietary exposure to tlutriafol resulted in centrilobular hepatocellular hypertrophy at300 ppm. These findings correlated with increased liver to body weight ratios in P parental animals, which are indicative ofan adaptive change to metabolic activation by a xcnobiotic and not a toxic response due to the administration ofllutriafol. At 150 ppm, 80 ppm and 30 ppm, no test item-related effects were noted. Therewere no treatment-related differences in reproductive parameters bet\Hentreated animals and controls. Therewere no treatment-related differences in litterparameters bcnveen treated groups and controls
. Based on these results, 300 ppm (15.6 mg/kg bw/day for males and 20.7 mglkg bw/day for females) is the NOAEL for parental toxicity and is the NOEL for effects on reproductive function. The NOEL for parentnl toxicity is 150 ppm. The results ofthis new studyconfirm the earlierstudy that tlutriafol is not a reproductive toxicant to rats. In the rat developmental toxicit) study, tlutriafolwas orally administered at doses ofO, 2, 5, 10 or75 mglkg bw/da)'. The maternal toxicit)· NOAELwas 10 mglkg bw/day based on reduced bod} weight gain and food consumption. The developmental toxicity NOAEL was 10 mg/kg bw/da} based on increased late resorptions and specific malformations/variations, includinghyoid arch absent, interrupted, and/or misshapen. In the rabbit developmentalstudy,flutriafol was administered at doses of0, 2.5, 7.5 or 15 mglkg bll/day. The NOAEL formaternal toxicity was 7.5 mg/kg bw/day based on reduced bodyweight gain and food consumption. The NOAEL for developmental to"ticit) \\as7.5 mglkg b·n/day based on an increase in postimplantation losses and a reduction in the numberofviable fetuses. Flutriafol is neither a reproductive nor developmental toxicant in the absence ofpaternal/maternal toxicity. 4 \'uhchmni< toxiciry The short-term toxicity oftlutriafol was investigated in several subchronic studies includinga 90-day feeding study in rats and a 90-day studyin dogs. A 28-day dermal

**to~icit)** study in rats was also performed. The90-day rat feeding studywas conducted with dietary concentrations of0, 20,200 or2000 ppm. TheNOAEL of200 ppm (14 mglkg bw/day for males and 22 mg/kg bw/day for females) was based on decreased body weight gain and food consumption and liver toxicity (increased absolute and relative liverweights, increased endoplasmic reticulum proliferation in the male rats and increased APOM activit)). In the 90-da} study in dogs, tlutriafol\las administered at concentrations of 0, 1, 5 or 15 mglkg bw/da} "·ia capsule. The NOAEL was 5 mg/kg bw/day based on reduced body""eight gain in females, changes in hematology and clinical chemistry parameters in both sexes, and effects in the livers ofmales and females and in the4 spleens of the males at the IS mglkg bn/da}. In the 28-day dermal toxicity study in rats, there was no evidence of systemic

toxicity and the NOAEL was >1000 mglkg bw/day. 5 . ( 'hronic toxicity . A one-year oral study in the dog was conducted at concentrations of 0, 1, 5 or 20 mglkg bw/day. The NOAEL was 5 mglkg bw/day based on adverse liver findings (increased liver neights, increased lipid content of hepatocytes, 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 se,es; decreased body weight gain, and increased adrenal weights in females. In a two-year 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 mglkg bw/day in males and 12.2 mglkg bw/day in females) based on reduced body neight, bod} \Hight gain, and food consumption in both sexes and adverse liver effects (increased lil · er "'eights, fatty change, bile duct proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer cells and centrilobular hypertrophy) and clinical chemistry findings. There was no evidence of carcinogenicit) in this study. In at\\ o-year 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 by EPA to be 5.9 mglkg bw/da} in males and 7.4 mglkg bw/day in females) based on reduced body weight and body weight gain in males and females, increased liver weight, and hepatocellular hypertrophy and centrilobular fatty change in the liver. There was no evidence of carcinogenicity in this study. 6. Neurotm;icin In an acute neurotoxicity study, rats were administered flutriafol by gavage at doses ofO, 125,250 or 750 mg/kg bw. EPA concluded that the systemic NOAEL was 250 mglkg 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 mglkg bw. In a subchronic neurotoxicity study, flutriafol was administered in the diet to rats at doses ofO, 500, 1500 or 3000 ppm . The systemic NOAEL was 1500 ppm (84.3 mglkg b'ft/day in males and 97.6 mglkg bw/day in females) based on decreased body weight gain and decreased abso lute and relative food consumption. The neurotoxicity NOAEL was >3000 ppm (>172.1 mglkg bw/day in males and >185.0 mglkg bw/day in females). 7 lmmunmoricit v In an immunotoxicity study, flutriafol was administered to 10 Cri:CDl(TCR) female mice/group in the diet at dose le, · els ofO, 50,250,500 and 1000 ppm (equivalent to 0, 9.8, 46.8, 94.0 and 208.0 mglkg bw/day, respectively) for 28 consecutive days. Immunotoxicity was evaluated by assessment of the spleen lgM antibody response to the T-dependent antigen, sheep red blood cells (sRBCs).5 TheNOAEL forgeneral toxicit) in female CO-l mice nas50 ppm (9.8 mglkg bw/day) based on increased absolute and relative liver weights and hematology effects (decreased mean corpuscularvolume). Therewere no significant effects on absolute and relatiH spleen weights, spleen cell number and spleen lgl\1 antibod) response to theT cell-dependent antigen,sheep erythrocytes at any dose level. Therefore,the immunotoxic NOELis 1000 ppm (208 mg/kg bw/day), the highest dose tested
. 8 1nimalmelahofi,m Based on a series ofstudies, flutriafol is extensivel} metabolized in the rat and the metabolic processes are well understood. Flutriafol was quantitatively absorbed afteroral administration to rats and the extent ofabsorption was in the range of90% to 99% ofthe administered dose. Flutriafol is rapidly distributed, metabolized and eliminated in rats for all dosing regimes afteroral administration

. Aftersingle oral administration 78% and 91 % of the dose given wasexcreted in urine and bile /feces within 72 hours and47% to 79% ofthe dose was eliminated with bile
. Only0
.8'Yo to J0.4% ofthe dose given was

**directl~** excreted with feces
. Afterrepeated oral administration, excretion in urine and feces 24 hours afterthe first and last dose was comparable

. Themajor route of excretion was urinary accounting for approximately 50% to 61 % ofthe daily dose excreted within 24 hours afterdosing, while fecal excretion accounted for approximate!} 30% to 40%
. Residues in carcass 168 hours afterthe last of 14

**dail~** doses offlutriafol were found to be less than 3% ofadministered doses. Flutriafol is distributed systemically resulting in highest tissue levels in whole blood, kidneys, liver, and muscle within the range of0.7% to 1.46% ofdaily dose. Themetabolites identified indicated that the 2-fluorophenyl ringofflutriafol was the main sitefor biotransformation. Theinitial metabolic step probably involved epoxidation followed by eitherrearrangementto form the dihydrodiol isomer s offlutriafol orto form hydroxy ordihydrox} metabolites. The hydroxyl groups on these primary metabolites may then beeitherconjugated with glucuronic acid ormethylated

. A second, minor route, for the metabolism offlutriafol was via the removal ofthe triazole ringto form 1-(2 fluorophenyl)-1-(4

-fluorophenyl)- ethandiol,which is then conjugated with glucuronic acid. Theresults demonstrated that absorption, distribution, metabolism, and excretion offlutriafol was comparablein both sexes and also similar aftersingle low, single high, or repeated low-dose scenario. Thedata indicatethat flutriafol and /or its metabolites do notbioaccumulate. ) \letaholile fOXI('OioKJ. Data regardingthe potential toxicity ofthe three metabolites commonto triazoles have been developed and submitted by the US TriazoleTask Force. TheTaskForcehas entered into a data access agreement with Cheminova A/S by which it has authorized Cheminova to rely on all ofthe studies, data and information thattheTask Force has submitted to EPA. This includes the comprehensive riskassessment ofthese three metabolites. Cheminova hereby6 incorporates and relies on the Task Force studies, data and information in support of its pesticide action. This includes relying on the T -D metabolite risk assessment submitted to the EPA by the Task Force. 10. Endocrine disruption. AU guideline studies conducted to characterize the toxicological profile showed no endocrine-related toxicity or tumorigenicity. C. Aggregate Etposure 1. DieiW) ' exposure . Tolerances are proposed for residues of flutriafol in

several raw agricultural commodities. For the purposes of assessing the potential dietary exposure for the proposed tolerances, an exposure assessment was conducted using the Dietary Exposure Evaluation Model-Food Consumption Intake

Database (DEEM-FCIDTM) software, consumption data derived from the 2003-2008 NHANES What We Eat in America Surveys, and residues at proposed tolerance levels. Estimated potential concentrations in drinking water were incorporated directly into the dietary exposure assessments. Acute Dietary Exposure. The acute population adjusted dose (aPAD) for females 13-49 years old is 0.075 mg/kg bw (NOAEL of 7.5 mglkg/day from the

rabbit developmental toxicity study with a J 00-fold uncertainty factor). The aPAD for other subpopulations is 2.5 mg/kg bw (NOAEL of 250 mglkg from the acute neurotoxicity screening battery with a 1 00-fold uncertainty factor). These endpoints were used to characterize the risk associated with acute dietary exposures. Cheminova has conducted an acute dietary exposure Tier I analysis with DEEMFCID using the proposed tolerances that are the subject of this petition in addition to the previously registered and pending tolerances. Additional assumptions included 100% crop treated and default processing factors, where appropriate. Tolerances for grain sorghum, corn (field and pop), cotton, peanut, wheat and triticale commodities were multiplied by a factor of 2.2 and tolerances for indirect residues on corn, sweet commodities were multiplied by factors of 1.3 or 2.5 (depending on commodity matrix) to account for total residues of concern for risk assessment purposes (i.e., free and conjugated flutriafol and defluorinated flutriafol). Anticipated residues in livestock commodities were estimated using maximum total residue dietary burdens calculated with the appropriate factors to account for the presence of conjugated and defluorinated flutriafol residues in

animal feed items. Potential residues in water were included using the peak concentration in ground water modeled with PRZM-GW (version 1.01, December 26, 2012) of 170 ppb, based on the proposed use pattern on cotton (1 in-furrow atplant application at 0.26 lb ail A and two foliar applications at 0.114 lb ai/A). The acute dietary assessment was conducted for the overall US population and select subpopulations (i.e., all infants <1 year old, children aged 1-2 years old, children aged 3-5 years old, children aged 6-12 years old , youths aged 13-19 years old, adults aged 20-49 years old, adults 50+ years old, and females aged 13-49 years old). The results of this Tier I acute analysis indicate that the most highly exposed population is children 1-2 years old, with an estimated acute exposure of 0.0639')9 mg/kg bw at the 95th percentile, which corresponds to 2.56% of the aP AD of 2.5 mg/kg bw . For7 the O\'erall US population, the acute e:\posure atthe 95th percentile is 0.026878 mg/kg bw, which corresponds to 1.08% ofthe aPAD. Forfemales 13-49 years old, the acute exposure atthe 95th percentileis 0.021750

**m~/k~** bw, which corresponds to 29.00%, ofthe population-specific aPAD of0.075

**m~/kg** bw. Cllro11ic DietaryExposure. Thechronicpopulation adjusted dose (cPAD) of 0.05 mglkg bw/da) (NOAEL of5 mg/kg/d from the one-yearfeeding study in the dogwith a 100-fold uncertaintyfactor) was used to characterize risk associated with chronic dietary exposures. Chemino,·a has conducted a dieta11 exposure Tier t analysis with DEEM-FCID using the proposed that arethe subject ofthis petition in addition to the

**pre~iously** registered and pending tolerances. Additional assumptions included tOO% crop treated and defaultprocessingfactors, where appropriate. Tolerances for grain sorghum,corn (field and pop), cotton, peanut, wheatand triticale commodities were multiplied by a factor of2.2 and tolerances for indirect residues on corn, sweet commodities were multiplied by factors of 1.3 or 2.5 (depending on commodity matrix) to accountfor total residues ofconcern for risk assessment purposes (i.e., free and conjugated nutriafol and denuorinated nutriafol). Anticipated residues in lh·estock commodities were estimated using maximum total residue dietary burdens calculated with the appropriate factors to accountfor the presence ofconjugated and dcnuorinated nutriafol residues in animal feed items. In addition, potential residues in waterwere included using the post-breakthrough average concentration in ground watermodeled with PRZMGW (version 1.01, December26, 2012) of 157 ppb, based on the use pattern for grapes (6 applications at0.0813 lb ail A) and the proposed use pattern on cotton (1 in-furrow at-plant application at0.26 lb ai/A and two foliar applications at O.lt
... lb ail A). The chronic dietary assessmentwas conducted for the overall US population and select subpopulations (i.e., all infants <I )earold, children aged t-2 years old, children aged 3-5years old, children aged 6-t2 )earsold, youths aged 13-19 years old, adults aged 20-49 years old, adults 50+years old, andfemales aged 13-49years old). The results ofthisTier t chronic analysis indicate that the most highly exposed population is children aged 1-2 years old,with an estimated chronic exposure of0.030833 mglkg bw/day, which corresponds to 61.7% ofthe cPAD. For the overall US population, the chronic exposure is calculated to be 0.00964-i mglkg bw/day, which corresponds to 19.3% ofthe cPAD. 2 \ on-dit?IWJ'

**''7~owre** Flutriafol is currently not registered for use on an)· residential non-food site. Therefore, residential exposure to nutriafol residues will be through dietary exposure only
. D ( 'umulative l;.'ffects Flutriafol is a member ofthe triazole class offungicides. Othermembers of this class are registered for use in the United States. Although flutriafol and other triazoles

**ma~** have similarfungicidal modes ofaction, there are no available data to determinewhethernutriafol has a common mechanism ofmammalian toxicity with othertriazoles orinformation on how to include this pesticide in a cumulativerisk8 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 , \ ' afeH • Determinarion l. US. 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 proposed crop uses will be J .08% of the aP AD and 19.3% of the cP AD for the overall US population. For females 13-49 years old, the population-specific aPAD is

0.075 mglkg bw and estimated acute dietary exposures accounted for 29.00% of the aP AD. EPA generally has no concern for exposures below 1 00% of the PAD because the PAD represents the level at or below which daily aggregate exposures will not pose appreciable 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 . Jnjams 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 9.56% of the aPAD and**~61.** 7% of the cPAD for infants and children. In assessing the potential for additional sensitivity of infants and children to residues of Outriafol, 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 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 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 Tolerance,· 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);9 

### and wheatstraw and fodder, dry (8 ppm). Codex MRLs areunderreview for grapes (0.8 ppm) and dried grapes (2 

### ppm). There areno established tolerances for flutriafo) on any crops in Canada and Mexico.