EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

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 Chemin ova, Inc., 1600 Wilson Blvd., Suite 700, Arlington, VA 22209-2510, 

proposing. pursuant to section 408( d) of the I cdcral food. Drug. and Cosmcttc Act 

(l·FDCA). 21 U.S.C. 346a(d}. to amend 40 Cl·R part 180.629 

fc1r residues of the fungicide flutriafol (chemical name is (RS)-2,4'-difluoro-a-(lHl ,2,4-triazol-1-ylmethyl)benzhydryl alcohol) in or on the foliO\\ ing fU\\ agricultural 

commodltH;~ and processl.'d food produLts. 

by establishing tolerances for residues of flutriafol for Brassica, head and 

stem, Subgroup SA at 1.5 ppm; Brassica, leafy greens, Subgroup SB at 7.0 ppm; 

egg at 0.01 ppm; hog, liver at 0.05 ppm; hog, meat byproducts, except liver at 

0.02 ppm; hog, muscle at 0.01 ppm; leaf petioles, Subgroup 4B at 3.0 ppm; leafy 

greens, Subgroup 4A, except head lettuce at 10 ppm; lettuce, head at 1.5 ppm; 

poultry, meat byproducts at 0.02 ppm; radicchio at 1.5 ppm; sorghum, grain, 

forage at 2.0 ppm; sorghum, grain, grain at 1.5 ppm; and sorghum, grain, stover 

at 6.0 ppm; 

by amending tolerances for residues of flutriafol for cotton, gin byproducts 

from 0.5 ppm to 5.0 ppm; cotton, undelinted seed from 0.35 ppm to 0.5 ppm; 

grain, and aspirated grain fractions from 2.2 ppm to 6.0 ppm; 

and by deleting tolerances for residues of flutriafol for cotton, meal at 0.5 

ppm; cotton, refined oil at 0.5 ppm; and hog, meat byproducts at 0.02 ppm. 

EPA has detcnnined that the petition contains data or information regarding the 

clements set forth in section 408 (d)(2) of i·H)('A: hO\\C\cr. EPA has not full) e\aluated 

the sutlicicnc) of the suhmitted data at this time or \\hether the data supports granting of 

tht: petition. Additional data may be needed hefon~ EPA ruJes on thl! petition. 

A. Re.\idue ( 'hcmi\11') 

1 Plam metaho/i.\J11. 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. Anah tit a/ mt?tlwcl Adequate enforcement analytical methods for 
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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 LC50 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 administered 
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to groups of rats at concentrations of 0, 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 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 metabolic activation by a xcnobiotic and not a toxic response due to the 

administration of llutriafol. At 150 ppm, 80 ppm and 30 ppm, no test item-related 

effects were noted. 

There were no treatment-related differences in reproductive parameters 

bet\Hen treated animals and controls. There were no treatment-related differences 

in litter parameters 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 of this new study confirm 

the earlier study that tlutriafol is not a reproductive toxicant to rats. 

In the rat developmental toxicit) study, tlutriafol was orally administered at 

doses ofO, 2, 5, 10 or 75 mglkg bw/da)'. The maternal toxicit)· NOAEL was 

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, including hyoid arch absent, 

interrupted, and/or misshapen. 

In the rabbit developmental study, flutriafol was administered at doses of 0, 

2.5, 7.5 or 15 mglkg bll/day. The NOAEL for maternal toxicity was 7.5 mg/kg 

bw/day based on reduced body weight gain and food consumption. The NOAEL for 

developmental to"ticit) \\as 7.5 mglkg b·n/day based on an increase in postimplantation 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 \'uhchmni< toxiciry The short-term toxicity of tlutriafol 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 to~icit) 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 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 liver weights, 

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 of males and females and in the 
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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 absolute 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 lmmunmoricitv 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 

The NOAEL for general toxicit) in female CO-l mice nas 50 ppm (9.8 mglkg 

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 relatiH spleen weights, spleen cell number and spleen lgl\1 antibod) 

response to the T cell-dependent antigen, sheep erythrocytes at any dose level. 

Therefore, the immunotoxic NOEL is 1000 ppm (208 mg/kg bw/day), the highest 

dose tested. 

8 1nimal melahofi,m Based on a series of studies, flutriafol is extensivel} 

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 

regimes 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'Yo to J 0.4% of the dose given was 

directl~ excreted with feces. After repeated 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 daily dose 

excreted within 24 hours after dosing, while fecal excretion accounted for 

approximate!} 30% to 40% . Residues in carcass 168 hours after the last of 14 dail~ 

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 of0.7% to 1.46% of daily dose. 

The metabolites identified indicated that the 2-fluorophenyl ring of flutriafol 

was the main site for biotransformation. The initial metabolic step probably 

involved epoxidation followed by either rearrangement to form the dihydrodiol 

isomers of flutriafol or to form hydroxy or dihydrox} metabolites. The hydroxyl 

groups on these primary metabolites may then be either conjugated with glucuronic 

acid 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. 

) \letaholile fOXI('OioKJ. 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 Cheminova 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 hereby 
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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. For 
7 

the O\'erall US population, the acute e:\posure at the 95th percentile is 

0.026878 mg/kg bw, which corresponds to 1.08% of the aPAD. For females 13-49 

years old, the acute exposure at the 95th percentile is 0.021750 m~/k~ bw, which 

corresponds to 29.00%, of the population-specific aPAD of0.075 m~/kg bw. 

Cllro11ic Dietary Exposure. The chronic population adjusted dose (cPAD) of 

0.05 mglkg bw/da) (NOAEL of 5 mg/kg/d from the one-year feeding study in the 

dog with a 100-fold uncertainty factor) 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 are the subject of this petition in 

addition to the pre~iously registered and pending tolerances. Additional 

assumptions included tOO% 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 nutriafol and denuorinated 

nutriafol). Anticipated residues in lh·estock commodities were estimated using 

maximum total residue dietary burdens calculated with the appropriate factors to 

account for the presence of conjugated and dcnuorinated nutriafol residues in 

animal feed items. In addition, potential residues in water were included using the 

post-breakthrough average concentration in ground water modeled with PRZMGW (version 1.01, December 26, 2012) of 157 ppb, based on the use pattern for 

grapes (6 applications at 0.0813 lb ail A) and the proposed use pattern on cotton (1 

in-furrow at-plant application at 0.26 lb ai/A and two foliar applications at O.lt ... lb 

ail A). The chronic dietary assessment was conducted for the overall US population 

and select subpopulations (i.e., all infants <I ) ear old, children aged t -2 years old, 

children aged 3-5 years old, children aged 6-t 2 ) ears 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 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% of the cPAD. For 

the overall US population, the chronic exposure is calculated to be 

0.00964-i mglkg bw/day, which corresponds to 19.3% of the cPA D. 

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 of the triazole class of fungicides. Other members of 

this class are registered for use in the United States. Although flutriafol and other 

triazoles ma~ have similar fungicidal modes of action, there are no available data to 

determine whether nutriafol has a common mechanism of mammalian toxicity with 

other triazoles or information on how to include this pesticide in a cumulative risk 
8 

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 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 

flutriafo) on any crops in Canada and Mexico.