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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 establishing 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, sweet, 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 FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data 

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 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 established 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 popcorn. Consequently, Cheminova believes that the 

field corn data are applicable to this petition and support the proposed 
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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 

conducted, 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 analyzed 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. Total 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 LC50 in rats is >5.20 mg/L. Flutriafol 

displayed mild eye 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 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 in vitro. No clastogenic 

potential in in vitro and in vivo cytogenetic studies was demonstrated, and no 

induction of forward mutations was observable in vitro. Furthermore, 

flutriafol did not induce unscheduled DNA synthesis 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.
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In three genotoxicity 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 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 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 weight gain and food 

consumption, and effects on the liver (increased liver weights, centrilobular 

hypertrophy and fatty 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 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 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 

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 and is the NOEL for effects 

on reproductive function. The NOEL for parental 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, flutriafol was orally 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 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.

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 body weight gain and food consumption. The 
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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 reproductive 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 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).

In the 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 weight 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 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-year 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 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 sexes; 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 mg/kg bw/day in males 

and 12.2 mg/kg bw/day in females) based on reduced body weight, 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 hypertrophy) and clinical chemistry findings. There was no 

evidence of carcinogenicity in this study.
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In a two-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 mg/kg bw/day in males and 7.4 mg/kg 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. 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. 

In an 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. 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 

erythrocytes 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 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 oral 
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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 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 

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-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 dihydroxy 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.

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 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 

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

All guideline studies conducted to characterize the toxicological profile 

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. 
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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 Examination 

Survey (NHANES), assuming tolerance-level residues and 100% crop 

treated. Estimated potential concentrations in drinking water were 

incorporated directly 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, 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 

proposed crop uses will be 1.08% of the aPAD and 19.4% of the cPAD for 

the overall US population. For females 13-49 years old, the populationspecific 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 appreciable 
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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 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 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 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 MRLs 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.