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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [Hope Johnson, 703-305-5410]

INSTRUCTIONS: Please utilize this outline in preparing 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 in 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 agricultural commodity [hops, dried cones] at [20]

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. Appropriate residue field trials have been conducted 

to support the use of flutriafol on hops as proposed in this petition. All raw agricultural 

commodities in all fied trials were analyzed for flutriafol and three triazole metabolites –
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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. 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.

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 
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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 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 
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(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.

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 
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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 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. A tolerance is proposed for residues of flutriafol on hops, 

dried cones. For the purposes of assessing the potential dietary (food and drinking water) 

exposure, an exposure 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 National Health and Nutrition Examination Survey

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

commodities and calculated anticipated residues in livestock commodities. Estimated 
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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.

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 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 analysis 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 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 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. 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 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 1.07, dated 

May 14, 2014) of 152 ppb based on the pending use pattern on cotton (one at-plant infurrow 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 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 1 acute analysis indicate that the most highly exposed population is children 1-2 

years old, with an estimated acute exposure of 0.061006 mg/kg bw at the 95th percentile, 

which corresponds to 2.44% of the aPAD of 2.5 mg/kg bw. For the overall US 

population, the acute exposure at the 95th percentile is 0.026195 mg/kg bw, which 

corresponds to 1.05% of the aPAD. For females 13-49 years old, the acute exposure at 

the 95th percentile is 0.021614 mg/kg bw, which corresponds to 28.82% 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 (NOAEL of 5 mg/kg/d from the one-year feeding study in the dog 
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with a 100-fold uncertainty factor) was used to characterize risk associated with chronic 

dietary exposures. Cheminova has conducted a dietary exposure Tier 1 analysis with 

DEEM-FCID using the proposed temporary 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. To 

account for total residues of concern for risk assessment purposes in animal diets (i.e., 

free and conjugated flutriafol 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 residues 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 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. In addition, potential residues in water were 

included using the post-breakthrough average concentration in ground water modeled 

with PRZM-GW (version 1.07, dated May 14, 2014) of 137 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 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 1 chronic analysis indicate that the most highly

exposed population is children aged 1-2 years old, with an estimated chronic exposure of 

0.028747 mg/kg bw/day, which corresponds to 57.5% of the cPAD. For the overall US 

population, the chronic exposure is calculated to be 0.009533 mg/kg bw/day, which 

corresponds to 19.1% of the cPAD.

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 
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food and drinking water exposure to flutriafol from all registered, pending and proposed 

crop uses will be 1.05% of the aPAD and 19.1% of the cPAD for the overall US 

population. For females 13-49 years old, the population-specific aPAD is 0.075 mg/kg 

bw and estimated acute dietary exposures accounted for 28.82% 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 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 

<2.44% of the aPAD and <57.5% 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 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) 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); 

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.