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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Marcel Howard at (703) 305-6784

TEMPLATE:

Bayer CropScience

3F8190

EPA has received a pesticide petition from Bayer CropScience, 2 T.W. 

Alexander Drive, Research Triangle Park, NC 27709 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 fluopyram (N-[2-[3-

chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide) in or on 

the raw agricultural commodity soybean, seed at 0.04 ppm, cotton, seed at 0.01 ppm, 

cotton, gin by-products at 0.80 ppm peanut at 0.09 ppm, grain, cereal, , group 15

except rice at 0.03 ppm, grain, cereal, forage, fodder and straw, group 16; forage at

1.5 ppm and grain, cereal, forage, fodder and straw, group 16; hay, straw and stover 

at 2.0 ppm and for residues of fluopyram and its metabolite 2-

(trifluoromethyl)benzamide, expressed in parent equivalents in or on milk at 0.10

ppm, beef, fat at 0.10 ppm, beef, byproducts at 0.70 ppm, beef, muscle at [0.10] ppm, , 

egg at 0.15 ppm, poultry, fat at 0.10 ppm, poultry, meat at 0.10 ppm, poultry, meat 

byproducts at 0.20 ppm, hog, fat at 0.05 ppm, hog, meat at 0.10 ppm and hog, meat 

byproducts at 0.70 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. Plant metabolism studies with fluopyram were 

performed in grapes, potatoes, and beans after spray applications, on red bell 

pepper after drip irrigation and wheat after seed treatment. The metabolism in all 

cases was very similar. The main reactions involved were hydroxylation of the 

parent compound to AE C656948-7-hydroxy and AE C656948-8-hydroxy,

conjugation of the hydroxylated parent compound mainly with sugars, and cleavage 

of the molecule leading to AE C656948-benzamide, AE C656948-pyridyl-acetic acid 

(PAA) and AE C656948-carboxylic acid (PCA).
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2. Analytical method. Fluopyram is the residue of concern for enforcement 

and risk assessment in plant commodities required for analysis based on the 

metabolic profile, except for legumes and oilseeds where flupopyram-benzamide is 

also included for risk assessment purposes. In animal commodities, the residue of 

concern is fluopyram and fluopyram-benzamide. In animal commodities the residue 

of concern for risk assessment concern includes fluopyram and its metabolites 

AE C656948-benzamide, AE C656948-E-olefine, AE C656948-Z-olefine and 

AE C656948-7-hydroxy (cattle only). The analytical methods involve solvent 

extraction, filtration and addition of an isotopically labeled internal standards

followed by solid phase extraction. Quantitation is by high performance liquid 

chromatography-electrospray ionization/tandem mass spectrometry (LC/MS/MS).

3. Magnitude of residues. Magnitude of the residue trials were conducted in 

the various required regions across the United States in accordance with EPA 

guidance for crop field trials under OCSPP 860.1500 to support the requested 

tolerances.

B. Toxicological Profile

1. Acute toxicity. Fluopyram has low acute toxicity to mammals irrespective 

of the route of exposure (oral, percutaneous or inhalation exposure). It is not a skin 

sensitizer, it is non-irritating to skin and causes only a minimal reversible redness of 

the conjunctivae in the rabbit eye. Overall it is classified as Toxicity Classification 

III. In an acute neurotoxicity study a NOAEL of 125 mg/kg and 50 mg/kg was 

established for males and females, respectively based on slight decreases in 

measures of motor and locomotor activity, clinical signs and decreased body 

temperature. 

2. Genotoxicty. Genotoxicity potential was evaluated in a series in vitro and in 

vivo tests. There was no indication of genotoxicity in the presence or absence of 

metabolic activation in either the bacterial reverse mutation, mammalian gene 

mutation tests. In vitro chromosome aberration test, or the in vivo mouse 

micronucleus test. These studies demonstrated that fluopyram has no genotoxic 

potential.

3. Reproductive and developmental toxicity. In the rat two-generation 

reproduction study, the parental systemic NOAEL was 220 ppm (14.5 mg/kg/day in 

males, 17.2 mg/kg/day in females) based on clinical pathology changes, increased 

liver weight, protein droplet nephropathy (males) and centrilobular hypertrophy. 

The reproductive NOAEL was 1200 ppm in both males and females (82.8 mg/kg/day 

in males and 93.1 mg/kg/day females), based on the lack of reproductive findings 

observed in the highest dose tested. The offspring NOAEL was 220 ppm 

(17.0 mg/kg/day) based on maternal effects leading to secondarily-mediated effects 

on pup weight and pup weight gain. Also noted was a slight delay in preputial 

separation and decreased spleen and thymus weights for F2-pups (both findings 

considered secondary to pup weight decrease). In a rat developmental toxicity 
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study, the maternal NOAEL was 30 mg/kg/day, based on a transient reduction on 

maternal body weight gain and food consumption. The fetal NOEL was 150 

mg/kg/day based on decreased fetal body weight and the incidence of two minor 

variations at both the visceral and skeletal evaluation. In a rabbit developmental 

toxicity study the NOEL was 25 mg/kg/day both in the dam (reduced body weight 

gain and food consumption) and in terms of fetal development (decreased fetal body 

weight) in the New Zealand White rabbit. 

4. Subchronic toxicity. Subchronic studies showed that the liver is the major 

target organ in rats, mice, and dogs. The effects observed were consistent with the 

induction of cytochrome P450. In addition to the liver, the thyroid and kidney 

(males) were also target organs in rats. In the male rat, hyaline droplet nephropathy 

was observed. The thyroid gland effects were secondary to the liver toxicity. In mice 

adrenal glands, a lower incidence of ceroid pigment was noted in males, whilst a 

greater incidence of minimal to slight cortical vacuolation was observed in females.

The most sensitive species is considered to be the rat. The dog appeared to be less 

sensitive than the rat but of similar sensitivity to the mouse. Overall, the lowest 

NOAEL was observed in the subchronic rat study. In this study the NOAEL for the 

rat was established at 3.6 and 14.6 mg/kg bw/day in males and females, respectively. 

However, the NOAEL in the male rats was based on the specific hyaline droplet 

nephropathy (and associated effects) observed at the dose level of 12.5 mg/kg/day 

which is known to be non-relevant for humans since this specific nephropathy is due 

to an accumulation of 2μ-globulin in the proximal tubules, a protein that is only 

found in trace amounts in humans. Therefore the relevant NOAEL was considered 

to be 12.5 mg/kg/day since there was no other adverse effect at this dose level. This 

NOAEL is also comparable with the NOAEL in the 1-year dog study (13.2 

mg/kg/day) and the parental and offspring NOAELs (14.5 and 17.0 mg/kg/day, 

respectively) in the reproduction study. 

In a 90-day neurotoxicity study at 0, 100, 500 and 2500 ppm, no evidence of 

neurotoxicity was observed at any treatment level. Treatment-related findings of 

general toxicity at the high dose consisted of decreased body weight, total body 

weight gain and food consumption in males and females, increased cholesterol and 

triglyceride levels in males and/or females and decreased terminal body weight in 

females. Also, liver and kidney weights (absolute and relative) were increased in 

high-dose males and liver weight (absolute and relative) was increased in high-dose 

females. The only finding at the mid-dose was decreased food consumption in 

females, which was not associated with any effect on body weight. Based on 

neurotoxicology endpoints, a NOAEL of 2500 ppm was established for males and 

females (164.2 and 197.1 mg/kg for male and female rats, respectively).

In a four week dermal toxicity study in rats, a NOAEL of 300 mg/kg/day was 

established based on increased serum cholesterol levels in females, an increased 

prothrombin time in males and effects on the liver (increased liver weights for males 

and females associated with hepatic hypertrophy). The increased liver weights and 

hypertrophy in the high dose group were attributed to hepatic enzyme induction 

and thus were considered to be an adaptive response to fluopyram.
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5. Chronic toxicity. In the rat combined chronic toxicity and carcinogenicity 

study, retinal atrophy was observed only in high dose females. There was marked 

treatment-related liver toxicity together with nephropathy in the kidney and 

follicular cell hypertrophy in the thyroid gland. Liver cell tumors (carcinoma and 

adenoma) were observed in high dose females. Mechanistic data support a nongenotoxic, threshold phenobarbital-like mode of action resulting in liver cell tumor

formation in the female rat. The mode of action for phenobarbital-like inducers is 

considered to be of limited relevance to humans.

In a mouse carcinogenicity study, the target organs were the liver, kidney and 

thyroid gland. Nephropathy was observed in the kidney in high dose females. The 

principal change noted in the liver was centrilobular to panlobular hypertrophy, 

which was seen in both sexes, and hepatocellular single cell degeneration /necrosis in 

males. Treatment-related follicular cell hyperplasia was observed in both sexes. 

Thyroid gland follicular cell adenomas were observed in high dose males. 

Mechanistic data support a non-genotoxic indirect phenobarbital-like mode of 

action (secondary to liver effects that increased elimination of thyroid hormones ) 

for which a clear NOAEL was established at 30 ppm (1.20 and 1.68 mg/kg/day in 

males and females, respectively). And as in the rat, a phernobarbital-like mode of 

action is considered to be limited relevance to humans. 

6. Animal metabolism. Metabolism studies show that fluopyram is rapidly and 

almost completely absorbed by rats following oral gavage administration.

Fluopyram was extensively metabolized as evidenced by the low percentage of 

eliminated unchanged parent compound. The metabolism of fluopyram in male and 

female rats was principally oxidative and took place mainly at the ethylene bridge of 

the molecule. Some cleavage of the rings was observed as was conjugation of several 

hydroxylated metabolites with glucuronic acid and to a lesser extent with sulfate. 

The metabolic transformation of the parent compound was generally more 

pronounced in male rats.

7. Metabolite toxicology. Not applicable as parent is the principal toxicant.

8. Endocrine disruption. Fluopyram showed no indication of endocrine 

disrupting potential within any of the reproductive, developmental, or repeat-dose 

study.

C. Aggregate Exposure

1. Dietary exposure. The toxicological and exposure database for fluopyram is 

considered complete. There was no indication of an increased sensitivity of the 

young in any studies including the reproductive and developmental studies in rats 

and rabbits. Therefore, the special FQPA safety factor can be reduced to 1X and an

uncertainty factor of 100 is adequate to account for inter- and intra- species 

variability. Acute and chronic Population Adjusted Doses (aPAD and cPAD) are, 

therefore, the same as the reference doses for the populations and subpopulations of 
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interest. Acute dietary exposure was expressed as a percentage of the aPAD of 0.5 

mg/kg bw/day from a NOAEL of 50 mg/kg bw/day established for females, based on 

slight decreases in measures of motor and locomotor activity in the acute 

neurotoxicity study, with an uncertainty factor of 100. Chronic dietary exposure 

was expressed as a percentage of the chronic Population Adjusted Dose (cPAD) of 

0.012 mg/kg bw/day based on a NOAEL of 1.2 mg/kg bw/day in the rat 

chronic/carcinogenicity study with an uncertainty factor of 100. Mechanistic studies 

which show that the mouse thyroid and rat liver cell tumors mentioned in the 

chronic section above, are not relevant to humans and thus a q1* assessment is not 

required, have been submitted to the Agency for review by the Cancer Assessment 

Review Committee (CARC). In the interim, a cancer dietary assessment with the 

q1* derived from the rat liver cell tumors (0.0115) has been conducted.

i. Food. A Tier 1 acute and non-cancer chronic and a Tier 3 cancer dietary 

risk assessments were conducted to evaluate the dietary exposure of the U.S. 

population and selected subpopulations to fluopyram residues. This assessment 

includes all current crop uses and the proposed uses of fluopyram as seed treatment 

on soybean and cotton and soil application on cotton and peanuts. In addition, new 

field trial residues for rotational crops grains CG15 (except rice) and CG16 and 

revised secondary residues in tissues and milk were included in dietary assessments. 

Tier 3 assessments adjustments were made to the crop residue values to represent 

the effects of commercial and domestic preparation and processing and 

incorporated Projected Percent Crop Treated (PPCT) based on the market leader 

method guidance developed by BEAD/EPA. For rotational crops, the PPCT was 

estimated based on primary crop acres and proportion of rotational crop acres. The 

acute/chronic (Tier 1) and cancer (Tier 3) assessments were conducted using 

DEEM-FCID Version 3.14. Consumption data used in this program were taken 

from NHANES/WWEIA 2003-2008. Acute exposure (95th percentile) for food only 

utilizes 1.9% of the aPAD for the US Population and 5.5% for Children 1-2 yrs. old, 

the most highly exposed subpopulation. Chronic exposure utilizes 1.4% of the 

cPAD for the US Population and 6.3% of the cPAD for Children 1-2 yrs. old, the 

most highly exposed subpopulation. The cancer risk for food only for the U.S. 

Population is 1.51 x 10-6.

ii. Drinking water. The new proposed uses of fluopyram on soybean, cotton 

and peanuts would not have a significant impact on drinking water concentrations 

since these uses are as seed treatment and soil applications. Therefore, the 

Estimated Drinking Water Concentrations (EDWCs) associated with fluopyram use

on cotton, soybeans, vegetables, grapes, fruits, turf, ornamentals and industrial 

crops were calculated using the EPA's screening-level models, SCI-GROW and 

PRZM/EXAMS to calculate Tier I ground water and Tier II surface water EDWCs, 

respectively. EDWCs were calculated for fluopyram parent, which is considered the 

residue of concern based on laboratory and field studies which showed limited 

degradation products. The maximum shallow ground water concentration 

estimated by SCI-GROW was 0.49 ppb, indicating that the potential exposure to 

fluopyram in drinking water from ground water sources is low. In surface water, 
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the peak (acute) EDWCs was 13 ppb and the annual average (chronic) EDWCs was 

4.9 ppb. The highest 30 year average chronic (cancer) value was 3.5 ppb. These 

EDWCs are highly conservative values generated from Tier I models and based on 

default PCAs (Percent Crop Area). 

The addition of the acute estimated drinking water concentration (EDWC) of 13 

ppb resulted in 2.0% of the aPAD utilized for the US Population and 5.6% utilized 

for Children 1-2 yrs. old, the most highly exposed subpopulation. The addition of 

the chronic EDWC of 4.9 ppb utilized 2.2% of the cPAD for the US Population and 

7.5% of the cPAD for Children 1-2 yrs. old, the most highly exposed subpopulation. 

The cancer risk for food and drinking water for the US Population is 2.65 x 10-6. In 

conclusion, the results of the acute, chronic and cancer dietary exposure analyses 

(including drinking water) are acceptable for all population subgroups examined. 

Therefore, there is a reasonable certainty that no harm will result from exposure to 

potential residues of fluopyram in food and water.

2. Non-dietary exposure. There are no residential uses currently proposed for 

fluopyram. 

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” 

concerning the cumulative effects of a particular pesticide’s residues and “other 

substances that have a common mechanism of toxicity.” Fluopyram is a novel 

fungicide of the chemical class of pyridylethylamides. EPA has not made a common 

mechanism of toxicity finding as to fluopyram and any other substances and 

fluopyram does not appear to produce a toxic metabolite produced by other 

substances.

E. Safety Determination

1. U.S. population. Risk assessments for fluopyram are based on a complete 

and reliable toxicity data package and highly conservative assumptions. Chronic 

aggregate dietary exposure (food and water) will utilize 2.2% of the cPAD for the 

US Population. Acute aggregate dietary exposure (food and water) for U.S. adult 

population, utilizes 2.0% of the aPAD. A conservative cancer risk estimate results 

in a risk of 2.65 x 10-6. Therefore, there is a reasonable certainty that no harm will 

occur to the US Population from aggregate exposure (food, drinking water and nondietary) to residues of fluopyram.

2. Infants and children. The toxicological and exposure database for 

fluopyram is considered complete. There was no indication of an increased 

sensitivity of the young in any studies including the reproductive and developmental 

studies in rats and rabbits. Therefore, the special FQPA safety factor can be 

reduced to 1X and an uncertainty factor of 100 is adequate. Chronic aggregate 
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dietary exposure (food and water) will utilize 7.5% of the cPAD for Children 1-2

yrs. old, the most highly exposed subpopulation. Acute aggregate dietary exposure 

(food and water) utilizes 5.6% of the aPAD for Children 1-2 yrs. old, the most highly 

exposed subpopulation. Therefore, there is a reasonable certainty that no harm will 

occur to infants and children from aggregate exposure (food, drinking water and 

non-dietary) to residues of fluopyram.

F. International Tolerances

Tolerances for soybean have been established as 0.2 ppm in the EU and 

0.1 ppm in Canada (as a rotational crop). In the EU, tolerances for fluopyram have 

been established for: barley, buckwheat, millet and oats (0.1 ppm); maize 

(0.02 ppm); rye and wheat (0.8 ppm), sorghum (1.5 ppm), peanut (0.02 ppm) and 

cotton seed (0.10 ppm). In Canada, tolerances for fluopuram have been established 

as follows: barley, buckwheat, millet and oats (1.5 ppm); maize (1.5 ppm); rye and 

wheat (1.5 ppm) and sorghum (1.5 ppm) as rotational crops. Tolerances for milk 

have been established as 0.07 ppm by CODEX and 0.10 ppm in the EU. In the EU 

tolerances have been established in livestock as follows: Beef fat (0.10 ppm), beef, 

byproducts (0.70 ppm), beef, muscle (0.10 ppm), egg (0.15 ppm), poultry fat (0.10 

ppm), poultry, meat (0.10 ppm), poultry meat byproducts (0.20 ppm), swine, fat 

(0.05 ppm), swine, meat (0.10 ppm), and swine meat byproducts (0.70 ppm).