EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [insert name and telephone number with area 

code] 

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: 

[ Bayer CropScience] 

[PP# 8F7358] 

 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 [grape] at [2.0] parts per million (ppm), 

[strawberry] at [2.0] ppm and [tomato] at [1.0] 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 and on red bell 

pepper after drip irrigation. The metabolism of fluopyram in cereals after seed 

dressing was determined from the first rotation in the confined rotational crop 

metabolism studies. The metabolism in all plants 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).] 
2

 2. Analytical method. [Fluopyram was determined to be the only analyte 

required for analysis based on the metabolic profile in plants, the short pre-harvest 

intervals analyzed, and results from preliminary residues trials in Europe. The 

analytical method involves solvent extraction, filtration, and addition of an 

isotopically labeled internal standard 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 residue trials were conducted in the 

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

for crop field trials under OPPTS 860.1500 to support the requested tolerances. 

Additional trials, including greenhouse trials in selected crops, have been conducted 

in the European Union as supporting data to propose harmonized tolerances 

between the U.S., Canada and the European Union.] 

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 and a follow-up 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 of tests 

including in vitro and in vivo tests. There was no indication of gene mutation either 

in the presence or absence of metabolic activation in both the bacterial reverse 

mutation and mammalian gene mutation tests. The in vitro chromosome aberration 

test and the in vivo mouse micronucleus test were also both negative. 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 no 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 decrease 

in spleen and thymus weights for F2-pups (both findings considered secondary to 

pup weight decrease). In a rat developmental toxicity study, the maternal NOAEL 
3

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 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, specific nephropathy 

(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 α2μ-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 an increased cholesterol concentration 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.]
4

 5. Chronic toxicity. [In the rat combined chronic toxicity and carcinogenicity 

study eye lesions were observed in high dose females. There was marked treatmentrelated 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. Additional data support an indirect, non-genotoxic, 

phenobarbital-like mechanism of action regarding the liver cell tumor formation 

observed 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 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. Additional mechanistic data support the hypothesis of a non-genotoxic 

indirect threshold mechanism (likely to be secondary to the liver effect) for the 

formation of thyroid follicular cell adenomas in male mice for which a clear 

NOAEL was established at 30 ppm (1.20 and 1.68 mg/kg/day in males and females, 

respectively) in the oncogenicity study. Furthermore, the relevance of this 

mechanism to humans is considered as limited since it is well recognized and 

accepted that humans are considerably less sensitive than rodents to elevated TSH 

level or alteration of the thyroid function and to thyroid follicular cell tumors.]

 6. Animal metabolism. [Available metabolism studies have established that 

fluopyram is rapidly and almost completely absorbed (>93% of the dose in bile 

fistulation experiments) by rats following oral administration by gavage. Fluopyram 

was extensively metabolized with unchanged parent compound found only in low 

percentages of the recovered dose. 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 compound of 

concern.]

 8. Endocrine disruption. [There is no evidence to suggest that fluopyram has 

any primary endocrine disruptive potential. Reproductive and developmental 

findings provided no evidence of an enhanced sensitivity of the young. Bayer 

CropScience will conduct any studies that may be required under EPA’s Endocrine 

Disrupter Screening Program.]

C. Aggregate Exposure

 1. Dietary exposure. [The toxicological and exposure database for fluopyram 
5

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 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 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. A second petition [PP# 8F7463] to establish 

further tolerances for fluopyram was submitted to EPA on October 16, 2008. For 

completeness potential exposure from all pending submissions has been assessed 

and described below.] 

 i. Food. [Tier 3 acute and chronic 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 proposed crops and secondary 

residues in tissues and milk. Projected Percent Crop Treated (PPCT) were generally 

based on the market leader except for the PPCT of two crops, lettuce and spinach, 

which were high contributors and were further refined to appropriately reflect the 

disease spectrum against which they will be used. Adjustments were made to the 

crop residue values to represent the effects of commercial and domestic preparation 

and processing. The Tier 3 acute and chronic assessments were conducted using 

CARES Version 3.0 software. Consumption data used in this program were taken 

from USDA’s CSFII, 1994-1996, 1998. Acute exposure (99.9th percentile) for food 

only utilizes 4.3% of the aPAD for the US Population and 6.8% for Children 1-2, the 

most highly exposed subpopulation. Chronic exposure utilizes 6.3% of the cPAD for 

the US Population and 21.4% of the cPAD for Children 1-2, the most highly exposed 

subpopulation.]

 ii. Drinking water. [Estimated Drinking Water Concentrations (EDWCs) 

associated with fluopyram use on vegetables, grapes, fruits, turf, ornamentals and 

industrial crops were calculated using the EPA's screening-level models, SCIGROW (Screening Concentration in Ground Water: Version 2.3, July 28, 2003) and 

FIRST (FQPA Index Reservoir Screening Tool: Version 1.1.1, March 25, 2008) to 

calculate Tier I ground water and 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, the peak (acute) EDWCs 

ranged from 13.8 ppb to 29.3 ppb and the annual average (chronic) EDWCs ranged 

from 5.7 ppb to 12.2 ppb. The values from the highest exposure scenarios were 
6

incorporated into the dietary risk. 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 29.3 ppb 

resulted in 4.5% of the aPAD utilized for the US Population and 7.1% utilized for 

Children 1-2, the most highly exposed subpopulation. The addition of the chronic 

EDWC of 12.2 ppb utilized 8.5% of the cPAD for the US Population and 24.7% of 

the cPAD for Children 1-2, the most highly exposed subpopulation. In conclusion, 

the results of the acute and chronic Tier 3 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 is a potential for short-term post-application 

exposures for golfers based on the proposed use of fluopyram. An MOE of 100 is 

adequate to ensure protection of golfers from fluopyram via the dermal exposures. 

Golfer exposure is expected through minimal hand contact with the golf ball and 

dermal contact to the lower legs from treated plant surfaces. EPA uses a TC 

(transfer coefficient) of 500 cm2/hr and an exposure duration of 4 hours to estimate 

post-application exposure. Exposure estimates were assessed on the day of 

treatment. The appropriate endpoint for short term dermal exposure is the 12.5 

mg/kg/day NOAEL from the 90-day rat oral toxicity study. Because the study 

involved oral administration, the dermal exposure is adjusted for the dermal 

absorption potential of fluopyram. The dermal absorption adjustment factor of 

1.7% is based on a in vivo rat dermal absorption factor of 12% adjusted by a 7-fold 

factor for the relative difference between rat and human skin in an in vitro dermal 

absorption study. The calculated MOE for the golfer is 416,600 and, therefore, does 

not exceed EPA’s level of concern. Furthermore golfer exposure is clearly minimal 

and will have no significant impact on the aggregate exposure calculate for dietary 

exposure from food and water.]

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 less than 10% of the cPAD 
7

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

adult population, utilizes less than 5% of the aPAD. Non-dietary exposure to golfers 

is minimal. Therefore, there is a reasonable certainty that no harm will occur to the 

US Population from aggregate exposure (food, drinking water and non-dietary) 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 can be reduced to 1X and 

an uncertainty factor of 100 is adequate. Chronic aggregate dietary exposure (food 

and water) will utilize less than and 25% of the cPAD for Children 1-2, the most 

highly exposed subpopulation. Acute aggregate dietary exposure (food and water) 

utilizes less than 10% of the aPAD for Children 1-2, the most highly exposed 

subpopulation. Non-dietary exposure to children is not anticipated. 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

 [No tolerances have been established for fluopyram. Fluopyram is being 

reviewed as an OECD Joint Review between the European Union (Germany as 

Rapporteur), the U.S. and Canada. Harmonized tolerances have been proposed to 

minimize trade barriers between the participating regions.]