Document ID: EPA-HQ-OPP-2013-0662-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-05-23T04:00Z

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).

	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 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 2u-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.

	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 non-genotoxic, 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 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, 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 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 safety factor can be reduced to 1X and an uncertainty factor of 100 is adequate.  Chronic aggregate 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).