Document ID: EPA-HQ-OPP-2015-0443-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-08-28T04:00Z

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]

[Insert petition number]

	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:

1) 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 commodities [artichoke, globe] at [4.0] ppm,  [aspirated grain fractions] at [50.0] ppm, [peanut hay] at [40.0] ppm, [hops] at [60.0] ppm, [root vegetables; except beet, sugar, root, crop subgroup 1B] at [0.30] ppm, [tuberous and corm vegetables, crop subgroup 1C] at [0.10] ppm, [potato wet peel] at [0.30] ppm, [vegetables, leaves of root and tuber, crop group 2] at [30.0] ppm, [bulb vegetables, bulb onion (crop subgroup) 3-07A] at [0.30] ppm, [bulb vegetables, green onions (crop subgroup 3-07B] at [15.0] ppm [Leafy greens (crop subgroup 4A), without spinach] at [20.0] ppm, [Leafy greens (crop subgroup 4A), Spinach] at [40.0] ppm, [leafy petioles subgroup, celery  (crop subgroup 4B)] at [20.0] ppm, [brassica leafy vegetables: head and stem (crop subgroup 5A)] at [4.0] ppm, [brassica leafy vegetables: leafy greens(crop subgroup 5B)] at [50.0] ppm, [soybean, seed] at [0.30] ppm, [soybean forage] at [9.0] ppm, [soybean hay] at [30.0] ppm, [legume vegetables: edible podded (crop subgroup 6A)] at [4.0] ppm, [legume vegetables: succulent shelled peas and beans (crop subgroup 6B)] at [0.20] ppm, [legume vegetables: dried shelled peas and beans (crop subgroup 6C)] at [0.70] ppm, [Vegetable, foliage of legume vegetables, forage, hay and vines, forage (crop group 7)] at [90.0] ppm, [fruiting vegetables, tomato subgroup (crop subgroup 8-10A)] at [1.00] ppm, [fruiting vegetables, pepper/eggplant subgroup (crop subgroup 8-10B)] at [3.00] ppm, [cucurbit vegetables (crop group 9A), melon subgroup] at [0.90] ppm, [cucurbit vegetables (crop group 9B), cucumber/squash subgroup] at [0.30] ppm, [citrus fruits (crop group 10-10)] at [0.90] ppm, [citrus oil] at [8.0] ppm, [pome fruit (crop group 11-10)] at [2.0] ppm, [stone fruit (crop group 12-12A), cherry subgroup] at [2.00] ppm, [stone fruit (crop group 12-12B), peach Subgroup] at [1.00] ppm, [stone fruit (crop group 12-12C), plum Subgroup] at [0.50] ppm,  [berries and small fruit: caneberry (crop subgroup 13-07A] at [5.0] ppm, [berries and small fruit: bushberry (crop subgroup 13-07B] at [7.0] ppm, [raisins] at [4.0] ppm, [berries and small fruit, small fruit vine climbing, except fuzzy kiwi (crop subgroup 13-07F)] at [1.5] ppm, [berries and small fruit: low growing berry (crop subgroup 13-07G)] at [2.0] ppm,  [sorghum, grain] at [1.5] ppm, [wheat milled by-products] at [2.0] ppm, [grass forage, fodder and hay: forage (crop group 17)] at [80.0] ppm, [herb crop (subcrop group 19A)] at [70.0] ppm, [Dill seed] at [70.00] ppm, [herbs, dried ] at [400] ppm, [oilseeds, rapeseed, canola (crop subgroup 20A)] at [0.70] ppm, [oilseeds, sunflower, seed (crop subgroup 20B)] at [0.70] ppm, [oilseeds: cottonseed (crop subgroup 20C)] at [0.80] ppm,; and and in or on animal commodities: [chicken,  meat byproducts] at [0.40] ppm, [chicken, fat] at [0.15] ppm, [chicken, meat] at [0.10] ppm, , [goat, fat] at [4.00] ppm, [goat, meat] at [4.00] ppm; and

2) amending existing tolerances for residues of [fluopyram (N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide)] in or on the raw agricultural commodities [peanut] at [0.20] ppm, [sugar beet, roots] at [0.09] ppm, [soybean forage] at [9.0] ppm, [soybean hay] at [30.0] ppm, [tree nuts (crop group 14)] at [0.04] ppm, [almond hulls] at [10.00] ppm, [Grain, Cereal , except rice and sorghum(crop group 15)] at [0.90] ppm, [cereal grain, except rice, forage, fodder and straw (crop group 16)] at [20.0] ppm,  [cotton gin by-product] at [30.00] ppm; and in or on animal commodities: [cattle, meat byproducts] at [40.00] ppm, [cattle, fat] at [4.00] ppm, [cattle, meat] at [4.00] ppm, [milk, cattle] at [2.00] ppm, [eggs, chicken] at [0.20] ppm, [hog, meat byproducts] at [0.40] ppm, [hog, fat] at [0.04] ppm, , and [hog, meat] at [0.04] ppm, [horse, meat byproducts] at [40.00] ppm, [horse, fat] at [4.00] ppm, [horse, meat] at [4.00] ppm, [goat, meat byproducts] at [40.00] ppm, [sheep, meat byproducts] at [40.00] ppm, [sheep, fat] at [4.00] ppm, [sheep, meat] at [4.00] ppm; and  

3) deleting existing single tolerances for residues of [fluopyram (N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide)] in or on the raw agricultural commodities [apple] at [0.30] ppm, [bean, dry] at [0.09] ppm, [beet, sugar , roots] at [0.04] ppm, [apple wet pomace] at [0.60] ppm, [cherry] at [0.60] ppm, [grape, wine] at [2.0] ppm, [potato] at [0.02] ppm, [strawberry] at [1.5] ppm, [watermelon] at [1.0] ppm; and

4) establishing tolerance for indirect or inadvertent residues of [fluopyram (N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide)] in or on the raw agricultural commodities [sugarcane,  cane ] at [0.08] 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 in plant commodities required for analysis based on the metabolic profile, except for legumes and oilseeds where AE C656948-benzamide is also included for risk assessment purposes.  Fluopyram and AE C656948-benzamide are the residues of concern in milk, eggs and animal tissues.  The analytical methods for crops and animal matrices are similar and involve 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 and Canada in accordance with EPA guidance for crop field trials under OPPTS 860.1500 to support the requested tolerances.  Magnitude of the residue trials were conducted in greenhouses in Europe to support uses in selected crops.] 

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 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 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 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.]

	5. Chronic toxicity. [In the rat combined chronic toxicity and carcinogenicity study eye lesions were observed 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. 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 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 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 support the hypothesis that the mouse thyroid and rat liver tumors seen in the chronic studies are from a non-genotoxic indirect threshold mechanism and are not relevant to humans. A cancer (q1*) dietary risk assessment is not required. 
	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 method guidance developed by BEAD/EPA. 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 DEEM-FCID Ver.3.16 software.  Consumption data used in this program were taken from NHANES WWEIA 2003-2008.  Acute exposure (99.9th percentile) for food only utilizes 24% of the aPAD for the US Population and 42% for Children 1-2, the most highly exposed subpopulation. Chronic exposure utilizes 18% of the cPAD for the US Population and 61% 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 all crops were calculated using PRZM-GW (ver 1.07) and FIRST (FQPA Index Reservoir Screening Tool: Version 1.1.1, March 25, 2008) to calculate 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 acute and chronic ground water concentrations estimated by PRZM-GW were 69.5 ppb and 65 ppb, respectively, and were higher than the surface water estimates.The value from the highest PRZM-GW exposure scenarios were incorporated into the dietary risk assessment.  The addition of the acute estimated drinking water concentration (EDWC) of 69.5 ppb resulted in 25% of the aPAD utilized for the US Population and 43% utilized for Children 1-2, the most highly exposed subpopulation.  The addition of the chronic EDWC of 65 ppb utilized 29% of the cPAD for the US Population and 77% 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 exposure from non-dietary turf and ornamental proposed uses.  Fluopyram may be applied using foliar spray or chemigation to turf in golf courses, sport fields, residential, institutional, municipal, and commercial areas as well as field grown and container ornamentals (Christmas trees, ornamental sunflowers, and non-bearing cherries, pome fruit trees, tree-nuts, grapes, stone fruit trees, and citrus) in landscapes, nurseries, and greenhouses, lathhouses, shadehouses, interiorscapes and other enclosed structures.  All products are intended for professional use however, the possibility that a homeowner could obtain and apply these products.  Therefore, a potential for residential handler short-term exposure exists.  There is also a potential for short-term post-application exposure for golfers as well as adults and toddlers in residential settings.  An MOE of 100 is adequate to ensure protection of these populations from fluopyram via the dermal exposures.  For toddlers, an MOE of 100 is adequate to ensure protection via incidental oral exposures (hand-to-mouth, object-to-mouth, soil ingestion).  For all populations, exposure estimates were assessed based on the day of treatment.  All of the calculated MOEs were greater than 900 which is above the level of concern.

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 29% of the cPAD for the US Population. Acute aggregate dietary exposure (food and water) for the U.S. population, utilizes 25% of the aPAD.  Non-dietary and aggregate  MOEs (food, drinking water, and non-dietary) are above the Level of Concern.  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) utilizes 77% of the cPAD for Children 1-2, the most highly exposed subpopulation.  Acute aggregate dietary exposure (food and water) utilizes 43% of the aPAD for Children 1-2, the most highly exposed subpopulation.  The aggregate (food, drinking water, and incidental oral exposure) risk for Children 1-2 had a combined MOE = 108 which is above the level of concern (100).  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

	[In the EU, tolerances for fluopyram were established for: barley, buckwheat, millet and oats (0.1 ppm); maize (0.02 ppm); rye and wheat (0.8 ppm) and sorghum (1.5 ppm); artichoke, globe (0.5 ppm); hops (0.01 ppm); sugar beet roots (0.1 ppm); potatoes, root vegetables and corm vegetables (0.1 ppm); bulb vegetables (2 ppm); leafy vegetables (1.5 ppm); brassicas (0.7 ppm); soybean (0.2 ppm); legume, edible pod (0.9 ppm); fruiting vegetables (0.9 ppm); citrus (0.01 ppm); apple (0.6 ppm); stone fruit (1.5 ppm); grapes (1.5 ppm); tree nut (0.05 ppm); rape seed (canola) (0.6 ppm); sunflower, seed (0.1 ppm); cottonseed (0.1 ppm); meat (0.1 ppm); milk (0.3 ppm) and eggs (0.3).  In CODEX, tolerances for fluopyram were established for: sugar beet roots (0.04 ppm); potatoes, root vegetables and corm vegetables (0.03 ppm); bulb vegetables (1.5 ppm); leafy vegetables (1.5 ppm); brassicas (0.8 ppm); legume, dry bean (0.07 ppm); legume, chickpeas and dried lentils (0.07 ppm); apple (0.3 ppm); stone fruit (1.5 ppm); grapes (2.0 ppm); tree nut (0.04 ppm); rape seed (canola) (1.8 ppm); meat (0.5 ppm); milk (0.4 ppm) and eggs (0.3).  In Canada, tolerances for fluopyram were 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); artichoke, globe (0.02 ppm); sugar beet roots (0.1 ppm); potatoes, root vegetables and corm vegetables (0.02 ppm); soybean (0.01 ppm); legume, dry bean (0.09 ppm); legume, chickpeas and dried lentils (0.4 ppm); apple (0.5 ppm); stone fruit (1.5 ppm); grapes (2.0 ppm); tree nut (0.05 ppm); cottonseed (0.01 ppm); meat (0.4 ppm); milk (0.06 ppm) and eggs (0.06). ]