EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

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[ 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 Cosme tic 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 info rmation regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully eval uated the sufficiency of the submitted data at this time or whether the data supports gr anting 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 metaboli sm of fluopyram in cereals after seed dressing was determined from the first ro tation 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, conju gation of the hydroxylated parent compound mainly with sugars, and cleavage of the molecule leading to AE C656948- benzamide, AE C656948-pyridyl-acetic ac id (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 extr action, 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 a nd causes only a minimal reversible redness of the conjunctivae in the rabbit eye. Overall it is classified as T oxicity Classification III. In an acute neurotoxicity study a nd 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 locomo tor activity, clinical signs and decreased body temperature.]

2. Genotoxicty. [Genotoxicity potential was eval uated 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 offs pring NOAEL was 220 ppm (17.0 mg/kg/day) based on maternal effects leading to seco ndarily-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 developmen tal toxicity study, the maternal NOAEL3

was 30 mg/kg/day, based on a transient reduc tion 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 varia tions at both the visceral and skeletal evaluation. In a rabbit developmental to xicity study the NOEL was 25 mg/kg/day both in the dam (reduced body weight gai n and food consumption) and in terms of fetal development (decreased fetal body weig ht) 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 additi on to the liver, the thyroid and kidney (males) were also target organs in rats. In the male rat, specific nephropathy (hyaline droplet nephropathy) was observ ed. The thyroid gland effects were secondary to the liver toxicity. In mice adre nal 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 mo st sensitive species is considered to be the rat. The dog appeared to be less sensitiv e 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 drople t 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 α 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 treatmen t 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 female s 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 t oxicity 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 carcinogenicitystudy eye lesions were observed in high dose females. There was marked treatmentrelated liver toxicity together with nephrop athy 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 s upport the hypothesis of a non-genotoxic indirect threshold mechanism (likely to be secondary to the liver effect) for the formation of thyroid follic ular cell adenomas in male mice for which a clear NOAEL was established at 30 ppm (1.20 a nd 1.68 mg/kg/day in males and females, respectively) in the oncogenicity stud y. Furthermore, the relevance of this

mechanism to humans is considered as lim ited since it is well recognized and accepted that humans are considerably less sensitive than rodent s to elevated TSH level or alteration of the thyroid functi on and to thyroid fo llicular 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 unchang ed parent compound found only in low percentages of the recovered dose. The meta bolism of fluopyram in male and female rats was principally oxidative and took pla ce mainly at the ethylene bridge of the molecule. Some cleavage of the rings was observed as was conjugation of several hydroxylated metabolites with glucuronic ac id and to a lesser extent with sulfate.

The metabolic transformation of th e 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 potentia l. 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 fluopyram5

is considered complete. There was no indica tion of an increased sensitivity of the young in any studies including the reproduc tive and developmental studies in rats and rabbits. Therefore, the special FQPA ca n be reduced to 1X and an uncertainty factor of 100 is adequate to account for in ter- 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 establ ished for females, based on slight

decreases in measures of motor and locomo tor activity in the acute neurotoxicity study, with an uncertainty factor of 100. Chronic dietary exposure was expressed as a percentage of the chronic Populatio n Adjusted Dose (cPAD) of 0.012 mg/kg bw/day based on a NOAEL of 1.2 mg/kg bw/d ay in the rat chronic/carcinogenicity study with an uncertainty factor of 100. A second petition [PP# 8F7463] to establish

further tolerances for fl uopyram 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 ri sk assessments were conducted to evaluate the dietary exposure of the U.S. population and selected subpopulations to fluopyram residues. This assessment in cludes 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 PP CT of two crops, lettuce and spinach, which were high contributors and were furth er 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 da ta 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. Chro nic exposure utilizes 6.3% of the cPAD for the US Population and 21.4% of the cPAD fo r Children 1-2, the most highly exposed subpopulation.]

ii. Drinking water. [ Estimated Drinking Water Concentrations (EDWCs) associated with fluopyram use on vegetabl es, 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 Screenin g Tool: Version 1.1.1, March 25, 2008) to calculate Tier I ground water and surf ace water EDWCs, respectively. EDWCs were calculated for fluopyram parent, whic h is considered the residue of concern based on laboratory and field studies whic h showed limited degradation products. The maximum shallow ground water concen tration 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 were6

incorporated into the dietary risk. Thes e EDWCs are highly conservative values generated from Tier I models and based on default PCAs (Percent Crop Area). The

addition of the acute estimated drinki ng 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 subpo pulation. The addition of the chronic EDWC of 12.2 ppb utilized 8.5% of the cP AD 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 ha rm will result from exposure to potential residues of fluopyram in food and water.]

2. Non-dietary exposure

. [There is a potential for sh ort-term post-application exposures for golfers based on the proposed use of fluopyram. An MOE of 100 is adequate to ensure protection of golfers fr om fluopyram via the dermal exposures. Golfer exposure is expected through mini mal 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 cm 2/hr and an exposure duration of 4 hours to estimate post-application exposure. Exposure es timates 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 d ermal 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 be tween rat and human skin in an in vitro dermal absorption study. The calculated MOE fo r the golfer is 416,600 and, therefore, does

not exceed EPA’s level of concern. Furth ermore 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, wh en considering whether to establish, modify, or revoke a tolerance, the Ag ency consider “available information” concerning the cumulative effects of a pa rticular pesticide’s residues and “other

substances that have a common mechanism of toxicity.” Fluopyram is a novel fungicide of the chemical class of pyridy lethylamides. 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 hi ghly conservative assumptions. Chronic aggregate dietary exposure (food and water) will utilize less than 10% of the cPAD7

for the US Population. Acute aggregate diet ary 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 ha rm 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 in cluding 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 agg regate 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 ha rm will occur to infants and children from aggregate exposure (food, drinking wat er and non-dietary) to residues of fluopyram.]

F. International Tolerances

[No tolerances have been establishe d for fluopyram. Fluopyram is being

reviewed as an OECD Joint Review betw een the European Union (Germany as Rapporteur), the U.S. and Canada. Harmonized tolerances have been proposed to minimize trade barriers between the participating regions.]