EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

Bayer CropScience

PP# 5 F8380

EPA has received a pesticide petition ( PP# 5 F8380 ) from Bayer CropScience, 2 T.W. Alexander Drive, P.O. Box 12014, Research Triangle Park, NC 27709 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21

U.S.C. 34 6a(d), to amend 40 CFR part 180 by establishing tolerances and/or changing existing tolerances for residues of trifloxystrobin (Benzeneacetic acid, (E,E)

- α

- (methoxyimino )

- 2

- [[[[1

- [3

- (trifluoromethyl) phenyl]ethylidene]amino]oxy]methyl]

- methyl ester) and the free form of its acid metabolite CGA

– 321113 ( ( E,E )

- methoxyimino

- [2

- [1

- (3

- trifluoromethyl

- phenyl)

- ethylideneaminooxymethyl]

- phenyl]acetic acid ) in or on the raw agricultural commodity cotton, unde linted seed, (Crop subgroup 20C at 0 .5 parts per million (ppm)

, cotton, gin byproducts at 3 parts per million (ppm ) and corn, field, forage at 8 parts per million (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 d a ta 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. The metabolism of trifloxystrobin in plants (cucumbers, apples, wheat, sugar beets and peanuts) is well understood. Identified metabolic pathways are substantially similar in plants and animals (goat, rat and hen). EPA has determined that trifloxystrobin parent and its metabolite CGA

- 321113 are the residues of concern for purposes of tolerance setting and risk assessment.

2. Analytical method. A practical analytical methodology for detecting and measuring levels of trifloxystrobin in or on raw agricultural commodities has been submitted. The limit of detection (LOD) for each analyte of this method is 0.08 ng injected, and the limit of quantitati on (LOQ) is 0.02 ppm. The method is based on crop specific cleanup procedures and determination by gas chromatography with nitrogen

phosphorus detection. A newer analytical method is available employing identical
solvent mixtures and solvent to matrix rat io (as the first method), deuterated internal standards, and liquid chromatography/mass spectrometry

- mass spectrometry (LC/MS

MS) with an electrospray interface, operated in the positive ion mode . The limits of detection (LOD) for total trifloxystrobin ra nge from 0.00 3 ppm to 0. 01 ppm, depending on the crops, and the limit of quantitation is 0.01 ppm.2

3. Magnitude of residues. Cotton: Foliar application: T welve field trials were conducted to measure the magnitude of prothioconazole and trifloxystrobin residues in/on cotton (representative test system for Crop Subgroup 20C, Cottonseed) following three
foliar applications of Proline 480 SC with Gem 500 SC Fungicide

. For all applications, individual application rates ranged from 0.196 to 0 .206 kg a.i. /ha for prothioconazole (0.175 to 0.184 lb a.i. /A) and from 0.137 to 0.146 kg a.i. /ha for trifloxystrobin (0.123 to
0.130 lb a.i. /A). Intervals between applications ranged from 12 to 15 days, and applications were made when the cotton plants w ere between BBCH 65 and 89 (BBCH 65: full flowering or “mid bloom”; BBCH 89: about 90% of bolls open). Total seasonal application rates ranged from 0.60 to 0.61 kg a.i. /ha for prothioconazole (0.53 to 0.55 lb
a.i. /A) and from 0.41 to 0.43 kg a.i. /ha for t rifloxystrobin (0.37 to 0.39 lb a.i. /A). In the harvest trials, seed cotton samples were collected at 27 to 31

- day pre

- harvest intervals (PHI)

. In three decline trials, seed cotton samples were collected at PHIs of 23

- to 26

- , 29

- to 30

- , 34

- to 36

- , 38

- to 40

- , and 43

- to 44

- day. Three trials (two decline and one harvest) were designated as stripper cotton trials to be harvested using stripper equipment. The HAFT total trifloxystrobin residues in/on cotton, undelinted seed following three foliar broadcast applications at a target PHI of 3 0 days was 0.27 ppm , with a maximum residue of 0.27 ppm

. The HAFT total trifloxystrobin residues in/on cotton, gin byproducts following three foliar broadcast applications at a target PHI of

3 0 days was 0 .99 ppm , with a maximum residue of 1.10 ppm

.

Two field trials were also conducted to measure the magnitude of trifloxystrobin residues in/on cotton processed commodities following 3 foliar applications at a 5X rate (0.625 lbs ai/A).

In

- furrow applicati on: Twelve field trials were conducted to measure the magnitude of trifloxystrobin residues in/on cotton (representative test system for Crop Subgroup 20C, Cottonseed) after a single in

- furrow spray application at planting of trifloxystrobin 50

WG Fungici de . The target application rate was 0.125 lbs a.i./A. The total trifloxystrobin residues were below the LOQ (<0.05 ppm) for all seed harvested at maturity. In two cotton processing trials, plots were treated at a 5X rate (283 g a.i./A). These trials yi elded no detectable total trifloxystrobin residues (<0.05 ppm) in all samples analyzed (gin trash, undelinted seed and refined oil).

Corn: Three field trials were conducted to measure the magnitude of prothioconazole and trifloxystrobin residues in/on corn forage, grain, and stover at a target 0

- day pre

- harvest interval (PHI) for corn forage and a target 14

- day PHI for corn grain and stover following applications of PROLINE SC4, Trilex 2.5 GAL, and GEM 500 SC FUNGICIDE via seed

treatment , in

- furrow application, and foliar spray applications. PROLINE SC4 is a suspension concentrate formulation containing 480 g prothioconazole per liter. Trilex 2.5 GAL is a suspension concentrate formulation containing 240 g trifloxystrobin per liter,
and GEM 500 SC FUNGICIDE is a suspension concentrate formulation containing 500 g trifloxystrobin per liter.

There was one control plot and four treated plots per trial. The first Treated plot received four foliar applications for the collection of forage a t a PHI of zero days.3

The second treated plot received four foliar applications for the collection of stover and grain at a PHI of 14 days. The third treated plot received treated seed followed first by an

in

- furrow application at planting, then by three foliar applications for the collection of corn forage at a PHI of zero days. The fourth treated plot received treated seed followed first by an in

- furrow application at planting, then by three foliar applications for the collection of corn stover and grain at a PHI of 14 days.

All applications were made with adjuvants (Induce, a non

- ionic surfactant, at 0.125 v/v%) using ground

- based equipment. Duplicate composite samples of corn forage, grain, and stover from the treated plots, along with single untreated control samples, were collected at crop maturity; this corresponded to BBCH 85 for corn forage (BBCH85 = Dough stage; kernels yellowish to yellow) and BBCH 87

– 89 for corn grain and stover (BBCH 87 = Physiological maturity, black dot/layer visible at base of kernels; BBCH 89 = Fully ripe; kernels hard and shiny).

The residues of trifloxystrobin (and its metabolite trifloxystrobin acid) were quantitated by high

- pressure liquid chromatography/triple stage quadrupole mass spectrometry (LC

MS/MS) using stable isotopically

- labeled internal standards. The individual analyte residues (parent and metabolite) were summed to give a total residue. Residue measurements below the analyte LOQ were summed into the total residue value as the analyte LOQ value.

Freezer sto rage stability studies indicate that total trifloxystrobin residues would be stable in corn during frozen storage for at least 24 months. Corn forage, stover, and grain were held in frozen storage for a maximum of six months prior to extraction.

The "tota l" trifloxystrobin residues in corn treated with four foliar applications were as follows: field corn forage samples (collected at a nominal 0

- day PHI) ranged from 2.35 ppm to 7.43 ppm with a HAFT of 6.60 ppm. Field corn stover samples (collected at a
nomi nal 14

- day PHI) ranged from 0.30 ppm to 2.54 ppm with a HAFT of 2.35 ppm. There were no trifloxystrobin residues (<0.020 ppm) in any of the corn grain samples (collected at a nominal 14

- day PHI).

The "total" trifloxystrobin residues in corn treated with a combination of seed treatment,

in

- furrow and foliar applications were as follows: field corn forage samples (collected at
a nominal 0

- day PHI) ranged from 1.89 ppm to 5.99 ppm with a HAFT of 4.75 ppm. Field corn stover samples (collected at a nominal 14

- day PHI) ranged from 0.42 ppm to 3.29 ppm with a HAFT of 2.57 ppm. There were no trifloxystrobin residues (<0.020 ppm) in any of the corn grain samples (collected at a nominal 14

- day PHI).

B. Toxicological Profile

1. Acute toxicity. There is a full battery of acute toxicity studies for trifloxystrobin. Trifloxystrobin is of mild acute toxicity by oral, dermal, or inhalation routes of exposure (Cat. I V ), however it is a strong dermal sensitizer. Trifloxystrobin is a mild ocular (Cat I I I ) and dermal irritant (Cat IV).4

2. Genotoxicty. No genotoxic activity is expected of trifloxystrobin under in

- vivo or physiological conditions. The compound has been tested for its potential to induce gene mutation and chromosom al changes in five different test systems. The only positive finding was seen in the in vitro test system (Chinese hamster V79 cells) as a slight increase in mutant frequency at a very narrow range (250

– 278  g /mL) of cytotoxic and precipitating concentrations (compound solubility in water was reported to be 0.61

 g /mL; precipitate was visually noted in culture medium at 150  g /mL). The chemical
was found to be non

- mutagenic in the in vivo system or all other in vitro systems. Consequently, the l imited gene mutation activity in the V79 cell line is considered a nonspecific effect under non

- physiological in vitro conditions and not indicative of a real mutagenic hazard.

3. Reproductive and developmental toxicity. In a developmental study in rats, reductions in body weight gain and food consumption were observed in the dams at 100 mg/kg/day. No teratogenic effects or any other effects were seen on pregnancy or fetal parameters except for the increased incidence of enlarg ed thymus at 1000 mg/kg/day. The developmental NOEL was 1000 mg/kg/day.

In the rabbit developmental study, body weight loss and reduced food consumption were observed in the dams at 50 mg/kg. No teratogenic effects or any other effects were seen on pregn ancy or fetal parameters except for the increase in skeletal anomaly of fused sternebrae

- 3 and

- 4 at the top dose level of 500 mg/kg. This finding is regarded as a marginal effect on skeletal development that could have resulted from the

40

- 65% lower food intake during treatment at this dose level. The developmental NOEL was 250 mg/kg.

In the 2

- generation rat reproduction study, body weight gain and food consumption were decreased at 750 ppm (55.3 mg/kg/day) , especially in females during lactation. Conseq uently, the reduced pup weight gain during lactation ( 750 ppm) and the slight delay in eye opening (1500 ppm) are judged to be a secondary effect of maternal toxicity. No other fetal effects or any reproductive changes were noted. The low developmental NO EL, 50 ppm (3.8 mg/kg) seen in this study was probably due to the lack of intermediate dose levels between 50 and 750 ppm. The reproductive NOAEL was 1500 ppm (=110.6 mg/kg/day)

.

4. Subchronic toxicity. In a subchronic study in r ats a NOAEL of 500 ppm (30.6

- 32.8 mg/kg/day) was found based on decreased body weights (males), hypertrophy of hepatocytes (males), and pancreatic atrophy observed at the LOAEL of 2000 pp m (127

- 133 mg/kg/day).

In mice, a NOAEL was determined at 500 ppm (76.9

- 110 mg/kg/day) based on increased liver weights and necrosis of hepatocytes observed at the LOAEL of 2000 pp m (315

- 425 mg/kg/day).5

A subchronic feeding study in dogs resulted in a NOAEL = 30 mg/kg/day. Increased liver weight and hepatocyte hypertrop hy in males were observed at the LOAEL of 150 mg/kg/day

.

In a 28

– day dermal toxicity study in rat s t he NOAEL was found at 100 mg/kg/day. Increased liver and kidney weight were observed at the LOAEL of 1,000 mg/kg/day

.

5. Chronic toxicity. A chronic feeding study in dogs established a no

- observed adverse effect level (NOAEL) of 5 mg/kg bw/day. The lowest effect level (LOAEL) for this study was found at 50 mg/kg bw/day, based on clinical signs, increased liver weight and hepatocellular hypert rophy

.

In a carcinogenicity study in mice liver effects were observed at doses of and above the
LOAEL of 1000 ppm (131.1 mg/kg/day). The NOAEL was determined to be 300 ppm (39.4 mg/kg/day).

A chronic toxicity/carcinogenicity study in rats established a NOAEL of 250 ppm (9.81

– 11.37 mg/kg/day). Decreased mean body weight and decreased mean body weight gain (compared to control) were observed at the LOAEL of 750 ppm (29.7

– 34.5 mg/kg/day).

The compound did not cause any treatment

- related increase in general tumor incidence, any elevated incidence of rare tumors, or shortened time to the development of palpable or rapidly lethal tumors in the 18

- month mouse and the 24

- month rat studies. An ad hoc
subcommittee of the Cancer Assessment Review Committee on May 27, 1999
determined that trifloxystrobin should be classified as a "Not Likely Human Carcinogen,"
based on the lack of evidence for carcinogenicity in rats and mice.

6. Animal metabolism. Trifloxystrobin is moderately absorbed f rom the gastrointestinal tract of rats and is rapidly distributed. Subsequent to a single oral dose, the half life of elimination is about 2 days and excretion is primarily via bile. Trifloxystrobin is extensively metabolized by the rat into about 35 metab olites, but the primary actions are on the methyl ester (hydrolysis into an acid), the methoxyimino group (O

- demethylation), and the methyl side chain (oxidation to a primary alcohol). Metabolism is dose dependent as it was almost complete at low doses but only about 60% complete at high doses.

In the goat, elimination of orally administered trifloxystrobin is primarily via the feces. The major residues were the parent compound and the acid metabolite (CGA

- 321113) plus its conjugates. In the hen, trifloxystrobin is found as the major compound in tissues and in the excreta, but hydroxylation of the trifluormethyl

- phenyl moiety and other transformations, including methyl ester hydrolysis and demethylation of the methoxyimino group, are also seen. In conclusion, the major pathways of metabolism in the rat, goat, and hen are the same.

7. Metabolite toxicology

. Metabolism of trifloxystrobin has been well characterized in plants, soil, and animals. In plants and soil, photolytically induced6

isomerization results in a few minor metabolites not seen in the rat; however, most of the applied materials remained as parent compound as shown in the apple and cucumber studies. All quantitatively major plant and/or soil metabolit es were also seen in the rat. The toxicity of the major acid metabolite, CGA

- 321113 (formed by hydrolysis of the methyl ester), has been evaluated in cultured rat hepatocytes and found to be 20

- times less cytotoxic than the parent compound. Additional toxi city studies were conducted for several minor metabolites seen uniquely in plants and/or soil. The studies indicate that these metabolites, including CGA

- 357261, CGA

- 373466, and NOA

- 414412, are not mutagenic to bacteria and are of low acute toxicity (LD50 >2000 mg/kg). In conclusion, the metabolism and toxicity profiles support the use of an analytical enforcement method that accounts for parent trifloxystrobin

.

8. Endocrine disruption

. Trifloxystrobin does not belong to a class o f chemicals known for having adverse effects on the endocrine system. Developmental toxicity studies in rats and rabbits and reproduction study in rats gave no indication that trifloxystrobin might have any effects on endocrine function related to developm ent and reproduction. The subchronic and chronic studies also showed no evidence of a long

- term effect related to the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. Assessments, using the DEEM FCID Version 4.02 software, were conducted to evaluate potential risks due to chronic and acute dietary exposure of the U.S. population and selected population subgroups to residues of trifloxystrobin. Consumption data used in this program were from NHANES WWEIA 200 5

- 20 10

. These analyses cover all registered crops plus the previous proposed increase in tolerances to Crop Group 4A (leafy greens), 4B (leafy petioles), 5A ( head and stem brassica ), 5B (leafy brassica greens), 19A (herbs), and 19B (spices except black pepper)

, as well as, new proposed tolerance for cotton

. EPA conducted a previous human health risk

assessment on April 14, 2014 (D4 13712 )

.

The EPA has established an acute Population Adjusted Dose (aPAD) of 2.5 mg/kg/day for acute dietary risk assessments based on a NOAEL of 250 mg/kg bw/day from a rabbit developmental toxicity study and an uncertainty factor or 100. The FQPA safety factor
was reduced to 1 x based on toxicological considerations, the conservative residue assumptions used in the dietary exposure ri sk assessments, and the completeness of the residue chemistry and environmental fate databases. For chronic dietary analyses, the EPA established a chronic Population Adjusted Dose (cPAD) of 0.038 mg/kg/day based
on a NOAEL of 3.8 mg/kg bw /day from the ra t reproducti on toxicity study and an uncertainty factor of 100.

Results from the acute and chronic dietary exposure analyses described below demonstrate a reasonable certainty that no harm to the overall U.S. population or any population subgroup will result from the use of trifloxystrobin on currently registered

uses plus the proposed changes tolerances.7

i. Food. The unrefined acute assessment used 100% crop treated and tolerance level residue values. The refined chronic assessment used 100% crop treated, with both
tolerance residue levels and average field trial residues for apple, grape

, orange, and pear (as per previous EPA dietary assessment (D413712, 2014). Additional refinements were made using average residues for leafy greens (4A), leaf petioles (4B), head and stem brassica (5A), le afy brassic (5B), herb (19A), spice (19B), strawberry, and rice. Default processing factors were used for both acute and chronic dietary assessments. Acute

exposure for food only , expressed at the 95 th percentile of exposure, was 2. 4 % of the
aPAD for F emales 13

- 49 years old (only population subgroup of concern). The chronic

exposure was 17 % cPAD for the T otal US P opulation and 43 % cPAD for the most sensitive population, Children 1

- 2 year s old.

ii. Drinking water

. Estimated Drinking Water Concentrations (EDWCs) associated with trifloxystrobin use on all crops were calculated using PRZM

- GW and

PRZM

- EXAMS to calculate ground water and surface water EDWCs, respectively. The
maximum acute and chronic ground water concentration s estimated by PRZM

- GW w ere 427 ppb and 365 ppb , respectively, and were higher than the surface water estimates (EPA, 2014)

. The value from the highest PRZM

- GW exposure scenarios were incorporated into the dietary risk assessment . The additi on of the acute estimated drinking water concentration (EDWC) of 427 ppb resulted in 2.9 5 % of the aPAD utilized
for females 13

- 49 yrs. old. The addition of the chronic EDWC of 365 ppb utilized 36 % of the cPAD for the US Population and 9 2 % of the cPAD for Infants (<1 yr) , the most highly exposed subpopulation. In conclusion, the results of the conservative acute and
chronic dietary exposure analyses (including drinking water) are acceptable for all population subgroups examined. Therefore, there is a reas onable certainty that no harm will result from exposure to potential residues of trifloxystrobin in food and water

.

2. Non

- dietary exposure

. The exposures from the proposed new uses are similar to those exposures already registered for corn . As such, non

- dietary exposures from these changes are covered by previous non

- dietary risk assessments performed by EPA. As published in the Federal Register (FR Vol 68, no. 175, 10

- Sep

- 03, FR Vol 73, no. 1,
02

- Jan

- 08), the EPA considered chro nic, short term and intermediate term risk from residential uses of trifloxystrobin. The EPA determined that the risk did not exceed the Agency’s level of concern

.

D. Cumulative Effects

EPA has determined, as published in the Federal Register ( FR Vol 73, no. 1,

02

- Jan

- 08) ), that unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, trifloxystrobin does not appear to produce a toxic metabolite produced by other sub stances. Therefore EPA has not assumed that trifloxystrobin has a common mechanism of toxicity with other substances.8

E. Safety Determination

1. U.S. population. Risk assessments for trifloxystrobin are based on a complete
and reliable toxicity data package and highly conservative assumptions. C hronic aggregate dietary (food and water) exposure will utilize about 17 % of the cPAD for the US Population

. Acute aggregate dietary exposure (food and water) for the fema les 13

- 49 yrs. old (the only popu lation of concern) utilized 3 % of the aPAD. Therefore, there is a reasonable certainty that no harm will occur to the US Population from aggregate exposure (food and drinking water) to residues of trifloxystrobin

.

2. Infants and children

. EPA has determined that the toxicology database for trifloxystrobin regarding potential pre

- and post

- natal effects in children is complete and does not indicate any particular developmental or reproductive concerns. The special FQPA SF has been reduced to 1X. Using the conservative assumptions described in the exposure section above, chronic dietary exposure to residues of trifloxystrobin in food
and water for Infants (< 1 yr.) (the most highly exposed sub group) is less than 92 % of
the cPAD. There is no acute endpoint of concern for children and infants. There are no

non

- dietary concerns for infants and children. Therefore, there is a reasonable certainty that no harm will occur to infants and children from aggregate exposure to r esidues of trifloxystrobin.

F. International Tolerances

In ternational tolerances and CODEX tolerances for trifloxystrobin are established for many crops in various countries. No tolerances exist yet in Canada or Mexico for the new proposed uses.