EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: T ony Kish (703) 308

- 9443

Bayer CropScience

Peti tion 4F8288

EPA has received a pesticide petition 4 F8288 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. 346a(d), to amend 40 CFR part 180 by establishing tolerances and/or changing existing
tolerance s for residues of trifloxystrobin ( Benzeneacetic acid, (E,E)

- α

- (methoxyimino)

- 2

- [[[[1

- [3

- (trifluorome thyl) 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 leafy gre ens , sub group 4 A at 30 parts per million (ppm)

, leafy petioles , group 4 B at 9 parts per million (ppm ), h erb

, sub group 19 A at 200 parts per million (ppm)

, spice, subgroup 19B, except black pepper at 30 parts per million (ppm)

, head and stem brassica, subgro up 5A at 2 parts per million (ppm), leafy brassica greens, subgroup 5B at 30 parts per million (ppm)

, tuberous and corm vegetables, subgroup 1C

at 0.04 parts per million (ppm), small fruit vine climbing subgroup (except fuzzy kiwifruit), subgroup 13

- 07F at 2.0 parts per million (ppm), and low growing berry, subgroup 13

- 07G at 1.5 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 residue of concern for tolerance setting purposes.

2. Analytical method. A practical analytical methodology for detecting and measuring levels of trifloxystrobin in or on raw agricult ural commodities has been submitted. The limit of detection (LOD) for each analyte of this method is 0.08 ng injected, and the limit of quantitation (LOQ) is 0. 02 ppm. The method is based on crop specific cleanup procedures and determination by gas chromat ography with nitrogen

phosphorus detection . A newer analytical method is available employing identical2

solvent mixtures and solvent to matrix ratio ( as the first method )

, deuterated internal standards, and liquid chromatography/mass spectrometry

- mass spec trometry (LC/MS

MS) with an electrospray interface, operated in the positive ion mode

. The limits of detection (LOD) for trifloxystrobin range from 0.00 2 ppm to 0.0 1 ppm , depending on the

crops, and the limit of quantitation is 0.01 ppm.

3. Magnitude of residues. Subgroup 4A Field trials were conducted to measure the magnitude of trifloxystrobin residues in/on
leaf and head lettuce following two foliar spray applications and two banded applications of Trifloxystrobin 500 SC

. The foliar application was made at an actual rate
of 0.117 to 0.132 lb ai/A/application with an interval between applications of 4 to

7 days. The banded applications received rates from 0.122 to 0.133 lb ai/A/application. Two of the lettuce trials receiving banded applications the total applied rates were only
25% of the target rate due to protocol misunderstanding. The actual application rates for these plots ranged from 0.018 to 0.021 lb ai/A/application

. Residues observed in plots receiving banded applications were always much lower than residues observed in plots receiving the broadcast foliar applications so application errors had no effect on establishing a tolerance on leaf or head lettuce. All applications were made using ground

- based equipment. The HAFT total triflo xystrobin residues in/on leaf lettuce at commercial maturity for the foliar broadcast applications at a PHI of 0 days was 4.13 mg/kg, with a maximum residue of 4.44 mg/kg. The HAFT total trifloxystrobin residues in/on leaf lettuce at commercial maturity f or the banded applications at a PHI of 20 to

120 days was 0.03 mg/kg, with a maximum residue of 0.03 mg/kg. The HAFT total trifloxystrobin residues in/on head lettuce at commercial maturity for the foliar broadcast application at a PHI of 0 days was 2.50 mg/kg, with a maximum residue of

2.53 mg/kg. The HAFT total trifloxystrobin residues in/on head lettuce at commercial maturity for the banded applications at a PHI of 18

- 120 days was <0.01 mg/kg, with a
maximum residue of 0.01 mg/kg.

Field trials were conducted to measure the magnitude of total trifloxystrobin residue s in/on spinach following two foliar spray applications of Trifloxystrobin 500 SC at a ctual application rate s ranging from 0.124 to 0.131 lb ai/A/application . The target application
interv al was 5 days. All applications were made using ground

- based equipment. The HAFT total trifloxystrobin residue in/on spinach at commercial maturity at a PHI of 0 days was 10.4 mg/kg, with a maximum residue of 10.7 mg/kg.

Subgroup 4B

Field trials were co nducted to measure the magnitude of total trifloxystrobin residue s in/on celery following two foliar spray applications of Trifloxystrobin 500 SC at actual application rates rang ing from 0.122 to 0.131 lb ai/A/application

. The target interval between appl ications was 5 days. All applications were made using ground

- based equipment. The HAFT total trifloxystrobin residue in/on celery at commercial maturity3

at a PHI of 0 days was 5.22 mg/kg, with a maximum residue of 5.49 mg/kg.

Subgroup 5A

Field trials we re conducted to measure the magnitude of total trifloxystrobin residues in/on cabbage heads (with wrapper leaves) following two foliar spray applications of Trifloxystrobin 500 SC to the treated plots at actual application rates ranging from 0.124

to 0.130 lb ai/A/application. The target interval between applications was 5 days. All applications were made using ground

- based equipment. At a PHI of 0 days, the HAFT total trifloxystrobin residues in cabbage heads with wrapper leaves was 0.597 mg/kg
and the maximum residue was 0.759 mg/kg at commercial maturity.

Field trials were conducted to measure the magnitude of total trifloxystrobin residues in/on broccoli heads and stalks following two foliar spray applications of Trifloxystrobin 500 SC at actual appl ication rates ranging from 0.120 to

0.132 lb ai/A/application. The target interval between applications was 5 days. All applications were made using ground

- based equipment. At a PHI of 0 days, the HAFT total trifloxystrobin residue in broccoli heads and stalks was 0.700 mg/kg and the
maximum residue was 0.806 mg/kg at commercial maturity.

Field trials were conducted to measure the magnitude of total trifloxystrobin residue s in/on cauliflower heads and stalks following two foliar spray applications of Trifloxystrobin 500 SC at actual application rates rang ing from 0.125 to

0.134 lb ai/A/application. The target interval between applications was 5 days. All applications were made using ground

- based equipment. At a PHI of 0 days, the HAFT total trifloxy strobin residue in cauliflower heads and stalks was 0.356 mg/kg and the
maximum residue was 0.404 mg/kg at commercial maturity.

Subgroup 5B
Eight field trials were conducted to measure the magnitude of total trifloxystrobin
residue s in/on mustard greens f ollowing two foliar spray applications of Trifloxystrobin 500 SC at a ctual application rates rang ing from 0.122 to

0.129 lb ai/A/application. The target interval between applications was 5 days. All applications were made using ground

- based equipment. A t a PHI of 0 days, the HAFT trifloxystrobin residue in mustard greens was 9.66 mg/kg and the maximum residue was

10.58 mg/kg at commercial maturity.

Subgroup 19A
Field trials were conducted to measure the magnitude of total trifloxystrobin residue s in/on herbs (i.e. basil and chives ) following two foliar spray applications of Trifloxystrobin 500 SC at a ctual application rates rang ing from 0.122 to

0.134 lb ai/A/application (0.137 to 0.150 kg ai/ha/application). The target interval between applications wa s 0 days. All applications were made using ground

- based equipment. The HAFT total trifloxystrobin residue in/on green basil leaves at4

commercial maturity at a PHI of 0 days was 21.71 mg/kg, with a maximum residue of 25.32 mg/kg. The HAFT total trifloxys trobin residue in/on dried basil leaves at commercial maturity at a PHI of 0 days was 84.81 mg/kg, with a maximum residue of 87.24 mg/kg. The HAFT total trifloxystrobin residue in/on chives (whole plant without roots) at commercial maturity at a PHI of 0 d ays was 10.18 mg/kg, with a maximum residue of 11.22 mg/kg.

S ubgroup 19B , Except Black Pepper
Field trials were conducted to measure the magnitude of total trifloxystrobin residue s in/on dill following two foliar spray applications of Trifloxystrobin 500 SC at a ctual application rates rang ing from 0.123 to 0.129 lb ai/A/application. The target interval between applications was 14 days. All applications were made using ground

- based equipment. The HAFT total trifloxystrobin residue in/on dill seed at comm ercial maturity at a PHI of 14 days was 12.11 mg/kg, with a maximum residue of 14.14 mg/kg.

Subgroup 1C Bayer CropScience is proposing to convert the current potato tolerance of 0.04 ppm to a

T uberous and corm vegetable

, Subgroup 1C tolerance maintaining the same tolerance of 0.04 ppm.

Subgroup 13

- 07F Bayer CropScience is proposing to convert the current grape tolerance of 2.0 ppm to a Small fruit vine climbing subgroup except fuzzy kiwifruit, Subgroup 13

- 07F tolerance maintaining the same tolerance of 2 .0 ppm.

Subgroup 13

- 07G Bayer CropScience is proposing to convert the current strawberry tolerance to a Low growing berry subgroup, Subgroup 13

- 07G tolerance increasing the current tolerance from 1.1 ppm to 1.5 ppm.

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 oc ular ( Cat I II ) and dermal irritant (Cat IV)

.

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 a nd chromosomal 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 / m L ) of cytotoxic and precipitati ng concentrations (compound solubility in water was reported
to be 0.61  g /mL ; precipitate was visually noted in culture medium at 150  g /mL ). The5

chemical was found to be non

- mutagenic in the in vivo system or all other in vitro systems. Consequently, th e limited 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 10 0 0 mg/kg /day

.

In the rabbit developmental study, body weight loss and reduced food consumption were observed in the dam s 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 stud y 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 (7 6.9

- 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).

A subchronic feeding study in dogs resulted in a NOAEL = 30 mg/kg/day. Increased liver weight and hepatocyte hypertrophy 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

.6

5. Chronic toxicity. A chronic fe eding 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 hypertrophy

.

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
incid ence, 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 det ermined 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 from the
gast rointestinal 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 metabolites, 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 fo und 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 induced
isomeri zation 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 metabolites 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

-7

times less cytotoxic than the parent compound. Additional toxicity studies were
conducted fo r 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, t he 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 of chemicals known for having a dverse 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 development and reproduction. The subc hronic 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 3.16 software,
were conducted to eva luate 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 taken from NHANES WWEIA 2003

- 2008

. These analyses cover al l registered crops plus the 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)

.

The EPA has established an acut e 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 toxico logical considerations, the conservative residue assumptions used in the dietary exposure risk assessments, and the completeness of the residue chemistry and environmental fate databases. For chronic dietary analyses, the EPA established a chronic Populat ion Adjusted Dose (cPAD) of 0.038 mg/kg/day based
on a NOAEL of 3.8 mg/kg bw /day from the rat reproducti on toxicity study and an uncertainty factor of 100.

Results from the acute and chronic dietary exposure analyses described below
demonstrate a reasona ble 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

.

i. Food. For food, Tier 1 acute and chronic dietary exposure assessments were performed. The acute Tier 1 assessments used 100% crop treated and tolerance level residue values. The refined chronic Tier 1 assessment used 100% crop treated, with both tolerance residue levels and average field trial for apple, grapes, and oranges. Acute exposure for food only , expressed at the 95 th percentile of exposure, was 2.5 % of8

the aPAD for F emales 13

- 49 years old (only population subgroup of concern). The chronic exposure was 41.5 % cPAD for the T o tal US P opulation and 74.7 % 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 (ver. 1.07) and GENEEC to calculate ground water and surface water EDWCs, respectively. The

maximum acute and chronic ground water concentration s estimated by PRZM

- GW w ere 309 ppb and 249 ppb , respectively, and were higher than the surface water estimates.
The valu e 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 309 ppb resulted in 2.85 % of the aPAD utilized for females 13

- 49 yrs. old. The ad dition of the chronic EDWC of 249 ppb utilized 55.2 % of the cPAD for the US Population and 94.5 % of the cPAD for Children 1

- 2 yrs. old , the most highly exposed subpopulation. In conclusion, the results of the acute and chronic Tier 1 dietary exposure anal yses (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 trifloxystrobin in food and water

.

2. Non

- dietary exposure

. The exposure from the proposed new uses are below
th ose exposures already registered. As such, non

- dietary exposure from these changes are covered by previous non

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

- Sep

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

- Jan

- 08 ), the EPA considered chronic, 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

conc ern

.

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 substances. Therefore EPA has not assumed that trifloxystrobin has a common mechanism of toxicity with other
substances.

E. Safety Determination

1. U.S. p opulation. 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 55 % of the cPAD fo r the US Population

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

- 49 yrs. old (the only population of concern), utilized 2 .9 % of the aPAD. Therefore, there9

is a reasonable certainty that no harm will occur to the US Population fro m 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
doe s 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 Children 1

- 2 yrs. old (the most highly exposed sub group) is less than 95 %
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 reason able certainty that no harm will occur to infants and children from aggregate exposure to
residues of trifloxystrobin

.

F. International Tolerances

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