EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Tony Kish (703) 308-9443

Bayer CropScience

Petition 4F8288

EPA has received a pesticide petition 4F8288 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

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 leafy greens, subgroup 4A at 30 parts per million (ppm), leafy

petioles, group 4B at 9 parts per million (ppm), herb, subgroup 19A at 200 parts per 

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

head and stem brassica, subgroup 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 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. 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 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 quantitation (LOQ) is 0.02 ppm. The method is based on crop 

specific cleanup procedures and determination by gas chromatography with nitrogenphosphorus detection. A newer analytical method is available employing identical 
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solvent mixtures and solvent to matrix ratio (as the first method), deuterated internal 

standards, and liquid chromatography/mass spectrometry-mass spectrometry (LC/MSMS) with an electrospray interface, operated in the positive ion mode. The limits of 

detection (LOD) for trifloxystrobin range from 0.002 ppm to 0.01 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 trifloxystrobin 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 for 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 residues

in/on spinach following two foliar spray applications of Trifloxystrobin 500 SC at actual 

application rates ranging from 0.124 to 0.131 lb ai/A/application. The target application 

interval 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 conducted to measure the magnitude of total trifloxystrobin residues

in/on celery following two foliar spray applications of Trifloxystrobin 500 SC at actual 

application rates ranging from 0.122 to 0.131 lb ai/A/application. The target interval 

between applications was 5 days. All applications were made using ground-based 

equipment. The HAFT total trifloxystrobin residue in/on celery at commercial maturity 
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at a PHI of 0 days was 5.22 mg/kg, with a maximum residue of 5.49 mg/kg.

Subgroup 5A

Field trials were 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 application 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 residues

in/on cauliflower heads and stalks following two foliar spray applications of 

Trifloxystrobin 500 SC at actual application rates ranging 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 trifloxystrobin 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 

residues in/on mustard greens following two foliar spray applications of 

Trifloxystrobin 500 SC at actual application rates ranging 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. At 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 residues

in/on herbs (i.e. basil and chives) following two foliar spray applications of 

Trifloxystrobin 500 SC at actual application rates ranging from 0.122 to 

0.134 lb ai/A/application (0.137 to 0.150 kg ai/ha/application). The target interval 

between applications was 0 days. All applications were made using ground-based 

equipment. The HAFT total trifloxystrobin residue in/on green basil leaves at 
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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 trifloxystrobin 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 days was 10.18 mg/kg, with a maximum 

residue of 11.22 mg/kg.

Subgroup 19B, Except Black Pepper

Field trials were conducted to measure the magnitude of total trifloxystrobin residues

in/on dill following two foliar spray applications of Trifloxystrobin 500 SC at actual 

application rates ranging 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 commercial 

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 

Tuberous 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. IV), however it is a strong dermal sensitizer. Trifloxystrobin is a 

mild ocular (Cat III) 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 and 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/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 
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chemical was found to be non-mutagenic in the in vivo system or all other in vitro

systems. Consequently, the 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 enlarged 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 pregnancy 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. Consequently, 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 NOEL, 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 rats 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 ppm (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 ppm (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 rats the NOAEL was found at 100 mg/kg/day.

Increased liver and kidney weight were observed at the LOAEL of 1,000 mg/kg/day.
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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 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

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 from 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 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 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 induced 

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 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-
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times less cytotoxic than the parent compound. Additional toxicity 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 of 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 development 

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 3.16 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 taken from NHANES WWEIA 2003-2008. 

These analyses cover all 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 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 1x based on toxicological 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 Population Adjusted Dose (cPAD) of 0.038 mg/kg/day based 

on a NOAEL of 3.8 mg/kg bw/day from the rat reproduction 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. 

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 95th percentile of exposure, was 2.5% of 
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the aPAD for Females 13-49 years old (only population subgroup of concern). The 

chronic exposure was 41.5% cPAD for the Total US Population and 74.7% cPAD for the 

most sensitive population, Children 1-2 years 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 concentrations estimated by PRZM-GW were 

309 ppb and 249 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 309 ppb resulted in 2.85% of the aPAD utilized for females 13-

49 yrs. old. The addition 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 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 trifloxystrobin in food and water.

2. Non-dietary exposure. The exposure from the proposed new uses are below 

those 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 Federal 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 

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 substances. Therefore EPA has not 

assumed that trifloxystrobin has a common mechanism of toxicity with other 

substances.

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. Chronic 

aggregate dietary (food and water) exposure will utilize about 55% of the cPAD for 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, there 
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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 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 reasonable 

certainty that no harm will occur to infants and children from aggregate exposure to 

residues of trifloxystrobin.

F. International Tolerances

International 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.