EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(7/1/2007)

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 ([insert petition number]) 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.

(Options (pick one)

1. by establishing tolerances and/or changing existing tolerances for residues of

2. to establish an exemption from the requirement of a tolerance for

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 [alfalfa, forage] at 0.01 parts per million (ppm) and 

[alfalfa, hay] at 0.01 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
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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 

nitrogen-phosphorus detection. A newer analytical method is available employing 

identical solvent mixtures and solvent to matrix ratio (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 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.

Alfalfa seed, treated with [benzeneacetic-phenyl-UL-14C] trifloxystrobin at rates of

0.0039 lb. ai/100 lb. seed and 0.0125 lb. ai/100 lb. seed (0.83X the target maximum 

rate of 0.015 lb. ai/100 lb. seed), was planted, and alfalfa was grown to maturity.

The alfalfa raw agricultural commodity (RAC) of forage was collected from three 

cuttings at BBCH 61 to 65 (10% flowering to 50% flowering). Additionally, alfalfa 

hay samples were collected, following drying, from the second and third cuttings.

All RAC samples were homogenized and radioassayed. The limit of quantitation 

(LOQ) for detection of total radioactive residue from all RACs was 0.0028 ppm. The 

total radioactive residue (TRR) in both alfalfa forage and hay from seed treated at 

both application rates was comparable to that of control samples at all three

cuttings (net residue <0.0028 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 invivo 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 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 
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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, resulting in a maternal 

NOEL of 50mg/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, 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 of 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.

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

adverse effect level (NOAEL) of 5 mg/kg/day. The lowest effect level (LOAEL) for 

this study was found at 50 mg/kg/day, based on clinical signs, increased liver weight 

and hepatocellular hypertrophy.
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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 elimination half life 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 trifluormethylphenyl 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 material 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-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 
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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 2.0, 1994-

1996, 98 CSFII 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. These analyses cover all registered and 

pending uses including the proposed use as a seed treatment in alfalfa. 

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 SF was reduced to 1x based on toxicological considerations 

by the FQPA Safety Factor Committee (HED Doc. No. 013545, B. Tarplee, 

01/JUL/1999), the conservative residue assumptions used in the dietary and 

residential exposure risk assessments, and the completeness of the residue chemistry 

and environmental fate databases (DP Num: 3 17330, B. O'Keefe,1 6/AUG/2006). 

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 to corn and sweet corn tolerances. 

i. Food. For food, a Tier 1 acute and chronic dietary exposure assessments 

were performed. Acute exposure, expressed at the 95th percentile of exposure, was 

1.5 % of the aPAD for Females 13-49 years old (only population subgroup of 

concern). The chronic exposure was 36.2 % cPAD for the Total US Population and 

69.6 % cPAD for the most sensitive population, Children 1-2 years old.

ii. Drinking water. Acute and chronic exposure estimates from water are 

included in the exposure values given above for food. These exposure estimates for 

water are based on EPA’s surface water estimated environmental concentrations 

(EECs) of trifloxystrobin and CGA-321113 for acute exposure and for chronic 

exposures at 140 ppb. These values are listed in the Federal Register (71 FR 55313).
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2. Non-dietary exposure. There is no potential for dermal or incidental oral 

exposure during or post application of trifloxystrobin when applied as a seed 

dressing to alfalfa. As such, non-dietary exposure from these new tolerances 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. Based on the information supplied above under Aggregate 

Exposure, there is reasonable certainty that exposure from trifloxystrobin will 

result in no harm to the adult U.S. population.

2. Infants and children. Based on the information supplied above under 

Aggregate Exposure, there is reasonable certainty that exposure from 

trifloxystrobin will result in no harm to the infants and children.

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.