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

PP# 3F8180

EPA has received a pesticide petition (PP#3F8180) 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 180.555

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 [pea, dry, seed] at 0.06 parts per million (ppm); [pea, field, 

hay] at 15 parts per million (ppm); [pea, field, vines] at 4.0 parts per million (ppm);

[chickpea, seed] at 0.06 parts per million (ppm); and [lentil, seed] at 0.06 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, 
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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 LODs for trifloxystrobin range from 0.002 ppm to 0.01 ppm, 

depending on the crops, and the LOQ of each analyte is 0.01 ppm.

3. Magnitude of residues.

Nine field-residue trials (eight harvest, one decline) were established across Canada 

(three trials in Crop Growing Region 7, five in Crop Growing Region 14) and the 

US (1 in Crop Growing Regions 7) where dry peas are commonly grown. The 

treated plot received two foliar spray applications of FOX 325 SC at 0.88 L FOX 

325 SC/ha/application (286 g ai/ha/application) for a total target seasonal rate of 572 

g ai/ha. FOX 325 SC active ingredient is comprised of 150 g trifloxystrobin/L and 

175 g prothioconazole/L. The corresponding target rate for trifloxystrobin was 132 g 

trifloxystrobin/ha/application for a total seasonal rate of 264 g trifloxystrobin/ha. 

The residue data from this study with dry peas is intended to support proposed 

tolerances for dry peas, chickpeas and lentils.

Dry pea vines (forage) and hay were collected at PHIs of 6 to 8 days in the eight 

harvest trials and at 0, 3, 7, and 13 days in the single decline trial. Dry pea seed was 

collected at PHIs of 29 to 31 days in the harvest trials and at 20, 25, 31, 34, and 40 

days in the decline trial. Vines, hay, and seed samples were collected from the 

control plots at the same time the 7 day vine and pea and the 30-day seed samples 

were collected from the treated plots. All samples were placed in frozen storage 

within 81⁄4 hours after collection. The samples were analyzed for residue of total 

trifloxystrobin (sum of trifloxystrobin and trifloxystrobin acid). The residue of total 

trifloxystrobin was quantitated by high-pressure liquid chromatography/triple stage 

quadrupole mass spectrometry (LC/MS/MS) using stable-labeled internal 

standards. The limit of quantitation (LOQ) for total trifloxystrobin residue was 0.02 

ppm for dry pea vines, hay, and seed. 

Total trifloxystrobin residue in dry pea seed ranged from <0.020 ppm to a 

maximum of 0.033 ppm for individual samples collected at the desired PHI of 30 

days. The HAFT residue found in/on dry pea seed was 0.032 ppm.
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Total trifloxystrobin residue in dry pea hay ranged from 2.1 ppm to a maximum of 

8.4 ppm for individual samples collected at the desired PHI of 7 days. The HAFT 

residue found in/on dry pea hay was 7.1 ppm. 

Total trifloxystrobin residue in dry pea vines ranged from 0.58 ppm to a maximum 

of 2.3 ppm for individual samples collected at the desired PHI of 7 days. The HAFT 

residue found in/on dry pea vines was 2.0 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 

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/day, resulting in a maternal 

NOEL of 50 mg/kg/day. 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/day. 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/day.

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; 110.6 mg/kg/day) were judged 

to be a secondary effect of maternal toxicity. No other fetal effects or any 
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reproductive changes were noted. The low developmental NOEL, 50 ppm (3.8

mg/kg/day) 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 1000 mg/kg/day.

5. Chronic toxicity. A chronic feeding study in dogs established a NOAEL of 5 

mg/kg/day. The LOAEL for this study was found at 50 mg/kg/day, based on clinical 

signs, increased liver weight and hepatocellular hypertrophy.

In a carcinogenicity study in mice liver effects were observed at doses at 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 
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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 

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. Dietary risk assessments, using the DEEM-FCID 

software Version 3.14 with USDA’s National Health and Nutrition Examination 

Survey (NHANES) from 2003 to 2008 nationwide continuing surveys of food intake 

by individuals, 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 uses on dry peas, chickpeas and lentils.

A Tier 1 dietary assessment was evaluated based on established tolerances for all 

registered uses and 100% crop treated. For the proposed use on dry peas, chickpeas

and lentils, the proposed tolerance of 0.06 ppm was used in this assessment. 
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Chickpeas and dry peas can be used as alternative feedstuff serving as a source of 

roughage and protein. The proposed uses are not feed to feedlot beef. Addition of 

the proposed uses on feed items will have minimal effect on total burden for dairy 

cattle. The current risk assessments are based on established livestock tolerances 

(milk = 0.02 ppm) which are more conservative than residues estimated from 

Maximum Reasonably Balanced Diets (MRBD). 

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 and proposed uses on dry peas, chickpeas and lentils.

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

were performed. Acute exposure for food only, expressed at the 95th percentile of 

exposure, was 1.3% of the aPAD for Females 13-49 years old (only population 

subgroup of concern). The chronic exposure for food only was 27% cPAD for the 

Total US Population and 59% 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 48 ppb and 47 ppb respectively as given in EPA’s Human Health Risk 

Assessment for a Section 3 Petition Proposing Increased Tolerances for Residues 

in/on Field, Sweet, and Pop Corn (February 25, 2010, DP Barcode 369104). 

2. Non-dietary exposure. There is no potential for dermal or incidental oral 

exposure during or post application of trifloxystrobin when applied to dry peas, 

chickpeas and lentils. As such, non-dietary exposure from this new tolerance is

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 
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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. Acute and chronic dietary risk estimates associated with 

exposure to trifloxystrobin in food and water are expected to be well below the 

Agency's level of concern. The Tier I acute exposure analysis performed for all 

currently registered and proposed food uses show that exposure to trifloxystrobin 

utilizes 2% of the aPAD for Females 13-49 years old (only population subgroup of 

concern). The Tier I chronic exposure analysis performed for all currently 

registered and proposed food uses show that exposure to trifloxystrobin utilizes 

30% of the cPAD for the U.S. population and 62% of the cPAD for children 

1-2 years old, the subpopulation at greatest exposure. This analysis was conducted 

assuming 100% crop treated and tolerance level residue values for all crops. The 

contribution of trifloxystrobin residues in drinking water to acute and chronic 

aggregate exposure was minimal. Therefore, Bayer CropScience concludes that 

even when considering the potential incremental risk resulting from the proposed 

use on dry peas, chickpeas and lentils, there is a reasonable certainty that no harm 

will result from aggregate exposure to trifloxystrobin residues.

2. Infants and children. No indication of increased susceptibility of rat or 

rabbit fetuses to in utero and/or postnatal exposure was noted in the developmental 

and reproductive toxicity studies. The Agency has previously determined that no 

additional safety factor to protect infants and children is necessary for this product. 

Using the conservative assumptions described in the exposure section above, 

aggregate exposure to trifloxystrobin from currently registered food uses will utilize 

39% of cRfD for infants, and 62% of the cRfD for children 1-2 years old, the 

subpopulation at greatest exposure. Even when considering the potential 

incremental dietary risk resulting from the proposed use on chickpeas, lentils, and 

dry peas, the potential for exposure to residues in drinking water and from nondietary, non-occupational exposure, the aggregate exposure to trifloxystrobin is 

expected to be well below the level of concern. Bayer CropScience concludes that 

there is a reasonable certainty that no harm will result to infants and children from 

aggregate exposure to trifloxystrobin residues.

F. International Tolerances

International and CODEX tolerances (MRLs) for trifloxystrobin are 
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established for many crops in various countries. At this time, there are no 

international tolerances established for trifloxystrobin on dry pea, chickpea, or 

lentil.