TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: August 2, 2011

SUBJECT: Trifloxystrobin. Human Health Risk Assessment for Proposed New Use on 

Imported Coffee.

PC Code: 129112 DP Barcode: 385972

Decision No.: 440437 Registration No.: NA

Petition No.: 0E7789 Regulatory Action: Tolerance (no S3)

Risk Assessment Type: Single Chemical/Aggregate Case No.: NA

TXR No.: NA CAS No.: 141517-21-7

MRID No.: NA 40 CFR: 180.555

FROM: Nancy Tsaur, Chemist, Risk Assessor

Whang Phang, Toxicologist

Risk Assessment Branch 3

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief

Risk Assessment Branch 3

Health Effects Division (7509P)

TO: Tony Kish/Janet Whitehurst, Risk Manager Team 22

Fungicides Branch

Registration Division (7505P)
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Table of Contents

1.0 Executive Summary........................................................................................................... 4

2.0 HED Recommendations.................................................................................................... 6

2.1 Data Deficiencies (Prior Conditions of Registration) ................................................. 6

2.2 Tolerance Considerations.............................................................................................. 6

2.2.1 Enforcement Analytical Method ............................................................................... 6

2.2.2 International Harmonization..................................................................................... 7

2.2.3 Recommended Tolerances......................................................................................... 7

2.3 Label Recommendations................................................................................................ 7

3.0 Introduction........................................................................................................................ 7

3.1 Chemical Identity ........................................................................................................... 8

3.2 Physical/Chemical Characteristics ............................................................................... 8

3.3 Pesticide Use Pattern...................................................................................................... 9

3.4 Anticipated Exposure Pathways................................................................................... 9

3.5 Consideration of Environmental Justice.................................................................... 10

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 10

4.1 Toxicology Studies Available for Analysis................................................................. 11

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 11

4.3 Toxicological Effects .................................................................................................... 11

4.4.1 Completeness of the Toxicology Database.............................................................. 12

4.4.2 Evidence of Neurotoxicity........................................................................................ 12

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 12

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 13

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 13

4.5.1 Dose-Response Assessment...................................................................................... 13

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment ...... 14

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 14

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment............................................................................................................................... 14

4.6 Endocrine Disruption................................................................................................... 16

5.0 Dietary Exposure and Risk Assessment......................................................................... 17

5.1 Metabolite/Degradate Residue Profile ....................................................................... 17

5.1.1 Summary of Plant and Animal Metabolism Studies............................................. 17

5.1.2 Summary of Environmental Degradation.............................................................. 18

5.1.3 Comparison of Metabolic Pathways....................................................................... 18

5.1.4 Residues of Concern Summary and Rationale ...................................................... 18

5.2 Food Residue Profile .................................................................................................... 19

5.3 Water Residue Profile.................................................................................................. 20

5.4 Dietary Risk Assessment.............................................................................................. 21

5.4.1 Acute Dietary Risk Assessment............................................................................... 21

5.4.2 Chronic Dietary Risk Assessment........................................................................... 21

5.4.3 Cancer Dietary Risk Assessment............................................................................. 22

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 22

6.1 Residential Handler Exposure .................................................................................... 22

6.2 Post-Application Exposure.......................................................................................... 23
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6.3 Combined Exposure..................................................................................................... 23

6.4 Residential Bystander Post-Application Inhalation Exposure ................................ 24

6.5 Spray Drift.................................................................................................................... 24

7.0 Aggregate Exposure/Risk Characterization.................................................................. 24

7.1 Acute Aggregate Risk................................................................................................... 25

7.2 Short-Term Aggregate Risk........................................................................................ 25

7.4 Chronic Aggregate Risk .............................................................................................. 26

7.5 Cancer Aggregate Risk ................................................................................................ 26

8.0 Cumulative Exposure/Risk Characterization ............................................................... 26

Appendix A. Toxicology Profile and Executive Summaries................................................ 27

A.1 Toxicology Data Requirements................................................................................... 27

A.2 Toxicity Profile of Trifloxystrobin Technical............................................................ 28

Appendix B. Metabolism Summary Table ............................................................................ 31

Appendix C. Physical/Chemical Properties........................................................................... 31

Appendix D. International Residue Limit Summary ........................................................... 32
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1.0 Executive Summary

Trifloxystrobin belongs to the MAEs (β-methoxyacryl esters) class of fungicides, which are 

synthetic analogs of strobilurin A. It is a broad-spectrum preventative fungicide used for control 

of many plant diseases in various fruit, nut, vegetable, and field crops, including corn and 

soybean.

In PP#0E7789, Bayer Cropscience (Bayer) petitioned for the establishment of a new tolerance

for combined residues of the fungicide 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-

(trifluoromethylphenyl)-ethylideneaminooxymethyl]-phenyl]acetic acid] in/on the following raw 

agricultural commodities (RAC):

Coffee, green bean ................................................. 0.02 ppm

Pending submission of a revised Section F, there are no residue chemistry issues that would 

preclude establishment of permanent tolerances for combined residues of trifloxystrobin and its 

acid metabolite CGA-321113 in/on imported coffee.

The most recent human health risk assessment was conducted for use on alfalfa (DP#378917, B. 

Hanson, 01/25/2011). Other than a waiver for a subchronic 28-day inhalation toxicity study, no 

new hazard data have been submitted since the issuance of the last human health risk assessment.

A summary of the findings and an assessment of human health risk resulting from the proposed 

and registered uses of trifloxystrobin are provided in this document and its attachments. The 

residue chemistry data submitted in support of this petition were reviewed by Nancy Tsaur, the 

toxicology reevaluation was performed by Whang Phang, and the drinking water assessment was 

conducted by James Wolf. Subsequently, the dietary exposure and overall human health risk 

assessments were conducted by Nancy Tsaur.

Use Profile

Bayer submitted a partial English translation of the Sphere® Max draft specimen label to be used 

on imported coffee grown in Latin America. Sphere® Max is a multiple active ingredient (MAI) 

suspension concentrate (SC) formulation consisting of 375 g ai/L trifloxystrobin and 160 g ai/L

cyproconazole. However, this document only addresses the application use pattern of 

trifloxystrobin. Note: the submitted data are all based on Sphere® 535 SC, an SC end-use 

product (EP) that is identical to Sphere® Max with regard to the formulation and the MAI 

mixture composition.

Toxicity/Hazard

The risk assessment for trifloxystrobin is based on a well-characterized and complete toxicology

database, with the exception of acute and subchronic neurotoxicity and immunotoxicity studies 

which are now required as part of the toxicology data requirements for registration of a pesticide 

(food and non-food uses).
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With repeated dosing by either the oral or dermal route, the liver is consistently the target organ 

for trifloxystrobin. Trifloxystrobin does not produce malformation in either rat or rabbit 

developmental toxicity studies and does not produce reproductive effects. Trifloxystrobin was 

determined not to be carcinogenic in mice or rats following long-term dietary administration.

However, it is positive for mutagenicity in Chinese Hamster V79 cells at cytotoxic dose levels 

while testing negative in the remaining mutagenicity studies.

Trifloxystrobin exhibits low acute toxicity following single oral, dermal, and inhalation 

exposures (Toxicity Category III or IV). It is a strong dermal sensitizer and a mild dermal and 

eye irritant.

Although acute and subchronic neurotoxicity and immunotoxicity studies are needed to complete 

the database, there are no concerns for neurotoxicity or immunotoxicity based on the results of 

the existing studies. The FQPA factor was reduced to 1X because trifloxystrobin showed no 

evidence of increased susceptibility of the young. The acute dietary risk assessment is based on 

increased incidence of fused sternebrae in fetuses observed in a developmental toxicity study in 

rabbits; therefore, the acute assessment was assessed for females of childbearing age (13-49 

years old) only. The chronic dietary risk assessment is based on decreases in body weight, body

weight gains, reduced food consumption, and histopathological lesions in the liver, kidneys, and 

spleen of parental animals in a multi-generation reproduction study in rats.

Drinking Water

The Environmental Fate and Effects Division (EFED) previously determined estimated drinking 

water concentrations (EDWCs) of trifloxystrobin in surface and ground water for use on turf 

(1.02 lb ai/A) (DP Barcode: 244219, 7/28/1999). The GENEEC surface water estimates for 

acute and chronic exposure concentrations were 47.98 and 47.31 μg/L (ppb), respectively.

Dietary Exposure

An unrefined acute dietary (food plus drinking water) assessment assuming tolerance-level 

residues and 100% crop treated for all commodities with existing and proposed tolerances 

yielded exposure estimates below HED’s level of concern; acute dietary exposure utilized 1.9% 

of the aPAD for females 13-49 years old at the 95th percentile. A partially refined chronic 

dietary (food + drinking water) assessment assuming mostly tolerance-level residues with some 

anticipated residues (apples, grapes, and oranges) yielded exposure estimates below HED’s level 

of concern; chronic dietary exposure utilized 34% of the cPAD for the general U.S. population

and 64% of the cPAD for children 1-2 years old (the population subgroup with the highest 

estimated chronic dietary exposure to trifloxystrobin).

Residential Exposure

No residential uses are being requested at this time; therefore, no residential risk assessment has 

been conducted. However, the label for the trifloxystrobin product CompassTM includes 

residential use on turfgrass and ornamentals. Previously calculated non-occupational postapplication margins of exposure (MOEs) are greater than 100 on the day of application and do 

not exceed HED’s level of concern (DP Barcode: D319131, J. Arthur, 7/14/2005). The MOEs 

ranged from 750 to 220,000 for adult and child residential scenarios.
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Aggregate Risk

Acute, short-term, and chronic aggregate risk estimates resulting from aggregate exposure to 

trifloxystrobin in food and drinking water, and residential settings are below HED’s level of 

concern. The estimated acute dietary exposure (food plus drinking water) for females 13-49 

years old is representative of the acute aggregate risk and the estimated chronic dietary exposure 

assessment (food plus drinking water) is representative of the chronic aggregate risk. For shortterm (1 to 30 days) aggregate risk, food plus drinking water and residential exposures are 

considered. Residential exposure for dermal and oral routes must be assessed separately, since 

dermal and oral endpoints were different and cannot be combined. The resulting MOEs for all 

short-term aggregate scenarios for adults and children are below HED’s level of concern (adult 

dermal MOE = 1100, children dermal MOE = 650, children incidental oral MOE = 130).

2.0 HED Recommendations

Pending submission of a revised Section F, HED recommends for the establishment of a 

permanent tolerance for the use of trifloxystrobin on imported coffee. Additional data 

deficiencies based on new guideline requirements have been noted as conditions of registration 

for prior domestic registrations as outlined in Section 2.1 below. The specific tolerance 

recommendations are discussed in Section 2.2, and there are no necessary label modifications.

2.1 Data Deficiencies (Prior Conditions of Registration)

Data Deficiencies

Toxicology [870.3465 28-Day Inhalation Toxicity]

Toxicology [870.6200 Neurotoxicity Screening Battery]

Toxicology [870.7800 Immunotoxicity]

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate gas chromatography/nitrogen phosphorus detection (GC/NPD) method based on 

crop-specific cleanup procedures, Method AG-659A, is available for enforcing tolerances for the 

combined residues of trifloxystrobin and CGA-321113 in crop and livestock commodities. This 

method was validated by the Agency and forwarded to the Food and Drug Administration (FDA)

for inclusion in the Pesticide Analytical Manual (PAM), Vol. II. The limit of detection (LOD; 

the lowest concentration of an analyte that can be determined to be statistically different from a 

blank untreated control sample) for each analyte of this method is 0.08 ng injected, and the limit 

of quantitation (LOQ; the lowest analyte fortification level at which acceptable recovery through 

the analytical method was achieved) is 0.02 ppm. 

In addition, a newer analytical enforcement method, Method No. 200177, is available. Method 

No. 200177 employs identical solvent mixtures and solvent to matrix ratio as Method AG-659A, 

deuterated internal standards, and high performance liquid chromatography with an electrospray
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interface and tandem mass spectrometry, operated in the positive ion mode (HPLC/MS/MS). 

The LOQ for each analyte is 0.01 ppm.

2.2.2 International Harmonization

There are currently no established Mexican, Canadian, or Codex maximum residue limits 

(MRLs) or tolerances for trifloxystrobin on coffee (see Appendix D).

2.2.3 Recommended Tolerances

As shown in Table 2.2.3, the proposed tolerance commodity term has to be corrected in a revised 

Section F to agree with the Agency’s Food and Feed Commodity Vocabulary. 

TABLE 2.2.3. Tolerance Summary for Trifloxystrobin.

Commodity

Tolerance (ppm) Comments

Established Proposed Recommended Correct Commodity Definition

40 CFR §180.609(a)(1)

Coffee, green, bean a-- 0.02 0.02 Coffee, green bean

a No domestic registration has been established as of August 2, 2011.

The 40 CFR tolerance expression for trifloxystrobin has been properly revised in accordance 

with HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 05/27/2009).

2.3 Label Recommendations

None.

3.0 Introduction

Trifloxystrobin belongs to the MAEs (β-methoxyacryl esters) class of fungicides, which are 

synthetic analogs of strobilurin A. These fungicides are also designated quinone inhibitors 

(QoIs) and are assigned to the Fungicide Resistance Action Committee (FRAC) Group 11. 

Trifloxystrobin is a broad-spectrum preventative fungicide used for control of many plant 

diseases in various fruits, nuts, vegetables, and field crops, including corn and soybean.

Bayer is petitioning for a tolerance for residues of trifloxystrobin in/on imported coffee and has 

submitted a partial English translation of the draft specimen label to be used in Latin America. 

The submitted label indicates that up to three broadcast foliar applications may be made using 

airblast backpacks at the rate of 0.084 to 0.14 lb ai/A/application for a maximum seasonal 

application rate of 0.25 to 0.27 lb ai/A, with a 30-day preharvest interval (PHI).

Tolerances are currently established for the combined residues of trifloxystrobin and its free 

form acid metabolite CGA–321113 in/on various crop and livestock commodities ranging from 

0.02 ppm (milk) to 38 ppm (citrus oil) [40 CFR §180.555(a)].
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3.1 Chemical Identity

The chemical structure and nomenclature of trifloxystrobin and its regulated metabolite are 

presented in Table 3.1.

TABLE 3.1. Test Compound Nomenclature.

Chemical Structure 

of Parent Compound

Empirical Formula C20H19F3N2O4 

Common Name trifloxystrobin

Company Experimental Name BO17211 or CGA-279202

IUPAC Name methyl (E)-methoxyimino-{(E)-α-[1-(α,α,α-trifluoro-mtolyl)ethylideneaminooxy]-o-tolyl}acetate

CAS Name methyl (αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-

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

CAS Registry # 141517-21-7

End-Use Products (EPs) Sphere® Max (375 g ai/L trifloxystrobin + 160 g ai/L cyproconazole)

Sphere® 535 SC (375 g ai/L trifloxystrobin + 160 g ai/L cyproconazole)

Chemical Class Strobilurin, methoxyacrylates

Known Impurities of Concern None

Chemical Structure

of Metabolite CGA-321113 

Common Name trifloxystrobin acid

Company Code CGA-321113

CAS Name (αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-

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

CAS # 252913-85-2

3.2 Physical/Chemical Characteristics

Trifloxystrobin has a low vapor pressure (2.55 x 10-7 mmHg at 25 C); therefore, inhalation via 

chemical vaporization is unlikely. The decline of parent trifloxystrobin (half-life <3 days) and 

O

N

CF3

N

O

O

CH3

O

H C3

CH3

O

N

CF3

N

OH

O O

H3C

CH3
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formation of CGA-321113 appears to be quite rapid; however, the decline of CGA-321113 is 

much slower (half-life >180 days). The physicochemical properties of trifloxystrobin are 

summarized in Appendix C.

3.3 Pesticide Use Pattern

Bayer submitted a partial English translation of the Sphere® Max draft specimen label to be used 

on imported coffee grown in Latin America. Sphere® Max is a MAI SC formulation consisting 

of 375 g ai/L trifloxystrobin and 160 g ai/L cyproconazole. However, this document only

addresses the application use pattern of trifloxystrobin. A summary of the directions for use of 

Sphere® Max on imported coffee are listed in Table 3.3. Note: the submitted data are all based 

on Sphere® 535 SC, an SC EP that is identical to Sphere® Max with regard to the formulation 

and the MAI mixture composition.

TABLE 3.3. Summary of Directions for Use of Trifloxystrobin.

Applic. Timing, 

Type, and Equip. Formulation

Applic. 

Rate

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. 

Rate

PHI Use Directions and Limitations

lb ai/A lb ai/A days

Coffee, green bean

Airblast Backpack

Suspension 

Concentrate

Sphere®

535 SC 

or 

Sphere® Max

0.084 3 0.25

30

To control Rust (Hemileia 

vastatrix) and Cercospora 

(Cercospora coffeicola): The 

first application should be made 

preventatively in December in 

the phase of “start of fruiting,” 

and the second and third 

applications should be 

performed at intervals of 40-45 

days.

0.13-

0.14 2 0.26-0.27

To control Rust during critical 

period of disease: The first 

application should be made 

preventatively in December in 

the phase of “start of fruiting” 

and the second application 

should be made 60-80 days 

after the first.

Coffee Use Directions: Add methylated soybean oil, 0.25%. Dilute the recommended dose in water: 250-500 L/ha.

Note: the submitted data are all based on Sphere® 535 SC, an SC EP that is identical to Sphere® Max with regard to 

the formulation and the MAI mixture composition.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of trifloxystrobin on imported coffee. As a result of existing domestic uses of 

trifloxystrobin, several risk assessments have been previously prepared for the existing uses of 

trifloxystrobin. This risk assessment considers exposure pathways based on the proposed new 

use of trifloxystrobin, but also considers the existing uses as well, particularly for the dietary

exposure assessment. Humans may be exposed to trifloxystrobin in food and drinking water 
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since trifloxystrobin may be applied directly to growing crops and application may result in 

trifloxystrobin reaching surface and ground water sources of drinking water. There are also 

residential uses of trifloxystrobin; thus, there is likely to be exposure in residential or nonoccupational settings.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Trifloxystrobin is considered a synthetic strobilurin A analog, belonging to the MAE (βmethoxyacryl ester) class of fungicides. The strobilurin pesticidal mode of action is biochemical 

interference with the mitochondria respiration system in fungi leading to inhibition of spore 

germination and mycelial growth. More specifically, the mode of action consists of interaction 

with the ubiquinone binding site of the mitochondrial bc1 complex (complex III) in fungal cells, 

thereby preventing the oxidation of ubihydroquinone and the transfer of electrons to cytochrome 

c. The interruption of the electron transport chain prevents oxidative phosphorylation, thus 

causing a severe reduction in the availability of adenosine triphosphate (ATP; the main energy

currency of the cell). This shortage of energy has a very wide range of biochemical 

consequences, such as the breakdown of essential membrane potentials and concentration 

gradients and the inhibition of nucleic acid and protein biosynthesis. Fungal spore germination, 

mycelial growth and the development of infection structures are thus prevented. However, the 

available mammalian toxicity data do not provide a clear set of results to demonstrate a similar 

mode of action on mammals.
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4.1 Toxicology Studies Available for Analysis

The toxicology database of trifloxystrobin provides sufficient information for selecting toxicity

endpoints and points of departure for risk assessment. The available toxicology studies include 

(1) subchronic oral toxicity studies in rats, mice, and dogs; (2) a 28-day dermal toxicity study in 

rats; (3) developmental toxicity studies in rats and rabbits; (4) a 2-generation reproduction study

in rats; (5) chronic toxicity studies in rats and dogs; (6) carcinogenicity studies in rats and mice;

(7) a battery of the required genotoxicity studies; and (8) metabolism studies in rats. A waiver 

for a subchronic 28-day inhalation toxicity study has been submitted and is currently under 

review.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

With low dose oral administration of trifloxystrobin to rats, approximately 56% and 65% of the 

administered dose was absorbed, with 41% and 47% in the bile of male and female rats, 

respectively. With high dose administration, the absorption was 41% and 27%, with 35% and 

19% in the bile of male and female rats, respectively. The percentage of absorption was similar 

with either single dose administration or repeated dosing in both sexes. The time to peak blood 

concentration was 12-24 hours. The blood, liver, and kidneys were found to have the highest 

residues. Most of the examined tissues had somewhat higher residue levels in the females than 

in the males (by up to two-fold). A majority of the administered dose was eliminated in the 

feces. Less than 0.1% of the administered dose was found in the expired air. The total tissue and 

carcass contained 0.3-0.5% of the administered dose indicating essentially no tissue 

accumulation. The parent compound was extensively metabolized to approximately 35 

metabolites.

Dermal Absorption

A dermal penetration study is not available; however, a 28-day dermal toxicity study is available 

for selecting dermal toxicity endpoints and points of departure for risk assessment.

4.3 Toxicological Effects

With repeated dosing by either the oral or dermal route, the liver is consistently the target organ 

for trifloxystrobin. Liver effects were seen in rats, mice, and dogs, characterized by an increase

in liver weights and an increase in incidences of hepatocellular hypertrophy and/or hepatocellular 

necrosis. The effects of reduced body weights and food consumption were also found in the 

majority of the toxicity studies. Intestinal disturbances, as indicated by diarrhea and vomiting, 

were seen in dogs and rats at higher dose levels relative to that which caused liver and body

weight effects. This finding was consistent with those produced by other members of the 

strobilurin class.

In the rabbit developmental toxicity study, an increase in the incidence of fused sternabrae was 

seen at a dose 10 times higher than the maternal LOAEL. In the rat reproduction study, both 

parents and offspring showed decreases in body weight during lactation. The rat and rabbit 
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developmental and the rat reproduction toxicity data do not demonstrate an increase in 

susceptibility in either fetal animals or offspring.

Trifloxystrobin was determined not to be carcinogenic in mice or rats following long-term 

dietary administration. However, it is positive for mutagenicity in Chinese Hamster V79 cells at 

cytotoxic dose levels while testing negative in the remaining mutagenicity studies.

Trifloxystrobin exhibits low acute toxicity following single oral, dermal and inhalation exposures

(Toxicity Category III or IV). It is a strong dermal sensitizer and a mild dermal and eye irritant.

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.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The trifloxystrobin risk assessment team evaluated the quality of the toxicity and exposure data 

and recommended that the FQPA SF be reduced to 1X.

4.4.1 Completeness of the Toxicology Database

The toxicity database for trifloxystrobin is adequate for selecting toxicity endpoints and points of 

departure for risk assessment. However, 40 CFR Part 158 now requires neurotoxicity and 

immunotoxicity testing for pesticide registration. Although neurotoxicity (acute and subchronic)

and immunotoxicity studies are needed to complete the database, the selected toxicity endpoints 

and points of departure for risk assessment are based on the most sensitive and relevant data. 

Currently, there are no concerns for neurotoxicity or immunotoxicity based on the results of the 

existing studies. The toxicological database for trifloxystrobin does not show any evidence of 

treatment-related effects on the immune system. Further, there is no evidence of neurotoxicity at 

the limit dose in an unacceptable acute neurotoxicity study or in the other subchronic and chronic 

studies in the database. HED does not believe that conducting neurotoxicity or immunotoxicity

studies will result in a dose less than the points of departure already used in this risk assessment 

and an additional database uncertainty factor for potential neurotoxicity and/or immunotoxicity

does not need to be applied. A waiver for a subchronic 28-day inhalation toxicity study has been 

submitted and is currently under review.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in subchronic and chronic toxicity studies (rats, dogs, 

mice), in developmental toxicity studies (rats, rabbits), or in a reproductive toxicity study (rats).

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no indication of increased quantitative or qualitative susceptibility to trifloxystrobin in 

rats or rabbits. In the prenatal developmental study in rats, there was no developmental toxicity

at the limit dose. In the prenatal developmental study in rabbits, developmental toxicity was 
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seen at a dose that was higher than the dose that caused maternal toxicity. In the multigeneration 

study, offspring and parental LOAELs are at the same dose level.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure assessments will not underestimate the potential dietary (food and drinking water) 

or non-dietary exposures for infants and children from the use of trifloxystrobin. The dietary

drinking water assessment utilizes water concentration values generated by models and

associated modeling parameters which are designed to provide conservative, health protective, 

high-end estimates of water concentrations, and are not likely to be exceeded. In addition, the 

residential post-application assessment is based upon the residential SOPs employing surrogate 

study data. These data are reliable and are not expected to underestimate risk to adults or 

children. The residential SOPs are based upon reasonable “worst-case” assumptions and are not 

expected to underestimate risk.

4.5 Toxicity Endpoint and Point of Departure Selections

The trifloxystrobin risk assessment team has examined the toxicity endpoints and points of 

departure used in the most recent risk assessment and in the context of the currently available 

data, the team determined that selections are valid and reflecting the current policy of HED

(DP#378917, B. Hanson, 01/25/2011). The toxicity endpoints and points of departure are 

presented in Tables 4.5.4a and 4.5.4b.

4.5.1 Dose-Response Assessment

As mentioned in Section 4.3, the available toxicology database demonstrate that trifloxystrobin 

produces liver effects, body weight reduction, and intestinal disturbance which manifests as

increased incidence of diarrhea. These three effects are often seen with repeated dosing. Gastrointestinal effects produced by trifloxystrobin seem to occur at higher dose level than the levels 

where body weight and liver effects are seen. The only possible effects which could be 

attributed to a single dose were increased fetal skeletal anomalies seen in the rabbit 

developmental toxicity study. These effects were selected as the endpoint for acute dietary

exposure assessments.

The effects selected for the chronic toxicity endpoint from the two-generation reproduction study

include liver toxicity and decreases in body weight. The two-generation reproduction study

provides the lowest point of departure for risk assessment and is protective of all other toxicity

seen in the trifloxystrobin database.

The dermal toxicity endpoint for dermal exposure assessment is based on a 28-day dermal 

toxicity study where statistically significant increases in absolute and relative kidney and liver 

weights were found at 1000 mg/kg/day (LOAEL at the limit dose). The point of departure is 100 

mg/kg/day which is 10X lower than the LOAEL.
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4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

For short, intermediate, and long-term aggregate risk assessments, oral and inhalation routes can 

be combined due to the selection of a common toxicological endpoint of concern (the oral 

equivalent was used for inhalation exposure). However, the dermal exposures cannot be 

combined with oral or inhalation exposures for any time period.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Based on the absence of significant tumor increases in two adequate rodent carcinogenicity

studies, trifloxystrobin is classified as: “Not likely to be Carcinogenic to Humans.” Cancer risk 

assessments do not need to be conducted.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

The summary of toxicological doses and endpoints for human health risk assessment are 

presented below in two separate tables: (1) Dietary and Non-Occupational Exposures in Table 

4.5.4a and (2) Occupational Exposures in Table 4.5.4b.

TABLE 4.5.4a. Summary of Toxicological Doses and Endpoints for Trifloxystrobin for Use in Dietary 

and Non-Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(Females 13-

49 Only)

NOAEL = 

250 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute RfD = 

2.5 

mg/kg/day

aPAD = 2.5 

mg/kg/day

Developmental - Rabbit

LOAEL = 500 mg/kg/day based on 

increased fetal skeletal anomalies.

Acute Dietary

(General 

Population, 

including 

Infants and 

Children)

There were no appropriate toxicological effects attributable to a single exposure (dose) 

observed in oral toxicity studies including maternal effects in developmental studies in rats and 

rabbits. Therefore, a dose and endpoint were not identified for this risk assessment.

Chronic 

Dietary (All 

Populations)

NOAEL = 

3.8 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Chronic RfD 

= 0.038

mg/kg/day

cPAD = 

0.038

mg/kg/day

Two-Generation Reproduction - Rat

LOAEL = 55.3 mg/kg/day based on 

decreases in body weight, body weight 

gains, reduced food consumption, and 

histopathological lesions in the liver, 

kidneys, and spleen.

Oral ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL = 

3.8 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Two-Generation Reproduction - Rat

LOAEL = 55.3 mg/kg/day based on 

reduced pup body weights during 

lactation.
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TABLE 4.5.4a. Summary of Toxicological Doses and Endpoints for Trifloxystrobin for Use in Dietary 

and Non-Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal 

Short-Term

(1-30 days) 

and 

IntermediateTerm (1-6 

months)

NOAEL = 

100

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

28-Day Dermal - Rat

LOAEL = 1000 mg/kg/day based on

statistically significant increases in mean 

absolute and relative liver and kidney 

weights.

Dermal 

Long-Term

(>6 months)

NOAEL =

13.8

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Dermal absorption 

rate = 33%

Residential 

LOC for 

MOE = 100

Two-Generation Reproduction - Rat

LOAEL = 55.3 mg/kg/day based on 

decreases in body weight, body weight 

gains, reduced food consumption, and 

histopathological lesions in the liver, 

kidneys, and spleen.

Inhalation 

Short-Term

(1-30 days), 

IntermediateTerm (1-6 

months), and 

Long-Term

(>6 months)

NOAEL = 

3.8 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Inhalation 

absorption rate = 

100%

Residential 

LOC for 

MOE = 100

Two-Generation Reproduction - Rat

LOAEL = 55.3 mg/kg/day based on 

decreases in body weight, body weight 

gains, reduced food consumption, and 

histopathological lesions in the liver, 

kidneys, and spleen.

Cancer (oral, 

dermal, 

inhalation)

Trifloxystrobin is classified as “Not Likely Human Carcinogen” based on the lack of evidence 

of carcinogenicity in mouse and rat cancer studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern.
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TABLE 4.5.4b. Summary of Toxicological Doses and Endpoints for Trifloxystrobin for Use in 

Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days)

IntermediateTerm (1-6 

months)

NOAEL = 

100

mg/kg/day

UFA = 10X

UFH = 10X

SF = 1X

Occupational 

LOC for 

MOE = 100

28-Day Dermal Toxicity Study in Rats

LOAEL = 1000 mg/kg/day based on 

increases in liver and kidney weights.

Inhalation 

Short-Term (1-

30 days) and 

IntermediateTerm (1-6 

months) a

NOAEL = 3.8 

mg/kg/day

UFA = 10X

UFH = 10X

SF = 1X

Inhalation 

absorption rate = 

100%

Occupational 

LOC for 

MOE = 100

Two-generation reproduction - Rat

LOAEL = 55.3 mg/kg/day based on 

decreases in pup body weights during 

lactation.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant 

tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). SF = safety factor. MOE = margin of exposure. 

LOC = level of concern.

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for trifloxystrobin was assessed using an oral toxicity study. The Agency sought expert advice 

and input on issues related to this route to route extrapolation approach (i.e. the use of oral 

toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and 

Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the 

SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, reexamine and develop new 

policies and procedures for conducting inhalation risk assessments, including route to route 

extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may

revisit the need for an inhalation toxicity study for trifloxystrobin and/or reexamine of the 

inhalation toxicity risk assessment.

4.6 Endocrine Disruption

As required under FFDCA Section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a quantitative relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Trifloxystrobin is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p), the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP orders/data call-ins for all 

Registration Review cases, including those for which EPA has already opened a Registration 

Review docket for a pesticide active ingredient. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment 

References:

- Trifloxystrobin. Petition for Establishment of a Tolerance on Imported Coffee and its Processed Commodities. 

Submission of Coffee Field Trials Conducted in Latin America. Summary of Analytical Chemistry and Residue 

Data. DP#387200, Nancy Tsaur, 07/08/2011.

- Trifloxystrobin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk 

Assessment for the Petition for Establishment of a Tolerance on Imported Coffee. DP#387201, Nancy Tsaur, 

07/13/2011.

- Drinking Water Assessment for Tolerance Petition for New Uses of Trifloxystrobin in Fluopyram/Trifloxystrobin 

500 SC Fungicide [EPA Reg. No. 264-RNON]. DP#360307, James Wolf, 10/07/2009.

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue in plants and livestock commodities is adequately 

understood based on acceptable metabolism studies reflecting direct application of 

trifloxystrobin to apples, cucumbers, peanuts, sugar beets, and wheat, as well as metabolism 

studies of lactating goats and poultry. HED has concluded that both trifloxystrobin and its acid 

metabolite, CGA-321113, are of concern for both regulatory and risk assessment purposes for 

both plant and livestock commodities. HED also determined that for livestock commodities, the 

metabolite L7a (taurine conjugate of trifloxystrobin) in liver should also be included in the risk 

assessment.
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Available confined rotational crop data are adequate to satisfy data requirements and to delineate 

the nature of the residue in rotated crop commodities. Adequate field rotational crop data are 

available, including a limited field rotational crop study and extensive field rotational crop 

studies. Based on the data from the primary plant metabolism studies and the confined rotational 

crop study, HED concluded that the residue of concern in plants, including rotational crops, is 

parent and its free acid metabolite CGA-321113. Rotational crop restrictions have been 

established; however, the proposed use on imported coffee does not affect rotational crops.

5.1.2 Summary of Environmental Degradation

The major routes of degradation and dissipation for trifloxystrobin are associated with alkalinecatalyzed hydrolysis, microbial-mediated metabolism, photodegradation, and soil binding. 

Hydrolysis of trifloxystrobin is most important under alkaline conditions. Dissipation of 

trifloxystrobin will also occur in the environment by spray drift, in runoff water and eroded soil. 

Volatilization is not an important dissipation pathway. Trifloxystrobin is expected to have low

mobility in the environment. The CGA-321113, on the other hand, is expected to be moderately

mobile to highly mobile in the environment. 

The major degradate by hydrolysis, metabolism and photodegradation is CGA-321113, the free 

acid degradation product of trifloxystrobin. CGA-321113 is persistent in aerobic soil, aerobic 

aquatic and anaerobic aquatic systems. The decline of parent trifloxystrobin (half-life <3 day) 

and formation of CGA-321113 appears to be quite rapid; however, the decline of CGA-321113 

is much slower (half-life >180 days). 

Due to the rapid degradation, low solubility (0.61 mg/L), and relatively low mobility, 

trifloxystrobin is thought to have a limited potential to contaminate water. Based upon the 

persistence in aquatic environments and its mobility, CGA-321113 is not likely to bind with 

sediment and thus will remain in the water column. The greater persistence, mobility, and 

solubility (30.9 mg/L) of CGA-321113 suggest that the CGA-321113 degradate is more likely to 

reach ground and surface water via leaching and runoff.

5.1.3 Comparison of Metabolic Pathways

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

and soil, photolytically induced isomerization of surface residues 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. Trifloxystrobin was extensively metabolized in the rat 

to approximately 35 metabolites as evidenced by the extensive metabolic profiles from liver, 

kidneys, and spleen.

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4 summarizes the metabolites and degradates included in the risk assessment and the 

tolerance expression.
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TABLE 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment and 

Tolerance Expression.

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Trifloxystrobin and CGA321113

Trifloxystrobin and CGA321113 Rotational Crop

Livestock

Ruminant

Trifloxystrobin and CGA321113; plus Metabolite L7a 

in liver and meat byproducts

Trifloxystrobin and CGA321113

Swine and Poultry Trifloxystrobin and CGA321113

Trifloxystrobin and CGA321113

Drinking Water Trifloxystrobin and CGA321113

Not Applicable

5.2 Food Residue Profile

Field Trials

DER 48219801 (2010 Coffee Field Trials), PP#0E7789

Trifloxystrobin residues on plants are mainly surface residues with only limited translocation 

within the plant. Residue reduction of various crops was previously investigated and residues of 

trifloxystrobin and CGA-321113 were found to be reduced with washing and cooking. To 

support the petition for tolerance, Bayer submitted adequate Latin American field trial data 

reflecting the proposed use patterns of trifloxystrobin on imported coffee (application rates of 

0.26-0.27 lb ai/A (2 applications at 0.13-0.14 lb ai/A/application) with a 30-day PHI). The 

residue decline studies show that combined residues of trifloxystrobin and trifloxystrobin acid 

(CGA-321113) do not increase with time. Samples were analyzed for residues of trifloxystrobin 

and trifloxystrobin acid using acceptable methods, and the studies are supported by adequate 

storage stability data. The results from these studies are summarized in Table 5.2a.

TABLE 5.2a. Summary of Residue Data from Crop Field Trials with Trifloxystrobin (Sphere® 535 SC).

Commodity

Total Applic. 

Rate PHI Residue Levels(ppm)

lb ai/A

(kg ai/ha) days n Min. Max. HAFT a Median Mean Std. Dev. STMdR STMR

Total Trifloxystrobin

Coffee, Green Beans 0.26 to 0.27

(0.29 to 0.30) 30 19 <0.010 0.013 <0.010 <0.010 <0.010 <0.010

a HAFT = Highest Average Field Trial.

These field trial data were used to determine tolerance levels for total trifloxystrobin residues of 

trifloxystrobin and its acid metabolite CGA-321113 on coffee. Except for one, all field trial 

residues (trifloxystrobin and CGA-321113) for coffee were below the LOQ (<0.01 ppm) at the 

30-day PHI. Thus, the recommended tolerance was not calculated by using the OECD method 

and HED recommends a tolerance of 0.02 ppm for coffee, green bean.
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Processed Food and Feed

DER 48219802 (Coffee Processed Food/Feed Study), PP#0E7789

Bayer submitted an acceptable processing study to support this petition for tolerance. The 

submitted coffee processing study indicates that following the exaggerated (5X) use of Sphere® 

535 SC on coffee plants and subsequent processing of green coffee beans (RAC) into the 

required commodities of dried instant or roasted coffee, total trifloxystrobin residues did not 

concentrate in dried instant coffee (processing factor <1X) or roasted coffee (processing factor 

<1X). The processing factor determined for trifloxystrobin residue in coffee is less than the

maximum theoretical concentration factor of 4.5X cited in the EPA Residue Chemistry Test 

Guideline OPPTS 860.1520. Acceptable methods were used for quantitation of residues in/on 

green coffee beans, roasted coffee, and instant coffee. Acceptable storage stability data are also 

available to support the study. The results from this study are summarized in Table 5.2b.

TABLE 5.2b. Residue Data from Green Coffee Beans Processing Study with Trifloxystrobin.

Processed Commodity

Total Rate PHI Residues Processing 

Factor lb ai/A a

(g ai/ha) days ppm

NA (RAC) b

1.3

(1.5)

28

0.07

0.07

0.06

NA

Coffee, Instant NA

<0.010

<0.010

<0.010

<1X

Coffee, Roasted Beans NA

<0.010

<0.010

<0.010

<1X

a

Processing Factor = average residue in the processed sample (coffee, instant or coffee, roasted) divided by the average residue 

in the unprocessed sample (green coffee beans).

b NA = not applicable. RAC = raw agricultural commodity.

Meat, Milk, Poultry, and Eggs

The potential exists for secondary residues to occur in some livestock commodities from 

registered uses. There are no livestock feedstuffs associated with the proposed uses on imported 

coffee. The dietary burdens for trifloxystrobin residues in livestock diets will not be affected by

the subject action; therefore, data requirements pertaining to meat, milk, poultry, and eggs are 

not relevant to the proposed uses. The dietary burdens were previously calculated and estimated 

at 3.40 and 7.76 ppm for beef and dairy cattle, and 0.80 ppm for poultry and swine (DP#378917, 

B. Hanson, 01/25/2011). 

5.3 Water Residue Profile

The highest and most protective EDWCs for trifloxystrobin in drinking water are those estimated 

in the GENEEC Tier I drinking water assessment for turf (3 applications at 0.34 lbs ai/A; 1.02 lb 

ai/A/year). The GENEEC estimates for acute and chronic (56-day) average exposure 

concentrations were 47.98 and 47.31 μg/L (ppb) for CGA-321113, respectively (summarized in 

Table 5.3). The model and its description are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water/.
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TABLE 5.3. Summary of Estimated Surface Water Concentrations for Trifloxystrobin.

Scenario Surface Water Conc., ppb a

Acute (1 in 10 year peak) 47.98

Chronic, Non-Cancer (1 in 10 year annual mean) 47.31

5.4 Dietary Risk Assessment

A conservative acute and a partially refined chronic dietary exposure assessment were performed 

for trifloxystrobin. The assumptions included tolerance-level residues for the acute assessment 

with partial refinements using anticipated residues for the chronic assessment, 100% crop 

treated, and DEEM default processing factors. For cattle, goats, horses, and sheep, value of 0.20 

ppm was added for Metabolite L7a in addition to the recommended tolerance level for liver; 

therefore, meat byproducts and liver of cattle, goats, horses, and sheep were assessed in the 

dietary assessment at 0.3 ppm (DP#318618, B. O’Keefe, 08/07/2006). The maximum theoretical 

dietary burden was lower for pork. Therefore, pork was included in the DEEM at the established 

tolerance level of 0.05 ppm; pork, liver was included at 0.16 ppm (DP#267787, L. Cheng, 

01/17/2002). Residue reduction data on strawberries from a single trial were previously 

provided which demonstrated that residues of trifloxystrobin and CGA-321113 declined in/on 

strawberries after washing and cooking; because additional dietary refinements are not needed, 

the default processing factor of 1 was retained. The EDWC for acute exposure of 47.98 μg/L

(the 1-in-10 year peak surface water EDWC for an existing turf use) and the EDWC for chronic 

exposure of 47.31 μg/L (1-in-10 year annual mean surface water) were incorporated directly into 

the dietary assessments (DP#360307, J. Wolf, 10/07/2009). 

5.4.1 Acute Dietary Risk Assessment

There were no appropriate toxicological effects attributable to a single exposure (dose) for the 

general population or any other population subgroups other than females 13-49 years old; 

therefore these population subgroups were not included in this assessment. An acute dietary

(food plus drinking water) assessment assuming tolerance-level residues for all commodities 

with existing and proposed tolerances yielded exposure estimates below HED’s level of concern; 

acute dietary exposure utilized 1.9% of the aPAD for females 13-49 years old at the 95th

percentile. The result of the acute dietary exposure analysis is reported in Table 5.4.4.

5.4.2 Chronic Dietary Risk Assessment

A partially refined chronic dietary (food + drinking water) assessment assuming mostly

tolerance-level residues with some anticipated residues (apples, grapes, and oranges) yielded 

exposure estimates below HED’s level of concern; chronic dietary exposure utilized 34% of the 

cPAD for the general U.S. population and 64% of the cPAD for children 1-2 years old (the 

population subgroup with the highest estimated chronic dietary exposure to trifloxystrobin). The 

results of the chronic dietary exposure analyses are reported in Table 5.4.4.
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5.4.3 Cancer Dietary Risk Assessment

Trifloxystrobin is classified as “not likely to be carcinogenic to humans;” therefore, no cancer 

risk is expected and cancer risk assessments were not conducted.

5.4.4 Summary Table

TABLE 5.4.4. Summary of Dietary Exposure and Risk for Trifloxystrobin.

a

Population Subgroup

Acute Dietary

(Food Only)

Chronic Dietary

(Food and Drinking Water)

Dietary Exposure % cPAD* Dietary Exposure % cPAD*

mg/kg/day mg/kg/day

General U.S. Population

N/A

0.013067 34

All Infants (< 1 year old) 0.016858 44

Children 1-2 years old 0.024165 64

Children 3-5 years old 0.020873 55

Children 6-12 years old 0.014334 38

Youth 13-19 years old 0.011057 29

Adults 20-49 years old 0.012222 32

Adults 50+ years old 0.011801 31

Females 13-49 years old 0.047424 1.9 0.012206 32

a Values for the population with the highest risk for each type of risk assessment are bolded. 

b NA = Not Applicable; no acute dietary endpoint was identified for these population subgroups.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

References:

- Occupational and Residential Risk Assessment for Section 3 Petition to Register New Uses of Trifloxystrobin on 

Barley, Oats, Sweet Corn, and for the Treatment of Sweet Corn Seed. DP#319193, Jack Arthur, 07/14/2005.

While it is assumed that most residential use will result in short-term (1 to 30 days) postapplication exposures, it is also believed that intermediate-term exposures (> 30 days to 180 

days) are possible, although unlikely.

6.1 Residential Handler Exposure

According to the labels, the currently registered residential products are restricted to use by

Certified Pest Control Operators (PCOs) only. Therefore, an assessment for residential handlers 

was not conducted (DP#319193, J. Arthur, 07/14/2005).
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6.2 Post-Application Exposure

There is potential for post-application dermal and oral exposure to homeowners and children in 

residential areas previously treated with trifloxystrobin from existing registered domestic uses of 

trifloxystrobin. As a result, risk assessments have been completed for residential postapplication scenarios.

Use of trifloxystrobin on turf may result in individuals of varying ages potentially being exposed 

from activities in areas that have been treated. Potential routes of exposure include dermal 

(adults and children) and incidental oral ingestion (children three to less than six years old only). 

Since no acute hazard has been identified for children, an assessment of episodic granular 

ingestion was not conducted. 

All calculated non-occupational post-application MOEs are greater than 100 on the day of 

application, and do not exceed HED's level of concern (DP#319131, J. Arthur, 07/14/2005). The 

MOEs range from 750 to 220,000 for adult and child residential scenarios (i.e., post-application 

dermal exposure from pesticide residues on lawns, incidental non-dietary ingestion of pesticide 

residues on lawns from hand-to-mouth transfer, incidental non-dietary ingestion of residues from 

pesticide-treated turfgrass from object-to-mouth activities, and incidental non-dietary ingestion 

of soil from pesticide-treated residential areas). The calculated risks represent screening level 

estimates and are thought to be conservative. Although both short- and intermediate-term 

exposures were calculated, the residential exposure duration is believed to be mostly short-term 

based on the use pattern. A summary of the estimated residential post-application exposures and 

risks is presented below in Table 6.2.

TABLE 6.2. Short- and Intermediate-Term Residential Post-Application Exposure and Risk Estimates 

for Trifloxystrobin.

Lifestage Post-Application Exposure Scenario

Dose 1

MOE 2

mg/kg/day

Adult Mowing Turf

High Contact Dermal 0.079 1,300

Child

High Contact Dermal 0.13 760

Treated Lawns

Hand to Mouth 0.0051 750

Object to Mouth 0.0013 3,000

Incidental Soil Ingestion 0.000017 220,000

1 Dose calculated based on maximum application rate values found on registered label (EPA Reg. No. 66330-379).

2 MOE Baseline Dermal = NOAEL/Dermal Dose. Short- and Intermediate-Term Dermal NOAEL = 100 mg/kg/day. Short- and 

Intermediate-Term Incidental Oral NOAEL = 3.8 mg/kg/day.

6.3 Combined Exposure

FQPA requires residential exposures that could reasonably be expected to occur on the same day

be combined and compared to the appropriate toxicity endpoint. Because trifloxystrobin is not 

applied by residential handlers, the only multiple-residential exposure scenario involves

children's exposure from dermal and oral routes following turfgrass treatment by a PCO. For 

incidental oral exposure to children three to less than six years old in residential settings, the 

three scenarios that would reasonably be expected to occur on the same day are incidental 

ingestion of residues on turf from hand-to-mouth activities, object-to-mouth activities, and direct 
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 24 of 32

ingestion of soil. When combined, these daily exposures total 0.006417 mg/kg/day. When the 

combined exposure is compared to the short-term incidental oral NOAEL (3.8 mg/kg/day), the 

MOE = 590. Because the toxicity endpoints for dermal and oral exposure are not the same, risks 

from these different routes of exposure are not combined. Thus, the combined risk from 

incidental oral exposures anticipated for children three to less than six years old (i.e. an MOE of

590) does not exceed HED’s level of concern. 

6.4 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for trifloxystrobin at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (2.55 x 10-7 mmHg), and the low 

turf use rate (0.34 lb ai/A). However, volatilization of pesticides may be a source of postapplication inhalation exposure to individuals nearby pesticide applications. The Agency sought 

expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for trifloxystrobin.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for trifloxystrobin. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 25 of 32

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. For trifloxystrobin, potential exposures from food, drinking water, and 

residential scenarios were aggregated.

7.1 Acute Aggregate Risk

There were no appropriate toxicological effects attributable to a single exposure (dose) for the 

general population; therefore, a dose and endpoint were not identified for this risk assessment. 

The aPAD for females 13-49 years old was 2.5 mg/kg/day. To assess the aggregate acute risk, 

EDWCs were incorporated directly into the dietary exposure analysis. Refer to Section 5.4.1 for 

this risk estimate.

7.2 Short-Term Aggregate Risk

There is potential short-term exposure to trifloxystrobin via dietary (which is considered 

background exposure) and residential (which is considered primary) pathways. For adults, these 

pathways lead to exposure via oral (background) as well as dermal and inhalation (primary) 

routes. For children, these pathways lead to exposure via the oral (background) as well as

incidental oral and dermal (primary) routes. 

The adult (dermal) and children’s (dermal and oral) aggregate MOEs are greater than 100, which 

indicates that exposure and risk do not exceed HED’s level of concern. The children’s aggregate 

estimate for incidental oral exposure only incorporates hand-to-mouth oral exposure because it is 

considered to be a conservative upper bound estimate of oral post-application exposure. 

Additionally, the dietary exposure estimates (food and water) are conservative. Further 

refinement using additional anticipated residues and empirical processing factors may need to be 

incorporated in future assessments.

TABLE 7.2. Short- and Intermediate Term Aggregate Risk Calculations.

Population

Short- and Intermediate-Term Scenario

NOAEL

LOC 1

Average 

Food and 

Water 

Exposure

Residential

Dermal

Exposure 2

Residential 

Oral 

Exposure 2

Total 

Exposure 3

Aggregate 

MOE (food, 

water, and 

residential) 4

mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day

Adult 100 100 0.03067 0.079 NA 50.092067 1,100

Children

1-2 years old

(Dermal Exposure)

100 100 0.024165 0.13 NA 0.154165 650

Children

1-2 years old

(Oral Exposure)

3.8 100 0.024165 NA 0.0051 0.029265 130

1

Indicate in this footnote the basis for the LOC (inter- and intra- species uncertainty factors total 100X).

2 Residential Dermal and Oral Exposures cannot be combined (Table 6.2).

3 Total Exposure = Avg Food & Water Exposure + Residential Exposure).

4 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)].

5 NA = Not Applicable.
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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7.3 Intermediate-Term Aggregate Risk

An intermediate-term aggregate risk assessment (1 to 6 months of exposure to trifloxystrobin 

residues from food, drinking water, and residential pesticide uses) is not expected to occur based 

on the short soil half-life (about 2 days). Therefore, an intermediate-term aggregate risk 

assessment was not performed.

7.4 Chronic Aggregate Risk

There is potential chronic exposure via dietary (food and drinking water) exposure. Refer to 

Section 5.4.2.

7.5 Cancer Aggregate Risk

Trifloxystrobin is classified as “not likely to be carcinogenic to humans;” therefore, an aggregate 

cancer assessment has not been conducted.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to trifloxystrobin and any other substances and trifloxystrobin does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

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

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR § 158.340) for food use for trifloxystrobin are in Table A.1. Use of 

the new guideline numbers does not imply that the new (1998) guideline protocols were used.

TABLE A.1. Satisfication of Trifloxystrobin Toxicology Data Requirements.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity.........................................................

870.1200 Acute Dermal Toxicity ....................................................

870.1300 Acute Inhalation Toxicity................................................

870.2400 Primary Eye Irritation......................................................

870.2500 Primary Dermal Irritation ................................................

870.2600 Dermal Sensitization........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent).................................................

870.3150 Oral Subchronic (nonrodent)...........................................

870.3200 21-Day Dermal ................................................................

870.3250 90-Day Dermal ................................................................

870.3465 90-Day Inhalation............................................................

yes

yes

yes

CR1

CR2

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent).....................................

870.3700b Developmental Toxicity (nonrodent)...............................

870.3800 Reproduction ...................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)................................................

870.4100b Chronic Toxicity (nonrodent)..........................................

870.4200a Oncogenicity (rat)............................................................

870.4200b Oncogenicity (mouse)......................................................

870.4300 Chronic/Oncogenicity......................................................

- 

yes

-

yes

yes

-

yes

-

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.......................

870.5300 Mutagenicity—Gene Mutation - mammalian..................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations.....

870.5xxx Mutagenicity—Other Genotoxic Effects.........................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen).................................

870.6100b 90-Day Neurotoxicity (hen).............................................

870.6200a Acute Neurotoxicity Screening Battery (rat) ...................

870.6200b 90-Day Neurotoxicity Screening Battery (rat).................

870.6300 Develop. Neurotoxicity ...................................................

no

no

yes

yes

CR3

-

-

no

no

-

870.7485 General Metabolism ........................................................

870.7600 Dermal Penetration..........................................................

870.7800 Immunotoxicity ...............................................................

yes

yes

yes

yes

yes

no

CR1= Conditionally required based on previous domestic registration action; CR2= The Agency is in the process of 

evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for 

conducting inhalation risk assessments, including route to route extrapolation of toxicity data; CR3= Determination 

of requirement is pending submission of acceptable guideline acute and subchronic neurotoxicity batteries.
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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A.2 Toxicity Profile of Trifloxystrobin Technical

TABLE A.2.1. Trifloxystrobin Acute Toxicity Profile.

Guideline No. Study Type MRID Results Toxicity 

Category

870.1100 Acute Oral – Rats 44496622

44496623 LD50 > 5 g/kg IV

870.1200 Acute Dermal – Rabbits 44496626

44496627 LD50 > 2 g/kg IV

870.1300 Acute Inhalation – Rats 44496630 LC50 > 4.65 mg/L IV

870.2400 Primary Eye Irritation – Rabbits 44496632 mild irritant III

870.2500 Primary Skin Irritation – Rabbits 44496635 mild irritant IV

870.2600 Dermal Sensitization – Guinea Pigs 44496637

44496638 strong sensitizer N/A

TABLE A.2.2. Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile.

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

870.3100 28-Day rangefinding oral 

toxicity (rat)

44496643 (1994)

0, 200, 1000, 4000, or 

12000 ppm

M: 0, 16.5, 84.4, 337, 

1,074 mg/kg/day

F: 0, 16.4, 84.1, 327, or 

1,005 mg/kg/day

NOAEL = 84.1 mg/kg/day

LOAEL = 327 mg/kg/day based on decreased 

body weight and increased relative liver 

weight.

870.3100 90-Day oral 

toxicity (rat)

44496701 (1995)

Acceptable

0, 100, 500, 2000, or 

8000 (F only) ppm

M: 0, 6.44, 30.6, or 127 

mg/kg/day

F: 0, 6.76, 32.8, 133, or 

618 mg/kg/day

NOAEL = 30.6 mg/kg/day

LOAEL =127 mg/kg/day based on decreased 

body weight (males), hypertrophy of 

hepatocytes (males), and pancreatic atrophy.

870.3100 90-Day oral 

toxicity (mouse)

44496641(1994) 

Acceptable

0, 500, 2000, 7000 ppm

M: 0, 76.9, 315, or 1,275 

mg/kg/day

F: 0, 110, 425, 1649 

mg/kg/day

NOAEL = 76.9 mg/kg/day

LOAEL = 315 mg/kg/day based on

increased liver weights and necrosis of 

hepatocytes.

870.3150 90-Day oral 

toxicity (dog) 

[capsule]

44496702 (1994)

Acceptable 

0, 5, 30, 150, or 500 

mg/kg/day

NOAEL = 30 mg/kg/day

LOAEL = 150 mg/kg/day based on increased 

liver weight and hepatocyte hypertrophy; 

increased incidence of diarrhea and vomiting. 

870.3150

29-Day

subchronic 

range-finding 

oral toxicity 

(dog) [capsule]

44496642 (1994)

Unacceptable/nonguideline

(2 dog/sex/dsoe)

0, 20, 50, 150 mg/kg/day

NOAEL=50 mg/kg/day

LOAEL= 150 mg/kg/day based on increased 

incidence of diarrhea and vomiting and body 

weight reduction.
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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TABLE A.2.2. Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile.

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

870.3200 28-Day dermal 

toxicity (rat)

44496703 (1996)

Acceptable 

0, 10, 100, 1000 

mg/kg/day

NOAEL = 100 mg/kg/day.

LOAEL = 1000 mg/kg/day based on increased 

liver and kidney weight.

870.3700a Prenatal 

developmental in 

(rat) [gavage]

44496708 (1995)

Acceptable

0, 10, 100, 300 

mg/kg/day

Maternal NOAEL = 10 mg/kg/day. 

Maternal LOAEL = 100 mg/kg/day based on 

decreased body weight gain and food 

consumption.

Developmental NOAEL = 1000 mg/kg/day 

(HDT).

870.3700b Prenatal 

developmental in 

(rabbit) [gavage]

44496709 (1994)

Acceptable 

0, 10, 50, 250, 500 

mg/kg/day

Maternal NOAEL = 10 mg/kg/day. 

Maternal LOAEL of 50 mg/kg/day based on

decreased body weights and body weight gain, 

food consumption and efficiency.

Developmental NOAEL = 250 mg/kg/day. 

Developmental LOAEL = 500 mg/kg/day 

based skeletal anomalies (fused sternabrae #3 

& #4).

870.3800

Multigenerational 

reproduction and 

fertility effects

(rat)

44496710 (1997)

Acceptable

0, 50, 750, 1500 ppm

M: 0, 3.8, 55.3, 110.6 

mg/kg/day

F: 4.1, 58, 123.1 

mg/kg/day

Parental NOAEL = 3.8 mg/kg/day. 

Parental LOAEL = 55.3 mg/kg/day based on

decreased body weight and weight gain, 

decreased food consumption, liver, kidney and 

spleen effects.

Offspring NOAEL= 3.8 mg/kg/day

Offspring LOAEL = 55.3 mg/kg/day based on 

decreased pup body weights during lactation.

Reproductive NOAEL = 110.6 mg/kg/day

(HDT).

870.4100b Chronic toxicity 

(dog) [capsule]

44496704 (1997)

Acceptable

0. 2, 5, 50, 200 

mg/kg/day

NOAEL = 5 mg/kg/day. 

LOAEL = 50 mg/kg/day based on increased 

clinical signs, increased liver weight and 

hepatocellular hypertrophy. 

870.4200b Carcinogenicity

(mouse)

44496705 (1997)

Acceptable

0, 30, 300, 1000, 2000 

ppm

M: 0, 3.9, 39.4, 131.1, 

274 mg/kg/day

F: 0, 3.51, 35.7, 124.1, 

274 mg/kg/day

NOAEL = 39.4 mg/kg/day

LOAEL =131.1 mg/kg/day based on liver 

effects (single cell necrosis, hepatocellular 

hypertrophy).

There was non-statistically significant and nondose related increase in lymphoma incidence. 

Trifloxystrobin is classified as “Not Likely to 

be Carcinogenic to Humans.”

870.4300 Carcinogenicity 

chronic toxicity

(rat)

44496711 (1997)

0, 50, 250, 750, 1500 

ppm

M:0, 1.95, 9.81,29.7, 

62.2 mg/kg/day

F: 0, 2.22, 11.37, 34.5, 

72.8 mg/kg/day

NOAEL = 9.81 mg/kg/day

LOAEL= 29.7 mg/kg/day based on decreased

body weight and body weight gain.

No increase in tumor incidence. 

870.5100

In vitro bacterial 

reverse gene 

mutation -

Salmonella

44496712

44496715 

44496716

44496717

Negative
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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TABLE A.2.2. Trifloxystrobin Subchronic, Chronic and Other Toxicity Profile.

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

870.5300

Gene Mutation in 

Chinese Hamster 

Cultured V-79

44496713 Positive

870.5385

Structural 

Chromosome 

Aberration -

Micronucleus -

mouse

44496714 Negative

870.5385

Structural 

Chromosome 

Aberration -

Cytogenetics -

Chinese Hamster

44496718 Negative

870.5500 DNA Repair-Rat 

hepatocytes 44496719 Negative

870.6200a

Acute oral 

neurotoxicity 

screening battery 

(rat)

Acute oral rangefinding 

neurotoxicity 

(rat)

44496640 (1977)

Unacceptable

0, 2000 mg/kg/day

44840802 (1997)

0, 1000, 2000, 3500 

mg/kg/day (provides 

supplemental 

information).

NOAEL and LOAEL could not be determined

because the data on females were missing.

Piloerection and reduced activity were often 

found in 2000 and 3500 mg/kg test animals, 

and the effects peaked at 6 to 8 hours post 

dosing. No mortality and no effects on food 

consumption and body weights were found.

870.7485

Metabolism & 

pharmacokinetics 

(rat)

44496722 (1997)

44496821 (1996)

Acceptable 

0.5, 100 mg/kg/day

Oral administration of trifloxystrobin to rats 

resulted in 56% and 65% of the administered 

dose absorbed by male and female rats, 

respectively. The time to maximal blood 

concentration was 12-24 hours. 41% and 47% 

of the administered dose was found in the bile 

of males and females respectively. Highest 

residues were found in liver, kidneys, spleen 

and blood. Majority of the administered 

radioactivity was eliminated in the feces. Less 

than 0.1% of the administered dose was found 

in the expired air. Total tissue and carcass 

content was 0.3-0.5% of the administered dose. 

Parent compound was extensively metabolized 

to approximately 35 metabolites. 
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

Page 31 of 32

Appendix B. Metabolism Summary Table

TABLE B. Tabular Summary of Metabolites and Degradates.

Company Name Chemical Name Structure 1

trifloxystrobin

[parent]

methyl (αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-

(trifluoromethyl)phenyl]ethylidene]amino]oxy]

methyl]benzeneacetate

CGA-321113

[acid metabolite]

(αE)-α-(methoxyimino)-2-[[[[(1E)-1-[3-

(trifluoromethyl)phenyl]ethylidene]amino]oxy]

methyl]-benzeneacetic acid

Appendix C. Physical/Chemical Properties

TABLE C. Physicochemical Properties of the Technical Grade Test Compound: Trifloxystrobin. 

Parameter Value Reference

Melting Point/Range 72.9oC MRID 44502801

pH (25oC) 7.7 in 1% w/w aqueous dispersion MRID 44502801

Density (21oC) 1.36 g/cm2 MRID 44502801

Water Solubility (20oC) 0.00061 g/L MRID 44502801

Solvent Solubility (g/L at 25°C)

methanol 76

acetone >500

ethyl acetate >500

n-hexane 11

dichloromethane >500

toluene 500

n-octanol 18

MRID 44502801

Vapor Pressure (25°C) 3.4 x 10-6Pa, 2.55 x 10-7 mmHg MRID 44502801

Dissociation Constant (pKa) none at pH of 2-12 MRID 44502801

Octanol/Water Partition Coefficient 

(25oC) Log(KOW)

4.5 MRID 44502801

UV/Visible Absorption Spectrum

17,500 at 250.7 μm (neutral)

17,300 at 250.2 μm (acidic)

15,900 at 252.3 μm (basic)

MRID 44502801

O

N

CF3

N

O

O

CH3

O

H C3

CH3

O

N

CF3

N

OH

O O

H3C

CH3
TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 385972

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Appendix D. International Residue Limit Summary

Table E. Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition

US Canada Mexico 2 Codex

40 CFR 180.555: 

Plants/Livestock: sum 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, calculated as 

the stoichiometric equivalent of 

trifloxystrobin.

methyl (α,E)-α-(methoxyimino)-

2-[[[(E)-[1-[3-

(trifluoromethyl)phenyl]ethylide

ne]amino]oxy]methyl]benzene 

acetate, including the metabolite 

(α,E)-α-(methoxyimino)-2-

[[[(E)-[1-[3-

(trifluoromethyl)phenyl]ethylide

ne]-amino]oxy]methyl]benzene 

acetic acid, expressed as 

trifloxystrobin.

Plants: trifloxystrobin

Livestock: sum of 

trifloxystrobin and [(E,E)-

methoxyimino-{2-[1-(3-

trifluoromethylphenyl)eth

ylideneaminooxymethyl]

phenyl}acetic acid] (CGA 

321113), expressed as 

trifloxystrobin. The 

residue is fat-soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex

Coffee, green bean 0.02

Completed: : M. Negussie; 06/27/2011

1

Includes only commodities of interest for this action.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.