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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION

MEMORANDUM

DATE: March 19, 2013

SUBJECT: REVISED Trifloxystrobin. Human Health Assessment Scoping Document in 

Support of Registration Review.

PC Code: 129112 DP Barcode: D405469

Decision No.: 469960 Registration No.: NA

Petition No.: NA Regulatory Action: Registration Review

Risk Assessment Type: NA Case No.: 5072-1

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

MRID No.: NA 40 CFR: 180.555

FROM: Nancy Tsaur, Chemist

Sheila Healy, Ph.D., Toxicologist

Meheret Negussie, Chemist

Risk Assessment Branch 3 (RAB3)

Health Effects Division (7509P)

THRU: Christine Olinger, Branch Chief

Risk Assessment Branch 3

Health Effects Division (7509P)

and

Dana Vogel, Deputy Director

Jess Rowland, Acting Associate Director

Immediate Office (IO)

Health Effects Division (7509P)

TO: Moana Appleyard, Chemical Review Manager

Risk Management and Implementation Branch 5 (RMIB5)

Pesticide Re-Evaluation Division (7508P)
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Executive Summary

The HED Registration Review Team has evaluated the database for the fungicide trifloxystrobin

to determine whether sufficient data are available and whether any updates are needed to support 

Registration Review. HED has considered the most recent human-health risk assessments for 

trifloxystrobin; updates to the toxicity, exposure, and usage databases; and current Agency

science policy and risk assessment methodologies to determine the scope of work necessary to 

support Registration Review. In addition, HED has conducted an open literature search and 

determined that new information relevant to the human health risk assessment has not been 

published.

Trifloxystrobin is a strobilurin-class fungicide that controls foliar fungal diseases and 

soilborne/seedling fungal diseases. It works by interrupting mitochondrial respiration in plantpathogenic fungi, thus inhibiting spore germination and mycelial growth. Trifloxystrobin is

registered for use on a variety of agricultural crops including the following: almonds, artichokes, 

asparagus, citrus, cucurbit vegetables, fruiting vegetables, grapes, grasses grown for seed, hops,

leafy petiole vegetables, pecans, pistachios, pome fruits, potatoes, rice, root vegetables, stone 

fruits, strawberries, sugar beets, tree nuts, tropical fruits, and wheat. In addition to agricultural 

uses, trifloxystrobin is registered for foliar use on sod farms and turfgrass (including landscapes 

and interiorscapes of residential, recreational, commercial, industrial, and public areas); and 

ornamentals (grown in greenhouses, shadehouses, and fields). Furthermore, trifloxystrobin is

registered for use as a seed treatment on the following commodities: canola, cotton, cucurbit 

vegetables, fruiting vegetables, field corn, mustard seed, rapeseed, popcorn, rice, sorghum, sugar 

beets, wheat, potatoes, peanuts, turf grass, conifers, ornamental flowers, soybeans, beans and 

peas, and sweet corn.

The toxicology database for trifloxystrobin is incomplete. Trifloxystrobin exhibits low acute 

mammalian toxicity via oral (Toxicity Category IV), dermal (Toxicity Category IV), and 

inhalation (Toxicity Category IV) routes of exposure. Trifloxystrobin is a mild eye and skin 

irritant and is a strong dermal sensitizer. The primary target organ of toxicity is the liver in dogs, 

mice, and rats in subchronic (including dermal) and chronic studies. The effects of reduced body

weight and food consumption were also found in the majority of the toxicity studies.

There is no evidence of developmental or reproductive toxicity in the trifloxystrobin toxicology

database. There is no evidence of neurotoxicity at the limit dose of an acute neurotoxicity study

or in the other subchronic and chronic studies in the database; the requirement for a subchronic 

neurotoxicity study has been waived (TXR0056150, 01/05/2012, D. Smegal). An 

immunotoxicity study in rats has been submitted by the registrant and is under review. Upon 

preliminary screen, no functional immunotoxicity is observed at the highest dose tested (263 

mg/kg/day). Trifloxystrobin is classified as “Not likely to be Carcinogenic to Humans” based on 

the lack of evidence of carcinogenicity in mice and rats. Trifloxystrobin is not mutagenic in vivo

and in vitro.

HED’s Hazard and Science Policy Committee (HASPOC) determined that a route-specific 

subchronic inhalation study is required to assess risk from inhalation exposure from occupation 

use based on a weight-of-evidence (WOE) approach considering all of the available hazard and 
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exposure information for trifloxystrobin, including the Margins of Exposure (MOEs) from the 

most recent risk assessment. The use of an oral POD resulted in the MOE of 47 for pressurized

hand gun applications that is lower than the HED Level of Concern (MOE=1000) therefore, a 

route specific study was requested to address the uncertainty resulting from the use of an oral 

study.

The toxicological endpoints and the Food Quality Protection Act (FQPA) safety factor will need 

to be re-evaluated for the registration review risk assessment, including the results of the 

inhalation toxicity study. There are no residual uncertainties in the exposure database.

The residue chemistry database is sufficient to support existing registrations of trifloxystrobin. 

The nature of the residue in plants and livestock has been defined. Adequate field trial data, 

rotational crop data, and storage stability data are available. 

A new risk assessment will be needed pending review of an inhalation toxicity study. HED has 

identified inhalation toxicity as a data gap and will apply an additional 10X safety factor for all 

inhalation exposures accordingly. Residential exposure and risk assessments also need to be 

reassessed based on current Residential Standard Operating Procedures (SOPs). Occupational 

exposure assessments need to be reassessed based on current occupational exposure and risk 

assessment policies. In addition, the Agency may need to consider off-target movement of 

pesticides into residential settings.

Introduction

HED has evaluated the existing human health risk assessments for trifloxystrobin to determine 

whether sufficient data are available and whether a new human health risk assessment is needed 

to support Registration Review. HED has considered the most recent risk assessments for 

trifloxystrobin, updates to its toxicity, exposure and usage databases, and current Agency science 

policies and risk assessment methods. The most recent risk assessment for trifloxystrobin was 

conducted in August 2011 to set a tolerance on imported coffee (DP385972, N. Tsaur, 

08/02/2011).

Hazard Identification/Toxicology

Trifloxystrobin is a strobilurin-class fungicide that controls foliar fungal diseases and 

soilborne/seedling fungal diseases. It works by interrupting mitochondrial respiration in plantpathogenic fungi, thus inhibiting spore germination and mycelial growth.

On January 5, 2012, the HASPOC has determined that a repeat-dose (28-day) inhalation toxicity

study is required based on trifloxystrobin’s use pattern and exposure scenarios, and the 

unacceptable MOEs that resulted form the use of an oral POD (TXR0056150). Since that 

HASPOC meeting, the registrant has responded with a rebuttal indicating that the MOEs used by

the HASPOC were outdated and unreliable. On November 29, 2012, the HASPOC reviewed and 

reconsidered the registrant’s waiver request and re-affirmed its earlier decision that a routespecific (inhalation) study is required to address the uncertainty of using an oral POD and to 

assess risk from occupational exposure (DP405845, K. Rury, 01/30/2013, TXR0056527). A 
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10X database uncertainty factor (UFDB) will be retained for the lack of this study only for 

inhalation risk assessments (i.e., MOE of 1000).

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.

Trifloxystrobin is not a developmental toxicant and does not produce reproductive effects. The 

rat and rabbit developmental and the rat reproduction toxicity data demonstrate no increase in 

susceptibility in either fetal animals or pups.

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

dietary administration. 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. It is a strong dermal sensitizer and a mild dermal and eye irritant.

Conclusions: The toxicology database is adequate for FQPA assessment, with the exception of 

data on subchronic inhalation. Submission of a subchronic inhalation study will require 

reevaluation of toxicity endpoints and safety factors.

Residue Chemistry

There are no residue chemistry deficiencies. 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)]. 

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

understood based on the data from the primary plant metabolism studies and the confined 

rotational crop study, as well as metabolism studies on lactating goats and poultry. HED 

concluded that the residues of concern in plants (including rotational crops) and livestock 

commodities are parent and its free acid metabolite CGA-321113 for regulatory and risk 

assessment purposes (for chemical names and structures, refer to Attachment 1). HED also 

determined that for livestock commodities, the metabolite L7a (taurine conjugate of 

trifloxystrobin) in liver should also be included in the risk assessment. The toxicity of the 

metabolites are assumed to be toxicologically equivalent to the parent compound.

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

AG-659A) is available for enforcing tolerances for the combined residues of trifloxystrobin and 
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CGA-321113 in plant and livestock commodities. This method was validated by the Agency and 

forwarded to FDA for inclusion in the Pesticide Analytical Manual (PAM), Vol. II.

Adequate multiresidue methods test data are available. Trifloxystrobin gave adequate responses 

through protocol C, and was completely recovered from fortified apple samples when analyzed 

through protocols D and E. Acid metabolite CGA-321113 was recoverable through protocol B 

and residues from apples fortified with CGA-321113 were completely recovered through Section 

402 E2/C1 (extraction with methylene chloride). These data were forwarded to the Food and 

Drug Administration (FDA).

Adequate storage stability data are available to support storage durations for trifloxystrobin.

Conclusions: The chemistry database is complete and adequate for considering dietary risk 

estimates. Additional residue and metabolism data are not required for all registered uses of 

trifloxystrobin.

Dietary Exposure

The residue chemistry and environmental fate data are adequate to assess human exposure. 

Although somewhat refined, the acute and chronic dietary food and water exposure assessments 

are based on reliable data and will not underestimate exposure/risk.

An acute and chronic aggregate dietary (food and drinking water) exposure and risk assessment 

was conducted on trifloxystrobin using the Dietary Exposure Evaluation Model, DEEM-FCIDTM, 

Version 2.03, which uses food consumption data from the U.S. Department of Agriculture’s 

Continuing Surveys of Food Intakes by Individuals (CSFII). The surveys were taken from 1994-

1996 and included a supplemental children’s survey taken in 1998. 

Residue Data used for Acute and Chronic Dietary Food and Drinking Water Exposure 

Assessments

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

general U.S. population. However, because a developmental effect that could result from a 

single dose was identified in the toxicology database, an endpoint was selected for the acute 

dietary assessment of the population subgroup females 13-49 years old.

The acute assessment was based on the assumption of tolerance-level residues for all 

commodities while the chronic assessment incorporated anticipated residues (ARs) for grapes, 

apples, and oranges. ARs were calculated by averaging the residue values over the entire field 

trial data and using the limit of quantitation for non-detect samples. Both assessments assumed

100% of the crops were treated. For the dietary assessments only, a value of 0.20 ppm was 

added for the 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

assessments at 0.3 ppm. For pork liver, a value of 0.11 ppm was added to the pork established 

tolerance (0.05 ppm); thus pork liver was included in the DEEM at 0.16 ppm (DP267787, L.

Cheng, 01/17/2002). A separate tolerance was set for grape, raisin; therefore, the processing 

factor for this commodity was set at 1X. For all other processed commodities, DEEMTM 7.81 
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default processing factors were used. 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; however, the default processing factor of 

1X was retained because further refinements are not needed.

The drinking water estimates include residues of trifloxystrobin and CGA-321113. The acute 

drinking water estimate of 47.98 μg/L (ppb) and chronic drinking water estimate of 47.31 μg/L 

(ppb), provided by the Environmental Fate and Effects Division (EFED), were directly 

incorporated into the acute and chronic assessment, respectively.

Acute Dietary (Food and Drinking Water) Exposure Results

The acute dietary risk assessment for trifloxystrobin yielded exposure estimates below HED’s 

level of concern (i.e. <100% aPAD); acute dietary exposure utilized 1.9% of the aPAD for 

females 13-49 years old at the 95th percentile.

Chronic Dietary (Food and Drinking Water) Exposure Results 

The chronic dietary risk assessment for trifloxystrobin yielded exposure estimates below HED’s 

level of concern (i.e. <100% cPAD). For the general U.S. population the exposure for food and 

drinking water utilized 34% of the cPAD. The chronic dietary risk estimate for the highest 

reported exposed population subgroup, children 1-2 years old, is 64% of the cPAD. 

Trifloxystrobin is classified as “Not Likely to be Carcinogenic to Humans” based on the lack of 

evidence of carcinogenicity in mouse and rat cancer studies; therefore, no cancer risk is expected 

and cancer risk assessments were not conducted.

Conclusions: Up-to-date drinking water estimates will be needed from EFED based on new 

modeling policies; therefore, a new dietary assessment for trifloxystrobin will be required for the 

purpose of registration review. Furthermore, although a new version of DEEM (Version 3.16) 

has been released and a new Screening Level Usage Analysis (SLUA) was provided (May 15, 

2012) by BEAD, a new dietary risk assessment may not be needed since it is anticipated that 

these updates will not affect the risk conclusion. The updated SLUA will lower risk estimates 

since %CT data were not incorporated in the assessment. 

Residential Exposure 

Registered residential uses include application to residential turfgrass, ornamentals, and 

recreational turf areas. The duration of exposure for residential handler and post-application 

exposures is expected to be short-term (1-30 days) only; intermediate- and long-term exposures 

are not anticipated. The level of concern (LOC) for risk estimates is a margin of exposure 

(MOE) of less than 100 for short-term dermal and oral exposure and 1000 for short-term

inhalation exposure. Existing residential handler and post-application exposure and risk 

assessments do not show risk estimates of concern.

Turf Transferable Residue (TTR): In accordance with the updated Part 158 data requirements 

(2007), a TTR study is required for all occupational (e.g., sod farms, golf courses, parks, and 

recreational areas) or residential turf uses. As part of the recent revision to the Health Effects 
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Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, 

HED analyzed all available data and selected new liquid and granular default values for the 

fraction of the application rate available for transfer after a turf application (FAR).1 These 

defaults are 1% for formulations applied as liquids (i.e., emulsifiable concentrates, liquids, 

wettable powders, dry flowables, etc.) and 0.2% for granular formulations. Of the available TTR 

studies submitted to the Agency, the maximum FAR value seen using a liquid product was 6.1% 

or 6.1 times higher than the default residue transfer value. The maximum FAR value seen in a 

TTR study using a granular product was 0.69% or 3.5X the default residue transfer value. 

Therefore, for both liquid and granular formulations, a calculated MOE of approximately 10 

times higher than the level of concern (e.g., an MOE > 1,000 if the LOC = 100) using the default 

residue transfer values would provide an adequate margin of safety for any potentially higher 

residues seen in a chemical-specific TTR study (Guidance for Requiring/Waiving Turf 

Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies. 6/7/2012, 

Exposure Science Advisory Council). A TTR study is required for trifloxystrobin at this time 

since the hand-to-mouth MOE is less than 1,000 (MOE = 720) based on default values for the 

fraction of application rate available for transfer after a turf application.

Residential exposures resulting from off-site transport (e.g. spray drift or volatilization) may

occur as a result of applications of trifloxystrobin. The Agency is in the process of evaluating 

these types of exposures and will examine the need for spray drift and volatilization assessments 

for trifloxystrobin during registration review.

Conclusion: There is sufficient information available to assess residential exposure, with the 

exception of TTR data. However, all residential exposure scenarios were not assessed 

adequately based on current HED policy; an up-to-date quantitative residential risk assessment 

may be needed to account for additional scenarios that were not assessed in the past, or if there is 

a change in endpoints and safety factors.

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. In 

the most recent human health risk assessment (DP385972, N. Tsaur, 08/02/2012), short-term 

aggregate risk estimates were estimated using chronic food and drinking water exposure 

estimates along with short-term residential exposure estimates. As previously mentioned, these 

aggregate risk estimates were below HED’s LOC.

Conclusions: There is sufficient information available to assess aggregate human health 

exposure and risk; however, updated aggregate assessments are required to incorporate changes 

in residential exposure and risk policies, new data (e.g. a subchronic inhalation toxicity study), 

and an up-to-date drinking water assessment.

Occupational Exposure 

Trifloxystrobin is registered for several agricultural uses and non-crop areas. The durations of 

exposure are expected to be short-term (1-30 days) and intermediate-term (1-6 months); long-

 

1

http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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term exposures are not anticipated. The LOC for dermal risk estimates is a MOE of less than 

100 for short- and intermediate-term exposure. The LOC for inhalation risk estimates is a MOE 

of less than 1000 for short- and intermediate-term exposure. Occupational handler and postapplication exposure and risk assessments have been conducted on a majority of the registered 

occupational (agricultural and non-crop) uses, resulting in risk estimates that are not of concern. 

The current HED policy incorporates new scenarios that were previously unassessed (e.g. 

handheld equipment for turf and ornamentals).

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

exposure assessment has not been performed for trifloxystrobin at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. 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. 

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 as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for trifloxystrobin.

Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements 

(2007), one or more DFR studies are required when a pesticide has residential or occupational 

uses that could result in post-application dermal exposure. As part of the recent revision to the 

Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide 

Exposure Assessment, HED analyzed a number of DFR studies and selected a new default value 

for the fraction of the application rate available to be dislodged after a foliar application (FAR). 

This default value is 25% and is based on an analysis of 19 DFR studies where the FAR value 

ranged from 2% to 89%. This value is recommended for use in both residential and occupational 

postapplication assessments. Of the analyzed DFR studies, the maximum FAR value seen was 

89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided 

that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 

400 if the LOC = 100) using the default dislodged residue values would provide an adequate 

margin of safety for any potentially higher residues seen in a chemical-specific DFR study

(Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar 

Residue (DFR) Studies. 6/7/2012, Exposure Science Advisory Council). A DFR study is 

required for trifloxystrobin at this time since some dermal MOEs are less than 400 (the lowest 

MOEs are 140 for girdling/turning grapes and 270 for tying/training grapes, and 140 for 

harvesting hops) based on default values for the fraction of application rate available for transfer 

after a foliar application.

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures, with the exception of DFR data. However, all occupational exposure 
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scenarios were not assessed adequately based on current HED policies. An up-to-date

quantitative occupational risk assessment may be required to account for the correct registered 

application rates, the changes in unit exposures, the changes in transfer coefficients (TCs), and 

any possible changes to endpoints and safety factors. Updated risk estimates may result in some 

risks of concern.

Public Health and Pesticide Epidemiology Data

For this evaluation, both OPP Incident Data System (IDS) and the Centers for Disease Control 

and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel 

Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were 

consulted for pesticide incident data on trifloxystrobin (DP407067, S. Recore, 11/27/2012). 

Based on the low frequency and severity of incident cases reported for trifloxystrobin in both 

IDS and NIOSH SENSOR, there does not appear to be a concern at this time that would warrant 

further investigation. The Agency will continue to monitor the incident information and if a 

concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Codex and Canada have established maximum residue limits (MRLs) for trifloxystrobin on 

various crop commodities. The U.S. and Canadian tolerance expressions are in harmony 

whereas Codex is not (plant only). Residue definition in the U.S. is parent and the metabolite. 

The Codex residue definition is expressed in terms of the parent only for plant commodities and 

parent and the metabolite for livestock commodities; therefore harmonization of tolerances/

MRLs is not possible. 

Most of the available Codex MRL values are not in harmony with the U.S.; the Codex MRLs for 

beet sugar (dried pulp, molasses, and roots), corn field, citrus fruits, tree nuts, strawberry, and 

cucurbit vegetables are lower than the U.S. tolerances. MRL values are harmonized on citrus dry

pulp, eggs, grape raisins, hog meat, hog meat byproducts (liver only), poultry meat and meat 

byproducts, milk, and livestock feedstuffs. The U.S. tolerances for livestock commodities (meat 

and meat byproducts) of cattle, goat, hog, horse, and sheep (0.1 ppm) are not harmonized with 

the Codex value (0.04 ppm).

The U.S. tolerances on fruiting vegetables (0.50 ppm) and root and tubers (subgroup 1B) (0.1 

ppm) were established as a crop group/subgroup while Codex MRLs were established on 

individual crops, peppers (0.3) and tomatoes (0.7) and carrots (0.1) and potatoes (0.02), 

respectively. The carrot MRL (0.1 ppm) is the same as the U.S. subgroup 1B tolerance.

There are Codex MRLs on banana, Brussels sprouts, cabbages head, flower head Brassica, leek, 

and peanut fodder that do not have U.S. equivalent.

The available Canadian MRLs are in harmony with the U.S., except for corn sweet kernel plus 

cob with husks removed, root and tuber vegetables subgroup 1B, fat, meat, and meat byproducts 

of cattle, hogs, horses, and sheep. The U.S. has recommended tolerances for livestock feed 

commodities, but by policy Canada does not establish MRLs for livestock feed commodities.
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There are Canadian MRLs on dry, edible-podded, succulent (beans and peas), mustard seed, and 

rapeseed; since these are no registered uses in the U.S., there are no U.S. tolerance equivalents.

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 

from the Continuing Surveys of Food Intakes by Individuals (CSFII) and/or the What We Eat in 

America Survey (WWEIA) 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.

Endocrine Disruptor Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include endpoints 

which may be susceptible to endocrine influence, including effects on endocrine target organ 

histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, 

reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates 

acute tests and chronic studies that assess growth, developmental and reproductive effects in 

different taxonomic groups. As part of its most recent registration decision, EPA reviewed these 

data and selected the most sensitive endpoints for relevant risk assessment scenarios from the 

existing hazard database. However, as required by FFDCA section 408(p), trifloxystrobin is 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the 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 
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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 

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 dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. 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. Trifloxystrobin

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

the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data 

call-ins, requiring the submission of EDSP screening assays for trifloxystrobin. For further 

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

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

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

Cumulative

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 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/.

Human Studies

The previous risk assessments rely in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide or other chemical. These studies, which comprise the 

PHED, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry

Task Force (ARTF), have been determined to require a review of their ethical conduct, and have 

received that review.

Data Requirements

Exposure 870.2100 Turf Transferable Residue Dissipation

A TTR study is required for trifloxystrobin at this time since the hand-to-mouth MOE is less than 

1,000 (MOE = 720) based on default values for the fraction of application rate available for 

transfer after a turf application.
Page 12 of 25

Exposure 870.2100 Dislodgeable Foliar Residue Dissipation

A DFR study is required for trifloxystrobin at this time since some dermal MOEs are less than 

400 (the lowest MOEs are 140 for girdling/turning grapes and 270 for tying/training grapes, and 

140 for harvesting hops) based on default values for the fraction of application rate available for 

transfer after a foliar application.

Toxicology 870.3465 Inhalation Toxicity

A subchronic inhalation study is required as the use pattern of this chemical indicates inhalation 

exposure can occur; a waiver for an inhalation toxicity study has not been granted.

References

Memoranda Relevant to Registration Review of Trifloxystrobin

Author DP/TXR

Barcode Date Title

L. Cheng DP267787 01/17/2002

Trifloxystrobin on Barley, Citrus, Corn (Field and 

Pop), Pecan, Pistachio, Rice, and Stone Fruit. Review 

of Analytical Methods and Residue Data.

K. Rury TXR 

0056527 01/30/2012

Trifloxystrobin: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of November 29, 

2012: Recommendations on waiver requests for 28-

day inhalation study for trifloxystrobin.

D. Smegal TXR 

0056150 01/05/2012

Trifloxystrobin: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of December 8, 

2011: Recommendations on waiver requests for 28-

day inhalation and subchronic neurotoxicity studies for 

trifloxystrobin.

N. Tsaur DP385972 08/02/2011 Trifloxystrobin. Human Health Risk Assessment for 

Proposed New Use on Imported Coffee.

N. Tsaur DP387201 07/13/2011

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.

J. Wolf DP360307 10/07/2009

Drinking Water Assessment for Tolerance Petition for 

New Uses of Trifloxystrobin in 

Fluopyram/Trifloxystrobin 500 SC Fungicide [EPA 

Reg. No. 264-RNON].
Page 13 of 25

Attachments

1. Chemical Identity Table

2. International Residue Limits

3. Endpoint Selection Table

4. Toxicology Data Requirements Table

5. Acute Toxicity profile

6. Subchronic, Chronic, and Other Toxicity Profile

Attachment 1

Chemical Identity Table

Table 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

Chemical Class Strobilurin

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

O

N

CF3

N

O

O

CH3

O

H C3

CH3

O

N

CF3

N

OH

O O

H3C

CH3
Page 14 of 25

Attachment 2

International Residue Limits

Table 2. Summary of U.S. and International Tolerances and Maximum Residue Limits

Residue Definition

U.S. Canada Mexico2 Codex3

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]ethyliden

e]amino]oxy]methyl]benzene 

acetate, including the metabolite 

(α,E)-α-(methoxyimino)-2-[[[(E)-

[1-[3-

(trifluoromethyl)phenyl]ethyliden

e]-amino]oxy]methyl]benzene 

acetic acid, expressed as 

trifloxystrobin.

Plants: trifloxystrobin

Livestock: sum of 

trifloxystrobin and 

[(E,E)-methoxyimino-

{2-[1-(3-

trifluoromethylphenyl)

ethylideneaminooxyme

thyl]

phenyl}acetic acid] 

(CGA 321113), 

expressed as 

trifloxystrobin. 

The residue is fatsoluble.

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

U.S. Canada Mexico2 Codex3

Alfalfa, forage 0.01

Alfalfa, hay 0.01

Almond, hulls 9.0 3

Apple, wet pomace 5.0

Artichoke, globe 1.0

Asparagus 0.07

Banana10.10 0.05

Barley, grain 0.05 0.05 0.5

Barley, hay 0.3

Barley, straw 5.0 7 barley straw and 

fodder, dry

Beet, sugar, dried pulp 0.4 0.2 sugar beet pulp, dry

Beet, sugar, molasses 0.2 0.1 sugar beet molasses

Beet, sugar, roots 0.1 0.1 sugar beet roots 0.05 sugar beet

Beet, sugar, tops 4.0

Canistel 0.7 0.7

Cattle, fat 0.1 0.04

Cattle, meat 0.1

0.04

0.05 (fat) (meat from 

mammals other than 

marine mammals)

Cattle, meat byproducts 0.1

0.04

0.04 (*) kidney of 

cattle

0.05 liver of cattle

Citrus, dried pulp 1.0 1 citrus pulp, dry

Citrus, oil 38 38

Coffee, green bean10.02

Corn, field, forage 6.0

Corn, field, grain 0.05 0.05 field corn 0.02 maize
Page 15 of 25

Table 2. Summary of U.S. and International Tolerances and Maximum Residue Limits

Residue Definition

U.S. Canada Mexico2 Codex3

Corn, field, stover 7 10 maize fodder (dry)

Corn, field, refined oil 0.1 0.1

Corn, pop, grain 0.05 0.05 popcorn grain

Corn, pop, stover 7

Corn, sweet, cannery waste 0.6

Corn, sweet, forage 7.0

Corn, sweet, kernel plus 

cob with husks removed

0.04 0.04

Corn, sweet, stover 4.0

Egg 0.04 0.04 0.04 (*)

Fruit, citrus, group 10 0.6 0.6 Australian (desert limes, 

finger limes, round limes), brown 

river finger limes, calamondin, 

citrus citron, citrus hybrids, 

grapefruits, Japanese summer 

grapefruit, kumquats, lemons, 

limes, Mediterranean mandarin, 

Mount white lime, New Guinea 

wild lime, oranges, pummelos, 

Russell river lime, Satsuma 

mandarins, sweet limes, tachibana 

oranges, tahiti limes, tangelos, 

tangerines, tangors, trifoliate 

oranges, uniq fruits 

0.5 citrus fruits

1 citrus pulp, dry

Fruit, pome 0.5 0.5 apples, asian pears, 

crabapples, loquats, mayhaws, 

pears, quinces

0.7 pome fruits

Fruit, stone, group 12 2 2.0 apricots, nectarines, peaches, 

plumcots, plums, prune plums, 

sweet cherries, tart cherries

3 stone fruits

Goat, fat 0.1 0.04

Goat, meat 0.1

0.04

0.05 (fat) (meat from 

mammals other than 

marine mammals)

Goat, meat byproducts 0.1

0.04

0.04 (*) kidney of 

goats

0.05 liver of goats

Grain, aspirated fractions 5.0

Grape 2.0 2.0 3 

Grape, raisin 5.0

5 raisins

5 Dried grapes 

(=currants, raisins and 

sultanas

Grass, forage 12

Grass, hay 17

Hog, fat 0.05 0.04

Hog, meat 0.05

0.04

0.05 (fat) (meat from 

mammals other than 

marine mammals)

Hog, meat byproducts 0.05 0.04 0.04 (*) kidney of pigs

0.05 liver of pigs

Hop, dried cones 11.0 40 hops, dry
Page 16 of 25

Table 2. Summary of U.S. and International Tolerances and Maximum Residue Limits

Residue Definition

U.S. Canada Mexico2 Codex3

Horse, fat 0.1 0.04

Horse, meat 0.1

0.04

0.05 (fat) (meat from 

mammals other than 

marine mammals)

Horse, meat byproducts 0.1 0.04

Leaf petioles subgroup 4B 3.5 1 celery

Mango 0.7 0.7

Milk 0.02 0.02 0.02 (*)

Nut, tree, group 14 0.04 0.04 almond; beech nuts; Brazil 

nuts; butternuts; cashew nuts; 

chestnuts; chinquapins; filberts; 

hickory nuts; macadamia nuts; 

pecans; walnuts, black and 

English

0.02 (*) tree nuts

Oat, forage 0.3

Oat, grain 0.05 0.05

Oat, hay 0.3

Oat, straw 5.0

Papaya 0.7 0.7

Peanut, hay 4.0

Peanut 0.05 0.02 (*)

0.02 (*) tree nuts

Pistachio 0.04 0.04 0.02 (*) tree nuts

Potato 0.04 0.04 0.02 (*) 

Poultry, fat 0.04 0.04

Poultry, meat 0.04 0.04 0.04 (*) (fat)

Poultry, meat byproducts 0.04 0.04 0.04 (*) poultry edible 

offal

Radish, tops 10

Rice, grain 3.5 3.5 rice 5

7 rice bran unprocessed

Rice, hulls 8

Rice, straw 7.5 10 rice straw and 

fodder, dry

Sapodilla 0.7 0.7

Sapote, black 0.7 0.7

Sapote, mamey 0.7 0.7

Sheep, fat 0.1 0.04

Sheep, meat 0.1

0.04

0.05 (fat) (meat from 

mammals other than 

marine mammals)

Sheep, meat byproducts 0.1

0.04

0.04 (*) kidney of 

sheep

0.05 liver of sheep

Soybean, forage 10.0

Soybean, hay 25.0

Soybean, seed 0.08 0.08 dry soybeans

Star apple 0.7 0.7

Strawberry 1.1 0.2
Page 17 of 25

Table 2. Summary of U.S. and International Tolerances and Maximum Residue Limits

Residue Definition

U.S. Canada Mexico2 Codex3

Vegetable, cucurbit, group 

9

0.50 0.5 balsam apples, balsam pears, 

cantaloupes, chayote fruit, 

Chinese cucumbers, Chinese 

waxgourds, citron melons, 

cucumbers, edible gourds, 

muskmelons (other than those 

listed in this item) pumpkins, 

summer squash, watermelons, 

west Indian gherkins, winter 

squash

0.3 Fruitng vegetables, 

cucurbit

Vegetable, fruiting 0.5 0.5 bell peppers, eggplant, 

groundcheries, non-bell peppers, 

pepinos, pepper hybrids, 

tomatillos, tomatoes 

0.3 Peppers, sweet 

(including pimento or 

pimiento)

0.7 tomato

Vegetable, root, except 

sugar beet, subgroup 1B

0.1 0.04 potatoes 0.1 carrot

0.02 potato

Wheat, bran 0.15 0.5 wheat bran, 

unprocessed

Wheat, forage 0.3

Wheat, grain 0.05 0.05 0.2

Wheat, hay 0.2

Wheat, straw 5 5 wheat straw and 

fodder, dry

MRLs with NO U.S. equivalent

Dry (adzuki beans, beans, 

blackeyed peas, broad 

beans, catjang seeds, 

chickpeas, cowpea seed, 

field peas, guar seeds, 

kidney beans, lablab beans, 

lentils, lima beans, moth 

beans, mung beans, navy 

beans, pigeon peas, pink 

beans, pinto beans, rice 

beans, southern peas, 

tepary beans, urd beans); 

edible podded (dwarf peas, 

jackbeans, moth beans, 

peas, pigeon peas, runner 

beans, snap beans, snow

peas, soybeans, sugar snap 

peas, sword beans, wax 

beans, yardlong beans); 

grain lupin; succulent 

shelled ( blackeyed peas, 

broad beans, cowpeas, 

english peas, garden peas, 

green peas, lima beans, 

peas, pigeon peas, southern 

peas

0.02
Page 18 of 25

Table 2. Summary of U.S. and International Tolerances and Maximum Residue Limits

Residue Definition

U.S. Canada Mexico2 Codex3

Mustard seeds (condiment 

type) 0.02

Mustard seeds (oilseed 

type) 0.02

Rapeseeds (canola) 0.02

Brussels sprouts 0.1

Cabbages, head 0.5

Flowerhead brassicas 

(includes Broccoli: 

broccoli, Chinese and 

Cauliflower

0.5

Leek 0.7

Peanut fodder 5

Completed: M. Negussie; 10/03/2012

1 There are no U.S. registrations for use on banana (as of September 27, 1999) and coffee, green bean (as of January 

18, 2012).

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

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on 

the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.
Page 19 of 25

Attachment 3

Summary of Endpoints, Points of Departure, and Toxicology

Data Requirements for Trifloxystrobin

Table 3.1. 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 Toxicity-Rat

LOAEL = 500 mg/kg/day based upon 

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 study-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 study-Rat

LOAEL = 55.3 mg/kg/day based on 

reduced pup body weights during 

lactation.

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 Toxicity Study-Rat

LOAEL = 1000 mg/kg/day based on 

increases in mean absolute and relative 

liver and kidney weights.

Dermal 

Long-Term

(>6 months)

NOAEL =

3.8

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Dermal absorption 

rate = 33%

Residential 

LOC for 

MOE = 100

Two-Generation reproduction study-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.
Page 20 of 25

Table 3.1. 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

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

UF = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 1000

Two-Generation reproduction study-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. N/A = not applicable

Table 3.2. 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-Rat

LOAEL = 1000 mg/kg/day based on 

increases in mean absolute and relative 

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

UF = 10X

SF = 10X

Occupational 

LOC for 

MOE = 1000

Two-Generation reproduction study-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)

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. SF = safety factor. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
Page 21 of 25

Attachment 4

Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses of trifloxystrobin are in Table 4. Use of the 

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

Table 4. Summary of Toxicological Data Requirements for Trifloxystrobin 

Test

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

NoYes

Yes

Yes

Yes

-

No

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

870.5385 Mutagenicity—Mammalian Bone Marrow

 Chromosome Aberration Aberrations

870.5550 Mutagenicity—Unscheduled DNA Synthesis

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

Yes

No1

No

Yes1

--

No

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

Yes

No

Yes

Yes

--

Yes

1 TXR0056150, 01/05/2012, D. Smegal. Trifloxystrobin: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of December 8, 2011: Recommendations on waiver requests for 28-day inhalation and 

subchronic neurotoxicity studies for trifloxystrobin.
Page 22 of 25

Attachment 5

Acute Toxicity Profile

Table 5. Acute Toxicity Profile Data on Trifloxystrobin 

Guideline No. Study Type MRID Results Toxicity 

Category

870.1100 Acute Oral – Rats 44496622

44496623 LD50 > 5g/kg IV

870.1200 Acute Dermal – Rabbits 44496626

44496627 LD50 > 2g/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

Attachment 6

Subchronic, Chronic, and Other Toxicity Profile

Table 6. Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin.

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 1275 

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. 
Page 23 of 25

Table 6. Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin.

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

Classification /Doses Results

870.3150

29-Day

subchronic 

range-finding 

oral toxicity 

(dog) [capsule]

44496642 (1994)

Unacceptable/nonguideline

(2 dog/sex/dose)

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.

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, 1000 

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 anomolies (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 

(highest dose tested: 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 was classified as “Not Likely 

Human Carcinogen.”
Page 24 of 25

Table 6. Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin.

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

Classification /Doses Results

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.

870.5300

Gene Mutation 

in Chinese 

Hamster 

Cultured V-79

44496713 Positive at cytotoxic concentration levels.

870.5385

Structural 

Chromosome 

Aberration -

Micronucleus -

mouse

44496714 Negative.

870.5385

Structural 

Chromosome 

Aberration -

Cytogenetics -

Chinese 

Hamster

44496718 Negative.

870.5500 DNA RepairRat hepatocytes 44496719 Negative.

870.6200a

Acute oral 

neurotoxicity 

screening 

battery (rat)

Acute oral 

range-finding 

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.

Limited results which include mortality, in-life 

observation, body weight, food consumption, & 

FOB only. No histological examination. 

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.

870.6200b

Subchronic 

neurotoxicity 

screening 

battery (rat )

Waived.
Page 25 of 25

Table 6. Subchronic, Chronic, and Other Toxicity Profile Data on Trifloxystrobin.

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

Classification /Doses Results

870.7485

Metabolism & 

pharmacokineti

cs (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 was 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.