TRIFLOXYSTROBIN Human Health Risk Assessment DP No. 388187/388434

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: June 14, 2012

SUBJECT: REVISED Trifloxystrobin. Human Health Risk Assessment Analysis for 

Proposed New Use on Globe Artichokes and Waiver Requests for 28-Day

Inhalation Toxicity and Subchronic Neurotoxicity Studies.

PC Code: 129112 DP Barcode: 388187, 388434

Decision No.: 445968, 445971 Registration No.: 264-776, 777, 826

Petition No.: 1F7845 Regulatory Action: Section 3

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

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)

RD requested that HED provide an evaluation of the proposed tolerance for trifloxystrobin in/on

artichoke, globe. HED concludes that a new human health aggregate risk assessment is not 

needed for this petition.

There are no changes to trifloxystrobin dietary exposure from food and/or drinking water, nor 

any changes to residential exposure resulting from the proposed tolerance of 1.0 ppm.

In addition to the tolerance evaluation, this document addresses the responses to two waiver

requests for: 28-Day Inhalation Exposure Toxicity and Subchronic Neurotoxicity.
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Table of Contents

1.0 Executive Summary........................................................................................................... 3

2.0 HED Recommendations.................................................................................................... 3

2.1 Data Deficiencies/Conditions of Registration .............................................................. 3

2.2 Recommended Tolerances............................................................................................. 4

3.0 Introduction........................................................................................................................ 4

3.1 Chemical Identity ........................................................................................................... 4

3.2 Pesticide Use Pattern...................................................................................................... 5

4.0 Hazard Characterization and Dose-Response Assessment............................................ 6

4.1 Safety Factor for Infants and Children (FQPA Safety Factor) ................................. 6

4.1.2 Evidence of Neurotoxicity.......................................................................................... 6

4.1.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.......... 7

4.1.4 Residual Uncertainty in the Exposure Database ..................................................... 7

5.0 Dietary Exposure and Risk Assessment........................................................................... 7

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................... 8

7.0 Aggregate Exposure/Risk Characterization.................................................................... 8
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1.0 Executive Summary

In PP#1F7845, Bayer Cropscience (Bayer) has 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):

Artichoke, globe....................................................... 1.0 ppm

The most recent human health risk assessment was conducted for use on imported coffee in 

which the hazard characterization and toxicity endpoints for risk assessment were reported 

(DP#379110, N. Tsaur, 02/28/2011). Since then, a waiver request for a 28-day inhalation 

exposure toxicity study was submitted and denied, and a waiver request for a subchronic 

neurotoxicity (SCN) study was submitted and accepted. Other then the waiver requests, the 

hazard characterization and toxicity endpoints for risk assessment remain unchanged. The 

details of the hazard characterization and the rationale for toxicity endpoint selection will not be 

repeated in this risk assessment. However, the salient features for the Food Quality Protection 

Act (FQPA) safety factor will be summarized.

A summary of the findings and a discussion of human health risk resulting from the proposed 

tolerance of trifloxystrobin are provided in this document. This assessment has been conducted 

by Nancy Tsaur.

2.0 HED Recommendations

There are no data deficiencies that preclude establishment of a permanent tolerance for combined 

residues of trifloxystrobin in/on globe artichokes.

2.1 Data Deficiencies/Conditions of Registration

Toxicology [870.7800 Immunotoxicity]

In 2007, the Agency revised 40CFR Part 158.500 Toxicology data requirements to include 

functional immunotoxicity testing and granted a 2-year grace period to allow time for 

registrants to develop the required data. The registrant has informed the Agency of their 

intent to submit an immunotoxicity study as a condition of registration (the study was 

scheduled to be conducted in 2011).

Toxicology [870.3465 28-Day Inhalation Toxicity]

Prior to 2010, the Agency frequently relied on oral toxicity studies to conduct inhalation risk 

assessments. In December 2009, the Agency sought expert advice and input from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) on issues 

related to this route to route extrapolation approach in the absence of an inhalation toxicity

study (i.e. the use of oral toxicity studies for inhalation risk assessment). Based on the SAP’s 

recommendations in the March 2, 2010 Final Report 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html), the Agency has 
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increased its focus on the uncertainties associated with route-to-route extrapolation and is 

presently requiring inhalation toxicity studies more frequently. The Agency has concluded 

that an inhalation toxicity study is required as a condition of registration to fully characterize 

the risk from inhalation exposure to trifloxystrobin.

2.2 Recommended Tolerances

Table 2.2. Tolerance Summary for Trifloxystrobin

Commodity

Tolerance (ppm) Comments

Established Proposed Recommended Correct Commodity Definition

40 CFR §180.609(a)(1)

Artichoke, globe -- 1.0 1.0

3.0 Introduction

In 2010 (PP#8F7464), Bayer submitted a petition for tolerance on globe artichokes. 

Subsequently, HED reviewed the submitted field trial data and concluded that the data did 

support the proposed tolerance of 1.0 ppm in a previous risk assessment (B. Hanson, 

DP#360305, 12/09/2010). To support the risk assessment recommendation, both acute and 

chronic dietary risk estimates incorporated the proposed tolerance level of 1.0 ppm for globe 

artichokes (B. Hanson, DP#379505, 09/28/2010). However, Bayer later withdrew the petition 

for tolerance in/on globe artichokes prior to the establishment of a permanent tolerance.

Now, in 2011 (PP#1F7845), Bayer has submitted a new petition for a tolerance of 1.0 ppm for 

residues of trifloxystrobin in/on globe artichokes. With the petition, Bayer has submitted 

amended labels for Flint® Fungicide (EPA Reg. No. 264-777) and GemTM 500 SC Fungicide 

(EPA Reg. No. 264-826) to include use on globe artichokes. Flint® is a water dispersible 

granule (WG) formulation consisting of 50% trifloxystrobin by weight whereas GemTM 500 SC 

is a suspension concentrate (SC) formulation consisting of 4.17 lb trifloxystrobin per gallon of 

product.

Along with this petition for tolerance, Bayer has submitted two waiver requests: one for a 28-day

inhalation exposure toxicity study (Guideline 870.3465), and one for the subchronic 

neurotoxicity (SCN) study of the neurotoxicity battery (Guideline 870.6200b). Upon review of 

the waiver requests, HED determined that a 28-day inhalation exposure toxicity study will be 

required based on a weight of evidence approach: HED considered the trifloxystrobin use 

pattern, all relevant hazard and exposure information, in addition to the current OPP guidance for 

waiving inhalation studies. Therefore, HED concluded to deny the waiver request for the 28-

day inhalation exposure toxicity study. However, regarding the SCN, HED determined that 

there is no concern for neurotoxicity for trifloxystrobin based on the available database, limited 

findings in an acute neurotoxicity (ACN) study, and lack of neurotoxicity in other fungicides of 

the strobilurin class. Therefore, HED concluded to grant the waiver request for an SCN 

study (DP#385650, TXR#0056113, Sheila Healy, 01/06/2012).

3.1 Chemical Identity
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Trifloxystrobin is a strobilurin-class fungicide (also termed methoxyacrylates) that controls foliar 

fungal diseases and soilborne/seedling fungal diseases. It works by interrupting mitochondrial 

respiration in plant-pathogenic fungi, thus inhibiting spore germination and mycelial growth. 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. Trifloxystrobin is described in 

Table 3.1.

Table 3.1. Trifloxystrobin Nomenclature

Chemical Structure

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 Number 141517-21-7

End-Use Products (EPs) Flint® Fungicide (50% ai); GemTM 500 SC (4.17 lb ai/gallon)

Chemical Class Strobilurin, methoxyacrylates

Known Impurities of Concern None

3.2 Pesticide Use Pattern

Bayer submitted amended labels for Flint® Fungicide (EPA Reg. No. 264-777) and GemTM 500 

SC Fungicide (EPA Reg. No. 264-826) to include use on globe artichokes. Flint® WG 

formulation consisting of 50% trifloxystrobin by weight whereas GemTM 500 SC is an SC 

formulation consisting of 4.17 lb trifloxystrobin per gallon of product. A summary of the 

directions for use are listed in Table 3.2.

Table 3.2. Summary of Directions for Use of Trifloxystrobin

Applic. 

Timing, Type, 

and Equip.

Formulation 

(EPA Reg. No.)

Applic. 

Rate

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

PHI 

Use Directions and Limitations

lb ai/A lb ai/A days

Peanut

Groundboom,

Aerial,

Airblast, or

Chemigation

Flint®

Water Dispersible 

Granule

(264-777) 0.10 -

0.125 2 0.25 0

To control Powdery mildew

(Leveillula taurica). 

Applications should begin when 

conditions are favorable for 

diseases but before infection. 

RTI = 7 to 10 days.

GemTM 500 SC

Suspension 

Concentrate

(264-826)

O

N

CF3

N

O

O

CH3

O

H C3

CH3
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4.0 Hazard Characterization and Dose-Response Assessment

References:

- Trifloxystrobin. Human Health Risk Assessment for Proposed New Use on Imported Coffee. DP#385972, Nancy 

J. Tsaur, 08/02/2011.

A detailed hazard characterization with a list of available toxicity studies for trifloxystrobin is 

presented in the previous risk assessment (DP#385972, N. Tsaur, 08/02/2011). The submitted 

toxicology studies are of good quality and provide sufficient information to determine whether 

trifloxystrobin poses a human health hazard. 

In addition to the existing database, Bayer has submitted two waiver requests: one for a 28-day

inhalation exposure toxicity study (Guideline 870.3465), and one for the SCN study of the 

neurotoxicity battery (Guideline 870.6200b). Upon review of the waiver requests, HED 

determined that a 28-day inhalation exposure toxicity study will be required based on a weight of 

evidence approach: HED considered the trifloxystrobin use pattern, all relevant hazard and 

exposure information, in addition to the current OPP guidance for waiving inhalation studies. 

Therefore, HED concluded to deny the waiver request for the 28-day inhalation exposure 

toxicity study. However, regarding the SCN, HED determined that there is no concern for 

neurotoxicity for trifloxystrobin based on the available database, limited findings in an ACN 

study, and lack of neurotoxicity in other fungicides of the strobilurin class. Therefore, HED 

concluded to grant the waiver request for an SCN study (DP#385650, TXR#0056113, Sheila 

Healy, 01/06/2012).

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

The toxicology and exposure data and have been evaluated and trifloxystrobin has been 

determined to be safe for infants and children, supporting the reduction of the FQPA safety 

factor to 1X.

4.1.1 Completeness of the Toxicology Database

The toxicity database for trifloxystrobin is complete with the exception of an immunotoxicity

study and a 28-day inhalation toxicity study. A waiver for a subchronic neurotoxicity study has 

been granted. Although immunotoxicity and inhalation studies are needed to complete the 

database, the entire trifloxystrobin toxicity database was examined; the database of this chemical 

shows no indication that this chemical directly targets the immune system, and there are no 

uncertainties with respect to residential inhalation exposures. 

4.1.2 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). 

There is no concern for neurotoxicity for trifloxystrobin based on the available database, limited 

findings in an ACN study, and lack of neurotoxicity in other fungicides of the strobilurin class.
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4.1.3 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 

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.

4.1.4 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 main 

contribution to total aggregate exposure is from the dietary route. The acute dietary assessment 

was unrefined, assuming conservative upper bound inputs including 100% crop treated and 

tolerance-level residues. The chronic dietary assessment was partially refined, assuming 100% 

crop treated and tolerance-level residues for all commodities except for apples, grapes, and 

oranges where the average field trial residues were used. Although the chronic assessment 

included these minor refinements, the use of representative field trial data ensures that actual 

exposures/risks from residues in food will not be underestimated. 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 postapplication exposure assessment is based upon the residential SOPs employing surrogate study

data, including conservative exposure assumptions based on Day 0 dermal contact to turf treated 

at the maximum application rate. 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.

4.2 Summary of Points of Departure and Endpoints Used in Human Risk Assessment

The summary of toxicological doses and endpoints supporting this petition remain unchanged 

and have been summarized in the previous human health risk assessment (DP#385972, N. Tsaur, 

08/02/2011) as well as the most recent Federal Register Notice (EPA-HQ-OPP-2011-0456-0004, 

FRN Vol. 76, No. 217, pp. 69648, 11/09/2011).

5.0 Dietary Exposure and Risk Assessment 

References:

- 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 J. Tsaur, 

07/13/2011.

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. The 

most recent acute and chronic dietary exposure assessments conducted for trifloxystrobin

included the proposed tolerance for globe artichokes. The results of both acute and chronic 

dietary exposure analyses remain unchanged and are reported in Table 5.0. The acute dietary
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(food + drinking water) assessment was unrefined, and the chronic dietary (food + drinking 

water) assessment was partially refined, assuming 100% crop treated and tolerance-level residues 

for all commodities except for apples, grapes, and oranges where the average field trial residues

were used. Trifloxystrobin is classified as “not likely to be carcinogenic to humans” and thus

cancer risk is not expected.

Table 5.0. Summary of Dietary Exposure and Risk for Trifloxystrobin

Population Subgroup

Acute Dietary

(Food and Drinking Water)

Chronic Dietary

(Food and Drinking Water)

Dietary Exposure % aPAD* Dietary Exposure % cPAD* mg/kg/day mg/kg/day

General U.S. Population N/A 0.013067 34

Children 1-2 years old 0.024165 64

Females 13-49 years old 0.047424 1.9 0.012206 32

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.

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. Additionally, residential risk estimates cannot be combined because the 

toxic effects are different via different routes of exposure. Thus, the risk estimates resulting 

from post-application exposure scenarios remain unchanged from the previous assessment and 

are summarized in Table 6.0.

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

Trifloxystrobin

Population

Post-Application Exposure 1

mg/kg/day

Residential PostApplication Total 

Exposure

mg/kg/day

MOE

Dermal Inhalation Oral

Adult 0.079 NA NA 0.079 1300

Child 0.13 NA NA 0.13 770

NA NA 0.0051 0.0051 750

1

Post-application exposure represents high end incidental oral exposure for the relevant exposure duration (hand-to-mouth).

7.0 Aggregate Exposure/Risk Characterization

The aggregate risk calculation remains unchanged since the last risk assessment because the 

proposed tolerance for globe artichokes has been previously incorporated into the dietary risk 

estimates, and residential risk estimates remain unchanged. Chronic exposures via the dietary

(food and drinking water) route are summarized in Section 5.0. Short- and intermediate-term 

risk estimates are summarized in Table 7.0. An aggregate cancer assessment was not conducted 

because trifloxystrobin is classified as “not likely to be carcinogenic to humans.”
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This assessment has taken into consideration the changes in the new Residential Standard 

Operating Procedures (SOPs) to be implemented in January of 2012. HED finds no changes that 

would affect the aggregate safety finding and confirms that there are no risks of concern 

resulting from setting a tolerance for trifloxystrobin in/on globe artichokes, nor from utilizing the 

new Residential SOPs to estimate residential exposure and risk.

Table 7.0. 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 0.092067 1,100

Children (Dermal)

1-2 years old 100 100 0.024165 0.13 NA 0.154165 650

Children (Oral)

1-2 years old 3.8 100 0.024165 NA 0.0051 0.029265 130

1 LOC = level of concern.

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)].