Triflumizole Human-Health Risk Assessment DP# 407679 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: October 29,2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Triflumizole: Human-Health Risk Assessment for the Proposed Uses on 

Greenhouse-Grown Tomato and Cucumber; Pome Fruit Group 11-10, Small Fruit 

Vine Climbing except Fuzzy Kiwifruit Subgroup 13-07F and Low Growing Berry 

Subgroup 13-07G, Except Cranberry. 

PC Code: 128879 

Decision No.: 472282 

Petition No.: 2E81 19 

Risk Assessment Type: Single Chemical 

Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D407679 

Registration No.: 400-436, -518, -521 

Regulatory Action: Section 3 

Case No.: NA 

CAS No.: 68694-11-1 

40 CFR: § 180.476 

FROM: Seyed Tadayon, Risk Assessor ~""~~"'V-?~-~---­ John Liccione, Ph.D., Toxicologi 

William Donovan, Ph.D., Chemis 

Risk Assessment Branch V 

Health Effects Division (HED; 7509P) 

THROUGH: MichaelS. Metzger, Branch Chief jf/ /}17 /) } -- Risk Assessment Branches V & VII ~ · 1/ l) 

HED (7509P) 

TO: Barbara Madden/Andrew Ertman, RM 05 

Risk Integration, Minor Use, and Emergency Response Branch 

Registration Division (RD; 7505P) 

The Registration division has requested that HED evaluate hazard and exposure data and conduct 

dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the 

risk to human health that will result from the proposed Section 3 registration uses of the active 

ingredient (ai) triflumizole ( 1-[( 1 E)-1-[[ 4-chloro-2-(trifluoromethyl)phenyl]imino ]-2 

propoxyethyl)-1 H-imidazole), on tomato and cucumber (grown in green house), pome fruit 

group 11-10, small fruit vine climbing except fuzzy kiwifruit subgroup 13-07F and low growing 

berry subgroup 13-070, except cranberry. 

The most recent human-health risk assessment for triflumizole was completed for registration 

review on 02-May-20 12 (Memo, S.Tadayon, et al.; D393221 ). 

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Tritlumizole Human-Health Risk Assessment DP# 407679 

Table of Contents 

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

2.0 HED Recommendations ............................................... .... .................... ........ ................. .... 8 

2.1 Data Deficiencies ............. ... ..... ...................... .... ... ................. .... ... ..................... .... ......... 8 

2.2 Tolerance Considerations ................. ........................ .... .... ........................... .................. 8 

2.2.1 Enforcement Analytical Method .......... ....... ........................ ............................. .... .... . 8 

2.2.2 Recommended Tolerances ................................... .... ............................ .... .................. 8 

2.2.3 Revisions to Petitioned-For Tolerances ............................. .... .... ......................... .... .. 9 

2.2.4 International Harmonization ...... ................................... .... .... ......................... ........ ... 9 

3.0 Introduction .................. ... .... .... ........................................... ............................ .... ................ 9 

3.1 Chemical Identity ................... .... ........... .... ............................ .... .... .... ..................... ...... 10 

3.2 Physical/Chemical Characteristics .................. ........ ......................... .. ......... .... ........... 11 

3.3 Pesticide Use Pattern ................. ........ ............................... .... .... .... .... .. ................... .... ... 11 

3.4 Anticipated Exposure Pathways ..................... ............................................................ 12 

3.5 Consideration of Environmental Justice ... ........ ......................................................... 12 

4.0 Hazard Characterization and Dose-Response Assessment .................... ...................... 13 

4.1 Toxicology Studies Available for Analysis ...................................... .... ....................... 13 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ........................... .. 13 

4.2.1 Dermal Absorption ............................................ ............................ .... .... .... ..... .......... 14 

4.3 Toxicological Effects ....... .... .............................................. ........ ....... ..... ....................... 14 

4.3.1 Summary of Toxicological Effects ........... ........ ..................................... ............ ....... 14 

4.4 Safety Factor for Infants and Children (FQPA SF) .......... ........................................ 16 

4.4.1 Completeness of the Toxicology Database ..... ................................................. .... .... 17 

4.4.2 Evidence of Neurotoxicity ........ : .................................. .... ........ .... ............................. 17 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. .. .... 17 

4.4.4 Residual Uncertainty in the Exposure Database ............. ........... ........................... 17 

4.5 Toxicity Endpoint and Point of Departure Selections .................................... .......... 18 

4.5.1 Dose-Response Assessment ............... ............................................... ..... ........ ........... 18 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment .. ... 19 

4.5.3 Cancer Classification and Risk Assessment Recommendation ............................ 19 

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

Assessment .... ....... ........... ... ........... ........... ............................................................... .... ......... .... 19 

5.0 Dietary Exposure and Risk Assessment.. .......... .... ................ ......................................... 21 

5.1 Residues of Concern Summary and Rationale ................................................. ........ . 21 

5.2 Food Residue Profile .......................................................... .... .... .... ........... ................... 22 

5.3 Water Residue Profile ......... ... ........ .... ............ .............................................................. 23 

5.4 Dietary Risk Assessment .................................................................. ......... ........ ........... 23 

5.4.1 Description of Residue Data Used in Dietary Assessment ................. ................... 23 

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 24 

5.4.4 Chronic Dietary Risk Assessment ........................... ....... .... ........ .. .. .... .... .... ..... .... .... 24 

5.4.5 Cancer Dietary Risk Assessment.. ...... .... .... ........ .... ................................................. 25 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................... ......... 25 

6.1 Residential Bystander Post-Application Inhalation Exposure ..... ............ ........ .... .......... 26 

6.2 Spray Drift ..... ... .... ... .... ... .... ........... .... ................... .... ............ ....... ................................... 26 

7.0 Aggregate Exposure/Risk Characterization .................... ............................... .... ......... .. 26 

7.1 Acute Aggregate Risk ... ................................................................................................ 27 

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7.2 Short-Term Aggregate Risk ........................................................................................ 27

7.3 Intermediate-Term Aggregate Risk ........................................................................... 27

7.4 Chronic Aggregate Risk .............................................................................................. 27

8.0 Cumulative Exposure/Risk Characterization ............................................................... 28

9.0 Occupational Exposure/Risk Characterization ............................................................ 28

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 28

9.2.1 Dermal Post-Application Risk................................................................................. 29

9.2.2 Inhalation Post-Application Risk............................................................................ 31

Appendix A. Toxicology Profile and Executive Summaries....................................................... 32

Appendix B. Review of Human Research................................................................................ 37

Appendix C. Residential Exposure Tables. ................................................................................ 38

Appendix D. International Residue Limits Table ........................................................................ 44
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1.0 Executive Summary

Triflumizole is a broad spectrum, imidazole fungicide (group 3) that inhibits ergosterol 

biosynthesis in fungi. In the U.S., triflumizole is registered to Chemtura USA Corporation and is 

formulated as 50% water soluble packets (WS), 50% water dispersible granules (WDG), and as 

480SC (suspension concentrate) at approximately 42% active ingredient (ai). It is registered for 

use on many agricultural crops, ornamentals in greenhouses/shade houses, interior scapes, and 

Christmas trees/conifers on nurseries and plantations. It is also used as a pre-plant seed piece 

treatment on pineapples. Triflumizole can also be applied to trees, shrubs, and vines in 

residential settings. There are no registrations on turf and garden vegetable uses. 

HED has reviewed residue chemistry database relevant to the proposed uses and has conducted 

dietary, occupational, and residential exposure assessments as part of an aggregate assessment to 

support the proposed uses of the active ingredient (a.i.) triflumizole on greenhouse-grown 

cucumber and tomato, pome fruit group 11-10, small fruit vine climbing except fuzzy kiwifruit 

subgroup 13-07F and low growing berry subgroup 13-07G, except cranberry. The end-use 

products are Procure® 480 SC and Terraguard® SC (EPA Reg # 400-518 and EPA Reg# 400-

521, respectively), at 4 lb ai/gallon liquid formulations. The maximum single application rate 

proposed is 0.5 lbs.ai/A via ground and aerial application to pome fruit.

 

In conjunction with this petition, IR-4 has requested the establishment of permanent tolerances 

for the residues of the triflumizole, including its metabolites and degradates, in or on the 

commodities summarized in Table 2.2.2.

For plant commodities, the tolerance expression and risk assessments include parent and all 

metabolites containing the 4-chloro-2-trifluoromethylaniline moiety. For livestock commodities, 

the tolerance expression and risk assessments include parent, the metabolite 4-chloro-2-hydroxy6-trifluoromethylaniline sulfate, and other metabolites containing the 4-chloro-2-

trifluoromethylaniline moiety. The drinking water risk assessment includes parent and all 

metabolites containing the 4-chloro-2-trifluoromethylaniline moiety. Tolerances are currently 

established in/on a variety of crops (40 CFR §180.476). 

Hazard Assessment: 

The toxicology database for triflumizole is complete. The database of laboratory animal studies 

spans multiple routes of exposure (oral, dermal, inhalation) and animal species (rat, mouse, dog) 

and consists of studies ranging from a single exposure (acute) to subchronic and chronic 

exposures. Additionally, there are developmental toxicity studies in rats and rabbits, a rat 

reproductive toxicity study, an immunotoxicity study, and acute and subchronic neurotoxicity 

studies. A 28-day inhalation study was identified as a data gap but a waiver request for the 28-

day inhalation toxicity study was granted (September 2004). A summary of the current toxicity 

data available for triflumizole is included in the toxicity profile in Appendix A. 

The liver is the primary target organ of triflumizole in the rat, mouse, and dog as evidenced by 

increased liver weight, hepatocyte fatty vacuolization, hypertrophy, inflammation, fatty 

degeneration, and necrosis. Specific subchronic effects included increased absolute and relative 

liver weights, accumulation of fat droplets, and slight hepatocyte centrilobular swelling. Chronic 

effects included hepatocyte fatty vacuolization; hepatocyte hypertrophy, focal inflammation, and 

necrosis; fatty degeneration; eosinophilic foci of hepatocyte alteration; hepatic nodules; bile duct 
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hyperplasia; and hyaline degeneration/fibrosis of the bile duct. Liver effects were seen in rat and 

mouse subchronic and chronic/carcinogenicity studies.

Triflumizole is classified as not likely to be carcinogenic to humans, based on a weight of 

evidence determination including the lack of evidence of carcinogenicity in studies in rats and 

mice and the absence of a mutagenicity concern. 

Clinical signs of neurotoxicity (neuromuscular impairment and decreased locomotor activity)

were noted in the acute neurotoxicity study at mid and high doses. There was no evidence of 

neurotoxicity in the subchronic neurotoxicity study in the rat with triflumizole. In oral rat 

developmental studies, fetal effects (decreased numbers of viable fetuses, increased dead or 

resorbed fetuses, increased numbers of late resorptions, decreased fetal body weight and 

increased incidences of cervical ribs) were seen in the fetuses at the same doses at which 

maternal toxic effects were noted. Reproductive toxicity, manifested as increased gestation 

length, was observed at the high dose. There is no evidence for quantitative or qualitative 

susceptibility following in utero exposure or following pre-and post natal exposure. 

Since the last risk assessment, an immunotoxicity dietary study in female BALB/c mice has been 

submitted and reviewed. The study revealed a significant decrease in the anti-SRBC IgM 

response at a dose level of 285.7 mg/kg/day. The NOAEL was 28.6 mg/kg/day. The results of 

the immunotoxicity study do not impact the point of departures (PODs) selected for dietary and 

non-dietary exposure risk assessments (W. Cutchin, D363719, 4/1/09). 

The toxicological endpoint selected for dietary and non-dietary risk assessments are presented in 

Appendix A. Separate acute endpoints and PODs were selected for females of child-bearing age 

(13-49) and the general population including infants and children. For females 13-49, a 

developmental endpoint was selected with a NOAEL = 10 mg/kg/day and a LOAEL = 35 

mg/kg/day. For the general population the POD was the NOAEL = 25 mg/kg/day and a LOAEL 

= 100 mg/kg/day at which functional observational battery (FOB) findings (neuromuscular 

impairment) and decreased locomotor activity were observed following a single exposure. An 

uncertainty factor of 100x (10x for inter-species extrapolation and 10x intra-species variation) 

was applied to derive the acute Reference Doses (aRfD) and the acute Population Adjusted Dose 

(aPAD) for these population groups. The chronic dietary endpoint is liver toxicity observed at 

3.5 mg/kg/day, the lowest dose tested in the combined chronic toxicity/carcinogenicity study in 

rats; a NOAEL was not established. An uncertainty factor of 300x (10x for inter-species 

extrapolation, 10x intra-species extrapolation and 3x for the use of a LOAEL (UFL)) was used to 

derive the chronic RfD and chronic population adjusted dose. An oral NOAEL of 3.5 mg/kg/day 

for offspring toxicity seen at 8.5 mg/kg/day from a two-generation reproduction study was used 

for assessing dermal and inhalation risk resulting from short-term exposures. A Margin of 

Exposure (MOE) of 100 is adequate for these exposure scenarios. An oral LOAEL of 3.5 

mg/kg/day based on liver toxicity in the combined chronic toxicity/carcinogenicity was used for 

assessing dermal and inhalation risks resulting from intermediate- and long term exposures. 

Since a LOAEL was used, the target MOE is 300 for these scenarios. An upper-bound estimate 

of dermal absorption of 3.5% was calculated by comparing the maternal LOAEL from the rat 

developmental study with the NOAEL from the rat dermal study. Since oral doses were used, a 

dermal (3.5%) absorption factor was used for route-to-route extrapolation, and inhalation toxicity 

was assumed to be equivalent to oral toxicity. 
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The toxicology data base is complete and there are no residual uncertainties for pre-and post 

natal toxicity. The oral rat developmental study showed an increased qualitative susceptibility of 

the fetus to triflumizole in utero, however, the use of the rat developmental NOAEL for the 

derivation of the aRfD for females 13 – 49 would be protective of potential pre-natal toxicity 

following an acute dietary exposure. Likewise, the use of the NOAEL for offspring and 

reproductive effects for incidental oral and short-term dermal and inhalation exposure scenarios 

would address concerns for the increased qualitative susceptibility noted in the 3-generation 

reproductive toxicity study. The FQPA Safety Factor is reduced (1x) for acute dietary and short 

term (dermal and inhalation) exposure scenarios. However, a 3X FQPA Safety Factor is retained 

in the form of a LOAEL to NOAEL factor (UFL) for assessing chronic dietary and intermediateand long term dermal and inhalation risks from occupational use. The Agency has determined 

that a 3x for the use of a LOAEL (as opposed to the default 10x) is adequate based on the 

following weight of evidence considerations: 

o The most sensitive endpoint in the target organ (liver) for this chemical and class of 

compounds (conazole fungicide) is used for assessing chronic risk.

o There is low concern for the observed effects since the observed lesions (eosinophilic 

foci in male rats and fatty vacuolation and inflammation and necrosis in female rats) did 

not progress into malignancy. 

o The extrapolated NOAEL of 1.2 mg/kg/day (3.5/3 = 1.2) is supported by a comparable 

NOAEL (2.5 mg/kg/day) used for deriving the chronic RfD for a structurally-related 

chemical (Imazalil).

Based on these factors, the Agency is confident that the risk assessment would not under 

estimate dietary and non-dietary risks from chronic exposure to triflumizole.

Food Residue Profile: Adequate residue chemistry data have been provided in support of the 

triflumizole petition. The nature of the residue in plants and livestock is adequately understood. 

The requested pome fruit crop group tolerance is supported by previously submitted data for the 

representative crops of apple and pear. Tolerances for crop subgroups 13-07F and 13-07G, 

except cranberry are supported by translation from grape and strawberry, respectively. 

Organization for Economic Co-operation and Development (OECD) tolerance calculation 

procedures were used to compute the HED-recommended tolerance for greenhouse-grown 

tomato. For greenhouse-grown cucumber, the recommended tolerance was based on the results 

of the OECD calculator and international harmonization considerations. There is an adequate 

residue analytical method for the purposes of tolerance enforcement. There are no residue 

chemistry issues that would preclude establishing tolerances for residues of triflumizole and its 

metabolites, as outlined in Table 2.2.2.
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Exposure/Risk Assessment Characterization: Acute and chronic risk assessments were 

conducted for dietary exposure based on the existing and proposed uses. The acute and chronic 

assessments directly incorporated drinking water estimates. Assumptions for the acute 

assessment included tolerance-level residues for all foods, Dietary Exposure Evaluation Model 

(DEEM) 7.81 default processing factors (where appropriate), and 100% crop-treated (CT). 

Assumptions for the chronic dietary assessment included average field trial residues and average 

percent crop treated information. Some empirical processing factors were used in the chronic 

assessment along with DEEM 7.81 default processing factors, where applicable. All exposure 

and risk estimates were not of concern. A quantitative cancer dietary assessment was not 

conducted because triflumizole is classified as “not likely to be carcinogenic to humans.”

The registered non-occupational uses of triflumizole include a foliar spray by home owner and 

commercial applicators to landscape grown trees, shrubs and vines. Triflumizole is also 

registered for use on residential/non-commercially grown bearing apples, pears and grapes. 

Though not a restricted use pesticide, the product is intended for “commercial” use and “private 

residential” use. These label statements are not considered sufficient to preclude use by 

homeowners; therefore, these uses were assessed. There are no registered uses on lawns or turf. 

Short-term risk estimates to residential handlers do not exceed HED’s level of concern (i.e., 

MOEs > 100) for the residential scenarios assessed. Estimates for residential handlers margins of 

exposure (MOEs) for these scenarios range from 200 to 8,200. 

The acute and chronic aggregate risks are made up of dietary sources (food and drinking water). 

Short- and intermediate-term assessments, which are used to evaluate aggregate dietary and 

residential exposures, were performed. Because triflumizole is not carcinogenic, quantitative 

cancer aggregate risk assessments were not performed.

The occupational handler and post-application assessments were completed assuming the 

maximum label application rate. Based on the proposed use patterns, there is potential for shortand intermediate-term occupational exposure to triflumizole during mixing, loading, applying, 

and other handling tasks; and during post-application activities. Additionally, since the same 

endpoint and point of departure (POD) were selected for intermediate-term and chronic 

durations, intermediate-term exposure and risk estimates are protective of chronic exposure and 

risk. Chronic exposure is only expected for greenhouse uses on cucumber and tomato. The level 

of concern (LOC) for short-term and intermediate-term occupational dermal and inhalation 

exposures are margins of exposure (MOEs) <100 and <300, respectively. With the exception of 

grapes while performing short-term girdling activity, the short–term post-application risk 

estimates did not exceed HED’s LOC (i.e., MOEs ≥ 100) on day 0 using the highest relevant 

transfer coefficient; the intermediate-term post-application risk estimates did not exceed HED’s 

LOC (i.e., MOEs ≥ 300) on day 0 using the highest relevant transfer coefficient. The activity

with the highest estimated risk is girdling for grapes. The short-term MOE’s for girdling grapes 

are 79 on day zero and 100 on day 1; intermediate-term risks are not of concern (MOEs>300). 

HED is recommending that the REI be revised on the label to address risk concerns related to 

girdling grapes. 

The triflumizole label includes a personal-protective equipment (PPE) requirement that 

applicators and other handlers wear long-sleeved shirts, long pants, chemical-resistant gloves and

shoes plus socks.
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2.0 HED Recommendations

Pending submission of a revised Section B as described in Section 2.3, there are no residue 

chemistry, occupational, or toxicology data deficiencies that would preclude the establishment of 

permanent tolerances for residues of triflumizole and it metabolites and degradates as outlined in 

Table 2.2.2. 

2.1 Data Deficiencies

860.1200 Directions for Use

None

860.1550 Proposed Tolerances

Proposed and revised tolerance levels and commodity definitions are presented in Table 

2.2.2.

860.1650 Submittal of Analytical Reference Standards

An analytical standard for triflumizole is currently available in the EPA National Pesticide 

Standards Repository (personal communication with Theresa Cole, 8/20/2013), the reference

standard was received on 8/16/2013 and will expire on 01/31/2018. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate plant and livestock analytical enforcement methods are available to enforce tolerances 

for residues of triflumizole (D346779, W. Cutchin, 10/1/08). The appropriate analytical 

standards have been submitted to the BEAD standards repository.

2.2.2 Recommended Tolerances

The proposed tolerances and commodity definitions are appropriate. However, some 

recommendations for changes made in a previous review are not currently reflected in the 40

CFR § 180.476 (D346779, W. Cutchin, 10/1/08). The following tolerances should be deleted 

from 180.476(a)(1): apple, dry pomace; apple, wet pomace; grape, dried pomace; grape, raisin, 

waste; and grape, wet pomace. The commodity listed as “cilantro, leaves” should be changed to 

“coriander leaves.” Also, the following tolerances should be deleted from 180.476(a)(2): cattle, 

meat; egg; goat, meat; hog, fat; hog, meat; hog, meat byproducts; horse, meat; milk; poultry, fat; 

poultry, meat; poultry, meat byproducts; and sheep, meat. Tolerance levels for the following 

commodities should be lowered from 0.5 to 0.10 ppm: fat of cattle, sheep, goat, and horse. 

Tolerance levels for the following commodities should be lowered from 0.5 to 0.20 ppm: meat 

byproducts of cattle, sheep, goat, and horse. 
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Table 2.2.2. Tolerance Summary for Triflumizole1.

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Tomato 1.5 1.5 Greenhouse tomatoes only.

Fruit, pome, group 11-10 0.50 0.50

Fruit, small, vine climbing, 

except fuzzy kiwifruit, 

subgroup 13-07F

2.5 2.5

Berry, low growing, 

subgroup 13-07G, except 

cranberry

2.0 2.0

Vegetable, cucurbit, group 9 0.50

2

0.50

Includes established field uses for 

cucurbits and the proposed 

greenhouse use on cucumber.

1 These tolerances should be established under 40 CFR §180.476.

2 The established and proposed tolerances for crop group 9 are identical and cover the proposed use on greenhouse 

grown cucumber.

Note to RD: Upon establishment of the recommended tolerances listed above, tolerance listings 

for the following individual crops should be revoked since they will be included in the new crop 

group and crop subgroups listings: apple, pear, grape, and strawberry.

2.2.3 Revisions to Petitioned-For Tolerances

None

2.2.4 International Harmonization

Codex has not established Maximum Residue Limits (MRLs) for residues of triflumizole in/on 

raw agricultural or processed commodities. Tolerance definitions are harmonized between 

Canada and the U.S. Additionally, all Canadian MRLs are harmonized with the corresponding 

US tolerance levels (see Appendix D). Triflumizole is not registered for use in Canada. The 

Canadian MRLs for triflumizole were set to support the import of treated commodities. 

2.3 Label Recommendations

HED is recommending that the REI be revised on the label to address risk concerns related to 

girdling grapes (i.e., one day). Intermediate-term post-application risk estimates were not a 

concern on day 0 (12 hours following application) for all post-application activities assessed.

HED recommends that the rotational crop restriction be omitted from the greenhouse grown 

cucumber and tomato use directions since soils in greenhouses are not typically reused.

3.0 Introduction

Triflumizole is a broad spectrum, imidazole fungicide (group 3) that inhibits ergosterol 

biosynthesis in fungi. In the U.S., triflumizole is registered to Chemtura USA Corporation and is 

formulated as 50% water soluble packets (WS), 50% water dispersible granules (WDG), and as 

480SC (suspension concentrate) at approximately 42% active ingredient (ai). It is approved for 

broadcast foliar applications to a variety of agricultural crops, ornamentals in greenhouses/shade
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houses, interior scapes, pre-plant treatment of pineapple seed pieces and Christmas trees/conifers 

on nurseries and plantations. There are no registrations on turf or garden vegetable uses. 

3.1 Chemical Identity

Structure

Empirical formula C15H15N3OClF3

Common name Triflumizole

IUPAC1name (E)-4-chloro-α,α,α-trifluoro-N-(1-imidazol-1-yl-2-

propoxyethylidene)-o-toluidine

CAS2name 1-[(1E)-1-[[4-chloro-2-(trifluoromethyl)phenyl]imino]-2-

propoxyethyl]-1H-imidazole

CAS registry number 68694-11-1

End-use products (EPs) Procure®50WS; EPA Reg. No. 400-431

Procure®480SC; EPA Reg. No. 400-518

Chemical class Imidazole

Common moiety structure

Common name FA-1-1

IUPAC name 4-chloro-2-trifluoromethylaniline

Livestock metabolite

Common name FA-1-5

IUPAC name 4-chloro-2-hydroxy-6-trifluoromethylaniline

Livestock metabolite

Common name FA-1-5-S

IUPAC name 4-chloro-2-hydroxy-6-trifluoromethylaniline sulfate

1

IUPAC = International Union of Pure and Applied Chemistry

2 CAS = Chemical Abstracts Service

N

N

N Cl

F3C

O

CH2CH2CH3

H2N Cl

F3C
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3.2 Physical/Chemical Characteristics

Triflumizole’s physical and chemical properties are summarized below in Table 3.2.

TABLE 3.2. Physicochemical Properties of Triflumizole 

Parameter Value Reference

Melting point/range 63.5 °C DEB # 6410, J. Smith, 1/7/92

pH N/A

Bulk Density (at 20 oC) 0.50 – 0.70 

Water solubility (g/L at 20 °C) 0.0125 (at pH 5.9)

Solvent solubility (g/100 mL at 20 oC) Chloroform 222

Acetone 144

n-Hexane 1.76

Methanol 49.6

Xylene 63.9

Vapor pressure (25 °C) 1.4 x 10-6 mmHg

Dissociation constant (pKa at 25 °C) 3.7

Octanol/water partition coefficient KOW at 25 

oC

25

UV/visible absorption spectrum max = 204, 230, and 308 nm (acidic)

max = 204, 236, and 300 nm (neutral)

max = 232 and 292 nm (basic)

D368710, P. Savoia, 09-

NOV-2009

3.3 Pesticide Use Pattern

The proposed uses of active ingredient (a.i.) triflumizole are for greenhouse grown tomato and 

cucumber, pome fruit group 11-10, small fruit vine climbing except fuzzy kiwifruit subgroup

13-07F and low growing berry subgroup 13-07G, except cranberry. The end-use products are 

Procure®480 SC and Terraguard®SC (EPA Reg # 400-518 and EPA reg# 400-521), at 4 lb 

ai/gallon liquid formulations. The maximum single application rate proposed is 0.5 lbs. ai/A via 

ground and aerial application. The summary of use information is presented in Table 3.3.1.

Table 3.3.1. Summary of Directions for Proposed Uses of Triflumizole.

Applic. Timing;

Type; and

Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days) Use Directions and Limitations

Pome fruits Crop group 11-10 proposed

Broadcast foliar;

At first indication 

of disease;

Ground or aerial 

equipment

4 lb/gal FlC

[400-518]

0.5 4 2.0 14 A minimum RTI of 10 days is 

specified. Apply in a 

minimum of 50 gal/A for 

ground applications.

Grapes (Small fruit vine climbing crop subgroup 13-07F, Except fuzzy Kiwifruit) Proposed

Strawberries (low growing berry crop subgroup 13-07G)

Broadcast foliar;

At first indication 

of disease;

Ground and Aerial

equipment

4 lb/gal FlC

[400-518]

0.25 4 1.0 14 A minimum RTI of 21 days is 

specified. Apply in a 

minimum of 50 gal/A for 

ground applications.

(aerial application for grape is 

prohibited)

Greenhouse grown vegetable (Cucumber and Tomato) Proposed
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Table 3.3.1. Summary of Directions for Proposed Uses of Triflumizole.

Applic. Timing;

Type; and

Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days) Use Directions and Limitations

Manually and 

mechanically 

pressurized hand 

gun sprayer

4 lb/gal SC

[400-521]

0.25 5 1.25 0 Do not plant leafy or non-leafy 

Brassica vegetables or fruiting 

vegetables within 30 days after 

application. Do not plant bulb 

vegetables or root vegetables 

within 60 days after 

application. Do no plant 

cotton, small cereal grains and 

all other crops not registered on 

the label within one year after 

application.

REI: 12 hours.

Minimum RTI: 7 days.

The use directions are adequate to allow evaluation of the residue data relative to the proposed 

uses. The proposed maximum application rates, RTIs, and PHIs are supported by the submitted 

field trial data. Because greenhouse soils are not reused, there is no need for a rotational crop 

restriction for greenhouse grown vegetables. HED recommends removal of the proposed 

rotational crop restriction for greenhouse cucumber and tomato. 

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human-health risk to support the IR-4 proposed new uses 

on greenhouse-grown tomato and cucumber, pome fruit group 11-10, small fruit vine

climbing except fuzzy kiwifruit subgroup 13-07F and low growing berry subgroup 13-07G,

except cranberry. 

Humans may be exposed to triflumizole in food and drinking water, since triflumizole may be 

applied directly to growing crops and application may result in triflumizole reaching surface and 

ground water sources of drinking water. There are residential uses of triflumizole to trees, 

shrubs, and vines. There are no registrations on turf and garden vegetable uses. Residential uses 

could lead to potential residential handler and post-application dermal and inhalation exposure. 

In an occupational setting, applicators may be exposed while handling the pesticide prior to 

application, as well as during application. There is also a potential for post-application exposure 

for workers re-entering treated fields. 

This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed new uses of triflumizole, but also considers the existing residential registered uses as 

well, particularly for the dietary exposure assessment. 

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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). As a part of every 
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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 U.S. Department of 

Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat 

in America, (NHANES/WWEIA; 2003-2008) 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

4.1 Toxicology Studies Available for Analysis

The toxicology database for triflumizole is complete and is adequate for characterization of its 

hazard, toxicity endpoint selection, and FQPA SF consideration. In the last registration review 

risk assessment (S. Tadayon et. al., 02-May-2012; D393221), it was acknowledged that an 

immunotoxicity dietary study in female BALB/c mice had been submitted and reviewed. The 

study revealed a significant decrease in the anti-SRBC IgM response at a dose level of 285.7 

mg/kg/day. The NOAEL was 28.6 mg/kg/day. The results of the Immunotoxicity study do not 

impact endpoint selection or safety factors.

HED considered the toxicity database for triflumizole including this new Immunotoxicity study, 

the only new toxicity data submitted, as well as the most recent risk assessment (D363719, W. 

Cutchin, 4/1/09), to determine whether changes were needed to the endpoint selection, to safety 

factors including the FQPA factor, or to the cancer classification as part of the registration 

review assessment. HED concluded that no changes are required. 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Three metabolism studies in the rats have been conducted. No significant sex-related differences 

were observed in the absorption, metabolism, distribution, or excretion of triflumizole. 

Maximum concentrations of radioactivity in plasma were attained within 1 hour of dosing in 

both sexes. Excretion of the administered dose of the compound occurred primarily via the urine 

(74.0-78.9% dose), with the feces accounting for 14.6-20.5% of the dose. In both sexes, tissue 

radioactivity concentrations were highest in the liver. Based on a one-compartment model with a 

first-order process, the half-time for elimination was 13.2 and 14.8 hours for male and female 

rats, respectively, from the 10 mg/kg dose group.
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Based on the metabolic profile, biotransformation in rats primarily involves oxidation of the 

parent followed by sulfate and glucuronic acid conjugation. Hepatic microsomal enzyme 

induction was shown to occur in rats following oral administration. 

4.2.1 Dermal Absorption

A dermal absorption study on triflumizole is not available. An upper-bound estimate of dermal 

absorption of 3.5% was calculated by comparing the maternal LOAEL from the rat 

developmental study with the NOAEL from the rat dermal study. 

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects

The liver is the primary target organ of triflumizole. Liver effects were seen in rat and mouse 

subchronic and chronic/carcinogenicity studies. Subchronic effects included increased absolute 

and relative liver weights, accumulation of fat droplets, and slight hepatocyte centrilobular 

swelling. With increased length of exposure, the types of microscopic lesions noted increased in 

number and severity. Chronic effects included hepatocyte fatty vacuolization; hepatocyte 

hypertrophy, focal inflammation, and necrosis; fatty degeneration; eosinophilic foci of 

hepatocyte alteration; hepatic nodules; bile duct hyperplasia; and hyaline degeneration/fibrosis of 

the bile duct. The dog was less sensitive to the effects of triflumizole. In the dog chronic study, 

effects included increased liver weights, increased serum alkaline phosphatase levels, and a 

macroscopic hepatic lobular pattern and granular texture. A very mild, macrocytic anemia was 

also noted and was most likely secondary to liver effects. 

A special microsomal enzyme induction study showed that triflumizole can induce hepatic 

microsomal enzymes when administered orally at high doses. Kidney weights were increased in 

the rat and mouse also, but the only pathology seen microscopically was in the rat 

chronic/carcinogenicity study in which cortical cysts were noted. Other organ effects were 

observed microscopically at the highest dose tested in the chronic rat study, which mainly 

involved cystic or hyperplastic lesions in endocrine glands and/or lymph nodes. Body weight 

decrements were noted in the rat and/or mouse subchronic, chronic and carcinogenicity studies 

and the developmental and reproduction studies.

Long-term dietary administration of triflumizole did not result in an overall treatment-related 

increase in incidence of tumor formation in rats or mice. The former RfD/Peer Review 

Committee classified triflumizole as a “Group E” (evidence for non-carcinogenicity for humans) 

chemical by all routes of exposure based upon lack of evidence of carcinogenicity in rats and 

mice. The risk assessment team concurs with that evaluation.

Triflumizole did not show evidence of mutagenicity in in vitro or in vivo studies.

The oral rat developmental study showed an increased qualitative susceptibility of the fetus to 

triflumizole in utero. Decreased numbers of viable fetuses, increased dead or resorbed fetuses, 

increased numbers of late resorptions, decreased fetal body weight and increased incidences of 

cervical ribs was seen in the fetuses at the same doses at which maternal toxic effects were noted. 

In addition, increased incidences of 14th rudimentary ribs were observed at the next highest dose. 

Maternal toxic effects in the rat were decreased body weight gain and decreased food 
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consumption, increased placental weight, and increased maternal spleen and liver weights. The 

use of the rat developmental NOAEL for the derivation of the aRfD for females 13 – 49 would 

be protective of potential pre-natal toxicity following an acute dietary exposure. 

No increased susceptibility of the fetus was noted in utero in the rabbit developmental study. 

Fetal effects included increased fetal and litter incidences of lumbar ribs and decreased placental 

weights, which was also included as a maternal toxic effect. Maternal toxic effects in the rabbit 

included decreased body weight gain, decreased food consumption, and decreased placental 

weights. 

In the 3-generation reproductive toxicity study in the rat, offspring effects included decreased 

pup weights, survival indices, and litter sizes in both F3 litters, reduced litter size in the F1a litter, 

increased total-litter mortality in the F3a litter, and developmental effects in the F1b and F2b

progeny. Reproductive toxicity, manifested as increased gestation length, was increased in the 

F0 dams which were pregnant with F1 offspring. Since the increased gestation length can be due 

to either effect in the dams and/or the offsprings, offspring sensitivity should be assessed relative 

to the F0 dams. In rats, this alteration in normal reproductive function can result in adverse 

consequences in both dams and offspring. Based on this comparison, there is no increased

quantitative susceptibility of the fetus. There is increased qualitative susceptibility in pups; 

however, the use of the NOAEL of 3.5 mg/kg/day (offspring and reproductive effects) for 

incidental oral scenarios and short-term dermal and inhalation scenarios would be protective of 

potential toxicity following pre- and post-natal exposures. 

In acute oral toxicity studies in the rat and mouse and an acute inhalation study in the rat, 

animals developed neurotoxic signs within 30 to 60 minutes of administration, which resolved 

within 24 hours in surviving animals. Signs included ataxia, hypotonia, ventral positioning, 

urinary incontinence, decreased respiration and heart rates, decreased locomotor movement, 

lacrimation, salivation, ptosis and/or rhinorrhea. No treatment-related histopathological effects 

were found in surviving animals. In the chronic rat study, convulsions were observed 

sporadically in all dosage groups, but the incidences were significantly higher in the high-dose 

females. The majority of the convulsions were noted within the first year. Cholinesterase 

activity was also affected during the first year of the study, but not in a consistent manner. Highdose males had decreased plasma and erythrocyte cholinesterase activity while high-dose 

females had decreased plasma cholinesterase activity only. There were no treatment-related 

effects on cholinesterase activity in the brain in either sex at any dose and no neuropathology 

was noted. No neurotoxic effects were observed in the rat subchronic oral toxicity study or the 

mouse subchronic oral toxicity and carcinogenicity studies.

The lack of acute and subchronic neurotoxicity studies at the time of previous risk assessments 

triggered the application of a UFDB of 3x for lack of acute and subchronic neurotoxicity studies

(DP 361545; March 4, 2009 memo from ARIA team, RD). Signs of neurotoxicity were seen in 

the acute oral and inhalation studies in the rat and mouse, although neurotoxicity studies were 

not submitted until 2003 (acute) and 2004 (subchronic). The submitted studies were reviewed in 

2005 (R. Fricke, 6/1/05, DP Num: 304654). Signs of neurotoxicity (neuromuscular impairment 

and decreased locomotor activity) were noted in the acute neurotoxicity study at mid and high 

doses. As a result, the endpoint from this study was used to assess acute dietary risks from oneday exposures to triflumizole in the diet of the general population. No evidence of neurotoxicity 

was seen in the submitted subchronic neurotoxicity studies (R. Fricke, 6/1/05, DP 304654). 

Based upon the acute and subchronic neurotoxicity studies, the 3x UFDB was reduced to 1x. 
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The evidence does not support the need for a DNT study. This conclusion is supported by lack 

of neurotoxic signs noted in the rat subchronic study at any dose, and in the adult or offspring in 

the developmental and reproductive toxicity studies in the rat. In an immunotoxicity dietary 

study in female BALB/c mice, a significant decrease in the anti-SRBC IgM response was 

observed at a dose level of 285.7 mg/kg/day. The NOAEL was 28.6 mg/kg/day. 

4.4 Safety Factor for Infants and Children (FQPA SF)

The risk assessment team has re-evaluated the exposure and hazard data and, based on these 

data, recommended that the FQPA SF for acute risk assessment, incidental oral (short- and 

intermediate term), and short-term dermal and inhalation exposure scenarios remain at 1x, and 

for chronic risk assessment remain at 3X. These recommendations are based on the following: 

The toxicity database is complete for FQPA assessment. 

There was no quantitative or qualitative evidence of increased susceptibility in the 

rabbit fetuses following in utero exposure. 

There was evidence of qualitative susceptibility in the developmental rat study, 

however, there are no residual uncertainties, and the use of the developmental 

NOAEL and the endpoint for the aRfD for females 13-49 would be protective of the 

pre-natal toxicity following an acute dietary exposure. 

There was evidence of qualitative susceptibility in the 3-generation reproductive 

toxicity study in the rat, but there are no residual uncertainties, and the use of the 

offspring NOAEL for the incidental oral, and short-term dermal and inhalation 

exposure scenarios would be protective of potential pre- and post-natal toxicity.

The chronic dietary food exposure assessment is somewhat refined and utilizes ARs 

and % CT data for some existing uses; however, this assessment is still considered 

conservative since it incorporates field trial data and some default processing factors. 

For all proposed uses, tolerance-level residue and 100% CT is assumed. 

The dietary drinking water assessment utilizes water concentration values generated by models 

for which the model input parameters provide conservative, health protective, high-end estimates 

of water concentrations that are not likely to be exceeded.

A 3x FQPA SF is retained for the chronic RfD because it is derived from the use of a LOAEL 

established in the combined chronic toxicity/carcinogenicity study in rats. A 3x FQPA SF for 

use of LOAEL instead of a NOAEL (as opposed to a 10x) is viewed to be adequate because: 

o The most sensitive endpoint in the target organ (liver) for this chemical and class of 

compounds (conazole fungicide) is used for assessing chronic risk.

o There is low concern for the observed effects since the lesions did not progress into 

malignancy. 

o The extrapolated NOAEL of 1.2 mg/kg/day (3.5/3 = 1.2) is supported by a comparable 

NOAEL (2.5 mg/kg/day) used for deriving the chronic RfD for a structurally-related 

chemical (Imazalil).
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4.4.1 Completeness of the Toxicology Database

The toxicology data for triflumizole are sufficient and are of good quality for selecting toxicity 

endpoints and points of departure for risk assessment. The database includes acceptable studies 

on developmental, reproductive/fertility, neurotoxic, subchronic, chronic, carcinogenic, 

immunotoxic, and mutagenic effects, as well as information on the metabolism and 

pharmacokinetics of triflumizole. A special study on hepatic enzyme induction is also available. 

4.4.2 Evidence of Neurotoxicity

Signs of neurotoxicity were seen in the acute oral and inhalation studies in the rat and mouse. 

Signs of neurotoxicity (neuromuscular impairment and decreased locomotor activity) were noted 

in the acute neurotoxicity study at mid and high doses. As a result, the endpoint from this study 

was used to assess acute dietary risks from one-day exposures to triflumizole in the diet of the 

general population. There were no treatment-related neuropathological findings observed in 

either sex in the acute neurotoxicity study. No evidence of neurotoxicity was seen in the 

submitted subchronic neurotoxicity study. Likewise, neuropathological evaluation of study 

animals in the subchronic neurotoxicity study did not reveal any treatment-related histological 

effects of the central and peripheral nervous systems. 

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

There is evidence of increased qualitative susceptibility following in utero exposure to rats in a 

developmental study. Developmental toxicity resulted in fetal death as compared to maternal 

toxicity which included decreases in body weight gain and food consumption and increases in 

placental, spleen and liver weights.

No quantitative or qualitative evidence of increased susceptibility was seen following in utero

exposure to rabbits in a developmental study. In the rabbit developmental study, the endpoint 

relating to 24-hour fetal survival after cesarian section is not a robust parameter since it is 

associated with a confounding factor. This endpoint involves removal of pups from the dams 

and maintaining them under artificially controlled conditions that deviates from normal pup 

developmental conditions. Pups treated in this fashion are no longer subject to maternal care 

which is critical to the survival of the pups, and hence it is difficult to discern if the decreased 

24-hour fetal survival is treatment-related or due to the lack of critical maternal care. 

Evidence of increased qualitative susceptibility in pups was evident in the 3-generation 

reproductive toxicity study in the rat (discussed in Section 4.3.1); however, the use of the 

NOAEL of 3.5 mg/kg/day (offspring and reproductive effects) for incidental oral scenarios and 

short-term dermal and inhalation scenarios would be protective of potential toxicity following 

pre- and post-natal exposures. 

The uncertainties associated with the lack of acute and subchronic neurotoxicity studies have 

been resolved. Following the review and acceptance of those studies, 1) an acute endpoint for 

the general U.S. population (including infants and children) was selected; and 2) the 3x UFDB

FQPA SF was removed.

4.4.4 Residual Uncertainty in the Exposure Database
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The acute dietary food exposure assessment utilizes established and recommended tolerancelevel residues, DEEM 7.81 default processing factors (where available), and 100% CT 

information for all commodities. By using these screening-level assessments, actual 

exposures/risks will not be underestimated.

The chronic dietary food exposure assessment utilizes average field trial residues, and percent 

crop treated information, where available. Some empirical processing factors were used in the 

chronic assessment along with DEEM 7.81 default processing factors (where available). The 

chronic assessment is partially refined; however, since it is based on reliable, high-end data, it 

will not underestimate exposure/risk.

The dietary drinking water assessments utilize water concentration values generated by the 

PRZM-EXAMS model. The resulting screening-level estimated drinking water concentrations 

(EDWCs) provide conservative, health-protective, high-end estimates of water concentrations 

that will not likely be exceeded.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for humanhealth risk assessment. Acute and chronic dietary and short- and intermediate-term inhalation 

and dermal exposure scenarios were assessed. 

Acute Dietary Endpoints: Separate acute endpoints were selected for females of child-bearing 

age (13-49) and the general population. For females 13-49, a developmental endpoint was 

selected with a NOAEL = 10 mg/kg/day and a LOAEL = 35 mg/kg/day. For the general 

population the PoD was the NOAEL = 25 mg/kg/day and a LOAEL = 100 mg/kg/day at which 

FOB findings (neuromuscular impairment) and decreased locomotor activity were observed. 

Thus, the acute reference dose (aRfD) and population-adjusted dose (aPAD) are equivalent at 

0.25 mg/kg bw for general population and 0.1 mg/kg bw for female 13-49 years.

Chronic Dietary (All Populations): This dietary endpoint was based on liver toxicity in rats at 

the LOAEL of 3.5 mg/kg bw/day (NOAEL not determined). The standard combined UF of 

100X is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation and 

(3X) for the lack of NOAEL. Thus, the chronic reference dose (cRfD) and population-adjusted 

dose (cPAD) are equivalent at 0.012 mg/kg bw for all populations 

Dermal and Inhalation [Short-term (1-30 days)- Occupational: 

The NOAEL of 3.5 mg/kg/day was based on decreased pup body weight, mortality, reduced 

litter size and increased incidence of hydroureter and space between the body wall and organs at 

8.5 mg/kg/day. In addition, gestation length was increased in the dams of F1a, F2a, and F3a

intervals at the LOAEL of 8.5 mg/kg/day.

Dermal and Inhalation [Intermediate-term (30-180 days)- Occupational: 

The LOAEL of 3.5 mg/kg/day was based on liver toxicity (eosinophilic foci in male rats and 

fatty vacuolation and inflammation and necrosis in female rats). The NOAEL is <3.5 mg/kg/day 

because the lowest dose tested is the LOAEL. A 300-fold UF (10x for interspecies 

extrapolation, 10x for intraspecies variation, and 3x for lack of a NOAEL) is required. 
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A DAF of 3.5% was estimated based on comparing the maternal LOAEL from the rat 

developmental study with the NOAEL from the rat dermal study. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational exposure, dermal and inhalation exposures will be combined since the 

toxicological effects of concern are the same and were identified from the same study. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Triflumizole is classified as not likely to be carcinogenic to humans, based on a weight of 

evidence determination including the lack of evidence of carcinogenicity in studies in rats and 

mice and the absence of a mutagenicity concern. 

 

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

Assessment

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary, and NonOccupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL= 

25 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 

0.25 mg/kg/day

aPAD = 0.25 

mg/kg/day

Acute Neurotoxicity Study – Rat

LOAEL = 100 mg/kg/day based on FOB 

findings (neuromuscular impairment) and 

decreased locomotor activity.

Acute Dietary

(Females 13-

49 years of 

age)

NOAEL = 

10 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1x

Acute RfD = 0.1 

mg/kg/day

Developmental Toxicity Study – Rat

Developmental LOAEL = 35 mg/kg/day 

based on decreased numbers of viable 

fetuses, increased dead or resorbed 

fetuses, increased numbers of late 

resorptions, decreased fetal body weight, 

and increased incidences of cervical ribs.

Chronic 

Dietary (All 

Populations)

LOAEL=3.5 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 3x

Chronic RfD = 

0.012

mg/kg/day

cPAD = 0.012 

mg/kg/day

Combined Chronic Toxicity/Carcinog. 

Study - Rat

Based on liver toxicity (eosinophilic foci 

in male rats and fatty vacuolation and 

inflammation and necrosis in female rats).

Incidental Oral 

Short-Term (1-

30 days)

NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 1x

Residential LOC 

for MOE = 100

Multi-generation Reproduction Study -

Rat

LOAEL = 8.5 mg/kg/day based on 

decreased pup body weight, mortality, 

reduced litter size and increased incidence 

of hydroureter and space between the 

body wall and organs were observed at 

8.5 mg/kg/day. In addition, gestation 

length was increased in the dams of F1a, 

F2a, and F3a intervals at the LOAEL of 8.5 

mg/kg/day.
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary, and NonOccupational Human Health Risk Assessments

Incidental Oral 

IntermediateTerm (1-6 

months)

NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

Residential LOC 

for MOE = 100

Multi-generation Reproduction Study -

Rat

LOAEL = 8.5 mg/kg/day based on 

decreased pup body weight, mortality, 

reduced litter size and increased incidence 

of hydroureter and space between the 

body wall and organs In addition, 

gestation length was increased in the dams 

of F1a, F2a, and F3a animals.

Dermal ShortTerm (1-30 

days)

NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

Residential LOC 

for MOE = 100

Multi-generation Reproduction Study -

Rat

LOAEL = 8.5 mg/kg/day based on 

decreased pup body weight, mortality, 

reduced litter size and increased incidence 

of hydroureter and space between the 

body wall and organs were observed at 

8.5 mg/kg/day. In addition, gestation 

length was increased in the dams of F1a, 

F2a, and F3a intervals at the LOAEL of 8.5 

mg/kg/day.

Dermal 

Intermediateand LongTerm (1-6 

months and 6 

months and 

longer)

LOAEL= 

3.5

mg/kg/day

UFA= 10x

UFH= 10x

UFDB= 3x

Residential LOC 

for MOE = 300

Combined Chronic Toxicity/Carcinog. 

Study - Rat

Based on liver toxicity (eosinophilic foci 

in male rats and fatty vacuolation and 

inflammation and necrosis in female rats).

Inhalation 

Short- Term 

(1-30 days)

NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

Residential LOC 

for MOE = 100

Multi-generation Reproduction Study -

Rat

LOAEL = 8.5 mg/kg/day based on 

decreased pup body weight, mortality, 

reduced litter size and increased incidence 

of hydroureter and space between the 

body wall and organs were observed at 

8.5 mg/kg/day. In addition, gestation 

length was increased in the dams of F1a, 

F2a, and F3a intervals at the LOAEL of 8.5 

mg/kg/day.

Inhalation 

Intermediateand LongTerm (1-6 

months and 6 

months and 

longer)

LOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

UFDB= 3x Residential LOC 

for MOE = 300

Combined Chronic Toxicity/Carcinog. 

Study - Rat

Based on liver toxicity (eosinophilic foci 

in male rats and fatty vacuolation and 

inflammation and necrosis in female rats).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based a weight of evidence 

determination including the lack of evidence of carcinogenicity in studies in rats and mice and the 

absence of a mutagenicity concern. 

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. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 
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date (i.e., lack of a critical study). 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 4.5.4.2 Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Occupational 

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days)

NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

Occupational

LOC for MOE = 

100

Multi-generation Reproduction Study -

Rat

LOAEL = 8.5 mg/kg/day based on 

decreased pup body weight, mortality, 

reduced litter size and increased incidence 

of hydroureter and space between the 

body wall and organs were observed at 

8.5 mg/kg/day. In addition, gestation 

length was increased in the dams of F1a, 

F2a, and F3a intervals at the LOAEL of 8.5 

mg/kg/day.

Dermal 

Intermediateand LongTerm (1-6 

months and 6 

months and 

longer)

LOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

UFDB= 3x

Occupational

LOC for MOE = 

300

Combined Chronic Toxicity/Carcinog. 

Study - Rat

Based on liver toxicity (eosinophilic foci 

in male rats and fatty vacuolation and 

inflammation and necrosis in female rats).

Inhalation 

Short- Term 

(1-30 days)

NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

Occupational 

LOC for MOE = 

100

Multi-generation Reproduction Study -

Rat

LOAEL = 8.5 mg/kg/day based on 

decreased pup body weight, mortality, 

reduced litter size and increased incidence 

of hydroureter and space between the 

body wall and organs were observed at 

8.5 mg/kg/day. In addition, gestation 

length was increased in the dams of F1a, 

F2a, and F3a intervals at the LOAEL of 8.5 

mg/kg/day.

Inhalation 

Intermediateand LongTerm (1-6 

months and 6 

months and 

longer)

LOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

UFDB= 3x

Occupational 

LOC for MOE = 

300

Combined Chronic Toxicity/Carcinog. 

Study - Rat

Based on liver toxicity (eosinophilic foci 

in male rats and fatty vacuolation and 

inflammation and necrosis in female rats).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based a weight of evidence 

determination including the lack of evidence of carcinogenicity in studies in rats and mice and the 

absence of a mutagenicity concern. 

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The Metabolism Assessment Review Committee (MARC) determined that residues of concern 

should include parent triflumizole and all metabolites containing the 4-chloro-2-

trifluoromethylaniline moiety (D280869, J. Tyler, 3/13/02). Based on structural considerations, 
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parent triflumizole and metabolites containing the 4-chloro-2-trifluoromethylaniline moiety are 

assumed to have similar toxicity. As they were found to comprise >10% TRR in the plant 

metabolism studies, it is appropriate to include these compounds in the risk assessment. Further, 

it is also appropriate to include these metabolites in the tolerance expression since a common 

moiety enforcement method is available.

Table 5.1 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 Triflumizole and all metabolites 

containing the 4-chloro-2-

trifluoromethylaniline moiety

Triflumizole and all metabolites containing 

the 4-chloro-2-trifluoromethylaniline 

moiety

Livestock Triflumizole, 4-chloro-2-hydroxy-6-

trifluoromethylaniline sulfate, and other 

metabolites containing the 4-chloro-2-

trifluoromethylaniline moiety

Triflumizole, 4-chloro-2-hydroxy-6-

trifluoromethylaniline sulfate, and other 

metabolites containing the 4-chloro-2-

trifluoromethylaniline moiety

Drinking Water Triflumizole and all metabolites 

containing the 4-chloro-2-

trifluoromethylaniline moiety

Not Applicable

5.2 Food Residue Profile

D413698, W. Donovan, 29-OCT-2013

Adequate residue chemistry data have been provided for triflumizole. Field trials are of adequate 

number and geographic representation. Data analyses employed validated analytical methods 

and are supported by adequate storage stability data. Residues of triflumizole demonstrated 

stability in frozen storage except for fortified samples of cucumber, where residues declined 38% 

over 832 days. Accordingly, magnitude of the residue data for cucumber was corrected for 

degradation during frozen storage. No tomato processing studies were submitted because 

triflumizole use is limited to greenhouse tomato varieties, and these are not expected to be 

processed for economic reasons.

The recommended tolerances for triflumizole were derived by 1) use of the OECD MRL 

calculation procedures for tomato, and 2) direct translation for crop group 10-11, and crop 

subgroups 13-07F and 13-07G. The computed tolerance level for greenhouse-grown cucumber 

was 0.80 ppm, based on OECD MRL calculation procedures. However, HED concludes that the 

established tolerance of 0.5 ppm for cucurbit vegetables group 9 is adequate to cover greenhouse 

cucumber for the following reasons: 1) the greenhouse cucumber HAFT is 0.34 ppm (less than 

the crop group 9 tolerance), and 2) keeping the established crop group 9 tolerance at 0.5 ppm 

retains harmonization with the PMRA MRL.

To reiterate conclusions from previous triflumizole reviews (D346779, W. Cutchin, 10/1/08), the 

following tolerances should be deleted from 180.476(a)(1): apple, dry pomace; apple, wet 

pomace; grape, dried pomace; grape, raisin, waste; and grape, wet pomace. The commodity 

listed as “cilantro, leaves” should be changed to “coriander, leaves.” Also, the following 

tolerances should be deleted from 180.476(a)(2): cattle, meat; egg; goat, meat; hog, fat; hog, 

meat; hog, meat byproducts; horse, meat; milk; poultry, fat; poultry, meat; poultry, meat 

byproducts; and sheep, meat. Tolerance levels for the following commodities should be lowered 
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from 0.5 to 0.10 ppm: fat of cattle, sheep, goat, and horse. Tolerance levels for the following 

commodities should be lowered from 0.5 to 0.20 ppm: meat byproducts of cattle, sheep, goat, 

and horse. 

The following PBIs are appropriate for rotated crops: 30 days for spinach and fruiting 

vegetables; 60 days for root and tuber vegetables; and 1 year for cotton, small cereal grains, and 

any other crops without registered uses for triflumizole. No rotational crop restrictions are 

needed for greenhouse grown crops because the soils are not reused.

5.3 Water Residue Profile

EFED provided ground and surface water EDWCs for triflumizole (D407680, C. Koper et. al., 

5/20/13) Updated EDWCs were provided to include the use on ornamentals. The highest 

ground water EDWCs were based on the aerial use pattern for cherries, consisting of 6 

applications at 0.5 lb ai/A, with a 7-day retreatment interval (RTI). This same use pattern was 

selected for calculation of the chronic surface water EDWC; the acute surface water EDWC was 

modeled on the use pattern for ornamentals [FL nursery]: 3 applications at 1.0 lb ai/A, with a 7-

day RTI. Modeled values were provided since there are no comprehensive monitoring data for 

triflumizole in ground or surface water.

Table 5.3 summarizes the maximum EDWCs for triflumizole. In order to account for degradates 

containing the 4-chloro-2-trifluoromethylaniline moiety, EFED used the total toxic residue 

approach to account for both triflumizole and the additional residues of concern. Detailed 

information on how the individual modeling input parameters were derived can be obtained from 

the memo “Tier II Drinking Water Assessment to Establish Tolerances of Triflumizole on 

Greenhouse Vegetables (Cucumber and Tomato), Pome Fruit Subgroup 11-10, Small Fruit Vine 

Climbing Subgroup 13-07F and Low Growing Berry Subgroup 13-07G (excluding Cranberry)” 

5/20/13, C.M. Koper, S. Sankula, and E. Odenkirchen, D407680. 

Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations for Triflumizole.

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 98 3.1

Chronic (non-cancer) 22 3.1

Chronic (cancer) 15 3.1

a

From the Tier II PRZM-EXAMS - Index Reservoir model. 

b

From the SCI-GROW model.

Bolded values selected for use in the dietary exposure assessments.

5.4 Dietary Risk Assessment

D413699, W. Donovan, 22-AUG-2013

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary-exposure (food plus water) and risk assessments were conducted using 

DEEM-FCID, Version 3.16, which uses food consumption data from the USDA’s 

NHANES/WWEIA survey from 2003 through 2008. The assessments were performed for the 

general U.S. population and all population subgroups. Assumptions for the acute assessment 

included tolerance-level residues for all foods, DEEM 7.81 default processing factors (where 
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applicable), and 100% CT. Assumptions for the chronic dietary assessment included anticipated 

residues (average field trial values) for most crops and average percent crop treated information 

as available (see Section 5.4.2). Thus, the chronic dietary analysis may be considered a partially 

refined assessment. Some empirical processing factors were used in the chronic assessment 

along with DEEM 7.81 default processing factors (where applicable). Drinking water estimates 

were provided by EFED. The EDWC values were generated using the ornamental and cherry

use patterns for acute and chronic exposures, respectively. The resulting screening-level EDWC 

estimates of 0.098 and 0.022 ppm were used for the acute and chronic assessments, respectively. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Updated percent crop treated (%CT) information was provided by the Office of Pesticide 

Program’s (OPP’s) Biological and Economic Analysis Division (BEAD) for apples, cantaloupes, 

cherries, cucumbers, grapes, hazelnuts (filberts), honeydew melons, pears, pumpkins, squash, 

strawberries, and watermelons in a Screening Level Usage Analysis (SLUA) dated 30-JAN2013. Although BEAD provided maximum and average %CT information, only the average 

%CT values were utilized in the dietary exposure analysis. 

The following average percent crop treated estimates (30-JAN-2013 Triflumizole SLUA) were 

used in the chronic dietary risk assessments for the following crops that are registered for 

triflumizole: apple: 25%; cantaloupe: 10%; cherry: 25%; cucumber: 2.5%; filbert: 5%; grape: 

5%; honeydew: 15%; pear: 45%; pumpkin: 5%; squash: 5%; strawberry: 25%; and watermelon: 

5%.

 5.4.3 Acute Dietary Risk Assessment

Acute dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The assessment was unrefined and the highest 

exposure estimate was for the population subgroup children 1-2 years old, which utilized 40% of 

the aPAD for triflumizole. The acute exposure estimate for the general U.S. population utilized 

25% of the aPAD. The acute exposure estimate for females 13-49 was based on a lower POD 

than for other population subgroups, and utilized 66% of the aPAD. A summary table of dietary 

exposure and risk for triflumizole is provided in Section 5.4.6. 

5.4.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The assessment was partially refined and the 

highest exposure and risk estimates were for the population subgroup children 1-2 years old, 

which utilized 39% of the cPAD for triflumizole. The chronic exposure estimate for the general 

U.S. population utilized 21% of the cPAD. A summary table of dietary exposure and risk for 

triflumizole is provided in Section 5.4.6. Although further refinement to the analysis is not 

required at this time, future assessments could be refined through the incorporation of monitoring 

data. 
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5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not performed because triflumizole was classified as “not likely 

to be carcinogenic to humans.”

5.4.6 Summary Table of Dietary Exposure and Risk

Table 5.4.6: Summary of Dietary (Food and Drinking Water) Exposure and Risk for 

Triflumizole.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.063555 25 0.002571 21

N/A N/A

All Infants (< 1 year old) 0.046533 19 0.002625 22

Children 1-2 years old 0.099738 40 0.004641 39

Children 3-5 years old 0.090227 36 0.003741 31

Children 6-12 years old 0.058912 24 0.002281 19

Youth 13-19 years old 0.048310 19 0.001728 14

Adults 20-49 years old 0.062830 25 0.002563 21

Adults 50-99 years old 0.062045 25 0.002602 22

Females 13-49 years old 0.066279 66 0.002531 21

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The registered non-occupational uses of triflumizole include a foliar spray by home owner and 

commercial applicators to landscape grown trees, shrubs and vines. Triflumizole is also 

registered for use on residential/non-commercially grown bearing apples, pears and grapes. 

Though not a restricted use pesticide, the product is intended for “commercial” use and “private 

residential” use. There are no registered uses on lawns or turf. 

Residential short-term (1-30 days) dermal and inhalation exposures are expected for triflumizole 

handler activities associated with use on ornamental plants and bearing pome fruit trees. For 

triflumizole the dermal and inhalation endpoints are based on the same toxicological effect, 

therefore the MOEs are combined to determine a total risk estimates. The results of the 

residential handler exposure and risk assessment are presented in Appendix C. The total shortterm margins of exposure (MOEs) are not of concern (i.e. an MOE > 100) with baseline attire 

(shorts, short-sleeves, shoes and socks). 

Post-application exposure from triflumizole use on landscape ornamentals for children (1-2 

years) is expected to be negligible based on the following factors: 1) Children young enough to 

exhibit hand-to-mouth behavior would not typically play in ornamental beds or tree plots; 2) If 
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present, leaf to skin residue transfer would be negligible because of the minimal frequency and 

duration of contact. There is also the potential for post-application exposure for adult and 

children (6-11 years old), exposed as a result of being in an environment that has been previously 

treated with triflumizole. All the short-term dermal post-application MOEs for each scenario are 

greater than the LOC of 100, and are not of concern. 

6.1 Residential Bystander Post-Application Inhalation Exposure

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

assessment was not performed for triflumizole at this time. However, volatilization of pesticides 

may be a source of post-application 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

6.2 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 triflumizole. 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.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios; flagger risks were 

not of concern. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate triflumizole exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 
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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.

7.1 Acute Aggregate Risk

In examining acute aggregate risk, HED has assumed that the only pathway of exposure relevant 

to the acute time frame is dietary exposure. Therefore, the acute aggregate risk is comprised of 

exposures to triflumizole residues in food and drinking water and is equivalent to the acute 

dietary risk estimates summarized in Table 5.4.6. The acute risk estimates are well below HED’s 

level of concern for all population subgroups.

7.2 Short-Term Aggregate Risk

The residential post-application exposure for adults exposed to home garden and trees 

represent the highest estimated risk (children 6-11 show lower exposure due to shorter time spent 

in the garden), and was therefore combined with the chronic dietary exposure for adults (General 

US population), to estimate the highest aggregate exposure and risk. Despite the numerous 

conservative assumptions in developing these estimates, the MOE is above the LOC of 100, and 

is not of concern (Table 7.2.1). 

Table 7.2.1. Short-Term and/or Intermediate Term Aggregate Risk Calculations

Population

Short- or Intermediate-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult Male 3.5 100 0.035 0.00257 0.0165 0.0191 180

Child (6-11 yrs) 3.5 100 0.035 0.00281 0.003 0.00581 600

1 The LOC is based on the standard inter- and intra- species uncertainty factors totaling 100. The FQPA Safety 

Factor has been reduced to 1X.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Dermal exposure + Inhalation Exposure]. 

4 Total Exposure = Avg Food + Drinking Water Exposure + Residential Exposure). 

5 Aggregate MOE = NOAEL of 3.5 mg/kg/day/ (Avg Food + Drinking Water Exposure + Residential Exposure)

7.3 Intermediate-Term Aggregate Risk

There are no current residential uses which result in intermediate-term exposure. Therefore, an 

intermediate-term aggregate risk assessment was not performed nor required.

7.4 Chronic Aggregate Risk

In examining chronic aggregate risk, HED has assumed that the only pathway of exposure 

relevant to this time frame is dietary exposure. Therefore, chronic aggregate risk is comprised of 

exposures to triflumizole residues in food and drinking water and is equivalent to the chronic 

dietary risk summarized in Table 5.4.6. The chronic risk estimates are below HED’s level of 

concern for all population subgroups. Because triflumizole is not a carcinogen, no cancer risk 

assessment was conducted.
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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 triflumizole and any other substances, and triflumizole 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 triflumizole 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/.

9.0 Occupational Exposure/Risk Characterization

An occupational exposure assessment of the proposed uses was provided in a HED 

memorandum dated 29-OCT-2013 (S. Tadayon; D414029). For the proposed use sites, there is a 

potential for short- and intermediate-term occupational exposure to triflumizole during mixing, 

loading, applying, and other handling tasks; and during post-application activities. Additionally, 

since the same endpoint and point of departure (POD) were selected for intermediate-term and 

chronic durations, intermediate-term risk estimates are protective of chronic exposure and risk. 

Chronic exposure is only expected for the proposed green house uses of cucumber and tomato. 

9.1 Short- and Intermediate-Term Handler Risk

The scenarios assessed for occupational handlers include mixing/loading liquids to support 

aerial, airblast, groundboom, and chemigation applications, applying sprays with aerial, airblast, 

groundboom equipment, hand held equipments and flagging for liquid aerial applications. 

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task 

Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or 

other registrant-submitted occupational exposure studies. Some of these data are proprietary 

(e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting handler exposure that are used in this assessment, known as 

“unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table1,” which, along with additional information on HED policy on use of surrogate 

data, including descriptions of the various sources, can be found at the Agency website2. 

Estimates of dermal and inhalation exposure were calculated for various levels of PPE. Results 

are presented for “baseline,” defined as a single layer of clothing consisting of a long-sleeved 

shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline 

with various levels of PPE as necessary (e.g., gloves, respirator, etc.). The triflumizole product 

labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirts, long 

 

1 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

2 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
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pants, chemical-resistant gloves, shoes plus socks, and protective eyewear. 

The occupational handler exposure and risk estimates indicate that short- and intermediate-term 

dermal and inhalation combined MOEs are not of concern to HED (i.e., MOEs > 100 for short –

term and MOEs > 300 for intermediate-term) with baseline and label recommended attire. The

dermal plus inhalation MOEs range from 350 to 28,000 (see Appendix C). HED has no data to 

assess exposures to pilots using open cockpits. The only data available is for exposure to pilots 

in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control 

(enclosed cockpits) and baseline attire (long-sleeved shirt, long pants, shoes, and socks); pilots 

are not required to wear protective gloves. With this level of protection, there are no risk 

estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for 

human flaggers where appropriate, agricultural aviation has changed dramatically over the past 

two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of 

their membership, the use of the Global Positioning System (GPS) for swath guidance in 

agricultural aviation has grown steadily from the mid 1990s. Over the same time period, the use 

of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 

1990s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor 

all available information sources to best assess and characterize the exposure potential for human 

flaggers in agricultural aerial applications.

9.2 Short- and Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

HED expects that post-application exposure will occur since triflumizole is applied as a foliar 

spray. Based on the proposed uses, short- and intermediate-term exposures are expected since 

there is the potential for multiple applications at the maximum application rate for most crops. . 

Additionally, since the same endpoint and point of departure (POD) were selected for 

intermediate-term and chronic durations, intermediate-term exposure and risk estimates are 

protective of chronic exposure and risk. 

HED default assumptions, triflumizole-specific DFR data (MRID # 45375401) and the revised 

Agricultural Re-entry Task Force (ARTF) data base were used in assessing exposure from postapplication activities. The standard values recommended for use in predicting post-application 

exposure that are used in this assessment, known as “transfer coefficients,” are presented in the 

“Science Advisory Council for Exposure (ExpoSAC) Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/postapp-exposure-data.html.

The short- and intermediate-term post-application exposure scenarios associated with the 

proposed uses for triflumizole are summarized in Appendix C. 
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Table 9.2.1: Summary of Short- term Occupational/Commercial Post-application Risk Estimates for Triflumizole.

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

DFR1 Dermal Dose 

(mg/kg/day)2

MOE3

Day zero

Tomato and cucumber 

(greenhouse)

All activities (except irrigation) 1200

0.563

0.002742 1,300

Irrigation (Hand set) 1900 0.00434 800

Irrigation (Hand Watering) 230 0.000525 7,000

Fruit, small vine 

climbing, except fuzzy 

kiwifruit

Scouting, Hand pruning, Hand weeding 640 0.001462 2,400

Irrigation 1,900 0.004341 800

Tying/training/Leaf pulling 5,500 0.012566 300

Hand harvesting 10,100 0.023075 150

Girdling 19,300 0.044094 79

0.0354 (day 1) 100

Pome fruit crop group 

11-10

Orchard maintenance 100 0.000228 15,000

Scouting, Hand pruning 580 0.001325 2,600

Hand harvesting 1,400 0.003198 1,100

Thinning fruit 3,600 0.008225 400

Berry (13-07G)

Hand weeding 70 0.00016 22,000

Transplanting 230 0.000525 7,000

Irrigation 1,900 0.004341 800

1. DFR = Chemical-specific DFR = day zero predicted grape vine DFR data (0.563 ug/cm2) for short –term exposure 

estimate 

2. Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (69kg).

3. Dermal MOE = POD (3.5 mg/kg/day) / Daily Dermal Dose. LOC=100

Table 9.2.2: Summary of Intermediate-term Occupational/Commercial Post-application Risk Estimates for Triflumizole.

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

DFR1 Dermal Dose 

(mg/kg/day)2 MOE3

Tomato and cucumber 

(greenhouse)

All activities (except irrigation) 1200

0.130

0.000546 6,400

Irrigation (Hand set) 1900 0.000865 4,000

Irrigation (Hand Watering) 230 0.000105 33,000

fruit, small vine 

climbing, except fuzzy 

kiwifruit

Scouting, Hand pruning, Hand weeding 640 0.000291 12,000

Irrigation 1,900 0.000865 4,000

Tying/training/Leaf pulling 5,500 0.002503 1,400

Hand harvesting 10,100 0.004596 800

Girdling 19,300 0.008782 400

Pome fruit crop group 

11-10

Orchard maintenance 100 4.55E-05 77,000

Scouting, Hand pruning 580 0.000264 13,000

Hand harvesting 1,400 0.000637 5,500

Thinning fruit 3,600 0.001638 2,000

Berry (13-07G)

Hand weeding 70 3.19E-05 110,000

Transplanting 230 0.000105 33,000

Irrigation 1,900 0.000865 4,000

1. DFR = DFR = Chemical-specific DFR = average 21 days residue (0.130 ug/cm2) data for intermediate-term exposure 

estimate for all crops. 

2. Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (80kg).

3. Dermal MOE = POD (3.5 mg/kg/day) / Daily Dermal Dose. LOC=300

The 12-hour REI specified on the proposed label is based on the acute toxicity of triflumizole. 

Triflumizole is classified as Toxicity Category III for acute oral and Category IV for acute 

dermal toxicity, Toxicity Category IV for acute inhalation toxicity, and Toxicity Category III for 

primary eye irritation. Triflumizole is not an irritant to the skin of rabbits (Toxicity Category 
Triflumizole Human-Health Risk Assessment DP# 407679

Page 31 of 44

IV), but was shown to be a mild skin sensitizer in mice. Short- term post-application risk 

estimates were not a concern on day 0 (12 hours following application) for most post-application 

activities except for girdling of grapes (acceptable MOE reached 1day after treatment). 

Therefore, HED is recommending that the REI be revised on the label to address risk concerns 

related to girdling grapes. Intermediate-term post-application risk estimates were not a concern 

on day 0 (12 hours following application) for all post-application activities assessed”

9.2.2 Inhalation Post-Application Risk

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

assessment was not performed for triflumizole. However, there are multiple potential sources of 

post-application inhalation exposure to individuals performing post-application 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, and 

received the SAP’s final report on March 2, 20103. The Agency is in the process of evaluating 

the SAP report as well as available post-application inhalation exposure data generated by the 

ARTF 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 triflumizole.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios; handler inhalation risk estimates are not of concern.

10.0 References

Previous Risk Assessments: S. Tadayon, et al., 02-May-2012; D393221.

Chemistry Memo: W. Donovan; 29-OCT-2013; D413698.

Drinking Water Memo: C. Koper; 20-May-2013; D 407680

Dietary Memo: W. Donovan; 22-Aug-2013; D413699.

Occupational Exposure Memo: S. Tadayon; 29-OCT-2013; D414029

List of Appendices:

Appendix A. Toxicology Profile and Executive Summaries

Appendix B. Review of Human Research

Appendix C. Occupational and Residential Exposure Tables

Appendix D. International Residue Limits Table

 

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Triflumizole Human-Health Risk Assessment DP# 407679

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.476) for Food Use for triflumizole are presented below.

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

no

yes

no

no

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

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5375 Chromosome aberration

870.5395 Micronucleus assay

870.5500 DNA Damage

870.5550 Unscheduled DNA Synthesis

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotox. Screening Battery (rat)

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

870.6300 Develop. Neurotoxicity

no

no

yes

yes

no

-

-

yes

yes

-

870.7485 General Metabolism

870.7600 Dermal Penetration

yes

no

yes

-

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

-

-

-
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A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile –Triflumizole Technical.

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 00144463 LD50 = 1362 mg/kg III

870.1200 Acute dermal [rat] 00144465 LD50 > 5000 mg/kg IV

870.1300 Acute inhalation [rat] 00144466 LC50 > 3.2 mg/L IV

870.2400 Acute eye irritation [rabbit] 00144467 Slight ocular irritant III

870.2500 Acute dermal irritation [rabbit] 00144468 Not a dermal irritant IV

870.2600 Skin sensitization [Guinea pig] 00144469 Mild dermal sensitizer N/A

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Triflumizole Technical.

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

Classification /Doses Results

870.3100 90-Day oral 

toxicity (rat)

45498001 (1980)

Acceptable/guideline

0, 20, 200, 2000 ppm

M: 0, 1.4, 15.3, or 176.5 

mg/kg/day 

F: 0, 1.8, 17.2, or 217.9 

mg/kg/day

NOAEL = Males: 15.3 mg/kg/day; Females: 

17.2 mg/kg/day

LOAEL = Males: 176.5 mg/kg/day; Females: 

217.9 mg/kg/day based on increased kidney 

and liver weights and the accumulation of fat 

droplets in the liver.

870.3100

90-Day oral 

toxicity rodents 

(mouse)

45498002 (1980)

Acceptable/guideline

0, 20, 200, 2000 ppm

M: 0, 3.2, 33.1, or 380.7 

mg/kg/day 

F: 0, 4.2, 42.6, or 466.2 

mg/kg/day

NOAEL = Males: 33.1 mg/kg/day; Females: 

42.6 mg/kg/day

LOAEL = Males: 380.7 mg/kg/day; Females 

466.2 mg/kg/day based on reduced growth.

870.3150 90-Day oral 

toxicity 

(nonrodents)

NA NA

870.3200 21/28-Day dermal 

toxicity (rat)

41706601 (1990)

Acceptable/guideline

0, 10, 100, or 1000 

mg/kg/day 6 hr/day, 7 

d/week

NOAEL ≥1000 mg/kg/day

LOAEL = not identified

870.3250 90-Day dermal 

toxicity NA NA

870.3465 90-Day inhalation 

toxicity NA NA

870.3700a Prenatal developmental in rodents 

(rat)

00157075 (1986)

Acceptable/non-guideline 

(complimentary)

F:0 or 3 mg/kg/day

Must be considered with MRID 45458001

LOAELs/NOAELs not assigned

870.3700a Prenatal developmental in rodents 

(rat)

00164384 (1986)

Acceptable/non-guideline 

(repeat)

F: 0, 3, 7, or 35 

mg/kg/day

Must be considered with MRID 45458001

LOAELs/NOAELs not assigned
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Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Triflumizole Technical.

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

Classification /Doses Results

870.3700a Prenatal developmental in rodents 

(rat)

45458001 (1983)

Acceptable/non-guideline 

F: 0, 10, 35, or 120

mg/kg/day

Maternal NOAEL = 10 mg/kg/day

LOAEL = 35 mg/kg/day based on decreased 

body weight gain and food consumption,; 

increased placental weight, and increased 

maternal spleen and liver weights.

Developmental NOAEL = 10 mg/kg/day

LOAEL = 35 mg/kg/day based on decreased 

numbers of viable fetuses, increased dead or 

resorbed fetuses, increased numbers of late 

resorptions, decreased fetal body weight,and 

increased incidences of cervical ribs.

870.3700b Prenatal developmental in nonrodents (rabbit)

00156546 (1985)

Acceptable/guideline

F: 0, 50, 100, or 200 

mg/kg/day

Maternal NOAEL = 50 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased 

body weight gains, food consumption, and 

placental weights.

Developmental NOAEL = 50 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased 

24-hour survival, decreased placental weights, 

and increased fetal and litter incidences of 

lumbar ribs.

870.3700b Prenatal developmental in nonrodents (rabbit)

40752003 (1988)

Unacceptable/guideline

F: 0, 5, 25, or 50 

mg/kg/day

Must be considered with MRID 00156546

Maternal NOAEL = 50 mg/kg/day

LOAEL = not identified

Developmental NOAEL = 50 mg/kg/day

LOAEL = not identified

870.3800 Reproduction and 

fertility effects

(rat)

00162176 (1986)

00156548 (1984)

40301602 (1987)

Acceptable/guideline with 

MRID 156547

0, 30, 70, or 170 ppm

P: 0, 1.5, 3.5, or 8.5 

mg/kg/day

Parental/Systemic NOAEL = 8.5 mg/kg/day

LOAEL = not established

Reproductive NOAEL = 3.5 mg/kg/day 

(reproductive NOAEL), based upon increased 

gestation length in the dams of F1a, F2a, and F3a

intervals at the LOAEL of 8.5 mg/kg/day.

Offspring NOAEL = 3.5 mg/kg/day

LOAEL = 8.5 mg/kg/day based on decreased 

pup weights, survival indices, and litter sizes in 

both F3 litters, reduced litter size in the F1a

litter, increased total-litter mortality in the 

F3alitter, and developmental effects in the F1b

and F2b progeny.

870.4100a Combined chronic 

toxicity/carcinoge

nicity (rats)

00156545 (1984)

Acceptable/guideline

0, 100, 400, or 1600 ppm

M: 0, 3.5-3.7, 14.1-15.1, 

or 59.4-62.0 mg/kg/day

F: 0, 4.5-4.6, 18.0-18.1, or 

77.0-78.0 mg/kg/day

LOAEL = 3.5 mg/kg/day, based on liver 

toxicity (eosinophilic foci in male rats and fatty 

vacuolation and inflammation and necrosis in 

female rats). 

NOAEL is <3.5 mg/kg/day because the lowest 

dose tested is the LOAEL 
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Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Triflumizole Technical.

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

Classification /Doses Results

870.4100b Chronic toxicity 

(dog)

00149848 (1984)

Acceptable/guideline

0, 100, 300, or 1000 ppm

M: 0, 3.33, 10.00, or 

34.10 mg/kg/day

F: 0, 3.27, 10.69, or 35.17 

mg/kg/day

NOAEL = Males: 10.00 mg/kg/day; Females: 

10.69 mg/kg/day

LOAEL = Males: 34.10 mg/kg/day; Females: 

35.17 mg/kg/day based on increased alkaline 

phosphatase activity and a mild, macrocytic 

anemia in males, increased absolute and 

relative liver weights in both sexes, and on 

macroscopic findings in the liver of both sexes.

870.4200 Carcinogenicity

(rat) NA; see 870.4300 NA

870.4300 Chronic Toxicity/

Carcinogenicity

(mouse)

00156544 (1984)

Acceptable/guideline

0, 100, 400, or 1600 ppm

M: 0, 16.2, 67.4, or 296.1 

mg/kg/day

F: 0, 21.7, 86.1, or 362.2 

mg/kg/day

NOAEL = Males: 16.2 mg/kg/day; Females: 

21.7 mg/kg/day

LOAEL = Males: 67.4 mg/kg/day; Females: 

86.1 mg/kg/day based on microscopic lesions 

of the liver.

No evidence of carcinogenicity

870.5100 Bacterial reverse 

mutation

40494409 (1987)

Acceptable

seven concentrations 

ranging from 5 to 5000 

μg/plate

Negative with or without S9 activation at 5000 

μg/plate and less.

870.5100 Bacterial reverse 

mutation

45502203 (1983)

Acceptable

concentrations ranging 

from 8 to 8000 μg/plate

Negative with or without S9 activation at 8000 

μg/plate and less.

870.5375

In vitro

mammalian 

chromosome 

abberation (CHL)

40494408 (1987, 1988)

Acceptable

5 to 40 μg/mL

Negative with or without S9.

870.5395

In vitro

mammalian 

cytogenetics 

(mouse bone 

marrow)

00160620 (1986)

Acceptable

M&F: 160, 533 and 1600 

mg/kg (single oral dose)

Negative. Not clastogenic for the production of 

micronuclei in bone marrow polychromatic 

erythrocytes in mice at single oral doses up to 

1600 mg/kg.

870.5500 DNA 

damage/repair 

REC assay

45502204 (1983)

Unacceptable

concentrations range from 

24 to 24,000 mg/disk

Negative. No evidence of DNA damage up to 

24,000 mg/disk. Study is unacceptable because 

a metabolic activation system was not used.

870.5550 UDS in primary 

rat hepatocytes

45502205 (1984)

Acceptable

12.5 to 30 μg/mL

Negative. No evidence of unscheduled DNA 

synthesis up to cytotoxic concentrations.

870.6200a Acute 

neurotoxicity 

screening battery

46202502 (year)

NOAEL = 25 mg/kg/day

LOAEL = 100 mg/kg/day, based on FOB 

findings (neuromuscular impairment, as 

evidenced by decreased hind-and fore-limb grip 

strength, impaired gait and mobility, abnormal 

righting reflex) and decreased locomotor 

activity

870.6200b Subchronic 

neurotoxicity 

screening battery

46202502, 46259401

Acceptable/guideline

NOAEL = 2000 ppm (133.3 mg/kg bw/day), 

HDT.

870.6300 Developmental 

neurotoxicity NA NA
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Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Triflumizole Technical.

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

Classification /Doses Results

870.7485

Metabolism and 

pharmacokinetics 

(rat)

40789101 (1988)

Acceptable/guideline with 

41606201 and 41606202

M&F: 10 mg/kg as single 

oral dose

Following oral treatment of rats with [phenylU14C]-NF-114, no sex-related differences were 

observed in absorption, metabolism, 

distribution or excretion. Maximum 

concentrations of radioactivity in plasma were 

attained within 1 hour of dosing in both sexes. 

Low levels of radioactivity were detectable in 

all tissue, organ, and blood samples. 

Radioactivity in urine accounted for 69.5-

74.4% of the dose and feces accounted for 

21.7-21.9% of the dose. Based on the 

metabolite profile, the metabolism in rats 

primarily involves oxidation to FM-8-1 and 

FA-1-5, followed by sulfation and 

glucuronidation.

870.7485 Metabolism and 

pharmacokinetics

(rat)

41606201 (1983)

41606202 (1984)

Acceptable/guideline with 

40789101

M&F: 10 or 300 mg/kg as 

single oral dose

Following oral treatment of rats with [phenylU14C]-NF-114, approximately 93.8-100.6% of 

the administered dose was recovered. Urine 

was the major route of excretion. Low levels of 

radioactivity were detectable in all tissue, 

organ, and blood samples collected 2 days (10 

mg/kg group) or 4 days (300 mg/kg group) 

post-dose with tissue concentrations generally 

higher in males than females. The metabolite 

profile in the excreta was quantitatively and 

qualitatively similar between the sexes and 

dose groups. Based on the metabolite profile, 

the biotransformation of NF-114 in rats 

primarily involved oxidation of parent to FM-8-

1 and FA-1-5, followed by conjugation yielding 

sulfate and glucuronic acid conjugates.

870.7600 Dermal 

penetration NA NA

Hepatic enzyme 

induction Special studies

40830401 (1988)

Acceptable/nonguideline

M&F: 0 or 200 mg/kg/day 

as oral dose for five 

consecutive days

The study provides evidence that triflumizole 

induces hepatic microsomal enzymes when 

administered orally. However, no correlation 

between the increased enzyme activities and 

hepatic lesions observed following chronic 

administration was made since no 

histopathology was performed.

870.7800 Immunotoxicity 48086101

Acceptable/guideline

LOAEL = 2000 ppm (285.7 mg/kg/day) based 

on significant decrease in the anti-SRBC IgM 

response.

NOAEL = 200 ppm (28.6 mg/kg/day)
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Appendix B. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website4. 

 

4

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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Appendix C. Occupational and Residential Exposure Tables.

a) Based on registered labels ( Procure 480SC, EPA REG Number 400-518) 

b) Exposure Science Advisory Council Policy #9.1

c) Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/A or gal) x Amount Treated or Handled (A or gallons/day) x DAF (3.5%)/BW (69 kg)

d) Dermal MOE = Dermal NOAEL (3.5 mg/kg/day)/Dermal Dose (mg/kg/day)

e) Inhalation Dose = Inhalation Unit Exposure (mg/kg) x Application Rate (lb ai/A or gal) x Amount Treated or Handled (A or gallons/day) /BW (69 kg)

f) Inhalation MOE = Inhalation NOAEL (3.5 mg/kg/day)/ Inhalation Dose (mg/kg/day)

g) Total MOEs =1/[(1/Dermal MOE) + (1/Inhalation MOE)]. Level of concern = 100

Short-Term Residential Handler Exposure and Risk Estimates for Triflumizole

Exposure Scenario Target 

MOE

Dermal 

Unit 

Exposure

Inhalation 

Unit 

Exposure

Maximum 

Application 

Rate a

Amount Treated 

or Handled Daily 

b

Dermal Inhalation Total 

Dose c MOEd Dose e MOEf MOEg

Mixer/Loader/Applicator

Manually-pressurized handwand

Broadcast(Gardens/Trees)

100 63 0.018 0.05lb ai/gal 5gals 0.007989 440 6.5E-05 54,000 440

Manually-pressurized handwand

Spot treatment(Gardens/Trees)

100 63 0.018 0.000012lb ai/ft21200ft2 0.00046 7600 3.8E-06 932,000 7,500

Hose end sprayer Spot 

treatment(Gardens/Trees)

100 58 0.0014 0.000012lb ai/ft21200ft2 0.000424 8300 2.9E-07 1,198,000 8,200

Hose end sprayer Broadcast 

(Gardens/Trees)

100 58 0.0014 0.05 lb ai/gal 11 0.016181 220 1.1E-05 314,000 220

Back Pack sprayer 

Broadcast(Gardens/Trees)

100 130 0.14 0.05 lb ai/gal 5 gals 0.016486 200 5.1E-04 6,900 200

Back Pack sprayer Spot 

treatment(Gardens/Trees)

100 130 0.14 0.000012lb ai/ft2 1200ft2

0.00095 3700 2.9E-05 120,000 3,500
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Residential Post-application Non-cancer Exposure and Risk Estimates for Triflumizole.

Lifestage

Post-application Exposure Scenario Application Rate1 Dose (mg/kg/day)2 MOEs3

Use Site Route of Exposure

Adult Gardens Dermal

1lb ai/A

0.005 660

Child (6-11 yrs) 0.003 1,100

Adult Fruit Trees Dermal 0.0005 7,200

Child (6-11 yrs) 0.00029 12,000

1 Based on the proposed tree use on registered labels for tree and garden use.

2 Dose (mg/kg/day) equations: See Appendix A

3 Dermal MOE = Dermal NOAEL (3.5 mg/kg/day) ÷ Dermal Dose (mg/kg/day).
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 Short-Term Occupational Exposure and Risk Estimates for Triflumizole

Exposure Scenario Crop or Target Dermal Unit 

Exposure 1

mg /lb ai

Inhalation 

Unit 

Exposure 1

mg /lb ai

Application 

Rate 2

lb ai/A

Amount 

Treated Daily 3

Acre or Gallon

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/Loader

Mixing/Loading Liquids for 

Aerial Applications

Pome fruits 

(subgroup11-10)

0.0376

SL/G

0.000219 0.5 350 0.00334 1,000 0.00056 6300 900

Strawberry(subgroup 

13-07G) and tomato

0.22

SL/NG

0.000219 0.25 350 0.0098 360 0.00028 13,000 350

Mixing/Loading Liquids for 

Chemigation Applications

Strawberry(subgroup 

13-07G)

0.25 350 0.0098 360 0.00028 13,000 350

Mixing/Loading Liquids for 

Groundboom Applications

Strawberry(subgroup 

13-07G) and tomato

0.25 80 0.0022 1,600 0.000063 55,000 1,500

Mixing/Loading Liquids for 

Airblast Applications

Pome fruits

(subgroup11-10)

0.5 40 0.0022 1,600 0.000063 55,000 1,500

Grape

(Subgroup 13-07F)

0.25 40 0.0011 3,100 0.000032 110,000 3,000

Applicator

Applying Sprays via Aerial 

Equipment

Pome fruits 

(subgroup11-10)

0.00208

Eng. control

0.0000049 0.5 350 0.000248 14,000 0.0000124 282,000 14,000

Strawberry(subgroup 

13-07G) and tomato

0.25 350 0.000496 28,000 0.0000249 564,000 28,000

Applying Sprays via Open 

Cab Air

blast Equipment

Pome fruits 

(subgroup11-10)

0.141

G, DL, 

chemical 

resistant hat

0.0041 0.5 40 0.0014 2,400 0.0014 2,600 2,400

Grape

(subgroup 13-07F)

1.77 0.0041 0.25 40 0.009 390 0.0007 5,100 360

Applying Sprays via Open 

Cab groundboom 

Equipment

Strawberry(subgroup 

13-07G) and tomato

0.079 0.00034 0.25 80 0.0008 4,400 0.0001 36,000 3,900

Flagger

Flagging for Aerial Sprays 

Applications

All Crops

Except grapes

0.011 0.00035 0.5 350 0.0010 3,600 0.0009 3,900 1,900
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 Short-Term Occupational Exposure and Risk Estimates for Triflumizole

Exposure Scenario Crop or Target Dermal Unit 

Exposure 1

mg /lb ai

Inhalation 

Unit 

Exposure 1

mg /lb ai

Application 

Rate 2

lb ai/A

Amount 

Treated Daily 3

Acre or Gallon

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/loader/Applicator

Mixer/Loader/Applicator, 

Backpack Sprayer

Green house grown 

vegetable (Tomato 

and Cucumber)

13.2 0.140

0.00125 gal

40 0.0003 10,000 0.0001 35,000 8,000

Mixer/Loader/Applicator, 

Manually-pressurized 

handwand

100 0.03

40 0.0025 1,400 0.00002 160,000 1,400

Mixer/Loader/Applicator, 

Mechanically-pressurized 

Handgun Sprayer

3.5 0.120

1000 0.0022 1,600 0.0022 1,600 800

1 PHED/ORETF (level of mitigation: Baseline, PPE, Eng. Controls)

2 Based on registered or proposed label 

3 Exposure Science Advisory Council Policy #9.1

4 Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) x DAF (3.5%)/BW (69kg)

5 Dermal MOE = Dermal NOAEL (3.5 mg/kg/day)/Dermal Dose (mg/kg/day)

6 Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) /BW (69kg)

7 Inhalation MOE = Inhalation NOAEL (3.5 mg/kg/day)/ Inhalation Dose (mg/kg/day)

8 Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)
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 Intermediate-Term/ Occupational Exposure and Risk Estimates for Triflumizole. 

Exposure Scenario Crop or Target Dermal Unit 

Exposure 1

mg /lb ai

Inhalation 

Unit 

Exposure 1

mg /lb ai

Application 

Rate 2

lb ai/A

Amount 

Treated Daily 3

Acre or Gallon

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/Loader

Mixing/Loading Liquids for 

Aerial Applications

Pome fruits 

(subgroup11-10)

0.0376

SL/G

0.000219 0.5 350 0.002881 1,200 0.000483 7,200 1,000

Strawberry(subgroup 

13-07G) and tomato

0.22

SL/NG

0.000219 0.25 350 0.008453 400 0.000242 14,500 400

Mixing/Loading Liquids for 

Chemigation Applications

Strawberry(subgroup 

13-07G)

0.25 350 0.008453 400 0.000242 14,500 400

Mixing/Loading Liquids for 

Groundboom Applications

Strawberry(subgroup 

13-07G) and tomato

0.25 80 0.001898 1,800 5.43E-05 64,000 1,800

Mixing/Loading Liquids for 

Airblast Applications

Pome fruits

(subgroup11-10)

0.5 40 0.001898 1,800 5.43E-05 64000 1,800

Grape

(Subgroup 13-07F)

0.25 40 0.000949 3,700 2.76E-05 127,000 3600

Applicator

Applying Sprays via Aerial 

Equipment

Pome fruits 

(subgroup11-10)

0.00208

Eng. control

0.0000049 0.5 350 0.000214 1,6000 1.07E-05 327,000 16,000

Strawberry(subgroup 

13-07G) and tomato

0.25 350 0.000428 8,000 2.15E-05 163,000 8,000

Applying Sprays via Open 

Cab Air

blast Equipment

Pome fruits 

(subgroup11-10)

0.141

G, DL, 

chemical 

resistant hat

0.0041 0.5 40 0.001208 3,000 0.001208 2,900 1,500

Grape

(subgroup 13-07F)

1.77 0.0041 0.25 40 0.007763 450 0.000604 6000 400

Applying Sprays via Open 

Cab groundboom 

Equipment

Strawberry(subgroup 

13-07G) and tomato

0.079 0.00034 0.25 80 0.000690 5,000 8.63E-05 41,000 4,500

Flagger

Flagging for Aerial Sprays 

Applications

All Crops

Except Grapes

0.011 0.00035 0.5 350 0.000863 4,000 0.000776 4,500 2,100
Triflumizole Human-Health Risk Assessment DP# 407679

Page 43 of 44

 Intermediate-Term/ Occupational Exposure and Risk Estimates for Triflumizole. 

Exposure Scenario Crop or Target Dermal Unit 

Exposure 1

mg /lb ai

Inhalation 

Unit 

Exposure 1

mg /lb ai

Application 

Rate 2

lb ai/A

Amount 

Treated Daily 3

Acre or Gallon

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/loader/Applicator

Mixer/Loader/Applicator, 

Backpack Sprayer

Green house grown 

vegetable (Tomato 

and Cucumber)

13.2 0.140

0.00125 gal

40 0.000259 13500 8.63E-05 4,1000 10,000

Mixer/Loader/Applicator, 

Manually-pressurized 

handwand

100 0.03

40 0.002156 1600 1.73E-05 203,000 1,600

Mixer/Loader/Applicator, 

Mechanically-pressurized 

Handgun Sprayer

3.5 0.120

1000 0.001898 1800 0.001898 1,800 900

1 PHED/ORETF (level of mitigation: Baseline, PPE, Eng. Controls)

2 Based on registered or proposed label 

3 Exposure Science Advisory Council Policy #9.1

4 Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) x DAF (3.5%)/BW (80kg)

5 Dermal MOE = Dermal NOAEL (3.5 mg/kg/day)/Dermal Dose (mg/kg/day)

6 Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) /BW (80kg)

7 Inhalation MOE = Inhalation NOAEL (3.5 mg/kg/day)/ Inhalation Dose (mg/kg/day)

8 Total MOE = 1/ (1/Dermal MOE + 1/Inhalation MOE)
Triflumizole Human-Health Risk Assessment DP# 407679

Page 44 of 44

Appendix D. International Residue Limits Table

Triflumizole (128879; 09/12/2013)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

40 CFR 40 CFR §180.476

Plants: parent compound triflumizole, 1-(1-((4-

chloro-2-(trifluoromethyl)phenyl)imino)-2-

propoxyethyl)-1 H -imidazole, and its 

metabolites containing the 4-chloro-2-

trifluoromethylaniline moiety, calculated as 

stoichiometric equivalent of the parent 

compound.

1-[1-[[4-chloro-2-

(trifluoromethyl)phenyl]imino]-2-

propoxyethyl]-1H-imidazole, 

including metabolites

containing the 4-chloro-2-

trifluoromethylaniline moiety,

expressed as triflumizole

None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Tomato 1.5

Fruit, pome, group 11-10 0.50 0.5 apples, pears

Fruit, small, vine climbing, except 

fuzzy kiwifruit, subgroup 13-07F 2.5 2.5 grapes

Berry, low growing, subgroup 13-

07G, except cranberry 2.0 2 strawberries

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

Completed: M. Negussie; 09/13/13

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

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