Triflumizole Human Health Risk Assessment DP No. 420633 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: June 05, 2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Triflumizole: Human Health Risk Assessment for Registration Review 

PC Code: 128879 

Decision No.: 491745 

Petition No.: 

Risk Assessment Type: Registration Review 

TXRNo.: 

MRIDNo.: NA 

FROM: Seyed Tadayon, Risk Assessor ~~~-:>-""X'/ 

John Liccione, Ph.D., Toxicologis 

William Donovan, Ph.D., Chemis 

Risk Assessment Branch V 

Health Effects Division (7509P) 

DP Barcode: D420633 

Registration No.: 

Regulatory Action: 

Registration Review 

Case No.: NA 

CAS No.: 68694-11-1 

40CFR: §180.476 

. / 

Office of Pesticide Programs 

THROUGH: Michael S Metzger, Branch Chief 1 ~ /) P. [ iJ---- . Risk Assessment Branch V L{ ~ v( ' U 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Steven Snyderman, Chemical Review Manager 

Risk Management and Implementation Branch III 

Pesticide Re-evaluation Division (7508P) 

This is a revision of the original Human Hea~th Risk Assessment for Registration Review, 

(S. Tadayon May 02, 2012, D393221). This document has been revised to address changes in 

Re-Entry Intervals (REI) for grape and hop. The changes are on pages 3, 14 and 30. 

Page 1 of30 
Triflumizole Human Health Risk Assessment DP No. 420633 

This document provides the Health Effects Division's (HED's) risk assessment conducted in 

support of registration review for triflumizole. The emphasis of the present memo is on changes 

since the most recent assessments. The supporting documents are listed below. 

Triflumizole- Human Health Risk Assessment. W. Cutchin, D363719, 4/1109. 

Triflumizole- Residue Chemistry Assessment. W. Cutchin, D346779, 10/1108. 

Triflumizole- Seeping Assessment. C. Eiden, D332497, 4/2/07. 

Triflumizole - Drinking Water Assessment, C. Koper, D395021, 1/9/12. 

Triflumizole- Dietary Exposure Assessment, W. Donovan, D397935, 3/28112. 

Triflumizole SLUA, BEAD, 9/2/11. 

Triflumizole- Results of the MARC Meeting, J. Tyler, 3/12/02. 

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 used as a pre-plant seed piece 

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

no registrations on turf and garden vegetable uses. 

HED reviewed the toxicity database for triflumizole, as well as the most recent risk assessment 

(DP 363719, Cutchin, W., 4-1-09), and concluded that no changes in point of departures (PODs), 

endpoints of concern or FQP A Safety Factors are warranted. Since the last risk assessment, an 

immunotoxicity study in mice was submitted and reviewed. The results of this study did not 

impact the overall risk assessment. 

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. 

Adequate residue chemistry data have been provided for all crop uses oftriflumizole. However, 

previously recommended changes to 40 CFR 180.476 are still needed (see Recommended 

Tolerances). 

Revised dietary exposure assessments were conducted to incorporate updated percent crop 

treated information from the Biologic and Economic Analysis Division (BEAD) and updated 

estimated drinking water concentrations (EDWCs) from the Environmental Fate and Effects 

Division (EFED). Drinking water was incorporated directly in the dietary assessments. 

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The acute dietary (food + water) exposure assessments used tolerance level residues and 100% 

crop treated (CT) for all registered uses. These assessments demonstrate that the acute dietary 

risk estimates are not of concern for the general U.S. population (26% aPAD, 0.065598 

mg/kg/day) and all population subgroups. Children 1-2 years old was the most highly exposed 

population subgroup at 39% aPAD and 0.096453 mg/kg/day. Exposure was equivalent to 

0.068075 mg/kg/day or 68% of the aPAD for females 13-49 years old.

The chronic dietary exposure assessment used anticipated residues (ARs) from average field trial 

results and the most recent % CT information from BEAD. This assessment shows that the 

chronic dietary exposure estimates are not of concern for the general U.S. population (19% 

cPAD) and all population subgroups. The most highly exposed population subgroup is children 

1-2 years old at 32% cPAD. A cancer assessment was not performed because triflumizole is not 

carcinogenic.

HED has recently revised the Agricultural Re-entry Task Force (ARTF) and Pesticide Handler 

Exposure Database (PHED), and has conducted new occupational risk assessments for 

triflumizole. Based on this updated occupational exposure and risk assessment, HED is 

recommending the following label revisions: 

When applying sprays with open cab air blast equipment on apple, pear and cherry, handlers 

must wear a chemical resistant hat to achieve the target MOE ≥ 300. The MOE with the current

label PPE recommendations (single layer and glove) is 230. The Restricted Entry Interval (REI)

for grapes (table and raisin) should be extended from the current REI (zero days) to 1 day, and 

for hops to 3 days to achieve the target MOE ≥ 100. The current 12-hour REI for wine grapes is 

adequate. The restricted reentry interval for hops may not be necessary since the longer PHI (7 

days) would provide the necessary restricted entry for this activity.

Data Deficiencies

HED has examined the toxicology and residue chemistry databases for triflumizole and found 

both to be complete.

Tolerance Considerations

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). 

International Harmonization

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

various raw agricultural and 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 B). 
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Recommended Tolerances

HED recommends that the residue definition for the tolerance expression for triflumizole be 

modified in accordance with current policy on tolerance definitions (S. Knizner, 5/27/09), to 

read as follows for 40 CFR § 180.476(a)(1):

“Tolerances are established for residues of triflumizole (1-[(1E)-1-[[4-chloro-2-

(trifluoromethyl)phenyl]imino]-2-propoxyethyl]-1H-imidazole), including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified is to be determined by measuring only those triflumizole 

residues convertible to 4-chloro-2-trifluoromethylaniline, expressed as the stoichiometric 

equivalent of triflumizole, in or on the commodity.”

Similarly, 40 CFR § 180.476(a)(2) should be revised to:

“Tolerances are established for residues of triflumizole (1-[(1E)-1-[[4-chloro-2-

(trifluoromethyl)phenyl]imino]-2-propoxyethyl]-1H-imidazole), including its metabolites

and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified is to be determined by measuring those triflumizole residues 

convertible to 4-chloro-2-trifluoromethylaniline plus the metabolite 4-chloro-2-hydroxy6-trifluoromethylaniline sulfate, expressed as the stoichiometric equivalent of

triflumizole, in or on the commodity.”

No changes to tolerance levels have occurred as a result of this registration review. 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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Chemical Identity

Table 3.1 Trifumizole and Metabolite Nomenclature

Chemical 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 common moiety 

structure

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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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 Not available

Bulk Density 0.50-0.70 (at 20oC)

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

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

Acetone 144

n-Hexane 1.76

Methanol 49.6

Xylene 63.9

Vapor pressure (at 25oC) 1.4 x 10-6 mmHg

Dissociation constant, pKa 3.7

Octanol/water partition coefficient, 

Log(KOW) at 25oC

25

UV/visible absorption spectrum Not available

Toxicology 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 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 

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 the lack of 

evidence of carcinogenicity in studies in rats and mice and the absence of a mutagenicity 

concern. 

There was no evidence of neurotoxicity in the acute and subchronic neurotoxicity studies in the 

rat with triflumizole.
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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 increased 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 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 (RfD) for these population groups. The chronic dietary endpoint is based 

on 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. 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, a MOE of 300 is required 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,

dermal (3.5%) and inhalation (100%) absorption factors are used for route-to-route extrapolation. 

The toxicology data base is complete and there are no residual uncertainty for pre-and post natal 

toxicity. 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 intermediate- and 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 class of compounds 

(conazole fungicide) is used for assessing chronic risk.
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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 available data does not show this chemical to be a potent toxicant following short 

and long-term dietary exposure since clear NOAELs were established in all the other 

studies such as the reproduction (3.5 m/k/d), subchronic rat (15.3 m/k/d), subchronic

mouse (33.1 m/k/d); chronic dog 10 m/k/d) and the mouse carcinogenicity (16.2 m/k/d) 

studies.

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

NOAEL (2.5 m/k/d) 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.

Endocrine Disruption Screening Program

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

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

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

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

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

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

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

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

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

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

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

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

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

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

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

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

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

Although triflumizole is not among the group of pesticide active ingredients on the initial list to 

be screened under the EDSP, it is included in a second lists of chemicals considered for Tier 1 

screening. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. 

Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active 

ingredients. For further information on the status of the EDSP, the policies and procedures, the 

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

http://www.epa.gov/endo/.
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Residue Chemistry Assessment

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. Sufficient processing studies were 

submitted to elucidate the fate of triflumizole in processed commodities. Wet apple pomace and 

pineapple processed residue are the only livestock feedstuffs. As neither is fed to poultry or 

swine, all poultry and hog tolerances should be revoked. Finite residue levels of triflumizole are 

possible in fat and meat byproducts of ruminants, and these tolerances should be retained, but at 

lower levels than currently listed in 40 CFR 180.476. Lower livestock commodity tolerance 

levels are appropriate because of the lower dietary burden recently determined (D346779, W. 

Cutchin, 10/1/08). Confined rotational crops studies show that the metabolism of triflumizole in 

rotated crops is similar to that in primary crops, although relatively less parent and more 

metabolites were found. Results from the limited rotational crop field trials also indicated that 

the following current plant-back intervals are appropriate for rotated crops: 30 days for leafy 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. 

Dietary Exposure Assessment

Revised dietary exposure assessments were conducted to incorporate updated percent crop 

treated information from BEAD and updated EDWCs from EFED. Drinking water was 

incorporated directly in the acute and chronic dietary assessments. 

Drinking Water Residues

D395021, C. Koper, 1/9/12 

EFED provided ground and surface water EDWCs for triflumizole. 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 1 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 residues of concern. Detailed information on 

how the individual modeling input parameters were derived can be obtained from the “Tier I 

Estimated Drinking Water Concentrations for Triflumizole Including Degradates” memo (S. 

Ramasamy, March 3, 2002) (D281356).
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Table 1.Summary of Estimated Surface Water and Groundwater Concentrations for Triflumizole.

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

Acute 85 3.1

Chronic (non-cancer) 21 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.

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 02-SEP2011. Although BEAD provided maximum and average %CT information, only the chronic 

dietary risk assessment required the percent crop treated refinement; therefore, only the average 

%CT values were utilized in the dietary exposure analysis. 

Acute Dietary Risk Assessment

D397935, W. Donovan, 3/28/12

The results of the acute dietary risk analysis are reported in Table 2. The acute dietary (food + 

drinking water) exposure assessment used tolerance-level residues and 100% CT for all 

registered crops; thus, the acute dietary analysis may be considered an unrefined assessment. 

Drinking water was incorporated directly in the dietary assessment using the maximum 

concentration for surface water generated by the PRZM/EXAMS model. These assessments 

demonstrate that the acute dietary risk estimates (95th percentile) are not of concern (<100% 

aPAD) for the general U.S. population (26% aPAD, 0.065598 mg/kg/day) and all population 

subgroups. Children 1-2 years old was the most highly exposed population subgroup at 39% 

aPAD and 0.096453 mg/kg/day. Exposure was equivalent to 0.068075 mg/kg/day or 68% of the 

aPAD for females 13-49 years old.

Chronic Dietary Risk Assessment

D397935, W. Donovan, 3/28/12

The results of the chronic dietary exposure analysis are reported in Table 2. The chronic dietary 

exposure assessment used anticipated residues (ARs; average field trial values) for most crops 

and tolerance level residues for hazelnuts. The assessment used % CT information for apples, 

cantaloupes, cherries, cucumbers, grapes, hazelnuts (filberts), honeydew melons, pears, 

pumpkins, squash, strawberries, and watermelons; and 100% CT for all other crops. Thus, the 

chronic dietary analysis may be considered a partially refined assessment. The chronic dietary 

(food + drinking water) risk assessment was conducted for the general U.S. population and 

various population subgroups. Drinking water was incorporated directly into the dietary 

assessment using the chronic (annual average) concentration for surface water generated by the 

PRZM/EXAMS model. This assessment concludes that the chronic dietary risk estimates are 
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below the Agency’s level of concern (<100% cPAD) for the general U.S. population (19% 

cPAD) and all population subgroups. The most highly exposed population subgroup is children 

1-2 years old at 32% cPAD.

Table 2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Triflumizole.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancera

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.065598 26 0.002274 19

N/A N/A

All Infants (< 1 year old) 0.041970 17 0.002517 22

Children 1-2 years old 0.096453 39 0.003785 32

Children 3-5 years old 0.086183 34 0.003259 28

Children 6-12 years old 0.067224 27 0.002189 19

Youth 13-19 years old 0.055321 22 0.001771 15

Adults 20-49 years old 0.065771 26 0.002211 19

Adults 50+ years old 0.060108 24 0.002236 19

Females 13-49 years old 0.068075 68 0.002168 19

a

 Because triflumizole is not a carcinogen, no cancer risk assessment was conducted.

Residential Risk Assessment

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 Handler Exposure

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

handler activities associated with use on ornamental plants. The results of the residential handler 

exposure and risk assessment are presented in Appendix C. The total short-term margins of 

exposure (MOEs) are not of concern (i.e. an MOE > 100) with baseline attire (shorts, shortsleeves, shoes and socks). 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.

Post-Application Exposure
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Post-application exposure from triflumizole use on landscape ornamentals 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 present, leaf to skin 

residue transfer would be negligible because of the minimal frequency and duration of contact. 

Based on the low frequency of application and low likelihood for significant post-application 

exposure, there are no residential risk concerns for post-application exposure. Therefore, a 

quantitative post-application residential exposure and risk assessment was not conducted. 

Aggregate Risk Assessment

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 

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.

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 2 above. The acute risk estimates are well below 

HED’s level of concern for all population subgroups.

Short-Term Aggregate Risk

The residential handler exposure from applying triflumizole using a hand held pump sprayer was 

the exposure scenario with the highest estimated risk, 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 3). 

Table 3. 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 0.002274 0.025 0.027 130

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)

Intermediate-Term Aggregate Risk
Triflumizole Human Health Risk Assessment DP No. 420633

Page 13 of 30

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

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

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 2 above. 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.

Occupational Risk Assessment

Short-/Intermediate-term Handler Risk

Triflumizole products can be applied to apples, pears, cherries, cucurbit vegetables, grapes, 

strawberries, hazelnuts, brassica leafy greens and for pre-plant treatment of pineapple seed pieces

for foliar disease control via airblast, groundboom, aircraft, dip tank, or chemigation. Handler 

exposure is expected to be short- or intermediate-term based on information provided on the 

labels. The labels state that all handlers must wear the proper personal protective equipment 

(PPE): a long-sleeved shirt, long pants, chemical resistant gloves, shoes, and socks. Based on this 

assessment, triflumizole’s labels need to be amended to include a requirement to wear chemical 

resistant hat for application with open cab air blast equipment in order to meet the target MOE of 

300. The MOE with the current label PPE recommendations (single layer and glove) is 230. 

The maximum application rate for each exposure scenario is presented as the worst case 

scenario. All handler scenarios (mixer/loader, applicator, and flagger) are considered to be short 

and intermediate-term. Both short- and intermediate-term total (dermal and inhalation) MOEs 

were above the target exposure levels of 100 and 300, respectively, and therefore do not exceed 

HED’s level of concern (Appendix C).

Short-/Intermediate-Term Post-Application 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 post application 

activities. The short-term Restricted Entry Interval (REI) for grapes (table and raisin) should be 

extended from the current REI (zero days) to 1 day, and 3 days for hops to achieve the target 

MOE ≥ 100. 

Inhalation Postapplication Risk

Although a quantitative occupational postapplication 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 
Triflumizole Human Health Risk Assessment DP No. 420633

Page 14 of 30

higher exposure than postapplication exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of occupational postapplication inhalation 

exposure scenarios. Since handler inhalation exposure is not of concern, post-application 

inhalation exposure is not of concern.

Restricted Entry Interval

For grapes (table and raisin) the short-term post-application risk estimates did not exceed HED’s 

LOC (i.e., MOEs ≥ 100) on day one. For wine grape reentry is acceptable on day zero. This is a 

change from the previous risk assessment due to revised ARTF data which was used to calculate 

exposure and risk at various reentry intervals. The activities with the highest estimated risk are 

mechanically assisted harvesting for hops and girdling for table and raisin grapes. The label 

REIs are currently based on the acute toxicity of technical chemical material. Under the Worker 

Protection Standard WPS, active ingredients classified as acute toxicity category III or IV for 

acute dermal and primary skin irritation are assigned a 12-hour REI. Thus, with the exception of 

hops and grapes (raisin and table only) the 12-hour REI on the triflumizole label is acceptable.

The post-application occupational exposure exceeds the Agency’s level of concern for grapes

(raisin and table only) at day zero. For all types of grapes and hops the target MOE ≥ 100; 

therefore, the current REI of zero days for table and raisin grapes and hops must be extended to 1

day and 3 days respectively to achieve risks below the Agency levels of concern.

Hops has a seven day Pre Harvest Interval (PHI), the restricted entry interval (3 days) for 

mechanically assisted harvesting may not be necessary since the longer PHI would provide the 

necessary restricted entry for this activity. 
Triflumizole Human Health Risk Assessment DP No. 420633

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Appendix A. Toxicity Profile and Endpoint Selection

Acute Toxicity Profile – Triflumizole

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

Subchronic, Chronic and Other Toxicity Profile

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
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Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

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

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.
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Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

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 

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.
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Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

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

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
Triflumizole Human Health Risk Assessment DP No. 420633

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Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

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). 

Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary and Non-Occupational Human 

Health Risk Assessments

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:UF

LOAEL→NOAEL

= 3x

Chronic RfD = 

0.0117

mg/kg/day

cPAD = 

0.0117mg/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).

Dermal Short-Term 

(1-30 days)

NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

Residential and 

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 (NOAEL = 3.5 

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 

(NOAEL = 3.5 mg/kg/day). 

Dermal Intermediateand Long-Term (1-6 

months and 6 months 

and longer)

LOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x 

UFLOAEL→NOA

EL= 3x

Residential and 

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).
Triflumizole Human Health Risk Assessment DP No. 420633

Page 20 of 30

Summary of Toxicological Doses and Endpoints for Triflumizole for Use in Dietary and Non-Occupational Human 

Health Risk Assessments

Inhalation ShortTerm (1-30 days)NOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

Residential and 

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 (NOAEL = 3.5 

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 

(NOAEL = 3.5 mg/kg/day).

Inhalation 

Intermediate- and 

Long-Term (1-6 

months and 6 months 

and longer)

LOAEL= 

3.5 

mg/kg/day

UFA= 10x

UFH= 10x

UFLOAEL→NOA

EL= 3x

Residential and 

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 on the absence of significant 

tumor increases in two adequate rodent carcinogenicity studies.
Triflumizole Human Health Risk Assessment DP No. 420633

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Appendix B: International Harmonization

Summary of US and International Tolerances and Maximum Residue Limits : Triflumizole (PC 

Code 128879) 

Residue Definition:

US Canada Mexico1 Codex

40 CFR §180.476 

Plant: 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

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

US Canada Mexico1 Codex

Apple 0.5 0.5

Apple, dry pomace 2.0

Apple, wet pomace 2.0

Brassica,head and stem, subgroup 

5A

8.0

Brassica, leafy greens, subgroup 

5B

40

Canistel 2.5

Cherry, sweet 1.5 1.5

Cherry, tart 1.5 1.5

Cilantro, leaves 35

Grape 2.5 2.5

Grape, dried pomace 15

Grape, raisin, waste 10

Grape, wet pomace 15

Hazelnut 0.05

Hop, dried cones 50

Leafy greens subgroup 4A, except 

spinach

35

Mango 2.5

Papaya 2.5

Pear 0.5 0.5

Pineapple 4.0

Sapodilla 2.5

Sapote, black 2.5

Sapote, mamey 2.5

Star apple 2.5

Strawberry 2.0 2.0

Swiss chard 18

Turnip,greens 40

Vegetable, cucurbit, group 9 0.5 0.5 balsam apples, balsam pears, cantaloupes, 

chayote fruit, Chinese cucumbers, Chinese 

waxgourds, citron melons, cucumbers, edible 

gourds (other than those listed in this item), 

muskmelons (other than those listed in this item) 

pumpkins, summer squash, watermelons, west 

Indian gherkins, winter squash
Triflumizole Human Health Risk Assessment DP No. 420633

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Summary of US and International Tolerances and Maximum Residue Limits : Triflumizole (PC 

Code 128879) 

Residue Definition:

US Canada Mexico1 Codex

40 CFR §180.476

Livestock: parent compound triflumizole, 1-

(1-((4-chloro-2-

(trifluoromethyl)phenyl)imino)-2-

propoxyethyl)-1 H -imidazole, the metabolite 

4-chloro-2-hydroxy-6-trifluoromethylaniline 

sulfate, and other metabolites containing the 4-

chloro-2-trifluoromethylaniline moiety, 

calculated as the parent compound

None None

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

US Canada Mexico1 Codex

Cattle, fat 0.5

Cattle, meat 0.05

Cattle, meat byproduct 0.5

Egg 0.05

Goat, fat 0.5

Goat, meat 0.05

Goat, meat byproduct 0.5

Hog, fat 0.5

Hog, meat 0.05

Hog, meat byproduct 0.5

Horse, fat 0.5

Horse, meat 0.05

Horse, meat byproduct 0.5

Milk 0.05

Poultry, fat 0.05

Poultry, meat 0.05

Poultry, meat byproduct 0.1

Sheep, fat 0.5

Sheep, meat 0.05

Sheep, meat byproduct 0.5

Completed: : M. Negussie; 02/16/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Triflumizole Human Health Risk Assessment DP No. 420633

Page 23 of 30

Appendix C. Residential and Occupational Exposure and Risk Estimates for Triflumizole

a. Based on registered labels 

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 

(80 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 (80 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

Table 1: Short-Term Residential Handler Exposure and Risk Estimates for Triflumizole

Exposure Scenario Target 

MOE

Dermal 

Unit 

Exposure

Inhalatio

n Unit 

Exposure

Maximum 

Application 

Rate a

Amount 

Treated or 

Handled 

Daily b

Dermal Inhalation Total 

Dose c MOE d Dose e MOE f

MOEg

Mixer/Loader/Applicator

M/L/A Broadcast Hand Held 

Pump Sprayer (Gardens) 100 38 0.0027 1 (lb ai/A) 1 A 0.017 210 0.000034 100,000 210

M/L/A Broadcast Application 

Hand Held Pump Sprayer 

(Fruit Trees and Ornamentals)

100 56 0.0038 1 (lb ai/A) 1 A 0.025 140 0.000048 7,4000 140

M/L/A Spot Treatment 

Hand Held Pump Sprayer for 

(Gardens) 

100 38 0.0027 1 (lb ai/A) 0.023 A 0.00038 9,200 7.8E-07 4,500,000 9,100

M/L/A Spot Treatment 

Hand Held Pump Sprayer 

(Fruit Trees and Ornamentals)

100 56 0.0038 1 (lb ai/A) 0.023 A 0.00056 6,200 0.0000011 3,200,000 6,200

M/L/A Hand Held Pump 

Sprayer (Gardens) 100 38 0.0027 0.0025 (lb ai/gal) 5 gal 0.00021 17,000 4.2E-07 8,300,000 17,000

M/L/A Hand Held Pump 

Sprayer (Fruit Trees and 

Ornamentals)

100 56 0.0038 0.0025 (lb ai/gal) 5 gal 0.00031 11,000 5.9E-07 5,900,000 11,000
Triflumizole Human Health Risk Assessment DP No. 420633

Page 24 of 30

Table 2: Short-/Intermediate- 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

Broccoli; Chinese Broccoli, 

Brussels Sprouts, Cabbage, 

Chinese Cabbage (Napa), 

Chinese Mustard Cabbage, 

Cauliflower, Cavalo 

Broccoli, And Kohlrabi, 

Cucumber, Gherkin, Gourds, 

Melons, Pumpkin, Squash 

,Apples, Pear, Cherry Leafy 

Greens(except spinach)

0.22

(single 

layer/no 

glove

0.000219 0.25 350 0.0084 420 0.00024 15,000 400

Hops 0.0376 

single 

layer/glove

0.375 0.0022 1,600 0.00036 9,700 1,400

Strawberry 0.22

(single 

layer/no 

glove

0.125 0.0042 830 0.00012 29,000 810

Hazelnut 0.19 0.0064 550 0.00018 19,000 530

Mixing/Loading 

Liquids for 

Chemigation 

Applications

Strawberry 0.125 0.0042 830 0.00012 29,000 810

Broccoli; Chinese Broccoli, 

Brussels Sprouts, Cabbage, 

Chinese Cabbage (Napa), 

Chinese Mustard Cabbage, 

Cauliflower, Cavalo 

Broccoli, And Kohlrabi], 

Cucumber, Gherkin, Gourds, 

Melons, Pumpkin, Squash, 

Leafy green (except spinach)

0.25 350 0.0084 420 0.00024 15,000 400

Mixing/Loading 

Liquids for 

Groundboom 

Applications

Broccoli; Chinese Broccoli, 

Brussels Sprouts, Cabbage, 

Chinese Cabbage (Napa), 

Chinese Mustard Cabbage, 

0.25 80 .0019 1,800 0.000055 64,000 1,800
Triflumizole Human Health Risk Assessment DP No. 420633

Page 25 of 30

Table 2: Short-/Intermediate- 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

Cauliflower, Cavalo 

Broccoli, And Kohlrabi, 

Cucumber, Gherkin, Gourds, 

Melons, Pumpkin, Squash 

Strawberry 0.125 0.00096 3,600 0.000027 130,000 3,500

Mixing/Loading 

Liquids for 

Airblast 

Applications

Apples, Pear, Cherry 0.5 40 0.0019 1,800 0.000055 64,000 1,800

Canistel, Mango, Papayas, 

Sapodilla, Sapote, Star apple 

0.31 0.0012 2,900 0.000034 100,000 2,900

Hazelnut (filbert) 0.19 0.00073 4,800 0.000021 170,000 4,700

Hops 0.375 0.0014 2,400 0.000041 85,000 2,400

Grape 0.25 0.00096 3,600 0.000027 130,000 3,500

Pineapple 0.005/lb/gal 100 gals 0.00048 73,000 0.0000014 2,600,00

0

71,000

Mixing/Loading 

Wettable 

Powders (WSP) 

for Aerial 

Applications

Apples, Pear 0.0098

(single 

layer/no 

glove with

water 

soluble 

packages

0.00024 0.5 350 0.00075 4,700 0.00053 6,700 2,700

Mixing/Loading 

Wettable 

Powders for 

Airblast 

Applications

Grape 0.17

Single 

layer/glove

0.0434 0.25 40 0.0075 4800 0.0055 640 600

Mixing/Loading 

Wettable 

Powders for 

Apples, Pear 0.17

single 

layer/glove

0.0434 0.25 0.0007 4700 0.0054 650 600
Triflumizole Human Health Risk Assessment DP No. 420633

Page 26 of 30

Table 2: Short-/Intermediate- 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

Airblast 

Applications

Mixing/Loading 

Wettable 

Powders (WSP) 

for Aerial 

Applications

Apples, Pear, Cherry 0.0098

water 

soluble 

packages

0.00024 0.5 350 0.00075 4,700 0.00053 6,700 2,700

Cucumber, Gherkin, Gourds, 

Melons, Pumpkin, Squash, 

Strawberries

0.25 0.00038 9,300 0.00026 13,000 5,500

Hazelnut 0.19 0.00029 12,000 0.0002 18,000 7,200

Hops 0.375 0.00056 6200 0.00039 8,900 3,700

Mixing/Loading 

Wettable 

Powders(WSP) 

for Airblast 

Applications

Grape 0.25 40 0.000043 82,000 0.00003 116,000 48,000

Hazelnut 0.19 0.000033 110,000 0.000023 150000 63,000

Apples, Pear, Cherry 0.50 0.000086 41000 0.00006 58,000 24,000

Mixing/Loading 

Wettable 

Powders (WSP) 

for 

Groundboom 

Applications

Cucumber, Gherkin, Gourds, 

Melons, Pumpkin, Squash, 

Strawberries

0.25 80 0.000086 41000 0.00006 58,000 24,000

Mixing/Loading 

Wettable 

powder (WSP) 

via Dip

Pineapple 0.005lb ai/gal 100gals 0.000021 160,000 0.000015 230,000 96,000
Triflumizole Human Health Risk Assessment DP No. 420633

Page 27 of 30

Table 2: Short-/Intermediate- 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

Mixing/Loading 

Dry Flowables 

for Airblast 

Applications

Apples, Pear 0.227 0.00896 0.25 40 0.0010 3,500 0.0011 3,100 1,700

Applicator

Applying 

Sprays via 

Aerial 

Equipment

Broccoli; Chinese Broccoli, 

Brussels Sprouts, Cabbage, 

Chinese Cabbage (Napa), 

Chinese Mustard Cabbage, 

Cauliflower, Cavalo 

Broccoli, And Kohlrabi, 

Cucumber, Gherkin, Gourds, 

Melons, Pumpkin, Squash 

,Apples, Pear, Cherry , Leafy 

Greens(except spinach) , 

strawberry

0.005

eng. control

0.000068 0.25 350 0.00019 18,000 0.000074 47,000 13,000

Hops 0.375 0.00029 12,000 0.00011 31,000 8,800

Hazelnut 0.19 0.00015 24,000 0.000057 62,000 17,000

Applying 

Sprays via 

Groundboom 

Equipment

Broccoli; Chinese Broccoli, 

Brussels Sprouts, Cabbage, 

Chinese Cabbage (Napa), 

Chinese Mustard Cabbage, 

Cauliflower, Cavalo 

Broccoli, And Kohlrabi, 

Cucumber, Gherkin, Gourds, 

Melons, Pumpkin, Squash , 

Strawberry 

0.0786

open cab

0.00034 0.25 80 0.0007 5,100 0.000085 41,000 4,500

Applying 

Sprays via 

Apples, Pear, Cherry 0.215

glove/chemi

0.00471 0.5 40 0.0019 1,900 0.0012 3,000 1,100

Grape 0.25 0.00095 3,800 0.0006 6,000 2,200
Triflumizole Human Health Risk Assessment DP No. 420633

Page 28 of 30

Table 2: Short-/Intermediate- 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

Open Cab Air 

blast 

Equipment

Canistel, Mango, Papayas, 

Sapodilla, Sapote, Star apple 

cal resistant 

hat

0.31 0.0012 3,000 0.00073 4,800 1,800

Hazelnut (filbert) 0.19 0.00071 4,900 0.00045 7,800 3,000

Flagger

Flagging for 

Aerial Sprays 

Applications

All Crops 0.011 0.00035 0.5 350 0.0084 4,200 0.0077 4,600 2,200

Mixer/loader/Applicator

Mixing/Loading

/App 

Mixing/Loading

/App Wettable 

Powder with 

Mechanicallypressurized 

Handgun 

(ORETF)

Ornamentals 1.3

single 

layer/glove

0.0039 0.005lb ai/gal 1000gals 0.0028 1200 0.0002 11000 1100

Orchard crops 0.5 40 acres 0.011 310 0.0010 3600 300

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)

Applicator with open cab air blast equipment on grapes, apple, pear and cherry must wear a chemical resistant hat to achieve the target 

MOE ≥ 300. The MOE with the current label PPE recommendations (single layer and glove) is 230. 
Triflumizole Human Health Risk Assessment DP No. 420633

Page 29 of 30

 Table 3: Dermal Post-application Exposure and Risk Using Chemical-Specific DFR Data.

Crop 

Group

Proposed 

Crop

Highest Transfer 

Coefficient for 

Crop (cm2/hr) 

and Associated 

Activity

Days after 

Treatment

Study 

Test 

Site

Chemical-specific DFRa

(ug/cm2)

Dermal Doseb

(mg/kg/day)

ShortTerm

MOEc

IntermediateTerm MOEc

Short -

Term

IntermediateTermShort -

Term

IntermediateTerm

Deciduous 

tree fruit

Apple, Pear, 

Cherry

Thinning fruit

(3600) 0

CA

0.563 0.130

0.014 0.003 250 1100

Evergreen 

tree fruit

Canistel, 

Mango, 

Papayas, 

Sapodilla, 

Sapote, Star 

apple 

Thinning fruit

(3600) 0

CA 0.009 0.002 400 1700

Brassica

Broccoli; 

Chinese 

Broccoli, 

Brussels 

Sprouts, 

Cabbage, 

Chinese 

Cabbage 

(Napa), 

Chinese 

Mustard 

Cabbage, 

Cauliflower, 

Cavalo 

Broccoli, 

And 

Kohlrabi

Hand harvesting

(4200) 0

CA 0.0083 0.0019 420 1800

Cucurbit 

vegetables

Cucumber, 

Gherkin, 

Gourds, 

Melons, 

Pumpkin, 

Squash

Irrigation

(1900) 0

CA 0.0037 0.0009 930 4000
Triflumizole Human Health Risk Assessment DP No. 420633

Page 30 of 30

 Table 3: Dermal Post-application Exposure and Risk Using Chemical-Specific DFR Data.

Crop 

Group

Proposed 

Crop

Highest Transfer 

Coefficient for 

Crop (cm2/hr) 

and Associated 

Activity

Days after 

Treatment

Study 

Test 

Site

Chemical-specific DFRa

(ug/cm2)

Dermal Doseb

(mg/kg/day)

ShortTerm

MOEc

IntermediateTerm MOEc

Short -

Term

IntermediateTermShort -

Term

IntermediateTerm

Leafy 

vegetable

Leafy 

Vegetable 

(except 

spinach)

Hand weeding

(4200) 0

CA

0.0083 0.0019 420 1800

Berry low Strawberry Irrigation (1900) 0 0.004 0.001 930 4000

Tree nut Hazelnut 

(filbert)

Thinning

(3600) 0 0.005 0.001 650 2800

Bunch and 

bundle Hops

Mechanically 

assisted 

harvesting(19,300)

3

d 0.034 0.011 100

Day 3

330

Day 1

Vine/trellis Grapes

Girdling, 

Turning(19,300) for 

table and raisin 

grapes

1 0.035 0.009 100

Day 1

400

Day 0

Tying/Training/Hand 

harvesting for wine 

grapes (10,100)

0 0.023 0.005 150

Day 0

760

Day 0

a. Chemical- specific DFR = day zero predicted grape vine DFR data adjusted for application rate (0.375 for hops) are 0.563 ug/cm2 and 0.84 ug/cm2 and used 

for short –term exposure estimates. The predicted grape vine average -21 days residue data was adjusted for application rate (0.375 lb ai/A for hops and 0.25 lb 

ai/A for grapes) are 0.130 ug/cm2for grapes and 0.20 ug/cm2 for hops used for intermediate-term exposure estimates. 

b. Dermal Dose = [DFR (ug/cm2) x TC (cm2/hr) x 0.001 mg/ ug x DAF (3.5%) x 8 hrs/day]  body weight (69 kg short- term, 80 kg Intermediate term).

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

d Hops has a seven day Pre Harvest Interval (PHI), the restricted entry interval (3 days) for mechanically assisted harvesting may not 

be necessary since the longer PHI would provide the necessary restricted entry for this activity.