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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 16-December-2014

Subject: Flutriafol: Human Health Risk Assessment in Support of Tolerance for Residues in/on 

Cotton; Grain Sorghum; Leafy Vegetables, Except Brassica, Crop Group 4; and 

Brassica Leafy Vegetables Crop Group 5. 

PC Code: 128940 DP Barcode: D415849

Decision No.: 482872 Registration Nos.: 67760-75 and 67760-120

Petition No.: 3F8199 Regulatory Action: Section 3 Registrations

Risk Assessment Type: single chemical Case No.: 7060

TXR No.: not applicable CAS No.: 76674-21-0

MRID No: not applicable 40 CFR: 180.629

From: Tom Bloem, Chemist

Kelly M. Lowe, Environmental Scientist

Anwar Y. Dunbar, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

Through: Charles W. Smith III, Branch Chief

George F. Kramer, Ph.D., Senior Chemist

RAB1/HED (7509P)

To: Hope Johnson/Tamue Gibson, RM 21

Registration Division (RD; 7505P)

HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. RD of OPP 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 all registered 

and proposed uses of flutriafol ((±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-

ethanol). A summary of the findings and an assessment of human health risk resulting from the 

registered and proposed uses for flutriafol are provided in this document. The aggregate risk 

assessment, dietary risk assessment, and residue chemistry review were provided by Tom Bloem

(RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), the 

occupational/residential exposure (ORE) and risk assessment were provided by Kelly Lowe

(RAB1), and the drinking water assessment was provided by James K. Wolf of the 

Environmental Fate and Effects Division (EFED).
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Table of Contents

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

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

2.1 Data Deficiencies/Data Needs.........................................................................................................................6

2.2 Tolerance Considerations................................................................................................................................7

2.2.1 Enforcement Analytical Method .........................................................................................................7

2.2.2 Recommended Tolerances...................................................................................................................7

2.2.3 Revisions to Petitioned-For Tolerances...............................................................................................8

2.2.4 International Harmonization................................................................................................................8

2.3 Label Recommendations.................................................................................................................................8

3.0 Ingredient Profile ..............................................................................................................................................9

3.1 Chemical Identity ............................................................................................................................................9

3.2 Physical/Chemical Properties..........................................................................................................................9

3.3 Proposed Use Pattern ....................................................................................................................................10

3.4 Anticipated Exposure Pathways.................................................................................................................11

3.5 Consideration of Environmental Justice........................................................................................................11

4.0 Hazard Characterization and Dose-Response Assessment..............................................................................12

4.1 Absorption, Distribution, Metabolism, & Elimination (ADME)...................................................................12

4.2 Toxicological Effects ....................................................................................................................................13

4.3 Safety Factor for Infants and Children (FQPA SF).......................................................................................14

4.3.1 Completeness of the Toxicology Database........................................................................................14

4.3.2 Evidence of Neurotoxicity.................................................................................................................14

4.3.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ....................................14

4.3.4 Residual Uncertainty in the Exposure Database................................................................................15

4.4 Toxicity Endpoint and POD Selections.........................................................................................................15

4.5 Recommendation for Combining Routes of Exposure for Risk Assessment ................................................16

5.0 Dietary Exposure and Risk Assessment..........................................................................................................18

5.1 Metabolite/Degradate Residue Profile ..........................................................................................................18

5.2 Food Residue Profile.....................................................................................................................................18

5.3 Drinking Water Residue Profile ....................................................................................................................19

5.4 Dietary (Food + Drinking Water) Risk Assessment......................................................................................20

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ..................................................................21

6.1 Spray Drift.....................................................................................................................................................21

6.2 Residential Bystander Post-Application Inhalation Exposure.......................................................................21

7.0 Aggregate Exposure/Risk Characterization ....................................................................................................22

8.0 Cumulative Exposure/Risk Characterization ..................................................................................................22

9.0 Occupational Exposure/Risk Characterization................................................................................................23

9.1 Handler Risk Assessment..............................................................................................................................23

9.2 Post-Application Risk Assessment................................................................................................................25

9.2.1 Inhalation Post-Application Risk Assessment...................................................................................25

9.2.2 Restricted Entry Interval....................................................................................................................27

Appendix A. Toxicology Profile and Executive Summaries......................................................................................28

Appendix B. Chemical Names and Structures............................................................................................................34
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1.0 Executive Summary

Flutriafol ((±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethanol) is a contact and 

systemic Group 3 triazole fungicide which acts primarily as an inhibitor of ergosterol biosynthesis, 

thereby interfering with synthesis of fungal cell membranes. Tolerances for residues of flutriafol 

are established in/on numerous commodities, including livestock commodities, at 0.01-30 ppm. A 

Section 18 Emergency Exemption has also been granted for application of flutriafol to cotton with 

time-limited tolerances of 0.35-0.50 ppm (tolerances expire on 31-Dec-2014). 

Cheminova, Inc. requested Section 3 Registrations and the establishment of permanent tolerances 

for residues of flutriafol in/on cotton; grain sorghum; leafy vegetables, except Brassica, crop group 

4; and Brassica leafy vegetables crop group 5. In addition, the petitioner is requesting the 

establishment of permanent tolerances in/on egg and several livestock commodities (see Table 

2.2.2.1 for proposed tolerances). 

Hazard Assessment: Flutriafol is categorized as having high oral acute toxicity in the mouse 

(Category II). It has low acute toxicity via the oral, dermal and inhalation routes (Categories III, 

III, and IV, respectively) in rats. It is minimally irritating to the eyes (Category III) and is not a 

dermal irritant (Category IV). Flutriafol was not shown to be a skin sensitizer when tested in 

guinea pigs (Buehler method). 

Short-term, subchronic, and chronic flutriafol toxicity studies in rats, mice, and dogs identified the 

liver as the target organ. Hepatotoxicity occurred at similar dose levels across several species and 

durations of exposure. 

The potential impact of in utero and perinatal flutriafol exposure was investigated in three 

developmental toxicity studies (two in rats, one in rabbits) and two multi-generation reproduction 

toxicity studies in rats. In the first of two rat developmental toxicity studies, increased quantitative 

susceptibility was observed with developmental effects (delayed ossification or non-ossification of 

the skeleton in the fetuses) seen at a lower dose than maternal effects. In the second rat 

developmental study, a qualitative susceptibility was noted. Although developmental toxicity

occurred at the same dose level that elicited maternal toxicity, the developmental effects (external, 

visceral, and skeletal malformations; embryo lethality; skeletal variations; a generalized delay in 

fetal development; and fewer live fetuses) were more severe than the decreased food consumption 

and body-weight gains observed in the dams. For rabbits, intrauterine deaths occurred at a dose 

level that also caused adverse effects in maternal animals. In the two-generation reproduction 

studies, a qualitative susceptibility was also seen. Effects in the offspring [decreased litter size and

percentage of live births (increased pup mortality) and liver toxicity] can be attributed to the 

systemic toxicity of the parental animals (decreased body weight and food consumption and liver 

toxicity).

Effects that may be considered signs of neurotoxicity (decreased motor activity and hindlimb grip 

strength, ptosis, lost righting reflex, hunched posture, and ataxia) were reported in the acute and 

subchronic neurotoxicity studies at the highest dose only. These effects, however, were primarily 

seen in animals that were agonal (at the point of death) and, thus, are not indicative of 

neurotoxicity. This conclusion is further reinforced by the observation that there was no evidence 

of neurotoxicity in any additional short-term or long-term studies in rats, mice, and dogs. It is also 

important to note that in the acute neurotoxicity study, for animals that did not die in the study or 

were sacrificed in extremis, all effects resolved by Day 8.
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In the guideline immunotoxicity study for flutriafol, there was no evidence of immunotoxicity up 

to the highest dose tested.

All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. 

Several triazoles are carcinogenic. Flutriafol is classified as “not likely to be carcinogenic to 

humans” based on the results of the carcinogenicity studies in rats and mice. 

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The flutriafol risk assessment 

team concludes that the 10x FQPA SF should be reduced to 1x since the toxicology database is 

adequate for assessment of the proposed/registered uses, flutriafol is not considered to be neurotoxic, 

there are clear no-observed adverse-effect levels (NOAELs) for the observed fetal/offspring effects, 

and the conservative nature of the dietary exposure analyses are unlikely to underestimate exposure 

(tolerance-level residues and 100% crop treated; no residential uses).

Dose Response Assessment: Tables 4.4.1 and 4.4.2 provides a summary of toxicological doses and 

endpoints used for assessment of dietary and occupational exposure, respectively, to flutriafol. The 

rabbit developmental study (NOAEL = 7.5 mg/kg/day) was selected for assessment of acute dietary

(females 13-49 years old) and short-/intermediate-term occupational dermal/inhalation exposures. 

The neurotoxicity screening battery (NOAEL = 250 mg/kg/day) study was selected for assessment 

of acute dietary (all populations excluding females 13-49 years old) exposure. The chronic toxicity

(dog) study was selected for assessment of chronic dietary exposure (NOAEL = 5 mg/kg/day). For 

all exposure scenarios, a 100x uncertainty factor (UF) was applied (10x interspecies extrapolation; 

10x for intraspecies variation; 1x FQPA SF (when applicable)). 

Dietary Risk Estimates (Food + Drinking Water): Acute and chronic aggregate dietary (food and 

drinking water) exposure and risk assessments were conducted using the Dietary Exposure 

Evaluation Model - Food Consumption Intake Database (DEEM-FCID, ver. 3.16) which 

incorporates the food consumption data from the United States Department of Agriculture (USDA) 

National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA; 

2003-2008). The acute and chronic analyses assumed tolerance-level residues or tolerance-level 

residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and 

modeled drinking water estimates. Since adequate processing studies have been submitted which 

indicate that tolerances for residues in/on apple juice, grape juice, dried prunes, and tomato puree are 

unnecessary and since tolerances for residues in/on raisins and tomato paste are established, the 

DEEM (ver. 7.81) default processing factors for these commodities were reduced to 1. The DEEM

(ver. 7.81) default processing factors were retained for the remaining relevant commodities. The 

resulting acute (≤44% acute population-adjusted dose (aPAD); females 13-49 years occupied the 

highest % of the aPAD) and chronic (≤74% cPAD; children (1-2 years old) had the highest 

exposure) dietary risk estimates are not of concern to HED. 

Residential (Non-Occupational) Exposure and Risk Assessment: There are no residential uses 

proposed or currently registered for flutriafol. Therefore, residential handler and post-application 

exposure/risk were not assessed. 
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Aggregate-Risk Estimates: In accordance with FQPA, HED must consider and aggregate pesticide 

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

Because there are no uses for flutriafol that result in residential (non-occupational) exposures, the 

aggregate assessment need only consider food and drinking water. Since the dietary exposure 

analysis included both food and drinking water, the discussion and exposure estimates presented in 

the dietary section represent aggregate acute and chronic exposure to flutriafol and those metabolites 

identified as being toxicologically identical to flutriafol. All aggregate flutriafol risk estimates are not 

of concern to HED. 

Application of flutriafol also results in exposure to T (1,2,4-triazole), TA (triazolylalanine), TAA

(triazolylacetic acid), and TLA (triazole lactic acid). These compounds are considered to be 

toxicologically different from flutriafol. HED previously conducted an aggregate exposure analysis 

for these compounds, which resulted in aggregate exposure less than HED’s level of concern 

(D414952, T. Morton, 24-Oct-2013). The proposed new uses and label amendments do not require a 

revision to this most recent aggregate assessment. 

Occupational Exposure and Risk Assessment: A quantitative assessment of occupational exposure 

has been conducted for all of the proposed uses. The occupational handler exposure and risk 

estimates for the remaining crops indicate that the short- and intermediate-term dermal and inhalation 

combined margins of exposure (MOEs) are not of concern to HED (i.e., MOE > 100) with the use of 

chemical-resistant gloves as directed by the label. At the baseline level of personal protection (i.e., no 

gloves and no respirator), only one scenario results in a risk estimate below the level of concern 

(LOC) with a combined (dermal + inhalation) MOE of 82; this scenario is mixing/loading a liquid 

formulation for aerial application to high-acreage crops. With the addition of gloves, the combined 

dermal + inhalation MOE is 470, which is not of concern. All other scenarios result in risk estimates 

greater than 220 with baseline attire.

The occupational post-application dermal exposure and risk estimates are greater than the LOC on the 

day of application with MOEs ranging from 230 to 4,600 depending on crop and activity. Since the 

post-application assessment is not a concern on Day 0 (12 hours following application), the restrictedentry interval (REI) is based on the acute toxicity of flutriafol technical material. Flutriafol has low 

acute toxicity via the oral, dermal and inhalation routes (Toxicity Categories III and IV), is minimally

irritating to the eyes (Toxicity Category III), and is not a dermal irritant (Toxicity Category IV). 

Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method). 

Therefore, the acute toxicity categories for this chemical require a 12-hour REI under 40 CFR 

156.208 (c)(2)(iii). The 12-hour REI, which currently appears on the labels, is adequate for the 

proposed uses.

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

inhalation exposure assessment was not performed for flutriafol at this time. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational postapplication inhalation exposure assessment for flutriafol.

Environmental Justice Considerations: 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.”
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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 Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler 

Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (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 following Agency websites: http://www.epa.gov/ 

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

2.0 Recommendations

Provided revised Sections B and F are submitted, HED concludes that the toxicological, residue 

chemistry, and ORE databases support the establishment of the proposed Section 3 Registrations and 

the permanent tolerances listed in Section 2.2.2. 

2.1 Data Deficiencies/Data Needs

Residue Chemistry: The following field rotational crop residue data conducted as specified in 

OPPTS 860.1900 are requested (trials should employ a seasonal rate of 0.228 lb ai/acre): sweet corn 

- NAFTA Growing Zones 1 (n=2), 3 (n=1), 10 (n=1), 11 (n=1), and 12 (n=1); cotton - North

American Free Trade Agreement (NAFTA) Growing Zones 6 (n=1), 8 (n=4), and 10 (n=3). These 

data were previously requested and remain outstanding (D397075, T. Bloem, 20-Dec-2011). If the 

petitioner would like to permit rotation to sweet corn and cotton following application at a higher rate 

and/or different interval, then a full set of field rotational crop data conducted at the desired rate and 

interval should be submitted. The additional data are requested to ensure that the resulting rotational 

crop tolerances are reflective of conditions for growers in all relevant regions. Based on the existing 

sweet corn and cotton field rotational crop residue data (residues ≤0.035 ppm) and the unrefined 

nature of the current dietary exposure analyses (≤44% aPAD; ≤74% cPAD), HED concludes that the 

requested data will not have a significant effect on the human health risk assessment. 

In addition, the ruminant feeding study monitored for residues of only flutriafol with the residues of 

concern (ROC) for risk assessment estimated using factors derived from the ruminant metabolism 

study. The factors range from 2-77x and reflect the fact that parent was not the major residue in some 

of the matrices. In order to facilitate refinements in the dietary exposure analysis which may be 

necessary as part of future registrations, HED advises the petitioner to analyze the ruminant feeding 

study samples for some or all of the ROC for risk assessment (storage stability data will also be 

required). HED notes that the ruminant residue estimates employed in the dietary analyses are 

conservative as they are comparable to, or significantly higher than, the TRRs from the metabolism 

study (30-ppm dietary burden) and due to the conservative nature of the dietary burden calculations. 
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Tolerance Enforcement Method - Plants: Adequate methods are available to enforce the 

currently established plant tolerances (D362421, T. Bloem, 11-Mar-2009; D340513, T. Bloem, 

11-Mar-2009; D388603, T. Bloem, 16-Jun-2011). The flutriafol method employed in the 

magnitude of the residues studies is based on the current tolerance enforcement method. Since 

adequate method validation data were provided as part of the magnitude of the residue studies, 

HED concludes that the current tolerance enforcement method is adequate to enforce the 

tolerances associated with this petition. In addition, the QuEChERS method has been shown to 

adequately quantify residues of flutriafol (http://www.crlpesticides.eu/library/docs/fv/CRLFV_Multiresidue_methods.pdf). 

Tolerance Enforcement Method - Livestock: Method ICIA AM00306 (revisions of 13-Aug2007 and 8-Oct-2007) has been determined to be sufficient for enforcement of the currently

established ruminant tolerances (D362421, T. Bloem, 23-Apr-2014). The flutriafol method 

employed in the ruminant (49059703.der) and poultry (47510201.der1) magnitude of the residue 

studies are based on this method. Since adequate method validation data were provided as part 

of these studies, HED concludes that the current tolerance enforcement method is adequate to 

enforce the tolerances associated with this petition. 

2.2.2 Recommended Tolerances

Table 2.2.2.1 is a summary of the proposed and HED-recommended tolerances for residues of 

flutriafol per se. A revised Section F is requested. With the establishment of the cotton 

tolerances listed in Table 2.2.2.1, the cotton tolerances established in 40 CFR 180.629(d) for 

residues resulting from crop rotation should be deleted. HED notes that cotton tolerances are also 

established in 40 CFR 180.629(b) as a result of Section 18 emergency exemptions (expire on 31-

Dec-2014). HED recommends allowing these tolerances to expire rather than deleting them. 

Table 2.2.2.1: Tolerance Summary.

Commodity

Proposed 

Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments

40 CFR 180.629(a)

cotton, undelinted seed 0.5 0.50

Based on the available data and the OECD tolerance-calculation procedure, 

the indicated tolerances are appropriate. 

cotton, gin byproducts 5.0 6.0

sorghum, grain, forage 2.0 2.0

sorghum, grain, grain 1.5 1.5

sorghum, grain, stover 6.0 6.0

grain, aspirated fractions 6.0 6.0

Brassica, head and stem,

crop subgroup 5A 1.5 1.5

Brassica, leafy greens, crop 

subgroup 5B 7.0 7.0
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Table 2.2.2.1: Tolerance Summary.

Commodity

Proposed 

Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments

40 CFR 180.629(a)

leaf petioles (subgroup 4B) 3.0 --

Based on the available head lettuce, leaf lettuce, spinach, and celery residue 

data and the OECD tolerance-calculation procedure, tolerances of 1.5 ppm, 

5.0 ppm, 10 ppm, and 3.0 ppm, respectively, were determined to be 

appropriate (these are the representative crops for crop group 4). The 

celery, spinach, and head lettuce data are sufficiently similar to set a crop 

group 4 tolerance at 10 ppm (residues/tolerances were within 5x). 

However, setting a head lettuce tolerance at 10 ppm, and by extension 

radicchio, would be at a level which is too high to allow for label 

enforcement (tolerance/residues >5x; head lettuce represents only radicchio 

in crop group 4 - HED Standard Operating Procedure (SOP) 2000.1). 

Based on the OECD tolerance calculation procedures and the unique 

morphology of head lettuce and radicchio as compared to the other corps in 

the group, HED concluded that a crop group tolerance, except head lettuce 

and radicchio, at 10 ppm and head lettuce and radicchio tolerances at 1.5 

ppm, were appropriate. 

leafy greens (subgroup 4A), 

except head lettuce 10 --

vegetable, leafy, except 

Brassica, crop group 4, 

except head lettuce and 

radicchio

-- 10

lettuce, head 1.5 1.5

radicchio 1.5 1.5

poultry, meat byproducts 0.02 0.01

Based on the current MRDB and the results of the feeding studies, HED 

concludes that the indicated tolerances are appropriate. 

poultry, fat -- 0.01

egg 0.01 0.01

liver (cattle, goat, horse, 

sheep) -- 1.0

milk -- 0.02

hog, liver 0.05 --

hog, meat byproducts, 

except liver 0.02 --

hog, meat byproducts -- 0.05

hog, muscle 0.01 --

A tolerance of 0.01 ppm was recommended as part of an earlier petition 

(D415068, T. Bloem, 23-Apr-2014).

2.2.3 Revisions to Petitioned-For Tolerances

See the comments column of Table 2.2.2.1. 

2.2.4 International Harmonization

There are no Canadian, Codex, or Mexican maximum residue limits (MRLs) in/on the proposed 

commodities; therefore, tolerance harmonization is not an issue for this petition. 

2.3 Label Recommendations

A revised Section B is requested which specifies “grain sorghum” rather than “sorghum,” a 

maximum application rate for grain sorghum of 2 x 0.114 lbs ai/acre, a 30-day preharvest 

interval (PHI) for grain sorghum forage/grain/stover, and the following rotational crop 

restrictions: (1) application rates ≤0.228 lbs ai/acre/season - labeled crops may be planted 

immediately and cotton and sweet corn may be planted 180 days after application (rotation to 

any other crop is prohibited) and (2) application rates >0.228 lbs ai/acre/season - treated field 

may only be rotated to a labeled crop. 
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3.0 Ingredient Profile

3.1 Chemical Identity

The chemical structure and nomenclature of flutriafol and the triazole metabolites are presented 

in Tables 3.1.1. 

Table 3.1.1: Flutriafol Nomenclature.

Chemical structure

Common name Flutriafol

Company experimental name PP450 (ICI/Syngenta until 2001); CHA 1310-05 (Cheminova code)

IUPAC name (RS)-2,4’-difluoro-α-(1H-1,2,4-triazol-1-ylmethyl)benzhydryl alcohol

CAS name (±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethanol

CAS registry number 76674-21-0

1,2,4-triazole (T)

triazolylalanine (TA) triazolylacetic Acid (TAA)

3.2 Physical/Chemical Properties

Table 3.2.1 is a summary of the physical/chemical properties for flutriafol. Flutriafol has a low 

vapor pressure and a low Henry’s law constant (9.16 x 10-12 atm m3/mol).

Table 3.2.1: Physicochemical Properties of Flutriafol.

Melting point/range -- Not available

pH 6.1 in a 1% aqueous dilution CSF for Flutriafol Technical dated 3/23/07 Density 0.99 g/cm3

Water solubility 95 mg/L at 20 oC

PP#7F7197 administrative materials

Solvent solubility

At 21 oC g/L

1,2-Dichloroethane 19-20

Acetone 116-135

Ethyl acetate 29-34

Methanol 115-134

n-Heptane <10

Xylene <10

Vapor pressure 4 x 10-7Pa at 20 oC

Dissociation constant, pKa 2.3 at 25 oC

Log(KOW) log POW = 2.3 at 20 oC

UV/visible absorption spectrum -- Not available

N N

N

F

OH

F

HN

N

N

N

N

N

HO

NH2

O

N

N

N

HO

O
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3.3 Proposed Use Pattern

Cheminova requested Section 3 Registrations for application of flutriafol to cotton; sorghum; 

leafy vegetables, except Brassica, crop group 4; and Brassica leafy vegetables crop group 5. 

Table 3.3.1 is a summary of the end-use products and target pests and Table 3.3.2 is a summary

of the proposed application scenarios. The proposed labels also specify the following: (1) 

application through irrigation is prohibited; (2) treated fields may be rotated to a labeled crop 

immediately after application and to sweet corn 180 days after application; rotation to any other 

crop is not allowed; (3) adjuvants may be added to the spray solution; (4) for ground application, 

the minimum spray volume is 10 gallons per acre (GPA) for all except at-planting soilapplication to cotton where a spray volume of 6-10 GPA is indicated; for aerial application, the 

minimum spray volume is 5 GPA; (5) applicators and other handlers must wear long-sleeved 

shirt and long pants, chemical-resistant gloves, and shoes plus-socks; and (5) a 12-hour REI is 

specified for the proposed crops. . 

Provided a revised Section B is submitted which specifies “grain sorghum” rather than 

“sorghum,” a maximum application rate for grain sorghum of 2 x 0.114 lbs ai/acre, a 30-day PHI 

for grain sorghum forage/grain/stover, and the following rotational crop restrictions, HED 

concludes that the proposed application scenarios are supported by the available data: (1) 

application rates ≤0.228 lbs ai/acre/season - labeled crops may be planted immediately and 

cotton and sweet corn may be planted 180 days after application (rotation to any other crop is 

prohibited) and (2) application rates >0.228 lbs ai/acre/season - treated field may only be rotated 

to a labeled crop. 

Table 3.3.1: Summary of End-Use Products.

Trade Name Conc. Formulation Label Date Target Crops Target Pests

Topguard® 

Fungicide

(EPA Reg. No. 

67760-75)

1.04 lb 

ai/gal

suspension 

concentrate 

(SC)

not 

indicated

cotton (foliar 

application only)

Alternaria leaf spot, boll rot (Alternaria spp.); Anthracnose 

boll rot (Glomerella spp.); Asochyta blight, boll rot (Ascochyta 

gossypii); Cercospora blight and leaf spot (Cercospora spp.); 

Diplodia boll rot (Diplopia spp.); Fusarium boll rot (Fusarium

spp.); Phoma blight, boll rot (Phoma spp.); Rust (Puccinia spp. 

And Phykopsora spp.); Stemphyllium leaf spot (Stemphyllium

spp.); and Target Spot (Corynespora cassiicola)

grain sorghum

Anthracnose leaf blight (Colletotrichum graminicola); Ergot 

(Claviceps sorghi); Gray Leaf Spot (Cercospora sorghi); Leaf 

blight (Exserohilum turcicum; Setosphaeria turcica); Common 

rust (Puccinia purpuria); Ladder leaf spot (Cercospora 

fusimaculans); Rough spot (Ascochyta sorghi); Sooty stripe 

(Ramulispora sorghi); Target leaf spot (Bipolaris cookei); and 

Aonate leaf spot and sheath blight (Gloecercospora sorghi)

Flutriafol®

250 g/L 

Fungicide

(EPA Reg. No. 

67760-120)

2.08 lb 

ai/gal

suspension 

concentrate 

(SC)

not 

indicated

leafy vegetables 

(except Brassica) 

group 4

Alternaria leaf spot (Alternaria sonchi); Anthracnose 

(Microdochium panattonianum, Colletotrichum dematium); 

Cercospora leaf spot, early blight (Cercospora spp.); Powdery 

mildew (Eyrisiphe cichoracearum); Septoria leaf spot 

(Septoria petroselini); and Late blight (Septoria apiicola) 

Brassica leafy 

vegetables group 5

Black spot (Alternaria spp.), Cercospora leaf spot (Cercospora

spp.), Powdery Mildew (Erysiphe polygoni)

Flutriafol®

500 g/L 

Fungicide

(EPA Reg. No. –

not specified)

4.16 lb 

ai/gal

suspension 

concentrate 

(SC)

not 

indicated

cotton (soil 

application only)

Cotton root rot (Phymatotrichopsis omnivore)
Flutriafol Human Health Risk Assessment D415849

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Table 3.3.2: Summary of Proposed Application Scenarios.

App. Timing; 

Type; and Equip. Formulation

Single App. 

Rate

(lb ai/acre)

Max. #. App. 

per Season

Max. Seasonal 

App. Rate 

(lb ai/acre)

PHI

(days) Use Directions and Limitations

Cotton

at planting soil 

application using 

T-band or modified 

in-furrow methods1

SC

(4.16 lb ai/gal) 0.130-0.260 1

0.488 (soil and 

foliar) 30 -7-day retreatment interval (RTI)

broadcast foliar 

application

SC

(1.04 lb ai/gal) 0.057-0.114 2

Sorghum

broadcast foliar 

application

SC

(1.04 lb ai/gal) 0.057-0.114 2 0.228 7 -7-day RTI

Leafy vegetables, except Brassica, crop group 4 (amaranth; arugula; Cardoon; celery; Chinese celery; celtuce; chervil; chrysanthemum 

(edible and garland); corn salad; cress (garden and upland); dandelion; dock; endive; fennel (Florence); lettuce (head and leaf); orach; 

parsley; purslane (garden and winter); radicchio; rhubarb; spinach; spinach (New Zealand and vine); and Swiss chard. Including cultivars 

and/or hybrids of these crops. 

broadcast foliar 

application

SC

(2.08 lb ai/gal) 0.081-0.114 4 0.455 7 -7-day RTI

Brassica leafy vegetable crop group 5 (broccoli; broccoli (Chinese and raab); Brussels sprouts; cabbage; cabbage; cabbage (Chinese, bok 

choy, Chinese mustard/gai choy); cauliflower; cavalo broccolo; collards; kale; kohlrabi; mustard greens; mustard spinach; and rape greens. 

Including all cultivars and/or hybrids of these crops. 

broadcast foliar 

application

SC

(2.08 lb ai/gal) 0.081-0.114 4 0.455 7 -7-day RTI

1

 T-band = Apply in a concentrated 3-4 inch wide band at planting perpendicular to row direction after furrow opening and seed 

placement but prior to furrow closure. Modified in-furrow application = apply using a splitter/Y application mechanism that 

directs the product on the sides of the seed furrow and not direct contact with the seed. 

3.4 Anticipated Exposure Pathways

Based on the proposed/registered flutriafol application scenarios, dietary exposure is an 

anticipated exposure pathway as residues of flutriafol may be found in/on crops, livestock, and 

drinking water. Exposure in the residential (non-occupational) setting is not anticipated. Based 

on the registered/proposed application scenarios and the results of a fish bioaccumulation study, 

residues in fish/shellfish are expected to be insignificant (D407105, T. Bloem, 27-Mar-2013; this 

includes consumption at the subsistence level). The current action is expected to result in shortand intermediate-term occupational exposures (handler and post-application). 

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://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

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

Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized 

by subgroups based on age, season of the year, ethnic group, and region of the country. 
Flutriafol Human Health Risk Assessment D415849

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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 

postapplication 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

No new toxicity and/or metabolism data have been received since the last flutriafol risk assessment 

(D411360, T. Bloem et al., 23-Apr-2014). The following flutriafol toxicological information is a 

summary of the information presented in D382902 (K. Lowe et al., 19-Oct-2011). 

It is noted that the HED Hazard and Science Policy Committee (HASPOC) evaluated all existing 

hazard and exposure data, as well as current registered/proposed use patterns for flutriafol, and 

concluded using a weight-of-evidence approach that a subchronic inhalation toxicity study is not 

required at this time (TXR# 0056856). 

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

Flutriafol is quickly absorbed, extensively metabolized, and quickly eliminated (within 48 hours) 

regardless of sex, dose, or whether exposure was to single or multiple dosing regimens. More than 

78% of the dose was recovered in the bile and urine. In the blood, radioactivity partitioned into the 

red blood cells. In both sexes and all groups, concentrations of radioactivity were relatively high in 

whole blood, liver, and kidneys. Other organs with high concentrations included the adrenal 

glands, spleen, and pituitary. The total amount of radioactivity isolated in the tissues and carcass 

was <1-3%. Bioaccumulation was considered unlikely. The parent was isolated in only trace 

amounts in the urine and feces and more than 19 metabolites were isolated, indicating extensive 

metabolism. The primary site for metabolism was the 2-fluorophenyl ring. The initial metabolic 

step was epoxidation followed by rearrangement to form either the dihydrodiol isomers or the 

hydroxy or dihydroxy metabolites. The hydroxyl groups on these primary metabolites may then be 

either conjugated with glucuronic acid or methylated. A second, minor route for metabolism of 

flutriafol was via the removal of the triazole ring to form 1-(2 fluorophenyl)-1-(4-fluorophenyl)-

ethandiol, which is then conjugated with glucuronic acid. 

An in vivo rat dermal-absorption study (MRID #47090415) is available for flutriafol that is 

acceptable and indicates that the absorption is 17%, 21%, and 11%, respectively, at 2, 20, and 200 

μg/cm2, following a 10-hour exposure. A value of 21% is appropriate (most protective) for dermal 

risk assessments.
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4.2 Toxicological Effects

Flutriafol is a member of the conazole triazole class of pesticides. The triazole fungicides inhibit 

C14-demethylase, a fungal cytochrome P450, which plays a role in sterol production. Sterols, such 

as ergosterol, are needed for fungal membrane structure and function, and are essential for the 

development of functional cell walls. Mammals, particularly humans, also express cytochrome 

P450 enzymes (hepatic and extra-hepatic). Thus, exposure to chemicals such as flutriafol in 

sufficient quantities may lead to toxicity. 

Flutriafol is categorized as having high oral acute toxicity in the mouse (Toxicity Category II). It is 

categorized as having low acute toxicity via the oral, dermal and inhalation routes (Toxicity

Categories III, III, and IV, respectively) in rats. Flutriafol is minimally irritating to the eyes 

(Toxicity Category III) and is not a dermal irritant (Toxicity Category IV). Flutriafol was not 

shown to be a skin sensitizer when tested in guinea pigs (Buehler method). 

Short-term, subchronic, and chronic toxicity studies in rats, mice, and dogs identified the liver as 

the primary target organ of flutriafol. Hepatotoxicity was first evident in the subchronic studies 

(rats and dogs) in the form of increases in liver enzyme release (alkaline phosphatase), liver 

weights, and histopathology findings ranging from hepatocyte vacuolization to centrilobular 

hypertrophy and slight increases in hemosiderin-laden Kupffer cells. It is noteworthy that with 

chronic exposures, there are no indications of progression of liver toxicity in all species. After over 

one year of exposure, hepatotoxicity in rats, dogs, and mice took the form of (1) minimal to severe 

fatty changes; (2) bile duct proliferation/cholangiolar fibrosis; (3) hemosiderin accumulation in 

Kupffer cells; (4) centrilobular hypertrophy, and (5) increases in alkaline phosphatase release. 

Slight indications of effects in the hematopoietic system are sporadically seen in the database. 

These effects are manifested in the form of slight anemia (rats and dogs) and increased platelet, 

white blood cell, neutrophil, and lymphocyte counts (mice). These effects, however, were minimal 

in severity.

In a 28-day dermal toxicity study, there were no signs of toxicity for flutriafol up to the limit dose 

(1000 mg/kg/day).

The potential impact of in utero and perinatal flutriafol exposure was investigated in three 

developmental toxicity studies (two in rats, one in rabbits) and two multi-generation reproduction 

toxicity studies in rats. In the first of two rat developmental toxicity studies, increased quantitative 

susceptibility was observed with developmental effects (delayed ossification or non-ossification of 

the skeleton in the fetuses) seen at a lower dose than maternal effects. In the second rat 

developmental study, a qualitative susceptibility was noted. Although developmental toxicity

occurred at the same dose level that elicited maternal toxicity, the developmental effects (external, 

visceral, and skeletal malformations; embryo lethality; skeletal variations; a generalized delay in 

fetal development; and fewer live fetuses) were more severe than the decreased food consumption 

and body-weight gains observed in the dams. For rabbits, there was in increased qualitative fetal 

susceptibly. Intrauterine deaths occurred at a dose level that also caused adverse effects in maternal 

animals. In the two-generation reproduction studies, a qualitative susceptibility was also seen. 

Effects in the offspring [decreased litter size and percentage of live births (increased pup mortality)

and liver toxicity] can be attributed to the systemic toxicity of the parental animals (decreased body

weight and food consumption and liver toxicity).
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Effects that may be considered signs of neurotoxicity (decreased motor activity and hindlimb grip 

strength, ptosis, lost righting reflex, hunched posture, and ataxia) were reported in the acute and 

subchronic neurotoxicity studies at the highest dose only. These effects, however, were primarily 

seen in animals that were agonal (at the point of death) and, thus, are not indicative of 

neurotoxicity. This conclusion is further reinforced by the observation that there was no evidence 

of neurotoxicity in any additional short-term studies in rats, mice, and dogs, or in the long-term 

toxicity studies in rats, mice, and dogs. It is also important to note that in the acute neurotoxicity

study, for animals that did not die in the study or were sacrificed in extremis, all effects resolved by 

Day 8.

In the guideline immunotoxicity study for flutriafol, there was no evidence of immunotoxicity up to 

the highest dose tested.

All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. 

Several triazoles are carcinogenic. Even though structure-activity relationiship (SAR) analysis 

indicates that flutriafol has the potential to produce thyroid and/or liver tumors in rodents, neither 

the chronic/carcinogenicity study in rats or the carcinogenicity study in mice revealed treatmentrelated increases in tumor incidences. Flutriafol is classified as “not likely to be carcinogenic to 

humans” based on the results of the carcinogenicity studies in rats and mice. 

4.3 Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team concluded that the FQPA SF could be reduced to 1x based on the 

following considerations outlined in more detail in the sections below: 1) the toxicology database 

for flutriafol is adequate for risk assessment; 2) flutriafol is not considered neurotoxic; 3) clear 

NOAELs are established to protect for the fetal/offspring effects observed; and 4) the exposure 

databases are sufficient and unlikely to underestimate exposure.

4.3.1 Completeness of the Toxicology Database

The toxicology database for flutriafol is adequate for quantification of risk for dietary, 

residential, and occupational uses and FQPA SF evaluation. The following acceptable studies 

are available for evaluation: developmental toxicity studies in rats (2) and rabbits (1), twogeneration reproduction studies in rats (2), and acute and subchronic neurotoxicity studies in rats. 

4.3.2 Evidence of Neurotoxicity

There is no concern for neurotoxicity with flutriafol. Signs of neurotoxicity were reported in the 

acute and subchronic neurotoxicity studies at the highest dose only; however, these effects were 

primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of 

neurotoxicity. In addition, there was no evidence of neurotoxicity in any additional short-term or 

long-term toxicity studies in rats, mice, and dogs. A developmental-neurotoxicity study (DNT) 

study was not required.

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

There are no concerns or residual uncertainties for pre- and/or post-natal toxicity. There is 

evidence of increased quantitative and qualitative susceptibility in developmental and 

reproduction toxicity studies (see Section 4.2); however, there is no concern since: 1) clear 

NOAELs and lowest observed adverse effect levels (LOAELs) were established in the 
Flutriafol Human Health Risk Assessment D415849

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fetuses/offspring; 2) the dose-response for these effects are well defined and characterized; 3) 

developmental endpoints are used for assessing acute dietary risks to the most sensitive 

population (females 13-49) as well as all other short- and intermediate-term exposure scenarios; 

4) the acute reference dose for females 13-49 is 1000-fold lower than the dose at which 

quantitative susceptibility in the first developmental rat study was observed; and 5) the chronic 

reference dose is greater than 300-fold lower than the doses at which the offspring effects were 

observed in the two-generation reproduction studies.

4.3.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary exposure assessment is 

conservative in nature (utilizes tolerance-level residues and 100% crop treated). In addition, 

there are no proposed or registered residential uses.

4.4 Toxicity Endpoint and POD Selections

The points of departure, UFs, and toxicity endpoints for dietary exposure assessment and 

occupational exposure assessment are presented in Tables 4.4.1 and 4.4.2, respectively. 

Acute Dietary Endpoint (General Population): The acute neurotoxicity screening battery in the rat 

was selected for the acute dietary endpoint for the general population. An UF of 100x (10x for 

interspecies extrapolation, 10x for intraspecies variability, and 1x for FQPA SF) was applied to the 

NOAEL of 250 mg/kg to generate the acute reference dose (aRfD) of 2.5 mg/kg for the general 

population. The LOAEL is 750 mg/kg based on decreased body weight, body-weight gain, 

absolute and relative food consumption, agonal effects in both sexes (dehydration, urine-stained 

abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, 

muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, and scant feces), 

in males (red or tan perioral substance, chromodacryorrhea, chromorhinorrhea, labored breathing, 

and slight ataxia), and in females (piloerection and bradypnea). This study is protective of the 

general population and is appropriate for the expected duration of exposure.

Acute Reference Dietary Endpoint (Females 13-49 years old): The prenatal developmental 

toxicity study in rabbits was selected for the acute dietary endpoint for females 13-49 years of age. 

An UF of 100x (10x for interspecies extrapolation, 10x for intraspecies variability, and 1x for 

FQPA SF) was applied to the developmental NOAEL of 7.5 mg/kg to generate the aRfD of 0.075 

mg/kg for females 13-49 years of age. The developmental LOAEL of 15 mg/kg is based on 

decreased number of live fetuses, complete litter resorptions, and increased post-implantation loss. 

The NOAEL selected provides the lowest NOAEL from any toxicity study in the flutriafol 

database in which a toxic response could be the outcome of 1-2 days of single dosing. The only 

other studies considered for this endpoint were the prenatal developmental studies in rats, where 

the developmental NOAELs were 10 mg/kg in both studies with developmental LOAELs of 50 

mg/kg/day (1982) and 75 mg/kg/day (2008). The rabbit study is therefore protective of the effects 

seen in these rat studies and provides the most protective endpoint for the population of concern 

(pregnant females and fetuses).

Chronic Dietary Endpoint (All populations): The chronic dog toxicity study was selected for the 

chronic dietary endpoint for the general population. An UF of 100x (10x for interspecies 

extrapolation, 10x for intraspecies variability, and 1x for FQPA SF) was applied to the NOAEL of 
Flutriafol Human Health Risk Assessment D415849

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5 mg/kg/day to generate the chronic reference dose (cRfD) of 0.05 mg/kg/day for all populations. 

The LOAEL is 20 mg/kg/day based upon adverse liver findings (increased liver weights, increased 

centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin, and 

triglycerides), increased adrenal cortical vacuolization of the zona fasciculata, and marked 

hemosiderin pigmentation in the liver and spleen in both sexes, mild anemia (characterized by 

decreased hemoglobin, hematocrit, and red blood cell count) in the males, and initial body-weight 

losses, decreased cumulative body-weight gains, and increased adrenal weights in the females. 

This NOAEL is lower than any NOAEL in the database for chronic effects. In addition, the study

duration is appropriate for the duration of exposure. Both the 28-day rat and 90-day dog oral 

toxicity studies provide similar NOAEL/LOAEL values and toxic effects (adverse liver effects) as 

the chronic dog study. Other studies considered for this endpoint were the chronic/carcinogenicity 

studies (mouse and rat), as well as the two-generation reproduction studies where similar effects 

were seen at slightly higher doses.

Short- and Intermediate-Term Dermal and Inhalation Endpoint: The prenatal developmental 

toxicity study in rabbits was selected for the short- and intermediate-term dermal and inhalation 

endpoints. The developmental NOAEL is 7.5 mg/kg/day and the LOAEL is 15 mg/kg/day, 

based on decreased number of live fetuses, complete litter resorptions and increased postimplantation loss. Although maternal and developmental toxicity were observed at the same 

dose, the maternal effects were restricted to moderate decreases in bodyweight and food 

consumption, and were less severe than the effects observed in the offspring. In addition, 

although decreased body weight was an adverse effect observed in non-pregnant animals with 

flutriafol, results of this study indicate that pregnant animals were more sensitive to this effect. 

The route-specific 28-day dermal toxicity study was also considered for dermal exposures, but 

there was no toxicity observed up to the limit dose (1000 mg/kg/day) and developmental effects 

were not evaluated. The selected study provides the most protective endpoint for the populations 

of concern (pregnant females and fetuses). The only other studies considered for this endpoint 

were the 90-day dog and the two-generation reproduction studies (parental effects) where liver 

toxicity (the target organ) was observed at similar doses. However, the severity of these liver 

effects does not increase with duration, and, thus, the fetal mortalities in the rabbit study are 

considered more severe. The LOC for the dermal and inhalation endpoints is 100 based upon a 

10x for interspecies extrapolation, and a 10x for intraspecies variability. Using a dermalabsorption factor of 21%, the dermal-equivalent NOAEL is ~35.7 mg/kg/day (NOAEL of 7.5 

mg/kg/day / 21% dermal absorption = 35.7 mg/kg/day). Inhalation exposure is assumed to be 

equivalent to oral exposure.

Cancer Classification and Risk Assessment Recommendation: Flutriafol is classified as “lot 

likely to be carcinogenic to humans” based on the results of the carcinogenicity studies in rats 

and mice.

4.5 Recommendation for Combining Routes of Exposure for Risk Assessment

Since the POD/endpoint for short- and intermediate-term dermal and inhalation endpoints are 

identical, exposure via these routes may be combined. 
Flutriafol Human Health Risk Assessment D415849

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Table 4.4.1: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/

Scenario POD Uncertainty/FQPA SFs

RfD, PAD, LOC for 

Risk Assessment Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL = 

250 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Acute RfD = 2.5 

mg/kg/day

aPAD = 2.5 

mg/kg/day

Neurotoxicity screening battery – rat; LOAEL = 750 

mg/kg, based on decreased body weight, body-weight gain, 

absolute and relative food consumption, and clinical signs 

of toxicity in both sexes: dehydration, urine-stained 

abdominal fur, ungroomed coat, ptosis, decreased motor 

activity, prostration, limp muscle tone, muscle flaccidity, 

hypothermia, hunched posture, impaired or lost righting 

reflex, scant feces; in males: red or tan perioral substance, 

chromodacryorrhea, chromorhinorrhea and labored 

breathing, and in females: piloerection and bradypnea.

Acute Dietary

(Females 13-

49 years of 

age)

NOAEL = 7.5 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Acute RfD = 0.075 

mg/kg/day

aPAD = 0.075 

mg/kg/day

Developmental study – rabbit; Developmental LOAEL = 

15 mg/kg, based on decreased number of live fetuses, 

complete litter resorptions and increased post-implantation 

loss. 

Chronic 

Dietary (All 

Populations)

NOAEL = 5 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Chronic RfD = 0.05

mg/kg/day

cPAD = 0.05 

mg/kg/day

Chronic toxicity – dog; LOAEL = 20 mg/kg/day, based on 

adverse liver findings (increased liver weights, increased 

centrilobular hepatocyte lipid in the liver, and increases in 

alkaline phosphatase, albumin, and triglycerides), 

increased adrenal cortical vacuolation of the zona 

fasciculata, and marked hemosiderin pigmentation in the 

liver and spleen in both sexes; mild anemia (characterized 

by decreased hemoglobin, hematocrit, and red blood cell 

count) in the males; and initial body weight losses, 

decreased cumulative body-weight gains, and increased 

adrenal weights in the females.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based on the carcinogenicity studies in rats and mice. 

Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no-observed adverse-effect level. 

LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populationadjusted dose (a = acute, c = chronic). RfD = reference dose. 

Table 4.4.2: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Occupational Human 

Health Risk Assessments.

Exposure/

Scenario POD UFs LOC Risk Assessment Study and Toxicological Effects

Dermal

Short (1-30 

days)- and 

Intermediate (1-

6 months) -Term 

NOAEL= 7.5 mg/kg/day 

1Dermal-absorption factor = 

21%

UFA = 10x

UFH = 10x

Occupational 

LOC for MOE 

< 100

Developmental toxicity – rabbit; Developmental 

LOAEL = 15 mg/kg/day, based on decreased 

number of live fetuses, complete litter resorptions 

and increased post-implantation loss. 

Inhalation Short 

(1-30 days)- and 

Intermediate (1-

6 months) -Term 

NOAEL = 7.5 mg/kg/day

Inhalation toxicity assumed to 

be equivalent to oral toxicity

UFA = 10x

UFH = 10x

Occupational 

LOC for MOE 

< 100

Developmental toxicity – rabbit; Developmental 

LOAEL = 15 mg/kg/day, based on decreased 

number of live fetuses, complete litter resorptions 

and increased post-implantation loss. 

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” based on the carcinogenicity studies in rats and 

mice.

1

 Dermal absorption factor was derived from the dermal penetration study (MRID 47090415). 

2

 Inhalation absorption factor is considered the worst-case scenario for inhalation exposure using an oral NOAEL (D372347, K. Lowe et al., 16-

Dec-2009). 

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). MOE = margin of exposure. LOC = level of concern. 
Flutriafol Human Health Risk Assessment D415849

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5.0 Dietary Exposure and Risk Assessment

D416089, T. Bloem, 16-Dec-2014 (residue chemistry summary for the current action)

D420505, T. Bloem, 16-Dec-2014 (dietary exposure analysis for the current action)

5.1 Metabolite/Degradate Residue Profile

Based on the available apple sugar beet, rapeseed, poultry, and ruminant metabolism studies and the 

confined rotational crop studies, HED concludes that the residue of concern for tolerance 

enforcement, in the proposed/registered primary crops, rotational crops, and livestock, is flutriafol. 

The residues of concern for risk assessment are defined in Table 5.1.1. HED notes that if the 

poultry and/or ruminant dietary burden exceeds the level employed in the metabolism studies, 

then metabolism studies conducted at this higher dietary burden with [carbinol14C]flutriafol 

and [triazole-3,5-

14C]flutriafol may be required. 

Table 5.0.1: Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance Enforcement.

Matrix ROC1

Risk Assessment Tolerance Enforcement

coffee, soybean seed, fruit, sugar 

beet, cucurbit vegetables, fruiting 

vegetables, tree nuts, and leafy 

vegetables (crop groups 4 and 5)

flutriafol (free), T, TA, and TAA

flutriafol (free)

cotton, peanut, and cereal grains

flutriafol (free and conjugated), defluorinated flutriafol, T, TA, and TAA; 

combined flutriafol (free and conjugated) and defluorinated flutriafol 

residues may be estimate by multiplying the free flutriafol residues by 2.2x2

rotational crops (excluding dried 

roughage feed commodities)

flutriafol (free and conjugated), M28, T, TA (free and conjugated), TAA, 

and TLA; combined flutriafol (free and conjugated) and M28 residue may 

be estimated by multiplying the free flutriafol residue by 1.3x2

rotational crops (dried roughage 

feed commodities)

same as that mentioned above but with multiplication of the free flutriafol 

residues by 2.0x2to account for the combined residues of flutriafol (free and 

conjugated) and M28

poultry3flutriafol (free), T, TA, and TAA

ruminant

flutriafol (free), M3, M3e, M4, M7, M10, T, TA, and TAA; combined 

flutriafol, M3, M3e, M4, M7, and M10 residues may be estimated by 

multiplying the free flutriafol residue by the following2: skim milk - 58x, 

cream - 15x, liver, 5.3x, kidney 77x, muscle - 6x, and fat - 2x 

water flutriafol and T --

1

 See Appendix B for names and structures of the metabolites. Separate risk assessments are required for T and TA/TAA/TLA; 

these compounds have been determined to be toxicologically different from flutriafol. 

2

 The indicated factors are based on results from the metabolism studies or confined rotational crop study.

3

 Decision will be reevaluated as the dietary burden increases (D416089, T. Bloem, 16-Dec-2014).

5.2 Food Residue Profile

The following paragraphs are summaries of the available magnitude of the residue data for the 

registered crops, proposed crops, rotational crops, and livestock. 

Registered Primary Crops: Adequate magnitude of the residue data have been submitted to 

support the currently-established tolerances. 

Magnitude of the Residue - Proposed Crops: The petitioner submitted adequate cotton, grain 

sorghum, celery, lettuce, spinach, cabbage, broccoli, and mustard green field trial studies and 

submitted an adequate cotton processing study. The residue data were generated using adequatelyvalidated analytical methods and satisfy the geographical requirements specified in OCSPP 

860.1500 (storage intervals have also been validated). Provided a revised Section B is submitted 
Flutriafol Human Health Risk Assessment D415849

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and based on the OECD tolerance-calculation procedure, HED concludes that the plant tolerances 

listed in Table 2.2.2.1 for residues of flutriafol per se are appropriate. 

Magnitude of the Residue - Rotational Crops: The proposed label indicates that treated fields may 

be rotated to a labeled crop at any time and to sweet corn 180 days after application (rotation to any

other crop is not permitted). In support of the 180-day plant-back interval (PBI), the petitioner cited 

previously submitted and reviewed sweet corn field rotational crop data that employed an 

application rate of 0.228 lb ai/acre and resulted in the establishment of tolerances for residues in/on 

sweet corn ear/forage/stover at 0.01-0.09 ppm. Adequate field rotational crop data conducted at 

seasonal rates >0.228 lb ai/acre are not available. Based on the available data, HED concludes that 

the following rotational crops restrictions are appropriate (revised Section B is requested): (1) 

application rates ≤0.228 lbs ai/acre/season - labeled crops may be planted immediately and sweet 

corn may be planted 180 days after application; rotation to any other crop is prohibited and (2) 

application rates >0.228 lbs ai/acre/season - treated field may only be rotated to a labeled crop. 

In order to fulfill the geographical data requirements specified in OCSPP 860.1500 for sweet 

corn, HED requests that the petitioner submit the following additional field rotational crop data 

(trials should employ a seasonal rate of 0.228 lb ai/acre): sweet corn – NAFTA Growing Zones 

1 (n=2), 3 (n=1), 10 (n=1), 11 (n=1), and 12 (n=1). These data were previously requested and 

remain outstanding (D388603, T. Bloem, 16-Jun-2011). If the petitioner would like to permit 

rotation to sweet corn following application at a higher rate and/or a different interval, then a full 

set of field rotational crop data conducted at the desired rate and interval should be submitted. 

Magnitude of the Residue - Livestock: The petitioner previously submitted adequate poultry and 

ruminant feeding studies (D340513, T. Bloem, 11-Mar-2009; D415068, T. Bloem, 23-Apr-2013). 

Based on these data and the current maximum reasonably-balanced dietary burdens (MRBDs), 

HED concludes that the livestock tolerances listed in Table 2.2.2.1 should be established. 

5.3 Drinking Water Residue Profile

Table 5.3.1 is a summary of worst case flutriafol per se surface-/ground-water estimated drinking 

water concentrations (EDWCs) when considering all proposed/registered uses (EFED; D412882, 

J. Wolf, 29-Oct-2013). The water estimates were incorporated directly into the dietary exposure 

analysis via the water sources direct (all sources) and indirect (all sources) commodities. The 

water models and their description are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water/. 

Table 5.3.1: Maximum Flutriafol EDWCs.

Model Application Rate Concentration (ppb)

Groundwater (PRZM-GW1)

stone fruit (4 x 0.114 lbs ai/acre at 7 day intervals) acute 310

grape (6 x 0.081 lbs ai/acre at 14 day intervals) chronic 202

Surface water (FIRST2) apples (6 x 0.114 lbs ai/acre at 7 day intervals)3 acute 40.55

chronic 4.03

1

 Pesticide Root Zone Model-Groundwater (PRZM-GW).

2

 FQPA Index Reservoir Screening Tool (FIRST ver. 1.1.1).

3

 The initially proposed application rate for apple which is higher than what was registered (D380493, T. Bloem, 16-Jun-2011). 
Flutriafol Human Health Risk Assessment D415849

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5.4 Dietary (Food + Drinking Water) Risk Assessment

The following text concerns exposure and risk to flutriafol and those metabolites identified as 

being toxicologically the same as flutriafol. For information concerning exposure and risk to T 

and TA/TAA/TLA, which HED has determined to be toxicologically different from flutriafol, 

see the Aggregate Section (7.0). 

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments 

were conducted using DEEM-FCID (ver. 3.16) which incorporates the food consumption data 

from USDA NHANES/WWEIA (2003-2008). The acute and chronic analyses assumed 

tolerance-level residues or tolerance-level residues adjusted to account for the residues of 

concern for risk assessment, 100% crop treated, and modeled drinking water estimates. Since 

adequate processing studies have been submitted which indicate that tolerances for residues in/on 

apple juice, grape juice, dried prunes, and tomato puree are unnecessary and since tolerances for 

residues in/on raisin and tomato paste tolerances are established, the DEEM (ver. 7.81) default 

processing factors for these commodities were reduced to 1. The DEEM default processing 

factors were retained for the remaining relevant commodities. The resulting acute (≤44% aPAD; 

females 13-49 years occupied the highest % of the aPAD and chronic (≤74% cPAD; children (1-

2 years old) had the highest exposure) dietary risk estimates are not of concern to HED. Table 

5.4.1 is a summary of the acute and chronic dietary risk estimates. 

Table 5.4.1: Summary of the Acute and Chronic Dietary Exposure and Risk.

Population aPAD 

(mg/kg/day)

Exposure 

(mg/kg/day)1 %aPAD1 cPAD (mg/kg/day)

Exposure 

(mg/kg/day) %cPAD

General U.S. Population

2.5

0.039637 1.6

0.05

0.013176 26

All Infants (<1 year old) 0.076724 3.1 0.023836 48

Children 1-2 years old 0.086479 3.5 0.037200 74

Children 3-5 years old 0.078018 3.1 0.028287 57

Children 6-12 years old 0.046496 1.9 0.016557 33

Youth 13-19 years old 0.027534 1.1 0.009270 19

Adults 20-49 years old 0.032401 1.3 0.010957 22

Adults 50-99 years old 0.032371 1.3 0.011695 23

Females 13-49 years old 0.075 0.033040 44 0.010990 22

1

 95th percentile (tier 1 analysis).
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential uses proposed or currently registered for flutriafol. Therefore, 

residential handler and post-application exposure/risk were not assessed. 

6.1 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for flutriafol. The Agency has been working with the Spray Drift Task Force 

(a task force composed of various registrants which was developed as a result of a Data Call-In 

issued by EPA), 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; http://www.epa.gov/opp00001/factsheets/spraydrift.htm) The 

Agency is also taking means to quantitatively and qualitatively address spray drift as a potential 

source of exposure in risk assessments for pesticides through existing programs such as Ag 

Drift® and chemical specific properties of pesticides. The potential for spray drift will be 

quantitatively evaluated for each pesticide during the Registration Review process, which ensures 

that all uses for that pesticide will be considered concurrently. 

6.2 Residential Bystander Post-Application Inhalation Exposure

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 has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP2014-0219). 

During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for specific 

chemicals.
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7.0 Aggregate Exposure/Risk Characterization

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from 

three major sources: food, drinking water, and residential exposures. Because there are no uses 

for flutriafol which result in residential (non-occupational) exposures, the aggregate assessment 

need only consider food and water. Since the dietary exposure analysis included both food and 

water, the discussion and exposure estimates presented in Section 5.4 represent aggregate acute 

and chronic exposure to flutriafol and those metabolites identified as being toxicologically

identical to flutriafol. All aggregate flutriafol risk estimates are not of concern to HED. 

Application of flutriafol also results in exposure to T and TA/TAA/TLA. These compounds are 

considered to be toxicologically different from flutriafol. HED previously conducted an 

aggregate exposure analysis for these compounds, which resulted in aggregate exposure less than 

HED’s level of concern (D414952, T. Morton, 24-Oct-2013). The proposed new uses and label 

amendments do not require a revision to this most recent aggregate assessment. 

8.0 Cumulative Exposure/Risk Characterization

Flutriafol is a member of the triazole-containing class of pesticides. Although conazoles act 

similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a 

relationship between their pesticidal activity and their mechanism of toxicity in mammals. 

Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to 

establish that the chemicals operate by the same, or essentially the same, sequence of major 

biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxicological 

responses is found; some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid 

tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. 

Furthermore, the conazoles produce a diverse range of biochemical events including altered 

cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood 

whether these biochemical events are directly connected to their toxicological outcomes. Thus, 

there is currently no evidence to indicate that conazoles share common mechanisms of toxicity

and EPA is not following a cumulative risk approach based on a common mechanism of toxicity

for the conazoles. For information regarding EPA’s procedures for cumulating effects from 

substances found to have a common mechanism of toxicity, see EPA’s website at 

http://www.epa.gov/pesticides/cumulative.
Flutriafol Human Health Risk Assessment D415849

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9.0 Occupational Exposure/Risk Characterization

D416213, K. Lowe, 24-Jan-2014

Based on the proposed new uses, it has been determined that the potential exposure scenarios 

that will need to be assessed include short- and intermediate-term occupational exposures 

(handler and post-application). It is HED policy to use the best available data to assess exposure. 

Several sources of generic data were used in this assessment as surrogate data in the absence of 

chemical-specific data, including the PHED 1.1, AHETF database, and ARTF database. Some 

of these data are proprietary, and subject to the data protection provisions of FIFRA. Additional 

information on HED policy on use of surrogate data, including descriptions of the various 

sources, can be found at the Agency website (http://www.epa.gov/pesticides/science/handlerexposure-data.html). 

9.1 Handler Risk Assessment

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. Based on the anticipated use patterns, and the current labeling regarding 

types of equipment and techniques that can be used, occupational handler exposure is expected. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: (1) mixing/loading liquids for aerial and groundboom applications; (2) 

applying sprays via aerial and groundboom equipment; and (3) flagging for aerial applications. 

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological 

effects for these exposure routes were similar. 

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm dermal and inhalation combined MOEs are not of concern to HED (i.e., MOE > 100) with 

the use of chemical-resistant gloves as personal protective equipment as directed by the label. At 

the baseline level of personal protection (i.e., no gloves and no respirator), only one scenario 

results in a risk estimate below the LOC with a combined (dermal + inhalation) MOE of 82; this 

scenario is mixing/loading a liquid formulation for aerial application to high acreage crops. With 

the addition of gloves, the combined dermal + inhalation MOE is 470, which is not of concern. 

All other scenarios result in risk estimates greater than 220 with baseline attire. Table 9.1.1 is a 

summary of the handler exposure and risk estimates. 
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Table 9.1.1: Occupational Handler Non-Cancer Exposure and Risk Estimates for Flutriafol. 

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate (lb 

ai/acre)2

Area 

Treated 

(acres)3

Dermal

(LOC = 100)

Inhalation

(LOC = 100)

Total

(LOC = 100)

Mitigation Level Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Aerial app.

of liquid 

formulation

Crop Groups 4 and 5 220 

(baseline)

0.219 

(baseline)

0.114

350 0.0267 280 0.000127 59,000 280

Cotton and Grain Sorghum 1200

0.0916 82

0.000435 17,000

82

37.6 

(single layer 

w/gloves)

0.0156 480 470

Groundboom 

app. of 

liquid 

formulation

Crop Groups 4 and 5

220 (baseline)

0.114 80 0.00612 1,200 0.000029 260,000 1,200

Grain Sorghum 200 0.0153 490 0.0000723 100,000 490

Cotton 0.26 200 0.0347 220 0.000165 45,000 220

Applicator

Aerial spray 

app.

Crop Groups 4 and 5 2.08

(engineering 

control)

0.0049

(engineering 

control)

0.114

350 0.000253 30,000 0.00000284 2,600,000 30,000

Cotton and Grain Sorghum 1200 0.000867 8,700 0.00000971 770,000 8,600

Groundboom 

spray app.

Crop Groups 4 and 5 78.6

(baseline)

0.34

(baseline)

0.114 80 0.00218 3,400 0.0000449 170,000 3,300

Grain Sorghum 0.114 200 0.00545 1,400 0.000112 67,000 1,400

Cotton 0.26 200 0.0124 600 0.000257 29,000 590

Flagger

Flagger for 

aerial spray 

app.

Crop Groups 4 and 5; Grain 

Sorghum; and Cotton

11

(baseline)

0.35

(baseline) 0.114 350 0.00134 5,600 0.000203 37,000 4,900

1

 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, PPE (gloves), Eng. Controls.

2 Based on proposed labels.

3

 Exposure Science Advisory Council Policy #9.1.

4

 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) × DAF (21 %) ÷ BW (69 kg).

5

 Dermal MOE = Dermal NOAEL (7.5 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6

 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) x inhalation absorption (100%) ÷ BW (69 kg).

7

 Inhalation MOE = Inhalation NOAEL (7.5 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8

 Total MOE = NOAEL (7.5 mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).
Flutriafol Human Health Risk Assessment D415849

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9.2 Post-Application Risk Assessment

HED uses the term post-application to describe exposures (inhalation and dermal) that occur 

when individuals are present in an environment that has been previously treated with a pesticide 

(also referred to as re-entry exposure). Such exposures may occur when workers enter 

previously treated areas to perform job functions, including activities related to crop production, 

such as scouting for pests or harvesting. Post-application exposure levels vary over time and 

depend on such things as the type of activity, the nature of the crop or target that was treated, the 

type of pesticide application, and the chemical’s degradation properties. In addition, the timing 

of pesticide applications, relative to harvest activities, can greatly reduce the potential for postapplication exposure.

9.2.1 Inhalation Post-Application Risk Assessment

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, 2010 

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

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the Agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for specific chemicals.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the Agency's risk assessments.

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 inhalation exposure. Therefore, it is expected that these 

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

inhalation exposure scenarios. 
Flutriafol Human Health Risk Assessment D415849

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9.2.2 Dermal Post-Application Risk Assessment

Short- and intermediate post-application dermal exposure is anticipated for the proposed crops with 

expected scenarios and resulting exposures and MOEs summarized in Table 9.2.2.1. All scenarios 

resulted in MOEs greater than the LOC of 100 (ranging from 230 to 4,600) on day 0 (12 hours after 

application; proposed REI) and, therefore, are not of concern to HED.

In accordance with 40 CFR158, dislodgeable foliar residue (DFR) data are required for all 

occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and 

vegetable gardens, pick your own farms, retail tree farms) uses that could result in post-application 

exposure to foliage. In the absence of chemical-specific DFR data, EPA uses default values. The 

2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an 

analysis of a number of DFR studies, which resulted in the selection of a revised default values for 

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

values are based on an analysis of 19 DFR studies. Since that time, the Agricultural Re-entry Task 

Force has submitted information (MRID 49299201) that corrects an application rate error made in 

the original submission of “ARF039 – Determination of Dermal and Inhalation Exposure to 

Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As 

a result, the range of FAR values was revised from 2% - 89% to 2% - 47%. In the data, a large range 

of transferability is observed and this variability can potentially be attributable to many factors such 

as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., 

humidity); or many other difficult to quantify factors. Although witnessed across multiple 

chemicals, this range in FAR values is not expected when considering DFR data for a single 

chemical. At this time, the ARTF submission did not alter the selection of 25% as the reasonable, 

high-end default value. Because DFR data are not available for flutriafol, EPA is using the default 

value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR 

value for flutriafol (i.e., there is a small chance that the FAR value may exceed the applicable default 

value), it is likely that the health-protective aspects of EPA’s occupational post-application 

assessment methodology will more than compensate for this potential uncertainty. For example, 

when assessing residential and occupational post-application exposure to gardens and ornamentals, 

EPA assumes the following: exposures occur to zero-day (i.e., day of application ) residues every

day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, 

it doesn’t rain, etc); individuals perform the same post-application activities performed in the 

transfer coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals 

engage in these post-application activities for a high-end amount of time every day (represented by 

data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that 

exposure is not being underestimated. 

Since the highest estimated occupational post-application exposure using default DFR values for 

flutriafol is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 

2 times higher than the level of concern, MOE = 230 compared to the LOC of 100); EPA is waiving 

the 40 CFR DFR data requirement. In this instance, it is unlikely that chemical-specific DFR data 

would be needed to further refine exposure assessments or would add appreciably to our overall 

understanding of the availability of dislodgeable foliar pesticide residues for flutriafol.

Table 9.2.2.1: Occupational Post-application Non-Cancer Exposure and Risk Estimates for Flutriafol.
Flutriafol Human Health Risk Assessment D415849

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Crop/Site Activities Transfer Coefficient 

(cm2/hr)

Proposed 

Application Rate 

(lb ai/A)

DFR1 Dermal Dose 

(mg/kg/day)2

MOE3

(LOC = 100)

Short- and Intermediate-term

Crop groups 4 

and 5

Scouting, Hand 

harvesting, Hand 

weeding, Topping

4,200

0.114 0.32

0.033 230

Cotton and Grain 

Sorghum Scouting 210 0.002 4,600

1

 DFR = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day. 

2

 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (21%)]  BW (69 kg).

3

 MOE = POD (7.5 mg/kg/day) / Daily Dermal Dose. 

9.2.2 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of flutriafol. Flutriafol has 

low acute toxicity via the oral, dermal and inhalation routes (Toxicity Categories III and IV). 

Flutriafol is minimally irritating to the eyes (Toxicity Category III) and is not a dermal irritant 

(Toxicity Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea 

pigs (Buehler method). Short- and intermediate-term post-application risk estimates were not a 

concern on day 0 (12 hours following application) for all post-application activities. Under 40 

CFR 156.208(c)(2)(iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and 

primary skin irrigation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker 

Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from 

post-application exposures to flutriafol. 

RDI: RAB1 (11-Jun-2014)

Appendix A. Toxicology Profile and Executive Summaries

Appendix B. Chemical Names and Structures
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Appendix A. Toxicology Profile and Executive Summaries

The requirements (40 CFR 158.340) for food uses for flutriafol are in Table A.1. Use of the new 

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

Table A.1. Study Requirements for Food Uses for Flutriafol

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5xxx Mutagenicity—Structural Chromosomal Aberrations

870.5xxx Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Develop. Neurotoxicity

no

no

yes

yes

no

-

-

yes

yes

-

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

 Acute Oral (rat)

 Subchronic Oral (rat)

 Six-month Oral (dog)

no

no

no

-

-

-

Table A.2: Acute Toxicity Profile – Flutriafol.

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

870.1100 Acute oral (rat) 47090336 LD50 = 1140 mg/kg (M); 1480 mg/kg (F) III

870.1100 Acute oral (mouse) 47090335 LD50 = 365 mg/kg bw (M); 179 mg/kg bw (F) II

870.1200 Acute dermal (rat) 4786101 LD50 >2000 mg/kg bw III

870.1300 Acute inhalation (rat) 47090338 LC50 >5.20 mg/L IV

870.2400 Primary eye irritation (rabbit) 47090339 Minimally irritating III

870.2500 Primary dermal irritation (rabbit) 47090341 Not a dermal irritant IV

870.2600 Dermal sensitization (mouse) 47090343 Not a sensitizer -
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Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.3050 28-Day oral toxicity 

(rat)

47090344 (1982)

Acceptable/non-guideline

0, 100, 300, 800, 2000, or 

5000 ppm (0, 10, 30, 80, 200, 

and 500 mg/kg/day)

NOAEL = 800 ppm (80 mg/kg/day).

LOAEL = 2000 ppm (200 mg/kg/day), based on liver 

toxicity (increased weight, centrilobular hepatocellular 

hypertrophy, fatty change, hydropic degeneration, smooth 

endoplasmic reticulum proliferation, and increased 

aminopyrine-N-demethylase activity) in both sexes and 

decreased body-weight gain and food consumption in 

males.

870.3100 90-Day oral toxicity 

(rat)

47090345 (1982) 

Acceptable/guideline

0, 20, 200, or 2000 ppm 

M: 0, 1.5, 14, and 158 

mg/kg/day)

F: 0, 1.6, 22, and 145 

mg/kg/day

NOAEL = 200 ppm (14/22 mg/kg/day in M/F) 

LOAEL = 2000 ppm (158/145 mg/kg/day in M/F), based on 

decreased body-weight gain, decreased food consumption 

and liver toxicity (increased absolute and adjusted liver 

weights, increased endoplasmic reticulum proliferation in 

the males, and increased APDM activity).

870.3150 90-Day oral toxicity 

(dog)

47090346 (1982) 

Acceptable/guideline

0, 1, 5, or 15 mg/kg bw/day

NOAEL = 5 mg/kg/day.

LOAEL = 15 mg/kg/day, based on adverse liver findings 

(increases in organ weight, alkaline phosphatase, 

aminopyrine N-demethylase activity, and incidence of 

hemosiderin-laden Kupffer cells) in both sexes, spleens 

with hemosiderin content slightly higher than controls in 

the males, and decreased cumulative body-weight gains and 

increased triglycerides in the females.

870.3200 28-Day dermal toxicity 

(rat)

47090347 (2007)

Acceptable/guideline

0, 250, 500, or 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day.

LOAEL was not established.

870.3700a Prenatal developmental 

(rat)

47090349 (1982)

Acceptable/guideline

0, 10, 50, or 125 mg/kg/day

Maternal NOAEL = 50 mg/kg/day.

LOAEL = 125 mg/kg/day, based on increased incidence of 

ventral/genital staining of the fur and decreased maternal 

body-weight gains and food consumption.

Developmental NOAEL = 10 mg/kg/day.

LOAEL = 50 mg/kg/day, based on delayed ossification or 

non-ossification of the skeleton in the fetuses.

870.3700a Prenatal developmental 

(rat)

47521303 (2008)

Acceptable/guideline

0, 2, 5, 10, or 755 mg/kg/day

Maternal NOAEL = 10 mg/kg/day.

LOAEL = 75 mg/kg/day, based on decreased body-weight 

gains and food consumption.

Developmental NOAEL = 10 mg/kg/day.

LOAEL = 75 mg/kg/day, based on increased late 

resorptions; malformations (cleft palate and multiple hyoid 

malformations) and variations in the hyoid; variations in the 

maxilla/mandible, rudimentary and long cervical ribs, 

pelvic girdle, and radius/ulna; numerous skeletal 

retardations detailed above and corresponding decrease in 

fetal weights.

870.3700b Prenatal developmental 

(rabbit)

47090350 (1982)

Acceptable/guideline

0, 2.5, 7.5, or 15 mg/kg/day

Maternal NOAEL = 7.5 mg/kg/day.

LOAEL = 15 mg/kg/day, based on decreased corrected and 

uncorrected body-weight gains and food consumption.

Developmental NOAEL = 7.5 mg/kg/day.

LOAEL = 15 mg/kg/day, based on decreased number of 

live fetuses, complete litter resorptions and increased postimplantation loss. 
Flutriafol Human Health Risk Assessment D415849

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Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.3800 2-gen. reproduction and 

fertility effects

(rat)

47090351 (1986)

Acceptable/guideline

0, 60, 240, or 1,000 ppm 

M: 0, 4.8, 20.6, and 88.7 

mg/kg/day)

F: 0, 5.5, 21.9, and 103 

mg/kg/day

Parental/Systemic NOAEL = 240 ppm (20.6/21.9 

mg/kg/day [M/F]).

LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on 

decreased body-weight gains and food consumption and on 

effects on the liver (increased liver weights, centrilobular 

hypertrophy, and fatty change).

Reproductive NOAEL = 1000 ppm (88.7/103 mg/kg/day 

[M/F]).

LOAEL was not determined.

Offspring NOAEL = 240 ppm (20.6/21.9 mg/kg/day 

[M/F]).

LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on 

decreased live birth index and litter size and on effects on 

the liver (fatty change/vacuolization).

870.3800 2-gen. reproduction and 

fertility effects

(rat)

48196921, 48196922 (2009)

Acceptable/guideline

0, 30, 80, 150, 300, 1000 ppm

0, 1.8/2.2, 4.8/5.85, 9/10.8, 

18.5/22.6, and 62.8/ 77.1 

mg/kg bw/day [M/F]

Parental/Systemic NOAEL = 150 ppm (9/10.8 mg/kg 

bw/day [M/F]).

Parental/Systemic LOAEL = 300 ppm (18.2/22.6 mg/kg 

bw/day [M/F]) based upon increased relative liver weights, 

fatty deposits in the liver in both sexes as well as 

hepatocellular hypertrophy in males. 

Reproductive NOAEL = 300 ppm (18.2/22.6 mg/kg 

bw/day [M/F].

Reproductive LOAEL was not observed. 

Offspring NOAEL = 150 ppm (9/10.8 mg/kg bw/day 

[M/F]). 

Offspring LOAEL = 300 ppm (18.5/22.6 mg/kg bw/day 

[M/F]) based upon increased pup mortality in the F1 pups at 

the first litter check and 0-4 postnatal days. 

870.4100 Chronic toxicity (1 

year; dog)

47090353 (1988)

Acceptable/guideline

0, 1, 5, or 20 mg/kg/day

NOAEL = 5 mg/kg/day.

LOAEL = 20 mg/kg/day, based on: adverse liver findings 

(increased liver weights, increased centrilobular hepatocyte 

lipid in the liver, and increases in alkaline phosphatase, 

albumin and triglycerides), increased adrenal cortical 

vacuolization of the zona fasciculata, and marked 

hemosiderin pigmentation in the liver and spleen in both 

sexes; mild anemia (characterized by decreased 

hemoglobin, hematocrit, and red blood cell count) in the 

males; and initial body weight losses, decreased cumulative 

body-weight gains, and increased adrenal weights in the 

females.

870.4200 Carcinogenicity

(mouse)

47090354 (1988)

Acceptable/guideline

0 (two control groups), 10, 50, 

or 200 ppm

M: 0, (0, 1.1, 5.9, and 24 

mg/kg/day)

F: 0, 1.4, 7.4, and 31 

mg/kg/day

NOAEL = 50 ppm (5.9/7.4 mg/kg/day in M/F).

LOAEL = 200 ppm (24/31 mg/kg/day in M/F), based on 

hepatotoxicity (increased fatty change) in both sexes.

No evidence of carcinogenicity

870.4300 Combined Chronic 

Toxicity/

Carcinogenicity

(rat)

47090352 (1986)

Acceptable/guideline

0, 20, 200, or 2000 ppm 

M: 0, 1.02, 10.0, and 102 

mg/kg/day)

F: 0, 1.27,12.2, and 122 

mg/kg/day

NOAEL = 200 ppm (10.0/12.2 mg/kg/day in 

males/females).

LOAEL = 2000 ppm (102/122 mg/kg/day in 

males/females), based on adverse liver effects (increased 

liver weights, fatty change, bile duct 

proliferation/cholangiolarfibrosis, hemosiderin 

accumulation in Kupffer cells and centrilobular 

hypertrophy), and clinical chemistry findings.

No evidence of carcinogenicity
Flutriafol Human Health Risk Assessment D415849

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Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.5100 In vitro Bacterial Gene 

Mutation (Salmonella 

typhimurium)/ 

mammalian activation 

gene mutation assay

47090401 (1988)

Acceptable/guideline

0, 1.6, 8, 40, 200, 1000, or 

5000 μg/plate ( Trial 1) or 0, 

8, 40, 200, 1000, 2500, or 

5000 μg/plate (Trial 2); Both 

trials were performed w/wo 

S9-activation

There were no marked increases in the mean number of 

revertants/plate in any strain. There was no evidence of 

induced mutant colonies over background.

870.5300 In Vitro Gene Mutation 

assay in mouse 

lymphoma cells

47090402 (1986)

Acceptable/guideline

0, 10, 33, 100, 333, or 1000 

μg/mL (+S9, Trial 1); 0, 150, 

300, 450, 600, or 750 μg/mL 

(-S9, Trial 1); 0, 150, 300, 

450, 600, 750, 900, 1050, or 

1200 μg/mL (+S9, Trial 2); or 

0, 200, 300, 400, 500, 600, 

700, or 800 μg/mL

(-S9, Trial 2)

There was a dose-related increase in mutant frequency (7.0-

9.0 x 10-5treated vs. 3.0 x 10-5controls) and absolute 

mutant numbers (70-148 colonies/plate vs. 63 controls) at 

100 μg/mL and above in Trial 1 and a marked increase in 

mutant frequency at 750 μg/mL (6. 5x 10-5treated vs. 1.2 x

10-5controls) in Trial 2 attributable to severe cytotoxicity

(2% relative survival). However, the increases in mutant 

frequency did not achieve the threshold value for a positive 

response (>10 x 10-5) in either trial and there was no 

marked increase in absolute mutant numbers at 750 μg/mL 

in Trial 2. In the absence of S9, there were no marked 

increases in mutant frequency or absolute mutant numbers 

compared to controls in either trial. There was no 

convincing evidence of induced mutant colonies over 

background in the presence or absence of S9-activation.

870.5300 In Vitro Gene Mutation 

assay in mouse 

lymphoma cells

48196918 (2006)

Acceptable/guideline

0, 25, 50, 100, 200, 400 and 

600 μg/mL (±S9, Trial 1); 0, 

12.5, 25, 50, 100, 200, 300 or 

400 μg/mL (-S9, Trial 1); 0, 

200, 300, 325, 350, 375, or 

400 μg/mL (+S9, Trial 2)

(-S9, Trial 2)

The mutagenicity criterion (threshold) of 126 colonies per 

106 cells above the solvent control was not reached for any 

valid data at any test concentration, with or without 

metabolic activation. Although linear regression analysis 

found a significant (p<0.05) dose dependent trend of the 

mutation frequency in Experiment 1 (culture 1, with 

metabolic activation), Experiment 2 (culture 1), and 

Experiment 3 (cultures 1 and 2), these statistical results 

were considered biologically irrelevant because the 

threshold for mutagenicity was not exceeded and all 

absolute values were within the range of historical negative 

and solvent controls.

870.5375 In vitro Mammalian 

Cytogenetics 

(Chromosomal 

Aberration Assay in 

Human Peripheral 

Blood Lymphocytes)

47090403 (1989)

Acceptable/guideline

0, 25, 125, or 250 μg/mL (+/-

S9)

No significant increases in the numbers of cells with 

aberrations (excluding gaps) were observed in either donor 

in the presence or absence of S9. There was no evidence of 

chromosome aberrations induced over background in the 

presence or absence of S9-activation.

870.5385 In vivo Mammalian 

Cytogenetics – [Bone 

Marrow Chromosomal 

Aberration Test

47090404 (1982)

Acceptable/guideline

0, 15, 70, or 150 mg/kg

There was no evidence of chromosome aberration induced 

over background.

870.5395 In Vivo Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus Assay in 

Mice

47090405 (1986)

Acceptable/guideline

0, 93.8, or 150 mg/kg

Decreased (p<0.01) polychromatic erythrocyte to 

normochromatic erythrocyte ratios (PCE:NCE) were 

observed in both doses at all time points, indicating that the 

test material was toxic to the bone marrow. There was no 

significant increase in the frequency of micronucleated 

polychromatic erythrocytes in bone marrow after any 

treatment time.

870.5450 Dominant Lethal Assay 

– Mice

47090406 (1982)

Acceptable/guideline

0, 25, 50, or 100 mg/kg/day 

(total doses of 0, 125, 250, or 

500 mg/kg)

Mortality (3/15 males) was noted at 100 mg/kg/day during 

dosing. Slight decreases (p<0.05) in body weight were 

observed at 50 mg/kg/day and above during dosing. There 

were no treatment-related effects on fertility, mean number 

of implantations, or the number of early or late deaths. 

There was no time-related positive response of increased 

pre- or post-implantation loss compared to controls.
Flutriafol Human Health Risk Assessment D415849

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Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.5550 Unscheduled DNA 

Synthesis in Primary 

Rat 

Hepatocytes/Mammalia

n Cell

47090407 (2003)

Acceptable/guideline

0, 250, 500, or 1000 mg/kg

The net nuclear grain (NNG) counts in the treated animals 

(–3.42 to –2.64) were well below the threshold of ≥5 NNG 

needed for a positive response, and no increase in the mean 

percent of cells in repair was observed. There was no 

evidence that unscheduled DNA synthesis, as determined 

by radioactive tracer procedures [nuclear silver grain 

counts] was induced.

870.6200a Acute neurotoxicity 

screening battery

47090408 (2005)

Acceptable/guideline

0, 125, 250, or 750 mg/kg

NOAEL = 250 mg/kg.

LOAEL = 750 mg/kg, based on decreased body weight, 

body-weight gain, absolute and relative food consumption, 

and clinical signs of toxicity, indicative of a moribund 

condition, in both sexes: dehydration, urine-stained 

abdominal fur, ungroomed coat, ptosis, decreased motor 

activity, prostration, limp muscle tone, muscle flaccidity, 

hypothermia, hunched posture, impaired or lost righting 

reflex, scant feces; in males: red or tan perioral substance, 

chromodacryorrhea, chromorhinorrhea and labored 

breathing, and in females: piloerection and bradypnea, and 

signs of neurotoxicity: hunched posture in females and 

ataxia in males.

870.6200b Subchronic 

Neurotoxicity – Feeding 

Study in Rats

47090410 (2007)

Acceptable/guideline

0, 500, 1500, or 3000 ppm 

(0/0, 28.9/32.6, 84.3/97.6, and 

172.1/185.0 mg/kg/day [M/F])

NOAEL = 1500 ppm (84.3/97.6 mg/kg/day [M/F]).

LOAEL = 3000 ppm (172.1/185.0 mg/kg/day [M/F]) based 

on decreased body-weight gain, absolute and relative food 

consumption; and decreased hindlimb grip strength in 

males.

870.7485 Metabolism and 

pharmacokinetics

(rat)

47090414 (2004),

47090412 (2006)

Acceptable/guideline

5 or 250 mg/kg

More than 78% of the dose was recovered in the bile and 

urine. Absorption was similar between sexes and between 

single and multiple dose regimes. Absorption is extensive. 

The dose was mostly eliminated within 48 hours. Only 

0.04-0.05% of the dose was found in the expired carbon 

dioxide. Most of the radioactivity was excreted in the bile 

(47-79% of the dose). The excretion profile was similar 

between sexes. In the blood, radioactivity partitioned into 

the red blood cells. In both sexes and all groups, 

concentrations of radioactivity were relatively high in 

whole blood, liver, and kidneys. Other organs with high

concentrations included the adrenal glands, spleen, and 

pituitary. The distribution profiles were similar between 

species, dose level, and single vs. multiple dose regime. In 

the whole blood, the concentrations were proportional to the 

dose. The total amount of radioactivity isolated in the 

tissues and carcass was <1-3%. Bioaccumulation was 

considered unlikely. The parent was isolated in only trace 

amounts in the urine and feces and more than 19 

metabolites were isolated, indicating extensive metabolism. 

Metabolism profiles were similar between sexes. The 

metabolic profiles were similar regardless of the matrix 

(feces, urine, or bile), the dose, and the sex. The primary 

site for metabolism was the 2-fluorophenyl ring. The initial 

metabolic step was epoxidation followed by either 

rearrangement to form the dihydrodiol isomers or to form 

hydroxy or dihydroxy metabolites. The hydroxyl groups on 

these primary metabolites may then be either conjugated 

with glucuronic acid or methylated. A second, minor route 

for metabolism of flutriafol was via the removal of the 

triazole ring to form 1-(2 fluorophenyl)-1-(4-fluorophenyl)-

ethandiol, which is then conjugated with glucuronic acid.
Flutriafol Human Health Risk Assessment D415849

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Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.7600 In vivo dermal 

penetration

(rat)

47090415 (2006)

Acceptable/guideline

0.002, 0.02, or 0.2 mg/cm2

skin were tested (10 μl/cm2

skin), and actual doses were 

0.00208, 0.0201, and 0.2154 

mg/cm2skin

Dermal ranged up to 15.8% of the applied dose. 

Absorption was minimal with only 4 h of exposure. 

Absorbable radioactivity (radioactivity in the skin at the 

application site and the adjacent skin) was minimal in 

groups that were exposed for 10 h and evaluated for an 

additional 158 h post-exposure. Thus, almost all of the 

dose isolated in the skin will be absorbed. Considering the 

sum of absorbable and absorbed doses, 4-37% of the 

applied dose was recovered in the treatment groups (11%). 

Absorption rate constants were calculated as 0.236, 0.190, 

and 0.072 h-1for the 2, 20, and 200 μg/cm2dose groups. 

Absorption mechanisms were saturated at the high dose. 

The elimination half-lives were calculated to be 31, 30, and 

37 h for the 2, 20, and 200 μg/cm2dose groups. A 

maximum of 36.56% of the applied dose was noted as 

absorbed/absorbable (observed after 24 h exposure to 2 

μg/cm2). The dose that is absorbed/absorbable following a 

10 h exposure is 16.54%, 21.31% and 11.39%, respectively, 

at 2, 20, and 200 μg/cm2.

870.7800 Immunotoxicity (mice) 48360301 (2011)

Acceptable/guideline

0, 50, 250, 500, 1000 ppm [F]

(0, 9.8, 46.8, and 208 

mg/kg/day [F]

Systemic NOEAL = 9.8 mg/kg/day.

Systemic LOAEL = 46.8 mg/kg/day) based on increased 

absolute and relative liver weights and hematological 

effects.

Immunotoxicity NOAEL = 208 mg/kg/day.

Immunotoxicity LOAEL was not established.
Flutriafol Human Health Risk Assessment D415849

Page 34 of 35

Appendix B. Chemical Names and Structures

Common name Chemical name Chemical structure

Flutriafol 

(±)-α-(2-fluorophenyl)-α-(4-

fluorophenyl)-1H-1,2,4-triazole-1-

ethanol

N N

N

F

OH

F

M1B

1-(2-fluoro-4-hydroxyphenyl)-1-(4-

fluorophenyl)-2-(1H-1,2,4-triazol-1-

yl)ethanol

N N

N

F

OH

F

OH

M28

glucoside of a flutriafol metabolite, 

possible a derivative hydroxylated on 

one phenyl ring

--

1,2,4-Triazole (T) 1H-1,2,4-triazole

N N

H

N

Triazolylalanine (TA) 2-amino-3-(1H-1,2,4-triazol-1-

yl)propanoic acid

NH2

OH

O

N N

N

Triazolylacetic acid (TAA) 1H-1,2,4-triazol-1-ylacetic acid

OH

O

N N

N

Triazole lactic acid (TLA) 1,2,4-triazole-1-lactic acid

Hydroxy flutriafol glucuronide 

(HFG; M3) --

OH OH

HO

OH

O

O

O

F

OH

N

N

N

F

OH
Flutriafol Human Health Risk Assessment D415849

Page 35 of 35

Common name Chemical name Chemical structure

Dihydroxy flutriafol (DHF; 

M3e) --

Flutriafol glucuronide (FG; M4) --

Methoxy flutriafol glucuronide 

(MFG; M7) --

Flutriafol sulfate (FS; M10) --

OH

F

OH

N

N

N

F

OH

OH OH

HO

OH

O

O

O

OH

N

N

N

F

F

CH3

O

OH

N

N

N

F

F

OH O

HO

OH OH

O

O

HO

N

N

N

F

HO S O

O

O

F