UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

From: 

Through: 

To: 

23-April-20 14 

Flutriafol: Human-Health Risk Assessment for Tolerances for Residues in/on Field 

Com, Popcorn, Peanut, Wheat, Strawberries, Cucurbit Vegetables, Fruiting Vegetables, 

and Tree Nuts. 

PC Code: 128940 DP Barcodes: D411 360, 412161 

Decision Nos.: 475694, 478287 Registration Nos.: 67760-75 and 67760-120 

Petition Nos.: 3F8156 and 3F8174 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 

Tom Bloem, Chemis~ ~ / 

Kelly M. Lowe, Environmental Scientist /1/J'JBt/ ;t .. / . _# r//L_// "' 

Anwar Y. Dunbar, Ph.D., Pharmacologist ~/,. · . 

Risk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED; 7509P) 

Char

George 

les 

F. 

W. 

Kramer

Smith 

, 

III

Ph.D.

, Branc

, Senior 

h hiChef iiliSt~~ ~-: RABl/HED (7509P) 

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 ( (± )-a -(2-fluorophenyl)-a-( 4-fluorophenyl)-1 H-1 ,2,4-triazole-1-

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

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

dietary risk assessment, and residue chemistry review were provided by Tom Bloem (RABl), the 

hazard characterization was provided by Anwar Dunbar (RAB 1 ), the occupational/residential 

exposure (ORE) and risk assessment were provided by Kelly Lowe, and the drinking water 

assessment was provided by James K. Wolf of the Environmental Fate and Effects Division 

(EFED). 

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Flutriafol Human-Health Risk Assessment D411 360 

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 .................................................................................................................. 8 

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

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

2.3 Label Recommendations ................................................................................................................................. 9 

3.0 Ingredient Profile ............................................................................................................................................ I 0 

3. 1 Chemical Identity .......................................................................................................................................... 10 

3.2 Physical/Chemical Properties ........................................................................................................................ I 0 

3.3 Proposed Use Pattern ........................................................................................................ ............................ I I 

3.4 Anticipated Exposure Pathways ................................................................................................................. l3 

3.5 Consideration of Environmental Justice ...................................................................................... ................. 13 

4.0 Hazard Characterization and Dose-Response Assessment ................................................................ ............. 14 

4.1 Absorption, Distribution, Metabolism, & Elimination (ADME) .................................................................. 14 

4.2 Toxicological Effects .................................................................................................................................... 14 

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

4.3.1 Completeness of the Toxicology Database ....................................................................................... 16 

4.3.2 Evidence of Neurotoxicity ................................................................................................................ 16 

4.3.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .................................... 16 

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

4.4 Toxicity Endpoint and POD Selections ........................................................................................................ 17 

4.5 Recommendation for Combining Routes of Exposure for Risk Assessment.. .............................................. 18 

5.0 Dietary Exposure and Risk Assessment. ......................................................................................................... 20 

5. 1 Metabolite/Degradate Residue Profile .......................................................................................................... 20 

5.2 Food Residue Profile ..................................................................................................................................... 21 

5.3 Drinking Water Residue Profile .................................................................................................................... 22 

5.4 Dietary (Food + Drinking Water) Risk Assessment ..................................................................................... 23 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................................................. 24 

6. 1 Spray Drift .................................................................................................................................................... 24 

6.2 Residential Bystander Post-Application Inhalation Exposure ....................................................................... 24 

7.0 Aggregate Exposure/Risk Characterization .................................................................................... ................ 25 

8.0 Cumulative Exposure/Risk Characterization .................................................................................................. 25 

9.0 Occupational Exposure/Risk Characterization ............................................................................................... 26 

9.1 Handler Risk Assessment.. ............................................................................................................................ 26 

9.2 Post-Application Risk Assessment ................................................................................................................ 29 

9.2.1 Inhalation Post-Application Risk Assessment.. ................................................................................. 29 

9.2 .2 Restricted Entry Interval ................................................................................................................... 30 

Appendix A. Toxicology Profile and Executive Summaries ...................................................................................... 3l 

Appendix B. Chemical Names and Structures ........................................................................................................... 37 

Page 2 of38 
Flutriafol Human-Health Risk Assessment D411360

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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 the following commodities at 0.01-2.4 ppm: banana (import), coffee (import), field 

corn, popcorn, sweet corn (rotational crop tolerance), cotton (rotational crop tolerance), grape, 

peanut, pome fruit (group 11-09), stone fruit (group 12-10), sugar beet, and soybean. As a result of 

secondary residues, ruminant (cattle, goat, horse, and sheep) and hog meat byproduct tolerances are 

also established for residues of flutriafol at 0.02-0.07 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 

(expires on 31-Dec-2014). 

Cheminova, Inc. requested Section 3 Registrations and permanent tolerances for residues of 

flutriafol in/on strawberries, cucurbit vegetables, fruiting vegetables, tree nuts, wheat, and triticale 

(see Table 2.2.2.1 for proposed tolerances). In addition, the petitioner is requesting the following 

amendments to the peanut, field corn, and popcorn registrations (see Table 2.2.2.1 for tolerances 

proposed as a result of these amendments): (1) removal of the peanut hay feeding restriction and (2) 

reduction in the current 80-day preharvest interval (PHI) for field corn and popcorn forage, stover, 

and grain to 0 days for forage and 7 days for stover and grain. 

Hazard Assessment: Flutriafol was 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. All genotoxicity studies on flutriafol showed no evidence of clastogenicity or 

mutagenicity. Flutriafol is classified as “Not likely to be Carcinogenic to Humans” based on the 

results of the carcinogenicity studies in rats and mice. 

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, a quantitative 

susceptibility was observed (delayed ossification or non-ossification of the skeleton in the fetuses) 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 
Flutriafol Human-Health Risk Assessment D411360

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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-relationship (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 treatment-related 

increases in tumor incidences. 

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 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 4.3.1 and 4.3.2 provides a summary of toxicological doses and 

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

rabbit developmental study (no-observed adverse-effect level (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. 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/recommended, 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 (≤31% acute population-adjusted dose (aPAD); females 

13-49 years occupied the highest % of the aPAD) and chronic (≤51% cPAD; children (1-2 years old) 

had the highest exposure) dietary risk estimates are not of concern to HED. 
Flutriafol Human-Health Risk Assessment D411360

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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. 

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 which 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 

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 (1,2,4-triazole) and 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; however, it was determined that an exposure 

assessment was not necessary for the corn amendment since corn is a registered use site and has been 

assessed previously. The proposed changes do not impact the use pattern or application rate for the 

registered use on corn, and, therefore, a revised occupational exposure assessment is not required. 

The previous corn assessment determined that provided applicators wore gloves and a 5-day reentry 

interval (REI) is established for detasseling corn, the resulting margins of exposure (MOEs) were not 

of concern to HED (these restrictions are on the proposed label). 

The occupational handler exposure and risk estimates for the remaining crops indicate that the shortand intermediate-term dermal and inhalation combined 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 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 of 

100 on the day of application, 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 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 for activities other than detasseling corn, which currently appears on the labels, is adequate for 

the proposed uses.
Flutriafol Human-Health Risk Assessment D411360

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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.”

Review of Human Research: This risk assessment relies in part on data from studies in which adult 

human subjects were intentionally exposed to a pesticide or other chemical. These data, which 

include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to 

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

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

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

be found at the following Agency websites: http://www.epa.gov/pesticides/science/handler-exposure-data.html

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

2.0 Recommendations

Provided the petitioner submits revised Sections B and F, 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 - Nort 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 so as 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 (≤31% aPAD; ≤51% 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. 
Flutriafol Human-Health Risk Assessment D411360

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ORE: In accordance with the updated Part 158 data requirements (2007), one or more 

Dislodgeable Foliar Residue (DFR) studies are required when a pesticide has residential or 

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

revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential 

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

default value for the fraction of the application rate available to be dislodged after a foliar 

application (FAR). This default value is 25% and is based on an analysis of 19 DFR studies 

where the FAR value ranged from 2% to 89%. This value is recommended for use in both 

residential and occupational post-application assessments. Of the analyzed DFR studies, the 

maximum FAR value seen was 89% or 3.6 times higher than the default residue transfer value.

Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the 

level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue 

values would provide an adequate margin of safety for any potentially higher residues seen in a 

chemical-specific DFR study (Guidance for Requiring/Waiving Turf Transferrable Residue 

(TTR) and Dislodgeable Foliar Residue (DFR) Studies. 12-Dec-2012, Exposure Science 

Advisory Council). A DFR study is not required for flutriafol at this time since the dermal 

MOEs are greater than 4 times the LOC (i.e., 400) based on default values for the fraction 

of application rate available for transfer after a foliar application.

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. Based 

on this and 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 and hog meat byproduct tolerances (D362421, T. Bloem, 11-Mar-2009). 

The flutriafol method employed in the ruminant magnitude of the residue studies is based on this 

method. Based on this and since adequate method validation data were provided as part of the 

magnitude of the residue study, HED concludes that the current tolerance-enforcement method is 

adequate to enforce the tolerances associated with this petition. 
Flutriafol Human-Health Risk Assessment D411360

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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.

Table 2.2.2.1: Tolerance Summary.

Commodity Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm) Comments

Strawberry 1.5 1.5 Based on the available field trial data and the Organization of 

Economic Cooperation and Development (OECD) tolerancecalculation procedure, the indicated tolerances are 

recommended (excluding wheat grain). For wheat grain, the 

OECD tolerance-calculation procedure recommended a 0.10-

ppm tolerance but this value was increased to 0.15 ppm to 

harmonize with Codex. In addition, based on the available 

data a wheat bran tolerance of 0.20 ppm would have been 

recommended but this value was increased to 0.30 ppm to 

harmonize with Codex.

HED notes that the currently established field corn grain and 

popcorn RAC and processed commodity tolerances are 

appropriate to cover the proposed label amendments. Based 

on 40 CFR 180.1(g), a tolerance on wheat covers triticale. 

Wheat, forage 30 30

Wheat, hay 15 15

Wheat, straw 9 9.0

Wheat, grain 0.10 0.15

Wheat, bran -- 0.30

Wheat, germ -- 0.25

Triticale, grain 0.10 --

Corn, field, forage1 5.0 5.0

Corn, field, stover1 15 15

Corn, pop, stover1 15 15

Peanut, hay 15 15

Almond hull 15 15 Based on the field trial data and the OECD tolerance 

calculation procedure, a 15-ppm tolerance is recommended. 

Almond 0.6 0.60

Based on the field trial data and the OECD tolerancecalculation procedure, pecan and almond tolerances of 0.02 

ppm and 0.60 ppm were recommended. Since the 

recommended tolerances are not within 5x, HED concludes 

that a crop group tolerance is inappropriate. 

The ChemSAC was consulted to determine if the almond and 

pecan tolerances may be translated to the remaining crops 

within the tree nut crop group 12-14 (almond and pecan are 

the representative crops). The ChemSAC determined that the 

pecan tolerances may be translated to the tree nut crops it 

represents but requested the submission of pistachio residue 

data to determine if translation of the almond data is 

appropriate (ChemSAC minutes 22-Jun-2011). Since the 

pistachio data has not been submitted, HED is recommending 

for tolerances in/on almond, pecan, and those tree nuts which 

are represented by pecan.

Pecan 0.015

0.02

African tree nut 0.015

Brazil nut 0.015

Bur oak 0.015

Butternut 0.015

Cajou 0.015

Cashew 0.015

Castanha-do-maranhao 0.015

Coconut 0.015

Coquito nut 0.015

Dika nut 0.015

Guiana chestnut 0.015

Hazelnut 0.015

Heartnut 0.015

Hickory nut 0.015

Japanese horse-chestnut 0.015

Macadamia nut 0.015

Mongongo nut 0.015

Monkey-pot 0.015

Pachira nut 0.015

Sapucaia nut 0.015

Walnut, black 0.015

Walnut, English 0.015

Vegetable, cucurbit, group 9 0.20 0.30

Based on the available field trial data and the OECD 

tolerance-calculation procedure, tolerances in/on cucumber, 

muskmelon, and summer squash of 0.15 ppm, 0.3 ppm, and 

0.15 ppm, respectively, were determined to be appropriate. 

Since the tolerances are within 5x, HED recommends that a 

crop group tolerance at 0.30 ppm be established. 
Flutriafol Human-Health Risk Assessment D411360

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Table 2.2.2.1: Tolerance Summary.

Commodity Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm) Comments

Vegetable, fruiting, group 8-10 0.60 1.0

Based on the available field trial data and the OECD 

tolerance-calculation procedure, tolerances in/on tomato, bell 

pepper, and nonbell pepper of 0.6 ppm, 0.3 ppm, and 0.6 

ppm, respectively, were determined to be appropriate. Since 

the tolerances are within 5x, a crop group tolerance at 0.60 

ppm would be appropriate. However, a tolerance of 1.0 ppm 

is recommended in order to harmonize with a Codex MRL 

in/on sweet pepper. 

Tomato, paste 1.5 1.5 Based on the field trial and processing data, a tolerance in/on 

tomato paste is required. 

Hog, fat -- 0.01

Based on the livestock maximum reasonable dietary burden 

(MRDB) and the feeding studies, HED concludes that the 

recommended tolerances are appropriate.

The currently established meat byproduct (cattle, goat, horse, 

sheep) tolerances should be deleted. 

Hog, muscle -- 0.01

Cattle, liver 1.0 0.80

Cattle, meat byproducts, except liver 0.10 0.05

Cattle, muscle 0.03 0.05

Cattle, fat -- 0.05

Goat, liver 1.0 0.80

Goat, meat byproducts, except liver 0.10 0.05

Goat, muscle 0.03 0.05

Goat, fat -- 0.05

Horse, liver 1.0 0.80

Horse, meat byproducts, except liver 0.10 0.05

Horse, muscle 0.03 0.05

Horse, fat -- 0.05

Sheep, liver 1.0 0.80

Sheep, meat byproducts, except liver 0.10 0.05

Sheep, muscle 0.03 0.05

Sheep, fat -- 0.05

Milk 0.01 0.01

1

 The currently established field corn forage/stover tolerances and popcorn stover tolerances should be increased to the indicated levels. 

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 or Mexican maximum residue limits (MRLs) in/on the proposed 

commodities (see Attachment 1). There are Codex MRLs for residues of flutriafol in/on peanut 

hay (20 ppm), dried chili peppers (10 ppm), sweet peppers (1 ppm), wheat straw (8 ppm), wheat 

grain (0.15 ppm), and wheat bran (0.3 ppm). The wheat grain and wheat bran tolerances are 

harmonized and HED determined that harmonization of the US fruiting vegetable with the 

Codex sweet pepper MRL was appropriate (HED does not set tolerances in/on dried pepper). 

Harmonization of the peanut hay and wheat straw tolerances were determined to be unnecessary

as these commodities do not normally enter international commerce. 

2.3 Label Recommendations

Provided a revised Section B is submitted which specifies the following rotational crop restrictions, 

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

application rates ≤0.225 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 >0.225 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.

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 10-7 Pa 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 strawberries, 

cucurbit vegetables, fruiting vegetables, tree nuts, wheat, and triticale. In addition, the petitioner 

is requesting the following amendments to the peanut, field corn, and popcorn registrations: (1) 

removal of the peanut hay feeding restriction and (2) reduction in the current 80-day PHI for 

field corn and popcorn forage, stover, and grain to 0 days for forage and 7 days for stover and 

grain. 

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) 12-

hour REI except for detasseling field corn where a 5-day REI is proposed; (2) applicators and 

other handlers must wear long-sleeved shirt and long pants, chemical-resistant gloves, and shoes 

plus socks; (3) application through irrigation is prohibited; (4) treated fields may be rotated to a 

labeled crop immediately after application and to cotton or sweet corn 180 days after application; 

rotation to any other crop is not allowed; (5) adjuvants may be added to the spray solution; and 

(6) for ground application, the minimum spray volume is 10 gallons per acre (GPA); for aerial 

application, the minimum spray volume is 10 GPA for tree nuts, 2 GPA for corn and wheat, and 

5 GPA for all other crops. 

Provided a revised Section B is submitted which specifies the following rotational crop 

restrictions, HED concludes that the proposed application scenarios are supported by the 

available residue chemistry data: (1) application rates ≤0.225 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 >0.225 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

1.04 lb 

ai/gal

suspension 

concentrate 

(SC)

not 

indicated

field corn popcorn gray leaf spot, southern corn blight, northern leaf blight, 

common rust, southern rust, eyespot, anthracnose leaf blight

wheat Rust, powdery mildew, leaf and glume botch, fusarium head 

blight (suppression)

peanut early/late leaf spot, peanut rust, leaf scorch, pepper spot, web 

blotch, and suppression of white mold/southern stem rot

cucurbits (excluding 

muskmelon) powdery mildew, gummy stem blight, and target spot

fruiting vegetables powdery mildew, anthracnose, cercospora leaf spot

tree nuts

scab, shot hole, powdery mildew, alternaria leaf and fruit 

spot, anthracnose, shothole, eastern filbert blight, brown rot 

blossom blight, leaf rust, downy spot, zonate leaf spot

Flutriafol®

250 g/L 

Fungicide

(EPA Reg. No. 

67760-120)1

2.08 lb 

ai/gal

suspension 

concentrate 

(SC)

not 

indicated

muskmelon powdery mildew

strawberry powdery mildew

1

 Full and supplemental labels for each were submitted. 
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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

corn (field corn, field corn grown for seed, and popcorn)

postemergence 

foliar broadcast 

spray

SC

(1.04 lb ai/gal) 0.057-0.114 2 0.228 0-forage7-stover/grain

-An adjuvant may be used prior to the V8 

growth stage and after the VT growth stage.

-7-day retreatment interval (RTI).

-Apply no later than the R4 stage (early 

dough stage)

wheat (spring and winter) and triticale

postemergence 

foliar broadcast 

spray

SC

(1.04 lb ai/gal) 0.081-0.114 2 0.228

0-forage

15-hay

30-grain

-7-day RTI

peanuts

postemergence 

foliar broadcast 

spray

SC

(1.04 lb ai/gal) 0.057-0.114 4 0.455 7 -14-day RTI

strawberry

postemergence 

foliar broadcast 

spray

SC

(2.08 lb ai/gal) 0.081-0.114 4 0.455 0 -7-day RTI

muskmelons (true cantaloupe, cantaloupe, casaba, Crenshaw melon, golden pershaw melon, honeydew melon, honey balls, mango melon, 

Persian melon, pineapple melon, Santa Claus melon, and snake melon

postemergence 

foliar broadcast 

spray

SC

(2.08 lb ai/gal) 0.081-0.114 4 0.455 0 -7-day RTI

cucurbit vegetables (excluding muskmelons): chayote (fruit), Chinese waxgourd, citron melon, cucumber, gherkin, edible gourd (includes 

hyotan, cucuzza, hechima, Chinese okra), Momordica spp. (includes balsam apple, balsam pear, bittermelon, Chinese cucumber), pumpkin,

summer squash, winter squash ( includes butternut squash, calabaza, hubbard squash, acorn squash, spaghetti squash), and watermelon

postemergence 

foliar broadcast 

spray

SC

(1.04 lb ai/gal) 0.081-0.114 4 0.455 0 -7-day RTI

fruiting vegetables (excluding tomatoes): African eggplant, bell pepper, eggplant, martynia, non-bell pepper, okra, pea eggplant, pepino, 

roselle, scarlet eggplant; cultivars and/or hybrids of these)

postemergence 

foliar broadcast 

spray

SC

(1.04 lb ai/gal) 0.114 4 0.455 0 -7-day RTI

bush tomato, cocona, currant tomato, garden huckleberry, goji berry, groundcherry, narnajilla, sunberry, tomatillo, tomato, tree tomato; 

cultivars and/or hybrids of these

postemergence 

foliar broadcast 

spray

SC

(2.08 lb ai/gal) 0.114 4 0.455 0 -7-day RTI

African tree nut, Brazil nut, bur oak, butternut, cajou, cashew, castanha-do-maranhoa, coconut, coquito, dika, Guiana chestnut, hazelnut, 

heartnut, hickory nut, Japanese horse-chestnut, macadamia nut, monogongo nut, monkey-pot, pachira nut, pecan, and sapucaia nut 

postemergence 

foliar broadcast 

spray

SC

(1.04 lb ai/gal) 0.057-0.114 4 0.455 14 -7-day RTI

almonds and walnuts

postemergence 

foliar broadcast 

spray

SC

(2.08 lb ai/gal) 0.057-0.114 4 0.455 14 -7-day RTI
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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 

commodities, 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 short- and intermediate-term occupational exposures (handler and postapplication). 

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. 

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.
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4.0 Hazard Characterization and Dose-Response Assessment

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

assessment (D405792, T. Bloem et al., 27-March-2013). The following flutriafol toxicological 

information is a summary of the information presented in D382902 (K. Lowe et al., 19-Oct2011). 

Since the last risk assessment, HED’s Hazard and Science Policy Committee (HASPOC) 

evaluated all existing hazard and exposure data, as well as current 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.

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 (Category II). It is 

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

III, III and IV, respectively) in rats. Flutriafol 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). 
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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, a 

quantitative susceptibility was observed (delayed ossification or non-ossification of the skeleton 

in the fetuses) 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 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.
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All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. 

Several triazoles are carcinogenic. Even though 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 treatment-related increases in tumor 

incidences. 

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 are 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 

studies in rats, mice, and dogs, or in the long-term toxicity studies in rats, mice, and dogs. A 

developmental-neurotoxicity study (DNT) study is 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 for increased qualitative susceptibility in a prenatal study in rats and rabbits and the two 

generation reproduction study in rats; however, there is no concern for these observations since: 

1) clear NOAELs and LOAELs were established in the 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.
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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, uncertainty factors, 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 uncertainty factor (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 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 appropriate for the 

expected duration of exposure, and is protective for potential neurotoxic effects due to acute 

exposure to flutriafol.

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 was10 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 (RfD): 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 5 mg/kg/day 

to generate the cRfD of 0.05 mg/kg/day for the general population. 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 bodyweight gains, and increased adrenal weights in the females. This NOAEL is lower than any 
Flutriafol Human-Health Risk Assessment D411360

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NOAEL in the database for chronic effects. In addition, the study duration is appropriate for the 

duration of exposure. Both the 28- 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 2-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. This 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 2-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 level of concern 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).

Cancer Classification and Risk Assessment Recommendation: Flutriafol is classified as “Not 

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 aggregated. 
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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. MOE = margin of exposure. LOC = level of concern. 

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

2

Inhalation-absorption factor = 

100%

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 D411360

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5.0 Dietary Exposure and Risk Assessment

D415068, T. Bloem, 23-Apr-2014 (residue chemistry summary for the current action)

D417188, T. Bloem, 23-Apr-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, 

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

[triazole-3,5-

14C]flutriafol may be required. 

Table 5.1.1: 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, and tree nuts

flutriafol, T, TA, and TAA

flutriafol (free)

cotton (Section 18 use)2, 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 

2.2x

5

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 1.3x5

rotational crops (dried roughage 

feed commodities)

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

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

conjugated) and M28

poultry3flutriafol, T, TA, and TAA

ruminant

4

flutriafol, 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 following5: 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

 Decision will be reevaluated if a Section 3 use is requested (additional data may be required). 

3

 HED notes that if the poultry dietary burdens increase, then these conclusions will be revisited and poultry metabolism studies 

conducted as specified in OPPTS 860.1300 with [carbinol14C]flutriafol and [triazole-3,5-

14C]flutriafol may be required. 

4

 HED notes that if the ruminant dietary burden increases, then these conclusions will be revisited and ruminant metabolism studies 

conducted as specified in OPPTS 860.1300 with [carbinol14C]flutriafol and [triazole-3,5-

14C]flutriafol may be required. 

5

 The indicated factors are based on results from the metabolism studies or confined rotational crop study.
Flutriafol Human-Health Risk Assessment D411360

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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 strawberry, 

cucurbit vegetable, fruiting vegetable, and tree nut field trial data which employed the proposed 

application scenario (adequate tomato processing data were also submitted). The geographical 

representation of the data satisfy the requirements specified in OPPTS 860.1500 and the 

analytical methods and storage intervals have also been validated. Based on these data, the 

OECD tolerance-calculation procedure, and taking into consideration the international residue 

limits, HED concludes that the plant tolerances listed in Table 2.2.2.1 for residues of flutriafol 

per se are appropriate. 

The petitioner previously submitted and HED reviewed adequate field corn (translated to 

popcorn), wheat (translated to triticale), and peanut field trial data which employed the proposed 

application scenario (adequate field corn, wheat, and peanut processing data were also submitted; 

D388603, T. Bloem, 16-Jun-2011). These data satisfied the geographical data requirements 

specified in OPPTS 860.1500 and the analytical methods and storage intervals were also 

validated. Due to uncertainties concerning the nature of the residue in ruminants at the dietary 

burden associated with these uses, HED concluded that the feeding of peanut hay should be 

prohibited and recommended for the field corn and popcorn uses provided the PHI was increased 

to 80 days (petitioner withdrew the wheat use). HED notes that the currently-established field 

corn grain, popcorn grain, and peanut nutmeat raw agricultural commodity (RAC) and processed 

commodity tolerances reflect the proposed application scenario. 

As part of the current petition, adequate ruminant metabolism/feeding studies were submitted 

which employed dietary burdens that encompass the maximum reasonably balanced diets 

(MRBDs) associated with the proposed field corn, popcorn, wheat, and peanut application 

scenarios. Based on these data, HED concludes that the livestock 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 anytime and to cotton and 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 and cotton field 

rotational crop data which employed an application rate of 0.228 lb ai/acre and resulted in the 

establishment of tolerances for residues in/on these crops 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 ≤0.225 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 >0.225 lbs 

ai/acre/season - treated field may only be rotated to a labeled crop. 
Flutriafol Human-Health Risk Assessment D411360

Page 22 of 38

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

corn and cotton, 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); cotton - NAFTA Growing 

Zones 6 (n=1), 8 (n=4), and 10 (n=3). 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 and cotton 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 an adequate poultry 

feeding study and, as part of the current request, the petitioner submitted an adequate dairy cattle 

feeding study (D340513, T. Bloem, 11-Mar-2009). Based on these data and the current MRBDs, 

HED concludes that the ruminant tolerances listed in Table 2.2.2.1 are appropriate. Based on the 

hog MRBD and the dairy cattle feeding study submitted as part of the current request, the 

established hog meat byproduct tolerance remains appropriate. Based on the available data, 

residues poultry commodities are anticipated to be insignificant (180.6(a)(3)). 

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. 
Flutriafol Human-Health Risk Assessment D411360

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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/recommended, 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 (≤31% aPAD; females 13-49 years occupied the highest % of the aPAD) and chronic 

(≤51% 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

0.027487 1.1

0.05

0.008896 18

All Infants (<1 year old) 0.065963 2.6 0.019913 40

Children 1-2 years old 0.060251 2.4 0.025382 51

Children 3-5 years old 0.046566 1.9 0.018434 37

Children 6-12 years old 0.029389 1.2 0.010803 22

Youth 13-19 years old 0.020440 <1 0.006565 13

Adults 20-49 years old 0.022428 <1 0.007519 15

Adults 50-99 years old 0.020955 <1 0.007621 15

Females 13-49 years old 0.075 0.023031 31 0.007469 15

1

 95th percentile (tier 1 analysis)
Flutriafol Human-Health Risk Assessment D411360

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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 qualitatively 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

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

assessment was not performed for flutriafol at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and the low vapor pressure (3.0 x 10-9 mmHg, 20°C). 

However, volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

(FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are developed, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for flutriafol.
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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 D411360

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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). The proposed changes to the field corn, field corn grown for 

seed, and popcorn application scenarios do not impact the use pattern or application rate, and, 

therefore, a revised occupational exposure assessment is not required. The previous corn 

assessment determined that, provided applicators were gloves and a 5-day REI is established for 

detasseling corn, the resulting MOEs were not of concern to HED (D383037, K. Lowe, 20-Sep2011); these restrictions are on the proposed label. 

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 Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural 

Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force 

(ORETF) database; and the Agricultural Reentry Task Force (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, groundboom, and airblast 

applications; (2) applying sprays via aerial, airblast 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. 
Page 27 of 38

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

Cucurbits, Pecans (and other tree 

nuts), Almonds and Walnuts, Peppers 

(and Other Fruiting Vegetables), 

Tomatoes, Strawberry

220 

(baseline)

0.219 

(baseline)

0.114

350 0.0267 280 0.000127 59,000 280

Cotton, Wheat (spring and winter) 

and Triticale, 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

Cucurbits, Pecans (and other tree 

nuts), Almonds and Walnuts, Peppers 

(and Other Fruiting Vegetables), 

Tomatoes, Strawberry

220 (baseline)

0.114

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

Wheat (spring and winter) and 

Triticale, Sorghum 200 0.0153 490 0.0000723 100,000 490

Cotton 0.26 200 0.0347 220 0.000165 45,000 220

Airblast app.

of liquid 

formulation

Pecans (and other tree nuts), Almonds 

and Walnuts 0.114 40 0.00304 2,500 0.0000145 520,000 2,500

Applicator

Aerial spray 

app.

Brassica (cole) leafy vegetables, 

Celery, Leafy Vegetables, Cucurbits, 

Pecans (and other tree nuts), Almonds 

and Walnuts, Peppers (and Other 

Fruiting Vegetables), Tomatoes, 

Strawberry

2.08

(engineering

control)

0.0049

(engineering 

control)

0.114

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

Cotton, Wheat (spring and winter) 

and Triticale, Sorghum 1200 0.000867 8,700 0.00000971 770,000 8,600
Flutriafol Human-Health Risk Assessment D411360

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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

Groundboom 

spray app.

Cucurbits, Pecans (and other tree

nuts), Almonds and Walnuts, Peppers 

(and Other Fruiting Vegetables), 

Tomatoes, Strawberry 78.6

(baseline)

0.34

(baseline)

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

Wheat (spring and winter) and 

Triticale, 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

Airblast 

spray app.

Pecans (and other tree nuts), Almonds 

and Walnuts

1770

(baseline)

4.71

(baseline) 0.114 40 0.0246 300 0.000312 24,000 300

Flagger

Flagger for 

aerial spray 

app.

Cucurbits, Pecans (and other tree 

nuts), Almonds and Walnuts, Peppers 

(and Other Fruiting Vegetables), 

Tomatoes, Strawberry, Cotton, Wheat 

(spring and winter) and Triticale, 

Sorghum

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 (Reg. No. 67760-REN, 67760-75, 67760-REA).

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) ÷ 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).
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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

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

assessment was not performed for flutriafol at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (3.0 x 10-9 mmHg, 20°C). 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory 

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010

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

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the ARTF and may, as appropriate, develop policies and procedures, to 

identify the need for and, subsequently, the way to incorporate occupational post-application 

inhalation exposure into the Agency's risk assessments. If new policies or procedures are put 

into place, the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for flutriafol.

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. 

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and 

mechanical harvesting of tree nuts is another potential source of post-application inhalation 

exposure. However, the airblast applicator scenario is believed to represent a reasonable worst 

case surrogate estimate of post-application inhalation exposure during these dusty mechanical 

harvesting activities. The non-cancer inhalation risk estimate for commercial airblast application 

is not of concern (i.e., MOE > 100).
Flutriafol Human-Health Risk Assessment D411360

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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.

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

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

Cucurbits Hand-set Irrigation 1,900

0.114 0.32

0.015 510

Pecans (and other 

tree nuts), 

Almonds and 

Walnuts

Hand harvesting 1,400 0.011 690

Peppers (and 

Other Fruiting 

Vegetables), 

Tomatoes

Hand-set Irrigation 1,900 0.015 510

Wheat (spring 

and winter) and 

Triticale

Scouting 1,100 0.009 880

Strawberry Hand harvesting 1,100 0.009 880

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 (22-Feb-2014)

T. Bloem:S10945:Potomac Yard 1:703-605-0217:7509P:RAB1

Appendix A. Toxicology Profile and Executive Summaries

Appendix B. Chemical Names and Structures
Flutriafol Human-Health Risk Assessment D411360

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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

no

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 -
Flutriafol Human-Health Risk Assessment D411360

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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 D411360

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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 hypertropy 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
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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-

9.0x10-5treated vs. 3.0x10-5controls) 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 (6.5x10-5treated vs. 

1.2x10-5controls) 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 (>10x10-5) 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.
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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.
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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/cm2 dose 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/cm2 dose 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.
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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-triaole-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 D411360

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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

O

OH

HO

OH OH

O

O

HO

N

N

N

F

HO S O

O

O

F