Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 1 of 45

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

DATE: 19-OCT-2011

SUBJECT: Flutriafol: Human Health Risk Assessment for Proposed Uses on Corn, Grapes, 

Peanuts, Pome Fruit (Crop Group 11), Stone Fruit (Crop Group 12), Sugar Beets, 

Wheat, Barley, Triticale, Buckwheat, Oats, Rye, Teosinte, and Imported Bananas.

PC Code: 128940 DP Barcodes: D382902, D382945

Decision Nos.: 438881, 438682 Registration No.: 67760-75

Petition Nos.: 0F7771, 0E7772, 0F7740 Regulatory Action: Section 3

Risk Assessment Type: Single Chemical/ 

Aggregate

Case No.: NA

TXR No.: NA CAS No.: 76674-21-0

MRID No.: NA 40 CFR: §180.629

FROM: Kelly M. Lowe, Environmental Scientist

Thomas Bloem, Chemist

Anwar Y. Dunbar, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

THROUGH: George F. Kramer, Ph.D., Branch Senior Chemist

Dana Vogel, Branch Chief 

RAB1/HED (7509P)

TO: Mary Waller, RM 21

Registration Division (RD; 7505P)

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

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from all registered 

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

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

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

and occupational/residential exposure assessment were provided by Kelly Lowe (RAB1), the 

dietary risk assessment and residue chemistry data review by Thomas Bloem (RAB1), the hazard 

characterization was provided by Anwar Dunbar (RAB1), and the drinking water assessment by 

James K. Wolf of the Environmental Fate and Effects Division (EFED).
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 2 of 45

Table of Contents

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

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

2.1 Data Deficiencies/Conditions of Registration ..........................................................................................6

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

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

2.2.2 International Harmonization............................................................................................................8

2.2.3 Recommended Tolerances................................................................................................................8

2.2.4 Revisions to Petitioned-For Tolerances.........................................................................................10

2.3 Label Recommendations .........................................................................................................................10

2.3.1 Recommendations from Residue Reviews.....................................................................................10

2.3.2 Recommendations from Occupational Assessment......................................................................10

3.0 Ingredient Profile ..........................................................................................................................................10

3.1 Chemical Identity.....................................................................................................................................11

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

3.3 Proposed Use Pattern...............................................................................................................................11

3.4 Anticipated Exposure Pathways .............................................................................................................13

3.5 Consideration of Environmental Justice ................................................................................................14

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

4.1 Toxicology Studies Available for Analysis.............................................................................................14

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) .........................................................15

4.2.1 Dermal Absorption..........................................................................................................................15

4.3 Toxicological Effects ................................................................................................................................15

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

4.4.1 Completeness of the Toxicology Database.....................................................................................16

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

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

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

4.5 Toxicity Endpoint and POD Selections..................................................................................................17

4.5.1 Dose-Response Assessment.............................................................................................................17

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

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

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment..19

4.6 Endocrine Disruption...............................................................................................................................21

5.0 Dietary Exposure and Risk Assessment......................................................................................................22

5.1 Metabolite/Degradate Residue Profile....................................................................................................22

5.1.1 Summary of Plant and Animal Metabolism Studies ....................................................................22

5.1.2 Summary of Environmental Degradation.....................................................................................25

5.1.3 Comparison of Metabolic Pathways..............................................................................................25

5.1.4 Residues of Concern Summary and Rationale .............................................................................26

5.2 Food Residue Profile ................................................................................................................................27

5.3 Drinking Water Residue Profile .............................................................................................................28

5.4 Dietary (Food + Drinking Water) Risk Assessment..............................................................................28

6.0 Residential (Non-Occupational) Exposure/Risk Characterization...........................................................29

6.1 Residential Bystander Post-application Inhalation...............................................................................29

6.2 Spray Drift................................................................................................................................................30

7.0 Aggregate Exposure/Risk Characterization ...............................................................................................30

8.0 Cumulative Exposure/Risk Characterization.............................................................................................31

9.0 Occupational Exposure/Risk Characterization..........................................................................................31

9.1 Short- and Intermediate-Term Handler Risk........................................................................................31

9.2 Short- and Intermediate-Term Post-Application Risk .........................................................................35

9.2.1 Dermal Post-Application Risk........................................................................................................35

9.2.2 Inhalation Post-Application Risk...................................................................................................37

10.0 References......................................................................................................................................................37

Appendix A. Toxicology Profile and Executive Summaries .................................................................................39

A.1 Toxicology Data Requirements..................................................................................................................39

A.2 Toxicity Profiles.........................................................................................................................................40
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 3 of 45

1.0 Executive Summary

Flutriafol [(±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethanol] is a systemic, 

triazole fungicide that can be used as a systemic eradicant and a protectant. It has a postinfection activity that can stop pathogen establishment in the early phases of disease 

development. Flutriafol is currently registered for application to apples and soybeans with 

tolerances ranging from 0.02 to 2.2 ppm (40 CFR §180.629).

Cheminova has proposed a Section 3 Registration (PP# 0F7771) for application of flutriafol to 

corn, grapes, peanuts, pome fruit (crop group 11), stone fruit (crop group 12), sugar beets, wheat, 

barley, triticale, buckwheat, oats, rye, and teosinte. Petitions were also submitted to establish 

tolerances for residues in rotational crops (cotton and corn; PP# 0F7740) and a tolerance for 

imported banana (PP# 0E7772). 

The proposed end-use product for the Section 3 registrations is Topguard®Fungicide (EPA Reg 

# 67760-75), a 1.04 pound (lb) active ingredient (ai)/gallon formulation. The maximum 

application rate proposed for corn, peanuts, stone fruit, sugar beets, wheat, barley, triticale, 

buckwheat, oats, rye, and teosinte is 14 fl oz/A (0.114 lb ai/A). The maximum application rate 

proposed for pome fruit is 13 fl oz/A (0.106 lb ai/A) and the maximum application rate proposed 

for grapes is 10 fl oz/A (0.08 lb ai/A). The labels submitted for imported bananas indicate a 

range of application rates from 0.069 to 0.167 lb ai/A. 

Hazard Assessment: Flutriafol has 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). 

Flutriafol appears to be generally equally toxic to rats, mice, and dogs with all three species 

having similar (within one order of magnitude) no-observed adverse-effect levels 

(NOAELs)/lowest-observed adverse-effect levels (LOAELs). The target organ is the liver in 

dogs, rats, and mice. Hepatotoxicity occurred at similar dose levels across several species and 

durations of exposure. Flutriafol is considered to be ―Not likely to be Carcinogenic to Humans‖ 

based on the results of the carcinogenicity studies in rats and mice. The results of the rat chronic 

toxicity/carcinogenicity study and the mouse carcinogenicity study are negative for 

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

mutagenicity. 

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 multigenerational

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 (skeletal malformations and embryo lethality). Although 

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

developmental effects were more severe than those observed in the dams. For rabbits, 

intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals. 

Similar to what was seen in the developmental study in rats, offspring effects occurred at the 

same dose level as parental effects in the multi-generation toxicity study in rats. However, the 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 4 of 45

nature of the effects in the offspring was more severe than in the dams. The level of concern is 

low for these developmental/ offspring effects because: 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; and 4) the chronic reference dose is greater than 300-fold lower than the doses at 

which the offspring effects were observed in the 2-generation reproduction studies. 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 (DNT) study is not 

required.

An in vivo rat dermal-absorption study 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 conservative dermal-absorption value of 21% is considered appropriate for 

dermal risk assessments. There is an absence of systemic toxicity at 1000 mg/kg/day in the 28-

day dermal toxicity study in the rat.

Dose Response Assessment: The acute and chronic reference doses (aRfD and cRfD) were 

calculated by dividing the NOAEL by 100 (10X for interspecies extrapolation and 10X for 

intraspecies variation). Since the Food Quality Protection Act (FQPA) Safety Factor (SF) has 

been reduced to 1X, the acute and chronic population-adjusted doses (aPAD and cPAD) are 

equal to the aRfD and cRfD, respectively. The aPAD for females 13+ years old is 0.075 

mg/kg/day and the aPAD for the general population is 2.5 mg/kg/day. The cPAD for the general 

population is 0.05 mg/kg/day. The point of departure (POD) for short- and intermediate-term 

dermal and inhalation risk assessments is 7.5 mg/kg/day. The dermal-absorption factor was 

estimated to be 21%. A 100% oral-equivalent inhalation absorption factor is assumed. The level 

of concern (LOC) for occupational dermal and inhalation exposures are for margins of exposure 

(MOEs) <100. 

FQPA SF Decision: The flutriafol risk assessment team recommends that the 10X FQPA SF be 

reduced to 1X since the toxicology database is complete, there are no residual uncertainties for 

pre and/or post natal toxicity, and the conservative nature of the dietary exposure analysis (i.e., 

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

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-FCIDTM, ver. 2.03) which 

incorporates the food consumption data from the United States Department of Agriculture 

(USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 1998). The 

proposed uses on field corn, popcorn, and small grains were not included in the dietary analysis, 

since HED is not recommending for those registrations due to several residue chemistry data 

deficiencies (issues concerning the nature/magnitude of the residue in ruminants at the dietary 

burdens associated with these crops). The analysis did consider the registered crops, the 

remaining proposed crops, and residues in/on field corn, popcorn, and cotton as a result of 

rotation to a treated field. 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 5 of 45

The acute and chronic analyses assumed tolerance-level residues, 100% crop treated, and 

modeled drinking water estimates. The default DEEMTM (ver 7.81) processing factors were 

retained for all commodities except for apple juice, grape juice and dried prunes since adequate 

processing studies were submitted for those commodities (processing factors reduced to 1). The 

resulting acute (≤24% aPAD; females 13-49 years old were the most highly exposed subgroup) 

and chronic [≤42% cPAD; all infants (<1 year old) were the most highly exposed subgroup] 

exposure estimates are not of concern to HED. 

Residential (Non-Occupational) Exposure and Risk Assessment: There are no registered or 

proposed uses of flutriafol that would result in residential exposure; therefore, a residential 

exposure assessment was not conducted.

Aggregate-Risk Estimates: Acute and chronic aggregate risks are assessed based on dietary 

exposure from food and drinking water sources only and are the same as reported for acute and 

chronic dietary exposure. Therefore, acute and chronic aggregate risks to flutriafol are not of 

concern to HED. There are no registered or proposed uses of flutriafol that would result in 

residential exposure; therefore, short- and intermediate-term aggregate risks were not assessed.

Application of flutriafol also results in exposure to 1,2,4-triazole (T) and its conjugated 

metabolites, which 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. Since the requested flutriafol uses do not 

result in an increase in the dietary or residential exposure estimates to T and its conjugated 

metabolites, this previous assessment remains valid. 

Occupational Exposure and Risk Assessment: Based on the proposed uses, occupational 

handlers may be potentially exposed to flutriafol during mixing/loading, applying, and flagging 

activities associated with aerial and groundboom applications. Short- and intermediate-term 

dermal and inhalation risks were assessed with a baseline layer of clothing, and with additional 

personal-protective equipment (PPE). The combined dermal and inhalation exposure risks for 

mixer/loaders are not of concern (i.e., MOEs >100) at baseline for all scenarios except for 

mixers/loaders for aerial application to corn, wheat (spring and winter), barley, triticale, 

buckwheat, oats, rye, and teosinte. For these high acreage crops, mixer/loaders must wear 

protective gloves. Gloves are listed as PPE on the proposed label; therefore, HED does not have 

concerns for this scenario. Following flutriafol application, occupational post-application 

exposure is possible. Post-application risks are not of concern (i.e., MOEs >100) on day 0 (12 

hours after application) for all crops and activities, except for detasselling of corn and 

girdling/turning of grapes. For these crop/activity combinations, an acceptable MOE (i.e., MOE 

> 100) is not reached until Day 5 after application. The high-contact activities for grapes are 

only expected to occur for cultivation of table grapes. The high-contact activity for corn is only 

expected to occur for field corn or popcorn grown for seed. RD should ensure that the 

appropriate restricted-entry interval (REI) is added to the label for these crops. In addition, 

under 40 CFR Part 158:1070, dislodgeable foliar residue (DFR) data are required to further 

refine risk estimates. 

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 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 6 of 45

Populations and Low-Income Populations,‖ 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

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 to determine their dermal and 

inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database 

(PHED), the Agricultural Handlers Exposure Task Force (AHETF) and the Agricultural Reentry 

Task Force (ARTF) Database. EPA has reviewed all the studies in these multi-pesticide generic 

exposure databases, and on the basis of available evidence has found them to have been neither 

fundamentally unethical nor significantly deficient relative to standards of ethical research 

conduct prevailing when they were conducted. There is no regulatory barrier to continued 

reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of 

Human Subjects of Research (40 CFR Part 26) have been satisfied.

Recommendations for Tolerances: A revised Section F is requested, that eliminates those 

commodities for which tolerances are unnecessary or inappropriate and specifies the correct 

commodity definition and/or numerical tolerance (see Table 2.2.3). As a result of the proposed 

uses, HED is establishing rotational crop tolerances [180.629(d)]. The tolerance expression for 

180.629(d) should be as follows (the current tolerance expression for 180.629(a) is appropriate): 

180.629(d): Tolerances are established for residues of flutriafol, including its metabolites and 

degradates, in or on the commodities listed below. Compliance with the following tolerance 

levels is to be determined by measuring only flutriafol ((±)-α-(2-fluorophenyl)-α-(4-

fluorophenyl)-1H-1,2,4-triazole-1-ethanol).

2.0 HED Recommendations

HED is not recommending for the proposed field corn, popcorn, and small grains registration due 

to several residue chemistry data deficiencies including issues concerning the nature/magnitude 

of the residue in ruminants at the dietary burdens associated with these crops. For a complete 

discussion of the residue chemistry data deficiencies associated with application of flutriafol to 

field corn, popcorn, and small grains see D388603 (T. Bloem, 16-Jun-2011). 

For the remaining proposed crops [pome fruit, stone fruit, grape, banana (import tolerance), 

peanut, and sugar beet], HED concludes that the toxicological, residue chemistry, and 

occupational/residential databases support the establishment of a conditional registration and the 

permanent tolerances listed in Section 2.2.3, provided revised Sections B and F are submitted. 

An unconditional registration may be established upon resolution of the deficiencies cited in 

Section 2.1.

2.1 Data Deficiencies/Conditions of Registration

Toxicology

None.

Residue Chemistry
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 7 of 45

HED is not recommending for the proposed field corn, popcorn, and small grains registration 

due to several residue chemistry data deficiencies including issues concerning the 

nature/magnitude of the residue in ruminants at the dietary burdens associated with these 

crops. For a complete discussion of the residue chemistry data deficiencies associated with 

application of flutriafol to field corn, popcorn, and small grains see D388603 (T. Bloem, 16-

Jun-2011). 

The following residue chemistry deficiencies are for the remaining proposed crops [pome 

fruit, stone fruit, grape, banana (import tolerance), peanut, and sugar beet]:

 Revised Section B with the following changes: 

 Removal of corn (field corn, field corn for seed, and popcorn) and small grain 

application instructions.

 Include minimum spray volume of 10 gallons per acre (GPA) for grape, pome 

fruit, and stone fruit.

 Add language to indicate that feeding of peanut hay to livestock is prohibited.

 Add language to indicate that addition of adjuvants to the sugar beet, peanut, 

grape, stone fruit, and pome fruit spray mixtures is prohibited.

 Add directions to indicate that following application to peanut, treated fields 

may only be rotated to a labeled crop.

 Add directions to indicate that following application to all other crops, treated 

fields may be rotated to a labeled crop at any time or may be rotated to cotton, 

sweet corn, field corn, field corn grown for seed, and popcorn 180 days after 

application; rotation to any other crop is prohibited. 

o Revised Section F specifying the following tolerances for residues of flutriafol: 

 Primary crops (§180.629(a))

fruit, pome, group 11-09: 0.40 ppm

fruit, stone, group 12-10: 1.5 ppm

grape: 1.5 ppm

grape, raisin: 2.4 ppm

banana: 0.30 ppm

peanut: 0.09 ppm

beet, sugar: 0.08 ppm

 Rotational crops (§180.629(d))

corn, sweet, forage: 0.09 ppm

corn, sweet, stover: 0.07 ppm

corn, sweet, kernel plus cob with husk removed: 0.01 ppm

corn, field, forage: 0.09 ppm

corn, field, stover: 0.07 ppm

corn, field, grain: 0.01 ppm

corn, field, refined oil: 0.02 ppm

corn, pop, stover: 0.07 ppm

corn, pop: 0.01 ppm

cotton, undelinted seed: 0.01 ppm

cotton, gin byproducts: 0.02 ppm 

 The following field rotational crop residue data conducted as specified in OPPTS 

860.1900 are requested: 

 sweet corn - North American Free Trade Agreement (NAFTA) Growing 

Zones 10 (n=1) and 11 (n=1), and

 cotton - NAFTA Growing Zones 8 (n=4) and 10 (n=3). 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 8 of 45

Occupational and Residential Exposure

Post-application dermal risks were identified for detasselling of corn and girdling/turning of 

grapes. For these crop/activity combinations, an acceptable MOE (i.e., MOE > 100) is not 

reached until Day 5 after application. The high-contact activities for grapes are only 

expected to occur for cultivation of table grapes. The high-contact activity for corn is only 

expected to occur for field corn or popcorn grown for seed. RD should ensure that the 

appropriate REI is added to the label for these crops. In addition, under 40 CFR Part 

158:1070, DFR data is required to further refine risk estimates. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical 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). The method employed in the 

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

adequate to enforce the recommended tolerances. 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). 

Livestock

HED has previously concluded that method ICIA AM00306 (revisions of 13-Aug-2007 and 8-

Oct-2007) is appropriate for enforcement of the currently established ruminant liver tolerances 

and forwarded the method to the Food and Drug Administration (FDA) for inclusion in the 

Pesticide Analytical Manual (PAM) (D362421, T. Bloem, 11-Mar-2009). HED is not currently 

recommending for the establishment of any new livestock tolerances. 

2.2.2 International Harmonization

Codex, Canadian, and Mexican maximum residue limits (MRLs) have not been established for 

flutriafol; therefore, harmonization is not an issue.

2.2.3 Recommended Tolerances

Table 2.2.3 is a summary of the HED-recommended tolerances for residues of flutriafol. As a 

result of the proposed uses, HED is establishing rotational crop tolerances (§180.629(d)). The 

tolerance expression for §180.629(d) should be as follows (the current tolerance expression for 

§180.629(a) is appropriate): 

§180.629(d): Tolerances are established for residues of flutriafol, including its metabolites and 

degradates, in or on the commodities listed below. Compliance with the following tolerance 

levels is to be determined by measuring only flutriafol ((±)-α-(2-fluorophenyl)-α-(4-

fluorophenyl)-1H-1,2,4-triazole-1-ethanol). 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 9 of 45

A revised Section F is requested, which eliminates those commodities for which tolerances are 

unnecessary or inappropriate and which specifies the correct tolerance definition, commodity 

definition, and/or numerical tolerance. 

Table 2.2.3. Tolerance Summary for Flutriafol.

Commodity

Proposed 

Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments

§180.629(a)

fruit, pome, group 11-09 0.60 0.40 Revised Section F with the correct commodity 

definition and/or tolerance level is requested. 

a Sugar beet top are no longer considered feed 

commodity and HED is requesting a revised Section 

B prohibiting the feeding of peanut hay to livestock; 

therefore, tolerances on these commodities are not 

recommended. 

b Based on the sugar beet processing study, refined 

sugar, molasses, and dried pulp tolerances are 

unnecessary. 

c HED concludes that the currently established 

ruminant and hog tolerances are adequate.

fruit, stone, group 12-10 0.80 1.5

grape 1.1 1.5

grape, raisin 2.5 2.4

banana 0.50 0.30

peanut 0.08 0.09

peanut, hay 18 --

a

beet, sugar 0.15 0.08

beet, sugar, top 2.5 --

a

beet, sugar, refined 0.70 --

b

beet, sugar, molasses 1.0 --

b

beet, sugar, dried pulp 1.0 --

b

cattle, liver 0.12 --

c

horse, liver 0.12 --

c

goat, liver 0.12 --

c

sheep, liver 0.12 --

c

milk 0.02 -- HED determined that registration for application 

of flutriafol to these crops and/or establishment of 

these tolerances is inappropriate; additional 

residue chemistry data are required. 

corn, field, forage 4.0 --

corn, field, stover 6.0 --

corn, field, grain 0.01 --

corn, field, flour 0.03 --

corn, field, refined oil 0.07 --

corn, field, meal 0.03 --

corn, pop 0.01 --

corn, pop, stover 6.0 --

wheat, forage 25 --

wheat, hay 9.0 --

wheat, straw 6.0 --

wheat, grain 0.15 --

wheat, bran 0.20 --

wheat, germ 0.20 --

triticale, grain not proposed --

barley, hay 9.0 --

barley, straw 6.0 --

barley, grain 0.15 --

barley, grain, bran 0.20 --

buckwheat, grain 0.15 --

oat, forage 25 --

oat, hay 9.0 --

oat, straw 6.0 --

oat, grain 0.15 --

oat, grain, bran 0.20 --

rye, forage 25 --

rye, straw 6.0 --

rye, grain 0.15 --

§180.629(d)

corn, sweet, forage 0.05 0.09 A revised Section F is requested which proposes the 

correct commodity definition and/or numerical 

tolerance is requested. 

corn, sweet, stover 0.09 0.07

corn, sweet, K+CWHR10.01 0.01

corn, field, forage 0.10 0.09

corn, field, stover 0.07 0.07

corn, field, grain 0.01 0.01
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 10 of 45

Table 2.2.3. Tolerance Summary for Flutriafol.

Commodity

Proposed 

Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments

corn, field, refined oil -- 0.02

corn, pop, stover not proposed 0.07

corn, pop not proposed 0.01

cotton, undelinted seed 0.01 0.01

cotton, gin byproducts 0.05 0.02

1. K + CWHR = kernel plus cob with husk removed.

2.2.4 Revisions to Petitioned-For Tolerances

HED is not recommending for the proposed field corn, popcorn, and small grains registration due 

to several residue chemistry data deficiencies including issues concerning the nature/magnitude 

of the residue in ruminants at the dietary burdens associated with these crops [for a full 

discussion see D388603 (T. Bloem, 16-Jun-2011)]. As a result, revisions to the currently 

established liver (cattle, goat, horse, and sheep) tolerances and establishment of a milk tolerance 

are unnecessary. In addition, sugar beet tops are no longer considered feed commodity and HED 

is requesting a revised Section B prohibiting the feeding of peanut hay to livestock; therefore, 

tolerances on these commodities are not recommended. For the remaining crops, the HEDrecommended tolerances are based on the magnitude of the residue data and the Organization for 

Economic Co-operation and Development (OECD) MRL Calculator. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Removal of corn (field corn, field corn for seed, and popcorn) and small grain application 

instructions.

Include minimum spray volume of 10 GPA for grape, pome fruit, and stone fruit.

Add language to indicate that feeding of peanut hay to livestock is prohibited.

Add language to indicate that addition of adjuvants to the sugar beet, peanut, grape, stone 

fruit, and pome fruit spray mixtures is prohibited.

Add directions to indicate that following application to peanut, treated fields may only be 

rotated to a labeled crop.

Add directions to indicate that following application to all other crops, treated fields may be 

rotated to a labeled crop at any time or may be rotated to cotton, sweet corn, field corn, field 

corn grown for seed, and popcorn 180 days after application; rotation to any other crop is 

prohibited. 

2.3.2 Recommendations from Occupational Assessment

RD should ensure that the appropriate REI is added to the label. 

3.0 Ingredient Profile
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 11 of 45

3.1 Chemical Identity

Table 3.1. Flutriafol Nomenclature.

Chemical structure

Common name Flutriafol

Company experimental name PP450 (ICI/Syngenta until 2001)

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

End-use product (EP) 1.04 lb ai/gal FlC formulation (TopguardTM Fungicide, EPA File Symbol No. 67760-

XXX)

3.2 Physical/Chemical Characteristics

Table 3.2. Physicochemical Properties of Flutriafol.

Melting point/range -- Not available

pH 6.1 in a 1% aqueous dilution CSF for Flutriafol Technical dated 

Density 0.99 g/cm3 3/23/07

Water solubility 95 mg/L at 20 oC

PP#7F7197 administrative materials

Solvent solubility

At 21 oC g/L

1,2-Dichloroethane 19-20

Acetone 116-135

Ethyl acetate 29-34

Methanol 115-134

n-Heptane <10

Xylene <10

Vapor pressure 4 x 10-7Pa at 20 oC

Dissociation constant, pKa 2.3 at 25 oC

Octanol/water partition coefficient, Log(KOW) log POW = 2.3 at 20 oC

UV/visible absorption spectrum -- Not available

3.3 Proposed Use Pattern

The petitioner submitted a draft label for the 1.04 lb ai/gal suspension-concentrate (SC) 

formulation (Topguard®Fungicide, EPA File Symbol No. 67760-75; equivalent to flowable 

concentrate (FlC)). Table 3.3.1 is a summary of the proposed formulation, crops, and targeted 

pests. Table 3.3.2 is a summary of the proposed application scenarios. Tables 3.3.1 and 3.3.2 

also include a summary of the Colombian, Brazilian, and Malaysian labels provided by the 

petitioner concerning application to imported bananas. 

For the remaining proposed crops, HED requests that the label be revised to indicate the 

following: (1) removal of corn (field corn, field corn for seed, and popcorn) and small grain 

application instructions; (2) minimum spray volume of 10 GPA for grape, pome fruit, and stone 

fruit; (3) feeding of peanut hay to livestock is prohibited; (4) addition of adjuvants to the sugar 

beet, peanut, grape, stone fruit, and pome fruit spray mixtures is prohibited; (5) following 

N N

N

F

OH

F
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 12 of 45

application to peanut, treated fields may only be rotated to a labeled crop; and (6) following 

application to all other crops, treated fields may be rotated to a labeled crop at any time or may 

be rotated to cotton, sweet corn, field corn, field corn grown for seed, and popcorn 180 days after 

application; rotation to any other crop is prohibited. 

Table 3.3.1. Summary of Proposed End-Use Products.

Trade Name EPA Reg. 

No. Concentration Formulation Type Label Date Target Crops Target Pests

Proposed U.S. Section 3 Registrations

Topguard®

Fungicide 7969-278 1.04 lb ai/gal SC not indicated

field corn

gray leaf spot, northern/southern 

leaf blight, rust, eyespot, 

anthracnose

grapes powdery mildew, black rot

peanuts early and late leaf spot, leaf rust, 

leaf scorch/pepperspot, web blotch

pome fruit scab, powdery mildew, quince 

rust, cedar apple rust, pear scab

stone fruit brown rot, powdery mildew, 

cherry leaf spot

sugar beets cercospora leafspot, powdery 

mildew

small grains rust, powdery mildew, leaf and 

glum blotch, fusarium head blight

Banana (import tolerance)

Pointer®250 

SC (Colombia)

-- 250 g ai/liter;

SC not 

indicated banana

black sigatoka

Potenzor®

(Brazil) -- 125 g ai/ liter leaf spot; black leaf straek

Pointer Racun 

Kulat -- 125 g ai/liter yellow sigatoka

Table 3.3.2. Summary of Proposed Application Scenarios.

App. Timing; 

Type; and 

Equip.

Formulation 

(EPA Reg. 

No.)

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)

Post-emergence; 

foliar broadcast

1.04 lb/gal SC

(67760-75) 0.057-0.114 2 0.228

0 - forage

7 - stover 

and grain

Apply in a minimum of 10 GPA 

with ground equipment or in a 

minimum of 5 GPA with aerial 

equipment. Minimum retreatment 

interval (RTI) of 7 days.

grape

Post-emergence 

(beginning at 6-

10 inch shoots); 

foliar broadcast

1.04 lb/gal SC

(67760-75) 0.065-0.081 6 0.488 14

Sufficient water to insure uniform 

coverage. Minimum RTI of 14 

days.

peanut

Post-emergence; 

foliar broadcast

1.04 lb/gal SC

(67760-75) 0.057-0.114 4 0.455 7

Apply in a minimum of 10 GPA. 

Minimum RTI of 14 days.

pome fruit 

(apple, crabapple, loquat, mayhaw, pear, Oriental pear, and Quince)

Post-emergence; 

foliar broadcast

1.04 lb/gal SC

(67760-75) 0.065-0.106 4 0.423 14

Sufficient water to insure uniform 

coverage. Minimum RTI of 10 

days.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 13 of 45

Table 3.3.2. Summary of Proposed Application Scenarios.

App. Timing; 

Type; and 

Equip.

Formulation 

(EPA Reg. 

No.)

App. Rate

(lb ai/acre)

Max. #. 

App. per 

Season

Max. Seasonal 

App. Rate (lb 

ai/acre)

PHI

(days) Use Directions and Limitations

stone fruit 

(sweet cherry, tart cherry, apricot, nectarine, peach, plum, chicksaw plum,

damson plum, Japanese plum, plumcot, and prune)

Post-emergence; 

foliar broadcast

1.04 lb/gal SC

(67760-75) 0.114 4 0.455 7

Sufficient water to insure uniform 

coverage. Minimum RTI of 7 days.

sugar beet

Post-emergence; 

foliar broadcast

1.04 lb/gal SC

(67760-75) 0.081-0.114 2 0.228 21

Apply in a minimum of 10 GPA 

with ground equipment or in a 

minimum of 5 GPA with aerial 

equipment. Minimum RTI of 21 

days.

wheat (spring and winter), barley, triticale, buckwheat, oats, rye, teosinte

Post-emergence; 

foliar broadcast

1.04 lb/gal SC

(67760-75) 0.057-0.114 2 0.228

0 - forage

15 - hay

30 - grain

Apply in a minimum of 10 GPA 

with ground equipment or in a 

minimum of 5 GPA with aerial 

equipment. Minimum RTI of 7 

days.

banana (import tolerance)

Post-emergence; 

foliar broadcast

125-250 g ai/L 

SC

0.089

(Colombia)

0.167

(Brazil)

0.138

(Malaysia)

8

(Colombia)

4

(Brazil)

5

(Malaysia)

0.712

(Colombia)

0.668

(Brazil)

0.690

(Malaysia)

0

(Colombia)

3

(Brazil)

14

(Malaysia)

The Brazilian label indicates the 

following: apply using knapsack or 

tractor mounted spray using a 

mineral oil adjuvant (25% or 100%); 

spray volumes of 4-5 GPA; and RTI 

= 14 days. 

The Colombian label indicates the 

following: dilute with water and 

apply using conventional equipment 

(spray volume and RTI are not 

indicated). 

The Malaysian label indicates the 

following: apply using knapsack or 

motorized sprayer; addition of a 

nonionic surfactant (0.1%) is 

recommended; spray volumes of 

~50 GPA; and RTI = 14 days. 

3.4 Anticipated Exposure Pathways

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

flutriafol on corn, grapes, peanuts, pome fruit (group 11), stone fruit (group 12), sugar beets, 

wheat, barley, triticale, buckwheat, oats, rye, and teosinte. Humans may be exposed to flutriafol 

in food and drinking water, since flutriafol may be applied directly to growing crops and 

application may result in flutriafol reaching surface and ground water sources of drinking water. 

There are no residential uses of flutriafol, so there is not likely to be exposure in residential or 

non-occupational settings. In an occupational setting, applicators may be exposed while handling 

the pesticide prior to application, as well as during application. There is also a potential for postapplication exposure for workers re-entering treated fields. 

Risk assessments have been previously prepared for the existing uses of flutriafol. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 14 of 45

uses of flutriafol, but also considers the existing uses as well, particularly for the dietary 

exposure assessment. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf. As a part of every 

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 

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 post-application are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

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

one specific enzyme, 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. 

4.1 Toxicology Studies Available for Analysis 

Flutriafol has been evaluated extensively for its toxicity and mode of action. Its toxicity database 

is adequate to support registration. In the last risk assessment (D372347, K. Lowe et al., 16-

Dec-2009), one toxicology data requirement was identified; a guideline immunotoxicity study. 

This study is now required under the 40 CFR Part 158 for conventional pesticide registration. 

This study has been recently submitted and is pending review. To confirm the results from 

earlier reproductive and genotoxicity data, Cheminova submitted newer reproduction (2) and 

genotoxicity (3) guideline studies. The preliminary 1-generation reproduction toxicity study is 

classified unacceptable/guideline and is supplemental to the 2-generation reproduction study. 

The evaluation of these reproductive toxicity studies and the genotoxicity studies are included in 

this hazard assessment. Finally in the last risk assessments, the 1982 rat prenatal developmental 

study was considered unacceptable/guideline. Upon further review, this study was found to be 

acceptable/guideline. No mistakes were found in this study, only a change in the classification 

has occurred.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 15 of 45

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

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

regardless of sex, dose, or 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 glands. The total amount of radioactivity isolated in the tissues and carcass was <1-3% 

of the total dose, and bioaccumulation was considered unlikely. The parent compound was 

isolated in only trace amounts in the urine and feces, and more than 19 metabolites were isolated, 

indicating extensive metabolism. 

4.2.1 Dermal Absorption

An in vivo rat dermal-absorption study 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.

4.3 Toxicological Effects

Flutriafol has 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. 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). 

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 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 16 of 45

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.

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 treatmentrelated increases in tumor incidences. Flutriafol is thus considered to be ―Not likely to be 

Carcinogenic to Humans‖ based on the results of these carcinogenicity studies in rats and mice. 

4.4 SF for Infants and Children (FQPA SF)

HED’s RAB1 risk assessment team concluded that based on toxicological considerations and the 

residue assumptions used in the dietary exposure analyses (no residential uses), the FQPA SF 

may be reduced to 1X. 

4.4.1 Completeness of the Toxicology Database

The toxicology database for flutriafol is adequate for FQPA consideration. The following 

acceptable studies are available:

Developmental toxicity studies in rats and rabbits (3) 

Two-generation reproduction studies in rats (2)

Acute (1) and Subchronic (1) neurotoxicity studies in rats

An Immunotoxicity study

The immunotoxicity study for flutriafol has been received. A preliminary review of the study 

indicates that there is no concern for immunotoxicity. A formal review is pending.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 17 of 45

4.4.2 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 

DNT study is not required.

4.4.3 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; and 4) the chronic reference dose is greater 

than 300-fold lower than the doses at which the offspring effects were observed in the 2-

generation reproduction studies.

4.4.4 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% CT). In addition, there are no 

proposed or registered residential uses.

4.5 Toxicity Endpoint and POD Selections

4.5.1 Dose-Response Assessment

There are no changes to the endpoints used in the last risk assessment (D372347, K. Lowe et al., 

16-Dec-2009). 

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

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

for interspecies extrapolation and 10-fold for intraspecies variability) 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. The only other study considered for this endpoint was the subchronic neurotoxicity 

study.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 18 of 45

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 100 (10-fold for interspecies extrapolation and 10-fold for intraspecies 

variability) was applied to the developmental NOAEL of 7.5 mg/kg to generate the aRfD of 

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

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

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

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

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

the developmental NOAELs were 10 mg/kg (both) and the developmental LOAELs were 50 

mg/kg based upon delayed ossification or non-ossification of the skeleton in the fetuses (1982), 

and 75 mg/kg based upon increased late resorptions, malformations (cleft palate and multiple), 

and variations in the hyoid (neck bone), 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 (2008). The rabbit study is protective of the effects seen 

in these rat studies. It also the most protective study for this 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 100 (10-fold for interspecies extrapolation 

and 10-fold for intraspecies variability) 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 

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

duration of exposure. Both the 28- and 90-day dog oral toxicity studies provide 

NOAEL/LOAELs and toxic effects of the same kind (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.

Dermal Absorption Factor: From the in vivo rat dermal-absorption study, a value of 21% is 

appropriate (most protective) for dermal risk assessments.

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 this endpoint, but there 

was no toxicity observed up to the limit dose (1000 mg/kg/day). Without being able to use the 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 19 of 45

route-specific repeated dose dermal study, this study is the most protective study 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. 

Using a dermal-absorption 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).

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for flutriafol is assessed using an oral toxicity study. A 100% inhalation-absorption factor will 

be assumed and applied for oral to inhalation extrapolation. The Agency sought expert advice 

and input on issues related to this route-to-route extrapolation approach (i.e., the use of oral 

toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency 

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, re-examine and develop new policies and 

procedures for conducting inhalation risk assessments, including route-to-route extrapolation of 

toxicity data. If any new policies or procedures are developed, then the Agency may revisit the 

need for an inhalation toxicity study for flutriafol and/or a re-examination of the inhalation 

toxicity risk assessment.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

Since short- and intermediate-term dermal and inhalation endpoints are based on oral studies, 

dietary exposure will be aggregated with residential dermal and inhalation exposures for all 

populations/durations. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Flutriafol is considered to be ―Not likely to be Carcinogenic to Humans‖ based on the results of 

the carcinogenicity studies in rats and mice. The results of the rat chronic 

toxicity/carcinogenicity study and the mouse carcinogenicity study are negative for 

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

mutagenicity. Although several triazoles are carcinogenic, many are not and flutriafol has been 

adequately tested and found not to be carcinogenic in long-term studies in rats and mice.

SAR analysis indicates that flutriafol may have the potential to produce thyroid and/or liver 

tumors in rodents. However, in the rat and mouse carcinogenicity studies, there were no 

treatment-related increases in tumor incidence when comparing treated animals to controls. 

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

Assessment

The points of departure, uncertainty factors, and toxicity endpoints are presented in Table 4.5.4a 

(dietary and non-occupational assessments) and Table 4.5.4b (occupational assessments).
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 20 of 45

Table 4.5.4a. 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

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

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute RfD = 0.075 

mg/kg/day

aPAD = 0.075 

mg/kg

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

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 = population-adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of 

concern. 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 21 of 45

Table 4.5.4b. 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 

1Dermalabsorption 

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

Inhalationabsorption 

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. 

4.6 Endocrine Disruption

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

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

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

produced by a ―naturally occurring estrogen, or other such endocrine effects as the 

Administrator may designate.‖ The EDSP employs a two-tiered approach to making the 

statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to 

identify the potential of a chemical substance to interact with the estrogen, androgen, or 

thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are 

found to have the potential to interact with E, A, or T hormonal systems will proceed to the 

next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are 

necessary based on the available data. Tier 2 testing is designed to identify any adverse 

endocrine related effects caused by the substance, and establish a dose-response relationship 

between the dose and the E, A, or T effect.

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

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

ingredients. This list of chemicals was selected based on the potential for human exposure 

through pathways such as food and water, residential activity, and certain post-application 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 22 of 45

agricultural scenarios. This list should not be construed as a list of known or likely 

endocrine disruptors.

Flutriafol was not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for 

all pesticide active ingredients.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

Based on structural similarity, HED concludes that the defluorinated, hydroxylated, and 

glucoside flutriafol metabolites identified in the plant and livestock metabolism studies are 

not likely to be more toxic than flutriafol. HED has previously reviewed toxicological data 

for T, triazole alanine (TA), triazole acetic acid (TAA), and triazole lactic acid (TLA) and 

concluded that the toxicological effects of T and TA/TAA/TLA are different from each 

other (D322215, M. Doherty et al., 07-Feb-2006). Based on these data and the flutriafol 

toxicological data, HED concludes that the toxicological effects of T and TA/TAA/TLA are 

different from that of flutriafol. 

5.1.1 Summary of Plant and Animal Metabolism Studies

Nature of the Residue - Primary Crops: The petitioner submitted adequate apple, sugar beet, 

and rapeseed metabolism studies conducted with [triazole-3,5-

14C]flutriafol and [carbinol14C]flutriafol (1 × 0.10-0.12 lb ai/acre). The radiolabel position did not affect total radioactive 

residues (TRRs) or the metabolic profile for rapeseed (forage, pod, and mature seed; PHI = 0-21 

days) or sugar beet tops (TRRs in root were too low for a comparison; PHI = 0-21 days); for 

apple (PHI = 64 days), TRRs were slightly higher following treatment with [triazole-3,5-

14C]flutriafol, but the resulting metabolic profiles did not vary with radiolabel position. 

Flutriafol (50-96% TRR) was the major residue identified in apple, rapeseed (foliage, pod, and 

seed), and sugar beet tops (TRR in roots too low for identification). Defluorinated flutriafol (12-

14% TRR) and conjugated flutriafol (27-28% TRR) were identified at significant concentrations 

in rapeseed pod. All other identified/unknowns were ≤8% TRR (T, TA, and TAA were not 

identified). HED notes that the petitioner also submitted wheat and barley metabolism studies 

(foliar and seed treatment). Although these studies were found to be unacceptable due to 

numerous deficiencies, the resulting metabolic profiles were similar to that for apple, sugar beet, 

and rapeseed. 

Based on these data, the HED Residues of Concern Knowledgebase Subcommittee (ROCKS) 

concluded that the residues of concern in apple and dried soybean seed are flutriafol, T, TA, and 

TAA, and the residue of concern for tolerance enforcement is flutriafol per se (D355605, R. 

Daiss, 03-Aug-08). Defluorinated flutriafol and conjugated flutriafol were not included as 

residues of concern as apple and dried soybean seed do not possess a commodity similar to 

rapeseed pod (label prohibits feeding/foraging soybean forage/hay and use will be restricted to 

only soybean harvested for the dried seed). T, TA, and TAA were included as residues of 

concern as they were identified in the apple and soybean field trial studies and/or to be consistent 

with the other triazole fungicides. 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 23 of 45

HED concludes that the previous decision regarding the residues of concern in apple and dried 

soybean seed may be translated to the requested fruit crops and to sugar beet (note the previous 

decision considered a sugar beet metabolism study). Adequate peanut and cereal grain 

metabolism studies have not been submitted; however, the petitioner has submitted adequate 

metabolism data on three diverse crops and these data resulted in a similar metabolic profile. 

Based on the available data (including the rapeseed pod data), HED concludes that the residues 

of concern in peanut and cereal grains for tolerance enforcement is flutriafol per se and the 

residues of concern for risk assessment are flutriafol (free and conjugated), defluorinated 

flutriafol, T, TA, and TAA. The combined residues of flutriafol (free and conjugated) and 

defluorinated flutriafol may be estimated by multiplying the free flutriafol residue by 2.2. Table 

5.1.4 is a summary of the residues of concern in the proposed/registered crops. 

Nature of the Residue - Rotational Crops: The petitioner recently submitted a confined 

rotational crop study, which involved a single bare soil application of [carbinol14C]flutriafol 

or [triazole-3,5-

14C]flutriafol at 0.22 lb ai/acre with wheat, lettuce, or radish planted 30, 120, 

and 365 days after application. Based on these data, HED concluded the following: (1) the 

residue of concern in rotational crops for tolerance enforcement is flutriafol per se; (2) the 

residues of concern for risk assessment in all rotational crops, excluding dried roughage feed 

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

and TLA [combined flutriafol (free and conjugated) and M28 may be estimated by 

multiplying the free flutriafol residue by 1.3x]; and (3) for the dried roughage feed 

commodities, the residues of concern for risk assessment will be same as that mentioned 

above, but with multiplication of the free flutriafol residues by 2.5x to account for the 

combined residues of flutriafol (free and conjugated), M28, and the uncharacterized residues 

in the post-extraction solids (PES) for wheat straw samples collected from the [carbinol14C]flutriafol treated plots. Table 5.1.4 is a summary of the residues of concern in rotational 

crops.

Nature of the Residue - Poultry: Based on the poultry metabolism studies conducted with 

[triazole-3,5-

14C]flutriafol (13.9 ppm) and [carbinol14C]flutriafol (11.6 ppm), ROCKS 

concluded that the residue of concern for tolerance enforcement was flutriafol per se and the 

residues of concern for risk assessment were flutriafol, T, TA, and TAA (D355605, R. 

Daiss, 03-Aug-08). Residues of TA and TAA were included as residues of concern due to 

their presence in feed commodities. M3 was excluded as a residue of concern since residues 

are expected to be negligible when normalized to the dietary burden at that time. HED 

noted that if the poultry dietary burden increased, then these conclusions would 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. 

With inclusion of the residues of concern in rotational crops and the conclusions concerning 

the residues of concern in peanut and small grains, the residue of concern in poultry for 

tolerance enforcement remains as flutriafol per se, while the residues of concern for risk 

assessment are now flutriafol (free and conjugated), defluorinated flutriafol, M28, T, TA 

(free and conjugated), TAA, and TLA. Residues of conjugated flutriafol, defluorinated 

flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of 

concern due to their presence in feed commodities. Table 5.1.4 is a summary of the residues 

of concern in poultry. 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 24 of 45

The poultry maximum reasonable dietary burdens (MRDBs) for tolerance enforcement/risk 

assessment as a result of all registered/proposed uses are 0.096/0.098 ppm (dietary burdens 

to flutriafol and the residues of concern identified as being toxicologically identical to 

flutriafol). Based on these dietary burdens, HED concludes that the previously submitted 

poultry metabolism studies are adequate and the conclusions concerning the residues of 

concern in poultry summarized in the previous paragraph and in Table 5.1.4 are appropriate. 

Nature of the Residue - Ruminants: Based on a dairy cow metabolism study conducted 

with [triazole-3,5-

14C]flutriafol (2 ppm), the ROCKS concluded that the residue of concern 

for tolerance enforcement is flutriafol per se and the residues of concern for risk assessment 

are flutriafol, M1B, T, TA, and TAA for the following reasons: (1) based on (a) the SAR 

analysis, which did not result in alerts for potential flutriafol metabolites without the triazole 

ring; (b) the rat metabolism study, which resulted in the identification of a metabolite 

without the triazole ring in urine and feces (M18; <1-8% of the administered dose); and (c) 

the fact that developmental toxicity demonstrated for many of the triazole fungicides, 

including flutriafol, is likely a result of the triazole ring, HED concludes that flutriafol 

metabolites without the triazole ring are not likely to be more toxic than parent (a [carbinol14C]flutriafol ruminant metabolism study has not been submitted); (2) based on the TRRs 

from the [triazole-3,5-

14C]flutriafol dairy cow metabolism study (10x the MRDB at that 

time) and because the hen metabolism study resulted in higher TRRs following dosing with 

[triazole-3,5-

14C]flutriafol as compared to [carbinol14C]flutriafol, residues in all ruminant 

commodities, excluding liver and kidney, are expected to be insignificant (TRRs from the 

[triazole-3,5-

14C] flutriafol ruminant metabolism study: liver - 0.291 ppm; kidney - 0.061 

ppm; all other tissues ≤0.01 ppm; and milk - ≤0.008 ppm (TRRs in milk appeared to plateau 

by day 4)); and (3) the ruminant feeding studies resulted in low flutriafol per se residues 

when normalized to 1x the MRDB at that time (liver ≤0.013 ppm; kidney ≤0.002 ppm; fat 

≤0.002 ppm; muscle ≤0.0008 ppm; and milk <0.001 ppm). Residues of TA and TAA were 

included as residues of concern due to their presence in feed commodities. HED noted that 

if the ruminant dietary burden increased, 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.

With inclusion of the residues of concern in rotational crops and the conclusions concerning 

the residues of concern in peanut and small grains, the residue of concern in ruminants for 

tolerance enforcement remains as flutriafol per se while the residues of concern for risk 

assessment are now flutriafol (free and conjugated), defluorinated flutriafol, M28, M1B, T, 

TA (free and conjugated), TAA, and TLA. Residues of conjugated flutriafol, defluorinated 

flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of 

concern due to their presence in feed commodities. Table 5.1.4 is a summary of the residues 

of concern in ruminants. 

The ruminant dietary burden from only the roughage commodities associated with peanut, 

field corn, popcorn, and wheat are 5.82 ppm, 12.38 ppm, 5.82 ppm, and 52.80 ppm, 

respectively (dietary burdens to flutriafol and the residues of concern identified as being 

toxicologically identical to flutriafol). At these dietary burdens, HED concludes that points 

(2) and (3) above are no longer applicable; therefore, the currently available ruminant 

metabolism study is not adequate. Ruminant metabolism studies conducted as specified in 

OPPTS 860.1300 with [carbinol14C]flutriafol and [triazole-3,5-

14C]flutriafol are required 

prior to registration of flutriafol for use on peanut, field corn, popcorn, and wheat. HED 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 25 of 45

notes that oat and barley field trial data are not available and these data are required for 

estimation of residues in barley, buckwheat, oat, rye, and teosinte. Based on the requested 

application scenario for these crops and the wheat field trial data, HED concludes that the 

requested ruminant metabolism studies will likely also be required for barley, buckwheat, 

oat, rye, and teosinte. For peanut, provided the petitioner prohibits the feeding of peanut hay 

to livestock, these ruminant metabolism studies will be unnecessary (feeding restrictions for 

corn and small grains are not permitted).

With inclusion of the registered crops and the remaining proposed crops (including peanut 

with the feeding restriction), the MRDBs for tolerance enforcement/risk assessment for beef 

cattle, dairy cattle, and swine are 0.225/0.273 ppm, 0.273/0.305 ppm, and 0.061/0.064 ppm, 

respectively. Based on these dietary burdens, HED concludes that the previously submitted 

ruminant metabolism study is adequate and the conclusions concerning the residues of 

concern in ruminants summarized above and in Table 5.1.4 are appropriate. 

5.1.2 Summary of Environmental Degradation

Flutriafol is expected to be persistent and moderately mobile in the environment, with its major 

routes of dissipation through biotic degradation. Flutriafol is expected to degrade with a half-life 

of more than one year in the environment. Batch equilibrium data on flutriafol suggest that the 

compound will sorb to soil with moderate affinity, and display moderate mobility (Kd values 

range from 2.0 to 13.6). The compound does not volatilize significantly, with a partial vapor 

pressure of 4 x 10-7 Pa at 20 °C. Therefore, dissipation in the environment is expected to occur 

via runoff of dissolved residues, and sorption to eroding sediments. Flutriafol leachate is 

expected to persist in both aerobic and anaerobic soil compartments.

Flutriafol biodegrades with half-lives of more than a year in both aerobic and anaerobic 

terrestrial and aquatic environments, and is expected to persist for years in both aerobic and 

anaerobic environments. Additionally, flutriafol is stable to both hydrolysis and aquatic 

photolysis. Dissipation occurred with half-lives of 106 to 13,566 days in terrestrial field studies, 

which is consistent with the submitted, laboratory-derived data. Due to the length of the studies, 

and the persistence of flutriafol, major degradates were not detected in either laboratory or field 

studies. Minor degradates of flutriafol (which were only reported in two studies: a soil 

photolysis study and an anaerobic aquatic metabolism study) include: T, TAA, TA, 2,4’-

difluorobenzophenone, and CO2. 

5.1.3 Comparison of Metabolic Pathways

In rat metabolism studies, parent was isolated in only trace amounts in the urine and feces 

(<0.5% of the administered dose) and more than 19 metabolites were isolated (<0.1-16% of the 

administered dose). In rats, the primary site for metabolism was the 2-fluorophenyl ring. The 

initial metabolic step was probably epoxidation followed by either rearrangement to form the 

dihydrodiol isomers or to form hydroxy or dihydroxy metabolites. The hydroxyl groups on these 

primary metabolites may then be either conjugated with glucuronic acid or methylated. A 

second, minor route for metabolism of flutriafol was via the removal of the triazole ring to form 

1-(2-fluorophenyl)-1-(4-fluorophenyl)-ethandiol, which is then conjugated with glucuronic acid.

Flutriafol (free and conjugated) was the major residue identified in the apple, sugar beet, and 

rapeseed metabolism studies; defluorinated flutriafol was also identified in rapeseed. The 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 26 of 45

ruminant metabolism study resulted in TRRs ≤0.01 ppm in all samples, except for liver and 

kidney. The major residues identified in liver and kidney were flutriafol and M1B (4-

hydroxyflutriafol), with minor amounts of M1D (4-hydroxy-5-methoxyflutriafol) also identified. 

The poultry metabolism study yielded sufficient radioactivity in all matrices for residue 

identification, with flutriafol and T being the major identified residues. An unknown, M3, was 

identified at significant concentrations following dosing with [carbinol14C]flutriafol; M5 

(hydroxylated flutriafol) was also identified, but at an insignificant concentration. The confined 

rotational crop study resulted in the identification of flutriafol (free and conjugated), TA (free 

and conjugated), TAA, and TLA along with M28, which was characterized as a glucoside of a 

flutriafol metabolite, possible a derivative hydroxylated on the phenyl ring. 

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4 is a summary of the residues of concern in primary crops, livestock, and rotational 

crops (see above for discussion concerning these decisions). Based on the indentified residues of 

concern and toxicological considerations, HED has determined that the following three dietary 

risk assessments are required when evaluating exposure to flutriafol: (1) T; (2) TA/TAA/TLA; 

and (3) flutriafol and the remaining residues of concern. 

Defluorinated flutriafol was identified in the canola metabolism study (pod without the seed - 12-

15% TRR (≤0.12 ppm); seed - 3% TRR (≤0.04 ppm)) indicating that flutriafol may contribute to 

fluoride dietary exposure. HED has previously conducted dietary exposure analyses for fluoride 

residues from the insecticides cryolite and sulfuryl fluoride as well as from naturally occurring 

fluoride residues in food and water (D309014, M. Doherty, 12-Oct-2004; D362183, M. Doherty, 

6-May-2009). For the following reasons, HED concludes that fluoride residues resulting from 

the application of flutriafol are insignificant and revisions to the previous fluoride dietary 

exposure analyses are unnecessary: (1) based on the identification of defluorinated flutriafol in 

only the canola metabolism study, HED concludes that defluorinated flutriafol may be present in 

only soybean seed and peanut (defluorinated flutriafol was not identified in the apple, sugar beet, 

rotational crop, and livestock metabolism studies or in the environmental fate/degradation 

studies) and (2) the fluoride dietary exposure analyses assumed a background fluoride residue of 

0.496 ppm in soybean seed and peanut nutmeat commodities, which is significantly greater than 

what would be expected based on the canola metabolism study. 

Table 5.1.4. Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance Enforcement.

Matrix Residues of Concern

Risk Assessment Tolerance Enforcement

soybean seed, fruit, and sugar beet flutriafol, T, TA, and TAA

flutriafol (free)

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 2.2

rotational crops (excluding dried 

roughage feed commodities)

flutriafol (free and conjugated), M283, T, TA (free and conjugated), TAA, 

and TLA; combined flutriafol (free and conjugated) and M283residue may 

be estimated by multiplying the free flutriafol residue by 1.3x

rotational crops (dried roughage 

feed commodities)

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

residues by 2.5x to account for the combined residues of flutriafol (free and 

conjugated), M283, and the uncharacterized residues in the PES for wheat 

straw samples collected from the [carbinol-14C]flutriafol treated plots 

poultry1 flutriafol (free and conjugated), defluorinated flutriafol,

M283, T, TA (free and conjugated), TAA, and TLA

ruminant2 flutriafol (free and conjugated), defluorinated flutriafol,

M283, M1B3, T, TA (free and conjugated), TAA, and TLA 

1. HED notes that if the poultry dietary burdens increase, these conclusions will be revisited and poultry metabolism studies conducted as 

specified in OPPTS 860.1300 with [carbinol-14C]flutriafol and [triazole-3,5-14C]flutriafol may be required. Residues of conjugated flutriafol, 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 27 of 45

defluorinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concern due to their presence in feed 

commodities.

2. HED notes that if the ruminant dietary burden increases, these conclusions will be revisited and ruminant metabolism studies conducted as 

specified in OPPTS 860.1300 with [carbinol-14C]flutriafol and [triazole-3,5-14C]flutriafol may be required. Residues of conjugated flutriafol, 

defluorinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concern due to their presence in feed 

commodities.

3. M28 = glucoside of a flutriafol metabolite, possible a derivative hydroxylated on the phenyl ring; M1B = 4-hydroxyflutriafol.

5.2 Food Residue Profile

HED is not recommending for the proposed field corn, popcorn, and small grains registration due 

to several residue chemistry data deficiencies including issues concerning the nature/magnitude 

of the residue in ruminants at the dietary burdens associated with these crops. For a complete 

discussion of the residue chemistry data deficiencies associated with application of flutriafol to 

field corn, popcorn, and small grains see D388603 (T. Bloem, 16-Jun-2011). The following text 

is a summary of the food residue profile for the remaining proposed crops (pome fruit, stone 

fruit, grape, imported banana, peanut, and sugar beet).

Magnitude of the Residue - Primary Crops: Provided a revised Section B is submitted, the 

pome fruit, stone fruit, grape, banana (import tolerance), peanut, and sugar beet processing 

and/or field trial data are adequate and support the establishment of the HED-recommended 

primary crop tolerances listed in Table 2.2.3 (revised Section F is requested). 

Magnitude of the Residue - Rotational Crops: Concurrent to the Section 3 registration being 

discussed here, HED reviewed residue data concerning the rotation of sweet corn, field corn, and 

cotton to soybean fields treated with flutriafol (application of flutriafol to soybeans is already 

registered). Based on these data, HED concluded that the rotational crop tolerances listed in 

Table 2.2.3 should be established and the following rotational crop restrictions following 

application of flutriafol to soybean are appropriate (revised Sections B and F are requested): 

treated fields may be rotated to a labeled crop at any time or may be rotated to cotton, sweet 

corn, field corn, field corn grown for seed, and popcorn 180 days after application; rotation to 

any other crop is prohibited. 

With elimination of field corn, popcorn, and the small grains as primary crops (see paragraph at 

the beginning of Section 5.2), the only proposed crops which are rotated are peanut and sugar 

beet. Based on the submitted field corn, sweet corn, and cotton rotational crop field trial data 

and the proposed peanut and sugar beet application scenarios, HED concludes the following 

concerning plant back intervals (PBIs) and residues in/on rotational crops (revised Sections B 

and F are requested): 

Peanut - Adequate field rotational crop data conducted at the peanut application rate are not 

available; therefore, the label should be revised to indicate that only a labeled crop may be 

rotated following application of flutriafol to peanut. 

Sugar Beet - The application scenario employed in the sweet corn, field corn, and cotton field 

rotational crop study are considered adequate to represent the magnitude of the residue following 

application of flutriafol to sugar beet. With the addition of sugar beet as a primary crop, the 

following field rotational crop residue data conducted as specified in OPPTS 860.1900 should be 

submitted: sweet corn - NAFTA Growing Zones 10 (n=1) and 11 (n=1); cotton - NAFTA 

Growing Zones 8 (n=4) and 10 (n=3). Based on the field rotational crop data, HED requests a 

revised Section B specifying the following rotational crop restrictions following application to 

sugar beet: treated fields may be rotated to a labeled crop at any time or may be rotated to 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 28 of 45

cotton, sweet corn, field corn, field corn grown for seed, and popcorn 180 days after application; 

rotation to any other crop is prohibited. 

Magnitude of the Residue - Poultry: Considering all proposed/registered crops, the poultry 

MRDBs for tolerance enforcement/risk assessment are 0.096/0.098 ppm (dietary burdens to 

flutriafol and the residues of concern identified as being toxicologically identical to flutriafol). 

Based on an adequate poultry feeding study and the current MRDB, residues in poultry 

commodities are expected to be ≤0.001 ppm. Based on these estimates, HED concludes that the 

establishment of poultry tolerances and inclusion of poultry in the risk assessment are 

unnecessary. 

Magnitude of the Residue - Ruminant: With elimination of field corn, popcorn, and the small 

grains (see paragraph at the beginning of Section 5.2), the beef cattle, dairy cattle, and swine 

MRDBs to the remaining proposed crops and to the registered crops for tolerance 

enforcement/risk assessment are 0.225/0.273 ppm, 0.273/0.305 ppm, and 0.061/0.064 ppm, 

respectively (dietary burdens to flutriafol and the residues of concern identified as being 

toxicologically identical to flutriafol). Based on an adequate feeding study and the current 

MRDBs, residues in all ruminant and hog commodities excluding liver are expected to be ≤0.003 

ppm; residues in liver are expected to be ≤0.019 ppm (note that cattle, goat, hog, horse, and 

sheep liver tolerance are currently established at 0.02 ppm). Based on these estimates, HED 

concludes that the currently established ruminant and hog tolerances are adequate (no additional 

ruminant and hog tolerances are required). Submission of storage stability data demonstrating 

the stability of flutriafol, T, TA, and TAA in ruminant liver (4.6 months) are needed to validate 

the ruminant feeding study (D380493, T. Bloem, 16-Jun-2011). 

5.3 Drinking Water Residue Profile

EFED provided modeled ground [Pesticide Root Zone Model-Groundwater (PRZM-GW)] and 

surface [FQPA Index Reservoir Screening Tool (FIRST ver. 1.1.1)] estimated drinking water 

concentrations (EDWCs) for flutriafol per se (EFED memorandum; D383005, J. Wolf, 27-Apr2011; D390213, J. Wolf, 31-May-2011). Table 5.3 is a summary of the flutriafol per se water 

estimates provided by EFED (bolded numbers were used in the assessment). 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. Maximum Tier I Flutriafol EDWCs.

Model Application Rate EDWC (ppb)

Groundwater 

(PRZM-GW)

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 

(FIRST) apple (6 x 0.114 lbs ai/acre at 7 day intervals)1 acute 48.5

chronic 5.70

1 The initially proposed application rate for apple. 

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). 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 29 of 45

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

were conducted using DEEM-FCIDTM (ver. 2.03), which incorporates the food consumption data 

from the USDA CSFII (1994-1996 and 1998). HED is not recommending for the proposed field 

corn, popcorn, and small grains registration due to several residue chemistry data deficiencies 

including issues concerning the nature/magnitude of the residue in ruminants at the dietary 

burdens associated with these crops (for further discussion see D388603 (T. Bloem, 16-Jun2011)); these uses were not included in the analysis. The analysis did consider the registered 

crops, the remaining proposed crops, and residues in/on field corn, popcorn, and cotton as a 

result of rotation to a treated field. 

The acute and chronic analyses assumed tolerance-level residues, 100% crop treated, and 

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

which indicate that tolerances in/on apple juice, grape juice, and dried prunes are unnecessary 

and since a raisin tolerance is being established, the DEEMTM (ver 7.81) default processing 

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

factors were retained for the remaining relevant commodities. In addition, since an adequate 

cottonseed processing study has not been submitted, the OPPTS 860.1520 default cottonseed oil 

processing factor was retained. The resulting acute (≤24% aPAD; females 13-49 years old were 

the most highly exposed subgroup) and chronic (≤42% cPAD; all infants (<1 year old) were the 

most highly exposed subgroup) exposure estimates are not of concern to HED. Table 5.4 is a 

summary of the acute and chronic dietary (food and water) exposure and risk estimates. 

Table 5.4. Summary of Acute and Chronic Dietary (Food + Drinking Water) Exposure and Risk.

Population aPAD 

(mg/kg/day)

Exposure 

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

Exposure 

(mg/kg/day) %cPAD

General U.S. Population

2.5

0.021798 <1

0.05

0.006197 12

All Infants (< 1 year old) 0.070570 2.8 0.021152 42

Children 1-2 years old 0.050188 2.0 0.016661 33

Children 3-5 years old 0.036759 1.5 0.012350 25

Children 6-12 years old 0.022167 <1 0.006793 14

Youth 13-19 years old 0.015224 <1 0.004121 8

Adults 20-49 years old 0.017447 <1 0.005043 10

Adults 50+ years old 0.016271 <1 0.005527 11

Females 13-49 years old 0.075 0.017880 24 0.005118 10

1

 95th percentile (tier 1 analysis)

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 Residential Bystander Post-application Inhalation 

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

assessment was not performed for flutriafol at this time primarily. 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 FIFRA 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 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 30 of 45

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

inhalation exposure assessment for flutriafol.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for flutriafol. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical-by-chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT®computer model 

to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic 

methods. After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

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

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

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

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

agricultural and commercial post-application inhalation exposure scenarios. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

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

are no residential uses for flutriafol, only food and water are included in the aggregate 

assessments. Since the dietary exposure analysis included the drinking water estimates, 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. A quantitative 

cancer aggregate risk assessment was not needed since there was no evidence of carcinogenicity. 

Application of flutriafol also results in exposure to T and its conjugated metabolites, which 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 (D388544, T. Bloem, 14-Apr-2011). Dietary exposure analyses to T and 

its conjugated metabolites conducted in support of the proposed flutriafol uses did not result in 

an increase in the dietary exposure estimates incorporated into this most recent aggregate 

assessment (D388469, T. Morton, 27-Apr-2011); therefore, a revised aggregate assessment is 

unnecessary. 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 31 of 45

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 is a triazole-derived pesticide. This class of compounds can form the common 

metabolite T and two triazole conjugates (TA and TAA). To support existing tolerances and to 

establish new tolerances for triazole-derivative pesticides, including flutriafol, U.S. EPA 

conducted a human-health risk assessment for exposure to T, TA, and TAA resulting from the 

use of all current and pending uses of any triazole-derived fungicide. The risk assessment is a 

highly conservative, screening-level evaluation in terms of hazards associated with common 

metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary 

and non-dietary exposures (i.e., high-end estimates of both dietary and non-dietary exposures). 

In addition, the Agency retained the additional 10X FQPA SF for the protection of infants and 

children. The assessment includes evaluations of risks for various subgroups, including those 

comprised of infants and children. The Agency’s complete risk assessment is found in the 

propiconazole reregistration docket at http://www.regulations.gov, Docket Identification (ID) 

Number EPA-HQ-OPP-2005-0497.

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

Flutriafol is a fungicide that can be used as a systemic eradicant and a protectant. Topguard®

Fungicide (EPA Reg # 67760-75) is already registered for use on apples and soybeans. The 

formulated product, an 11.8% (1.04 lb ai/gal) liquid formulation, is proposed for use on corn, 

grapes, peanuts, pome fruit (crop group 11), stone fruit (crop group 12), sugar beets, wheat, 

barley, triticale, buckwheat, oats, rye, and teosinte. An assessment for bananas was not 

performed since the petition was for an import tolerance only. The label allows for foliar 

applications via air and ground equipment. The label prohibits application via chemigation. The 

REI specified on the label is 12 hours.

Dermal and inhalation exposures/risks were estimated for handlers involved in mixing/loading 

activities for liquid formulations for aerial, groundboom and airblast equipment, applying sprays 

via aerial, groundboom and airblast equipment and flagging. The flutriafol product labels direct 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 32 of 45

mixers, loaders, applicators and other handlers to wear long-sleeved shirt and long pants, 

chemical-resistant gloves, and shoes plus socks. 

No chemical-specific handler exposure data were submitted in support of this Section 3 

registration. To assess handler exposures for regulatory actions when chemical-specific 

monitoring data are not available, HED relies on the most scientifically reliable surrogate data 

currently available from various sources such as PHED, AHETF, and ORETF. Some of this 

data, such as the industry task force data, is compensatory, subject to the data protection 

provisions of FIFRA. HED policy on use of surrogate data is described in more detail on the 

Agency's website (http://www.epa.gov/pesticides/science/handler-exposure-data.html). 

Scenario-specific surrogate exposure data, including their sources, are presented in the 

―Occupational Pesticide Handler Unit Exposure Surrogate Reference Table‖ 

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf). 

Typically, HED completes short- and intermediate-term assessments for occupational scenarios 

in all cases because these kinds of exposures are likely and acceptable use/usage data are not 

available to justify deleting intermediate-term scenarios. Based on use data and label 

instructions, HED believes that occupational exposures may occur over a single day or up to 

weeks at a time for many use-patterns and that intermittent exposure over several weeks may 

also occur. Some applicators may apply these products over a period of weeks, because they are 

commercial applicators who are completing multiple applications for multiple clients. Longterm exposures are not expected, therefore, a long-term assessment was not conducted. 

Table 9.1.2 presents the exposure/risks for short- and intermediate-term dermal and inhalation 

exposures at baseline. The combined dermal and inhalation exposure risks for mixer/loaders are 

not of concern (i.e., MOEs >100) at baseline for all scenarios except for mixers/loaders for aerial 

application to corn, wheat (spring and winter), barley, triticale, buckwheat, oats, rye, and 

teosinte. For these high-acreage crops, mixer/loaders must wear protective gloves. Gloves are 

listed as PPE on the proposed label; therefore, HED does not have concerns for this scenario.

HED has no data to assess exposures to pilots using open cockpits. The only data available are 

for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeved shirt, long pants, shoes, 

and socks); pilots are not required to wear protective gloves. With this level of protection, there 

are no risks of concern for applicators.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 33 of 45

Table 9.1.2. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Flutriafol. 

All estimates are at baseline (i.e., no gloves/respirator) except where noted 

Exposure Scenario Crop or Target

Dermal Unit 

Exposure1

Inhalation Unit 

Exposure1

Application 

Rate2

Amount 

Treated 

Daily3

Dermal Inhalation Total

Baseline (except 

where noted) Baseline Dose4 MOE5 Dose6 MOE7 MOE8

Mixer/Loader

Mixing/Loading 

Liquids for Aerial 

Applications

corn, wheat (spring 

and winter), barley, 

triticale, buckwheat, 

oats, rye and teosinte

0.22

0.000219 0.114 1200

0.11 71

0.0005 15,000

71

0.0376

(PPE gloves) 0.018 420 410

peanuts, stone fruit, 

sugar beets 0.22 0.000219 0.114 350 0.031 240 0.00015 51,000 240

pome fruit 0.22 0.000219 0.106 350 0.029 260 0.00014 55,000 260

grapes 0.22 0.000219 0.081 350 0.022 340 0.0001 72,000 340

Mixing/Loading 

Liquids for 

Groundboom 

Applications

corn, wheat (spring 

and winter), barley, 

triticale, buckwheat, 

oats, rye and teosinte

0.22 0.000219 0.114 200 0.018 430 0.000083 90,000 430

peanuts, sugar beets 0.22 0.000219 0.114 80 0.007 1,100 0.000033 230,000 1,100

Mixing/Loading 

Liquids for 

Airblast 

Applications

stone fruit 0.22 0.000219 0.114 40 0.0035 2,100 0.000017 450,000 2,100

pome fruit 0.22 0.000219 0.106 40 0.0033 2,300 0.000015 480,000 2,300

grapes 0.22 0.000219 0.081 40 0.0025 3,000 0.000012 630,000 3,000

Applicator

Applying Sprays 

via Aerial 

Equipment

corn, wheat (spring 

and winter), barley, 

triticale, buckwheat, 

oats, rye and teosinte

0.005 0.000068 0.114 1200 0.0024 3,100 0.00016 48,000 2,900

peanuts, stone fruit, 

sugar beets 0.005 0.000068 0.114 350 0.0007 11,000 0.000045 170,000 10,000

pome fruit 0.005 0.000068 0.106 350 0.00065 12,000 0.000042 180,000 11,000

grapes 0.005 0.000068 0.081 350 0.0005 15,000 0.000032 230,000 14,000

Applying Sprays 

via Groundboom 

Equipment

corn, wheat (spring 

and winter), barley, 

triticale, buckwheat, 

oats, rye and teosinte

0.0786 0.00034 0.114 200 0.0063 1,200 0.00013 58,000 1,200

peanuts 0.0786 0.00034 0.114 80 0.0025 3,000 0.000052 150,000 2,900
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 34 of 45

Table 9.1.2. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Flutriafol. 

All estimates are at baseline (i.e., no gloves/respirator) except where noted 

Exposure Scenario Crop or Target

Dermal Unit 

Exposure1

Inhalation Unit 

Exposure1

Application 

Rate2

Amount 

Treated 

Daily3

Dermal Inhalation Total

Baseline (except 

where noted) Baseline Dose4 MOE5 Dose6 MOE7 MOE8

Applying Sprays 

via Airblast 

Equipment

stone fruit 0.36 0.0045 0.114 40 0.0057 1,300 0.00034 22,000 1,200

pome fruit 0.36 0.0045 0.106 40 0.0053 1,400 0.00032 24,000 1,300

grapes 0.36 0.0045 0.081 40 0.0041 1,800 0.00024 31,000 1,700

Flagger

Flagging for Aerial 

Sprays 

Applications

corn, peanuts, stone 

fruit, sugar beets, 

wheat (spring and 

winter), barley, 

triticale, buckwheat, 

oats, rye and teosinte

0.011 0.00035 0.114 350 0.0015 4,900 0.00023 32,000 4,200

pome fruit 0.011 0.00035 0.106 350 0.0014 5,300 0.00022 35,000 4,600

grapes 0.011 0.00035 0.081 350 0.0011 6,900 0.00017 45,000 6,000

1

PHED/ORETF/AHETF (level of mitigation: Baseline and PPE (gloves).

2 Based on registered or proposed label (Reg. No. #67760-75).

3

Science Advisory Council for Exposure (ExpoSAC) Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre) x Amount Treated (A/day) x DAF (21%)/BW (60 kg).

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

6

Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre) x Amount Treated (A/day) /BW (60 kg).

7

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

8 Total MOE = NOAEL (mg/kg/day)/Dermal Dose + Inhalation Dose.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 35 of 45

9.2 Short- and Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

In the case of flutriafol, there is a potential for postapplication dermal exposure to field workers 

following foliar applications of flutriafol to agricultural crops. Flutriafol is a fungicide that can 

be applied at all stages of growth. For example, the proposed product, Topguard®Fungicide, can 

be applied to grapes beginning with 6 to 10-inch shoots up until 14 days prior to harvest. It can 

also be applied to pome fruit starting at the green tip growth stage and/or the Pink Bud growth 

stage up until 14 day prior to harvest. 

No post-application data were submitted in support of this registration action; therefore, dermal 

exposures during post-application activities were estimated using dermal transfer coefficients 

from the Science Advisory Council for Exposure (ExpoSAC) Policy Number 3 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), summarized in Table 9.2.1 below. 

This policy reflects adoption of all ARTF data. Use of the data in this policy requires 

compensation to the ARTF under FIFRA. 

In addition to the transfer coefficients, the following assumptions were used:

Application Rates = 0.114 lb ai/A for corn, wheat (spring and winter), barley, triticale, 

buckwheat, oats, rye and teosinte, peanuts, stone fruit, 

sugar beets

0.106 lb ai/A for pome fruit

0.081 lb ai/A for grapes

Exposure Duration = 8 hours per day

Body Weight = 60 kg for adult female

Dermal Absorption = 21%

The fraction of ai retained on foliage is assumed to be 20% (0.2) on the day of application (= % 

DFR after initial treatment) for agricultural crops. This fraction is assumed to further dissipate at 

the rate of 10% (0.1) per day on following days.

The post-application exposures associated with the proposed uses are summarized in Table 9.2.1. 

The resulting MOEs are greater than 100 on Day 0 (12 hours after application) for all crops and 

activities, except for detasselling of corn and girdling/turning of grapes. For these high-contact 

activities, an acceptable MOE (i.e., MOE > 100) is not reached until Day 5 after application. 

The high-contact activities for grapes are only expected to occur for cultivation of table grapes. 

The high-contact activity for corn is only expected to occur for field corn or popcorn grown for 

seed. 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 36 of 45

Table 9.2.1. Summary of Occupational/Commercial Postapplication Risks for Flutriafol.

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

Application 

Rate 

(lb ai/A)

DFR1

(ug/cm2)

Day 0 

MOE2

Day X at 

which MOE ≥ 

LOC

Short-and Intermediate-term

Corn

Hand weeding 70

0.114 0.26

15,000 0

Scouting (low crop height) 210 5,000 0

Scouting (high crop height) 1,100 950 0

Irrigation 1,900 550 0

Detasselling 17,600 60 5

Grapes

Transplanting 230

0.081 0.18

6,400 0

Scouting, Hand pruning, Hand 

weeding, Propagating, Bird 

control, Trellis repair

640 2,300 0

Irrigation 1,900 780 0

Tying / Training, Hand 

harvesting, Leaf pulling 5,500 270 0

Tying / Training, Hand 

harvesting, Leaf pulling 10,100 150 0

Girdling, Turning 19,300 76 5

Peanuts

Hand weeding 70

0.114 0.26

15,000 0

Scouting 210 5,000 0

Irrigation 1,900 550 0

Pome fruit (apple, 

crabapple, loquat, mayhaw, 

pear, oriental pear, quince)

Hand weeding, Propping, 

Orchard maintenance 100

0.11 0.24

11,000 0

Transplanting 230 4900 0

Scouting, Hand pruning, 

Training 580 1900 0

Hand harvesting 1,400 810 0

Thinning Fruit 3,600 310 0

Stone fruit (sweet cherries, 

tart cherries, apricot, 

nectarine, peach, plum, 

chicksaw plum, damson 

plum, Japanese plum 

plumcot, prune)

Hand weeding, Propping, 

Orchard maintenance 100

0.11 0.26

10,000 0

Transplanting 230 4,600 0

Scouting, Hand pruning, 

Training 580 1,800 0

Hand harvesting 1,400 750 0

Thinning Fruit 3,600 290 0

Sugar beet

Hand weeding; Thinning (plants) 70

0.114 0.26

15,000 0

Scouting 210 5,000 0

Hand harvesting 1,100 950 0

Wheat (spring and winter), 

barley, triticale, buckwheat, 

oats, rye, and teosinte

Hand weeding 70

0.114 0.26

15,000 0

Scouting 1,100 950 0

1. DFR = application rate (lb ai/A) x (1-daily dissipation rate)tx 4.54E8 μg/lb x 24.7E-9 A/cm2 x 20% DFR after initial treatment.

2. MOE = POD (NOAEL, 7.5 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR (μg/cm2) x TC x 0.001 mg/μg x 8 hrs/day x 21% 

dermal absorption] body weight (60-kg adult female). 

REI

Short- and intermediate-term post-application risks were not a concern on Day 0 (12 hours 

following application) for all post-application activities, except for 1) girdling/turning of table 

grapes, and 2) detasseling corn grown for seed. Risks were a concern until day 5 for table grape 

post-application activities and detasseling corn grown for seed. RD should ensure the 

appropriate REI is present on the label. In addition, under 40 CFR Part 158:1070, DFR data is 

required to further refine risk estimates.

For all other crops, the REI 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). Acute Toxicity Category III and IV chemicals via these routes are supported by a 

12-hour REI under the WPS. 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 37 of 45

9.2.2 Inhalation Post-Application Risk

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

exposure assessment was not performed for flutriafol at this time. However, there are multiple 

potential sources of post-application inhalation exposure to individuals performing postapplication 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 FIFRA 

SAP in December 2009. The Agency 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, then the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for flutriafol. 

10.0 References

U.S. Environmental Protection Agency. 2002. Guidance on Cumulative Risk Assessment of 

Pesticide Chemicals That Have a Common Mechanism of Toxicity. January 14, 2002. 

Memo, M. Doherty, D309014, 12-Oct-2004. ―Correction to the Dietary Exposure Assessment 

for Sulfuryl Fluoride and Fluoride Anion.‖

Memo, R. Daiss, D355605, 03-Aug-2008. "Flutriafol. Report of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS)"

Memo, M. Doherty et al., D322215, 07-Feb-2009. ―1,2,4-Triazole, Triazole Alanine, Triazole 

Acetic Acid: Human Health Aggregate Risk Assessment in Support of Reregistration and 

Registration Actions for Triazole-derivative Fungicide Compounds.‖

Memo, T. Bloem, D362421, 11-Mar-2009. ―Flutriafol. Enforcement Method Forwarded to FDA‖

Memo, T. Bloem, D340513, 11-Mar-2009. ―Flutriafol. Section 3 Registration for Application of 

Flutriafol to Apple and Soybean. Summary of Analytical Chemistry and Residue Data.‖

Memo, M. Doherty, D362183, 06-May-2009. ―Fluoride Chronic Dietary Exposure Analysis.‖

Memo, K. Lowe et al., D372347, 16-Dec-2009. ―Flutriafol. REVISED Human-Health Risk 

Assessment for Proposed Uses on Apple and Soybean.‖

Memo, T. Bloem, D388544, 14-Apr-2011. ―Common Triazole Metabolites. Updated Aggregate 

Human-Health Risk Assessment to Address Tolerance Petitions for Tetraconazole.‖

Memo, J. Wolf, D383005, 27-Apr-2011. ―Tier 1 Drinking Water Assessment Proposed New 

Uses (R190) for Flutriafol for the establishment of tolerances for residue in field and pop corn, 
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 38 of 45

grapes, peanuts, pome fruit (Crop Group 11) stone fruit (Crop Group 12), sugar beets, and 

wheat.‖

Memo, T. Morton, D388469, 27-Apr-2011. ―Common Triazole Metabolites: Updated Dietary 

(Food + Water) Exposure and Risk Assessment to Address The Amended Metconazole Section 3 

Registration to Add Uses on Tuberous and Corm Vegetables (Group 1C) and Bushberry 

Subgroup 13-07B.‖

Memo, T. Bloem, D388603, 16-Jun-2011. ―Flutriafol in/on Bananas (imported), Field Corn, 

Grapes, Peanuts, Pome Fruit, Stone Fruit, Sugar Beets, Wheat, Barley, Buckwheat, Oats, Rye, 

Teosinte, and Triticale. Summary of Analytical Chemistry and Residue Data.‖

Memo, T. Bloem, D380493, 16-Jun-2011. ―Flutriafol. Section 3 Registration for Application of 

Flutriafol to Apple and Soybean. Review of Amendments Dated 1-October-2009, 1-June-2010, 

and 1-July-2010 Submitted in Response to Residue Chemistry Deficiencies Identified in 

D340513 (T. Bloem, 11-Mar-2009).‖

Memo, T. Bloem, D383036, 16-Jun-2011. ―Flutriafol. Acute and Chronic Dietary Exposure and 

Risk Assessment for Application of Flutriafol to Field Corn, Popcorn, Grapes, Peanuts, Pome 

Fruit, Stone Fruit, Sugar Beets, Wheat, Barley, Buckwheat, Oats, Rye, Teosinte, and Triticale. ―

Memo, K. Lowe, D383037, 20-Sep-2011. ―Flutriafol: Occupational and Residential 

Exposure/Risk Assessment for Proposed Uses on corn, grapes, peanuts, pome fruit (crop group 

11), stone fruit (crop group 12), sugar beets, wheat, barley, triticale, buckwheat, oats, rye and 

teosinte.‖
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 39 of 45

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

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

-

-

-
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 40 of 45

A.2 Toxicity Profiles

Table A.2.1. 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 -

Table A.2.2. 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-Ndemethylase 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)

Unacceptable/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.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 41 of 45

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

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 bodyweight 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 post-implantation loss. 

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.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 42 of 45

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

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.

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.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 43 of 45

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

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.

870.5550 Unscheduled DNA 

Synthesis in Primary 

Rat 

Hepatocytes/Mammal

ian 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.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 44 of 45

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

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.

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/cm

2

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.
Flutriafol Human-Health Risk Assessment DP#: 382902, D382945 

Page 45 of 45

Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.7800 Immunotoxicity 

(mice)

48360301 (2011)

Classification: Pending

0, 50, 250, 500, 1000 ppm

[F]

(0, 10.8, 49.9, 101.8 and 

241.2 mg/kg/day [F]

Preliminary NOAEL = 10.8 mg/kg/day.

Preliminary LOAEL = 49.9 mg/kg/day, based on

statistically increased absolute and relative liver 

weights, and statistically significant increases in 

mean corpuscular volume.