Flutriafol Human-Health Risk Assessment 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

D405792 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

From: 

Through: 

To: 

27-March-2013 

Flutriafol: Human-Health Risk Assessment for Tolerances inion Imported 

Coffee. 

PC Code: 128940 DP Barcode: 0405792 

Decision No.: 469168 Registration No.: 67760-75 

Petition No.: 2E8074 Regulatory Action: Tolerance with no U.S. Registration 

Risk Assessment Type: single chemical Case No.: 7060 

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

MRID No: not applicable 40 CFR: 180.629 

Tom Bloem, Chern ~ .-· /} / 

Anwar Y. Dunbar, Ph.D., Pharmacologist ~ .AJ . .f/ ~~ Risk Assessment Branch 1 (RAB 1) tJ 

Health Effects Division (HED; 7509P) 

Dana Vogel Associate Director and Acting RAB 1 Branch Chief ~ 

George F. Kramer, Ph.D., Branch Senior Che~ ~~ 

RAB1/HED (7509P) 

Mary Waller/Tamue Gibson, RM 21 

Registration Division (RD; 7505P) 

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

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

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

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

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

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

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

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

(RAB 1 ), the hazard characterization was provided by Anwar Dunbar (RAB 1 ), and the drinking 

water assessment by James K. Wolf of the Environmental Fate and Effects Division (EFED). 

Page I of25 
Flutriafol Human-Health Risk Assessment D405792 

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Table of Contents 

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

2.0 HED Recommendations ....................................................................................................... 5

2.1 Data Deficiencies/Conditions of Registration .................................................................. 5

2.2 Tolerance Considerations ................................................................................................. 5

2.2.1 Enforcement Analytical Method ............................................................................... 5

2.2.2 International Harmonization ..................................................................................... 6

2.2.3 Recommended Tolerances ........................................................................................ 6

2.2.4 Revisions to Petitioned-For Tolerances .................................................................... 6

2.3 Label Recommendations .................................................................................................. 6

3.0 Ingredient Profile .................................................................................................................. 7

3.1 Chemical Identity ............................................................................................................. 7

3.2 Physical/Chemical Characteristics ................................................................................... 7

3.3 Proposed Use Pattern ....................................................................................................... 8

3.4 Anticipated Exposure Pathways ....................................................................................... 9

3.5 Consideration of Environmental Justice .......................................................................... 9

4.0 Hazard Characterization and Dose-Response Assessment ................................................ 10

4.1 Toxicological Effects ..................................................................................................... 10

4.2 SF for Infants and Children (FQPA SF)......................................................................... 11

4.2.1 Completeness of the Toxicology Database ............................................................. 11

4.2.2 Evidence of Neurotoxicity ...................................................................................... 11

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 11

4.2.4 Residual Uncertainty in the Exposure Database ..................................................... 12

4.3 Toxicity Endpoint and Point of Departure (POD) Selections ........................................ 12

5.0 Dietary Exposure and Risk Assessment ............................................................................. 14

5.1 Metabolite/Degradate Residue Profile ........................................................................... 14

5.2 Food Residue Profile ...................................................................................................... 15

5.3 Drinking Water Residue Profile ..................................................................................... 15

5.4 Dietary (Food + Drinking Water) Risk Assessment ...................................................... 16

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ..................................... 17

6.1 Residential Bystander Post-application Inhalation ........................................................ 17

6.2 Spray Drift ...................................................................................................................... 17

7.0 Aggregate Exposure/Risk Characterization ....................................................................... 18

8.0 Cumulative Exposure/Risk Characterization ..................................................................... 18

9.0 Occupational Exposure/Risk Characterization ................................................................... 18

Appendix A. Toxicology Profile and Executive Summaries ....................................................... 19

Appendix B. Summary of all Previously Selected Toxicological PODs ..................................... 25

 
Flutriafol Human-Health Risk Assessment D405792 

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1.0 Executive Summary 

Flutriafol is a contact and systemic Group 3 triazole fungicide which acts primarily as an 

inhibitor of ergosterol biosynthesis, thereby interfering with synthesis of fungal cell membranes. 

Tolerances for residues of flutriafol are established in/on the following commodities at 0.01-2.4 

ppm: banana (import), field corn, popcorn, sweet corn (rotational crop tolerance), cotton 

(rotational crop tolerance), grape, peanut, pome fruit (group 11-09), stone fruit (group 12-10), 

sugar beet, and soybean. As a result of secondary residues, ruminant (cattle, goat, hog, horse, 

and sheep) meat byproduct tolerances are also established for residues of flutriafol at 0.02-0.07 

ppm. A Section 18 Emergency Exemption has also be granted for application of flutriafol to 

cotton with time-limited tolerances of 0.35-0.50 ppm (expire on 31-Dec-2014). Cheminova, Inc. 

requested a tolerance for residues of flutriafol in/on imported green coffee bean and instant 

coffee at 0.20 ppm and 0.30 ppm, respectively. 

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

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

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

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

guinea pigs (Buehler method). 

The target organ for flutriafol 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. There is no evidence for carcinogenicity in mice or rats.. 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 including an increased of ventral/genital 

staining of the fur and decreased maternal body-weight gains and food consumption. . 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 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 years old) 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 (decreased live birth index and litter size) 

were observed in the two-generation reproduction studies. 
Flutriafol Human-Health Risk Assessment D405792 

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Signs of neurotoxicity were reported in the acute and subchronic neurotoxicity studies at the 

highest doses 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 short-term studies in rats, mice, and dogs, or in the long-term toxicity 

studies in rats, mice, and dogs. 

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

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

database is 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). 

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

calculated by dividing the NOAELs from the acute neurotoxicity study, the developmental rabbit 

study, and the chronic dog study by 100 (uncertainty factors of 10x for interspecies extrapolation 

and 10x for intraspecies variation). Since the FQPA 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 13-49 years of age 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. 

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. 3.16) which 

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

(USDA) National Health and Nutrition Examination Survey, What We Eat in America 

(NHANES/WWEIA; 2003-2008). The acute and chronic analyses assumed tolerance-level 

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

assessment, 100% crop treated, and modeled drinking water estimates. Since adequate processing 

studies have been submitted which indicate that tolerances 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. The 

resulting acute (≤27% aPAD; females 13-49 years old were the most highly exposed subgroup) 

and chronic (≤36% 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 flutriafol uses that result in residential (non-occupational) exposure (tolerance in/on 

imported coffee is proposed). Therefore, residential handler and post-application exposure/risks 

were not assessed. 

Aggregate-Risk Estimates: In accordance with FQPA, HED must consider and aggregate 

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

exposures. Because there are no uses for flutriafol which result in residential (non-occupational) 

exposures, the aggregate assessment need only consider food and drinking water. Since the 

dietary exposure analysis included both food and drinking water, the discussion and exposure 

estimates presented in Section 5.4 represent aggregate acute and chronic exposure to flutriafol and 

those metabolites identified as being toxicologically identical to flutriafol. All aggregate flutriafol 

risk estimates are not of concern to HED. 
Flutriafol Human-Health Risk Assessment D405792 

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

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

toxicologically different from flutriafol. HED previously conducted an aggregate exposure 

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

concern (D403619, T. Morton, 1-Aug-2012). The proposed tolerance in/on imported coffee does 

not require a revision to this most recent aggregate assessment. 

Occupational Exposure and Risk Assessment: The petitioner is proposing a tolerance in/on 

imported coffee. Therefore, an occupational exposure assessment is unnecessary for the current 

action. 

Environmental Justice Considerations: Potential areas of environmental justice concerns, to 

the extent possible, were considered in this human-health risk assessment, in accordance with 

U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations.” 

Review of Human Research: This risk assessment does not rely on data from studies in which 

adult human subjects were intentionally exposed to a pesticide to determine their dermal and 

inhalation exposure. 

2.0 HED Recommendations 

Provided a revised Section F is submitted, HED concludes that the toxicological and exposure 

databases are sufficient to support the establishment of the coffee tolerances listed in Table 2.2.3 

for residues of flutriafol. No additional data are required to support the establishment of these 

tolerances. 

2.1 Data Deficiencies/Conditions of Registration 

 None. 

2.2 Tolerance Considerations 

2.2.1 Enforcement Analytical Method 

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 submitted in support of the proposed tolerance is based on the 

current tolerance enforcement method. Based on this, and since adequate method validation data 

were provided as part of the magnitude of the residue studies, HED concludes that the current 

tolerance enforcement method is adequate to enforce the recommended tolerances. In addition, 

the QuEChERS method has been shown to adequately quantify residues of flutriafol 

(http://www.crl-pesticides.eu/library/docs/fv/CRLFV_ Multiresidue_methods.pdf). 

 
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2.2.2 International Harmonization 

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

in/on coffee. However, a Codex MRL for residues of flutriafol has been established in/on coffee 

bean at 0.15 ppm (instant coffee MRL has not been established). The HED-recommended green 

coffee bean tolerance definition and value are harmonized with the Codex MRL. 

2.2.3 Recommended Tolerances 

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

Table 2.2.3: Tolerance Summary for Flutriafol. 

Commodity Proposed 

Tolerance (ppm) 

HED-Recommended 

Tolerance (ppm) Comments 

coffee, green 

bean 0.20 0.15 Based on the available field trial data and in order to harmonize 

with Codex, a tolerance of 0.15 ppm is recommended. 

coffee, instant 0.30 0.30 -- 

2.2.4 Revisions to Petitioned-For Tolerances 

Based on the available field trial data and in order to harmonize with Codex, HED recommended 

for a green coffee bean tolerance of 0.15 ppm (revised Section F is requested). The proposed 

and HED-recommended instant coffee tolerances are identical. 

2.3 Label Recommendations 

 None. 

 
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3.0 Ingredient Profile 

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/cm 3/23/07 3

Water solubility 95 mg/L at 20 oC 

PP#7F7197 administrative materials 

Solvent solubility 

At 21 oC g/L 

1,2-Dichloroethane 19-20 

Acetone 116-135 

Ethyl acetate 29-34 

Methanol 115-134 

n-Heptane <10 

Xylene <10 

Vapor pressure 4 x 10-7 Pa at 20 oC 

Dissociation constant, pKa 2.3 at 25 oC 

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

UV/visible absorption spectrum -- Not available 

 

N N

N

F

OH

F
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3.3 Proposed Use Pattern 

Cheminova indicated that flutriafol is registered for application to coffee in Brazil, Malaysia, 

Columbia, and Vietnam with no pending registrations in other countries (email from P. Bodey 

(Cheminova) to T. Gibson (EPA RD); 29-Jan-2013, 3:21 pm). English translations of the 

Brazilian, Malaysian, and Columbian labels were provided and are summarized in Tables 3.3.1 

and 3.3.2. It is noted that the Brazilian label does not specify a maximum number of foliar 

applications; however, based on the 30-day retreatment interval (RTI) and the 30-day preharvest 

interval (PHI) indicated on the Brazilian label, it seems unlikely that more than 3-4 foliar 

applications will be made in a season. Although the Vietnamese label was not submitted, 

Cheminova indicated that the Vietnamese application scenario is similar to that indicated in the 

labels provided. HED concludes that the provided labels are sufficient and are supported by the 

available magnitude of the residue data. 

Table 3.3.1: Summary of End-Use Products. 

Trade Name Concentration Formulation Type Label Date Target Crops Target Pests 

Pointer® 

(Malaysia) 125 g ai/ liter SC not indicated coffee fungi of the ascomycete and basidiomycete groups

Potenzor® 

(Brazil) 125 g ai/ liter SC not indicated coffee coffee rust (Hemilela vastatrix) 

Impact® 125SC 

(Columbia) 125 g ai/liter SC not indicated coffee coffee rust (Hemilela vastatrix) 

Table 3.3.2: Summary of Coffee Application Scenarios. 

App. Timing; 

Type; and Equip. Formulation App. Rate (kg ai/ha) 

Max. #. 

App. per 

Season 

Max. Seasonal 

App. Rate 

(kg ai/ha) 

PHI 

(days) Use Directions and Limitations 

Malaysia 

postemergence; 

foliar broadcast 

125 g ai/L 

SC 0.250 4 1.00 30 RTI = 14 days; Apply in a spray volume of 500 liters/ha. 

Columbia 

postemergence; 

foliar broadcast 

125 g ai/L 

SC 0.100-0.125 3 0.375 30 RTI = 30-45 days. 

Brazil 

postemergence 

(flowering stage); 

soil 125 g ai/L 

SC 

0.438-0.688 1 0.688 120 

Make a single application of the undiluted product when 

the plant is in the flowering stage using a jet or nozzle 

sprayer directing the solution under the canopy. 

postemergence; 

foliar broadcast 0.188-0.250 not specified 30 

Apply in sufficient water to ensure through coverage of 

the plant avoiding runoff (500 liters/ha; motorized 

knapsack or tractor sprayer). RTI of 30 days. 

 
Flutriafol Human-Health Risk Assessment D405792 

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3.4 Anticipated Exposure Pathways 

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

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

commodities, and drinking water. Exposure in the residential (non-occupational) setting is not 

anticipated. Based on the registered/proposed application scenarios and the results of a fish 

bioaccumulation study, residues in fish/shellfish are expected to be insignificant (D407105, T. 

Bloem, 27-Mar-2013; this includes consumption at the subsistence level). The current action 

will not result in occupational exposure to U.S. residents. The dietary risk assessment conducted 

as part of the current risk assessment considers all proposed/registered uses. 

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 

NHANES/WWEIA (2003-2008) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

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

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups. 

 
Flutriafol Human-Health Risk Assessment D405792 

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4.0 Hazard Characterization and Dose-Response Assessment 

No new toxicity and/or metabolism data have been received since the D382902 risk assessment (K. 

Lowe et al., 19-Oct-2011). The following flutriafol toxicological information is a summary of the 

information presented in D382902. 

4.1 Toxicological Effects 

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

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

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

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

P450 enzymes (hepatic and extra-hepatic). 

Flutriafol was categorized as having high oral acute toxicity in the mouse (Category II). It has low 

acute toxicity via the oral, dermal and inhalation routes (Categories III, III and IV, respectively) in 

rats. 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 in rats, there were no signs of toxicity for flutriafol up 

to the limit dose (1000 mg/kg/day). 

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

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

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

susceptibility was observed (delayed ossification or non-ossification of the skeleton in the fetuses) 

at a lower dose than maternal effects. In the second rat developmental study, a qualitative 

susceptibility was noted. Although developmental toxicity occurred at the same dose level that 

elicited maternal toxicity, the developmental effects (external, visceral, and skeletal malformations; 

embryo lethality; skeletal variations; a generalized delay in fetal development; and fewer live 

fetuses) were more severe than the decreased food consumption and body-weight gains observed in 

the dams. For rabbits, intrauterine deaths occurred at a dose level that also caused adverse effects in 

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

seen. Effects in the offspring (decreased litter size and percentage of live births, increased pup 

mortality, and liver toxicity) can be attributed to the systemic toxicity of the parental animals 

(decreased body weight and food consumption and liver toxicity). 
Flutriafol Human-Health Risk Assessment D405792 

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

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

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

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

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

of neurotoxicity in any other 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. 

A preliminary review of a recently submitted immunotoxicity study indicates that there is no 

concern for immunotoxicity. A formal review is pending. 

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. 

4.2 SF for Infants and Children (FQPA SF) 

HED’s RAB1 risk assessment team concludes that the 10x FQPA SF should 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). Sections 4.2.1-4.2.4 provides more detail concerning 

this conclusion. 

4.2.1 Completeness of the Toxicology Database 

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

developmental toxicity studies in rats and rabbits, reproduction studies in rats, and the neurotoxicity 

screening batteries in rats are available for analysis. 

4.2.2 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. 

4.2.3 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 years old) 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 

two-generation reproduction studies.
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4.2.4 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 assumes 100% CT). In addition, 

there are no proposed or registered uses that result in residential exposure. 

4.3 Toxicity Endpoint and Point of Departure (POD) Selections 

The PODs, uncertainty factors (UFs), and toxicity endpoints are presented in Table 4.3.1. Since 

this is an import tolerance, only the dietary endpoints are presented in Table 4.3.1. Appendix B 

provides a summary of all previously selected toxicological PODs. 

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 (10x for 

interspecies extrapolation and 10x 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. 

Acute 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 (10x for interspecies extrapolation and 10x 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 is also the most protective study for this endpoint for the population of concern 

(pregnant females and fetuses). 

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

the chronic dietary endpoint for all populations. An UF of 100 (10x for interspecies 

extrapolation and 10x for intraspecies variability) was applied to the NOAEL of 5 mg/kg/day to 

generate the cRfD of 0.05 mg/kg/day for all populations. The LOAEL is 20 mg/kg/day based 

upon adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in 

the liver, and increases in alkaline phosphatase, albumin, and triglycerides), increased adrenal 
Flutriafol Human-Health Risk Assessment D405792 

Page 13 of 25 

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 two-generation reproduction studies where similar effects were 

seen at slightly higher doses. 

Short- and Intermediate-Term Residental Incidental Oral, Dermal and Inhalation Endpoint: 

Since this is an import tolerance and since residential exposures are not anticipated from the 

proposed/registered uses, selection of incidental oral, dermal, and inhalation PODs for 

assessment of residential exposure is unnecessary and has not been performed. 

Cancer (oral, dermal, inhalation): Flutriafol is classified as “Not likely to be Carcinogenic to 

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

Table 4.3.1: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Dietary and NonOccupational Human Health Risk Assessments. 

Exposure/ 

Scenario POD Uncertainty/FQPA 

SFs 

RfD, PAD, 

LOC for Risk 

Assessment 

Study and Toxicological Effects 

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children) 

NOAEL = 

250 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

aRfD = 2.5 

mg/kg/day 

aPAD = 2.5 

mg/kg/day 

Neurotoxicity screening battery – rat; LOAEL = 750 mg/kg, 

based on decreased body weight, body-weight gain, absolute 

and relative food consumption, and clinical signs of toxicity in 

both sexes: dehydration, urine-stained abdominal fur, 

ungroomed coat, ptosis, decreased motor activity, prostration, 

limp muscle tone, muscle flaccidity, hypothermia, hunched 

posture, impaired or lost righting reflex, scant feces; in males: 

red or tan perioral substance, chromodacryorrhea, 

chromorhinorrhea and labored breathing, and in females: 

piloerection and bradypnea. 

Acute Dietary 

(Females 13-

49 years of 

age) 

NOAEL = 7.5 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

aRfD = 0.075 

mg/kg/day 

aPAD = 0.075 

mg/kg/day 

Developmental study – rabbit; Developmental LOAEL = 15 

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

litter resorptions and increased post-implantation loss. 

Chronic 

Dietary (All 

Populations) 

NOAEL = 5 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

cRfD = 0.05 

mg/kg/day 

cPAD = 0.05 

mg/kg/day 

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

adverse liver findings (increased liver weights, increased 

centrilobular hepatocyte lipid in the liver, and increases in 

alkaline phosphatase, albumin, and triglycerides), increased 

adrenal cortical vacuolation of the zona fasciculata, and marked 

hemosiderin pigmentation in the liver and spleen in both sexes; 

mild anemia (characterized by decreased hemoglobin, 

hematocrit, and red blood cell count) in the males; and initial 

body weight losses, decreased cumulative body-weight gains, 

and increased adrenal weights in the females. 

Cancer (oral, 

dermal, 

inhalation) 

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

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

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

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

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populationadjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. 
Flutriafol Human-Health Risk Assessment D405792 

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5.0 Dietary Exposure and Risk Assessment 

D407104, T. Bloem, 27-Mar-2013 (residue chemistry summary for the current action) 

D407105, T. Bloem, 27-Mar-2013 (dietary exposure analysis for the current action)

5.1 Metabolite/Degradate Residue Profile 

Table 5.1 is a summary of the residues of concern for tolerance enforcement and risk assessment 

purposes in primary crops, rotational crops, livestock, and water. For further information 

concerning these conclusions see the following documents: (1) primary crops - D355605 (B. Daiss, 

3-Sep-2008); D388603 (T. Bloem, 16-Jun-2011); D397806 (W. Cutchin, 2-Feb-2012); and 

D407104 (T. Bloem, 27-Mar-2013); (2) rotational crops - D380493 (T. Bloem, 16-Jun-2011) and 

D396758 (T. Bloem, 13-Mar-2012); (3) livestock - D388603 (T. Bloem, 16-Jun-2011); and (4) 

water - D355605 (B. Daiss, 3-Sep-2008). 

HED has previously reviewed toxicological data for T, TA, and TAA and concluded that the 

toxicological effects of T and TA/TAA 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 are different from that of flutriafol. Therefore, 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. 

Table 5.1: Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance Enforcement. 

Matrix Residues of Concern 

Risk Assessment Tolerance Enforcement

coffee, soybean seed, fruit, and 

sugar beet flutriafol, T, TA, and TAA 

flutriafol (free) 

cotton (Section 18 use)1, 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), M284

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

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

be estimated by multiplying the free flutriafol residue by 1.3x 

rotational crops (dried roughage 

feed commodities) 

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

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

conjugated) and M283 

poultry2 flutriafol (free and conjugated), deflourinated flutriafol, 

M284

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

ruminant3 flutriafol (free and conjugated), deflourinated flutriafol, 

M284

, M1B4, T, TA (free and conjugated), TAA, and TLA 

water flutriafol and T -- 1

 Decision will be reevaluated if a Section 3 use is requested (additional data may be required). 2

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

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

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

due to their presence in feed commodities. 

3

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

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

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

due to their presence in feed commodities. 

4

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

 
Flutriafol Human-Health Risk Assessment D405792 

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5.2 Food Residue Profile 

Adequate magnitude of the residue data have been submitted to support the currently-established 

tolerances. It is noted that additional cotton and sweet corn field rotational crop data have been 

requested to support the established rotational crop tolerances (these data remain outstanding; 

D397075, T. Bloem, 20-Dec-2011). The additional data were requested so as to ensure that the 

rotational crop tolerances are reflective of conditions in all relevant regions. Based on the 

existing sweet corn and cotton field rotational crop residue data and the unrefined nature of the 

current dietary exposure analyses (≤24% aPAD; ≤42% cPAD), HED concludes that these data 

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

The number and locations of the coffee field trials submitted in support of the current action are 

adequate to satisfy HED guidance concerning the establishment of a tolerance on imported 

coffee. In addition, based on the submitted labels, the employed application scenarios are 

adequate. Based on these data and the Organization for Economic Cooperation and 

Development (OECD) tolerance-calculation procedure, a green coffee bean tolerance of 0.20 

ppm for residues of flutriafol is appropriate. HED notes that Codex has established a coffee bean 

MRL for residues of flutriafol at 0.15 ppm. Since the maximum flutriafol residue from the field 

trial study was 0.10 ppm and since the processing study which employed single/seasonal foliar 

application at 5.0x/2.5x the maximum labeled rate yielded flutriafol residues in/on green coffee 

bean of 0.17-0.20 ppm, HED concludes that harmonization with the Codex MRL is acceptable. 

Therefore, HED concludes that the available data support a green coffee bean tolerance for 

residues of flutriafol at 0.15 ppm; a revised Section F is requested. 

The petitioner also submitted an adequate coffee processing study. Following treatment at 

5.0x/2.5x the labeled maximum single/seasonal foliar application rate, green coffee bean samples 

were processed into cleaned green coffee beans, roasted coffee beans, spent coffee grounds, liquor 

extract, and instant coffee using simulated commercial practices. Residues of flutriafol were found 

to concentrate in only instant coffee (1.9-3.0x; average of 2.5x). Based on the 0.0966 ppm highestaverage field trial (HAFT) flutriafol residue in/on green coffee bean and the average processing 

factor for residues of flutriafol in instant coffee of 2.5x, HED concludes that the proposed instant 

coffee tolerance for residues of flutriafol of 0.30 ppm is appropriate. 

5.3 Drinking Water Residue Profile 

The proposed tolerance in/on imported coffee will not impact residues in U.S. drinking water. Table 

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

concentrations (EDWCs) previously provided by the Environmental Fate and Effects Division 

(EFED; D383005, J. Wolf, 27-Apr-2011; D390213, J. Wolf, 31-May-2011). The water estimates 

were incorporated directly into the dietary exposure analysis. The water models and their 

description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

Table 5.3: Maximum Flutriafol EDWCs.

Model Application Rate Concentration (ppb) 

Groundwater (PRZM-GW1) stone fruit (4 x 0.114 lbs ai/acre at 7 day intervals) acute 310 

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

Surface water (FIRST2) Apples (6 x 0.114 lbs ai/acre at 7 day intervals)3 acute 48.8 

chronic 5.70 1

 Pesticide Root Zone Model-Groundwater (PRZM-GW). 2

 FQPA Index Reservoir Screening Tool (FIRST ver. 1.1.1). 3

 The initially proposed application rate for apple. 

 
Flutriafol Human-Health Risk Assessment D405792 

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5.4 Dietary (Food + Drinking Water) Risk Assessment 

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

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

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

see the Aggregate Section (7.0). 

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

conducted using DEEM-FCIDTM (ver. 3.16) which incorporates the food consumption data from 

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

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

assessment, 100% crop treated, and modeled drinking water estimates. Since adequate processing 

studies have been submitted which indicate that tolerances 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. The resulting acute 

(≤27% aPAD; females 13-49 years old were the most highly exposed subgroup) and chronic (≤36% 

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 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 

0.022440 <1 

0.05 

0.006348 13 

All Infants (< 1 year old) 0.063256 2.5 0.017990 36

Children 1-2 years old 0.051296 2.0 0.018063 36 

Children 3-5 years old 0.035764 1.4 0.012316 25 

Children 6-12 years old 0.023104 <1 0.006785 14 

Youth 13-19 years old 0.016522 <1 0.004267 8.5 

Adults 20-49 years old 0.019428 <1 0.005453 11 

Adults 50-99 years old 0.017770 <1 0.005681 11 

Females 13-49 years old 0.075 0.019896 27 0.005508 11 1

 95th percentile (tier 1 analysis) 

 
Flutriafol Human-Health Risk Assessment D405792 

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6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

There are no registered or proposed flutriafol uses that result in residential (non-occupational) 

exposure (tolerance in/on imported coffee is proposed). Therefore, residential handler and postapplication exposure/risks were not assessed. 

6.1 Residential Bystander Post-application Inhalation 

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

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

inhalation toxicity (Toxicity Category IV) and low vapor pressure (3.0 x 10-9 mm Hg). However, 

volatilization of pesticides may be a source of postapplication inhalation exposure to individuals 

nearby to pesticide applications. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from its 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in 

December 2009. 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, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure 

into the Agency's risk assessments. If new policies or procedures are put into place, the Agency 

may revisit the need for a quantitative postapplication 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. 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). 

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. 

 
Flutriafol Human-Health Risk Assessment D405792 

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7.0 Aggregate Exposure/Risk Characterization 

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

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

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

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

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

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

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

Application of flutriafol also results in exposure to T and TA/TAA/TLA, 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 (D403619, T. Morton, 1-Aug-2012). The proposed tolerance in/on imported coffee does 

not require a revision to this most recent aggregate assessment. 

8.0 Cumulative Exposure/Risk Characterization 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

http://www.epa.gov/pesticides/cumulative. 

9.0 Occupational Exposure/Risk Characterization 

The petitioner is proposing a tolerance in/on imported coffee. Therefore, an occupational 

exposure assessment is unnecessary for the current action. 

RDI: RAB1 (13-Mar-2013) 

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

Appendix A. Toxicology Profile and Executive Summaries 

Appendix B. Summary of all Previously Selected Toxicological PODs 

 
Flutriafol Human-Health Risk Assessment D405792 

Page 19 of 25 

Appendix A. Toxicology Profile and Executive Summaries 

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

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

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

Study Technical 

Required Satisfied 

870.1100 Acute Oral Toxicity 

870.1200 Acute Dermal Toxicity 

870.1300 Acute Inhalation Toxicity 

870.2400 Primary Eye Irritation 

870.2500 Primary Dermal Irritation 

870.2600 Dermal Sensitization 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

no 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) 

870.3150 Oral Subchronic (nonrodent) 

870.3200 21-Day Dermal 

870.3250 90-Day Dermal 

870.3465 90-Day Inhalation 

yes 

yes 

yes 

no 

no 

yes 

yes 

yes 

- 

- 

870.3700a Developmental Toxicity (rodent) 

870.3700b Developmental Toxicity (nonrodent) 

870.3800 Reproduction 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) 

870.4100b Chronic Toxicity (nonrodent) 

870.4200a Oncogenicity (rat) 

870.4200b Oncogenicity (mouse) 

870.4300 Chronic/Oncogenicity 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial 

870.5300 Mutagenicity—Gene Mutation - mammalian 

870.5xxx Mutagenicity—Structural Chromosomal Aberrations 

870.5xxx Mutagenicity—Other Genotoxic Effects 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotoxicity (hen) 

870.6100b 90-Day Neurotoxicity (hen) 

870.6200a Acute Neurotoxicity Screening Battery (rat) 

870.6200b 90-Day Neurotoxicity Screening Battery (rat) 

870.6300 Develop. Neurotoxicity 

no 

no 

yes 

yes 

no 

- 

- 

yes 

yes 

- 

870.7485 General Metabolism 

870.7600 Dermal Penetration 

870.7800 Immunotoxicity 

yes 

yes 

yes 

yes 

yes 

yes 

Special Studies for Ocular Effects 

 Acute Oral (rat) 

 Subchronic Oral (rat) 

 Six-month Oral (dog) 

no 

no 

no 

- 

- 

- 

 
Flutriafol Human-Health Risk Assessment D405792 

Page 20 of 25 

Table A.2: Acute Toxicity Profile – Flutriafol.

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

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

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

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

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

870.2400 Primary eye irritation (rabbit) 47090339 Minimally irritating III 

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

870.2600 Dermal sensitization (mouse) 47090343 Not a sensitizer - 

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

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

Classification /Doses Results 

870.3050 28-Day oral toxicity 

(rat) 

47090344 (1982) 

Acceptable/non-guideline 

0, 100, 300, 800, 2000, or 5000 

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

500 mg/kg/day) 

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

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

toxicity (increased weight, centrilobular hepatocellular 

hypertrophy, fatty change, hydropic degeneration, smooth 

endoplasmic reticulum proliferation, and increased 

aminopyrine-N-demethylase activity) in both sexes and 

decreased body-weight gain and food consumption in 

males. 

870.3100 90-Day oral toxicity 

(rat) 

47090345 (1982) 

Acceptable/guideline 

0, 20, 200, or 2000 ppm 

M: 0, 1.5, 14, and 158 

mg/kg/day) 

F: 0, 1.6, 22, and 145 

mg/kg/day 

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

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

on decreased body-weight gain, decreased food 

consumption and liver toxicity (increased absolute and 

adjusted liver weights, increased endoplasmic reticulum 

proliferation in the males, and increased APDM activity). 

870.3150 90-Day oral toxicity 

(dog) 

47090346 (1982) 

Acceptable/guideline 

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

NOAEL = 5 mg/kg/day 

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

(increases in organ weight, alkaline phosphatase, 

aminopyrine N-demethylase activity, and incidence of 

hemosiderin-laden Kupffer cells) in both sexes, spleens 

with hemosiderin content slightly higher than controls in 

the males, and decreased cumulative body-weight gains 

and increased triglycerides in the females. 

870.3200 28-Day dermal toxicity 

(rat) 

47090347 (2007) 

Acceptable/guideline 

0, 250, 500, or 1000 mg/kg/day

NOAEL = 1000 mg/kg/day. 

LOAEL was not established. 

870.3700a Prenatal developmental 

(rat) 

47090349 (1982) 

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. 

870.3700a Prenatal developmental 

(rat) 

47521303 (2008) 

Acceptable/guideline 

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

Maternal NOAEL = 10 mg/kg/day. 

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

gains and food consumption. 

Developmental NOAEL = 10 mg/kg/day. 

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

resorptions; malformations (cleft palate and multiple hyoid 

malformations) and variations in the hyoid; variations in 

the maxilla/mandible, rudimentary and long cervical ribs, 

pelvic girdle, and radius/ulna; numerous skeletal 

retardations detailed above and corresponding decrease in 

fetal weights. 
Flutriafol Human-Health Risk Assessment D405792 

Page 21 of 25 

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

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

Classification /Doses Results 

870.3700b Prenatal developmental 

(rabbit) 

47090350 (1982) 

Acceptable/guideline 

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

Maternal NOAEL = 7.5 mg/kg/day. 

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

and uncorrected body-weight gains and food consumption.

Developmental NOAEL = 7.5 mg/kg/day. 

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

live fetuses, complete litter resorptions and increased postimplantation loss. 

870.3800 2-gen. reproduction and 

fertility effects 

(rat) 

47090351 (1986) 

Acceptable/guideline 

0, 60, 240, or 1,000 ppm 

M: 0, 4.8, 20.6, and 88.7 

mg/kg/day) 

F: 0, 5.5, 21.9, and 103 

mg/kg/day 

Parental/Systemic NOAEL = 240 ppm (20.6/21.9 

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

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

on decreased body-weight gains and food consumption 

and on effects on the liver (increased liver weights, 

centrilobular hypertrophy, and fatty change). 

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

[M/F]). 

LOAEL was not determined. 

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

[M/F]). 

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

on decreased live birth index and litter size and on effects 

on the liver (fatty change/vacuolization). 

870.3800 2-gen. reproduction and 

fertility effects 

(rat) 

48196921, 48196922 (2009) 

Acceptable/guideline 

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

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

18.5/22.6, and 62.8/ 77.1 mg/kg 

bw/day [M/F] 

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

bw/day [M/F]). 

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

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

fatty deposits in the liver in both sexes as well as 

hepatocellular hypertropy in males. 

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

bw/day [M/F]. 

Reproductive LOAEL was not observed. 

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

[M/F]). 

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

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

at the first litter check and 0-4 postnatal days. 

870.4100 Chronic toxicity (1 

year; dog) 

47090353 (1988) 

Acceptable/guideline 

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

NOAEL = 5 mg/kg/day. 

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

(increased liver weights, increased centrilobular 

hepatocyte lipid in the liver, and increases in alkaline 

phosphatase, albumin and triglycerides), increased adrenal 

cortical vacuolization of the zona fasciculata, and marked 

hemosiderin pigmentation in the liver and spleen in both 

sexes; mild anemia (characterized by decreased 

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

males; and initial body weight losses, decreased 

cumulative body-weight gains, and increased adrenal 

weights in the females. 

870.4200 Carcinogenicity 

(mouse) 

47090354 (1988) 

Acceptable/guideline 

0 (two control groups), 10, 50, 

or 200 ppm 

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

mg/kg/day) 

F: 0, 1.4, 7.4, and 31 mg/kg/day

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

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

hepatotoxicity (increased fatty change) in both sexes. 

No evidence of carcinogenicity. 
Flutriafol Human-Health Risk Assessment D405792 

Page 22 of 25 

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

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

Classification /Doses Results 

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 

(7.0-9.0x10-5 treated vs. 3.0x10-5 controls) 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 (6.5x10-5 treated vs. 

1.2x10-5 controls) in Trial 2 attributable to severe 

cytotoxicity (2% relative survival). However, the 

increases in mutant frequency did not achieve the 

threshold value for a positive response (>10x10-5) in either 

trial and there was no marked increase in absolute mutant 

numbers at 750 μg/mL in Trial 2. In the absence of S9, 

there were no marked increases in mutant frequency or 

absolute mutant numbers compared to controls in either 

trial. There was no convincing evidence of induced 

mutant colonies over background in the presence or 

absence of S9-activation. 

870.5300 In Vitro Gene Mutation 

assay in mouse 

lymphoma cells 

48196918 (2006) 

Acceptable/guideline 

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

600 μg/mL (±S9, Trial 1); 0, 

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

400 μg/mL (-S9, Trial 1); 0, 

200, 300, 325, 350, 375, or 400 

μg/mL (+S9, Trial 2) 

(-S9, Trial 2) 

The mutagenicity criterion (threshold) of 126 colonies per 

106 cells above the solvent control was not reached for any 

valid data at any test concentration, with or without 

metabolic activation. Although linear regression analysis 

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

mutation frequency in Experiment 1 (culture 1, with 

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

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

were considered biologically irrelevant because the 

threshold for mutagenicity was not exceeded and all 

absolute values were within the range of historical 

negative and solvent controls. 

870.5375 In vitro Mammalian 

Cytogenetics 

(Chromosomal 

Aberration Assay in 

Human Peripheral 

Blood Lymphocytes) 

47090403 (1989) 

Acceptable/guideline 

0, 25, 125, or 250 μg/mL (+/-

S9) 

No significant increases in the numbers of cells with 

aberrations (excluding gaps) were observed in either donor 

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

of chromosome aberrations induced over background in 

the presence or absence of S9-activation. 

870.5385 In vivo Mammalian 

Cytogenetics – [Bone 

Marrow Chromosomal 

Aberration Test 

47090404 (1982) 

Acceptable/guideline 

0, 15, 70, or 150 mg/kg 

There was no evidence of chromosome aberration induced 

over background. 
Flutriafol Human-Health Risk Assessment D405792 

Page 23 of 25 

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

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

Classification /Doses Results 

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/Mammalia

n Cell 

47090407 (2003) 

Acceptable/guideline 

0, 250, 500, or 1000 mg/kg 

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

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

needed for a positive response, and no increase in the 

mean percent of cells in repair was observed. There was 

no evidence that unscheduled DNA synthesis, as 

determined by radioactive tracer procedures [nuclear silver 

grain counts] was induced. 

870.6200a Acute neurotoxicity 

screening battery 

47090408 (2005) 

Acceptable/guideline 

0, 125, 250, or 750 mg/kg 

NOAEL = 250 mg/kg. 

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

body-weight gain, absolute and relative food consumption, 

and clinical signs of toxicity, indicative of a moribund 

condition, in both sexes: dehydration, urine-stained 

abdominal fur, ungroomed coat, ptosis, decreased motor 

activity, prostration, limp muscle tone, muscle flaccidity, 

hypothermia, hunched posture, impaired or lost righting 

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

chromodacryorrhea, chromorhinorrhea and labored 

breathing, and in females: piloerection and bradypnea, and 

signs of neurotoxicity: hunched posture in females and 

ataxia in males. 

870.6200b Subchronic 

Neurotoxicity – Feeding 

Study in Rats 

47090410 (2007) 

Acceptable/guideline 

0, 500, 1500, or 3000 ppm (0/0, 

28.9/32.6, 84.3/97.6, and 

172.1/185.0 mg/kg/day [M/F]) 

NOAEL = 1500 ppm (84.3/97.6 mg/kg/day [M/F]). 

LOAEL = 3000 ppm (172.1/185.0 mg/kg/day [M/F]) 

based on decreased body-weight gain, absolute and 

relative food consumption; and decreased hindlimb grip 

strength in males. 
Flutriafol Human-Health Risk Assessment D405792 

Page 24 of 25 

Table A.3: 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/cm2

skin 

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-1 for the 2, 20, and 200 μg/cm2

 dose groups. 

Absorption mechanisms were saturated at the high dose. 

The elimination half-lives were calculated to be 31, 30, 

and 37 h for the 2, 20, and 200 μg/cm2

 dose groups. A 

maximum of 36.56% of the applied dose was noted as 

absorbed/absorbable (observed after 24 h exposure to 2 

μg/cm2

). The dose that is absorbed/absorbable following a 

10 h exposure is 16.54%, 21.31% and 11.39%, 

respectively, at 2, 20, and 200 μg/cm2

. 

870.7800 Immunotoxicity (mice) 48360301 (2011) 

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. 

 
Flutriafol Human-Health Risk Assessment D405792 

Page 25 of 25 

Appendix B. Summary of all Previously Selected Toxicological PODs 

Table 4.3.1: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Dietary and NonOccupational Human Health Risk Assessments. 

Exposure/ 

Scenario POD Uncertainty/FQPA SFs 

RfD, PAD, LOC for 

Risk Assessment Study and Toxicological Effects 

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children) 

NOAEL = 

250 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

Acute RfD = 2.5 

mg/kg/day 

aPAD = 2.5 

mg/kg/day 

Neurotoxicity screening battery – rat; LOAEL = 750 

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

absolute and relative food consumption, and clinical signs 

of toxicity in both sexes: dehydration, urine-stained 

abdominal fur, ungroomed coat, ptosis, decreased motor 

activity, prostration, limp muscle tone, muscle flaccidity, 

hypothermia, hunched posture, impaired or lost righting 

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

chromodacryorrhea, chromorhinorrhea and labored 

breathing, and in females: piloerection and bradypnea. 

Acute Dietary 

(Females 13-

49 years of 

age) 

NOAEL = 7.5 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

Acute RfD = 0.075 

mg/kg/day 

aPAD = 0.075 

mg/kg/day 

Developmental study – rabbit; Developmental LOAEL = 

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

complete litter resorptions and increased post-implantation 

loss. 

Chronic 

Dietary (All 

Populations) 

NOAEL = 5 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 1x 

Chronic RfD = 0.05

mg/kg/day 

cPAD = 0.05 

mg/kg/day 

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

adverse liver findings (increased liver weights, increased 

centrilobular hepatocyte lipid in the liver, and increases in 

alkaline phosphatase, albumin, and triglycerides), 

increased adrenal cortical vacuolation of the zona 

fasciculata, and marked hemosiderin pigmentation in the 

liver and spleen in both sexes; mild anemia (characterized 

by decreased hemoglobin, hematocrit, and red blood cell 

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

decreased cumulative body-weight gains, and increased 

adrenal weights in the females. 

Cancer (oral, 

dermal, 

inhalation) 

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

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

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

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

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

Table 4.3.2: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Occupational Human 

Health Risk Assessments. 

Exposure/ 

Scenario POD UFs LOC Risk 

Assessment Study and Toxicological Effects 

Dermal 

Short (1-30 

days)- and 

Intermediate (1-

6 months) -Term 

NOAEL= 7.5 mg/kg/day 

1

Dermal-absorption factor = 

21% 

UFA = 10x 

UFH = 10x 

Occupational 

LOC for MOE 

= 100 

Developmental toxicity – rabbit; Developmental 

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

number of live fetuses, complete litter resorptions 

and increased post-implantation loss. 

Inhalation Short 

(1-30 days)- and 

Intermediate (1-

6 months) -Term 

NOAEL = 7.5 mg/kg/day 

Inhalation toxicity assumed to 

be equivalent to oral toxicity 

Inhalation-absorption factor = 

100% 

UFA = 10x 

UFH = 10x 

Occupational 

LOC for MOE 

= 100 

Developmental toxicity – rabbit; Developmental 

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

number of live fetuses, complete litter resorptions 

and increased post-implantation loss. 

Cancer (oral, 

dermal, 

inhalation) 

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

mice. 

1

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

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.