UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subj ect: 

From: 

Through: 

To: 

1-September-20 15 

Flutriafol: Human Health Risk Assessment in Support of a Section 3 Registration for 

Application to Hops. 

PC Code: 128940 DP Barcode: 0 42245 1 

Decision No.: 492995 Registra tion No.: 67760-75 

Petition No.: 4F8294 Regulatory Action: Section 3 Registration 

Risk Assessment Type: aggregate Case No.: 7060 

TXR No.: not applicable CAS No.: 76674-2 1-0 

MRID No: not applicable 40 CFR: 180.629 

Tom Bloem, Ch ~ /) / 

Anwar Y. Dunbar, Ph.D .. Pharmacologist ~ ~- J/~ 

Kelly M. Lowe, Environmental Scientist / 

Risk Assessment Branch I (RAB I) 

Health Effects Division (HED; 7509P) 

Hope Johnson/Maryam K. Muhammad, RM 21 

Registration Division (RD; 7505P) 

2<----------

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-tluorophenyl)-a-( 4-tluorophenyl)- 1 H-1,2,4-triazole-lethanol). A summary of the findings and an assessment of human health risk resulting from the 

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

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

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

exposure (ORE) was provided by Kelly Lowe (RAB I), and the drinking water assessment was 

provided by James K. Wolf of the Envirorunental Fate and Effects Division (EFED). 

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Flutriafol Human Health Risk Assessment D42245 1 

Table of Contents 

1.0 EXECUTIVE SUMMARY .............................................................................................................................. 3 

2.0 RECOMMENDATIONS ................................................................................................................................. 5 

2.1 Data Deficiencies/Data Needs ........................................................................................................................ 5 

2.2 Tolerance Considerations ............................................................................................................................... 6 

2.2. 1 Enforcement Analytical Method ......................................................................................................... 6 

2.2.2 Recommended Tolerances .................................................................................................................. 6 

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

2.2.4 International Hannonization ...................................................................................................................... 6 

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

3.0 

3.1 

3.2 

3.3 

3.4 

INGREDIENT PROFILE ................................................................................................................................ 7 

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

Proposed Use Pattern ...................................................................................................................................... 7 

Anticipated Exposure Pathways ..................................................................................................................... 8 

Consideration of Environmental Justice ......................................................................................................... 8 

4.0 HAZARD CHARACTERIZATION AN D DOSE-RESPONSE ASSESSMENT ........................................... 9 

4. 1 Tox icology Studies Available for Analysis .................................................................................................... 9 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) .................................................................... 9 

4.2. 1 Dermal Absorption ............................................................................................................................ 10 

4.3 Tox icological Effects ..................................................................................................................................... I 0 

4.4 Safety Factor for Infants and Children (FQPA SF) ....................................................................................... 1 I 

4.4. 1 Completeness of the Toxicology Database ........................................................................................ 11 

4.4.2 Evidence ofNeurotox icity ................................................................................................................. 11 

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

4.4.4 Residual Uncertainty in the Exposure Database ................................................................................ 11 

4.5 Toxicity Endpoint and Point of Departure Selections ................................................................................... 12 

5.0 

4.5.1 Dose-Response Assessment .............................................................................................................. 12 

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment.. ................................... 13 

4.5.3 Cancer Classification and Risk Assessment Recommendation ......................................................... 13 

5. 1 

5.2 

5.3 

5.4 

DIETARY EXPOSURE AND RJSK ASSESSMENT .................................................................................... 15 

Metabolite/Degradate Residue Profile ........................................................................................................... 15 

Food Residue Profile ..................................................................................................................................... 16 

Drinking Water Residue Profile .................................................................................................................... 16 

Dietary (Food + Drinking Water) Risk Assessment ...................................................................................... 17 

6.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION .......................... 18 

6. 1 Spray Drift ..................................................................................................................................................... 18 

6.2 Residential Bystander Post-Application Inhalation Exposure ....................................................................... 18 

7.0 AGGREGATE EXPOSURE/RJSK CHARACTERJZATION ........................................................................ 19 

8.0 CUMULATIVE EXPOSURE/RISK CHARACTERIZATION ...................................................................... 19 

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION ................................................................. 20 

9.1 Handler Risk Assessment .............................................................................................................................. 20 

9.2 Post-Application Risk Assessment ................................................................................................................ 20 

9.2. I Inhalation Post-Application Risk Assessment ................................................................................... 20 

9.2.2 Restricted Entry lnterval .................................................................................................................... 22 

APPENDIX A. TOXICOLOGY PROFILE AND EXECUTIVE SUMMARJES ...................................................... 23 

APPENDIX B. CHEMICAL NAMES AND STRUCTURES ................................................................................... 29 

APPENDIX C. PHYSICAL/CHEMICAL PROPERTIES . ........................................................................................ 3 1 

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Flutriafol Human Health Risk Assessment 0422451 

1.0 Executive Summary 

Flutriafol ((±)-a-(2-fluorophenyl)-a-( 4-fluorophenyl)-lH-1 ,2,4-tri azole-1-ethanol) is a contact 

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

biosynthesis, thereby interfering with synthesis of fungal cell membranes. Tolerances for 

residues of flutriafol are established in/on numerous commodities, including livestock 

commodities, at 0.01-30 ppm. Cheminova, Inc. requested a Section 3 Registration and the 

establishment of permanent tolerances for residues of flutriafol in/on hops. 

Hazard Assessment: Consistent with mammalian toxicity of the other triazole fungicides, the 

effects in the flutriafol database are indicative of hepatotoxicity. There were slight indications of 

effects in the hematopoietic system. There is no evidence of dermal toxicity, immunotoxicity or 

carcinogenicity. There is evidence of increased quantitative and qualitative pre- and postnatal 

susceptibility for tlutriafol in rats and rabbits. Flutriafol is classified as "not likely to be 

carcinogenic to humans" based on the results of the carcinogenicity studies in rats and rruce. 

Food Quality Protectio11 Act (FQPA) Saf ety Factor (SF) Decision: The flutriafol risk assessment 

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

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

neurotoxic, there are clear no-observed adverse-effect levels (NOAELs) for the observed 

fetal/offspring effects, and the conservative nature of the dietary exposure analyses are unlikely to 

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

Dose Response Assessment: Tables 4.4. l and 4.4.2 provides a summary of toxicological doses 

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

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

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

exposures. The acute neurotoxicity screening battery (NOAEL = 250 mg/kg/day) was selected for 

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

chronic toxicity (dog) study was selected for assessment of chronic dietary exposure (NOAEL = 5 

mg/kg/day). For all exposure scenarios, a lOOx uncertainty factor (UF) was applied (lOx 

interspecies extrapolation; l Ox for intraspecies variation; Ix FQPA SF (when applicable)). 

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

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

Evaluation Model - Food Consumption Intake Database (DEEM-FCID, ver. 3. 16) which 

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

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

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

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

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

studies have been submitted which indicate that tolerances for residues in/on apple juice, grape 

juice, dried prunes, and tomato puree are unnecessary and since tolerances for residues in/on 

raisins and tomato paste are established, the DEEM (ver. 7.81) default processing factors for these 

commoditi es were reduced to 1. The DEEM (ver. 7.81) default processing factors were retained 

for the remaining relevant commodities. The resulting acute 39% acute population-adjusted 

dose (aPAD); females 13-49 years occupied the highest % of the aPAD) and chronic (~96% 

chronic population-adjusted dose (cP AD); children ( 1-2 years old) had the highest exposure) 

dietary risk estimates are not of concern to H ED. 

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Flutriafol Human Health Risk Assessment 0422451 

Residential (Non-Occupational) Exposure and Risk Assessme11t: There are no residential uses 

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

exposure/risk were not assessed. 

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

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

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

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

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

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

identified as being toxicologically identical to flutriafol. All aggregate flutriafol risk estimates are 

not of concern to HEO. 

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

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

toxicologically different from flutriafol. HED conducted an aggregate risk assessment for these 

compounds with the resulting exposure estimates less than HED's level of concern (LOC; D426493, 

T. Morton, 9-Apr-2015). 

Occupational Exposure and Risk Assessme11t: Based on the proposed use pattern, it has been 

determined that the potential exposure scenarios are short- and intermediate-term handler and postapplication occupational exposures. A new occupational handler assessment was not conducted 

since the anticipated exposure scenarios (mixing/loading and applying via aerial and airblast 

equipment), maximum application rate (0. 114 lb ai/A), and recommended level of personalprotective equipment (PPE) have been assessed previously (04 16213, K. Lowe, 24-Jan-2014). The 

combined occupational dermal plus inhalation handler exposure and risk estimates were not of 

concern in those assessments (i.e., margin of exposure (MOE)~ I 00) at baseline and with the use of 

gloves, as is required on the proposed label. A post-application occupational assessment has been 

conducted since there are unique worker activities related to hops, which have not been previously 

assessed. The resulting occupational post-application dermal exposure and risk estimates are not of 

concern on the day of application (MO Es = 510-4,200). 

Since the post-application assessment is not a concern on Day 0 ( 12 hours following application), the 

restricted-entry interval (REI) is based on the acute toxicity of tlutriafol technical material. 

Flutriafol has low acute toxicity via the oral, dermal and inhalation routes (Toxicity Categories III 

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

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

(Buehler method). Therefore, the acute toxicity categories for this chemical require a 12-hour REI 

under 40 CFR 156.208 ( c) (2) (iii). The 12-hour REI, which currently appears on the proposed label, 

is adequate for the proposed use. 

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

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

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

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

extent possible, were considered in this human health risk assessment, in accordance with U.S. 

Executive Order 12898, ·'Federal Actions to Address Environmental Justice in Minority Populations 

and Low-Income Populations." 

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Flutriafol Human Health Risk Assessment 042245 1 

Review of Huma11 Research : This risk assessment reli es in part on data from studies in which 

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

which include studies from the Pesticide Handlers Exposure Database (PHED) 1.1, the 

Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task 

Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received 

that review, and (3) are compliant with applicable ethics requirements. For certain studies, the 

ethics review may have included review by the Human Studies Review Board. Descriptions of 

data sources, as well as guidance on their use, can be found at the fo llowing Agency websites: 

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

http://v.'WW.epa.gov/pesticides/science/post-app-exposure-data.html. 

2.0 Recommendations 

Provided the petitioner submits a revised Section B, HED concludes that the toxicological, residue 

chemistry, and occupational/residential exposure databases support the establishment of the 

permanent tolerance listed in Section 2.2.2. 

The most recent tl utriafol risk assessment recommended for the establishment of cotton tolerances 

in 180.629(a) and the del etion of the cotton tolerances in l 80.629(d) (0 415849, T. Bloem, l 6-Dec2014). The cotton tolerances were established in 180.629(a) but they were not deleted form 

l 80.629(d). HED request that the cotton tolerances from 180.629(d) be deleted. 

2.1 Data Deficiencies/Data Needs 

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

OPPTS 860. 1900 are requested (trials should employ a seasonal rate of 0.228 lb ai/acre): sweet 

corn - North American Free Trade Agreement (NAFTA) Growing Zones 1 (n=2), 3 (n=l). 10 

(n= l), 11 (n= l), and 12 (n= l). These data were previously requested and remain outstanding 

(0 397075, T. Bloem, 20-Dec-2011 ). The additional data were requested to ensure that the 

resulting rotational crop tolerances are reflective of conditions for growers in all relevant regions. 

Based on the existing sweet corn and cotton field rotational crop residue data (residues :50.035 

ppm) and the unrefined nature of the current dietary exposure analyses, HED concludes that the 

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

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

risk assessment estimated using factors derived from the ruminant metabolism study. The factors 

range from 2-77x and reflect the fact that parent was not the major residue in some of the matrices. 

In order to facilitate refinements in the dietary exposure analysis which may be necessary as part 

of future registrations, HED advises the petitioner to analyze the ruminant feeding study samples 

for some or all of the ROC for risk assessment (storage stability data will also be required). HED 

notes that the ruminant residue estimates employed in the dietary ana lyses are conservative as they 

are comparable to, or significantl y higher than, the total radioactive residues (TRRs) from the 

metabolism study (30-ppm dietary burden) and due to the conservative nature of the dietary burden 

calculations. 

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Flutriafol Human Health Risk Assessment 042245 1 

2.2 Tolerance Considerations 

2.2.1 Enforcement Analytical Method 

Tolerance £ 11/orcement Method - Pla11ts: Adequate methods are available to enforce the currently 

established plant tolerances (D362421 , T. Bloem, l l-Mar-2009; 03405 13, T. Bloem, 1 l-Mar-2009; 

0388603, T. Bloem, 16-Jun-2011). The tlutriafol method employed in the magnitude of the 

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

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

the current tolerance enforcement method is adequate to enforce the tolerances associated with this 

petition. In addition, the QuEChERS method has been shown to adequately quantify residues of 

flutriafol (http://www.crl-pesticides.eu/library/docs/fv/CRLFV Multiresidue methods.pdt). 

Tolerance Enforcement Method - Livestock: Method ICIA AM00306 (revisions of 13-Aug-2007 

and 8-0ct-2007) has been determined to be sufficient for enforcement of the currently established 

ruminant tolerances (D36242 l, T. Bloem, 23-Apr-20 14). The flutriafol methods employed in the 

ruminant (49059703.der) and poultry (47510201.derl) magnitude of the residue studies are based 

on this method. Since adequate method validation data were provided as part of these studies, 

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

tolerances associated with this petition. 

2.2.2 Recommended Tolerances 

Table 2.2.2.1 is a summary of the proposed and HED-recornmended tolerance for residues of 

flutriafol per se (proposed tolerance is appropriate). 

T a ble 2.2.2.1: Tolerance Summa ry. 

Commodity I Proposed Tolerance (ppm) I HED-Rccommcnded Tolerance (ppm~ Comments 

40 CFR 180.629(a) 

hop. dried cones I 20 I 20 I --

2.2.3 Revisions to Petitioned-For Tolerances 

None 

2.2.4 International Harmonization 

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

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

2.3 Label Recommendations 

A revised Section B is requested which indicates that following application to hops, the treated 

field may only be rotated to a labeled crop. 

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Flutriafol Human Health Risk Assessment 0422451 

3.0 Ingredient Profile 

3.1 Chemical Identity 

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

in Tables 3.1.1. The physiochemical properties for flutriafol are listed in Appendix C. 

Table 3. 1.1 : Flutr iafol Nomencla ture. 

N 

(~ N- N 

F 

Chemical structure 

I 

~ 

h0 11 I ~ 

hF 

Common name Flutriafol 

Company experimental name PP450 (ICl/Syngenta until 200 I); CHA 13 10-05 (Cheminova code) 

IUPAC name (RS)-2.4 · -dinuoro-a-( I //-1.2.4-triazol-1-ylmethyl)benzhydryl alcohol 

CAS name (±)-a-(2-nuoroohenvl)-a-( 4-0uoroohenvl -1 H-1.2.4-triazolc-I -ethanol 

CAS rcizistl)1 number 76674-21-0 

NH, N~ 

N~ 0 N~ 

HN---$ 

I N HO ~I N~N ~~ /,N HO -.....§ 

1.2.4-triazolc (T) 0 triazolylacetic Acid (TAA) triazolylalanine (TA) 

3.2 Proposed Use Pattern 

Cheminova requested Section 3 Registrations for application of flutriafol to hops. Table 3.2.1 is 

a summary of the end-use product and target pests and Table 3.2.2 is a summary of the proposed 

application scenario. Provided a revised Section B is submitted which indicates that following 

application to hops, the treated field may only be rotated to a labeled crop, HED concludes that 

the proposed application scenario is supported by the available residue chemistry data. 

Table 3.2. 1: S umm ary of End-Use Products. 

Trade Name Cone. Formulation Label Date Target Crops Target Pests 

Topguard® Fungicide 1.04 lb ai/gal suspension not indicated hops Powdery mildew (Podospltaera 

(EPA Reg. No. 67760-75) concentrate (SC) 111ac11laris. Spltaerotlieca macularis) 

Table 3.2.2: S ummary o f Proposed Ho p A pplication Scenario. 

Application Single App. Max.# App. Max. Seasonal Pill 

Type. Formulation Rate 

per Season App. Rate (days) Use Directions and Limitations 

(lb ai/acre) (lb ai/acre) 

-14-day rctreatmcnt interval (RTI) 

-minimum ground and aerial spray volumes of 30 and I 0 

GPA. respectively 

-application via chemigation is prohibited 

-REI = 12 hours 

broadcast SC 0.081-0.114 4 0.455 7 -PP~ listed on the proposed label includes long-sleeved 

fo liar spray ( 1.04 lb ai/gal) shirt and long pants. chemical-resistant gloves. and shoes 

plus socks 

-adjuvams may be included in the spray solution 

-rotation to a labeled crop is permitted at any time: 

rotation to cotton/sweet com is permitted 180 days after 

application: rotation to any other crop is prohibited 

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Flutriafol Human Health Risk Assessment 0422451 

3.3 Anticipated Exposure Pathways 

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

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

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

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

fish/shellfish are expected to be insignificant (0425447, T. Bloem, l-Sep-201 5; this includes 

consumption at the subsistence level). The current action is expected to result in short- and 

intermediate-term occupational exposures (handler and post-application). 

3.4 Consideration of Environmental Justice 

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

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

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

(http://epa.gov/compliance/ej/resources/policy/exec order 12898.pdf). As a part of every 

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

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

subgroups from pesticide exposures that are based on panems 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's 

NHANES/WWEIA, 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. 

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Flutriafol Human Health Risk Assessment D422451 

4.0 Hazard Characterization and Dose-Response Assessment 

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

C 14-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 

The hazard ata~ase for flutriafol is complete and adequate for dose-response and FQPA 

evaluation. Flutriafol was evaluated for the following: 

(1) Subchronic and chronic oral toxicity in rats, mice and dogs; 

(2) Developmental toxicity in rats and rabbits; 

(3) Reproductive and postnatal toxicity in rats; 

(4) Carcinogenicity in mice and rats; 

(5) Neurotoxicity in rats; 

(6) lmmunotoxicity in mice; and 

(7) Genetic toxicology studies. 

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

(0420442, T. Bloem et al. , 16-Dec-2014). 

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

hazard and exposure data, as well as current registered use patterns for :flutriafol, and concluded 

using a weight-of-evidence approach that a subchronic inhalation toxicity study was not required at 

that time (TXR# 0056856). Since the application scenario proposed for hops is similar to that 

evaluated by HASPOC, HED concludes that a subchronic inhalation toxicity study would not be 

required for evaluation of occupational exposure resulting from application to hops. 

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

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

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

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

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

blood, liver, and kidneys. The total amount of radioactivity isolated in the tissues and carcass was 

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

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

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

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

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

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

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

ethandiol, which is then conjugated with glucuronic acid. 

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Flutriafol Human Health Risk Assessment 0422451 

4.2.1 Dermal Absorption 

An in vivo rat dermal-absorption study (MRJD #4 7090415) 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 calculated as the sum of absorbed and potentially 

absorbable residues at the skin site. A value of 2 1 % is appropriate (most protective) for dermal 

risk assessments. 

4.3 Toxicological Effects 

Consistent with the mammalian toxicity profiles of the other triazole fungicides, the prevalent 

adverse effects following oral exposure to tlutriafol were in the liver. Effects consisted of; 

increases in liver enzyme release (alkaline phosphatase), liver weights. and histopathology 

findings (hepatocyte vacuolization to centrilobular hypertrophy and slight increases in 

hemosiderin-l aden Kupffer cells. minimal to severe fatty changes, and bile duct 

proliferation/cholangiolar fibrosis. Progression of toxicity occurred with time as some effects 

were only observed at chronic durations. These effects were consistent with the ADME data in 

terms of the amount of dose absorbed and bio transformed, and the tissues where the chemical 

was most significantly detected. 

Slight indications of effects in the hematopoietic system were sporadically seen in all species 

consisting of; slight anemia, increased platelets, white blood cells, neutrophils, and lymphocytes. 

The effects in the neurotoxicity screening batteries were observed only at higher doses and were 

considered secondary effects (decreased motor activity and hindlimb grip strength, ptosis, lost 

righting reflex, hunched posture, and ataxia). Flutriafol showed no evidence of dermal toxicity, 

or imrnunotoxicity. Flutriafol showed no evidence of carcinogenicity in rodents or in vitro. 

There is evidence of increased quantitative and qualitative pre- and postnatal susceptibility for 

flutriafol in rats and rabbits. In the first of two rat developmental toxicity studies, developmental 

effects (delayed ossification or non-ossification of the skeleton in the fetuses) were observed at a 

lower dose than that where maternal effects were observed. In the second rat developmental 

study, 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 darns at the 

same dose. For rabbits, intrauterine deaths occurred at a dose level that also caused adverse 

effects in maternal anima ls. Jn the two-generation reproduction studies, 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) observed at the same dose. 

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

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

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

(Toxicity Category III) and is not a de1mal irritant (Toxicity Category TV). Flutriafol was not 

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

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Flutriafol Human Health Risk Assessment 0422451 

4.4 Safety Factor for Infants and Children (FQPA SF) 

The RABI risk assessment team concluded that the FQPA SF could be reduced to Ix based on the 

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

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

NOAELs are established to protect for the fetal/offspring effects observed and selected endpoints 

are protective of these effects; and 4) the exposure databases are sufficient and unlikely to 

underestimate exposure. 

4.4.1 Completeness of the Toxicology Database 

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

and occupational uses and FQPA SF evaluation. The following acceptable studies are available for 

evaluation: developmental toxicity studies in rats (2) and rabbits (I), two-generation reproduction 

studies in rats (2), and acute and subchronic neurotoxicity studies in rats. 

4.4.2 Evidence of Neurotoxicity 

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

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

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

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

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

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 of increased quantitative and qualitative susceptibility in developmental and reproduction 

toxicity studies (see Section 4.2); however, there concern is low since: 1) clear NOAELs and 

lowest observed adverse effect levels (LOAELs) were established for effects in the 

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

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

(females 13-49) as well as all other short- and intermediate-term exposure scenarios; 4) the acute 

reference dose for females 13-49 is 1000-fold lower than the dose at which quantitative 

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

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

two-generation reproduction studies. 

4.4.4 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% crop treated). In addition, there 

are no proposed or registered residential uses. 

Page 11 of3 I 
Flurriafol Human Health Risk Assessment 0422451 

4.S Toxicity Endpoint and Point of Departure Selections 

4.5.1 Dose-Response Assessment 

The PODs, UFs, and toxicity endpoints for dietary exposure assessment and occupational exposure 

assessment are presented in Tables 4.4.1 and 4.4.2, respectively. 

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

rat was selected for the acute dietary endpoint for the general population. A total UF of lOOx (lOx 

for interspecies extrapolation, I Ox for intra.species variability, and 1 x for FQPA SF) was applied to 

the NOAEL of250 mg/kg to generate the acute reference dose (a.PAD) of2.5 mg/kg for the 

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

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

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

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

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

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

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

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

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

UF of lOOx (!Ox for interspecies extrapolation, !Ox for intra.species variability, and lx for FQPA 

SF) was applied to the developmental NOAEL of7.5 mg/kg to generate the a.PAD 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 I 0 mg/kg in both studies with developmental LOAELs of 50 

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

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

(pregnant females and fetuses). 

Chronic Dietary E11dpoi11t (All populatio11s): The chronic dog toxicity study was selected for the 

chronic dietary endpoint for the general population. A total UF of 1 OOx (1 Ox for interspecies 

extrapolation, l Ox for intraspecies variability, and lx for FQPA SF) was applied to the NOAEL of 

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

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

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

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

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

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

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

This NOAEL is protective of all effects seen following chronic exposure to flutriafol. In addition, 

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

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

effects) as the chronic dog study. Other studies considered for this endpoint were the 

chronic/carcinogenicity studies (mouse and rat), as well as the two-generation reproduction studies 

where similar effects were seen at slightly higher doses. 

Pagel2of31 
f lutriafol Human Health Risk Assessment 042245 1 

Sltort- and /11termediate-Term Dermal and J11/talatio11 E11dpoi11t: The rabbit prenatal 

developmental toxicity study 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 oflive fetuses, complete litter resorptions and increased 

post-implantation loss. Although maternal and developmental toxicity were observed at the same 

dose, the maternal effects were restricted to moderate decreases in body weight 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 routespecific 28-day dermal toxicity study was also considered for dermal exposures, but there was no 

toxicity observed up to the limit dose (I 000 mg/kg/day) and developmental effects were not 

evaluated. The selected study provides the most protective endpoint for the populations of concern 

(pregnant females and fe tuses). Other studies considered for dermal and inhalation scenarios were 

the 90-day dog and the two-generation reproduction studies (parenta l effects) where liver toxicity 

(the target organ) was observed at similar doses as the rabbit developmental study. The LOC for 

the dermal and inhalation endpoints is 100 based upon a 1 Ox for interspecies extrapolation, and a 

1 Ox for intraspecies variability. Using a dermal-absorption factor of 2 1 %, the dennal-equivalent 

NOAEL is - 35.7 mg/kg/day (NOAEL of 7.5 mg/kg/day I 2 1 % dermal absorption = 35.7 

mg/kg/day. Inhalation exposure is assumed to be equivalent to oral exposure). 

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment 

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

identical, exposure via these routes may be combined. 

4.5.3 Cancer Classification and Risk Assessment Recommendation 

Flutriafol is classi tied as "not likely to be carcinogenic to humans" based on the results of the 

carcinogenicity studies in rats and mice. 

Page 13 of3 I 
Flutriafol Human Health Risk Assessment 042245 1 

Table 4.5. l : Summary of Tox icological Doses and Endpoints for Flutriafol for Use in Dietary and NonOccuoational Human Health Risk Assessments. 

Exposure/ POD Uncertainry/FQPA RID, PAD. LOC for Study and Toxicological Effects Scenario SFs Risk Assessment 

Neurotoxicity screening battery - rat: LOAEL = 750 

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

Acute Dietary Acute RID = 2.5 absolute mid relative food consumption. and clinical signs 

(General NOAEL = UFA= IOx mg/kg/day of toxicity in both sexes: dehydration. urine-stained 

Population, 250 UFtt = !Ox abdominal fur. ungroomed coat. ptosis, decreased motor 

including mg/kg/day FQPA SF= Ix aPAD = 2.5 activity. prostration. limp muscle tone. muscle flaccidity. 

Infants and hypothermia. hunched posture, impaired or lost righting 

Children) mg/kg/day reflex. scmit feces: in males: red or tan perioral substance. 

chromodacryorrhea, chromorhinorrhea and labored 

breathin1.t. and in females: oiloerection mid bradvonea. 

Acute Dietary Acute RID = 0.075 Developmental study - rabbit: Developmental LOA EL = 

(Females 13- NOAEL = 7.5 UFA = IOx mg/kg/day 15 mg/kg, based on decreased number of live fetuses. UFtt = I Ox 49 years of mg/kg/day FQPA SF = Ix aPAD = 0.075 complete litter resorptions and increased post-implantation 

age) ml?./k11/dav loss. 

Chronic toxicity - dog: LOA EL = 20 mg/kg/day. based on 

adverse liver findings (increased liver weights. increased 

ccntrilobular hepatocyte lipid in the liver. and increases in 

Chronic RID = 0.05 alkaline phosphatase. albumin. and triglycerides). 

Chronic iNOAEL = 5 UFA= I Ox mg/kg/day increased adrenal cortical vacuolation of the zona 

Dietary (All UFtt = I Ox fasciculata, and marked hemosiderin pigmentation in the 

Populations) mg/kg/day FQPA SF= Ix cPAD = 0.05 liver and spleen in both sexes: mild anemia (characterized mg/kg/day 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, Classification: "'Not likely to be Carcinogenic to Humans'' based on the carcinogenicity studies in rats and mice. 

inhalation) 

Point of dcpanure (POD) = A da1a point or an csumated point that ts derived from observed dos<>response da1a and used to mark the bcgmn111g 

of extrapolation to dctcnninc risk associated with lower environmentally relevant human exposures. NOA EL= no-observed adversc.'-effect level. 

LOAEL = Jo,1cst-observed adverse-effect level. UF = unccnainty factor. UF" = extrapolation from animal to human (interspecies). UFH = 

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

Table 4.5.2: Summary of Toxicological Doses a nd Endpoints for Flutriafol for Use in Occupational Human 

Hea lth Ris k Assessments. 

Exposure/ POD UFs LOC Risk Study and Toxicological Effects Scenario Assessment 

Dermal INOAEL= 7.5 mg/kg/day Occupational Developmental toxicity- rabbit; Developmental 

Short ( 1-30 days)- 1 Dermal-absorption factor = UFA = !Ox LOC for LOA EL = 15 mg/kg/day. based on decreased 

and lntenncdiate ( 1- 21% UF11 = I Ox MOE < 100 number of live fetuses, complete liller 

6 months) -Tcm1 resorptions and increased post-implantation loss. 

Inhalation Short (I- NOA EL = 7.5 mg/kg/day Occupational Developmental toxicity - rabbit: Developmental 

30 days)- and Inhalation toxicity assumed to UFA= IOx LOC for LOA EL = 15 mg/kg/day. based on decreased 

Intcnnediatc ( 1-6 be equivalent to oral toxicity' UF11 = IOx MOE < 100 number of live fetuses. complete liner 

months) -Term resorotions and increased oost-imolantation loss. 

Cancer (oral. Classification: ·· ot likely to be Carcinogenic to I lumans"" based on the carcinogenicity studies in rats and 

dermal, inhalation) mice. 

1 Dcnnal absorption factor was denvcd from the demial pcnetra1ton study (MRID 47090415): 111hala1ton absorptton factor as considered the worst-case scenario for inhalation exposure using an ornl NOAF.L (0372347. K. Lowe et al .. 16-Dcc-2009). 

Point of departure (POD)= A da1a point or an estimated point that is derived from observed doso-rcsponsc data and used to mark the beginning 

of extrapolation to detcnninc risk associated with lower environmentally relevant human exposures. NOA EL= no-observed adver9:-effect level. 

LOA EL= lowest-observed adverse-effect level. UF 3 uncertainty factor. UF" extrap lati n from aninrnl to human (interspecies). UF11 = 

potential variation in sensitivity an1ong members of the l'l!man population (intraspccies). MOE = margin of exposure. LOC = levd of concern. 

Page 14 of3 I 
Flutriafol Human Health Risk Assessment 042245 1 

5.0 Dietary Exposure and Risk Assessment 

0425446, T. Bloem, l-Sep-20 15 (residue chemistry); 0425447, T. Bloem, 1-Sep-2014 (dietary exposure) 

5.1 Metabolite/Degradate Residue Profile 

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

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

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

flutriafol. The ROC for risk assessment are defined in Table 5. 1.1. 

Defluorinated flutriafol (single fluorine was removed) was identified in the canola metabolism 

study (pod without the seed - 12-15% TRR (S0.12 ppm); seed - 3% TRR (S0.04 ppm)) indicating 

that fl utriafol may contribute to fluoride dietary exposure. HED has previously conducted dietary 

exposure analyses for fluoride residues from the insecticides cryolite and sulfuryl fluoride uses as 

well as from naturally occurring fluoride residues in food and water (D385539, M. Doherty, 7-

Jan-2011 ). For the fo llowing reasons, HED concludes that fluoride exposure resulting from the 

application of flutriafol are insignificant when compared to exposure estimates generated in the 

D385539 memo (revised assessment is unnecessary): (1 ) based on the identification of 

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

tlutriafol may be present in onJy hops, cotton, 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); (2) a flouride residue estimate of 0.008 ppm can be 

calculated using the 0. 12 ppm detluorinated flutriafol residue from the canola metabolism study 

and assuming a one to one molar ratio (single fluorine was removed; defluorinated tl utriafol was 

not identified in the fate or rotational crops studies indicating that defluorination occurred in the 

plant); and (3) the fluoride dietary exposure analyses assumed a fluoride residue of 0.496 ppm in 

hops, cotton, soybean seed, and peanut and 0.1 52 ppm in cereal grains. 

Tab le 5. 1. l : S ummary of Metabolites a nd Del?radatcs of Concern fo r Ris k Assessmen t a nd Tole ra nce E nforceme nt. 

Matrix ROC1 

Risk Assessment Tolerance Enforcement 

coffee. soybean seed. fruit. sugar 

beet. cucurbit vegetables. fruiting flutriafol (free). T. TA. and TAA 

vegetables. tree nuts. and leafy 

vegetables (croo grouos 4 and 5) 

hops. cotton. peanut. and cereal flutriafol (free and conjugated). defluorinated flutriafol. T. TA. and T AA: 

grains combined nutriafol (free and conjugated) and dcnuorinated nutriafol 

residues may be estimate by multiolving the free flulriafol residues by 2.2x2 

rotational crops (excluding dried nutriafol (free and conjugated). M28. T. TA (free and conjugated). TAA, 

roughage feed commodities) and TLA: combined flutriafol (free and conjugated) and M28 residue may nutriafol (free) be estimated by multiplving the free nutriafol residue by I .3x2 

rotational crops (dried roughage same as that mentioned above but with multiplication of the free nutriafol 

residues by 2.0x to account for the combined residues of flutriafol (free and feed commodities) conjugated) and M28~ 

IPOU1trv3 nutriafol (free). T. TA. and TAA 

flutriafol (free), M3. M3c, M4. M7, M IO. T. TA. and TAA: combined 

Ruminant nutria fol. M3. M3c, M4. M7, and M I 0 residues may be estimated by 

multiplying the free nutriafol residue by lhe followini: skim milk - 58x. 

cream - I Sx, liver. 5.3x. kidney 77x. muscle - 6x. and fat - 2x 

Water flutriafo l and T -- 1 For information concerning these conclusions, see lhc following: 0355605. B. Oaiss. 3-Sep-2008: 0372347. K. Lowe et al.. 

16-Dec-2009: 0388603. T. Bloem. 16-Jun-2011: 0380493. T. Bloem. 16-Jun-2011: 0396758. T. Bloem. 13-Mar-20 12: 

04 16089. T. Bloem. l 6-Dcc-20 14. Separate risk assessments arc required for T and TAff AAfTLA (these compounds have been 

determined to be tox icologically different from flutriafol). 2 The indicated factors are based on results from the metabolism studies or confined rotational crop study. 3 Decision will be reevaluated as the dieiary burden increases. 

Page 15 of3 I 
Flutriafol Human Health Risk Assessment 0 42245 1 

5.2 Food Residue Profile 

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

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

Registered Primary Crops: Adequate magnin1de of the residue data have been submitted to 

support the currently-established tolerances. 

Magnitude of tile Residue - Hops: The submitted hop field trial data fulfi ll the data requirements 

specified in OCSPP 860.1500. The collected samples were analyzed for residues oftlutriafol, T, TA, 

and T AA using adequately validated methods (storage intervals have also been validated). No 

additional field trial data are required. Based on the Organization for Economic Co-operation and 

Development (OECD) tolerance-calculation procedure, HED concludes that the hop tolerance listed 

in Table 2.2.2. l for residues of flutriafol per se is appropriate. 

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

be rotated to a labeled crop at any time and to sweet com and cotton 180 days after application 

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

the petitioner cited previously submitted and reviewed sweet corn and cotton field rotational crop 

data which employed an application rate of 0.228 lb ai/acre (0.Sx) and resulted in the establishment 

of tolerances for residues in/on sweet com ear/forage/stover and cotton seed/gin byproducts at 0.01-

0.09 ppm. Since field rotational crop data conducted at seasonal rates >0.228 lb ai/acre are not 

available and based on the proposed seasonal application rate of 0.455 lb ai/acre, HED concludes 

that only a labeled crop may be rotated following application to hops (a revised Section Bis 

requested). 

Magnitude of tlte Residue - Livestock: Based on the OCSPP 860.1000 Table 1 (see feedstuff 

revision of 30-Jun-2008), there are not livestock feedstuffs associated with hops. Therefore, a 

discussion concerning the magnitude of the residue in livestock is unnecessary. 

5.3 Drinking Water Residue Profile 

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

water concentrations (EDWCs) when considering all proposed/registered uses (EFED; 0422918, 

J. Wolf, 4-Mar-2015). The bolded EDWCs from Table 5.3.1 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/oppef ed 1 /models/water/. 

Table 5.3. l : Maximum Flutriafol EDWCs. 

Model Aoolication Rate Concentration (ppb) 

groundwater (PRZM-GW') 4 x 0. 11 4 lbs ai/aere: RTI = 14 days acute 193 

chronic 165 

surface water (SWCC1) 4 x 0. 114 lbs ai/acre: RTI = 14 days 

acute 15.9 

chronic 5.39 .. 1 Pcs11e1de Root Zone Model-Groundwater (PRZM-GW): FQPA Index Reservoir Screenmg Tool (FIRST vcr. 1.1. 1 ): Surface 

Water Concentration Calculator (SWCC). 

Page 16 of3 I 
Flutriafol Human Health Risk Assessment 0422451 

5.4 Dietary (Food+ Drinking Water) Risk Assessment 

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

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

and TNT AAffLA, which HED has determined to be toxicologically different from flutriafol, 

see the Aggregate Section (7.0). 

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

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

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

tolerance-level residues or tolerance-level residues adjusted to account for the ROC for risk 

assessment, J 00% crop treated, and modeled drinking water estimates. Since adequate 

processing studies have been submitted which indicate that tolerances for residues inion apple 

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

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

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

factors were retained for the remaining relevant commodities. The resulting acute 39% aP AD; 

females 13-49 years occupied the highest % of the aPAD) and chronic (~96% cPAD; children 

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

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

Table 5.4. 1: Summary of the Acute and Chronic Dietary Exposure and Risk. 

Population aPAD Exposure o/oaPA01 cPAD Exposure %cPAO (mg/kg/day) (mg/kg/day)' (mg/kg/day) (mg/kg/day) 

General U.S. Population 0.040729 1.6 0.014570 29 

A ll Infants (<I year old) 0.071406 2.9 0.025073 50 

Children 1-2 years old 0.095739 3.8 0.048076 96 

Children 3-5 years old 

2.5 0.080001 3.2 0.033853 68 

Children 6-12 years old 0.047907 1.9 0.05 0.019337 39 

Youth 13-19 years old 0.026897 I. I 0.010276 2 1 

Adults 20-49 years old 0.029368 1.2 0.0 11 790 24 

Adults 50-99 years old 0.029925 1.2 0.0 12 109 24 

Females 13-49 years old O.o75 0.029546 39 0.011455 23 1 95•h percentile (tier I analysis). 

Page 17 of3 I 
Flurriafol Human Health Risk Assessment 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

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

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

6.1 Spray Drift 

0422451 

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

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

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

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

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

issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and 

other parties to develop the best spray drift management practices (see the Agency's Spray Drift 

website for more information; http://www.eoa.gov/opp00001 /factsheets/spraydrift.htm) The 

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

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

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

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

that all uses for that pesticide will be considered concurrently. 

6.2 Residential Bystander Post-Application Inhalation Exposure 

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals 

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

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP's fi nal report on March 

2, 20 I 0 (hnp://www.epa.gov/scipoly/SAP/meetings/2009/120 I 09meeting.html). The Agency has 

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

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

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

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

chemicals. 

Page 18 of3 l 
Flutriafol Human Health Risk Assessment 0422451 

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 T AfT AAITLA. These compounds are 

considered to be toxicologically different from flutriafol. HED conducted an aggregate risk 

assessment for these compounds with the resulting exposure estimates less than HED's LOC 

(D426493, T. Morton, 9-Apr-20 I 5). 

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. 

Furthennore, 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. 

Page 19of3 1 
Flutriafol Human Health Risk Assessment 0422451 

9.0 Occupational Exposure/Risk Characterization 

0426919, K. Lowe, l-Sep-2015 

9.1 Handler Risk Assessment 

Based on the anticipated use patterns, and the current labeling regarding types of equipment and 

techniques that can be used, occupational handler exposure is expected. The following exposure 

scenarios would be expected: ( 1) mixing/loading liquids for aerial and airblast applications; (2) 

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

scenarios have already been assessed at the proposed maximum application rate in a previous 

assessment for other registered crops offlutriafol (04162 13, K. Lowe, 24-Jan-2014), and no risk 

estimates of concern were identified. The dermal and inhalation combined MOEs were not of 

concern to HED (i.e., MOE 2: 100) at baseline and with the use of gloves, as is required on the 

proposed label. Combined occupational handler MOEs ranged from 280 to 30,000 for aerial and 

airblast applications with the use of gloves by mixers/loaders. 

9.2 Post-Application Risk Assessment 

HED uses the term post-application to describe exposures that occur when individuals are present in 

an environment that has been previously treated with a pesticide (also referred to as re-entry 

exposure). Such exposures may occur when workers enter previously treated areas to perform job 

functions, including activities related to crop production, such as scouting for pests or harvesting. 

Post-application exposure levels vary over time and depend on such things as the type of activity, the 

nature of the crop or target that was treated, the type of pesticide application, and the chemicar s 

degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, 

can greatly reduce the potential for post-application exposure. 

9.2.1 Inhalation Post-Application Risk Assessment 

There are multiple potential sources of post-application inhalation exposure to individuals performing 

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, and 

received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings 

/2009/120 I 09meeting.html). The agency has evaluated the SAP report and has developed a 

Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail:D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for flutriafol. 

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

data generated by the ARTF. Given these two efforts, the Agency will continue to identify the need 

for and, subsequently, the way to incorporate occupational post-application inhalation exposure into 

the agency's risk assessments. 

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

performed, an inhalation exposure assessment was performed for occupational/commercial handlers 

which resulted in exposure less the HED's LOC (see Section 9.1). Handler exposure resulting from 

application of pesticides outdoors is likely to result in higher exposure than post-application exposure. 

Therefore, it is expected that these handler inhalation exposure estimates would be protective of most 

occupational post-application inhalation exposure scenarios. 

Page 20 of3 I 
Flutriafol Human Health Risk Assessment 0 42245 1 

9.2.2 Dermal Post-Application Risk Assessment 

Short- and intermediate post-application dem1al exposure is anticipated with the expected scenarios, 

exposures, and MOEs summarized in Table 9.2.2. l. All scenarios resulted in MOEs greater than 

the LOC of 100 (ranging from 510-4200) on day 0 (1 2 hours after application; proposed REI) and, 

therefore, are not of concern to HED. Since chemical-specific data are not available, the exposure 

estimates were calculated using default dislodgeable foliar residue (DFR) assumptions (see below). 

Table 9.2.2.1: Occupational Post-application Non-Ca ncer Exposure and Ris k Estimates for Flutriafol. 

Transfer Proposed Dennal Dose MOE3 

Crop/Site Activities Coefficient Application Rate DFR' (mg/kg/day)2 (LOC = JOO) (cm21hr) (lb a i/acre) 

Short- and Intennediate-tenn 

Transplanting 230 0.0018 4,200 

Hand weeding, Stripping, 640 0.00498 1,500 

Hops Scouting, Tying(frain ing 0.11 4 0.32 

Mechanically-assisted harvesting 1.400 0.011 690 

Irrigation (hand-set) 1,900 0.0 15 5 10 

1 DFR - Apphcatton Rate x F x ( 1-D)' x 4.54E8 μg/lb x 2.47F.-8 acre/cm2: where F = 0.25 and D = 0.10 per day. 2 Daily Dermal Dose = IDFR (μg/cm2

) x Transfer Coefficieit x 0.001 mglμg x 8 hrs/day x dermal absorption (21 %)] + BW (69 kg). 3 MOE= PO D (7.5 mg/kg/day) I Daily Dcnnal Dose. 

DFR: As indicated above, a chemical specific DFR study is not available. In accordance with 

40CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) 

or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) 

uses that could result in post-application exposure to fo liage. In the absence of chemical-specific 

DFR data, EPA uses default values. The 2012 Standard Operating Procedures.for Residential 

Pesticide Exp osure Assessment includes an analysis of a number of DFR studies, which resulted 

in the selection of a revised de fault values for the fraction of the application rate available for 

transfe r after a foliar application (FAR). These values are based on an analysis of l 9 DFR studies. 

Since that time, the ARTF has submitted information (MRJD 49299201) that corrects an 

application rate error made in the original submission of "ARF039 - Determination of Dermal 

and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse" 

(EPA MRJD 45344501). As a result, the range of FAR values was revised from 2% - 89% to 2% 

- 47%. In the data, a large range of transferability is observed and this variability can potentially 

be attributable to many factors such as active ingredient; fonnulation; field conditions in the 

studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. 

Although witnessed across multiple chemicals, this range in FAR values is not expected when 

considering DFR data for a single chemical. At this time, the ARTF submission did not alter the 

selection of 25% as the reasonable, high-end default value. Because DFR data are not available 

for flutri afol, EPA is using the default value of 25%. Although there may be a small degree of 

uncertainty in the use of the default DFR value for flutriafol (i.e., there is a small chance that the 

FAR value may exceed the applicable default value), it is likely that the health-protective aspects 

of EPA 's occupational post-application assessment methodology will more than compensate for 

this potential uncertainty. For example, when assessing residential and occupational postapplication exposure to gardens and ornamentals, EPA assumes the following: exposures occur 

to zero-day (i.e .. day of application ) residues every day of the assessed exposure duration (i.e., 

Pagc2 1 of 3 1 
Flutriafol Human Health Risk Assessment 0 422451 

EPA assumes that no dissipation or degradation occurs, it doesn't rain, etc.); individuals perform 

the same post-application activities performed in the transfer coefficient study day after day (e.g., 

weeding, harvesting, pruning, etc.); and individuals engage in these post-application activities for 

a high-end amount of time every day (represented by data reflecting time spent gardening based 

on survey data). 

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

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

exposure is not being underestimated. 

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

flutriafol is minimal in comparison to the LOC (i.e., the calculated MOE is greater than 2 times 

higher than the LOC, MOE = 510 compared to the LOC of 100); EPA is waiving the 40 CFR 

DFR data requirement. In this instance, it is unlikely that chemi cal-specific DFR data would be 

needed to ft111her refine exposure assessments or would add appreciably to our overall 

understanding of the availability of dislodgeable foliar pesticide residues for flutri afol. 

9.2.2 Restricted Entry Interval 

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

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

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

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

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

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

CFR 156.208 (c) (2) (iii), ai's classified as Acute Ill or TV for acute dermal, eye irritation and 

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

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

post-application exposures to llutriafol. 

RDI: RABI ( 13-May-201 5) 

Appendix A. Toxicology Profile and Executive Summaries 

Appendix B. Chemical Names and Structures 

Appendix C. Physical/Chemica l Properties 

Page 22 of3 I 
Flutriafol Human Health Risk Assessment 0 42245 1 

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. I: Study Requirem ents for Food Uses fo r Flutriafol. 

Study Technical 

Required Satisfied 

870. 11 00 Acute Oral Toxicity yes yes 

870.1 200 Acute Dem1al Toxicity yes yes 

870.1 300 Acute Inhalation Toxicity yes yes 

870.2400 Primary Eye Irritation yes yes 

870.2500 Primary Demial Irritation yes yes 

870.2600 Dermal Sensitization yes yes 

870.3 100 Oral Subchronic (rodent) yes yes 

870.3 150 Oral Subchronic (nonrodent) yes yes 

870.3200 2 1-Day Dem1al yes yes 

870.3250 90-Day Demial no - 870.3465 90-Day Inhalation no - 870.3700a Developmenta l Tox icity (rodent) yes yes 

870.3700b Devclopmen1al Toxicity (nonrodent) yes yes 

870.3800 Reproduction yes YCS 

870.41 OOa Chronic Toxic ity (rodent) yes yes 

870.4 1 OOb Chronic Toxicity (nonrodent) yes yes 

870.4200a Oncogenicity (rat) yes yes 

870.4200b Oncogenic ity (mouse) yes yes 

870.4300 Chronic/Oncoe.enicity yes yes 

870.5100 Mutagcnicity- Gene Mutation - bacterial yes yes 

870.5300 Mutagenicity- Gene Mutation - mammalian yes yes 

870.5xxx Mutagenicity- Structural Chromosomal Aberrations yes yes 

870.5xxx Muta_genicity-Other Gcnotoxic Elfects yes yes 

870.6 1 OOa Acute Delayed Neurotoxicity (hen) no - 870.6100b 90-Day eurotoxicity (hen) no - 870.6200a Acute eurotoxicity Screening Battery (rat) yes yes 

870.6200b 90-Day Neurotoxic ity Screening Bat1ery (rat) yes yes 

870.6300 Develop. Neurotoxicitv no - 870.7485 General Metabolism yes yes 

870.7600 Dermal Penetration yes yes 

870.7800 lmmunotoxicity yes yes 

-- Table A .2 : Acute T oxic ity Profile - Flutriafol. 

Guideline No. Study Type MRJD(s) Results Toxicity Cate.izory 

870. 11 00 Acute ora l (rat) 47090336 LDso = I 140 mg/lrn (M): 1480 mg/ke. (F) Ill 

870. 1100 Acute oral (mouse) 47090335 1

LDso = 365 mg/kg bw (M): 179 mg/kg bw ff) II 

870.1200 Acute dermal (rat) 4786101 LDso>2000 mg/kQ bw 111 

870. 1300 Acute inhalation frat) 47090338 LCso >5.20 ml!.IL IV 

870.2400 Primarv eve irritation (rabbit) 47090339 Minimally irritatinJ?. Ill 

870.2500 Primary dermal irritation (rabbit) 4709034 1 Not a dennal irritant IV 

870.2600 Derma l sensitization (mouse) 47090343 Not a se it~ -

Page 23 of3 I 
Flutriafol Human Health Risk Assessment 0 422451 

Note: It is recognized that some studies in the tlutriafol database have conservative 

NOAEL/LOAEL values that are based on effects that are not considered adverse according to 

current HEO policy (e.g., body weight gain). These updates, however, would result in higher 

NOAEL/LOAEL values and would not impact the selected endpoints. Consequently, given the 

current risk picture for fl utriafol, the Agency did not find it necessary to update these studies at 

this time. 

Ta ble A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile- Flutriafol. 

Guideline No. Study Type 

870.3050 28-Day oral toxicity 

(rat) 

MRID No. (year)/ 

Classilication /Doses Results 

47090344 (1982) fNOAEL = 800 ppm (80 mg/kg/day). 

Acceptable/non-guideline ~OAEL = 2000 ppm (200 mg/kg/day). based on liver 

0. 100. 300. 800. 2000. or toxicity (increased weight, centrilobular hepatoccllular 

5000 ppm (0. 10. 30. 80. 200. lhypenrophy. fatly change. hydropic degeneration. smooth 

and 500 mg/kg/day) endoplasmic reticulum proliferation. and increased 

aminopyrine- -demethylase activity) in both sexes and 

decreased body-weight gain and food consumption in 

1--~~~~4-~~~~~~~-t-~~~~~~~~~~~~~~~~~~~~~~~ males. -~ 

870.3100 190-Day oral toxicity 147090345 (1982) :NOAEL = 200 ppm ( 14/22 mg/kg/day in M/F). 

870.3 150 

(rat) jAcccptablc/guidclinc LOAEL = 2000 ppm ( 1581145 mg/kg/day in M/F), based on 

90-Day oral toxicity 

(dog) 

l

o. 20, 20?· or 2000 ppm decreased body-weight gain. decreased food consumption 

M: 0, l.:i. 14. and 158 and liver tox icity (increased absolute and adjusted liver 

l

mg/kg/day) weights. increased endoplasmic reticulum proliferation in 

I': 0. 1.6. 22. and 145 the males, and increased APDM activity). 

mg/k.e,/day 

47090346 (1982) 

Acceptable/guideline 

0. I. 5. or 15 mg/kg bw/day 

iNOAEL = 5 mg/kg/day. 

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

(increases in organ weight, alkaline phosphatase. 

aminopyrine N-demcthylase activity, and incidence of l 

hemosiderin-ladcn KupfTer cells) in both sexes. spleens 

with hemosiderin content slightly higher than controls in I 

the males. and decreased cumulative body-weight gains and 

increased tril!.lvcerides in the females. 

870.3200 

870.3700a 

870.3700a 

28-Day dcnnal toxicity 

(rat) 

Prenatal developmental 

(rat) 

47090347 (2007) 

Acceptable/guideline 

0. 250. 500.or 1000 

mg/kl!/ day 

47090349 (1982) 

Acceptable/guideline 

0. I 0, 50. or 125 mg/kg/day 

Prenatal developmental 4 752 1303 (2008) 

(rat) Acceptable/guideline 

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

Page 24 of3 I 

NOAEL = I 000 mg/kg/day. I 

LOA EL was not established. 

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 OAEL = 10 mg/kg/day. 

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

non-ossification of the skeleton in the fetuses. 

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; malfonnations (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 I 

retardations detailed above and corresponding decrease in 

fetal weigl~ I 
Flutriafol Human Health Risk Assessment 042245 1 

Table A.3: Subchronic and Chronic Toxicit and Genotoxicit Profile - Flutriafol. 

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

Classification /Doses Results 

870.3700b 

870.3800 

Prenatal developmental 4 7090350 ( 1982) 

(rabbit) Acceptable/guideline 

0. 2. 5. 7 .5. or 15 mg/kg/day 

2-gen. reproduction and 47090351 ( 1986) 

fertility efTects Acceptable/guideline 

(rat) 0. 60. 240. or 1.000 ppm 

M: 0, 4.8. 20.6. and 88.7 

l

mg/kg/day) 

F: 0. 5.5, 21.9. and I 03 

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 OAEL = 7.5 mg/kg/day. 

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

live fetu ses. complete litter resorptions and increased postim lantation loss. 

Parental/Systemic NOAEL = 240 ppm (20 6/2 1 9 

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

LOA EL = I 000 ppm (88. 7 II 03 mg/kg/day [tvVF]) based on 

decreased body-weight gains and food consumption and on 

efTects on the liver (increased liver weights, centrilobular I 

hypertrophy. and fatty change). 

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

[M/Fl). 

LOAEL was not determined. 

Offspring NOAEL = 240 ppm (20.612 1.9 mg/kg/day 

[M/F]). 

LOAEL = I 000 ppm (88. 7/ 103 mg/kg/day [WP]) based on 

decreased live birth index and litter size and on efTects on 

.,,._--------r-----------1------------i-the_h·vcr fa y_chan~ge_l_va liz~_ti_o n) -----------i 

1

870.3800 2-gen. reproduction and 48196921, 48 196922 (2009) Parental/Systemic NOAEL = 150 ppm (9/ 10.8 mg/kg 

870.4 100 

870.4200 

fertility effects bw/day [M/F]). 

(rat) Acceptable/guideline Parental/Systemic LOA EL = 300 ppm ( 18.2122.6 mg/kg 

Chronic toxicity ( I 

year: dog) 

Carcinogenicity 

(mouse) 

0. 30. 80. 150, 300, 1000 ppm bw/day [M/FJ) based upon increased relative liver weights. 

0, 1.8/2.2. 4.8/5.85, 9/ 10.8, fatty deposits in the liver in both sexes as well as 

18.5/22.6. and 62.8/ 77. 1 hepatocellular hypertrophy in males. 

mg/kg bw/day [WFJ Reproductive NOAEL = 300 ppm ( 18.2/22.6 mg/kg 

bw/day [M/F]. 

4 7090353 ( 1988) 

Acceptable/guideline 

0. I, 5. or 20 mg/kg/day 

Reproductive LOAEL was not observed. 

Offs pring IQAEL = 150 ppm (9110.8 mg/kg bw/day 

[M/F]). 

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

ffVVFJ) based upon increased pup mortality in the Fl pups at 

the first litter check and 0-4 oostnatal da""vs_. ______ -i 

NOAEL = 5 mg/kg/day. 

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

(increased liver weightS. inm:ased centrilobular hepatocytc 

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. hematocriL 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. 

47090354 ( 1988) NOAEL = 50 ppm (5.917.4 mg/kg/day in M/F). 

Acceptable/guideline LOA EL = 200 ppm (24/3 1 mg/kg/day in WF), based on 

0 (two control groups). 10. 50. hepatotoxicity (increased fatty change) in both sexes. 

or 200 ppm 

M : 0, (0, I.I, 5.9. and 24 

mg/kg/day) 

F: 0. 1.4. 7.4. and 3 1 

m!?/kg/dav 

Page 25 ofJ I 

No evidence of carcinogenicity. 
Flutriafol Human Health Risk Assessment 0422451 

Table A.3: Subchronic and Chronic Tox icity and Genotox icitv Profile - Flutriafol. 

Guideline No. Study Type 

MRJD No. (year)/ Results I 

Classification /Doses I 

870.4300 Combined Chronic 47090352 (1986) NOAEL - 200 ppm ( I 0.0/ 12.2 mg/kg/day in 

Toxicity/ l Acceptable/guideline males/females). 

Carcinogenicity 0. 20, 200. or 2000 ppm LOA EL = 2000 ppm ( I 02/ 122 mg/kg/day in 

I (rat) M: 0. 1.02. 10.0. and 102 males/females), based on adverse liver effects (increased 

mg/kg/day) liver weights. fatty change. bile duct 

F: 0, 1.27 .12.2, and 122 prolifcration/ cholangiolarfibrosis. hemosiderin 

mg/kg/day 'accumulation in Kupffer cells and cemrilobular 

hypertrophy). and clinical chemistry findings. 

No evidence of carcinogenicity. 

870.5100 In vitro Oactcrial Gene 4 709040 I ( 1988) There were no marked increases in the mean number or 

Mutation (Salmonella Acceptable/guideline rcvcnants/plate in any strain. There was no evidence of 

typhimurium)/ O. 1.6. 8. 40, 200. I 000. or induced mutant colonies over background. 

mammalian activation 5000 11g/plate (Trial I) or 0. 

gene mutation assay 8.40.200. 1000. 2500.or 

5000 11g/plate (Trial 2); Both 

trials were performed w/wo 

S9-activation 

870.5300 In vitro Gene Mutation 4 7090402 ( 1986) There was a dose-related increase in mutant frequency (7.0-

assay in mouse Acceptable/guideline 9.0 x I o·S treated vs. 3.0 x I o·S controls) and absolute 

lymphoma cells 0. 10. 33. 100. 333. or 1000 mutant numbers (70- 148 colonies/plate vs. 63 controls) at 

11g/mL (+S9, Trial I); 0, 150, I 00 μg/mL and above in Trial I and a marked increase in 

300. 450. 600. or 750 11 g/mL mutant frequency at 750 μ g/mL (6. 5x 10·5 treated vs. 1.2 x 

(-S9, Trial I): O. 150. 300. 10-s controls) in Trial 2 attributable to severe cytotoxicity 

450. 600. 750. 900. I 050, or (2% relative survival). I lowever, the increases in mutant 

1 

1200 μg/mL (+S9. Trial 2): or frequency did not achieve the threshold value for a positive 

0. 200. 300. 400. 500. 600. l'e.pooso (> I 0 x IO·') io eiUo« t<i•I Md th"< w" oo 

700, or 800 μg/mL marked increase in absolute mutant numbers at 750 11g/mL I 

(-S9. Trial 2) 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 481969 18 (2006) The mutagcnicity criterion (threshold) of 126 colonies per 

assay in mouse Acceptable/guideline I 06 cells above the solvent control was not reached for any 

lymphoma cells 0. 25. 50. I 00. 200. 400. and valid data at any test concentration. with or without 

600 11g/mL (±S9. Trial I): 0. metabolic activation. Although linear regression analysis 

12.5. 25. 50. I 00. 200. 300 or found a sig nificant (p<0.05) dose dependent trend of the 

400 μglmL (-S9. Trial I): 0. mutation frequency in Experiment 1 (culture I. with 

200.300, 325,350. 375. or metabolic activation). Experiment 2 (culture I ). and 

400 μ g/mL (+S9. Trial 2) Experiment 3 (cultures 1 and 2), these statistical results 

(-S9. Trial 2) were considered biologically irrelevant because the 

threshold for mutagcnicity was not exceeded and all 

absolute values were within the range of historical negative 

and solvent controls. 

870.5375 In vitro Mammalian 4 7090403 ( 1989) No significant increases in the numbers of cells with 

Cytogenetics Acceptable/guideline aberrations (excluding gaps) were observed in either donor 

(Chromosomal 0. 25. 125. or 250 ~1g/mL (+/- r the presence or absence of S9. There was no evidence of 

Aberration Assay in S9) chromosome aberrations induced over background in the 

Human Peripheral lprescnce or absence of S9-activation. 

Blood Lymphoevtes} 

870.5385 In vivo Mammalian 47090404 ( 1982) i:rhere was no evidence of chromosome aberration induced I 

Cytogcnetics - I Bone Acceptable/guideline over background. 

Marrow Chromosomal 0. 15. 70. or 150 mg/kg 

Aberration Test --- 870.5395 In vivo Mammalian 4 7090405 ( 1986) Decreased (p<O.O I ) polychromatic erythrocyte to 

ICytogenetics - Acceptable/guideline nom1ochroma1ic erytJ1rocytc ratios (PCE: CE) were 

Erythrocyte 0. 93.8. or 150 mg/kg observed in both doses at all time points. indicating that the 

Micronucleus Assay in test material was toxic to the bone marrow. There was no 

Mice significant increase in the frequency ofmicronucleated 

polychromatic erythrocytes in bone marrow after any 

treatment time. I 

Page 26 of3 I 
Flutriafol Human Health Risk Assessment 0422451 

Table A.3: Subchronic and Chronic Toxicit and Gcnotoxici 

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

Classification /Doses 

870.5450 Dominant Lethal Assay 47090406 ( 1982) 

- Mice Acceptable/guideline 

0. 25, 50. or I 00 mg/kg/day 

(total doses of 0, 125. 250. or 

500 mg/kg) 

Profile - Flutriafol. 

Results 

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

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

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

were no treatment-related effects on fcnility. mean number 

of implantalions. or the number of early or late deaths. 

There was no time-related positive response of increased 

1----- --+-- ------- -1--- ------- -'l"--re=----=o-=-r,.1:..;;ost-im lantation loss com arcd to controls. 

870.6200a 

870.6200b 

Unscheduled DNA 47090407 (2003) 

Synthesis in Primary Acceptable/guideline 

Rat 0. 250. 500. or I 000 mg/kg 

I lepatocytes/Mammalia 

n Cell 

Acute neurotoxicity 47090408 (2005) 

screening battery Acceptable/guidel ine 

0. 125. 250. or 750 mg/kg 

Subchronic 4 70904 I 0 (2007) 

Neurotoxicity - Feeding Acceptable/guideline 

Study in Rats 0. 500. 1500. or 3000 ppm 

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 de1cnnincd 

by radioactive tracer procedures [nuclear silver grain 

counts! was induced. 

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 ofa 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 pcrioral substance. 

chromodacryorrhca. chromorhinorrhea and labored 

breathing, and in females: pilocrcction and bradypnea. and 

signs of ncurotoxicity: hunched posture in females and 

ataxia in males. 

NOAEL = 1500 ppm (84.3/97.6 mg/kg/day fM/FI). 

LOAEL = 3000 ppm ( 172.1 /185.0 mg/kg/day [M/FJ) based 

on decreased body-weight gain. absolute and relative food 

(010. 28.9/32.6. 84.3/97.6. and (onsumption: and decreased hindlimb grip strength in 

172. 1/185.0 mg!kg!'.day [Mtr-1} males. 

Page 27 of3 I 
Flutriafol Human Health Ris k Assessment 0422451 

Ta ble A.3: S ubchro n ic a nd C h ro nic T oxic ity a nd Geno toxicitl'. P rofile - F lutria fol. 

Guideline No. Study Type MRID No. (year)/ Results Classification /Doses 

870.7485 Metabolism and 47090414 (2004). More than 78% of the dose was recovered in the bile and 

phannacokinetics 47090412 (2006) urine. Absorption was similar between sexes and between 

(rat) J\cceptable/guidcline sing le and multiple dose regimes. Absorption is extensive. 

5 or 250 mg/kg 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 I 

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 primal)' 

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

metabolic step was epoxidation followed by e ither 

rearrangement to form the dihydrodiol isomers or to form 

hydroxy or clihydroxy metabolites. The hydroxyl groups on 

these primary metabolites may then be either conjugated 

with g lucuronic acid or methylated. A second. minor route 

for metabolism offlutriafol was via the removal of the 

triazole ring to form 1-(2 nuorophcnyl)-1-(4-fluorophcnyl)-

cthandiol. which is then conjugated with glucuronic acid. 

870.7600 In vivo dermal 4 70904 15 (2006) Dermal ranged up to 15.8% of the applied dose. 

penetration Acceptable/guideline Absorption was minimal with only 4 h of exposure. 

(rat) 10.002. 0.02. or 0.2 mg/cm2 J\bsorbablc radioactivity (radioactivity in the skin at the 

skin were tested (IO μl/cm2 application site and the adjacent skin) was minimal in 

lskin). and acnral doses were groups that were exposed for I 0 h and evaluated for an 

0.00208. 0.020 I. and 0.2154 additional 158 h post-t:xposurc. Thus, a lmost all of the 

mg/cm2 skin dose isolated in the skin wi ll be absorbed. Considering the 

sum of absorbablc and absorbed doses. 4-3 7% of the 

applied close 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 g/cm2 dose groups. 

Absorption mechanisms were saturated at the high dose. 

The elimination half-lives were calculated to be 3 1. 30. and 

37 h for the 2. 20. and 200 ~1 g/ 2 dose groups. A 

maximum of36.56% of the applied dose was noted as I 

absorbed/absorbable (observed after 24 h exposure to 2 

lμg/om'). Tho do.o '"" ;, >bso,b<d/ob>o,bobk follow;"g' I 

I 0 h exposure is 16.54%. 2 1.3 1% and 11.39%. respectively. 

at 2. 20. and 200 ugl'cm2• 

870.7800 lmmunotoxicity (mice) 48360301 (20 11 ) !Systemic NOAEL = 9.8 mg/kg/day. --, 

Acceptable/guideline Systemic LOJ\EL = 46.8 mg/kg/day) based on increased 

0. 50. 250. 500. I 000 ppm [FJ absolute and relative liver weights and hematological (0. 9.8. 46.8. and 208 effects. 

mg/kg/clay [Fl lmmunotoxicity NOA EL = 208 mg/kg/day. 

lmmunotoxicity LOAEL was not established. 

I 

Page 28 of3 I 
Flutriafol Human Health Risk Assessment 

Appendix B. Chemical Names and Structures 

Common name 

Flutriafol 

M IB 

M28 

1.2.4-Triazole (I') 

Triazolylalanine (TA) 

Triazolylacetic acid (TAA) 

Triazole lactic acid (TL/\) 

I lydroxy nutriafol glucuronide 

(HFG: M3) 

Chemical name 

( ± )-a-(2-n uoropheny 1)-a-( 4-

nuorophcny I)-I//-I .2.4-t riazo lc- 1-

ethanol 

1-(2-nuoro-4-h>·droxyphcnyl)-I -( 4-

nuorophcnyl)-2-( I /-/-1 .2.4-lriazol-1-

yl)cthanol 

glucoside of a nutria fol metabolite. 

possible a derivative hydroxylatcd on 

one phenyl ring 

I H-1 .2.4-triazolc 

2-amino-3-( I /-/-1 .2.4-triazol- lyl)propanoic acid 

I /-/-1 .2.4-triawl-1-ylacctic acid 

1,2.4-triazole-1-lactic acid 

Page 29 of J I 

F 

F 

Chemical structure 

N 

<~ NF 

I 

'..:::::: 

h- o~ 

I 

N 

(~ N- N 

~ 

,,,,;:. 

OH I 

H N-N 

I( ) 

N 

F 

~ 

,,,,;:. 

OH 

042245 1 
Flutriafol Human Health Risk Assessment 0 422451 

Common name Chemical name Chemical structure 

OH OH 

0 

Dihydroxy Outriafol (DH F: -- F H 

M3c) 

N:) 0 4 F 

Flutriafol glucuronidc (FG: M4) -- ~~ ,o 

~ ... ~~~ 

Mcthoxy Outriafol glucuronidc -- o/ (MFG: M7) 

f 

+ on 0 

Flutriafol sulfate (FS: M 10) -- HO 

0 

Page 30 of3 I 
Flutriafol Human Health Risk Assessment 042245 1 

Appendix C. Physical/Chemical Properties. 

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

vapor pressure and a low Henry's law constant (9. 16 x I 0-

12 atm m3/mol). 

Table C.l: Physicochemical Pro pe rties o f F lutriafol. 

Melting ooint/range -- Not available 

pll 6.1 in a 1% aqueous dilution CSP for Flutriafol Technical dated 3123/07 Density 0.99 g/cm3 

Water solubility 95 ml?/L at 20 °C 

At21 °C gL!, 

1.2-Dichloroethane 19-20 

Acetone 11 6-135 

Solvent solubi lity Ethyl acetate 29-34 

Methanol 11 5-134 PP#7177 I 97 administrative materials 

n-Heptane < 10 

Xylene < 10 

Vapor pressure 4 x 10-7 Pa at 20 °C 

Dissociation constant, oK. 2.3 at 25 °C 

Log(Kow) log Pow= 2.3 at 20 °C 

UV/visible absorption spectrum -- Not available 

Page 31 of 31