### Flutriafol Human-Health Ri s k A ss essment



## UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 D 4 05792

OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION



## MEMORANDUM

Date:

Subject:

From:

Through:

To: 27

- March

- 2013

Flutriafol : Human

- Health Risk Assessment for Tolerances inion Imported

Coffee.

PC Code: 128940 DP Barcode: 0405792

Decision No.: 4 69168 Registration No.: 67760-75

Petition No. : 2E8074 Regulatory Action: Tolera n ce with n o 

### U .S. Registration



### Risk Assessment Type: single chemical 

### Case No.: 7060

TXR No.: not applicable 

### CAS No.: 76674-21-0

MRID No: not applicable 

### 40 CFR: 180.629



## Tom Bloem

,

# Chern**~** . -· /} /

Anwar Y. Dunbar, Ph.D.

, P h a rmacol o gi s t

# ~ 

# .AJ

. .f/**~~** Risk Assessment Branch 1 (RAB 1) 

# tJ

Health Effect s Division ( HED; 7509P )

Dana Vogel Associate Director and Acting RAB 1 Branch Chief**~** 

## George F. Kramer, Ph.D

. , Branch Senior**Che ~** **~~** 

## RAB1/HED ( 7509P)

Mary Waller / Tamue Gibson

, RM 21 Registration Division (RD; 7505P)

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

health from exposure to pesticides. RD of OPP has requested that HED e v aluate 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-fluorophen y l)-a

- ( 4- fluorophenyl)-1 H-1

, 2

, 4-triazole-1

- ethanol). A summary of the findings and an assessment ofhuman risk resulting from the registered and proposed uses for flutriafol are provided in this document. The ri s k assessment, dietary risk asses s ment

, and residue chemistry data review were provided b y Tom Bloem (RAB 1 ), the hazard characterization was provided by Anwar Dunbar ( RAB 1 )

, and the drinking

w ater assessment by James K. 

## Wolf of the E nvironmental Fate and E f fects Di v i s ion (EF E D )

.

Page I of25

### Flutriafol Human-Health Risk Assessment D405792

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## Table of Contents

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

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

2.1 Data Deficiencies/Conditi ons of Registration .................................................................. 5

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

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

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

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

2.2.4 Revisions to Petitione d-For Tolerances .................................................................... 6

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

6.1 Residential Bystander Post -application I nhalation ........................................................ 17

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

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

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

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

Appendix A. Toxicology Prof ile and Executive Summaries ....................................................... 19

Appendix B. Summary of all Previous ly Selected Toxicological PODs ..................................... 25

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## 1.0 Executive Summary

Flutriafol is a contact and sy stemic Group 3 triazole fungicide which acts primarily as an inhibitor of ergosterol biosynthesi s, thereby interfering with synthe sis of fungal cell membranes.

Tolerances for residues of flutriafol are es tablished in/on the following commodities at 0.01-2.4 ppm: banana (import), field corn, popcorn, sweet corn (rotational crop tolerance), cotton (rotational crop tolerance), grape, peanut, pom e fruit (group 11-09), stone fruit (group 12-10), sugar beet, and soybean. As a re sult of secondary residues, ru minant (cattle, goat, hog, horse, and sheep) meat byproduct tolerances are also es tablished for residues of flutriafol at 0.02-0.07 ppm. A Section 18 Emergency Exemption has also be granted for applica tion of flutriafol to

cotton with time-limited tolerances of 0.35-0.50 ppm (expire on 31-Dec-2 014). Cheminova, Inc. requested a tolerance for residue s of flutriafol in/on imported green coffee bean and instant coffee at 0.20 ppm and 0.30 ppm, respectively.

Hazard Assessment: Flutriafol was categor ized as having high oral ac ute toxicity in the mouse (Category II). It has low acute toxicity via the oral, dermal and inhalatio n routes (Categories III, III, and IV, respectively) in rats. It is minimally irritating to the eyes (Category III) and is not a dermal irritant (Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method).

The target organ for flutriafol is the liver in dogs, rats, and mi ce. Hepatotoxicity occurred at similar dose levels across several species and durati ons of exposure. Flutriafol is considered to be “Not likely to be Carcinogenic to Humans” ba sed on the results of th e carcinogenicity studies

in rats and mice. There is no evidence for carci nogenicity in mice or rats.. All genotoxicity

studies on flutriafol showed no evidence of clastogenicity or mutagenicity.

The potential impact of in utero and perinatal flutriafol expos ure was investigated in three developmental toxicity studies (two in ra ts, one in rabbits) and two multigenerational reproduction toxicity studies in ra ts. In the first of two rat de velopmental toxicity studies, a quantitative susceptibility was observed (delayed ossification or non-ossification of the skeleton in the fetuses) at a lower dose than maternal effects including an increas ed of ventral/genital staining of the fur and decreased maternal body-we ight gains and food consumption. . In the second rat developmental study, a qualitative sus ceptibility was noted (skeletal malformations and embryo lethality). Although developmental t oxicity occurred at the same dose level that elicited maternal toxicity, the developmental effect s were more severe than those observed in the dams. For rabbits, intrauterine deaths occurred at a dose level that also caused adverse effects in

maternal animals. Similar to what was seen in the developmental study in rats, offspring effects

occurred at the same dose level as parental effects in the multi-ge neration toxicity study in rats. However, the nature of the effects in the offspri ng was more severe than in the dams. The level of concern is low for these developmental/o ffspring effects because: 1) clear NOAELs and

LOAELs were established in the fetuses/offspring; 2) the dose-re sponse for these effects are well defined and characterized; 3) de velopmental endpoints are used fo r assessing acute dietary risks to the most sensitive population (females 13-49 years old) as well as all other short- and intermediate-term exposure scenario s; and 4) the chronic referen ce dose is greater than 300-fold lower than the doses at which the offspring eff ects (decreased live birth index and litter size) were observed in the two-gene ration reproduction studies.

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## Signs of neurotoxicity were reported in the acut e and subchronic neurot oxicity studies at the highest doses only; however, these effects were prim arily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxi city. In addition, there was no evidence of neurotoxicity in any short-term studies in rats, mice, and dogs , or in the long-term toxicity studies in rats, mice, and dogs.

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

assessment team concludes that the 10x FQPA SF should be redu ced to 1x since the toxicology database is complete, there are no residual uncertain ties for pre and/or post natal toxicity, and the conservative nature of the dietary exposure anal ysis (i.e., tolerance-le vel residues and 100% crop treated; no resi dential uses).

Dose Response Assessment: The acute and chronic referenc e doses (aRfD and cRfD) were calculated by dividing the NOAELs from the acute neurotoxicity study, the developmental rabbit study, and the chronic dog study by 100 (uncertainty factors of 10x fo r interspecies extrapolation and 10x for intraspecies variation). Since the FQPA SF has been reduced to 1x, the acute and chronic population-adjusted doses (aPAD and cPAD) are eq ual to the aRfD and cRfD, respectively. The aPAD for females 13-49 years of age is 0.075 mg/kg/day and the aPAD for the general population is 2. 5 mg/kg/day. The cPAD for the ge neral population is 0.05 mg/kg/day.

Dietary Risk Estimates (Food + Drinking Water ): Acute and chronic aggregate dietary (food and drinking water) exposure a nd risk assessments were conduct ed using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCIDTM, ver. 3.16) which incorporates the food consumption data from the United States Department of Agriculture (USDA) National Health and Nutrition Exam ination Survey, What We Eat in America (NHANES/WWEIA; 2003-2008). The acute and chronic analyses assumed tolerance-level residues or tolerance-level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates. Since adequate processing

studies have been submitted which indicate that to lerances in/on apple juice, grape juice, and dried prunes are unnecessary and since a raisin tolerance is being established, the DEEMTM (ver. 7.81) default processing factors for these commod ities were reduced to 1. The DEEMTM (ver. 7.81) default processing factors were retained for the remaining relevant commodities. The resulting acute ( ≤ 27% aPAD; females 13-49 years old were the most highly exposed subgroup) and chronic ( ≤ 36% cPAD; all infants (<1 year old) we re the most highly exposed subgroup) exposure estimates are not of concern to HED.

Residential (Non-Occupational) Ex posure and Risk Assessment: There are no registered or proposed flutriafol uses that re sult in residential (non-occupati onal) exposure (tolerance in/on imported coffee is proposed). Therefore, resident ial handler and post-appl ication exposure/risks

were not assessed.

Aggregate-Risk Estimates: In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three majo r sources: food, drinking wa ter, and residential exposures. Because there are no uses for flutriaf ol which result in residential (non-occupational) exposures, the aggregate assessment need only co nsider food and drinking water. Since the dietary exposure analysis included both food and drinking water, the discussion and exposure estimates presented in Section 5.4 represent aggregate acute and chr onic exposure to flutriafol and

those metabolites identified as bei ng toxicologically identi cal to flutriafol. A ll aggregate flutriafol

risk estimates are not of concern to HED.

### Flutriafol Human-Health Risk Assessment D405792

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## Application of flutriafol also results in exposure to T (1,2,4-tri azole) and TA (triazolylalanine), TAA (triazolylacetic acid), and TLA (triazole lactic acid). These compounds are considered to be toxicologically different from flutriafol. HED previously conducted an aggregate exposure analysis for these compounds, which resulted in aggregate exposure less than HED’s level of concern (D403619, T. Morton, 1-Aug-2012). The pr oposed tolerance in/on imported coffee does not require a revision to this most recent aggregate assessment.

Occupational Exposure and Risk Assessment: The petitioner is pr oposing a tolerance in/on imported coffee. Therefore, an occupational expo sure assessment is unnecessary for the current

action.

Environmental Justice Considerations: Potential areas of environm ental justice concerns, to the extent possible, were considered in this human-health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations.”

Review of Human Research : This risk assessment does not rely on data from studies in which adult human subjects were intent ionally exposed to a pesticide to determine their dermal and inhalation exposure.

2.0 HED Recommendations

Provided a revised Section F is submitted, HED c oncludes that the toxicological and exposure databases are sufficient to support the establishm ent of the coffee tolera nces listed in Table 2.2.3

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

tolerances.

2.1 Data Deficiencies/Conditions of Registration

 None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available to enforce th e currently-established plant tolerances (D362421, T. Bloem, 11-Mar-2009; D340513, T. Bloem, 11-Mar-2009). The method employed in the magnitude of the residues studies submitted in support of the proposed tolerance is based on the

current tolerance enforcement method. Based on this, and since adequate method validation data were provided as part of the magnitude of the residue studies, HED concludes that the current

tolerance enforcement method is adequate to enforce the recomm ended tolerances. In addition, the QuEChERS method has been shown to ad equately quantify residues of flutriafol ( http://www.crl-pesticides.eu/library /docs/fv/CRLFV_ Multiresidue_methods.pdf ).

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## 2.2.2 International Harmonization

Canadian and Mexican maximum residue limits (MRL s) have not been established for flutriafol in/on coffee. However, a Codex MRL for residues of flutriafol has been established in/on coffee bean at 0.15 ppm (instant coffee MRL has not be en established). The HED-recommended green

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

2.2.3 Recommended Tolerances

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

Table 2.2.3: Tolerance Summary for Flutriafol.

Commodity Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) Comments

coffee, green

bean 

### 0.20 0.15 Based on the available field trial data and in order to harmonize with Codex, a tolerance of 0.15 ppm is recommended.

coffee, instant 0.30 0.30 --



## 2.2.4 Revisions to Petitioned-For Tolerances

Based on the available field trial data and in order to harmonize with Codex, HED recommended for a green coffee bean tolerance of 0.15 ppm (re vised Section F is requested). The proposed

and HED-recommended instant coffee tolerances are identical.

2.3 Label Recommendations

 None.

### Flutriafol Human-Health Risk Assessment D405792

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## 3.0 Ingredient Profile

3.1 Chemical Identity

Table 3.1: Flutriafol Nomenclature.

Chemical structure

Common name Flutriafol

Company experimental name PP450 (ICI/Syngenta until 2001)

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

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

CAS registry number 76674-21-0

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



## 3.2 Physical/Chemical Characteristics

Table 3.2: Physicochemica l Properties of Flutriafol.

Melting point/range -- Not available

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

3/23/07 Density 0.99 g/cm 3

Water solubility 95 mg/L at 20 oC

PP#7F7197 administrative materials Solvent solubility At 21 oC g/L 1,2-Dichloroethane 19-20

Acetone 116-135 Ethyl acetate 29-34

Methanol 115-134 n-Heptane <10 Xylene <10

Vapor pressure 4 x 10 -7 Pa at 20 oC

Dissociation constant, pKa 2.3 at 25 oC

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

UV/visible absorption spectrum -- Not available N N N

F OH F

### Flutriafol Human-Health Risk Assessment D405792

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## 3.3 Proposed Use Pattern

Cheminova indicated that flutriaf ol is registered for applicati on to coffee in Brazil, Malaysia, Columbia, and Vietnam with no pending registrati ons in other countries (email from P. Bodey (Cheminova) to T. Gibson (EPA RD); 29-Jan-201 3, 3:21 pm). English translations of the Brazilian, Malaysian, and Columb ian labels were provided and are summarized in Tables 3.3.1

and 3.3.2. It is noted that the Brazilian labe l does not specify a maxi mum number of foliar applications; however, based on the 30-day retreatm ent interval (RTI) and the 30-day preharvest interval (PHI) indicated on the Brazilian label, it seems unlikel y that more than 3-4 foliar applications will be made in a season. Although the Vietnamese label was not submitted, Cheminova indicated that the Vietnamese applicati on scenario is similar to that indicated in the labels provided. HED concludes that the provided labels are su fficient and are supported by the available magnitude of the residue data.

Table 3.3.1: Summary of End-Use Products.

Trade Name Concentration Formulation Type Label Date Target Crops Target Pests

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

Potenzor® (Brazil) 125 g ai/ liter SC not indi cated coffee coffee rust ( Hemilela vastatrix )

Impact® 125SC (Columbia) 125 g ai/liter SC not indica ted coffee coffee rust ( Hemilela vastatrix )



### Table 3.3.2: Summary of Co ffee Application Scenarios.

App. Timing; Type; and Equip. Formulation App. Rate (kg ai/ha) Max. #. App. per

Season Max. Seasonal App. Rate (kg ai/ha) PHI (days) Use Directions and Limitations

Malaysia

postemergence;
foliar broadcast 125 g ai/L

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

Columbia

postemergence;
foliar broadcast 125 g ai/L

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

Brazil

postemergence (flowering stage);

soil 125 g ai/L

SC 0.438-0.688 1 0.688 120 Make a single application of the undiluted product when the plant is in the flowering stage using a jet or nozzle sprayer directing the solution under the canopy.

postemergence;
foliar broadcast 0.188-0.250 not specified 30 Apply in sufficient water to ensure through coverage of the plant avoiding runoff (500 liters/ha; motorized knapsack or tractor sprayer). RTI of 30 days.

### Flutriafol Human-Health Risk Assessment D405792

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## 3.4 Anticipated Exposure Pathways

Based on the proposed/registered flutriafol appl ication scenarios, dietary exposure is an anticipated exposure pathway as residues of fl utriafol may be found in/on crops, livestock commodities, and drinking water. Exposure in th e residential (non-occupational) setting is not anticipated. Based on the registered/proposed ap plication scenarios and the results of a fish bioaccumulation study, residues in fish/shellfish are expected to be insignificant (D407105, T. Bloem, 27-Mar-2013; this includes consumption at the subsistence level). The current action will not result in occupational exposure to U.S. residents. The dietary risk assessment conducted as part of the current risk assessment considers all proposed/r egistered uses.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions

to Address Environmental Just ice in Minority Populations and Low-Income Populations" (http://www.hss.energy.gov/nuclearsa fety/env/guidance/jus tice/eo12898.pdf). As a part of every pesticide risk assessment, OPP considers a larg e variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consum ption patterns are compiled by the USDA NHANES/WWEIA (2003-2008) and are us ed in pesticide risk assessm ents for all registered food uses of a pesticide. These da ta are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the countr y. 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-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditi onal dietary patterns among specific subgroups.

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## 4.0 Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolis m data have been received si nce the D382902 risk assessment (K.

Lowe et al. , 19-Oct-2011). The following flutriafol toxi cological information is a summary of the information presented in D382902.

4.1 Toxicological Effects

Flutriafol is a member of the conazole triazole cl ass of pesticides. The tr iazole fungicides inhibit C14-demethylase, a fungal cytoch rome P450, which plays a role in sterol produc tion. Sterols, such as ergosterol, are needed for fungal membrane structure and f unction, and are essential for the development of functional cell walls. Mammals, particularly humans, also express cytochrome P450 enzymes (hepatic and extra-hepatic).

Flutriafol was categorized as having high oral acute toxicity in the mouse (Category II). It has low acute toxicity via the oral, dermal and inhalation routes (Cat egories III, III and IV, respectively) in rats. Flutriafol is minimally irritating to the eyes (Category III) and is not a dermal irritant (Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method).

Short-term, subchronic, and chronic toxicity studies in rats, mice, and dogs identified the liver as the primary target organ of flutri afol. Hepatotoxicity was first ev ident in the subchronic studies (rats and dogs) in the form of increases in li ver enzyme release (alk aline phosphatase), liver weights, and histopathology findi ngs ranging from hepatocyte vacuolization to centrilobular hypertrophy and slight increases in hemosiderin-la den Kupffer cells. It is noteworthy that with chronic exposures, there are no indi cations of progression of liver toxi city in all species. After over one year of exposure, hepatotoxici ty in rats, dogs, and mice took the form of (1) minimal to severe fatty changes; (2) bile duct pr oliferation/cholangiolar fibrosis ; (3) hemosiderin accumulation in Kupffer cells; (4) centrilobular hype rtrophy; and (5) increases in al kaline phosphatase release.

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

These effects are manifested in the form of sli ght anemia (rats and dogs) and increased platelet, white blood cell, neutrophil, and lymphocyte counts (mice). These effects, however, were minimal in severity. In a 28-day dermal t oxicity study in rats, there were no si gns of toxicity for flutriafol up to the limit dose (1000 mg/kg/day).

The potential impact of in utero and perinatal flutriafol expos ure was investigated in three developmental toxicity studies (two in rats, one in rabbits) and two multi-generation reproduction toxicity studies in rats. In th e first of two rat developmental toxicity studies, a quantitative susceptibility was observed (delayed ossification or non-ossification of the skeleton in the fetuses)

at a lower dose than maternal effects. In the second rat developmental study, a qualitative susceptibility was noted. Although developmental t oxicity occurred at the same dose level that elicited maternal toxicity, the developmental effect s (external, visceral, a nd skeletal malformations; embryo lethality; skeletal variations; a genera lized delay in fetal development; and fewer live fetuses) were more severe than the decreased food consumption and body-weight gains observed in the dams. For rabbits, intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals. In the two-generation reproduc tion studies, a qualitative susceptibility was also seen. Effects in the offspring (decreased litter size and percentage of live births, increased pup mortality, and liver toxicity) can be attributed to the systemic toxicity of the parental animals (decreased body weight and food c onsumption and liver toxicity).

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## Effects that may be considered signs of neurotoxicity (decreased motor activity and hindlimb grip strength, ptosis, lost righting re flex, hunched posture, and ataxia) were reported in the acute and subchronic neurotoxicity studies at the highest dose only. These e ffects, however, were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity. This conclusion is further reinforced by the observation that there was no evidence of neurotoxicity in any other shor t-term studies in rats, mice, and dogs, or in the long-term toxicity studies in rats, mice, and dogs. It is also importa nt to note that in the acute neurotoxicity study, for

animals that did not die in the study or were sacrificed in extremis, all effects resolved by Day 8.

A preliminary review of a recently submitted im munotoxicity study indicates that there is no concern for immunotoxicity. A formal review is pending.

All genotoxicity studies on flutri afol showed no evidence of clas togenicity or mutagenicity. Several triazoles are carcinogeni c. Even though structure-activity-relationship (SAR) analysis

indicates that flutriafol has the potential to produce thyr oid and/or liver tumors in rodents, neither the chronic/carcinogenicity study in rats or the ca rcinogenicity study in mice revealed treatmentrelated increases in tumor incidences.

4.2 SF for Infants and Children (FQPA SF)

HED’s RAB1 risk assessment team concludes th at the 10x FQPA SF should be reduced to 1x since the toxicology database is complete, there are no residual uncertainties for pre and/or post natal toxicity, and the conservative natu re of the dietary exposure analys is (i.e., tolerance-level residues and 100% crop treated; no residential uses). Sections 4.2.1-4.2.4 provides more detail concerning

this conclusion.

4.2.1 Completeness of the Toxicology Database

The toxicology database for flutriafol is ad equate for FQPA consid eration. Acceptable developmental toxicity studies in rats and rabbits, reproduction studies in rats, and the neurotoxicity screening batteries in rats are available for analysis.

4.2.2 Evidence of Neurotoxicity

There is no concern for neurotoxicity with flutriafol. Signs of ne urotoxicity were reported in the acute and subchronic neurotoxicity studies at the highe st dose only; however, these effects were primarily seen in animals that were agonal (at th e point of death) and, t hus, are not indicative of neurotoxicity. In addition, there was no evidence of neurotoxicity in any additional short-term studies in rats, mice, and dogs, or in the long-term toxicity studies in rats , mice, and dogs. A DNT study is not required.

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

There are no concerns or residual uncertainties for pre- and/or post-nata l toxicity. There is evidence for increased qualitative susceptibility in a prenatal study in rats and rabbits and the two generation reproduction study in rats; however, ther e is no concern for these observations since: 1) clear NOAELs and LOAELs were established in the fetuses/offspring; 2) the dose-response

for these effects are well defined and characteri zed; 3) developmental endpoints are used for assessing acute dietary risks to the most sensitive population (fema les 13-49 years old) as well as all other short- and intermediate-term exposure s cenarios; and 4) the ch ronic reference dose is greater than 300-fold lower than the doses at which the offspri ng effects were observed in the two-generation reproduction studies.

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## 4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncer tainties in the exposure database. The dietary exposure assessment is conservative in nature (utilizes tolerance leve l residues and assumes 100% CT). In addition, there are no proposed or registered uses that result in residential exposure.

4.3 Toxicity Endpoint and Point of Departure (POD) Selections

The PODs, uncertainty factors (UFs), and toxici ty endpoints are presented in Table 4.3.1. Since this is an import tolerance, only the dietary endpoints are presented in Table 4.3.1. Appendix B provides a summary of all previously selected toxicological PODs.

Acute Dietary Endpoint (general population): The acute neurotoxicity screening battery in the rat was selected for the acute dietary endpoint fo r the general population. An UF of 100 (10x for interspecies extrapolation and 10x for intraspecies variability) was applied to the NOAEL of 250 mg/kg to generate the aRfD of 2.5 mg/kg for the general population. The LOAEL is 750 mg/kg based on decreased body weight, body-weight ga in, absolute and relative food consumption, agonal effects in both sexes (dehydration, urine-st ained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostr ation, 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 br eathing, and slight ataxia), and in females (piloerection and bradypnea). This study is appr opriate for the expected duration of exposure, and is protective for potential neurotoxic eff ects due to acute exposure to flutriafol.

Acute Dietary Endpoint (females 13-49 years old): The prenatal developmental toxicity study in rabbits was selected for the acute dietary endp oint for females 13-49 years of age. An UF of 100 (10x for interspecies extrapolation and 10x for intraspecies variability) was applied to the developmental NOAEL of 7.5 mg/k g to generate the aRfD of 0.075 mg/kg for females 13-49 years of age. The developm ental LOAEL of 15 mg/kg is based on decreased number of live fetuses, complete litter resorp tions and increased post-implanta tion loss. The NOAEL selected provides the lowest NOAEL from a ny toxicity study in the flutriaf ol 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 pr enatal developmental studies in rats, where the developmental NOAELs were 10 mg/kg (both) and the deve lopmental LOAELs were 50 mg/kg based upon delayed ossification or non-ossification of the sk eleton in the fetuses (1982), and 75 mg/kg based upon increased late resorptions, malformations (cleft palate and multiple), and variations in the hyoid (neck bone), variations in the maxilla/mandi ble, rudimentary and l ong cervical ribs, pelvic girdle, and radius/ulna; numer ous skeletal retardations de tailed above, and corresponding decrease in fetal weights (2008). The rabbit study is protective of the effects seen in these rat

studies. It is also the most protective study for this endpoint for the population of concern (pregnant females and fetuses).

Chronic Dietary Endpoint (all populations): The chronic dog toxicity study was selected for the chronic dietary endpoint for all populations. An UF of 100 (10x for interspecies extrapolation and 10x for intraspe cies variability) was applied to the NOAEL of 5 mg/kg/day to generate the cRfD of 0.05 mg/kg/day for all populations. The LOAEL is 20 mg/kg/day based upon adverse liver findings (increased liver weight s, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase , albumin, and triglyceri des), increased adrenal

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## cortical vacuolization of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes, mild anemia (char acterized by decreased hemoglobin, hematocrit, and red blood cell count) in the males, and initia l body-weight losses, decreased cumulative bodyweight gains, and increased ad renal weights in the females. This NOAEL is lower than any

NOAEL in the database for chronic effects. In addition, the study duration is appropriate for the duration of exposure. Both the 28- and 90-day dog oral toxici ty studies provide

NOAEL/LOAELs and toxic effects of the same ki nd (adverse liver effects) as the chronic dog study. Other studies considered for this endpoi nt were the chronic/car cinogenicity studies (mouse and rat), as well as th e two-generation reproduction studies where similar effects were seen at slightly higher doses.

Short- and Intermediate-Term Residental Inci dental Oral, Dermal and Inhalation Endpoint: Since this is an import tolera nce and since residential exposur es are not anticipated from the proposed/registered uses, selection of incide ntal oral, dermal, a nd inhalation PODs for

assessment of residential e xposure is unnecessary and has not been performed.

Cancer (oral, dermal, inhalation): Flutriafol is classified as “N ot likely to be Carcinogenic to

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

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

Exposure/

Scenario POD Uncertainty/FQPA

SFs RfD, PAD,

LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) NOAEL =

250 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x aRfD = 2.5 mg/kg/day

aPAD = 2.5 mg/kg/day Neurotoxicity screening batter y – rat; LOAEL = 750 mg/kg, based on decreased body weight, body-weight gain, absolute and relative food consumption, a nd clinical signs of toxicity in both sexes: dehydration, ur ine-stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle fl accidity, hypothermia, hunched posture, impaired or lost righting reflex, scant feces; in males: red or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females: piloerection and bradypnea.

Acute Dietary (Females 13- 49 years of age) NOAEL = 7.5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x aRfD = 0.075 mg/kg/day

aPAD = 0.075 mg/kg/day Developmental study – rabbit; Developmental LOAEL = 15 mg/kg, based on decreased number of live fetuses, complete litter resorptions and increased post-implantation loss.

Chronic Dietary (All Populations) NOAEL = 5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x cRfD = 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day Chronic toxicity – dog; LOAEL = 20 mg/kg/day, based on adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin, an d triglycerides), increased adrenal cortical vacuolation of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes; mild anemia (characterized by decreased hemoglobin, hematocrit, and red blood cell count) in the males; and initial body weight losses, decreased cumulative body-weight gains,

and increased adrenal we ights in the females. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans ” based on the carcinogenicity studies in rats and mice.

Point of departure (POD) = A data point or an estimated point th at is derived from observed dose -response data and used to mar k the beginning of extrapolation to determine risk associ ated with lower environmentally relevant human exposures. NOAEL = no-observed adverse -effect level.

LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human popula tion (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populationadjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

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## 5.0 Dietary Exposure and Risk Assessment D407104, T. Bloem, 27-Mar-2013 (residue chemistry summary for the current action) D407105, T. Bloem, 27-Mar-2013 (dietary exposure analysis for the current action)



## 5.1 Metabolite/Degradate Residue Profile

Table 5.1 is a summary of the residues of concer n for tolerance enforcement and risk assessment purposes in primary crops, rotational crops, liv estock, and water. For further information concerning these conclusions see the following documents: (1) primary crops - D355605 (B. Daiss, 3-Sep-2008); D388603 (T. Bloem, 16-Jun-2011) ; D397806 (W. Cutchin, 2-Feb-2012); and D407104 (T. Bloem, 27-Mar-2013 ); (2) rotational crops - D380493 (T. Bloem, 16-Jun-2011) and D396758 (T. Bloem, 13-Mar-2012); (3) livestock - D388603 (T. Bloem, 16-Jun-2011); and (4)

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

HED has previously reviewed t oxicological data for T, TA, a nd TAA and concluded that the toxicological effects of T and TA/TAA are different from each other (D322215, M. Doherty et al.

, 07-Feb-2006). Based on these data and the flutriafol toxicological data, HED concludes that the toxicological effects of T and TA/T AA are different from that of flut riafol. Therefore, the following three dietary risk assessments are required when evaluating exposur e to flutriafol: (1) T; (2) TA/TAA/TLA; and (3) flutriafol and the remain ing residues of concern.

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

Matrix Residues of Concern

Risk Assessment Tolerance Enforcement
coffee, soybean seed, fruit, and sugar beet flutriafol, T, TA, and TAA

flutriafol (free) cotton (Section 18 use) 1 , peanut, and cereal grains flutriafol (free and conjugated), defl uorinated flutriafol, T, TA, and TAA; combined flutriafol (free and conjuga ted) and defluorinated flutriafol residues may be estimate by multiplyi ng the free flutriafol residues by 2.2

rotational crops (excluding dried roughage feed commodities) flutriafol (free and conjugated), M28 4 , T, TA (free and conjugated), TAA, and TLA; combined flutriafol (free and conjugated) and M28 residue may be estimated by multiplying the free flutriafol residue by 1.3x

rotational crops (dried roughage feed commodities) same as that mentioned above but with multiplication of the free flutriafol residues by 2.0x to account for the co mbined residues of flutriafol (free an d conjugated) and M28 3

poultry 2 flutriafol (free and conjugated ), deflourinated flutriafol,

M28 4 , T, TA (free and conjugated), TAA, and TLA

ruminant 3 flutriafol (free and conjugated ), deflourinated flutriafol,

M28 4 , M1B 4 , T, TA (free and conjugated), TAA, and TLA

water flutriafol and T
-- 1 Decision will be reevaluated if a Section 3 use is requested (addi tional data may be required).

2 HED notes that if the poultry dietary burdens increase, then these conclusions will be revisited and poultry metabolism studi es conducted as specified in OPPTS 860.1300 with [carbinol- 14 C]flutriafol and [triazole-3,5- 14 C]flutriafol may be required. Residues of conjugated flutriafol, deflourinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concer n due to their presence in feed commodities.

3 HED notes that if the ruminant dietary burden increases, then these conclusions will be revisited and ruminant metabolism stu dies conducted as specified in OPPTS 860.1300 with [carbinol- 14 C]flutriafol and [triazole-3,5- 14 C]flutriafol may be required. Residues of conjugated flutriafol, deflourinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concer n due to their presence in feed commodities.

4 M28 = glucoside of a flutriafol metabo lite, possible a derivative hydr oxylated on the phenyl ring; M1B = 4-hydroxyflutriafol.

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## 5.2 Food Residue Profile

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

tolerances. It is noted that a dditional cotton and sweet corn fiel d rotational crop data have been requested to support the establishe d rotational crop tolerances (t hese data remain outstanding; D397075, T. Bloem, 20-Dec-2011). The additional data were requested so as to ensure that the rotational crop tolerances are reflective of cond itions in all relevant regions. Based on the existing sweet corn and cotton fiel d rotational crop residue data a nd the unrefined nature of the current dietary exposure analyses ( ≤ 24% aPAD; ≤ 42% cPAD), HED concludes that these data will not have a significant effect on the human-health risk assessment.

The number and locations of the coffee field tria ls submitted in support of the current action are adequate to satisfy HED guidance concerning th e establishment of a tolerance on imported coffee. In addition, based on the submitted labels, the employed application scenarios are adequate. Based on these data and the Organization for Economic Cooperation and Development (OECD) tolerance-calculation proc edure, a green coffee bean tolerance of 0.20 ppm for residues of flutriafol is appropriate. HE D notes that Codex has established a coffee bean MRL for residues of flutriafol at 0.15 ppm. Sin ce the maximum flutriafol residue from the field trial study was 0.10 ppm and since the processi ng study which employed single/seasonal foliar application at 5.0x/2.5x the maximum labeled rate yielded flutriafol residues in/on green coffee bean of 0.17-0.20 ppm, HED concludes that harmoni zation with the Codex MRL is acceptable. Therefore, HED concludes that the available data support a gr een coffee bean tolerance for residues of flutriafol at 0.15 ppm; a revised Section F is requested.

The petitioner also submitted an adequate coffee processing study. Following treatment at 5.0x/2.5x the labeled maximum single/seasonal foliar application rate, green coffee bean samples were processed into cleaned gr een coffee beans, roasted coffee beans, spent coffee grounds, liquor extract, and instant coffee using simulated commerci al practices. Residues of flutriafol were found to concentrate in only instan t coffee (1.9-3.0x; average of 2.5x) . Based on the 0.0966 ppm highestaverage field trial (HAFT) flutri afol residue in/on green coffee bean and the average processing

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

coffee tolerance for residues of flutri afol of 0.30 ppm is appropriate.

5.3 Drinking Water Residue Profile

The proposed tolerance in/on importe d coffee will not impact residues in U.S. drinking water. Table 5.3 is a summary of worst-case flutriafol per se surface-/ground-water estimated drinking water concentrations (EDWCs) previously provided by the Environmental Fate and Effects Division (EFED; D383005, J. Wolf, 27-Apr-2011; D390213, J. Wolf, 31-May-2011). The water estimates were incorporated directly in to the dietary exposure analysis . The water models and their description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5.3: Maximum Flutriafol EDWCs.
Model Application Rate Concentration (ppb)

Groundwater (PRZM-GW 1 ) stone fruit (4 x 0.114 lbs ai/acre at 7 day intervals) acute 310 grape (6 x 0.081 lbs ai/acre at 14 day intervals) chronic 202

Surface water (FIRST 2 ) Apples (6 x 0.114 lbs ai/acre at 7 day intervals) 3 acute 48.8

chronic 5.70

1 Pesticide Root Zone M odel-Groundwater (PRZM-GW).

2 FQPA Index Reservoir Screen ing Tool (FIRST ver. 1.1.1).

3 The initially proposed a pplication rate for apple.

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## 5.4 Dietary (Food + Drinking Water) Risk Assessment

The following text concerns exposure and risk to flutriafol and those metabolites identified as being toxicologically the same as flutriafol. For information c oncerning exposure and risk to T and TA/TAA/TLA, which HED has determined to be toxicologically different from flutriafol, see the Aggregate Section (7.0).

Acute and chronic aggregate diet ary (food and drinking water) expos ure and risk assessments were conducted using DEEM-FCIDTM (ver. 3.16) which in corporates the food consumption data from USDA NHANES/WWEIA (2003-2008). The acute and chronic analyses assumed tolerance-level residues or tolerance-level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates. Since adequate processing

studies have been submitted which indicate that tole rances in/on apple juice, grape juice, and dried prunes are unnecessary and since a raisin tolera nce is being establishe d, the DEEMTM (ver. 7.81) default processing factors for these commoditie s were reduced to 1. The DEEMTM (ver. 7.81) default processing factors were reta ined for the remaining relevant commodities. The resulting acute ( ≤ 27% aPAD; females 13-49 years old were the mo st highly exposed subgroup) and chronic ( ≤ 36% cPAD; all infants (<1 year old) were the most highly exposed subgroup) exposure estimates are not of concern to HED. Table 5.4 is a summary of the acute and chronic diet ary risk estimates.

Table 5.4: Summary of Acute an d Chronic Dietary (Food + Drinki ng Water) Exposure and Risk.

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

General U.S. Population

2.5 0.022440 <1

0.05 0.006348 13
All Infants (< 1 year old) 0.063256 2.5 0.017990 36

Children 1-2 years old 0.051296 2.0 0.018063 36 Children 3-5 years old 0.035764 1.4 0.012316 25 Children 6-12 years old 0.023104 <1 0.006785 14 Youth 13-19 years old 0.016522 <1 0.004267 8.5 Adults 20-49 years old 0.019428 <1 0.005453 11 Adults 50-99 years old 0.017770 <1 0.005681 11 Females 13-49 years old 0.075 0.019896 27 0.005508 11

1 95 th percentile (tier 1 analysis)

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## 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered or proposed flutriafol us es that result in resi dential (non-occupational) exposure (tolerance in/on imported coffee is proposed ). Therefore, residential handler and postapplication exposure/risks were not assessed.

6.1 Residential Bystander Post-application Inhalation

Based on the Agency's current practices, a qua ntitative postapplication inhalation exposure assessment was not performed for flutriafol at this time primarily because of the low acute inhalation toxicity (Toxic ity Category IV) and low vapor pressure (3.0 x 10 -9 

## mm Hg). However, volatilization of pesticid es may be a source of postapplicatio n inhalation exposure to individuals nearby to pesticide applications.

The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the wa y to incorporate postapplic ation inhalation exposure into the Agency's risk assessments. If new polic ies or procedures are put into place, the Agency may revisit the need for a quantitative posta pplication inhalation e xposure assessment for

flutriafol.

6.2 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the ground application. The Agency has been working with the Spray Drift Task Force, EPA Regi onal Offices, and State Lead Ag encies for pesticide regulation and other parties to develop the best spray-drift-management pr actices (see the Agency’s Spray

Drift website for more information at http://www.epa.gov/opp00001/fact sheets/spraydrift.htm ). The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide regi strants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® 

## computer model to its risk assessments for pesticides applied by air, orch ard airblast, and ground hydraulic me thods. After the policy is in place, the Agency may impose further refinements in spray-drift-management practices to reduce off-target drift with specific products with significant ri sks associated with drift.

### Flutriafol Human-Health Risk Assessment D405792

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## 7.0 Aggregate Exposure/Risk Characterization

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and resi dential exposures. Becau se 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 pres ented in Section 5.4 represent aggregate acute and chronic exposure to flutriaf ol and those metabolites identi fied as being toxicologically identical to flutriafol. All aggr egate flutriafol risk estimates are not of concern to HED.

Application of flutriafol also results in exposure to T and TA/T AA/TLA, which are considered to be toxicologically different fr om flutriafol. HED previously conducted an aggregate exposure analysis for these compounds, which resulted in aggregate exposure less than HED’s level of concern (D403619, T. Morton, 1-Aug-2012). The pr oposed tolerance in/on imported coffee does not require a revision to this most recent aggregate assessment.

8.0 Cumulative Exposure/Ri sk Characterization

Flutriafol is a member of the triazole-containing class of pes ticides. Although conazoles act similarly in plants (fungi) by inhibiting ergoste rol biosynthesis, there is not necessarily a relationship between their pesticidal activity a nd 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 sa me, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, however, a variable patt ern of toxicological responses is found; some are he patotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, repr oductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse ra nge of biochemical even ts including altered cholesterol levels, stress res ponses, and altered DNA methylati on. It is not clearly understood whether these biochemical events are directly co nnected 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 appr oach 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 mechan ism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

9.0 Occupational Exposure/ Risk Characterization

The petitioner is proposing a tole rance in/on imported coffee. Therefore, an occupational exposure assessment is unnecessary for the current action.

RDI: RAB1 (13-Mar-2013)

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

Appendix A. Toxicology Profile and Executive Summaries Appendix B. Summary of all Previously Selected Toxicological PODs

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## Appendix A. Toxicology Prof ile and Executive Summaries

The requirements (40 CFR 158.340) for food uses for fl utriafol are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline pr otocols were used.

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

Study Technical Required Satisfied
870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization yes

yes

yes

yes

yes

yes yes

no

yes

yes

yes

yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21-Day Dermal 870.3250 90-Day Dermal 870.3465 90-Day Inhalation yes

yes

yes

no

no yes

yes

yes

-

- 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes

yes

yes

yes

yes yes

yes

yes

yes

yes 870.5100 Mutagenicity—Gen e Mutation - bacterial 870.5300 Mutagenicity—G ene Mutation - mammalian 870.5xxx Mutagenicity—Structu ral Chromosomal Aberrations 870.5xxx Mutagenicity—Other Genotoxic Effects yes

yes

yes

yes yes

yes

yes

yes 870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90-Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90-Day Neurotoxicity Screening Battery (rat) 870.6300 Develop. Neurotoxicity no

no

yes

yes

no -

- yes

yes

- 870.7485 General Metabolism

870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

yes

yes yes

yes

yes Special Studies for Ocular Effects Acute Oral (rat) Subchronic Oral (rat) Six-month Oral (dog) no

no

no -

-

-

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Page 20 of 25 Table A.2: Acute Toxicity Profile – Flutriafol.

Guideline No. Study Type MRID (s) Results Toxicity Category
870.1100 Acute oral (rat) 47090336 LD 50 = 1140 mg/kg (M); 1480 mg/kg (F) III 870.1100 Acute oral (mouse) 47090335 LD 50 = 365 mg/kg bw (M); 179 mg/kg bw (F) II 870.1200 Acute dermal (rat) 4786101 LD 50 >2000 mg/kg bw III 870.1300 Acute inhalation (rat) 47090338 LC 50 >5.20 mg/L IV 870.2400 Primary eye irritation (ra bbit) 47090339 Minimally irritating III 870.2500 Primary dermal irritation (ra bbit) 47090341 Not a dermal irritant IV 870.2600 Dermal sensitization (m ouse) 47090343 Not a sensitizer -

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

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

Classification /Doses Results

870.3050 28-Day oral toxicity (rat) 47090344 (1982)

Acceptable/non-guideline

0, 100, 300, 800, 2000, or 5000 ppm (0, 10, 30, 80, 200, and 500 mg/kg/day) NOAEL = 800 ppm (80 mg/kg/day). LOAEL = 2000 ppm (200 mg/kg/day), based on liver toxicity (increased weight, centrilobular hepatocellular hypertrophy, fatty change, hydropic degeneration, smooth endoplasmic reticulum proliferation, and increased aminopyrine-N-demethylase ac tivity) in both sexes and decreased body-weight gain and food consumption in

males.

870.3100 90-Day oral toxicity (rat) 47090345 (1982)

Acceptable/guideline

0, 20, 200, or 2000 ppm M: 0, 1.5, 14, and 158 mg/kg/day) F: 0, 1.6, 22, and 145 mg/kg/day NOAEL = 200 ppm (14/22 mg/kg/day in M/F) LOAEL = 2000 ppm (158/145 mg/kg/day in M/F), based on decreased body-weight gain, decreased food consumption and liver toxicity (increased absolute and adjusted liver weights, in creased endoplasmic reticulum proliferation in the males, and increased APDM activity).

870.3150 90-Day oral toxicity (dog) 47090346 (1982)

Acceptable/guideline

0, 1, 5, or 15 mg/kg bw/day NOAEL = 5 mg/kg/day LOAEL = 15 mg/kg/day, base d on adverse liver findings (increases in organ weight, alkaline phosphatase, aminopyrine N-demethylase activity, and incidence of hemosiderin-laden Kupffer cells ) in both sexes, spleens with hemosiderin content slight ly higher than controls in the males, and decreased cu mulative body-weight gains and increased triglycerides in the females.

870.3200 28-Day dermal toxicity (rat) 47090347 (2007)

Acceptable/guideline

0, 250, 500, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day.

LOAEL was not established.

870.3700a Prenatal developmental (rat) 47090349 (1982)

Unacceptable/guideline

0, 10, 50, or 125 mg/kg/day Maternal NOAEL = 50 mg/kg/day. LOAEL = 125 mg/kg/day, based on increased incidence of ventral/genital staining of th e fur and decreased maternal body-weight gains and food consumption. Developmental NOAEL = 10 mg/kg/day. LOAEL = 50 mg/kg/day, based on delayed ossification or

non-ossification of the skeleton in the fetuses.

870.3700a Prenatal developmental (rat) 47521303 (2008)

Acceptable/guideline

0, 2, 5, 10, or 755 mg/kg/day Maternal NOAEL = 10 mg/kg/day. LOAEL = 75 mg/kg/day, based on decreased body-weight gains and food consumption. Developmental NOAEL = 10 mg/kg/day. LOAEL = 75 mg/kg/day, based on increased late resorptions; malformations (cleft palate and multiple hyoid malformations) and variations in the hyoid; variations in the maxilla/mandible, rudime ntary and long cervical ribs, pelvic girdle, and radius/u lna; numerous skeletal

retardations detailed above and corresponding decrease in fetal weights.

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Page 21 of 25 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.3700b Prenatal developmental (rabbit) 47090350 (1982)

Acceptable/guideline

0, 2.5, 7.5, or 15 mg/kg/day Maternal NOAEL = 7.5 mg/kg/day. LOAEL = 15 mg/kg/day, based on decreased corrected and uncorrected body-weight gains and food consumption. Developmental NOAEL = 7.5 mg/kg/day. LOAEL = 15 mg/kg/day, based on decreased number oflive fetuses, complete litter resorptions and increased postimplantation loss.

870.3800 2-gen. reproduction and fertility effects (rat) 47090351 (1986)

Acceptable/guideline

0, 60, 240, or 1,000 ppm M: 0, 4.8, 20.6, and 88.7 mg/kg/day) F: 0, 5.5, 21.9, and 103 mg/kg/day Parental/Systemic NOAEL = 240 ppm (20.6/21.9 mg/kg/day [M/F]). LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on decreased body-weight gains and food consumption and on effects on the liver (increased liver weights, centrilobular hypertrophy, and fatty change). Reproductive NOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]).

LOAEL was not determined. Offspring NOAEL = 240 ppm (20.6/21.9 mg/kg/day [M/F]). LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based

on decreased live birth index and litter size and on effects on the liver (fatty change/vacuolization).

870.3800 2-gen. reproduction and fertility effects (rat) 48196921, 48196922 (2009)

Acceptable/guideline

0, 30, 80, 150, 300, 1000 ppm 0, 1.8/2.2, 4.8/5.85, 9/10.8, 18.5/22.6, and 62.8/ 77.1 mg/kg bw/day [M/F] Parental/Systemic NOAEL = 150 ppm (9/10.8 mg/kg bw/day [M/F]). Parental/Systemic LOAEL = 300 ppm (18.2/22.6 mg/kg

b w/day [M/F]) based upon increased relative liver weights, fatty deposits in the liver in both sexes as well as hepatocellular hypertropy in males. Reproductive NOAEL = 300 ppm (18.2/22.6 mg/kg bw/day [M/F]. Reproductive LOAEL was not observed. Offspring NOAEL = 150 ppm (9/10.8 mg/kg bw/day [M/F]). Offspring LOAEL = 300 ppm (18.5/22.6 mg/kg bw/day [M/F]) based upon increased pup mortality in the F1 pups at the first litter check and 0-4 postnatal days.

870.4100 Chronic toxicity (1 year; dog) 47090353 (1988)

Acceptable/guideline

0, 1, 5, or 20 mg/kg/day NOAEL = 5 mg/kg/day. LOAEL = 20 mg/kg/day, based on: adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin and trigly cerides), increased adrenal

cortical vacuolization of the zona fasciculat a, and marked hemosiderin pigmentation in the liver and spleen in both sexes; mild anemia (characterized by decreased hemoglobin, hematocrit, and red blood cell count) in the males; and initial body weight losses, decreased cumulative body-weight gains, and increased adrenal weights in the females.

870.4200 Carcinogenicity (mouse) 47090354 (1988)

Acceptable/guideline

0 (two control groups), 10, 50, or 200 ppm M: 0, (0, 1.1, 5.9, and 24 mg/kg/day) F: 0, 1.4, 7.4, and 31 mg/kg/day NOAEL = 50 ppm (5.9/7.4 mg/kg/day in M/F). LOAEL = 200 ppm (24/31 mg/kg/day in M/F), based on hepatotoxicity (increased fa tty change) in both sexes.

No evidence of carcinogenicity.

### Flutriafol Human-Health Risk Assessment D405792

Page 22 of 25 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.4300 Combined Chronic Toxicity/ Carcinogenicity (rat) 47090352 (1986)

Acceptable/guideline

0, 20, 200, or 2000 ppm M: 0, 1.02, 10.0, and 102 mg/kg/day) F: 0, 1.27,12.2, and 122 mg/kg/day NOAEL = 200 ppm (10.0/12.2 mg/kg/day in males/females). LOAEL = 2000 ppm (102/122 mg/kg/day in males/females), based on adverse liver effects (increased liver weights, fatty change, bile duct proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer cells and centrilobular hypertrophy), and clinic al chemistry findings.

No evidence of carcinogenicity.

870.5100 In vitro Bacterial Gene Mutation (Salmonella typhimurium)/

mammalian activation gene mutation assay 47090401 (1988)

Acceptable/guideline

0, 1.6, 8, 40, 200, 1000, or 5000 μg/plate ( Trial 1) or 0, 8, 40, 200, 1000, 2500, or 5000 μg/plate (Trial 2); Both trials were performed w/wo S9-

activation There were no marked increases in the mean number of revertants/plate in any strain. There was no evidence of

induced mutant col onies over background.

870.5300 In Vitro Gene Mutation assay in mouse lymphoma cells 47090402 (1986)

Acceptable/guideline

0, 10, 33, 100, 333, or 1000 μg/mL (+S9, Trial 1); 0, 150, 300, 450, 600, or 750 μg/mL (- S9, Trial 1); 0, 150, 300, 450, 600, 750, 900, 1050, or 1200 μg/mL (+S9, Trial 2); or 0, 200, 300, 400, 500, 600, 700, or 800 μg/mL (-S9, Trial 2) There was a dose-related increase in mutant frequency (7.0-9.0x10 -5 treated vs. 3.0x10 -5 controls) and absolute mutant numbers (70-148 colonies/plate vs. 63 controls) at 100 μg/mL and above in Trial 1 and a marked increase in mutant frequency at 750 μg/mL (6.5x10 -5 treated vs.

1.2x10 -5 controls) in Trial 2 attributable to severe cytotoxicity (2% relative survival). However, the increases in mutant frequency did not achieve the threshold value for a positive response (>10x10 -5 ) in either

trial and there was no marked increase in absolute mutant numbers at 750 μg/mL in Trial 2. In the absence of S9, there were no marked increases in mutant frequency or absolute mutant numbers compared to controls in either trial. There was no convincing evidence of induced mutant colonies over background in the presence or

absence of S9-activation.

870.5300 In Vitro Gene Mutation assay in mouse lymphoma cells 48196918 (2006)

Acceptable/guideline

0, 25, 50, 100, 200, 400 and 600 μg/mL (±S9, Trial 1); 0, 12.5, 25, 50, 100, 200, 300 or 400 μg/mL (-S9, Trial 1); 0, 200, 300, 325, 350, 375, or 400 μg/mL (+S9, Trial 2) (-S9, Trial 2) The mutagenicity criterion (threshold) of 126 colonies per

106 cells above the solvent cont rol was not reached for any valid data at any test con centration, with or without metabolic activation. Although linear regression analysis found a significant (p<0.05) dose dependent trend of the mutation frequency in Experiment 1 (culture 1, with metabolic activation), Experiment 2 (culture 1), and Experiment 3 (cultures 1 and 2), these statistical results were considered biologicall y irrelevant because the threshold for mutagenicity was not exceeded and all absolute values were within the range of historical negative and solvent controls.

870.5375 In vitro Mammalian Cytogenetics (Chromosomal Aberration Assay in Human Peripheral Blood Lymphocytes) 47090403 (1989)

Acceptable/guideline

0, 25, 125, or 250 μg/mL (+/- S9) No significant increases in the numbers of cells with aberrations (excluding gaps) were observed in either donor in the presence or absence of S9. There was no evidence of chromosome aberrations induced over background in the presence or absence of S9-activation.

870.5385 In vivo Mammalian Cytogenetics – [Bone

Marrow Chromosomal

Aberration Test 47090404 (1982)

Acceptable/guideline

0, 15, 70, or 150 mg/kg There was no evidence of chromosome aberration induced over background.

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Page 23 of 25 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.5395 In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in

Mice 47090405 (1986)

Acceptable/guideline

0, 93.8, or 150 mg/kg Decreased (p<0.01) polychr omatic erythrocyte to normochromatic erythrocyte ratios (PCE:NCE) were

observed in both doses at all time points, indicating that

the test material was toxic to the bone marrow. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any

treatment time.

870.5450 Dominant Lethal Assay

– Mice 47090406 (1982)

Acceptable/guideline

0, 25, 50, or 100 mg/kg/day (total doses of 0, 125, 250, or 500 mg/kg) Mortality (3/15 males) was noted at 100 mg/kg/day during dosing. Slight decreases (p<0.05) in body weight were observed at 50 mg/kg/day and above during dosing. There

were no treatment-related effe cts on fertility, mean number of implantations, or the number of early or late deaths. There was no time-related pos itive response of increased pre- or post-implantation lo ss compared to controls.

870.5550 Unscheduled DNA Synthesis in Primary

Rat Hepatocytes/Mammalia

n Cell 47090407 (2003)

Acceptable/guideline

0, 250, 500, or 1000 mg/kg The net nuclear grain (NNG) co unts 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 unsche duled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.

870.6200a Acute neurotoxicity screening battery 47090408 (2005)

Acceptable/guideline

0, 125, 250, or 750 mg/kg NOAEL = 250 mg/kg. LOAEL = 750 mg/kg, based on decreased body weight, body-weight gain, absolute and relative food consumption, and clinical signs of toxicity, indicative of a moribund condition, in both sexes: dehydration, urine-stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, scant feces; in males: re d or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females: piloerection and bradypnea, and signs of neurotoxicity: hunc hed posture in females and

ataxia in males.

870.6200b Subchronic Neurotoxicity – Feeding Study in Rats 47090410 (2007)

Acceptable/guideline

0, 500, 1500, or 3000 ppm (0/0, 28.9/32.6, 84.3/97.6, and 172.1/185.0 mg/kg/day [M/F]) NOAEL = 1500 ppm (84.3/97.6 mg/kg/day [M/F]). LOAEL = 3000 ppm (172.1/185.0 mg/kg/day [M/F]) based on decreased body-weight gain, absolute and relative food consumption; and decreased hindlimb grip strength in males.

### Flutriafol Human-Health Risk Assessment D405792

Page 24 of 25 Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile – Flutriafol.

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

Classification /Doses Results

870.7485 Metabolism and pharmacokinetics (rat) 47090414 (2004), 47090412 (2006)

Acceptable/guideline

5 or 250 mg/kg More than 78% of the dose was recovered in the bile and urine. Absorption was similar between sexes and between single and multiple dose regimes. Absorption is extensive. The dose was mostly eliminated within 48 hours. Only 0.04-0.05% of the dose was found in the expired carbon dioxide. Most of the radioactivity was excreted in the bile (47-79% of the dose). The excretion profile was similar between sexes. In the blood, radioactivity partitioned into the red blood cells. In both sexes and all groups, concentrations of radioactivity were relatively high in whole blood, liver, and kidneys. Other organs with high concentrations included the adrenal glands, spleen, and pituitary. The distribution pr ofiles were similar between species, dose level, and single vs. multiple dose regime. In the whole blood, the concentr ations were proportional to

the dose. The total amount of radioactivity is olated in the

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

amounts in the urine and feces and more than 19 metabolites were isolated, indicating extensive metabolism. Metabolism profiles were similar between sexes. The metabolic profiles were similar regardless of the matrix (feces, urine, or bile), the dose, and the sex. The primary site for metabolism was the 2-fluorophenyl ring. The initial metabolic step was epoxidation followed

b y either rearrangement to form the dihydrodiol isomers or to form hydroxy or dihydroxy metabolites. The hydroxyl groups on these primary metabo lites may then be either conjugated with glucuronic acid or methylated. A second,

minor route for metabolism of flutriafol was via the removal of the triazole ring to form 1-(2 fluorophenyl)-1- (4-fluorophenyl)-ethandiol, which is then conjugated with glucuronic acid.

870.7600 In vivo dermal penetration (rat) 47090415 (2006)

Acceptable/guideline

0.002, 0.02, or 0.2 mg/cm 2 skin were tested (10 μl/cm 2 skin), and actual doses were 0.00208, 0.0201, and 0.2154 mg/cm 2

skin Dermal ranged up to 15.8% of the applied dose. Absorption was minimal with only 4 h of exposure. Absorbable radioactivity (radioactivity in the skin at the application site and the adja cent skin) was minimal in groups that were exposed for 10 h and evaluated for an additional 158 h post-exposure. Thus, almost all of the

dose isolated in the skin will be absorbed. Considering the sum of absorbable and absorbed doses, 4-37% of the applied dose was recovered in th e treatment groups (11%). Absorption rate constants were calculated as 0.236, 0.190,

and 0.072 h -1 for the 2, 20, and 200 μg/cm 2 dose groups. Absorption mechanisms were sa turated at the high dose. The elimination half-lives were calculated to be 31, 30, and 37 h for the 2, 20, and 200 μg/cm 2 dose groups. A maximum of 36.56% of the applied dose was noted as absorbed/absorbable (observed after 24 h exposure to 2 μg/cm 2 ). The dose that is absorbed/absorbable following a 10 h exposure is 16.54%, 21.31% and 11.39%, respectively, at 2, 20, and 200 μg/cm 2

. 870.7800 Immunotoxicity (mice) 48360301 (2011)

Classification: Pending

0, 50, 250, 500, 1000 ppm [F]

(0, 10.8, 49.9, 101.8 and 241.2 mg/kg/day [F] Preliminary NOAEL = 10.8 mg/kg/day. Preliminary LOAEL = 49.9 mg/kg/day, based on statistically increased absolute and relative liver weights, and statistically signi ficant increases in mean corpuscular

volume.

### Flutriafol Human-Health Risk Assessment D405792

Page 25 of 25 

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

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

Exposure/

Scenario POD Uncertainty/FQPA

SFs RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) NOAEL =

250 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 2.5 mg/kg/day

aPAD = 2.5 mg/kg/day Neurotoxicity screening battery – rat; LOAEL = 750 mg/kg, based on decreased body weight, body-weight gain,

absolute and relative food cons umption, and c linical signs of toxicity in both sexes: dehydration, urine-stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, scant feces; in males: re d or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females: piloerection and bradypnea.

Acute Dietary (Females 13- 49 years of age) NOAEL = 7.5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 0.075 mg/kg/day

aPAD = 0.075 mg/kg/day Developmental study – rabbi t; Developmental LOAEL = 15 mg/kg, based on decreased number of live fetuses, complete litter resorptions an d increased post-implantation

loss.

Chronic Dietary (All Populations) NOAEL = 5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD = 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day Chronic toxicity – dog; LOAEL = 20 mg/kg/day, based on adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin , and triglycerides),

increased adrenal cortical vacuolation of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes; mild anemia (characterized by decreased hemoglobin, he matocrit, and red blood cell count) in the males; and in itial body weight losses, decreased cumulative body-weight gains, and increased adrenal weights in the females. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans ” based on the carcinogenicity studies in rats and mice.

Point of departure (POD) = A data point or an estimated point th at is derived from observed dose -response data and used to mar k the beginning of extrapolation to determine risk associated with lower environmentally relevant huma n exposures. NOAEL = no-observed adverse-ef fect level.

LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human popula tion (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populationadjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.



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

Health Risk Assessments.
Exposure/

Scenario POD UFs LOC Risk

Assessment Study and Toxicological Effects

Dermal Short (1-30 days)- and Intermediate (1- 6 months) -Term NOAEL= 7.5 mg/kg/day

1 Dermal-absorption factor =

21% UF A = 10x

UF H = 10x Occupational

LOC for MOE

= 100 Developmental toxicity – rabbit; Developmental LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, co mplete litter resorptions and increased post-imp lantation loss.

Inhalation Short (1-30 days)- and Intermediate (1- 6 months) -Term NOAEL = 7.5 mg/kg/day

Inhalation toxicity assumed to be equivalent to oral toxicity Inhalation-absorption factor =

100% UF A = 10x

UF H = 10x Occupational

LOC for MOE

= 100 Developmental toxicity – rabbit; Developmental LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, co mplete litter resorptions and increased post-imp lantation loss.

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Hu mans” based on the carcinogen icity studies in rats and

mice.

1 Dermal absorption factor was derived from the dermal penetration study (MRID 47090415). Point of departure (POD) = A data point or an estimated point th at is derived from observed dose -response data and used to mar k the beginning of extrapolation to determine risk associ ated with lower environmentally relevant human exposures. NOAEL = no-observed adverse -effect level.

LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human popula tion (intraspecies). MOE = margin of exposure. LOC = leve l of concern.