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### UNITED STA

**TES ENVIRONMENTA L PROTECTION A** **GENCY WA** **SHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND** 

**POLLUTION PREVENTION**



### MEMORANDUM **D ate**  **:** 16 - December - 20 1 4 **S ubject**  **: Flutriafol:**  Human Health Risk Assessment in Support of Tolerance for Residues in/on

Cotton; Grain Sorghum; Leafy Vegetables, Except Brassica , Crop Group 4; and Brassica Leaf

y Vegetables Crop Group 5. **PC Code:** 128940 **DP Barcode:** D41 5849 **Decision No.:** 482872 **Registration Nos. :**  67760 - 75 and 67760 - 120 **Petition No.:** 3F8199 **Regulatory Action:** Section 3 Registrations **Risk Assessment Type:** single chemical **Case No.:** 7060 **T XR No.:**  not applicable **CAS No.:** 76674 - 21 - 0 **MRID No:** not applicable **40 CFR:** 180.629 

### F **rom :**  Tom Bloem, Chemist

Kelly M. Lowe, Environmental Scientist Anwar Y. Dunbar, Ph.D., Pharmacologist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED; 7509P) **T hrough**  **:** Charles W. Smith III, Branch Chief

George F. Kramer, Ph.D., Senior Chemist RAB1/HED (7509P) **T o**  **:** Hope Johnson/Tamue Gibson , RM 21

Registration Division (RD; 7505P) HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered and proposed uses of flutriafol ((±) - α - (2 - fluorophenyl) - α - (4 - fluoropheny l) - 1 H - 1,2,4 - triazole - 1 - ethanol). A summary

of the findings and an assessment of human health risk resulting from the registered and proposed uses for flutriafol are provided in this document. The aggreg ate risk assessment , dietary

risk assessment , and residue chemistry review were provided by T om Bloem (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), the occupational/residential expos ure (ORE) and risk assessment were provided by Kelly L owe (RAB1) , and the drinking water assessment was provided b y James K. Wolf of the Environmental Fate and Effects Division (EFED).Flutriafol Human Health Risk Assessment D4 1584 9

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### Table of Contents 1.0 Executive Summary ................................ ................................ ................................ ................................ .......... 3 2.0 Recommendations ................................ ................................ ................................ ................................ ............. 6 2.1 Data Deficiencies/Data Needs ................................ ................................ ................................ ......................... 6 2.2 Tolerance Considerations ................................ ................................ ................................ ................................ 7 2.2.1 Enforcement Analytical Method ................................ ................................ ................................ ......... 7 2.2.2 Recommended Tolerances ................................ ................................ ................................ ................... 7 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ ............................... 8 2.2.4 International Harmonization ................................ ................................ ................................ ................ 8 2.3 Label Recommendations ................................ ................................ ................................ ................................ . 8 3.0 Ingredient Profile ................................ ................................ ................................ ................................ .............. 9 3.1 Chemical Identity ................................ ................................ ................................ ................................ ............ 9 3.2 Phy sical/Chemical Properties ................................ ................................ ................................ .......................... 9 3.3 Proposed Use Pattern ................................ ................................ ................................ ................................ .... 10 3.4 Anticipated Exposure Pathways ................................ ................................ ................................ ................. 11 3.5 Consideration of Environmental Justice ................................ ................................ ................................ ........ 11 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................................ .............. 12 4.1 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................ ................................ ... 12 4.2 Toxicological Effects ................................ ................................ ................................ ................................ .... 13 4.3 Safety Factor for Infants and Children (FQPA SF) ................................ ................................ ....................... 14 4.3.1 Com

pleteness of the Toxicology Database ................................ ................................ ........................ 14 4.3.2 Evidence of Neurotoxicity ................................ ................................ ................................ ................. 14 4.3.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ................................ .... 14 4.3.4 Residual Uncertainty in the Exposure Database ................................ ................................ ................ 15 4.4 Toxicity Endpoint and POD Selections ................................ ................................ ................................ ......... 15 4.5 Recommendation for Combining Routes of Exposure for Risk Assessment ................................ ................ 16 5.0 Dietary Exposure and Risk Assessment ................................ ................................ ................................ .......... 18 5.1 Metabolite/Degradate Residue Profile ................................ ................................ ................................ .......... 18 5.2 Food Residue Profile ................................ ................................ ................................ ................................ ..... 18 5.3 Drinking Water Residue Profile ................................ ................................ ................................ .................... 19 5.4 Dietary (Food + Drinking Water) Risk Assessment ................................ ................................ ...................... 20 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ ................................ .. 21 6.1 Spray Drift ................................ ................................ ................................ ................................ ..................... 21 6.2 Residential Bystander Post - Application Inhalation Exposure ................................ ................................ ....... 21 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ................................ .... 22 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ................................ .. 22 9.0 Occupational Exposure/Risk Characterization ................................ ................................ ................................ 23 9.1 Handler Risk Assessment ................................ ................................ ................................ .............................. 23 9.2 Post - Application Risk Assessment ................................ ................................ ................................ ................ 25 9.2.1 Inhalation Post - Application Risk Assessment ................................ ................................ ................... 25 9.2.2 Restricted Entry Interval ................................ ................................ ................................ .................... 27 Appendix A. Toxicology Profile and Executive Summaries ................................ ................................ ...................... 28 Appendix B. Chemical Names and Structures ................................ ................................ ................................ ............ 34Flutriafol Human Health Risk Assessment D4 1584 9

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### 1.0 **Executive Summary** Flutriafol ((±) - α - (2 - fluorophenyl) - α - (4 - fluorophenyl) - 1 H - 1,2,4 - triazole - 1 - ethanol) is a contact and sy stemic Group 3 triazole fungicide which acts primarily as an inhibitor of ergosterol bios ynthesis, thereb y interfering with synthesis of fungal cell membranes. Tolerances for residues of flutriafol are establi shed in/on numerous commodities, including livestock commodities, at 0.01 - 30 ppm. A Section 18 Emergency

Exemption has also been granted for application of flutriafol to cotton with time - limited tolerances of 0.35 - 0.50 ppm (tolerances expire on 31 - Dec - 201 4). Cheminova, Inc. requested Section 3 Registrations and the establishment of permanent tolerances for residues of flutriafol in/on c otton; grain sorghum; leafy vegetables, except Brassica , crop group 4; and Brassica leafy

vegetables crop group 5. In addition, the petitioner is requesting the establishment of permanent tolerances in/on egg and several livestock commodities (see Table 2.2.2.1 for proposed tolerances). **Hazard Assessment:** Flutriafol i s categorized as having high oral acute toxicity in the mouse (Category II). It has low acute toxicity via the oral, dermal and inhalation routes (Categories III, III, and IV, respectivel y) in rats. It is minimally irritating to the eyes (Category I II) and is not a dermal irritant (Category IV). Flutria fol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method). Short - term, subchronic, and chronic flutriafol toxicity studies in rats, mice , and dogs identified the liver as the target organ. Hepatotoxicity occurred at similar dose levels across several species and durations of exposure. The potential impact of in utero and perinatal flutriafol exposure was investigated in three developmental toxicity

studies (two in rats, one in rabbits) and two multi - ge neration reproduction toxicity studies in rats. In the first of two rat developmental toxicity studies, increased quantitative susceptibility

was observed with developmental effects ( delayed ossification or non - ossification of the skeleton in the fetuses) seen at a lower dose than maternal effects. In the second rat developmental study , a qualitative susceptibility was noted. Although developmental toxicity occurred at the same dose level that elicited maternal toxicity, the developmental effects (extern al, visceral, and skeletal malformations; embryo lethality ; skeletal variations; a generalized delay in fetal development; and fewer live fetuses) were more severe than the decreased food consumption and body- weight gains observed in the dams. For rabbits , intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals. In the two - generation reproduction studies, a qualitative susceptibility was also seen. Effects in the offspring [decreased litter size and percentage of live births (increased pup mortality) and liver toxicity] can be attributed to the sy stemic toxicity

of the parental animals (decreased body weight and food consumption and liver toxicity ). Effects that may

be considered signs of neurotoxicity (decreased motor activity and hindlimb grip strength, ptosis, lost righting reflex, hunched posture, and ataxia) were reported in the acute and subchronic neurotoxicity

studies at the highest dose only . These effects, however, were primaril y seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity . This conclusion is further reinforced by the observation that there was no evidence of neurotoxicity

in any additional short - term or long - term studies in rats, mice, and dog s. It is also important to note that in the acute neurotoxicity study , for animals that did not die in the study or were sacrificed in extremis, all effects resolved b y Day 8.Flutriafol Human Health Risk Assessment D4 1584 9

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### In the guid eline immunotoxicity study for flutriafol, there was no evidence of i mmunotoxicity up to the highest dose tested. All genotoxicity

studies on flutriafol showed no evidence of clastogenicity or mutagenicity. Several triazoles are carcinogenic. Flutriafol is classified as “not likel y to be carcinogenic to humans” based on the results of the carcinogenicity studies in rats and mice. **F ood Quality Protection Act (F**  **QPA ) Safety Factor (** 

**SF )**  **Decision:** The flutriafol risk assessment team concludes that the 10x FQPA SF should be reduced to 1x since the toxicology database is adequate for assessment of the proposed/registered uses, flutriafol is not considered to be neurotoxic, there are clear no - observed adverse - effect levels (NOAELs ) for the observed fetal/offspring effects, and the conservative nature o f the dietary exposure anal ys es are unlikel y to underestimate exposure (tolerance - level residues and 100% crop treated; no residential uses). **Dose Response Assessment:** T ables 4. 4 .1 and 4. 4 .2 provide s 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 neurotoxicity

screening battery

(NOAEL = 250 mg/kg/day) study was selected for assessment of acute dietary

(all populations excluding females 13 - 49 years old) exposure. The chronic toxicity (dog) study

was s e lected for assessment of chronic dietary e xposure (NOAEL= 5 mg/kg/day) . For all exposure scenarios, a 100x uncertainty factor (UF) was applied ( 10 x interspecies extrapolation ; 1 0 x for intraspecies variation ; 1x FQPA SF (when applicable ) ). **Dietary Risk Estimates (Food + Drinking**  **Water ):**  Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM - FCID, ver. 3.16) which incorporates the food consumption data from the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey , What We Eat in America (NHANES/WWEIA; 2003 - 2008). The acute and chronic analy ses assumed tolerance - level residues or tolerance - level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates. Since adequate processing studies have been submitted which indicate that tolerances for residues in/on apple juice, grape juice, dried pr unes, and tomato puree are unnecessary

and since tolerances for residues in/on raisin s and tomato paste are established , the DEEM (ver . 7.81) default processing factors for these commodities were reduced to 1. The DEEM (ver. 7.81) default processing facto rs were retained for the remaining relevant commodities. The resulting acute (≤44 % acute population - adjusted dose (aPAD); females 13 - 49 years occupied the highest % of the aPAD) and chronic (≤ 74 % cPAD; children (1 - 2 years old) had the highest exposure) di etary

risk estimates are not of concern to HED. **Residential (Non -**  **Occupational) Exposure and Risk Assessment:** There are no residential uses proposed or currentl y registered for flutriafol . Therefore, residential handler and post - application exposure/risk were not assessed.Flutriafol Human Health Risk Assessment D4 1584 9

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### Aggregate**-**

**Risk Estimates:** In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Because there are no uses for flutriafol that result in residential (non - occupational) exposures, the aggregate assessment need only consider food and drinking water. Since the dietary exposure anal ys is included both food and drinking water , the discussion and exposure estimates presented in the dietary

section represent aggregate acute and chronic exposure to flutriafol and those metabolites identified as being toxicologicall y identical to flutriafol. All aggregate flutriafol risk estimates are not of concern to HED. Application of flutriafol also results in exposure to T (1,2,4 - triazole) , 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 anal ys is for these compounds, which resulted in aggregate exposure less than HED’s level of concern (D 414952, T. Morton, 24 - Oct - 2013). The proposed new uses and label amendments do not require a revision to this most recent aggregate assessment. **Occupational Exposure and Risk Assessment:** A quantitative assessment of occupational exposure has been conducted for all of the proposed uses. The occupational handler exposure and risk estimates for the remaining crops indicate that the short - and intermediate - term dermal and inhalation combined margins of exposure ( MOEs ) are not of concern to HED (i.e., MOE > 100) with the use of chemical - resistant gloves as direct ed b y the label. At the baseline level of personal protection (i.e., no gloves and no respirator), only one scenario results in a risk estimate below the level of concern (LOC) with a combined (dermal + inhalation) MOE of 82; this scenario is mixing/loading a liquid formulation for aerial application to high - acreage crops. With the addition of gloves, the combined dermal + inhalation MOE is 470, which is not of concern. All other scenarios result in risk estimates greater than 220 with baseline attire. The occupational post - application dermal exposure and risk estimates are greater than the LOC on the day of application with MOEs ranging from 230 to 4,600 depending on crop and activity . Since the post - application assessment is not a concern on Day 0 (12 hours following application), the restricted entry interval ( REI ) is based on the acute toxicity of flutriafol technical material. Flutriafol has low acute toxicity

via the oral, dermal and inhalation routes (Toxicity Categories III and IV), is minimally irritating to the eyes (Toxicity Category I II), 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 REIunder 40 CFR 156.208 (c)(2)(iii). The 12 - hour REI , which currently appears on the labels, is adequate for the proposed uses. Based on the Agency's current practices, a quantitative non - cancer occupational post - application inhalation exposure assessment was not performed for flutriafol at this time. If new policies or procedures are put into place, the Agency may revisit the nee d for a quantitative occupational post application 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 a ssessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and L ow - In come Populations.”Flutriafol Human Health Risk Assessment D4 1584 9

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### Review of Human Research **:** This risk assessment relies in part on data from studies in which a dult 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 b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the following Agency website s: http://www.epa.gov/ pesticides/s cience/handler- exposure - data.html and http://www.epa.gov/pesticides/science/post - app exposure - data.html . **2.0 Recommendations**  Provided revised Sections B and F are submitted , HED concludes that the toxicological, residue chemistry , and ORE database s support the establishment of the proposed Section 3 Registrations and the permanent tolerances listed in Section 2.2.2. **2.1 Data Deficiencies/Data Needs**  **Residue Chemistry:**  The following field rotational crop residue data conducted as specified in OPPTS 860.1900 are requested (trials should employ a seasonal rate of 0.228 lb ai/acre): sweet corn

- NAFTA Growing Zones 1 (n=2), 3 (n=1), 10 (n=1), 11 (n=1), and 12 (n=1); cotton - North American Free Trade Agreement (NAFTA) Growing Zones 6 (n=1), 8 (n=4), and 10 (n=3). These data were previously

requested and remain outstanding (D397075, T. Bloem, 20 - Dec - 2011). If the petitioner would like to permit rotation to sweet corn and cotton following application at a higher rate and/or different interval, then a full set of field rotational crop data conducted at the desired rate and interval should be submitted. The additional data are requested to ensure that the resulting rotational crop tolerances are reflective of conditions for growers in all relevant regions. Based on the existing sweet corn and cotton field rotational crop residue data (residues ≤0.035 ppm) and the unrefined nature of the current dietary exposure an al ys es (≤ 44 % aPAD; ≤ 74 % cPAD), HED concludes that the requested data will not have a significant effect on the human health risk assessment. In addition, the ruminant feeding study monitored for residues of only flutriafol with the residues of concern ( ROC ) for risk assessment estimated using factors derived from the ruminant metabolism study . The factors range from 2 - 77x and reflect the fact that parent was not the major residue in some of the matrices. In order to facilitate refinements in the dietary exposure analysis which may be necessary as part of future registrations, HED advises the petitioner to anal yze 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 rum inant residue estimates employed in the dietary anal ys es are conservative as they

are comparable to, or significantly higher than, the TRRs from the me tabolism study (30 - ppm dietary

burden) and due to the conservative nature of the dietary burden calculations.Flutriafol Human Health Risk Assessment D4 1584 9

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### 2.2 **Tolerance Considerations 2.2.1**  **Enforcement Analytical Method Tolerance Enforcement Method**  **- Plants:**  Adequate methods are available to enforce the currentl y established plant tolerances (D362421, T. Bloem , 11 - Mar - 2009; D340513, T. Bloem, 11 - Mar- 2009; D388603, T. Bloem, 16 - Jun - 2011). The flutriafol method employed in the magnitude of the residues studie s is based on the current tolerance enforcement method. S ince adequate method validation data were provi ded 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 adequatel y quantify re sidues of flutriafol (http://www.crl pesticides.eu/library

/docs/fv/CRLFV_Multiresidue_methods.pdf ). **Tolerance Enforcement Method -**  **Livestock:** Method I CIA AM0030 6 (revisions of 13 - Aug 2007 and 8 - Oct - 2007) has been determined to be sufficient for enforcement of the currently established ruminant tolerances (D362421, T. Bloem, 23 - Apr - 2014). The flutriafol method employed in the ruminant (49059703.der) and poultry ( 47510201.der1) magnitude of the residue studies are based on this method. S ince 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 assoc iated with this petition. **2.2.2 Recommended Tolerances**  Table 2.2.2.1 is a summary of the proposed and HED - recommended tolerances for residues of flutriafol per se . A revised Section F is requested. With the establishment of the cotton tolerances listed in Table 2.2.2.1, the cotton tolerances established in 40 CFR 180.629(d) for residues resulting from crop rotation should be deleted. HED notes that cotton tolera nces are also established in 40 CFR 180.629(b) as a result of Section 18 emergency exemptions (expire on 31 - Dec - 2014). HED recommends allowing these tolerances to expire rather than deleting them. **Table 2.2.2.1: Tolerance Summary.** Commodity Proposed

Tolerance (ppm) HED Recommended Tolerance (ppm) Comments

40 CFR 180.629(a) cotton, undelinted seed 0.5 0.50 Based on the available data and the OECD tolerance - calculation procedure, the indicated tolerances are appropriate. cotton, gin byproducts 5.0 6.0 sorghum, grain, forage 2.0 2.0 sorghum, grain, grain 1.5 1.5 sorghum, grain, stover 6.0 6.0 grain, aspirated fractions 6.0 6.0 Brassica , head and stem , crop subgroup 5A 1.5 1.5 Brassica , leafy greens , crop subgroup 5B 7.0 7.0Flutriafol Human Health Risk Assessment D4 1584 9

Page 8 of 35 **Table 2.2.2.1: Tolerance Summary.** Commodity Proposed

Tolerance (ppm) HED Recommended Tolerance (ppm) Comments

40 CFR 180.629(a) leaf petioles (subgroup 4B) 3.0 -- Based on the available head lettuce, leaf lettuce , spinach, and celery residue data and the OECD tolerance - calculation procedure, tolerances of 1.5 ppm, 5.0 ppm, 10 ppm, and 3.0 ppm, respectively, were determined to be appropriate (these are the representative crops for crop group 4). The celery, spinach , and head lettuce data are sufficiently similar to set a crop group 4 tolerance at 10 ppm (residues/tolerances were within 5x). However, setting a head lettuce tolerance at 1 0 ppm, and by extension radicchio, would be at a level which is too high to allow for label enforcement (tolerance/residues >5x; head lettuce represents only radicchio in crop group 4 - HED Standard Operating Procedure (SOP) 2000.1) . Based on the OECD tol erance calculation procedures and the unique morphology of head lettuce and radicchio as compared to the other corps in the group, HED concluded that a crop group tolerance, except head lettuce and radicchio, at 10 ppm and head lettuce and radicchio tolerances at 1.5 ppm , were appro priate. leafy greens (subgroup 4A), except head lettuce 10 -- v egetable, leafy , except Brassica , crop group 4 , except head lettuce and radicchio -- 10 lettuce, head 1.5 1.5

radicchio 1.5 1.5 poultry, meat byproducts 0.02 0.01 Based on the current MRDB and the results of the feeding studies, HED concludes that the indicated tolerances are appropriate. poultry, fat -- 0.01 e gg 0.01 0.01 liver (cattle, goat, horse, sheep) -- 1.0 milk -- 0.02 hog, liver 0.05 -- hog, meat byproducts, except liver 0.02 -- hog, meat byproducts -- 0.05 hog, muscle 0.01 -- A tolerance of 0.01 ppm was recommended as part of an earlier petition (D415068, T. Bloem, 23 - Apr - 2014). 

### 2.2.3 **Revisions to Petitioned -**  **For Tolerances** See the comments column of Table 2.2.2.1. **2.2.4 International Harmonization**  There are no Canadian, Codex, or Mexican maximum 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 specifies “grain sorghum” rather than “sorghum,” a maximum application rate for grain sorghum of 2 x 0.114 lbs ai/acre, a 30 - day preharvest interval (PHI) for grain sorghum forage/grain/stov er, and the following rotational crop restrictions: (1) a

pplication rates ≤ 0.228 lbs ai/acre/season - labeled crops may be planted immediately

and cotton and sweet corn may be planted 180 day s after application (rotation to any other crop is prohibited) and (2) application rates > 0.228 lbs ai/acre/season - treated field may onl y be rotated to a labeled crop.Flutriafol Human Health Risk Assessment D4 1584 9

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### 3.0 **Ingredient Profile 3.1**  **Chemical Identity** The chemical structure and nomenclature of flutriafol and the triazole metabolites are presented i n Tables 3.1.1. **Table 3.1.1: Flutriafol Nomenclature** . Chemical structure

Common name Flutriafol Company experimental name PP450 (ICI/Syngenta until 2001); CHA 1310 - 05 (Cheminova code) IUPAC name (RS ) - 2,4’ - difluoro - α - (1 H

- 1,2,4 - triazol - 1 - yl methyl) benzhydryl alcohol CAS name (±) - α - (2 - fluorophenyl) - α - (4 - fluorophenyl) - 1 H - 1,2,4 - triazole - 1 - ethanol CAS registry number 76674 - 21 - 0

1,2,4 - triazole (T) triazolylalanine (TA) triazolylacetic Acid (TAA) 

### 3.2 **Physical/Chemical Properties** Table 3.2.1 is a summary of the phys ical/chemical properties for flutriafol. Flutriafol has a low vapor pressure and a low Henry ’s law constant (9.16 x 10 - 12 

### atm m 3 

### /mol). **Table 3.2.1: Physicochem ical Properties of Flutriafol.**  Melting point/range -- Not available pH 6.1 in a 1% aqueous dilution CSF for Flutriafol Technical dated 3/23/07 Density 0.99 g/cm3 Water solubility 95 mg/L at 20 oC

PP#7F7197 administrative materials Solvent solubility At 21 oC g/L 1,2 - Dichloroethane 19 - 20 Acetone 116 - 135 Ethyl acetate 29 - 34 Methanol 115 - 134 n - Heptane <10 Xylene <10 Vapor pressure 4 x 10 - 7 Pa at 20 oC Dissociation constant, pKa 2.3 at 25 oC Log(KOW) log P OW = 2.3 at 20 oC UV/visible absorption spectrum -- Not available N N N

F O H F

N H N N N N N O H N H 2 O N N N O H OFlutriafol Human Health Risk Assessment D4 1584 9

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### 3.3 **Proposed Use Pattern** Cheminova requested Section 3 Registrations for application of flutriafol to c otton; sorghum; leafy vegetables, except Brassica , crop group 4; and Brassica leafy vegetables crop group 5. T able 3.3.1 is a summary of the end - use products and target pests and Table 3.3.2 is a summary of the proposed application scenarios. The proposed labels also specify the following: (1) application through irrigation is prohibited; (2) treated fields may be rotated to a labeled crop immediate ly

after application and to sweet corn 180 day s after application; rotation to any other crop is not allowed; (3) adjuvants may be added to the spray

solution; (4) for ground application, the minimum spray

volume is 10 gallons per acre (GPA) for all except at - planting soil application to cotton where a spray volume of 6 - 10 GPA is indicated; for aerial application, the minimum spray

volume is 5 GPA ; (5) applicators and other handlers must wear long - sleeved shirt and long pants, chemical - resistant gloves, and shoes plus - socks; and (5) a 12 - hour REI is specified for the proposed crops. . Provided a revised Section B is submitted which specifies “grain sorghum” rather than “sorghum,” a maximum application rate for grain sorghum of 2 x 0.114 lbs ai/acre, a 30 - day PHI for grain sorghum forage/grain/stover, and the following rotational crop restrictions, HED concludes that the proposed application scenarios are supported b y the available data: (1) application rates ≤ 0.228 lbs ai/acre/season - labeled crops may be planted immediately and cotton and sweet corn may be planted 180 day s after application ( rotation to any other crop is prohibited) and (2) application rates > 0.228 lbs ai/acre/season - treated field may onl y be rotated to a labeled crop. **Table 3.3.1: Summary of End**  **- Use Products.**  Trade Name Conc. Formulation Label Date Target Crops Target Pests

Topguard® Fungicide (EPA Reg. No. 67760 - 75) 1.04 lb

ai/gal suspension

concentrate (SC) not

indicated cotton (foliar

application only) Alternaria leaf spot, boll rot ( Alternaria spp.); Anthracnose boll rot ( Glomerella spp.); Asochyta blight, boll rot ( Ascochyta gossypii); Cercospora blight and leaf spot ( Cercospora spp.); Diplodia boll rot (

Diplopia spp.); Fusarium boll rot ( Fusarium spp.); Phoma blight, boll rot ( Phoma spp.); Rust (

Puccinia spp. And Phykopsora spp.); Stemphyllium leaf spot (Stemphyllium spp.); and Target Spot ( Corynespora cassiicola ) grain sorghum Anthracnose leaf blight (Colletotrichum graminicola ); Ergot

( Claviceps sorghi); Gray Leaf Spot ( Cercospora sorghi); Leaf blight (Exserohilum turcicum; Setosphaeria turcica ); Common rust ( Puccinia purpuria ); Ladder leaf spot ( Cercospora fusimaculans ); Rough spot ( Ascochyta sorghi); Sooty stripe (Ramulispora sorghi); Target leaf spot ( Bipolaris cookei); and Aonate leaf spot and sheath blight ( Gloecercospora sorghi ) Flutriafol® 250 g/L Fungicide (EPA Reg. No. 67760 - 120) 2.08 lb

ai/gal suspension

concentrate (SC) not

indicated leafy vegetables

(except Brassica ) group 4 Alternaria leaf spot ( Alternaria sonchi); Anthracnose ( Microdochium panattonianum , Colletotrichum dematium ); Cercospora leaf spot, early blight ( Cercospora spp.); Powdery mildew (Eyrisiphe cichoracearum ); Septoria leaf spot (Septoria petroselini); and Late blight (S eptoria apiicola ) Brassica leafy vegetables group 5 Black spot ( Alternaria spp.), Cercospora leaf spot ( Cercospora spp.), Powdery Mildew (

Erysiphe polygoni) Flutriafol® 500 g/L Fungicide (EPA Reg. No.

– not specified) 4.16 lb

ai/gal suspension

concentrate (SC) not

indicated cotton (soil

application only) Cotton root rot ( Phymatotrichopsis omnivore )Flutriafol Human Health Risk Assessment D4 1584 9

Page 11 of 35 **Table 3.3.2: Summary of Proposed Application Scenarios.** App. Timing; Type; and Equip. Formulation Single App. Rate (lb ai/acre) Max. #. App.

per Season Max. Seasonal

App. Rate (lb ai/acre) PHI

(days) Use Directions and Limitations Cotton at planting soil application using T - band or modified in - furrow methods 1 SC

(4.16 lb ai/gal) 0.130 - 0.260 1 0.488 (soil and foliar) 30 - 7 - day retreatment interval ( RTI ) broadcast foliar application SC

(1.04 lb ai/gal) 0.057 - 0.114 2 Sorghum broadcast foliar application SC

(1.04 lb ai/gal) 0.057 - 0.114 2 0.228 7 - 7 - day RTI Leafy vegetables, except Brassica , crop group 4 (amaranth; arugula; Cardoon; celery; Chinese celery; celtuce; chervil; chrysanthemum (edible and garland); corn salad; cress (garden and upland); dandelion; dock; endive; fennel (Florence); lettuce (head and le af); orach; parsley; purslane ( garden and winter); radicchio; rhubarb; spinach; spinach (New Zealand and vine); and Swiss chard. Including cultivars and/or hybrids of these crops. broadcast foliar application SC

(2.08 lb ai/gal) 0.081 - 0.114 4 0.455 7 - 7 - day RTI Brassica leafy vegetable crop group 5 (broccoli; broccoli (Chinese and raab); Brussels sprouts; cabbage; cabbage; cabbage (Chinese, bo k choy, Chinese mustard/gai choy); cauliflower; cavalo broccolo; collards; kale; kohlrabi; mustard greens; mustard spinach; and ra pe greens. Including all cultivars and/or hybrids of these crops. broadcast foliar application SC

(2.08 lb ai/gal) 0.081 - 0.114 4 0.455 7 - 7 - day RTI 1 T - band = Apply in a concentrated 3 - 4 inch wide band at planting perpendicular to row direction after furrow opening and seed placement but prior to furrow closure. Modified in - furrow application = apply using a splitter/Y application mechanism that dire cts the product on the sides of the seed furrow and not direct contact with the seed. 

### 3.4 **Anticipated Exposure Pathways** Based on the proposed/registered flutriafol application scenarios , dietary exposure is an anticipated exposure pathway as residues of flutriafol may be found in/on crops, livestock, and drinking water . E xposure in the residential (non - occupational ) setting is not anticipated. B ased on the registered/proposed application scenarios and the results of a fish bioaccumulation st udy , residues in fish/shellfish are expected to be insignificant ( D407105, T. Bloem, 27 - Mar- 2013 ; this includes consumption at the subsistence level ). The current action is expected to result in short and intermediate - term occupational exposures (handler and post - application). **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations,” (http://epa.gov/compliance/ej/resources/policy /exec_order_12898.pdf

). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey

of Food Intake by

Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country .Flutriafol Human Health Risk Assessment D4 1584 9

Page 12 of 35 

### Additional ly , 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 associate d risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of s pecialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  No new toxicity

and/or metabolis m data have been received since the last flutriafol risk assessment (D4 11360 , T. Bloem et al. , 2 3 - Apr - 201 4 ). The following flutriafol toxicological information is a summary of the information presented in D382902 (K. Lowe et al. , 19 - Oct - 2011). It is no ted that the HED Hazard and Science Policy Committee (HASPOC) evaluated all existing hazard and exposure data, as well as current registered/proposed use patterns for flutriafol, and concluded using a weight - of - evidence approach that a subchronic inhalatio n toxicity study is not required at this time (TXR# 0056856). **4.1 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Flutriafol is quickly

absorbed, extensively

metabolized, and quickly eliminated (within 48 hours) regardless of sex, dose, or wh ether exposure was to single or multiple dosing regimens. More than 78% of the dose was recovered in the bile and urine. In the blood, radioactivity partitioned into the red blood cells. In both sexes and all groups, concentrations of radioactivity were relativel y high in whole blood, liver, and kidney s. Other organs with high concentrations included the adrenal glands, spleen, and pituitary . The total amount of radioactivity isolated in the tissues and carcass was <1 - 3%. Bioaccumulation was considere d 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 - fluorophenylring. The initial metabolic step was epo xidation fol lowed b y rearrangement to form either the dihydrodiol isomers or the hydrox y or dihydrox y m etabolites. The hydrox yl groups on these primary metabolites may

then be either conjugated with glucuronic acid or methyl ated. A second, minor route fo r metabolism of flutriafol was via the removal of the triazole ring to form 1 - (2 fluorophenyl ) - 1 - (4 - fluorophenyl ) - ethandiol, which is then conjugated with glucuronic acid. An in vivo rat dermal - absorption study (MRID # 47090415) is available for flutriafol that is acceptable and indicates that the absorption is 17%, 21%, and 11%, respectively , at 2, 20, and 200 μg/cm2 

### , following a 10 - hour exposure. A value of 21% is appropriate (most protective) for dermal risk assessments.Flutriafol Human Health Risk Assessment D4 1584 9

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### 4. **2 Toxicological E**  **ffects** Flutriafol is a member of the conazole triazole class of pesticides. The triazole fungicides inhibit C14 - demethylase, a fungal cy tochrome P450, which plays a role in sterol production. Sterols, such as ergosterol, are needed for fungal membrane s tructure and function, and are essential for the development of functional cell walls. Mammals, particularl y humans, also express cytochrome P450 enzy

mes (hepatic and extra - hepatic). Thus, exposure to chemicals such as flutriafol in sufficient quantities may

lead to toxicity . Flutriafol is categorized as having high oral acute toxicity in the mouse ( Toxicity Category I I). Itis categorized as having low acute toxicity via the oral, dermal and inhalation routes ( Toxicity Categories III, III , and IV, re spectively) in rats. Flutriafol is minimally irritating to the eyes ( Toxicity Category

III) and is not a dermal irritant ( Toxicity Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method). Short - term, subchronic, and chronic toxicity studies in rats, mice, and dogs identified the liver as the primary

target organ of flutriafol. Hepatotoxicity was first evident in the subchronic studies (rats and dogs) in the form of increases in liver enzy me release (alkaline phosphatase), liver weights, and histopathology findings ranging from hepatocy te vacuolization to centrilobular hy pertrophy and slight increases in hemosiderin - laden Kupffer cells. It is noteworthy that with chronic exposures, there are no indications of progression of liver toxicity in all species. After over one year of exposure, hepatotoxicity in rats, dogs, and mice took the form of (1) minimal to severe fatty changes; (2) bile duct proliferation/cholangiolar fibrosis; (3) hemosiderin accumulation in Kupffer cells; (4) centrilobular hy pertrophy , and (5) increases in alkaline phosphatase release. Slight indications of effects in the hematopoietic system are sporadicall y seen in the database. These effects are manifested in the form of slight anemia (rats and dogs) and increased platelet, white blood cell, neutrophil, and ly mphocy te counts (mice). These effects, however, were minimal in severity . In a 28 - day

dermal toxicity

study , there were no signs of toxicity for flutriafol up to the limit dose (1000 mg/kg/day). The potential impact of in utero and perinatal flutriafol exposure was investigate d in three developmental toxicity

studies (two in rats, one in rabbits) and two multi - generation reproduction toxicity studies in rats. In the first of two rat developmental toxicity studies, increased quantitative susceptibility

was observed with develop mental effects ( delayed ossification or non - ossification of the skeleton in the fetuses) seen at a lower dose than maternal effects. In the second rat developmental study , a qualitative susceptibility was noted. Although developmental toxicity occurred at the same dose level that elicited maternal toxicity, the developmental effects (external, visceral, and skeletal malformations; embryo lethality ; skeletal variations; a generalized delay in fetal development; and fewer live fetuses) were more severe than the decreased food consumption and body- weight gains observed in the dams. For rabbits, there was in increased qualitative fetal susceptibly . Intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals. In the two - generation reproduction studies, a qualitative susceptibility was also seen. Effects in the offspring [decreased litter size and percentage of live births (increased pup mortality) and liver toxicity] can be attributed to the sy stemic toxicity of the parental animals (decreased body weight and food consumption and liver toxicity ).Flutriafol Human Health Risk Assessment D4 1584 9

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### Effects that may

be considered signs of neurotoxicity (decreased motor activity and hindlimb grip strength, ptosis, lost righting reflex, hunched posture, and ataxia) were report ed in the acute and subchronic neurotoxicity

studies at the highest dose only . These effects, however, were primaril y seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity . This conclusion is further rein forced by the observation that there was no evidence of neurotoxicity

in any additional short - term studies in rats, mice, and dogs, or in the long - term toxicity studies in rats, mice, and dogs. It is also important to note that in the acute neurotoxicity study , for animals that did not die in the study or were sacrificed in extremis, all effects resolved b y Day 8. In the guideline immunotoxicity study for flutriafol, there was no evidence of immunotoxicity up to the highest dose tested. All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. Several triazoles are carcinogenic. Even though structure - activity relationiship (SAR) anal ys is indicates that flutriafol has the potential to produce thy roid and/or liver tumor s in rodents, neither the chronic/carcinogenicity study in rats or the carcinogenicity study in mice revealed treatment related increases in tumor incidences. Flutriafol is classified as “not likel y to be carcinogenic to humans” based on the results of th e carcinogenicity studies in rats and mice. **4. 3**  **S afety**  **F actor**  **for Infants and Children (FQPA SF)** The RAB1 risk assessment team concluded that the FQPA SF could be reduced to 1x based on the following considerations outlined in more detail in the sectio ns below: 1) the toxicology database for flutriafol is adequate for risk assessment; 2) flutriafol is not considered neurotoxic; 3) clear NOAELs are established to protect for the fetal/offspring effects observed; and 4) the exposure databases are suffici ent and unlikely to underestimate exposure. **4.3 .1**  **Completeness of the Toxicology Database** The toxicology

database for flutriafol is adequate for quantification of risk for dietary , residential, and occupational uses and FQPA SF evaluation. The following acceptable studies are available for evaluation: developmental toxicity studies in rats (2) and rabbits (1), two generation reproduction studies in rats (2), and acute and subchronic neurotoxicity studies in rats. **4.3 .2**  **Evidence of Neurotoxicity** There is no concern for neurotoxicity with flutriafol. Signs of neurotoxicity were reported in the acute and subchronic neurotoxicity studies at the highest dose onl y; however, these effects were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity . In addition, there was no evidence of neurotoxicity in any additional short - term or long - term toxicity

studies in rats, mice, and dogs. A developmental - neurotoxicity study (DNT) study was not required. **4.3 .3**  **Evidence of Sensitivity/Susceptibility in the Developing or Young Animal** There are no concerns or residual uncertainties for pre - and/or post - natal toxicity . There is evidence of increased quantitative and qualitative susceptibility in developmental and reproduction toxicity

studies (see Section 4.2); however, there is no conc ern since: 1) clear NOAELs and lowest observed adverse effect levels (L OAELs) were established in theFlutriafol Human Health Risk Assessment D4 1584 9

Page 15 of 35 

### fetuses/offspring; 2) the dose - response for these effects are well defined and characterized; 3) developmental endpoints are used for assessing acute die tary 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 fir st 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 . **4.3 .4**  **Residual Uncertainty in the Exposure Da tabase**  There are no residual uncertainties in the exposure database. The dietary exposure assessment is conservativ e in nature (utilizes tolerance - level residues and 100% crop treated). In addition, there are no proposed or registered residential uses. **4.4 Toxicity Endpoint and POD Selections**  The points of departure, UFs , and toxicity endpoints for dietary

exposure assessment and occupational exposure assessment are presented in Tables 4.4 .1 and 4.4 .2, respectivel y. **Acute Dietary Endpoint (General P opulation):**  The acute neurotoxicity screening battery

in the rat was selected for the acute dietary endpoint for the general population. An UF of 100x (10x for interspecies extrapolation, 10x for intraspecies variability , and 1x for FQPA SF) was applied to the NOAEL of 250 mg/kg to generate the acute reference dose (aRfD) of 2.5 mg/kg for the general population. The LOAEL is 750 mg/kg based on decreased body weight, body- weight gain, absolute and relative food consumption, agonal effects in both sexes (d ehydration, urine - stained abdominal fur, ungroomed coat, ptosis, decreased motor activity , prostration, limp muscle tone, muscle flaccidity , hy

pothermia, hunched posture, impaired or lost righting reflex, and scant feces), in males (red or tan perioral sub stance, 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 prenatal developmental toxicity study in rabbits was selected for the acute dietary endpoint for females 13 - 49 years of age. An UF of 100 x ( 10x for interspecies extrapolation, 10x for intraspecies variability , and 1x for FQPA SF) was applied to the developmental NOAELof 7.5 mg/kg to generate the aRfD of 0.075 mg/kg for females 13 - 49 years of age. The developmental L OAEL of 15 mg/kg is based on decreased number of live fetuses, complete litter res orptions , 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 day s of single dosing. The onl y other studies considered for this endpoint were the prenatal developmental studies in rats, where the developmental NOAEL s w ere 10 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 effe cts seen in these rat studies and provides the most protective 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 the general population. An UF of 100x (10x for interspecies extrapolation, 10x for intraspecies variability, and 1x for FQPA SF) was applied to the NOAEL ofFlutriafol Human Health Risk Assessment D4 1584 9

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### 5 mg/kg/day

to generate the chronic reference dose (cRfD) of 0.05 mg/kg/day for all populatio ns. The LOAEL is 20 mg/kg/day based upon adverse liver findings (increased liver weights, increased centrilobular hepatocy

te lipid in the liver, and increases in alkaline phosphatase, albumin, and trigl ycerides), increased adrenal cortical vacuolization o f the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes, mild anemia (characterized b y 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. 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 - day rat and 90 - day

dog oral toxicity studies provide similar NOAEL/L OAEL 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 rep roduction studies where similar effects were seen at slightly

higher doses. **Short -**  **and Intermediate -**  **Term Dermal and Inhalation Endpoint:** The prenatal developmental toxicity study in rabbits was selected for the short - and intermediate - term dermal and inhalation endpoints. The developmental NOAEL is 7.5 mg/kg/day and the LOAEL is 15 mg/kg/day , based on decreased number of live fetuses, comp lete 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 route - specific 28 - day dermal toxicity

study was also considered for dermal exposures, but there was no toxicity

observed up to the limit dose (1000 mg/kg/day) and developmental effects were not evaluated. The selected study provides the most protective end point for the populations of concern (pregnant females and fetuses). The only other studies considered for this endpoint were the 90 - day

dog and the two - generation reproduction studies (parental effects) where liver toxicity (the target organ) was observe d at similar doses. However, the severity of these liver effects does not increase with duration, and, thus, the fetal mortalities in the rabbit study are considered more severe. The LOC for the dermal and inhalation endpoints is 100 based upon a 10x for interspecies extrapolation, and a 10x for intraspecies variability . Using a dermal absorption factor of 21%, the dermal - equivalent NOAEL is ~35.7 mg/kg/day (NOAEL of 7.5 mg/kg/day

/ 21% dermal absorption = 35.7 mg/kg/day). Inhalation exposure is assumed to be equivalent to oral exposure. **Cancer Classification and Risk Assessment Recommendation:** F lutriafol is classified as “ l ot likely to be c arcinogenic to humans” based on the results of the carcinogenicity studies in rats and mice. **4. 5**  **Recommendation for Combining Routes of Exposure for Risk Assessment**  Since the POD/endpoint for short - and intermediate - term dermal and inhalation endpoints are identical, exposure via these routes may be combined .Flutriafol Human Health Risk Assessment D4 1584 9

Page 17 of 35 **Table 4.4 .1: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Dietary and Non**  **** **Occupational Hum an 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 consumption, and clinical signs of toxicity in both sexes: dehydration, urine - stained abdominal fur, ungroomed coat, ptos is, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, scant feces; in males: red or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females: piloerection and bradypnea. Acute Dietary (Females 13 - 49 years of age) NOAEL = 7.5

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 0.075

mg/kg/day aPAD = 0.075 mg/kg/day Developmental study

– rabbit; Developmental LOAEL =

15 mg/kg, based on decreased number of live fetuses, complete litter resorptions and increased post - implantation loss.

Chronic Dietary (All Populations) NOAEL = 5

mg/kg/day 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, hematocrit, and red blood cell count) in the males; and initial body weight losses, decreased cumulative body- weight gains, and increased adrenal weights in the females. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the carcinogenicity studies in rats and mice. Point of departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to hu man (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. **Table 4. 4**  **. 2: Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Occupational Hum**  **an 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, complete litter resorptions and increased post - implantation loss. Inhalation Short (1 - 30 days) - and Intermediate (1 - 6 months) - Term NOAEL = 7.5 mg/kg/day

Inhalation toxicity assumed to be equivalent to oral toxicity 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, complete litter resorptions and increased post - implantation loss. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the carcinogenicity studies in rats and

mice. 1 Dermal absorption factor was derived from the dermal penetration study (MRI D 47090415). 2 Inhalation absorption factor is considered the worst - case scenario for inhalation exposure using an oral NOAEL ( D372347, K. Lowe et al. , 16 - Dec - 2009 ). Point of departure (POD) = A data point or an estimated point that is derived from observed dose - response data an d used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern.Flutriafol Human Health Risk Assessment D4 1584 9

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### 5.0 **Dietary Exposure and Risk Assessment** D4 1 6089 , T. Bloem , 16 - Dec - 201 4 (residue chemistry summary for the current action) D4 20505 , T. Bloem, 16 - Dec - 201 4 (dietary exposure analysis for the current action) 

### 5.1 **Metabolite/Degradate Residue Profile** Based on the available apple sugar beet, rapeseed, poultry , and ruminant metabolism studies and the confined rotational crop studies, HED concludes that the residue of concern for tolerance enforcement, in the proposed/registered primary crops, rotational crops, and livestock, is flutriafol. The residues of concern for risk assessment are defined in Table 5.1.1 . **HED notes that if the poultry and/or ruminant dietary burden exceeds the level employed in the metabolism studies,**  **then metabolism studies conduc**  **ted at this higher dietary burden with [carbinol**   ** 14** 

### C]flutriafol **and [triazole -**  **3,5 -**  **14** 

### C]flutriafol may be required. **Table 5**  **.0.1: Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance Enforcement.**

Matrix ROC 1 Risk Assessment Tolerance Enforcement coffee, soybean seed, fruit, sugar beet, cucurbit vegetables, fruiting vegetables, tree nuts, and leafy vegetables (crop groups 4 and 5) flutriafol (free), T, TA, and TAA

flutriafol (free) cotton, peanut, and cereal grains flutriafol (free and conjugated), defluorinated flutriafol, T, TA, and TAA; combined flutriafol (free and conjugated) and defluorinated flutriafol residues may be estimate by multiplying the free flutriafol residues by 2.2x2 rotational crops (excluding dried roughage feed commodities) flutriafol (free and conjugated), M28, T, TA (free and conjugated), TAA, and TLA; combined flutriafol (free and conjugated) and M28 residue may be estimated by multiplying the free flutriafol residue by 1.3x2 rotational crops (dried roughage feed commodities) same as that mentioned above but with multiplication of the free flutriafol residues by 2.0x2 to account for the combined residues of flutriafol (free and conjugated) and M28 p oultry3 flutriafol (free), T, TA, and TAA ruminant flutriafol (free), M3, M3e, M4, M7, M10, T, TA, and TAA; combined flutriafol, M3, M3e, M4, M7, and M10 residues may be estimated by multiplying the free flutriafol residue by the following 2 : skim milk - 58x, cream - 15x, liver, 5.3x, kidney 77x, muscle - 6x, and fat - 2x water flutriafol and T -- 1 See A ppendix B for names and structures of the metabolites. Separate risk assessments are required for T and TA/TAA/TLA; these compounds have been determined to be toxicologically different from flutriafol. 2 The indicated factors are based on results from the metabolism studies or confined rotational crop study. 3 Decision will be reevaluated as the dietary burden increases (D 416089, T. Bloem, 16 - Dec - 2014). 

### 5.2 **Food Residue Profile** The following paragraphs are summaries of the available magnitude of the residue data for the registered crops, proposed crops, rotational crops, and livestock. **Registered Primary Crops:** Adequate magnitude of the residue data have been submitted to sup port the currently- established tolerances. **Magnitude of the Residue -**  **Proposed Crops :**  The petitioner submitted adequate cotton, grain sorghum, celery , lettuce, spinach, cabbage, broccoli, and mustard green field trial studies and submitted an adequate cotton processing study. The residue data were generated using adequatel yvalidated anal y

tical methods and satisfy

the geographical requirements specified in OCSPP 860.1500 (storage intervals have also been validated). Provided a revised Section B is submittedFlutriafol Human Health Risk Assessment D4 1584 9

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### and based on the OECD tolerance - calculation procedure, HED concludes that the plant tolerances listed in Table 2.2.2.1 for residues of flutriafol per se are appropriate. **Magnitude of the Residue -**  **Rotational Crops :**  The proposed label indicates that treated fields may be rotated to a labeled crop at any time and to sweet corn 180 days after application (rotation to any other crop is not permitted). In support of the 180 - day plant - back interval (PBI), the petitioner cited previously

submitted and reviewed sweet corn field rotational crop data that employed an application rate of 0.228 lb ai/acre and resulted in the establishment of tolerances for residues in/on sweet corn ear/forage/stover at 0.01 - 0.09 ppm. Adequate field rotational crop data conducted at seasonal rates >0.228 lb ai/acre are not available. Based on the available data, HED concludes that the following rotational crops restrictions are appropriate (revised Section B is requested): (1) application rates ≤ 0.228 lbs ai/acre/season - labeled crops may be planted immediately

and sweet corn may be planted 180 day s after application; rotation to any other crop is prohibited and (2) application rates > 0.228 lbs ai/acre/season - treated field may onl y be rotated to a labeled crop. In order to fulfill the geographical data requirements specified in OCSPP 860.1500 for sweet corn, HED requests that the petitioner submit the following additional field rotational crop data (trials should employ

a seasonal rate of 0.228 lb ai/acre): sweet corn

– NAFTA Growing Zones 1 (n=2), 3 (n=1), 10 (n=1), 11 (n=1), and 12 (n=1). These data were previously requested and remain outstanding (D388603, T. Bloem, 16 - Jun - 2011). If the petitioner would like to permit rotation to sweet corn following application at a higher rate and/or a different interval, then a full set of field rotational crop data conducted at the desired rate and interval should be submitted. **Magnitude of the Residue -**  **Livestock :**  The petitioner previousl y submitted adequate poultry and ruminant feeding studies (D340513, T. Bloem, 11 - Mar - 2009; D415068, T. Bloem, 23 - Apr - 2013 ). Based on these data and the current maximum reasonably- balanced dietary burdens (MRBDs), HED concludes that the livestock tolerances listed in Table 2.2.2.1 should be established. **5.3 Drinking**  **Water Residue Profile** Table 5 .3.1 is a summary of worst case flutriafol per se surface - /ground - water estimated drinking water concentrations (EDWCs) when considering all pro posed/registered uses ( EFED; D 412882 , J. Wolf, 29 - Oct - 201 3 ). The water estimates were incorporated directl y into the dietary exposure analysis via the water sources direct (all sources) and indirect (all sources) commodities. The water models and their description are available at the EPA internet site: http://www.epa.gov/oppefed1/m odels/water/ . **Table 5 .3.1**  **: 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 ) a pples (6 x 0.114 lbs ai/acre at 7 day intervals) 3 acute 40.55 chronic 4.03 1 Pesticide Root Zone Model - Groundwater (PRZM - GW). 2 FQPA Index Reservoir Screening Tool (FIRST ver. 1.1.1). 3 The initially proposed application rate for apple which is higher than what was registered (D380493, T. Bloem, 16 - Jun - 2011) .Flutriafol Human Health Risk Assessment D4 1584 9

Page 20 of 35 

### 5.4 **Dietary (Food + Drinking Water)**  **Risk Assessment** The following text concerns exposure and risk to flutriafol and those metabolites identified as being toxicologically

the same as flutriafol. For information concerning exposure and risk to T and TA/TAA/TLA, which HED has determined to be toxicologically different from flutriafol, see the Aggregate Section (7.0). Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM - FCID (ver. 3.16) which incorporates the food consumption data from USDA NHANES/WWEIA ( 2003 - 2008). The acute and chronic analy ses 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 processin g studies have been submitted which indicate that tolerances for residues in/on apple juice, grape juice, dried prunes, and tomato puree are unnecessary and since tolerances for residues in/on raisin and tomato paste tolerances are established, the DEEM (ver . 7.81) default processing factors for these commodities were reduced to 1. The DEEM default processing factors were retained for the remaining relevant commodities. The resulting acute (≤44 % aPAD; females 13 - 49 years o ccupied the highest % of the aPAD and chronic (≤ 74 % cPAD; children (1 - 2 years old) had the highest exposure ) dietary risk estimates are not of concern to HED. Table 5.4 .1 is a summary

of the acute and chronic dietary risk estimates. **Table 5.4.1**  **: Summary of the Acute and Chronic Dietary Exposure and Risk.** 

Population aPAD

(mg/kg/day) Exposure

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

(mg/kg/day) %cPAD General U.S. Population 2.5 0.039637 1.6

0.05 0.013176 26 All Infants (<1 year old) 0.076724 3.1 0.023836 48 Children 1 - 2 years old 0.086479 3.5 **0.037200 74**  Children 3 - 5 years old 0.078018 3.1 0.028287 57 Children 6 - 12 years old 0.046496 1.9 0.016557 33 Youth 13 - 19 years old 0.027534 1.1 0.009270 19 Adults 20 - 49 years old 0.032401 1.3 0.010957 22 Adults 50 - 99 years old 0.032371 1.3 0.011695 23 Females 13 - 49 years old 0.075 **0.033040 44**  0.010990 22 1 95 th percentile (tier 1 analysis).Flutriafol Human Health Risk Assessment D4 1584 9

Page 21 of 3 5 

### 6.0 **Residential (Non -**  **Occupational) Exposure/Risk Characterization** There are no residential uses proposed or currently registered for flutriafol. Therefore, residential handler and post - application exposure/risk were not assessed. **6.1 Spray Drift**  Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularl y 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) emplo yed for flutriafol. The Agency h as been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call - In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to devel op the best spray drift management practices (see the Agency ’s Spray Drift website for more information; http://www.epa.gov/opp00001/factsheets/spraydrift.htm) The Agency is also taking means to quantitatively and qualitatively address spray

drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift ® and chemical specific properties of pesticides. The potential for spray drift will be quantitatively

evaluated for each pesticide during the Registration Review process , which ensures that all uses for that pesticide will be considered concurrentl y. **6.2 Residential Bystander Post**  **- Application Inhalation E**  **xposure** Volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analy sis (http://www.regulations.gov/#!docketDetail;D=EPA - HQ - OPP 2014 - 0219). During Registration Review, the Agency will utilize this analy sis to determine if data (i.e., flux studies, route - specific inhalation toxicological studies) or further analy sis is required for specific chemicals.Flutriafol Human Health Risk Assessment D4 1584 9

Page 22 of 35 

### 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) expos ures, the aggregate assessment need onl y consider food and water. Since the dietary exposure anal ys is included both food and water, the discussion and exposure estimates presented in Section 5.4 represent aggregate acute and chronic exposure to flutriafol and those metabolites identified as being toxicologically identical to flutriafol. All aggregate flutriafol risk estimates are not of concern to HED. Application of flutriafol also results in exposure to T and TA/TAA/TLA . These compounds are considered to be toxicologically different from flutriafol. HED previously conducted an aggregate exposure anal ysis for these compounds, which resulted in aggregate exposure less than HED’s level of concern ( D414952, T. Morton, 24 - Oct - 2013 ). The proposed new use s and label amendments do not require a revision to this most recent aggregate assessment. **8.0 Cumulative Exposure/Risk Characterization**  Flutriafol is a member of the triazole - containing class of pesticides. Although conazoles act similarly in plants (fungi) by

inhibiting ergosterol biosy nthesis, 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 nee ded to establish that the chemicals operate b y 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 thy roid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation. It is not clearl y understood whether these biochemical events are directly connected to their toxicological outcomes. Thus, there is currentl y 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 htt p://www.epa.gov/pesticides/cumulative .Flutriafol Human Health Risk Assessment D4 1584 9

Page 23 of 35 

### 9.0 **Occupational Exposure/Risk Characterization** D416213, K. Lowe, 24 - Jan - 2014 

### Based on the proposed new uses, it has been determined that the potential exposure scenarios that will need to be assessed include short - and intermediate - term occupational exposures (handler and post - application). Itis HED policy to use the best availab le data to assess exposure. Several sources of generic data were used in this assessment as surrogate data in the absence of ch emical - specific data, including the PHED 1.1, AHETF database, and ARTF database . Some of these data are proprietary , and subjec t to the data protection provisions of FIFRA. A dditional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website (http://www.epa.gov/pesticides/science/handlerexposure - data.html ). **9.1 Handler Risk Assessment**  HED uses the term handlers to describe those individuals who are involved in the pesticide application process. Based on the anticipated use patterns, and the current labeling regarding ty pes of equipment and techniques that can be used, occupational handler exposure is expected. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenari os: (1) mixing/loading liquids for aerial and groundboom applications; (2) applying spray s via aerial and groundboom equipment; and (3) flagging for aerial applications. Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were similar. The occupational handler exposure and risk estimates indicate that the short - and intermediate term dermal and inhalation combined MOEs are not of concern to HED (i.e., MOE > 100) with the use of chemical - resistant gloves as personal protective equipment as directed by the label. At the baseline level of personal protection (i.e., no gloves and no respirator), only one scenario results in a risk estimate below the LOC with a combined (dermal + inhalation) MOE of 82; this scenario is mixing/loading a liquid formulation for aerial application to high acreage crops. With the addition of gloves, the combined dermal + inhalation MOE is 470, which is not of concern. All other scenarios result in risk estimates greater than 220 with baseline attire. Table 9.1.1 is a summary of the handler exposure and risk estimates.Flutriafol Human Health Risk Assessment D 41 5849

Page 24 of 35 **Table 9**  **.1.1 :**  **Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Flutriafol** . Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/ acre) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Total

(LOC = 100) Mitigation Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8 Mixer/Loader Aerial app . of liquid formulation C rop Groups 4 and 5 220 (baseline) 0.219

(baseline) 0.114 350 0.0267 280 0.000127 59,000 280 Cotton and Grain Sorghum 1200 0.0916 **82** 0.000435 17,000 **82** 37.6 (single layer w/ gloves) 0.0156 480 470 Groundboom app . of liquid formulation Crop Groups 4 and 5 220 (baseline) 0.114 80 0.00612 1,200 0.000029 260,000 1,200

Grain Sorghum 200 0.0153 490 0.0000723 100,000 490 Cotton 0.26 200 0.0347 220 0.000165 45,000 220 Applicator Aerial spray app . Crop Groups 4 and 5 2.08 (engineering control) 0.0049

(engineering control) 0.114 350 0.000253 30,000 0.00000284 2,600,000 30,000 Cotton and Grain Sorghum 1200 0.000867 8,700 0.00000971 770,000 8,600 Groundboom spray app . Crop Groups 4 and 5 78.6 (baseline) 0.34

(baseline) 0.114 80 0.00218 3,400 0.0000449 170,000 3,300 Grain Sorghum 0.114 200 0.00545 1,400 0.000112 67,000 1,400 Cotton 0.26 200 0.0124 600 0.000257 29,000 590 Flagger Flagger for aerial spray app . Crop Groups 4 and 5; Grain

Sorghum; and Cotton 11 (baseline) 0.35

(baseline) 0.114 350 0.00134 5,600 0.000203 37,000 4,900 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, PPE (gloves), Eng. Controls. 2 Based on proposed labels. 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre) × Area Treated (A/day) × DAF (21 %) ÷ BW (69 kg). 5 Dermal MOE = Dermal NOAEL (7.5 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre) × Area Treated (A/day) x inhalation absorption (100%) ÷ BW (69 kg). 7 Inhalation MOE = I

nhalation NOAEL (7.5 mg/kg/day) ÷ I nhalation Dose (mg/kg/day). 8 Total MOE = NO AE L (7.5 mg/kg/day) ÷ (Dermal Dose + I nhalation Dose).Flutriafol Human Health Risk Assessment D 41 5849

Page 25 of 35 

### 9.2 **Post -** **Application Risk Assessment** HED uses the term post - application to describe exposures (inhalation and dermal) that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re - entry exposure). Such exposures may occur when workers enter previously

treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the ty pe of activ ity , the nature of the crop or target that was treated, the ty pe of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for p ost application exposure. **9.2.1 Inhalation**  **Post -** **Application Risk Assessment** There are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously treated fields . These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, F ungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency has evaluated the SAP report and has develop ed a Volatilization Screening Tool and a subsequent Volatilization Screening Analy sis (http://www.regulations.gov/#!docketDetail;D=EPA - HQ OPP - 2014 - 0219 ). During Registration Review, the Agency will utilize this anal ys is to determine if data (i.e., flux studies, route - specific inhalation toxicological studies) or further anal ys is is required for specific chemicals. In addition, the Agency

is continuing to evaluate the available post - application inhalation exposure data generated by the Agricultural Reentry Task Force. 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. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application inhalation exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most oc cupational post - application inhalation exposure scenarios.Flutriafol Human Health Risk Assessment D 41 5849

Page 26 of 35 

### 9.2.2 **Dermal Post -** **Application Risk Assessment** Short - and intermediate post - application dermal exposure is anticipated for the proposed crops with expected scenarios and resulting exposures and MOEs summarized in Table 9 .2.2. 1 . All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 230 to 4,600) on day 0 (12 hours after application ; proposed REI ) and, therefore, are not of concern to HED. In accordance with 40 CFR158, dislodg eable foliar residue (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 foliage. In the absence of chemical - specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an anal ys is of a number of DFR studies, which resulted in the selection of a rev ised default values for the fraction of the application rate available for transfer after a foliar application (F AR

### ). These values are based on an analy sis of 19 DFR studies. Since that time, the Agricultural Re - entry Task Force has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chry santhemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR 

### 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; formulation; field conditions in the studie s; weather conditions (e.g., humidity ); or many

other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### 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 flutriafol, 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 F AR 

### 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 p otential uncertainty . For example, when assessing residential and occupational post - application 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 exp osure duration (i.e., 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 b y 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 m inimal in comparison to the level of concern (i.e., the calculated MOE is greater than 2 times higher than the level of concern, MOE = 230 compared to the LOC of 100); EPA is waiving the 40 CFR DFR data requirement. In this instance, it is unlikely that c hemical - specific DFR data would be needed to further refine exposure assessments or would add appreciabl y to our overall understanding of the availability of dislodgeable foliar pesticide residues for flutriafol. **Table 9.2.2.1: Occupational Post -**  **applicat ion Non**  **- Cancer Exposure and Risk Estimates for Flutriafol.** Flutriafol Human Health Risk Assessment D 41 5849

Page 27 of 35 Crop/Site Activities Transfer Coefficient (cm2/hr) Proposed

Application Rate (lb ai/A) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

(LOC = 100) Short - and Intermediate - term Crop groups 4 and 5 Scouting, Hand

harvesting, Hand weeding, Topping 4,200 0.114 0.32 0.033 230 Cotton and Grain Sorghum Scouting 210 0.002 4,600 1 DFR = Application Rate × F × (1 - D) t × 4.54E8 μg/lb × 2.47E - 8 acre/cm2 ; where F = 0.25 and D = 0.10 per day. 2 Daily Dermal Dose = [DFR (μg/cm2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (21%)]  BW (69 kg). 3 MOE = POD (7.5 mg/kg/day) / Daily Dermal Dose. 

### 9.2.2 **Restricted Entry Interval** The REI specified on the proposed label is based on the acute toxicity of flutriafol. Flutriafol has low acute toxicity

via the oral, dermal and inhalation routes (Toxicity Categories III and IV). Flutriafol is minimally

irritating to the eyes (Toxicity Category III) and is not a dermal irritant (Toxicity Category IV). Flutriafol was not shown to be a skin sensitizer when tested in guinea pigs (Buehler method). Short - and intermediate - term post - application risk estimates were not a concern on day

0 (12 hours following application) for all post - application activities. Under 40 CFR 156.208(c)(2)(iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12 - hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REIof 12 hours is adequate to protect agricultural workers from post - application exposures to flutriafol. RDI: RAB1 ( 11 - Jun - 201 4 ) Appendix A. Toxicology Profile and Executive Summaries Appendix B. Chemical Names and StructuresFlutriafol Human Health Risk Assessment D 41 5849

Page 28 of 35 

### 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 proto cols 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

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21 - Day Dermal 870.3250 90 - Day Dermal 870.3465 90 - Day Inhalation yes yes yes no no yes

yes yes

-

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

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

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation - bacterial 870.5300 Mutagenicity

— Gene Mutation - mammalian 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations 870.5xxx Mutagenicity

—Other Genotoxic Effects yes yes yes yes yes

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

- yes yes

- 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes yes yes yes

yes yes Special Studies for Ocular Effects

Acute Oral (rat) Subchronic Oral (rat) Six - month Oral (dog) no no no -

-

- **Table A.2: Acute Toxicity Profile –**  **Flutriafol.** Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral (rat) 47090336 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 (rabbit) 47090339 Minimally irritating III 870.2500 Primary dermal irritation (rabbit) 47090341 Not a dermal irritant IV 870.2600 Dermal sensitization (mouse) 47090343 Not a sensitizer -Flutriafol Human Health Risk Assessment D 41 5849

Page 29 of 35 **Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile –**  **Flutriafol.** Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3050 28 - Day oral toxicity

(rat) 47090344 (1982)

Acceptable/non - guideline 0, 100, 300, 800, 2000, or 5000 ppm (0, 10, 30, 80, 200, and 500 mg/kg/day) NOAEL = 800 ppm (80 mg/kg/day). LOAEL = 2000 ppm (200 mg/kg/day), based on liver toxicity (increased weight, centrilobular hepatocellular hypertrophy, fatty change, hydropic degeneration, smooth endoplasmic reticulum proliferation, and increased aminopyrine -N - demethylase activity) in both sexes and decreased body- weight gain and food consumption in males. 870.3100 90 - Day oral toxicity

(rat) 47090345 (1982)

Acceptable/guideline 0, 20, 200, or 2000 ppm M: 0, 1.5, 14, and 158 mg/kg/day) F: 0, 1.6, 22, and 145 mg/kg/day NOAEL = 200 ppm (14/22 mg/kg/day in M/F) LOAEL = 2000 ppm (158/145 mg/kg/day in M/F), based on decreased body- weight gain, decreased food consumption and liver toxicity (increased absolute and adjusted liver weights, increased endoplasmic reticulum proliferation in the males, and increased APDM activity). 870.3150 90 - Day oral toxicity

(dog) 47090346 (1982)

Acceptable/guideline 0, 1, 5, or 15 mg/kg bw/day NOAEL = 5 mg/kg/day . LOAEL = 15 mg/kg/day, based on adverse liver findings (increases in organ weight, alkaline phosphatase, aminopyrine N - demethylase activity, and incidence of hemosiderin - laden Kupffer cells) in both sexes, spleens with hemosiderin content slightly higher than controls in the males, and decreased cumulative body- weight gains and increased triglycerides in the females. 870.3200 28 - Day dermal toxicity

(rat) 47090347 (2007)

Acceptable/guideline 0, 250, 500, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day. LOAEL was not established. 870.3700a Prenatal developmental

(rat) 47090349 (1982)

Acceptable/guideline 0, 10, 50, or 125 mg/kg/day **Maternal** NOAEL = 50 mg/kg/day. LOAEL = 125 mg/kg/day, based on increased incidence of ventral/genital staining of the fur and decreased maternal body- weight gains and food consumption. **Developmental** NOAEL = 10 mg/kg/day. LOAEL = 50 mg/kg/day, based on delayed ossification or non - ossification of the skeleton in the fetuses. 870.3700a Prenatal developmental

(rat) 47521303 (2008)

Acceptable/guideline 0, 2, 5, 10, or 755 mg/kg/day **Maternal** NOAEL = 10 mg/kg/day. LOAEL = 75 mg/kg/day, based on decreased body- weight gains and food consumption. **Developmental** NOAEL = 10 mg/kg/day. LOAEL = 75 mg/kg/day, based on increased late resorptions; malformations (cleft palate and multiple hyoid malformations) and variations in the hyoid; variations in the maxilla/mandible, rudimentary and long cervical ribs, pelvic girdle, and radius/ulna; numerous skeletal retardations detailed above and corresponding decrease in fetal weights. 870.3700b Prenatal developmental

(rabbit) 47090350 (1982)

Acceptable/guideline 0, 2.5, 7.5, or 15 mg/kg/day **Maternal** NOAEL = 7.5 mg/kg/day. LOAEL = 15 mg/kg/day, based on decreased corrected and uncorrected body- weight gains and food consumption. **Developmental** NOAEL = 7.5 mg/kg/day. LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post implantation loss.Flutriafol Human Health Risk Assessment D 41 5849

Page 30 of 35 **Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile –**  **Flutriafol.** Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3800 2 - gen. reproduction and

fertility effects (rat) 47090351 (1986)

Acceptable/guideline 0, 60, 240, or 1,000 ppm M: 0, 4.8, 20.6, and 88.7 mg/kg/day) F: 0, 5.5, 21.9, and 103 mg/kg/day **Parental/Systemic** NOAEL = 240 ppm (20.6/21.9 mg/kg/day [M/F]). LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on decreased body- weight gains and food consumption and on effects on the liver (increased liver weights, centrilobular hypertrophy, and fatty change). **Reproductive** NOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]). LOAEL was not determined. **Offspring** NOAEL = 240 ppm (20.6/21.9 mg/kg/day [M/F]). LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on decreased live birth index and litter size and on effects on the liver (fatty change/vacuolization). 870.3800 2 - gen. reproduction and

fertility effects (rat) 48196921, 48196922 (2009)

Acceptable/guideline 0, 30, 80, 150, 300, 1000 ppm 0, 1.8/2.2, 4.8/5.85, 9/10.8, 18.5/22.6, and 62.8/ 77.1 mg/kg bw/day [M/F] **Parental/Systemic** NOAEL = 150 ppm (9/10.8 mg/kg bw/day [M/F]). **Parental/Systemic** LOAEL = 300 ppm (18.2/22.6 mg/kg bw/day [M/F]) based upon increased relative liver weights, fatty deposits in the liver in both sexes as well as hepatocellular hypertrophy in males. **Reproductive** NOAEL = 300 ppm (18.2/22.6 mg/kg bw/day [M/F]. **Reproductive** LOAEL was not observed. **Offspring** NOAEL = 15 0 ppm (9/10.8 mg/kg bw/day [M/F]). **Offspring** LOAEL = 300 ppm (18.5/22.6 mg/kg bw/day [M/F]) based upon increased pup mortality in the F1 pups at the first litter check and 0 - 4 postnatal days. 870.4100 Chronic toxicity (1

year; dog) 47090353 (1988) Acceptable/guideline 0, 1, 5, or 20 mg/kg/day NOAEL = 5 mg/kg/day. LOAEL = 20 mg/kg/day, based on: adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase , albumin and triglycerides), increased adrenal cortical vacuolization of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes; mild anemia (characterized by decreased hemoglobin, hematocrit, and red blood cell co unt) in the males; and initial body weight losses, decreased cumulative body- weight gains, and increased adrenal weights in the females. 870.4200 Carcinogenicity

(mouse) 47090354 (1988)

Acceptable/guideline 0 (two control groups), 10, 50, or 200 ppm M : 0, (0, 1.1, 5.9, and 24 mg/kg/day) F: 0, 1.4, 7.4, and 31 mg/kg/day NOAEL = 50 ppm (5.9/7.4 mg/kg/day in M/F). LOAEL = 200 ppm (24/31 mg/kg/day in M/F), based on hepatotoxicity (increased fatty change) in both sexes. **No evidence of carcinogenicity**

870.4300 Combined Chronic

Toxicity/ Carcinogenicity (rat) 47090352 (1986)

Acceptable/guideline 0, 20, 200, or 2000 ppm M: 0, 1.02, 10.0, and 102 mg/kg/day) F: 0, 1.27,12.2, and 122 mg/kg/day NOAEL = 200 ppm (10.0/12.2 mg/kg/day in males/females). LOAEL = 2000 ppm (102/122 mg/kg/day in males/females), based on adverse liver effects (increased liver weights, fatty change, bile duct proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer cells and centrilobular hypertrophy), and clinic al chemistry findings. **No evidence of carcinogenicity**Flutriafol Human Health Risk Assessment D 41 5849

Page 31 of 35 **Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile –**  **Flutriafol.** Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.5100 In vitro Bacterial Gene

Mutation (Salmonella typhimurium)/ mammalian activation gene mutation assay 47090401 (1988)

Acceptable/guideline 0, 1.6, 8, 40, 200, 1000, or 5000 μg/plate ( Trial 1) or 0, 8, 40, 200, 1000, 2500, or 5000 μg/plate (Trial 2); Both trials were performed w/wo S9 - activation There were no marked increases in the mean number of revertants/plate in any strain. There was no evidence of induced mutant colonies over background.

870.5300 In Vitro Gene Mutation

assay in mouse lymphoma cells 47090402 (1986)

Acceptable/guideline 0, 10, 33, 100, 333, or 1000 μg/mL (+S9, Trial 1); 0, 150, 300, 450, 600, or 750 μg/mL ( - S9, Trial 1); 0, 150, 300, 450, 600, 750, 900, 1050, or 1200 μg/mL (+S9, Trial 2); or 0, 200, 300, 400, 500, 600, 700, or 800 μg/mL ( - S9, Trial 2) There was a dose - related increase in mutant frequency (7.0 - 9.0 x 10 - 5 treated vs. 3.0 x 10 - 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. 5x 10 - 5 treated vs. 1.2 x 10 - 5 controls) in Trial 2 attributable to severe cytotoxic ity (2% relative survival). However, the increases in mutant frequency did not achieve the threshold value for a positive response (>10 x 10 - 5 ) in either trial and there was no marked increase in absolute mutant numbers at 750 μg/mL in Trial 2. In the ab sence of S9, there were no marked increases in mutant frequency or absolute mutant numbers compared to controls in either trial. There was no convincing evidence of induced mutant colonies over background in the presence or absence of S9 - activation. 870. 5300 In Vitro Gene Mutation

assay in mouse lymphoma cells 48196918 (2006)

Acceptable/guideline 0, 25, 50, 100, 200, 400 and 600 μg/mL (±S9, Trial 1); 0, 12.5, 25, 50, 100, 200, 300 or 400 μg/mL ( - S9, Trial 1); 0, 200, 300, 325, 350, 375, or 400 μg/mL (+S9, Trial 2) ( - S9, Trial 2) The mutagenicity criterion (threshold) of 126 colonies per 106 cells above the solvent control was not reached for any valid data at any test concentration, with or without metabolic activation. Although linear regression an alysis found a significant (p<0.05) dose dependent trend of the mutation frequency in Experiment 1 (culture 1, with metabolic activation), Experiment 2 (culture 1), and Experiment 3 (cultures 1 and 2), these statistical results were considered biologically irrelevant because the threshold for mutagenicity was not exceeded and all absolute values were within the range of historical negative and solvent controls. 870.5375 In vitro Mammalian

Cy togenetics (Chromosomal Aberration Assay in Human Peripheral Bl ood 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

Cy togenetics

– [B one Marrow Chromosomal Aberration Test 47090404 (1982) Acceptable/guideline 0, 15, 70, or 150 mg/kg There was no e vidence of chromosome aberration induced over background. 870.5395 In Vivo Mammalian

Cy togenetics - Erythrocyte Micronucleus Assay in Mice 47090405 (1986)

Acceptable/guideline 0, 93.8, or 150 mg/kg Decreased (p<0.01) polychromatic erythrocyte to normochromatic erythrocyte ratios (PCE:NCE) were observed in both doses at all time points, indicating that the test material was toxic to the bone marrow. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time. 870.5450 Dominant Lethal Assay

– Mice 47090406 (1982) Acceptable/guideline 0, 25, 50, or 100 mg/kg/day (total doses of 0, 125, 250, or 500 mg/kg) Mortality (3/15 males) was noted at 100 mg/kg/day during dosing. Sl ight decreases (p<0.05) in body weight were observed at 50 mg/kg/day and above during dosing. There were no treatment - related effects on fertility, mean number of implantations, or the number of early or late deaths. There was no time - related positive re sponse of increased pre - or post - implantation loss compared to controls.Flutriafol Human Health Risk Assessment D 41 5849

Page 32 of 35 **Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile –**  **Flutriafol.** Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.5550 Unscheduled DNA

Synthesis in Primary Rat Hepatocytes/Mammalia n Cell 47090407 (2003) Acceptable/guideline 0, 250, 500, or 1000 mg/kg The net nuclear grain (NNG) counts in the treated animals (

– 3.42 to

–2.64) were well below the threshold of ≥5 NNG needed for a positive response, and no increase in the mean percent of cells in repair was observed. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced. 870.6200a Acute neurotoxicity

screening battery 47090408 (2005)

Acceptable/guideline 0, 125, 250, or 750 mg/kg NOAEL = 250 mg/kg. LOAEL = 750 mg/kg, based on decreased body weight, body- weight gain, absolute and relative food consumption, and clinical signs of toxicity, indicative of a moribund condition, in both sexes: dehydration, urine - stained abdominal fur, ungroomed coat, ptosis , decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, scant feces; in males: red or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females: piloerection and bradypnea, and signs of neurotoxicity: hunched posture in females and ataxia in males. 870.6200b Subchronic

Neurotoxicity

– Feeding Study in Rats 47090410 (2007)

Acceptable/guideline 0, 500, 1500, or 3000 ppm (0/0, 2 8.9/32.6, 84.3/97.6, and 172.1/185.0 mg/kg/day [M/F]) NOAEL = 1500 ppm (84.3/97.6 mg/kg/day [M/F]). LOAEL = 3000 ppm (172.1/185.0 mg/kg/day [M/F]) based on decreased body- weight gain, absolute and relative food consumption; and decreased hindlimb grip strength in males. 870.7485 Metabolism and

pharmacokinetics (rat) 47090414 (2004),

47090412 (2006) Acceptable/guideline 5 or 250 mg/kg More than 78% of the dose was recovered in the bile and urine. Absorption was similar between sexes and between single and multiple dose regimes. Absorption is extensive. The dose was mostly eliminated within 48 hours. Only 0.04 - 0.05% of the dose was fo und in the expired carbon dioxide. Most of the radioactivity was excreted in the bile (47 - 79% of the dose). The excretion profile was similar between sexes. In the blood, radioactivity partitioned into the red blood cells. In both sexes and all groups, concentrations of radioactivity were relatively high in whole blood, liver, and kidneys. Other organs with high concentrations included the adrenal glands, spleen, and pituitary. The distribution profiles were similar between species, dose level, and single vs. multiple dose regime. In the whole blood, the concentrations were proportional to the dose. The total amount of radioactivity isolated in the tissues and carcass was <1 - 3%. Bioaccumulation was considered unlikely. The parent was isolated in only trace amounts in the urine and feces and more than 19 metabolites were isolated, indicating extensive metabolism. Metabolism profiles were similar between sexes. The metabolic profiles were similar regardless of the matrix (feces, urine, or bile), the dose, and the sex. The primary site for metabolism was the 2 - fluorophenyl ring. The initial metabolic step was epoxidation followed by either rearrangement to form the dihydrodiol isomers or to form hydroxy or dihydroxy metabolites. The hydroxyl groups on these primary metabolites may then be either conjugated with glucuronic acid or methylated. A second, minor route for metabolism of flutriafol was via the removal of the triazole ring to form 1 - (2 fluorophenyl) - 1 - (4 - fluorophenyl) - ethandiol, which is then conjugated with glucuronic acid.Flutriafol Human Health Risk Assessment D 41 5849

Page 33 of 35 **Table A.3: Subchronic and Chronic Toxicity and Genotoxicity Profile –**  **Flutriafol.** Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.7600 In vivo dermal

penetration (rat) 47090415 (2006)

Acceptable/guideline 0.002, 0.02, or 0.2 mg/cm2 skin were tested (10 μl/cm2 skin), and actual doses were 0.00208, 0.0201, and 0.2154 mg/cm2 skin Dermal ranged up to 15.8% of the applied dose. Absorption was minimal with only 4 h of exposure. Absorbable radioactivity (radioactivity in the skin at the application site and the adjacent skin) was minimal in groups that were exposed for 10 h and evaluated fo r an additional 158 h post - exposure. Thus, almost all of the dose isolated in the skin will be absorbed. Considering the sum of absorbable and absorbed doses, 4 - 37% of the applied dose was recovered in the treatment groups (11%). Absorption rate constants were calculated as 0.236, 0.190, and 0.072 h - 1 for the 2, 20, and 200 μg/cm 2 dose groups. Absorption mechanisms were saturated at the high dose. The elimination half

- lives were calculated to be 31, 30, and 37 h for the 2, 20, and 200 μg/cm2 dose group s. A maximum of 36.56% of the applied dose was noted as absorbed/absorbable (observed after 24 h exposure to 2 μg/cm2 ). The dose that is absorbed/absorbable following a 10 h exposure is 16.54%, 21.31% and 11.39%, respectively, at 2, 20, and 200 μg/cm2

. 870.7800 Immunotoxicity (mice) 48360301 (2011) Acceptable/guideline 0, 50, 250, 500, 1000 ppm [F] (0, 9.8, 46.8, and 208 mg/kg/day [F] Systemic NOEAL = 9.8 mg/kg/day . Systemic LOAEL = 46.8 mg/kg/day) based on increased absolute and relative liver weights and hematological effects. Immunotoxicity NOAEL = 208 mg/kg/day . Immunotoxicity LOAEL was not established.Flutriafol Human Health Risk Assessment D 41 5849

Page 34 of 35 

### Appendix B. Chemical Names and Structures **Comm on name**  **Chemical name Chemical structure** 

Flutriafol (±) - α - (2 - fluorophenyl) - α - (4 - fluorophenyl) - 1 H

- 1,2,4 - triazole - 1 - ethanol N N N

F O H F

M1B 1 - (2 - fluoro - 4 - hydroxyphenyl) - 1 - (4 - fluorophenyl) - 2 - (1 H

- 1,2,4 - triazol - 1 - yl)ethanol N N N

F O H F

O H M28 glucoside of a flutriafol metabolite, possible a derivative hydroxylated on one phenyl ring 

### -- 1,2,4 - Triazole (T) 1 H - 1,2,4 - triazole N N H N Triazolylalanine (TA) 2 - amino - 3 - (1 H - 1,2,4 - triazol - 1 - yl)propanoic acid NH 2 O H O N N N Triazolylacetic acid (TAA) 1 H - 1,2,4 - triazol - 1 - ylacetic acid 

### O H O N N N Triazole lactic acid (TLA) 1,2,4 - triazole - 1 - lactic acid

Hydroxy flutriafol glucuronide (HFG; M3) -- O H O H H O

O H O O O

F O H N N N F O HFlutriafol Human Health Risk Assessment D 41 5849

Page 35 of 35 **Comm on name**  **Chemical name Chemical structure**  Dihydroxy flutriafol (DHF; M3e) --

Flutriafol glucuronide (FG; M4) --

Methoxy flutriafol glucuronide (MFG; M7) --

Flutriafol sulfate (FS; M10) -- O H

F O H N N N F O H

O H O H H O

O H O O O

O H N N N F

F

C H 3 O

O H N N N

F F

O O H H O O H O H

O

O

H O N N N

F O S H O O O

F