                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460

                                                 	OFFICE OF CHEMICAL SAFETY AND
                               		POLLUTION PREVENTION

MEMORANDUM

Date:		16-December-2014

            Subject:		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 Leafy Vegetables Crop Group 5.

PC Code:  128940
DP Barcode:  D415849
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
TXR No.:  not applicable
CAS No.:  76674-21-0
MRID No:  not applicable
40 CFR:  180.629

From:		Tom Bloem, Chemist
      Kelly M. Lowe, Environmental Scientist
      Anwar Y. Dunbar, Ph.D., Pharmacologist
      Risk Assessment Branch 1 (RAB1)
            Health Effects Division (HED; 7509P)

Through:	Charles W. Smith III, Branch Chief
	George F. Kramer, Ph.D., Senior Chemist
            RAB1/HED (7509P)

To:		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-fluorophenyl)-1H-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 aggregate risk assessment, dietary risk assessment, and residue chemistry review were provided by Tom Bloem (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), the occupational/residential exposure (ORE) and risk assessment were provided by Kelly Lowe (RAB1), and the drinking water assessment was provided by James K. Wolf of the Environmental Fate and Effects Division (EFED).
                               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	Physical/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	Completeness 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	34

1.0	Executive Summary

Flutriafol ((+-)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethanol) is a contact and systemic Group 3 triazole fungicide which acts primarily as an inhibitor of ergosterol biosynthesis, thereby interfering with synthesis of fungal cell membranes.  Tolerances for residues of flutriafol are established in/on numerous commodities, including livestock commodities, at 0.01-30 ppm.  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-2014).

Cheminova, Inc. requested Section 3 Registrations and the establishment of permanent tolerances for residues of flutriafol in/on cotton; 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 <IP_ADDRESS> for proposed tolerances).

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

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-generation 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 (external, visceral, and skeletal malformations; embryo lethality; skeletal variations; a generalized delay in fetal development; and fewer live fetuses) were more severe than the decreased food consumption and body-weight gains observed in the dams.  For rabbits, intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals.  In the two-generation reproduction studies, a qualitative susceptibility was also seen.  Effects in the offspring [decreased litter size and percentage of live births (increased pup mortality) and liver toxicity] can be attributed to the systemic toxicity of the parental animals (decreased body weight and food consumption and liver toxicity).

Effects that may be considered signs of neurotoxicity (decreased motor activity and hindlimb grip strength, ptosis, lost righting reflex, hunched posture, and ataxia) were reported in the acute and subchronic neurotoxicity studies at the highest dose only.  These effects, however, were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity.  This conclusion is further reinforced by the observation that there was no evidence of neurotoxicity in any additional short-term or long-term studies in rats, mice, and dogs.  It is also important to note that in the acute neurotoxicity study, for animals that did not die in the study or were sacrificed in extremis, all effects resolved by Day 8.
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.  Flutriafol is classified as "not likely to be carcinogenic to humans" based on the results of the carcinogenicity studies in rats and mice.

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision:  The flutriafol risk assessment team concludes that the 10x FQPA SF should be reduced to 1x since the toxicology database is 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 of the dietary exposure analyses are unlikely to underestimate exposure (tolerance-level residues and 100% crop treated; no residential uses).

Dose Response Assessment:  Tables 4.4.1 and 4.4.2 provides a summary of toxicological doses and endpoints used for assessment of dietary and occupational exposure, respectively, to flutriafol.  The rabbit developmental study (NOAEL = 7.5 mg/kg/day) was selected for assessment of acute dietary (females 13-49 years old) and short-/intermediate-term occupational dermal/inhalation exposures.  The 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 selected for assessment of chronic dietary exposure (NOAEL = 5 mg/kg/day).  For all exposure scenarios, a 100x uncertainty factor (UF) was applied (10x interspecies extrapolation; 10x 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 analyses assumed tolerance-level residues or tolerance-level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates.  Since adequate processing studies have been submitted which indicate that tolerances for residues in/on apple juice, grape juice, dried prunes, and tomato puree are unnecessary and since tolerances for residues in/on raisins and tomato paste are established, the DEEM (ver. 7.81) default processing factors for these commodities were reduced to 1.  The DEEM (ver. 7.81) default processing factors 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) dietary risk estimates are not of concern to HED.

Residential (Non-Occupational) Exposure and Risk Assessment:  There are no residential uses proposed or currently registered for flutriafol.  Therefore, residential handler and post-application exposure/risk were not assessed.

Aggregate-Risk Estimates:  In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources:  food, drinking water, and residential exposures.  Because there are no uses for flutriafol that result in residential (non-occupational) exposures, the aggregate assessment need only consider food and drinking water.  Since the dietary exposure analysis included both food and drinking water, the discussion and exposure estimates presented in the dietary section represent aggregate acute and chronic exposure to 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 (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 analysis for these compounds, which resulted in aggregate exposure less than HED's level of concern (D414952, 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 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 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 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).  Therefore, the acute toxicity categories for this chemical require a 12-hour REI under 40 CFR 156.208 (c)(2)(iii).  The 12-hour REI, which currently appears on the 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 need 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 assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations."

Review of Human Research:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the following Agency websites:  http://www.epa.gov/ pesticides/science/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 databases 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 analyses (<=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 analyze the ruminant feeding study samples for some or all of the ROC for risk assessment (storage stability data will also be required).  HED notes that the ruminant residue estimates employed in the dietary analyses are conservative as they are comparable to, or significantly higher than, the TRRs from the metabolism study (30-ppm dietary burden) and due to the conservative nature of the dietary burden calculations.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

Tolerance Enforcement Method - Plants:  Adequate methods are available to enforce the currently established plant tolerances (D362421, T. Bloem, 11-Mar-2009; D340513, T. Bloem, 11-Mar-2009; D388603, T. Bloem, 16-Jun-2011).  The flutriafol method employed in the magnitude of the residues studies is based on the current tolerance enforcement method.  Since adequate method validation data were provided as part of the magnitude of the residue studies, HED concludes that the current tolerance enforcement method is adequate to enforce the tolerances associated with this petition.  In addition, the QuEChERS method has been shown to adequately quantify residues of flutriafol (http://www.crl-pesticides.eu/library/docs/fv/CRLFV_Multiresidue_methods.pdf).

Tolerance Enforcement Method - Livestock:  Method ICIA AM00306 (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.  Since adequate method validation data were provided as part of these studies, HED concludes that the current tolerance enforcement method is adequate to enforce the tolerances associated with this petition.

2.2.2	Recommended Tolerances

Table <IP_ADDRESS> 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 <IP_ADDRESS>, the cotton tolerances established in 40 CFR 180.629(d) for residues resulting from crop rotation should be deleted.  HED notes that cotton tolerances 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 <IP_ADDRESS>:  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
                                      7.0

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 10 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 tolerance 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 appropriate.
leafy greens (subgroup 4A), except head lettuce
                                      10
                                      --

vegetable, 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

egg
                                     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 <IP_ADDRESS>.

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/stover, and the following rotational crop restrictions:  (1) application rates <=0.228 lbs ai/acre/season - labeled crops may be planted immediately and cotton and sweet corn may be planted 180 days after application (rotation to any other crop is prohibited) and (2) application rates >0.228 lbs ai/acre/season - treated field may only be rotated to a labeled crop.

3.0	Ingredient Profile

3.1	Chemical Identity

The chemical structure and nomenclature of flutriafol and the triazole metabolites are presented in Tables 3.1.1.

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

                              1,2,4-triazole (T)

                             triazolylalanine (TA)

                          triazolylacetic Acid (TAA)

3.2	Physical/Chemical Properties

Table 3.2.1 is a summary of the physical/chemical properties for flutriafol.  Flutriafol has a low vapor pressure and a low Henry's law constant (9.16 x 10[-12] atm m[3]/mol).

Table 3.2.1:  Physicochemical Properties of Flutriafol.
Melting point/range
--
Not available
pH
6.1 in a 1% aqueous dilution
CSF for Flutriafol Technical dated 3/23/07
Density
0.99 g/cm[3]

Water solubility
95 mg/L at 20 ºC
PP#7F7197 administrative materials
Solvent solubility
At 21 ºC	g/L
1,2-Dichloroethane	19-20
Acetone	116-135
Ethyl acetate	29-34
Methanol	115-134
n-Heptane	<10
Xylene	<10

Vapor pressure
4 x 10[-7] Pa at 20 ºC

Dissociation constant, pKa
2.3 at 25 ºC

Log(KOW)
log POW = 2.3 at 20 ºC

UV/visible absorption spectrum
--
Not available

3.3	Proposed Use Pattern

Cheminova requested Section 3 Registrations for application of flutriafol to cotton; sorghum; leafy vegetables, except Brassica, crop group 4; and Brassica leafy vegetables crop group 5.  Table 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 immediately after application and to sweet corn 180 days 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 by 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 days after application (rotation to any other crop is prohibited) and (2) application rates >0.228 lbs ai/acre/season - treated field may only 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(R) 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(R)
                               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 (Septoria apiicola)

                       Brassica leafy vegetables group 5
Black spot (Alternaria spp.), Cercospora leaf spot (Cercospora spp.), Powdery Mildew (Erysiphe polygoni)
                                 Flutriafol(R)
                               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)

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 leaf); 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, bok choy, Chinese mustard/gai choy); cauliflower; cavalo broccolo; collards; kale; kohlrabi; mustard greens; mustard spinach; and rape 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 directs 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.  Exposure in the residential (non-occupational) setting is not anticipated.  Based on the registered/proposed application scenarios and the results of a fish bioaccumulation study, residues in fish/shellfish are expected to be insignificant (D407105, T. Bloem, 27-Mar-2013; this includes consumption at the subsistence level).  The current action 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 Low-Income Populations," (http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf).  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on 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 analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolism data have been received since the last flutriafol risk assessment (D411360, T. Bloem et al., 23-Apr-2014).  The following flutriafol toxicological information is a summary of the information presented in D382902 (K. Lowe et al., 19-Oct-2011).

It is noted 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 inhalation 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 whether 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 relatively high in whole blood, liver, and kidneys.  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 considered unlikely.  The parent was isolated in only trace amounts in the urine and feces and more than 19 metabolites were isolated, indicating extensive metabolism.  The primary site for metabolism was the 2-fluorophenyl ring.  The initial metabolic step was epoxidation followed by rearrangement to form either the dihydrodiol isomers or the hydroxy or dihydroxy metabolites.  The hydroxyl groups on these primary metabolites may then be either conjugated with glucuronic acid or methylated.  A second, minor route for metabolism of flutriafol was via the removal of the triazole ring to form 1-(2 fluorophenyl)-1-(4-fluorophenyl)-ethandiol, which is then conjugated with glucuronic acid.

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 ug/cm[2], following a 10-hour exposure.  A value of 21% is appropriate (most protective) for dermal risk assessments.

4.2	Toxicological Effects

Flutriafol is a member of the conazole triazole class of pesticides.  The triazole fungicides inhibit C14-demethylase, a fungal cytochrome P450, which plays a role in sterol production.  Sterols, such as ergosterol, are needed for fungal membrane structure and function, and are essential for the development of functional cell walls.  Mammals, particularly humans, also express cytochrome P450 enzymes (hepatic and extra-hepatic).  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 II).  It is categorized as having low acute toxicity via the oral, dermal and inhalation routes (Toxicity Categories III, III, and IV, respectively) in rats.  Flutriafol is minimally irritating to the eyes (Toxicity Category III) and is not a 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 enzyme release (alkaline phosphatase), liver weights, and histopathology findings ranging from hepatocyte vacuolization to centrilobular hypertrophy and slight increases in hemosiderin-laden Kupffer cells.  It is noteworthy that with chronic exposures, there are no indications of progression of liver toxicity in all species.  After over one year of exposure, hepatotoxicity in rats, dogs, and mice took the form of (1) minimal to severe fatty changes; (2) bile duct proliferation/cholangiolar fibrosis; (3) hemosiderin accumulation in Kupffer cells; (4) centrilobular hypertrophy, and (5) increases in alkaline phosphatase release.

Slight indications of effects in the hematopoietic system are sporadically seen in the database.  These effects are manifested in the form of slight anemia (rats and dogs) and increased platelet, white blood cell, neutrophil, and lymphocyte counts (mice).  These effects, however, were minimal in severity.

In a 28-day dermal toxicity study, there were no signs of toxicity for flutriafol up to the limit dose (1000 mg/kg/day).

The potential impact of in utero and perinatal flutriafol exposure was investigated in three developmental toxicity studies (two in rats, one in rabbits) and two multi-generation reproduction toxicity studies in rats.  In the first of two rat developmental toxicity studies, 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 (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 systemic toxicity of the parental animals (decreased body weight and food consumption and liver toxicity).
Effects that may be considered signs of neurotoxicity (decreased motor activity and hindlimb grip strength, ptosis, lost righting reflex, hunched posture, and ataxia) were reported in the acute and subchronic neurotoxicity studies at the highest dose only.  These effects, however, were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity.  This conclusion is further reinforced by the observation that there was no evidence of neurotoxicity in any additional short-term studies in rats, mice, and dogs, or in the long-term toxicity studies in rats, mice, and dogs.  It is also important to note that in the acute neurotoxicity study, for animals that did not die in the study or were sacrificed in extremis, all effects resolved by Day 8.

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) analysis indicates that flutriafol has the potential to produce thyroid and/or liver tumors in rodents, neither the chronic/carcinogenicity study in rats or the carcinogenicity study in mice revealed treatment-related increases in tumor incidences.  Flutriafol is classified as "not likely to be carcinogenic to humans" based on the results of the carcinogenicity studies in rats and mice.

4.3	Safety Factor 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 sections below:  1) the toxicology database for flutriafol is adequate for risk assessment; 2) flutriafol is not considered neurotoxic; 3) clear NOAELs are established to protect for the fetal/offspring effects observed; and 4) the exposure databases are sufficient 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 only; however, these effects were primarily seen in animals that were agonal (at the point of death) and, thus, are not indicative of neurotoxicity.  In addition, there was no evidence of neurotoxicity in any additional short-term 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 concern since: 1) clear NOAELs and lowest observed adverse effect levels (LOAELs) were established in the fetuses/offspring; 2) the dose-response for these effects are  well defined and characterized; 3) developmental endpoints are used for assessing acute dietary risks to the most sensitive population (females 13-49) as well as all other short- and intermediate-term exposure scenarios; 4) the acute reference dose for females 13-49 is 1000-fold lower than the dose at which quantitative susceptibility in the first developmental rat study was observed; and 5) the chronic reference dose is greater than 300-fold lower than the doses at which the offspring effects were observed in the two-generation reproduction studies.

4.3.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  The dietary exposure assessment is conservative in nature (utilizes tolerance-level residues and 100% crop treated).  In addition, there are no proposed or registered residential uses.

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, respectively.

Acute Dietary Endpoint (General Population):  The acute neurotoxicity screening battery in the rat was selected for the acute dietary endpoint for the general population.  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 (dehydration, urine-stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, and scant feces), in males (red or tan perioral substance, chromodacryorrhea, chromorhinorrhea, labored breathing, and slight ataxia), and in females (piloerection and bradypnea).  This study is protective of the general population and is appropriate for the expected duration of exposure.

Acute Reference Dietary Endpoint (Females 13-49 years old):  The prenatal developmental toxicity study in rabbits was selected for the acute dietary endpoint for females 13-49 years of age.  An UF of 100x (10x for interspecies extrapolation, 10x for intraspecies variability, and 1x for FQPA SF) was applied to the developmental NOAEL of 7.5 mg/kg to generate the aRfD of 0.075 mg/kg for females 13-49 years of age.  The developmental LOAEL of 15 mg/kg is based on decreased number of live fetuses, complete litter resorptions, and increased post-implantation loss.  The NOAEL selected provides the lowest NOAEL from any toxicity study in the flutriafol database in which a toxic response could be the outcome of 1-2 days of single dosing.  The only other studies considered for this endpoint were the prenatal developmental studies in rats, where the developmental NOAELs were 10 mg/kg in both studies with developmental LOAELs of 50 mg/kg/day (1982) and 75 mg/kg/day (2008).  The rabbit study is therefore protective of the effects seen in these rat studies and provides the most protective endpoint for the population of concern (pregnant females and fetuses).

Chronic Dietary 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 of 5 mg/kg/day to generate the chronic reference dose (cRfD) of 0.05 mg/kg/day for all populations.  The LOAEL is 20 mg/kg/day based upon adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin, and triglycerides), increased adrenal cortical vacuolization of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes, mild anemia (characterized by decreased hemoglobin, hematocrit, and red blood cell count) in the males, and initial body-weight losses, decreased cumulative body-weight gains, and increased adrenal weights in the females.  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/LOAEL values and toxic effects (adverse liver effects) as the chronic dog study.  Other studies considered for this endpoint were the chronic/carcinogenicity studies (mouse and rat), as well as the two-generation reproduction studies where similar effects were seen at slightly higher doses.

Short- and Intermediate-Term Dermal and Inhalation Endpoint:  The prenatal developmental toxicity study in rabbits was selected for the short- and intermediate-term dermal and inhalation endpoints.  The developmental NOAEL is 7.5 mg/kg/day and the LOAEL is 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post-implantation loss.  Although maternal and developmental toxicity were observed at the same dose, the maternal effects were restricted to moderate decreases in bodyweight and food consumption, and were less severe than the effects observed in the offspring.  In addition, although decreased body weight was an adverse effect observed in non-pregnant animals with flutriafol, results of this study indicate that pregnant animals were more sensitive to this effect.  The route-specific 28-day dermal toxicity study was also considered for 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 endpoint 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 observed at similar doses.  However, the severity of these liver effects does not increase with duration, and, thus, the fetal mortalities in the rabbit study are considered more severe.  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:  Flutriafol is classified as "lot likely to be carcinogenic 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.

Table 4.4.1:  Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Dietary and Non-Occupational Human Health Risk Assessments.
                                   Exposure/
                                   Scenario
                                      POD
                             Uncertainty/FQPA SFs
                       RfD, PAD, LOC for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL = 250 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Acute RfD = 2.5 mg/kg/day

aPAD = 2.5 mg/kg/day
Neurotoxicity screening battery  -  rat; LOAEL = 750 mg/kg, based on decreased body weight, body-weight gain, absolute and relative food consumption, and clinical signs of toxicity in both sexes: dehydration, urine-stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, scant feces; in males: red or tan perioral substance, chromodacryorrhea, chromorhinorrhea and labored breathing, and in females:  piloerection and bradypnea.
Acute Dietary
(Females 13-49 years of age)
NOAEL = 7.5 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Acute RfD = 0.075 mg/kg/day

aPAD = 0.075 mg/kg/day
Developmental study  -  rabbit; Developmental LOAEL = 15 mg/kg, based on decreased number of live fetuses, complete litter resorptions and increased post-implantation loss.
Chronic Dietary (All Populations)
NOAEL = 5 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Chronic RfD = 0.05
mg/kg/day
cPAD = 0.05 mg/kg/day
Chronic toxicity  -  dog; LOAEL = 20 mg/kg/day, based on adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin, and triglycerides), increased adrenal cortical vacuolation of the zona fasciculata, and marked hemosiderin pigmentation in the liver and spleen in both sexes; mild anemia (characterized by decreased hemoglobin, hematocrit, and red blood cell count) in the males; and initial body weight losses, decreased cumulative body-weight gains, and increased adrenal weights in the females.
Cancer (oral, dermal, inhalation)
Classification:  "Not likely to be Carcinogenic to Humans" based on the carcinogenicity studies in rats and mice.
Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = 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 Human Health Risk Assessments.
                                   Exposure/
                                   Scenario
                                      POD
                                      UFs
                              LOC Risk Assessment
                        Study and Toxicological Effects
Dermal
Short (1-30 days)- and Intermediate (1-6 months) -Term
NOAEL= 7.5 mg/kg/day
[1]Dermal-absorption factor = 21%
UFA = 10x
UFH = 10x
Occupational LOC for MOE < 100
Developmental toxicity  -  rabbit; Developmental LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post-implantation loss.
Inhalation Short (1-30 days)- and Intermediate (1-6 months) -Term
NOAEL = 7.5 mg/kg/day
Inhalation toxicity assumed to be equivalent to oral toxicity

UFA = 10x
UFH = 10x
Occupational LOC for MOE < 100
Developmental toxicity  -  rabbit; Developmental LOAEL = 15 mg/kg/day, based on decreased number of live fetuses, complete litter resorptions and increased post-implantation loss.
Cancer (oral, dermal, inhalation)
Classification:  "Not likely to be Carcinogenic to Humans" based on the carcinogenicity studies in rats and mice.
[1]  Dermal absorption factor was derived from the dermal penetration study (MRID 47090415).
[2]  Inhalation absorption factor is considered the worst-case scenario for inhalation exposure using an oral NOAEL (D372347, K. Lowe et al., 16-Dec-2009).
Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  MOE = margin of exposure.  LOC = level of concern.

5.0	Dietary Exposure and Risk Assessment
D416089, T. Bloem, 16-Dec-2014 (residue chemistry summary for the current action)
D420505, T. Bloem, 16-Dec-2014 (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 conducted 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 2.2x[2]

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 1.3x[2]

rotational crops (dried roughage
feed commodities)
same as that mentioned above but with multiplication of the free flutriafol residues by 2.0x[2] to account for the combined residues of flutriafol (free and conjugated) and M28

poultry[3]
                       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 Appendix 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 (D416089, 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 support 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 adequately-validated analytical methods and satisfy the geographical requirements specified in OCSPP 860.1500 (storage intervals have also been validated).  Provided a revised Section B is submitted and based on the OECD tolerance-calculation procedure, HED concludes that the plant tolerances listed in Table <IP_ADDRESS> 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 days after application; rotation to any other crop is prohibited and (2) application rates >0.228 lbs ai/acre/season - treated field may only 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 previously 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 <IP_ADDRESS> 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 proposed/registered uses (EFED; D412882, J. Wolf, 29-Oct-2013).  The water estimates were incorporated directly into the dietary exposure analysis via the water sources direct (all sources) and indirect (all sources) commodities.  The water models and their description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.

Table 5.3.1:  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])
apples (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).

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 analyses assumed tolerance-level residues or tolerance-level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates.  Since adequate processing studies have been submitted which indicate that tolerances 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 occupied 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).

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 particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for flutriafol.  The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information; http://www.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(R) and chemical specific properties of pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process, which ensures that all uses for that pesticide will be considered concurrently.

6.2	Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 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 Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).

During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for specific chemicals.

7.0	Aggregate Exposure/Risk Characterization

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  Because there are no uses for flutriafol which result in residential (non-occupational) exposures, the aggregate assessment need only consider food and water.  Since the dietary exposure analysis included both food and water, the discussion and exposure estimates presented in Section 5.4 represent aggregate acute and chronic exposure to flutriafol and those metabolites identified as being toxicologically identical to flutriafol.  All aggregate flutriafol risk estimates are not of concern to HED.

Application of flutriafol also results in exposure to T and TA/TAA/TLA.  These compounds are considered to be toxicologically different from flutriafol.  HED previously conducted an aggregate exposure analysis for these compounds, which resulted in aggregate exposure less than HED's level of concern (D414952, T. Morton, 24-Oct-2013).  The proposed new uses 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 biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mechanism of toxicity in mammals.  Structural similarities do not constitute a common mechanism of toxicity.  Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002).  In conazoles, however, a variable pattern of toxicological responses is found; some are hepatotoxic and hepatocarcinogenic in mice.  Some induce thyroid tumors in rats.  Some induce developmental, reproductive, and neurological effects in rodents.  Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation.  It is not clearly understood whether these biochemical events are directly connected to their toxicological outcomes.  Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles.  For information regarding EPA's procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA's website at http://www.epa.gov/pesticides/cumulative.

9.0	Occupational Exposure/Risk Characterization
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).  It is HED policy to use the best available data to assess exposure.  Several sources of generic data were used in this assessment as surrogate data in the absence of chemical-specific data, including the PHED 1.1, AHETF database, and ARTF database.  Some of these data are proprietary, and subject to the data protection provisions of FIFRA.  Additional 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/handler-exposure-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 types 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 scenarios:  (1) mixing/loading liquids for aerial and groundboom applications; (2) applying sprays 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.

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
                              Crop 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) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated (A/day) x DAF (21 %) / BW (69 kg).
[5]  Dermal MOE = Dermal NOAEL (7.5 mg/kg/day) / Dermal Dose (mg/kg/day).
[6]  Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated (A/day) x inhalation absorption (100%) / BW (69 kg).
[7]  Inhalation MOE = Inhalation NOAEL (7.5 mg/kg/day) / Inhalation Dose (mg/kg/day).
[8]  Total MOE = NOAEL (7.5 mg/kg/day) / (Dermal Dose + Inhalation Dose).

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 type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1	Inhalation Post-Application Risk Assessment

There are multiple potential sources of post-application inhalation exposure to individuals performing 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, 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 Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for 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 occupational post-application inhalation exposure scenarios.

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 <IP_ADDRESS>.  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, dislodgeable 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 analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (FAR).  These values are based on an analysis 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 Chrysanthemum Pinching in a Greenhouse" (EPA MRID 45344501).  As a result, the range of FAR values was revised from 2% - 89% to 2% - 47%.  In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors.  Although witnessed across multiple chemicals, this range in FAR values is not expected when considering DFR data for a single chemical.  At this time, the ARTF submission did not alter the selection of 25% as the reasonable, high-end default value.  Because DFR data are not available for 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 FAR value may exceed the applicable default value), it is likely that the health-protective aspects of EPA's occupational post-application assessment methodology will more than compensate for this potential uncertainty.  For example, when assessing residential and occupational 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 exposure 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 by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the highest estimated occupational post-application exposure using default DFR values for flutriafol is minimal in comparison to the 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 chemical-specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pesticide residues for flutriafol.

Table <IP_ADDRESS>:  Occupational Post-application Non-Cancer Exposure and Risk Estimates for Flutriafol.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/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 x F x (1-D)[t] x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day.
  [2]  Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x 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 REI of 12 hours is adequate to protect agricultural workers from post-application exposures to flutriafol.

RDI:  RAB1 (11-Jun-2014)

Appendix A.  Toxicology Profile and Executive Summaries
Appendix B.  Chemical Names and Structures

Appendix A.  Toxicology Profile and Executive Summaries

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

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

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
yes
yes
yes
yes
yes
yes
yes
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
LD50 = 1140 mg/kg (M); 1480 mg/kg (F)
                                      III
870.1100
Acute oral (mouse)
47090335
LD50 = 365 mg/kg bw (M); 179 mg/kg bw (F)
                                      II
870.1200
Acute dermal (rat)
4786101
LD50 >2000 mg/kg bw
                                      III
870.1300
Acute inhalation (rat)
47090338
LC50 >5.20 mg/L
                                      IV
870.2400
Primary eye irritation (rabbit)
47090339
Minimally irritating
                                      III
870.2500
Primary dermal irritation (rabbit)
47090341
Not a dermal irritant
                                      IV
870.2600
Dermal sensitization (mouse)
47090343
Not a sensitizer
                                       -

Table A.3:  Subchronic and Chronic Toxicity and Genotoxicity Profile  -  Flutriafol.
Guideline No.
Study Type
MRID No. (year)/ Classification /Doses
Results
870.3050

28-Day oral toxicity (rat)
47090344 (1982)
Acceptable/non-guideline
0, 100, 300, 800, 2000, or 5000 ppm (0, 10, 30, 80, 200, and 500 mg/kg/day)

NOAEL = 800 ppm (80 mg/kg/day).
LOAEL = 2000 ppm (200 mg/kg/day), based on liver toxicity (increased weight, centrilobular hepatocellular hypertrophy, fatty change, hydropic degeneration, smooth endoplasmic reticulum proliferation, and increased aminopyrine-N-demethylase activity) in both sexes and decreased body-weight gain and food consumption in males.
870.3100

90-Day oral toxicity (rat)

47090345 (1982)
Acceptable/guideline
0, 20, 200, or 2000 ppm
M:  0, 1.5, 14, and 158 mg/kg/day)
F:  0, 1.6, 22, and 145 mg/kg/day
NOAEL = 200 ppm (14/22 mg/kg/day in M/F)
LOAEL = 2000 ppm (158/145 mg/kg/day in M/F), based on decreased body-weight gain, decreased food consumption and liver toxicity (increased absolute and adjusted liver weights, increased endoplasmic reticulum proliferation in the males, and increased APDM activity).
870.3150

90-Day oral toxicity (dog)
47090346 (1982)
Acceptable/guideline
0, 1, 5, or 15 mg/kg bw/day
NOAEL = 5 mg/kg/day.
LOAEL = 15 mg/kg/day, based on adverse liver findings (increases in organ weight, alkaline phosphatase, aminopyrine N-demethylase activity, and incidence of hemosiderin-laden Kupffer cells) in both sexes, spleens with hemosiderin content slightly higher than controls in the males, and decreased cumulative body-weight gains and increased triglycerides in the females.
870.3200
28-Day dermal toxicity (rat)

47090347 (2007)
Acceptable/guideline
0, 250, 500, or 1000 mg/kg/day
NOAEL = 1000 mg/kg/day.
LOAEL was not established.
870.3700a
Prenatal developmental (rat)
47090349 (1982)
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.
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 = 150 ppm (9/10.8 mg/kg bw/day [M/F]).
Offspring LOAEL = 300 ppm (18.5/22.6 mg/kg bw/day [M/F]) based upon increased pup mortality in the F1 pups at the first litter check and 0-4 postnatal days.
870.4100

Chronic toxicity (1 year; dog)
47090353 (1988)
Acceptable/guideline
0, 1, 5, or 20 mg/kg/day

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

47090354 (1988)
Acceptable/guideline
0 (two control groups), 10, 50, or 200 ppm
M:  0, (0, 1.1, 5.9, and 24 mg/kg/day)
F:  0, 1.4, 7.4, and 31 mg/kg/day
NOAEL = 50 ppm (5.9/7.4 mg/kg/day in M/F).
LOAEL = 200 ppm (24/31 mg/kg/day in M/F), based on hepatotoxicity (increased fatty change) in both sexes.
No evidence of carcinogenicity
870.4300

Combined Chronic Toxicity/
Carcinogenicity
(rat)

47090352 (1986)
Acceptable/guideline
0, 20, 200, or 2000 ppm
M:  0, 1.02, 10.0, and 102 mg/kg/day)
F:  0, 1.27,12.2, and 122 mg/kg/day
NOAEL = 200 ppm (10.0/12.2 mg/kg/day in males/females).
LOAEL = 2000 ppm (102/122 mg/kg/day in males/females), based on adverse liver effects (increased liver weights, fatty change, bile duct proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer cells and centrilobular hypertrophy), and clinical chemistry findings.
No evidence of carcinogenicity
870.5100

In vitro Bacterial Gene Mutation (Salmonella typhimurium)/ mammalian activation gene mutation assay
47090401 (1988)
Acceptable/guideline
0, 1.6, 8, 40, 200, 1000, or 5000 ug/plate ( Trial 1) or 0, 8, 40, 200, 1000, 2500, or 5000 ug/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 ug/mL (+S9, Trial 1); 0, 150, 300, 450, 600, or 750 ug/mL (-S9, Trial 1); 0, 150, 300, 450, 600, 750, 900, 1050, or 1200 ug/mL (+S9, Trial 2); or 0, 200, 300, 400, 500, 600, 700, or 800 ug/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 ug/mL and above in Trial 1 and a marked increase in mutant frequency at 750 ug/mL (6. 5x 10[-5] treated vs. 1.2 x 10[-5] controls) in Trial 2 attributable to severe cytotoxicity (2% relative survival).  However, the increases in mutant frequency did not achieve the threshold value for a positive response (>10 x 10[-5]) in either trial and there was no marked increase in absolute mutant numbers at 750 ug/mL in Trial 2.  In the absence of S9, there were no marked increases in mutant frequency or absolute mutant numbers compared to controls in either trial.  There was no convincing evidence of induced mutant colonies over background in the presence or absence of S9-activation.
870.5300

In Vitro Gene Mutation assay in mouse lymphoma cells

48196918 (2006)
Acceptable/guideline
0, 25, 50, 100, 200, 400 and 600 ug/mL (+-S9, Trial 1); 0, 12.5, 25, 50, 100, 200, 300 or 400 ug/mL (-S9, Trial 1); 0, 200, 300, 325, 350, 375, or 400 ug/mL (+S9, Trial 2)
(-S9, Trial 2)
The mutagenicity criterion (threshold) of 126 colonies per 106 cells above the solvent control was not reached for any valid data at any test concentration, with or without metabolic activation.  Although linear regression analysis found a significant (p<0.05) dose dependent trend of the mutation frequency in Experiment 1 (culture 1, with metabolic activation), Experiment 2 (culture 1), and Experiment 3 (cultures 1 and 2), these statistical results were considered biologically irrelevant because the threshold for mutagenicity was not exceeded and all absolute values were within the range of historical negative and solvent controls.
870.5375

In vitro Mammalian Cytogenetics (Chromosomal Aberration Assay in Human Peripheral Blood Lymphocytes)
47090403 (1989)
Acceptable/guideline
0, 25, 125, or 250 ug/mL (+/-S9)
No significant increases in the numbers of cells with aberrations (excluding gaps) were observed in either donor in the presence or absence of S9.  There was no evidence of chromosome aberrations induced over background in the presence or absence of S9-activation.
870.5385

In vivo Mammalian Cytogenetics  -  [Bone Marrow Chromosomal Aberration Test
47090404 (1982)
Acceptable/guideline
0, 15, 70, or 150 mg/kg
There was no evidence of chromosome aberration induced over background.

870.5395
In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in Mice
47090405 (1986)
Acceptable/guideline
0, 93.8, or 150 mg/kg
Decreased (p<0.01) polychromatic erythrocyte to normochromatic erythrocyte ratios (PCE:NCE) were observed in both doses at all time points, indicating that the test material was toxic to the bone marrow.  There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.
870.5450

Dominant Lethal Assay  -  Mice
47090406 (1982)
Acceptable/guideline
0, 25, 50, or 100 mg/kg/day (total doses of 0, 125, 250, or 500 mg/kg)
Mortality (3/15 males) was noted at 100 mg/kg/day during dosing.  Slight decreases (p<0.05) in body weight were observed at 50 mg/kg/day and above during dosing.  There were no treatment-related effects on fertility, mean number of implantations, or the number of early or late deaths.  There was no time-related positive response of increased pre- or post-implantation loss compared to controls.
870.5550
Unscheduled DNA Synthesis in Primary Rat Hepatocytes/Mammalian Cell
47090407 (2003)
Acceptable/guideline
0, 250, 500, or 1000 mg/kg

The net nuclear grain (NNG) counts in the treated animals ( - 3.42 to  - 2.64) were well below the threshold of >=5 NNG needed for a positive response, and no increase in the mean percent of cells in repair was observed.  There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.
870.6200a
Acute neurotoxicity screening battery
47090408 (2005)
Acceptable/guideline
0, 125, 250, or 750 mg/kg

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

Subchronic Neurotoxicity  -  Feeding Study in Rats

47090410 (2007)
Acceptable/guideline
0, 500, 1500, or 3000 ppm (0/0, 28.9/32.6, 84.3/97.6, and 172.1/185.0 mg/kg/day [M/F])
NOAEL = 1500 ppm (84.3/97.6 mg/kg/day [M/F]).
LOAEL = 3000 ppm (172.1/185.0 mg/kg/day [M/F]) based on decreased body-weight gain, absolute and relative food consumption; and decreased hindlimb grip strength in males.
870.7485

Metabolism and pharmacokinetics
(rat)

47090414 (2004),
47090412 (2006)
Acceptable/guideline
5 or 250 mg/kg

More than 78% of the dose was recovered in the bile and urine.  Absorption was similar between sexes and between single and multiple dose regimes.  Absorption is extensive.  The dose was mostly eliminated within 48 hours. Only 0.04-0.05% of the dose was found in the expired carbon dioxide.  Most of the radioactivity was excreted in the bile (47-79% of the dose).  The excretion profile was similar between sexes.  In the blood, radioactivity partitioned into the red blood cells.  In both sexes and all groups, concentrations of radioactivity were relatively high in whole blood, liver, and kidneys.  Other organs with high concentrations included the adrenal glands, spleen, and pituitary.  The distribution profiles were similar between species, dose level, and single vs. multiple dose regime.  In the whole blood, the concentrations were proportional to the dose.  The total amount of radioactivity isolated in the tissues and carcass was <1-3%.  Bioaccumulation was considered unlikely.  The parent was isolated in only trace amounts in the urine and feces and more than 19 metabolites were isolated, indicating extensive metabolism.  Metabolism profiles were similar between sexes.  The metabolic profiles were similar regardless of the matrix (feces, urine, or bile), the dose, and the sex.  The primary site for metabolism was the 2-fluorophenyl ring.  The initial metabolic step was epoxidation followed by either rearrangement to form the dihydrodiol isomers or to form hydroxy or dihydroxy metabolites.  The hydroxyl groups on these primary metabolites may then be either conjugated with glucuronic acid or methylated.  A second, minor route for metabolism of flutriafol was via the removal of the triazole ring to form 1-(2 fluorophenyl)-1-(4-fluorophenyl)-ethandiol, which is then conjugated with glucuronic acid.
870.7600

In vivo dermal penetration
(rat)
47090415 (2006)
Acceptable/guideline
0.002, 0.02, or 0.2 mg/cm[2] skin were tested (10 ul/cm[2] skin), and actual doses were 0.00208, 0.0201, and 0.2154 mg/cm[2] skin
Dermal ranged up to 15.8% of the applied dose.  Absorption was minimal with only 4 h of exposure.  Absorbable radioactivity (radioactivity in the skin at the application site and the adjacent skin) was minimal in groups that were exposed for 10 h and evaluated for an additional 158 h post-exposure.  Thus, almost all of the dose isolated in the skin will be absorbed.  Considering the sum of absorbable and absorbed doses, 4-37% of the applied dose was recovered in the treatment groups (11%).  Absorption rate constants were calculated as 0.236, 0.190, and 0.072 h[-1] for the 2, 20, and 200 ug/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 ug/cm[2] dose groups.  A maximum of 36.56% of the applied dose was noted as absorbed/absorbable (observed after 24 h exposure to 2 ug/cm[2]).  The dose that is absorbed/absorbable following a 10 h exposure is 16.54%, 21.31% and 11.39%, respectively, at 2, 20, and 200 ug/cm[2].
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.

Appendix B.  Chemical Names and Structures

                                  Common name
                                 Chemical name
                              Chemical structure
Flutriafol
(+-)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethanol

M1B
1-(2-fluoro-4-hydroxyphenyl)-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol

M28
glucoside of a flutriafol metabolite, possible a derivative hydroxylated on one phenyl ring
                                      --
1,2,4-Triazole (T)
1H-1,2,4-triazole

Triazolylalanine (TA)
2-amino-3-(1H-1,2,4-triazol-1-yl)propanoic acid

Triazolylacetic acid (TAA)
1H-1,2,4-triazol-1-ylacetic acid

Triazole lactic acid (TLA)
1,2,4-triazole-1-lactic acid

Hydroxy flutriafol glucuronide (HFG; M3)
                                      --

Dihydroxy flutriafol (DHF; M3e)
                                      --

Flutriafol glucuronide (FG; M4)
                                      --

Methoxy flutriafol glucuronide (MFG; M7)
                                      --

Flutriafol sulfate (FS; M10)
                                      --