Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 1 of 45 

### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION



### MEMORANDUM

D ATE: 19

- O CT

- 20 11

SUBJECT: Flutriafol: Human Health Risk Assessment for Proposed Uses on Corn, Grapes,

Peanuts, Pome Fruit ( Crop Group 11), Stone Fruit ( Crop Group 12), Sugar Beets, Wheat, Barley, Triti cale, Buckwheat, Oats, Rye, Teosinte

, and Imported Bananas

.

PC Code: 128940 DP Barcode s : D382902, D382945

Decision No s .: 438881, 438682 Registration No

. : 67760

- 75

Petition No s .: 0F7771 , 0E7772, 0F7740 Regulatory Action: Section 3 Risk Assessment Type: Single Chemical / Aggregate Case No.: NA

T XR No.: NA CAS No.: 76674

- 21

- 0

MRID No.: NA 40 CFR: 

### §180.629

FROM: Kelly M. Lowe, Environmental Scientist

Thomas Bloem, Chemist

Anwar Y. Dunbar, Ph.D., Pharmacologist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED; 7509P)

THROUGH: George F. Kramer, Ph.D., Branch Senior Chemist

Dana Vogel, Branch Chief RAB1/HED (7509P)

TO: Mary Waller, RM 21

Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and a ggregate 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)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol). A summary of the findings and an a ssessment of human risk resulting from the registered and proposed uses for flutriafol are provided in this document. The risk assessment and occupational/residential exposure assessment were provided by Kelly Lowe (RAB1), the dietary risk assessment and residue chemistry data review by Thomas Bloem (RAB1), the hazard characterization was provided by Anwar Dunbar (RAB1), and the drinking water assessment by

James K. Wolf of the Environmental Fate and Effects Division (EFED).Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 2 of 45 

### Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ................................ ........ 3

2.0 HED Recommendations

................................ ................................ ................................ ................................ .. 6

2.1 Data D eficiencies/Conditions of Registration

................................ ................................ .......................... 6

2.2 Tolerance Considerations

................................ ................................ ................................ .......................... 8

2.2.1 Enforcement Analytical Method

................................ ................................ ................................ ...... 8

2.2.2 International Harmonization

................................ ................................ ................................ ............ 8

2.2.3 Recommended Tolerances

................................ ................................ ................................ ................ 8

2.2.4 Revisions to Petitioned

- For Tolerances

................................ ................................ ......................... 10

2.3 Label Recommendations

................................ ................................ ................................ ......................... 10

2.3.1 Recommendations from Residue Reviews

................................ ................................ ..................... 10

2.3.2 Recommendations from Occupational Assessment

................................ ................................ ...... 10

3.0 Ingredient Profile

................................ ................................ ................................ ................................ .......... 10

3.1 Chemic al Identity

................................ ................................ ................................ ................................ ..... 11

3.2 Physical/Chemical Characteristics

................................ ................................ ................................ ......... 11

3.3 Proposed Use Pattern

................................ ................................ ................................ ............................... 11

3.4 Anticipated Exposure Pathways

................................ ................................ ................................ ............. 13

3.5 Consideration of Environmental Justice

................................ ................................ ................................ 14

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ................................ ........ 14

4.1 Toxicology Studies Available for Analysis

................................ ................................ ............................. 14

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

................................ ......................... 15

4.2.1 Dermal Absorption

................................ ................................ ................................ .......................... 15

4.3 Toxicological Effects

................................ ................................ ................................ ................................ 15

4.4 SF for Infants and Children (FQPA SF)

................................ ................................ ................................ 16

4.4.1 Completeness of the Toxicology Database

................................ ................................ ..................... 16

4.4.2 Evidence of Neurotoxicity

................................ ................................ ................................ ............... 17

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

............................... 17

4.4.4 Residual Uncertainty in the Exposure Database

................................ ................................ .......... 17

4.5 Toxicity Endpoint and POD Selections

................................ ................................ ................................ .. 17

4.5.1 Dose

- Response Assessment

................................ ................................ ................................ ............. 17

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

.............................. 19

4.5.3 Cancer Classification and Risk Assessment Recommendation

................................ ................... 19

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

.. 19

4.6 Endocrine Disruption

................................ ................................ ................................ ............................... 21

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ................................ ...... 22

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ................................ .... 22

5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ................................ .... 22

5.1.2 Summary of Environmental Degradation

................................ ................................ ..................... 25

5.1.3 Comparison of Metabolic Pathways

................................ ................................ .............................. 25

5.1.4 Residues of Concern Summary and Rationale

................................ ................................ ............. 26

5.2 Food Residue Profile

................................ ................................ ................................ ................................ 27

5.3 Drin king Water Residue Profile

................................ ................................ ................................ ............. 28

5.4 Dietary (Food + Drinking Water) Risk Assessment

................................ ................................ .............. 28

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ........................... 29

6.1 Residential Bystander Post

- application Inhalation

................................ ................................ ............... 29

6.2 Spray Drift

................................ ................................ ................................ ................................ ................ 30

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ............................... 30

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ............................. 31

9.0 Occupational Exposure/Risk Characterization

................................ ................................ .......................... 31

9.1 Short

- and Intermediate

- Term Handler Risk

................................ ................................ ........................ 31

9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ................................ ......... 35

9.2.1 Dermal Post

- Application Risk

................................ ................................ ................................ ........ 35

9.2.2 Inhalation Post

- Application Risk

................................ ................................ ................................ ... 37

10.0 References

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

................................ ................................ ................. 39

A.1 Toxicology Data Requirements

................................ ................................ ................................ .................. 39

A.2 Toxicity Profiles

................................ ................................ ................................ ................................ ......... 40Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 3 of 45 

### 1.0 Executive Summary

Flutriafol [(±)

- α

- (2

- fluorophenyl)

- α

- (4

- fluorophenyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol] is a systemic, triazole fungicide that can be used as a systemic eradicant and a protectant. It has a post

infection activity that can stop pathogen establishment in the early phases of disease development. Flutriafol is currently registered for application to apples and soybeans with tolerances ranging from 0.02 to 2.2 ppm (40 CFR § 180.629).

Cheminova has proposed a Section 3 Registration (PP# 0F7771) for application of flutriafol to corn, grapes, peanuts, pome fruit ( crop group 11), stone fruit ( crop group 12), sugar beets, wheat, barley, triticale, buckwheat, oats, rye, and teosinte

. Petitions were also submitted to establish tolerances for residues in rotational crops (cotton an d corn; PP# 0F7740) and a tolerance for imported banana (PP# 0E7772)

.

The proposed end

- use product for the Section 3 registrations is Topguard ® 

### Fungicide (EPA Reg

# 67760

- 75) , a 1.04 pound ( lb ) active ingredient ( ai ) /gallon formulation. The maximum

app lication rate proposed for corn, peanuts, stone fruit, sugar beets, wheat, barley, triticale, buckwheat, oats, rye, and teosinte is 14 fl oz/A (0.114 lb ai/A). The maximum application rate proposed for pome fruit is 13 fl oz/A (0.106 lb ai/A) and the maxi mum application rate proposed for grapes is 10 fl oz/A (0.08 lb ai/A). The labels submitted for imported bananas indicate a range of application rates from 0.069 to 0.167 lb ai/A.

Hazard Assessment: Flutriafol has 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).

Flutriafol appears to be generally equally toxic to rats, mice, and dogs with all three species having similar (within one order of ma gnitude) no

- observed adverse

- effect levels (NOAELs)/lowest

- observed adverse

- effect levels (LOAELs). The target organ is the liver in dogs, rats, and mice. Hepatotoxicity occurred at similar dose levels across several species and durations of exposure. F lutriafol is considered to be ―Not likely to be Carcinogenic to Humans‖ based on the results of the carcinogenicity studies in rats and mice. The results of the rat chronic toxicity/carcinogenicity study and the mouse carcinogenicity study are negative fo r carcinogenicity. All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity.

The potential impact of in utero and perinatal flutriafol exposure was investigated in three developmental toxicity studies (two in rats, on e in rabbits) and two multigenerational reproduction toxicity studies in rats. In the first of two rat developmental toxicity studies, a quantitative susceptibility was observed ( delayed ossification or non

- ossification of the skeleton in the fetuses) at a lower dose than maternal effects. In the second rat developmental study, a qualitative susceptibility was noted (skeletal malformations and embryo lethality)

. Although developmental toxicity occurred at the same dose level that elicited maternal toxici ty, the developmental effects were more severe than those observed in the dams. For rabbits,

intrauterine deaths occurred at a dose level that also caused adverse effects in maternal animals. Similar to what was seen in the developmental study in rats, o ffspring effects occurred at the same dose level as parental effects in the multi

- generation toxicity study in rats. However, theFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 4 of 45 

### nature of the effects in the offspring was more severe than in the dams. The level of concern is low for these developmenta l/ offspring effects because: 1) clear NOAELs and LOAELs were established in the fetuses/offspring; 2) the dose

- response for these effects are well defined and characterized; 3) developmental endpoints are used for assessing acute dietary risks to the mos t sensitive population (females 13

- 49) as well as all other short

- and intermediate

- term exposure scenarios; and 4) the chronic reference dose is greater than 300

- fold lower than the doses at which the offspring effects were observed in the 2

- generation re production studies. 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 indicati ve of neurotoxicity. In addition, there was no evidence of neurotoxicity in any additional short

- term studies in rats, mice, and dogs, or in the long

- term toxicity studies in rats, mice, and dogs. A developmental

- neurotoxicity (DNT) study is not required

.

An in vivo rat dermal

- absorption study is available for flutriafol that is acceptable and indicates that the absorption is 17%, 21%, and 11%, respectively, at 2, 20, and 200 μg/cm 2 

### , following a

10

- hour exposure. A conservative dermal

- absorption value o f 21% is considered appropriate for dermal risk assessments. There is an absence of systemic toxicity at 1000 mg/kg/day in the 28

- day dermal toxicity study in the rat.

Dose Response Assessment: The acute and chronic reference doses (aRfD and cRfD) were calculated by dividing the NOAEL by 100 (10X for interspecies extrapolation and 10X for intraspecies variation). Since the Food Quality Protection Act (FQPA) Safety Factor (SF) has been reduced to 1X, the acute and chronic population

- adjusted doses (aPAD and cPAD) are equal to the aRfD and cRfD, respectively. The aPAD for females 13+ years old is 0.075 mg/kg/day and the aPAD for the general population is 2.5 mg/kg/day. The cPAD for the general population is 0.05 mg/kg/day. The point of departure (POD) f or short

- and intermediate

- term dermal and inhalation risk assessments is 7.5 mg/kg/day. The dermal

- absorption factor was

estimated to be 21%. A 100% oral

- equivalent inhalation absorption factor is assumed. The level of concern (LOC) for occupational de rmal and inhalation exposures are for margins of exposure (MOEs) <100.

FQPA SF Decision: The flutriafol risk assessment team recommends that the 10X FQPA SF be reduced to 1X since the toxicology database is complete, there are no residual uncertainties for pre and/or post natal toxicity, and the conservative nature of the dietary exposure analysis (i.e.,

to lerance

- level residues and 100% crop treated; no residential uses).

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 TM 

### , ver. 2.03) which incorporates the food consumption data from the United States Department of Agriculture (USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994

- 1996 and 1998 ). The proposed uses on field corn, popcorn

, and small grains were not included in the dietary analysis,

since HED is not recommending for those registrations due to several residue chemistry data deficiencies (issues concerning the nature/magnitude of the residue in ruminants at the dietary burdens associated with these crops). The analysis did consider the registered crops , the remaining proposed crops, and residues in/on field corn, popcorn, and cotton as a result of

rotation to a treated field.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 5 of 45 

### The acute and chronic analyses assumed tolerance

- level residues, 100% crop treated, and modeled drinking water estimates. Th e default DEEM TM 

### (ver 7.81) processing factors were retained for all commodities except for apple juice, grape juice and dried prunes since adequate processing studies were submitted for those commodities (processing factors reduced to 1). The resulting ac ute (≤24% aPAD; females 13

- 49 years old were the most highly exposed subgroup) and chronic [≤42% cPAD; all infants (<1 year old) were the most highly exposed subgroup] exposure estimates are not of concern to HED.

Residential (Non

- Occupational) Exposure and Risk Assessment: There are no registered or proposed uses of flutriafol that would result in residential exposure; therefore, a residential exposure assessment was not conducted.

Aggregate

- Risk Estimates: Acute and chronic aggregate risks are asse ssed based on dietary exposure from food and drinking water sources only and are the same as reported for acute and chronic dietary exposure. Therefore, acute and chronic aggregate risks to flutriafol are not of concern to HED. There are no registered or proposed uses of flutriafol that would result in residential exposure; therefore, short

- and intermediate

- term aggregate risks were not assessed.

Application of flutriafol also results in exposure to 1,2,4

- triazole (T) and its conjugated metabolites, whi ch 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. Since the requested flutriafol uses do not result in an increase in the dietary or residential exposure estimates to T and its conjugated metabolites, this previous assessment remains valid.

Occupational Exposure and Risk Assessment: Based on the proposed uses, occupational handlers may be potentially exposed to flutriafol during mixing/loading, applying, and flagging activities associated with aerial and groundboom applications. Short

- and intermediate

- term dermal and inhalation risks were assessed with a baseline layer of clothing, and wi th additional personal

- protective equipment (PPE). The combined dermal and inhalation exposure risks for mixer/loaders are not of concern (i.e., MOEs >100) at baseline for all scenarios except for mixers/loaders for aerial application to corn, wheat (spri ng and winter), barley, triticale, buckwheat, oats, rye, and teosinte. For these high acreage crops, mixer/loaders must wear protective gloves. Gloves are listed as PPE on the proposed label; therefore, HED does not have

concerns for this scenario. Following flutriafol application, occupational post

- application exposure is possible. Post

- application risks are not of concern (i.e., MOEs >100) on day 0 (12 hours after application) for all crops and activities, except for detasselling of corn and girdl ing/turning of grapes. For these crop/activity combinations, an acceptable MOE (i.e., MOE > 100) is not reached until Day 5 after application. The high

- contact activities for grapes are only expected to occur for cultivation of table grapes. The high

- co ntact activity for corn is only expected to occur for field corn or popcorn grown for seed. RD should ensure that the appropriate restricted

- entry interval (REI) is added to the label for these crops. In addition, under 40 CFR Part 158:1070, dislodgeable foliar residue (DFR) data are required to further

refine risk estimates.

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this human

- health risk assessment, in accordan ce with U.S. Executive Order 12898, ―Federal Actions to Address Environmental Justice in MinorityFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 6 of 4 5 

### Populations and Low

- Income Populations,‖ ( http://www.hss.energy.gov/nuc learsafety/env/guidance/justice/eo12898.pdf ).

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 to determine their dermal and inhalation exposure. M any such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the Agricultural Handlers Exposure Task Force (AHETF) and the Agricultural Reentry

Tas k Force (ARTF) Database. EPA has reviewed all the studies in these multi

- pesticide generic exposure databases, and on the basis of available evidence has found them to have been neither fundamentally unethical nor significantly deficient relative to stand ards of ethical research conduct prevailing when they were conducted. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) ha ve been satisfied.

Recommendations for Tolerances: A revised Section F is requested, that eliminates those

commodities for which tolerances are unnece ssary or inappropriate and specifies the correct commodity definition and/or numerical tolerance (see Ta ble 2.2.3). As a result of the proposed uses, HED is establishing rotational crop tolerances [180.629(d)]. The tolerance expression for 180.629(d) should be as follows (the current tolerance expression for 180.629(a) is appropriate):

180.629(d): To lerances are established for residues of flutriafol, including its metabolites and degradates, in or on the commodities listed below. Compliance with the following tolerance levels is to be determined by measuring only flutriafol ((±)

- α

- (2

- fluorophenyl)

- α

- (4

- fluorophenyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol).

2.0 HED Recommendations

HED is not recommending for the proposed field corn, popcorn, and small grains registration due to several residue chemistry data deficiencies including issues concerning the nature/magnitude of the residue in ruminants at the dietary burdens associated wi th these crops. For a complete discussion of the residue chemistry data deficiencies associated with application of flutriafol to field corn, popcorn, and small grains see D388603 (T. Bloem, 16

- Jun

- 2011).

For the remaining proposed crops [pome fruit, stone fruit, grape, banana (import tolerance), peanut, and sugar beet], HED concludes that the toxicological, residue chemistry, and occupational/residential databases support the establishment of a conditional registration and the permanent tolera nces listed in Section 2.2.3, provided revised Sections B and F are submitted. An unconditional registration may be established upon resolution of the deficiencies cited in

Section 2.1.

2.1 Data Deficiencies/Conditions of Registration

Toxicology

None.

Residue ChemistryFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 7 of 45 

### HED is not recommending for the proposed field corn, popcorn, and small grains registration due to several residue chemistry data deficiencies including issues concerning the nature/magnitude of the residue in ruminants at the dietary b urdens associated with these crops. For a complete discussion of the residue chemistry data deficiencies associated with application of flutriafol to field corn, popcorn, and small grains see D388603 (T. Bloem, 16

- Jun

- 2011). The following residue chemis try deficiencies are for the remaining proposed crops [pome fruit, stone fruit, grape, banana (import tolerance), peanut, and sugar beet]:

 Revised Section B with the following changes:

 Removal of corn (field corn, field corn for seed, and popcorn) and sm all grain application instructions.

 Include minimum spray volume of 10 gallons per acre (GPA) for grape, pome fruit, and stone fruit.

 Add language to indicate that feeding of peanut hay to livestock is prohibited.

 Add language to indicate that addition of adjuvants to the sugar beet, peanut, grape, stone fruit, and pome fruit spray mixtures is prohibited.

 Add directions to indicate that following application to peanut, treated fields may only be rotated to a labeled crop.

 Add directions to indicate that following application to all other crops, treated fields may be rotated to a labeled crop at any time or may be rotated to cotton, sweet corn, field corn, field corn grown for seed, and popcorn 180 days after application; ro tation to any other crop is prohibited.

o Revised Section F specifying the following tolerances for residues of flutriafol:

 Primary crops ( § 180.629(a))

fruit, pome, group 11

- 09: 0.40 ppm fruit, stone, group 12

- 10: 1.5 ppm grape: 1.5 ppm grape, raisin: 2.4 ppm banana: 0.30 ppm peanut: 0.09 ppm beet, sugar: 0.08 ppm

 Rotational crops ( § 180.629(d))

corn, sweet, forage: 0.09 ppm corn, sweet, stover: 0.07 ppm corn, sweet, kernel plus cob with husk removed: 0.01 ppm corn, field, forage: 0.09 ppm corn, field, stover: 0.07 ppm corn, field, grain: 0.01 ppm corn, field, refined oil: 0.02 ppm corn, pop, stover: 0.07 ppm corn, pop: 0.01 ppm cotton, undelinted seed: 0.01 ppm cotton, gin byproducts: 0.02 ppm

 The following field rotational crop residue data conducted as specified in OPPTS 860.1900 are requested:

 sweet corn

- North American Free Trade Agreement (NAFTA) Growing Zones 10 (n=1) and 11 (n=1), and

 cotton

- NAFTA Growing Zones 8 (n=4) and 10 (n=3).Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 8 of 45 

### Occupational and Residential Exposure

Post

- application dermal risks were identified for detasselling of corn and girdling/turning of grapes. For these crop/activity combinations, an acceptable MOE (i.e., MOE > 100) is not reached until Day 5 after app lication. The high

- contact activities for grapes are only expected to occur for cultivation of table grapes. The high

- contact activity for corn is only expected to occur for field corn or popcorn grown for seed. RD should ensure that the appropriate REI is added to the label for these crops. In addition, under 40 CFR Part 158:1070, DFR data is required to further refine risk estimates.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical 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). The method employed in the magnitude of the residues studies is based on the current soybean tolerance e nforcement method. Based on this, and since adequate method validation data were provided as part of the magnitude of the residue studies, HED concludes that the soybean tolerance enforcement method is adequate to enforce the recommended tolerances. In a ddition, the QuEChERS method has been shown to adequately quantify residues of flutriafol ( http://www.crl

pesticides.eu/library/docs/fv/CRLFV_Multiresidue_methods.pdf ).

Livestock HED has previously concluded that method ICIA AM00306 (revisions of 13

- Aug

- 2007 and 8

- Oct

- 2007) is appropriate for enforcement of the currently established ruminant liver tolerances and forwarded the method to the Food and Drug Administrati on (FDA) for inclusion in the Pesticide Analytical Manual (PAM) (D362421, T. Bloem, 11

- Mar

- 2009). HED is not currently recommending for the establishment of any new livestock tolerances.

2.2.2 International Harmonization

Codex, Canadian, and Mexican m aximum residue limits (MRLs) have not been established for flutriafol; therefore, harmonization is not an issue.

2.2.3 Recommended Tolerances

Table 2.2.3 is a summary of the HED

- recommended tolerances for residues of flutriafol. As a

result of the proposed uses, HED is establishing rotational crop tolerances ( § 180.629(d)). The tolerance expression for § 180.629(d) should be as follows (the current tolerance expression for § 180.629(a) is appropriate):

§ 180.629(d): Tolerances are established for residues of flutriafol, including its metabolites and degradates, in or on the commodities listed below. Compliance with the following tolerance levels is to be determined by measuring only flutriafol ((±)

- α

- (2

- fluorophenyl)

- α

- (4

- fluorophenyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol).Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 9 of 45 

### A revised Section F is requested, which eliminates those commodities for which tolerances are unnecessary or inappropriate and which specifies the correct tolerance definition, commodity

def inition, and/or numerical tolerance.

Table 2.2.3. Tolerance Summary for Flutriafol.

Commodity Proposed

Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments

§ 180.629(a)
fruit, pome, group 11

- 09 0.60 0.40 Revised Section F with the correct commodity definition and/or tolerance level is requested.

a Sugar beet top are no longer considered feed commodity and HED is requesting a revised Section B prohibiting the feeding of peanut hay to livestock; therefore, tolerances on these commodities are not

recommended.

b Based on the sugar beet processing stu dy, refined sugar, molasses, and dried pulp tolerances are

unnecessary.

c HED concludes that the currently established ruminant and hog tolerances are adequate. fruit, stone, group 12

- 10 0.80 1.5

grape 1.1 1.5 grape, raisin 2.5 2.4

banana 0.50 0.30

peanut 0.08 0.09 peanut, hay 18

-- a
beet, sugar 0.15 0.08 beet, sugar, top 2.5

-- a
beet, sugar, refined 0.70

-- b

beet, sugar, molasses 1.0

-- b

beet, sugar, dried pulp 1.0

-- b

cattle, liver 0.12

-- c

h orse
, liver 0.12

-- c
goat, liver 0.12

-- c sheep, liver 0.12

-- c

milk 0.02

-- HED determined that registration for application of flutriafol to these crops and/or establishment of these tolerances is inappropriate; additional residue chemistry data are required. corn, field, forage 4.0

-- corn, field, stover 6.0

-- corn, field, grain 0.01

-- corn, field, flour 0.03

-- corn, field, refined oil 0.07

-- corn, field, meal 0.03

--
corn, pop 0.01

-- corn, pop, stover 6.0

-- wheat, forage 25

-- wheat, hay 9.0

-- wheat, straw 6.0

-- wheat, grain 0.15

-- wheat, bran 0.20

-- wheat, germ 0.20

-- triticale, grain not proposed

-- barley, hay 9.0

-- barley, straw 6.0

-- barley, grain 0.15

-- barley, grain, bran 0.20

-- buckwheat, grain 0.15

-- oat, forage 25

-- oat, hay 9.0

-- oat, straw 6.0

-- oat, grain 0.15

-- oat, grain, bran 0.20

-- rye, forage 25

-- rye, straw 6.0

-- rye, grain 0.15

-- § 180.629(d)
corn, sweet, forage 0.05 0.09 A revised Section F is requested which proposes the correct commodity definition and/or numerical tolerance is requested. corn, sweet, stover 0.09 0.07
corn, sweet, K+CWHR 1 0.01 0.01 corn, field, forage 0.10 0.09
corn, field, stover 0.07 0.07 corn, field, grain 0.01 0.01Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 10 of 45 Table 2.2.3. Tolerance Summary for Flutriafol.

Commodity Proposed

Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments

corn, field, refined oil

-- 0.02

corn, pop, stover not proposed 0.07

corn, pop not proposed 0.01
cotton, undelinted seed 0.01 0.01 cotton, gin byproducts 0.05 0.02

1 . K + CWHR = kernel plus cob with husk removed.



### 2.2.4 Revisions to Petitioned

- For Tolerances

HED is not recommending for the proposed field corn, popcorn, and small grains registration due to several residue chemistry data deficiencies including issues concerning the nature/magnitude

of the residue in ruminants at the dietary burdens associated with these crops [for a full discussion see D388603 (T. Bloem, 16

- Jun

- 2011)]. As a result, revisions to the currently established liver (cattle, goat, horse, and sheep) tolerances and establishment of a milk tol erance are unnecessary. In addition, sugar beet tops are no longer considered feed commodity and HED is requesting a revised Section B prohibiting the feeding of peanut hay to livestock; therefore,

tolerances on these commodities are not recommended. For the remaining crops, the HED

recommended tolerances are based on the magnitude of the residue data and the Organization for

Economic Co

- operation and Development (OECD) MRL Calculator.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Removal of corn (field corn, field corn for seed, and popcorn) and small grain application

instructions. Include minimum spray volume of 10 GPA for grape, pome fruit, and stone fruit. Add language to indicate that feeding of peanut hay to livestoc k is prohibited. Add language to indicate that addition of adjuvants to the sugar beet, peanut, grape, stone fruit, and pome fruit spray mixtures is prohibited. Add directions to indicate that following application to peanut, treated fields may only be rotated to a labeled crop. Add directions to indicate that following application to all other crops, treated fields may be rotated to a labeled crop at any time or may be rotated to cotton, sweet corn, field corn, field corn grown for seed, and popcorn 180 days after application; rotation to any other crop is prohibited.

2.3.2 Recommendations from Occupational Assessment

RD should ensure that the appropriate REI is added to the label.

3.0 Ingredient ProfileFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 11 of 45 

### 3.1 Chemical Identity

Table 3.1. Flutr iafol Nomenclature.

Chemical structure

Common name Flutriafol

Company experimental name PP450 (ICI/Syngenta until 2001)

IUPAC name ( RS )

- 2,4’

- difluoro

- α

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)benzhydryl alcohol

CAS name (±)

- α

- (2

- fluorophenyl)

- α

- (4

- fluorophenyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol

CAS registry number 76674

- 21

- 0

End

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

- XXX)



### 3.2 Physical/Chemical Characteristics

Table 3.2. 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/cm3

Water solubility 95 mg/L at 20 oC

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

- Dichloroethane 19

- 20

Acetone 116

- 135 Ethyl acetate 29

- 34

Methanol 115

- 134

n

- Heptane <10 Xylene <10

Vapor pressure 4 x 10
- 7 Pa at 20 oC

Dissociation constant, pKa 2.3 at 25 oC

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

UV/visible absorption spectrum

-- Not available



### 3.3 Proposed Use Pattern

The petitioner submitted a draft label for the 1.04 lb ai/gal suspension

- concentrate (SC) formulation (Topguard ® 

### Fungicide, EPA File Symbol No. 67760

- 75; equivalent to flowable concentrate (FlC)). Table 3.3.1 is a summary of the proposed formulation, crops, and targeted pests. Table 3.3.2 is a summary of the proposed application scenarios. Tables 3.3.1 and 3.3.2 also include a summary of the Colombia n, Brazilian, and Malaysian labels provided by the petitioner concerning application to imported bananas.

For the remaining proposed crops, HED requests that the label be revised to indicate the following: (1) removal of corn (field corn, field corn for seed, and popcorn) and small grain application instructions; (2) minimum spray volume of 10 GPA for grape, pome fruit, and stone fruit; (3) feeding of peanut hay to livestock is prohibited; (4) addition of adjuv ants to the sugar beet, peanut, grape, stone fruit, and pome fruit spray mixtures is prohibited; (5) followingFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 12 of 45 

### application to peanut, treated fields may only be rotated to a labeled crop; and (6) following application to all other crops, treated fields may be rotated to a labeled crop at any time or may be rotated to cotton, sweet corn, field corn, field corn grown for seed, and popcorn 180 days after application; rotation to any other crop is prohibited.

Table 3.3.1. Summary of Proposed End

- Use Product s.

Trade Name EPA Reg.

No. Concentration Formulation Type Label Date Target Crops Target Pests

Proposed U.S. Section 3 Registrations

Topguard ®
Fungicide 7969

- 278 1.04 lb ai/gal SC not indicated field corn gray leaf spot, northern/southern leaf blight, rust, eyespot,
anthracnose

grapes powdery mildew, black rot

peanuts early and late leaf spot, leaf rust,

leaf scorch/pepperspot, web blotch

pome fruit scab, powdery mildew, quince

rust, cedar apple rust, pear scab

stone fruit brown rot, powdery mildew,

cherry leaf spot

sugar beets cercospora leafspot, powdery

mildew

small grains rust, powdery mildew, leaf and

glum blotch, fusarium head blight Banana (import tolerance)

Pointer ® 250 SC ( Colombia ) -- 250 g ai/liter;

SC not
indicated banana black sigatoka

Potenzor ®

(Brazil) -- 125 g ai/ liter leaf spot; black leaf straek

Pointer Racun

Kulat -- 125 g ai/liter yellow sigatoka

Table 3.3.2. Summary of Proposed Application Scenarios.

App. Timing; Type; and Equip. Formulation

(EPA Reg. No.) App. Rate

(lb ai/acre) Max. #.

App. per

Season Max. Seasonal

App. Rate (lb ai/acre) PHI

(days) Use Directions and Limitations

corn (field corn, field corn grown for seed, and popcorn)

Post

- emergence; foliar broadcast 1.04 lb/gal SC

(67760

- 75) 0.057

- 0.114 2 0.228 0

- forage

7

- stover and grain Apply in a minimum of 10 GPA

with ground equipment or in a

minimum of 5 GPA with aerial equipment. Minimum retreatment interval (RTI) of 7 days.

grape

Post

- emergence (beginning at 6

- 10 inch shoots);

foliar broadcast 1.04 lb/gal SC

(67760

- 75) 0.065

- 0.081 6 0.488 14 Sufficient water to insure uniform coverage. Minimum RTI of 14

days.

peanut

Post

- emergence; foliar broadcast 1.04 lb/gal SC

(67760

- 75) 0.057

- 0.114 4 0.455 7 Apply in a minimum of 10 GPA. Minimum RTI of 14 days.
pome fruit (apple, crabapple, loquat, mayhaw, pear, Oriental pear, and Quince)

Post

- emergence; foliar broadcast 1.04 lb/gal SC

(67760

- 75) 0.065

- 0.106 4 0.423 14 Sufficient water to insure uniform

coverage. Minimum RTI of 10

days.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 13 of 45 Table 3.3.2. Summary of Proposed Application Scenarios.

App. Timing; Type; and Equip. Formulation

(EPA Reg. No.) App. Rate

(lb ai/acre) Max. #.

App. per

Season Max. Seasonal

App. Rate (lb ai/acre) PHI

(days) Use Directions and Limitations

stone fruit (sweet cherry, tart cherry, apricot, nectarine, peach, plum, chicksaw plum,

damson plum, Japanese plum, plumcot, and prune)

Post

- emergence; foliar broadcast 1.04 lb/gal SC

(67760

- 75) 0.114 4 0.455 7 Sufficient water to insure uniform coverage. Minimum RTI of 7 days.
sugar beet

Post

- emergence; foliar broadcast 1.04 lb/gal SC

(67760

- 75) 0.081

- 0.114 2 0.228 21 Apply in a minimum of 10 GPA with ground equipment or in a

minimum of 5 GPA with aerial equipment. Minimum RTI of 21

days.
wheat (spring and winter), barley, triticale, buckwheat, oats, rye, teosinte

Post

- emergence; foliar broadcast 1.04 lb/gal SC

(67760

- 75) 0.057

- 0.114 2 0.228 0

- forage

15

- hay

30

- grain Apply in a minimum of 10 GPA

with ground equipment or in a

minimum of 5 GPA with aerial equipment. Minimum RTI of 7

days.
banana (import tolerance)

Post

- emergence; foliar broadcast 125

- 250 g ai/L

SC 0.089

( Colombia )

0.167 (Brazil)

0.138 (Malaysia) 8

( Colombia )

4 (Brazil)

5 (Malaysia) 0.712

( Colombia )

0.668 (Brazil)

0.690 (Malaysia) 0

( Colombia )

3 (Brazil)

14 (Malaysia) The Brazilian label indicates the

following: apply using knapsack or tractor mounted spray using a mineral oil adjuvant (25% or 100%); spray volumes of 4

- 5 GPA; and RTI

= 14 days.

The Colombia n label indicates the following: dilute with water and apply using conve ntional equipment (spray volume and RTI are not indicated).

The Malaysian label indicates the following: apply using knapsack or motorized sprayer; addition of a nonionic surfactant (0.1%) is recommended; spray volumes of ~50 GPA; and RTI = 14 days.



### 3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new uses of

flutriafol on corn, grapes, peanuts, pome fruit (group 11), stone fruit (group 12), sugar beets, wheat, barley, triticale, buckwhe at, oats, rye, and teosinte . Humans may be exposed to flutriafol in food and drinking water, since flutriafol may be applied directly to growing crops and application may result in flutriafol reaching surface and ground water sources of drinking water.

Th ere are no residential uses of flutriafol, so there is not likely to be exposure in residential or

non

- occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during applic ation. There is also a potential for post

application exposure for workers re

- entering treated fields.

Risk assessments have been previously prepared for the existing uses of flutriafol . This risk assessment considers all of the aforementioned exposure pathways based on the proposed newFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 14 of 45 

### uses of flutriafol, but also considers the existing uses as well, particularly for the dietary

exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential

setti ng. Extensive data on food consumption patterns are compiled by the USDA under the 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 e xposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OP P 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

Flutriafol is a member of the conazole triazole class of pesticides. The triazole fungicides inhibit one specific enzyme, 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 f lutriafol in sufficient quantities may lead to toxicity.

4.1 Toxicology Studies Available for Analysis

Flutriafol has been evaluated extensively for its toxicity and mode of action. Its toxicity database is adequate to support registration. In the last risk assessment ( D372347, K. Lowe et al. , 16

- Dec

- 2009 ), one toxicology data requirement was identified; a guideline immunotoxicity study. This study is now required under the 40 CFR Part 158 for conventional pesticide registration.

This stud y has been recently submitted and is pending review. To confirm the results from earlier reproductive and genotoxicity data, Cheminova submitted newer reproduction (2) and genotoxicity (3) guideline studies. The preliminary 1

- generation reproduction toxi city study is classified unacceptable/guideline and is supplemental to the 2

- generation reproduction study. The evaluation of these reproductive toxicity studies and the genotoxicity studies are included in

this hazard assessment. Finally in the last ris k assessments, the 1982 rat prenatal developmental study was considered unacceptable/guideline. Upon further review, this study was found to be acceptable/guideline. No mistakes were found in this study, only a change in the classification

has occurred.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 15 of 45 

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

Flutriafol is quickly absorbed, extensively metabolized, and eliminated within 48 hours regardless of sex, dose, or 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. I n 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 glands. The total amount of radioactivity isola ted in the tissues and carcass was <1

- 3% of the total dose, and bioaccumulation was considered unlikely. The parent compound was isolated in only trace amounts in the urine and feces, and more than 19 metabolites were isolated, indicating extensive metabo lism.

4.2.1 Dermal Absorption

An in vivo rat dermal

- absorption study is available for flutriafol that is acceptable and indicates that the absorption is 17%, 21%, and 11%, respectively, at 2, 20, and 200 μg/cm 2 

### , following a

10

- hour exposure. A value o f 21% is appropriate (most protective) for dermal risk assessments.

4.3 Toxicological Effects

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

Short

- term, subchroni c, 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 p hosphatase), 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 p rogression 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 K upffer 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 investigate d in three developmental toxicity studies (two in rats, one in rabbits) and two multi

- generation reproduction toxicity studies in rats. In the first of two rat developmental toxicity studies, a quantitative susceptibility was observed ( delayed ossificatio n or non

- ossification of the skeleton in the fetuses) at a lower dose than maternal effects. In the second rat developmental study, aFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 16 of 45 

### qualitative susceptibility was noted. Although developmental toxicity occurred at the same dose

level that elicited mate rnal 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 of fspring [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 r esolved by Day 8.

All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. Several triazoles are carcinogenic. Even though structure

- activity

- relationship (SAR) analysis indicates that flutriafol has the potential to produce thyroid and/or liver tumors in rodents, neither the chronic/carcinogenicity study in rats or the carcinogenicity study in mice revealed treatment

related increases in tumor incidences. Flutriafol is thus considered to be ―Not likely to be Carcinog enic to Humans‖ based on the results of these carcinogenicity studies in rats and mice.

4.4 SF for Infants and Children (FQPA SF)

HED’s RAB1 risk assessment team concluded that based on toxicological considerations and the residue assumptions used in the dietary exposure analyses (no residential uses), the FQPA SF may be reduced to 1X.

4.4.1 Completeness of the Toxicology Database

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

accepta ble studies are availa ble: Developmental toxicity studies in rats and rabbits (3)

T wo

- generation reproduction studies in rats (2)

Acute (1) and Subchronic (1) neurotoxicity studies in rats

An Immunotoxicity study

The immunotoxicity study for f lutriafol has been received. A preliminary review of the study indicates that there is no concern for immunotoxicity. A formal review is pending.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 17 of 45 

### 4.4.2 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

neurotoxicit y. In addition, there was no evidence of neurotoxicity in any additional short

- term studies in rats, mice, and dogs, or in the long

- term toxicity studies in rats, mice, and dogs. A DNT study is not required.

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

There are no concerns or residual uncertainties for pre

- and/or post

- natal toxicity. There is evidence for increased qualitative susceptibility in a prenatal study in rats and rabbits and the two generation reproduction s tudy in rats; however, there is no concern for these observations since: 1) clear NOAELs and LOAELs were established in the fetuses/offspring; 2) the dose

- response for these effects are well defined and characterized; 3) developmental endpoints are used f or assessing acute dietary risks to the most sensitive population (females 13

- 49) as well as all other

short

- and intermediate

- term exposure scenarios; and 4) the chronic reference dose is greater

than 300

- fold lower than the doses at which the offspring e ffects were observed in the 2

- generation reproduction studies

.

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and POD Selections

4.5.1 Dose

- Response Assessment

There are no changes to the endpoints used in the last risk assessment ( D372347, K . Lowe et al.

, 16

- Dec

- 2009 ).

Acute Dietary Endpoint (General Population): The acute neurotoxicity screening battery in the rat was selected for the acute dietary endpoint for the general population. An UF of 100 (10

- fold for interspecies extrapolation and 10

- fold for intraspecies variability) was applied to the NOAEL

of 250 m g/kg to generate the aRfD of 2.5 mg/kg for the general population. The LOAEL is 750 mg/kg based on decreased body weight, body

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

- stained abdominal fur, ung roomed coat, ptosis, decreased motor activity, prostration, limp muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired or lost righting reflex, and scant feces), in males (red or tan perioral substance, chromodacryorrhea, chromorhinorrhea, labored breathing, and slight ataxia), and in females (piloerection and bradypnea). This study is appropriate for the expected duration of exposure, and is protective for potential neurotoxic effects due to acute exposure to flutriafol. The only other s tudy considered for this endpoint was the subchronic neurotoxicity study.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 18 of 45 

### Acute Reference Dietary Endpoint (Females 13

- 49 years old ): The prenatal developmental toxicity study in rabbits was selected for the acute dietary endpoint for females 13

- 49 years of age. An UF of 100 (10

- fold for interspecies extrapolation and 10

- fold for intraspecies variability) was applied to the developmental NOAEL of 7.5 mg/kg to generate the aRfD of 0.075 mg/kg for females 13

- 49 years of age. The developmental LOAEL of 15 mg/kg is b ased 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 ou tcome of 1

- 2 days of single dosing. The only other studies considered for this endpoint were the prenatal developmental studies in rats, where the developmental NOAELs were 10 mg/kg (both) and the developmental LOAELs were 50 mg/kg based upon delayed ossi fication or non

- ossification of the skeleton in the fetuses (1982),

and 75 mg/kg based upon increased late resorptions, malformations (cleft palate and multiple), and variations in the hyoid (neck bone), variations in the maxilla/mandible, rudimentary and long cervical ribs, pelvic girdle, and radius/ulna; numerous skeletal retardations detailed above, and corresponding decrease in fetal weights (2008). The rabbit study is protective of the effects seen in these rat studies. It also the most protective st udy for this endpoint for the population of concern (pregnant females and fetuses).

Chronic Dietary Endpoint (RfD): The chronic dog toxicity study was selected for the chronic dietary endpoint for the general population. An UF of 100 (10

- fold for inters pecies extrapolation

and 10

- fold for intraspecies variability) was applied to the NOAEL of 5 mg/kg/day to generate the cRfD of 0.05 mg/kg/day for the general population. 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 bot h 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

- and 90

- day dog oral toxicity studies provide NOAEL/LOAELs and toxic effects of the same kind (adverse liver effects) as the chronic dog study. Other studies considered for this endpoint were the chronic/carcinogenicity studies (mouse and rat), as well as the 2

- generation reproduction studies where similar effects were seen at slightly higher doses.

Dermal Absorption Factor: From the in vivo rat dermal

- absorption study, a value of 21% is appropriate (most protective) for dermal risk assessments.

Short

- and Intermediate

- Term Dermal and Inhalation Endpoint: The prenatal developmental toxicity study in rabbits was selected for the short

- and intermediate

- term dermal and inhalation endpoints. The developmental NOAEL is 7.5 mg/kg/day and the LOAEL is 15 mg/kg/day, based on decreased number of live fetuses, comp lete litter resorptions and increased post

implantation loss. Although maternal and developmental toxicity were observed at the same dose, the maternal effects were restricted to moderate decreases in 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 r oute

- specific 28

- day dermal toxicity study was also considered for this endpoint, but there was no toxicity observed up to the limit dose (1000 mg/kg/day). Without being able to use theFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 19 of 45 

### route

- specific repeated dose dermal study, this study is the most pro tective study for the populations of concern (pregnant females and fetuses). The only other studies considered for this endpoint were the 90

- day dog and the 2

- generation reproduction studies (parental effects) where liver toxicity (the target organ) was o bserved 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.

Using a dermal

- absorption factor of 21%, the dermal

- equivalent NOAE L is ~35.7 mg/kg/day (NOAEL of 7.5 mg/kg/day / 21% dermal absorption = 35.7 mg/kg/day).

Based on the available toxicity database and the Agency's current practices, the inhalation risk for flutriafol is assessed using an oral toxicity study. A 100% inhal ation

- absorption factor will be assumed and applied for oral to inhalation extrapolation. The Agency sought expert advice and input on issues related to this route

- to

- route extrapolation approach (i.e., the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htm l 

### ). The Agency is in the process of evaluating the SAP report and may, as appropriate, re

- examine and develop new policies and procedures for conducting inhalation risk assessments, including route

- to

- route extrapolation of toxicity data. If any new poli cies or procedures are developed, then the Agency may revisit the need for an inhalation toxicity study for flutriafol and/or a re

- examination of the inhalation toxicity risk assessment.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Asses sment

Since short

- and intermediate

- term dermal and inhalation endpoints are based on oral studies, dietary exposure will be aggregated with residential dermal and inhalation exposures for all populations/durations.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Flutriafol is considered to be ―Not likely to be Carcinogenic to Humans‖ based on the results of the carcinogenicity studies in rats and mice. The results of the rat chronic toxicity/carcinogenicity study and the mouse carcinoge nicity study are negative for carcinogenicity. All genotoxicity studies on flutriafol showed no evidence of clastogenicity or mutagenicity. Although several triazoles are carcinogenic, many are not and flutriafol has been adequately tested and found not to be carcinogenic in long

- term studies in rats and mice.

SAR analysis indicates that flutriafol may have the potential to produce thyroid and/or liver tumors in rodents. However, in the rat and mouse carcinogenicity studies, there were no

treatment

- related increases in tumor incidence when comparing treated animals to controls.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

The points of departure, uncertainty factors, and toxicity endpoints are presented in Table 4.5.4a (dietary and non

- occupational assessments) and Table 4.5.4b (occupational assessmen ts).Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 20 of 45 Table 4.5.4a. 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 UF A = 10X

UF H = 10X FQPA SF = 1X Acute RfD = 2.5

mg/kg/day

aPAD = 2.5 mg/kg/day Neurotoxicity screening battery

– rat

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

- weight gain, absolute and relative food consumption, and clinical signs of toxicity in both sexes: dehydration, urine

- stained abdominal fur, ungroomed coat, ptosis, decreased motor activity, prostrati on, 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 brad ypnea.
Acute Dietary (Females 13

- 49 years of age) NOAEL =

7.5 mg/kg UF A = 10X

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

mg/kg/day

aPAD = 0.075 mg/kg 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 UF A = 10X

UF H = 10X FQPA SF = 1X Chronic RfD =

0.05 mg/kg/day

cPAD = 0.05 mg/kg/day Chronic toxicity

– dog

LOAEL = 20 mg/kg/day, based on adverse liver findings (increased liver weights, increased centrilobular hepatocyte lipid in the liver, and increases in alkaline phosphatase, albumin, and triglycerides), increas ed 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 wei ght losses, decreased cumulative body

- weight gains, and increased adrenal weights in the females. Cancer (oral, dermal, inhalation) Classification: ―Not likely to be Carcinogenic to Humans‖ based on the carcinogenicity studies in rats and mice.

Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed

adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies ). FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of

concern.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 21 of 45 Table 4.5.4b. Summary of Toxicological Doses and Endpoints for Flutriafol for Use in Occupational

Human Health Risk Assessments.
Exposure/

Scenario POD UFs LOC Risk

Assessment Study and Toxicological

Effects

Dermal Short (1

- 30 days)

- and

Intermediate (1

- 6 months)

- Term NOAEL= 7.5

mg/kg/day

1 Dermal

absorption

factor = 21% UF A = 10X

UF H = 10X Occupational

LOC for MOE

= 100 Developmental toxicity

–

rabbit Developmental LOAEL = 15 mg/kg/day, based on

decreased number of live fetuses, 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

2 Inhalation

absorption

factor = 100% UF A = 10X

UF H = 10X Occupational

LOC for MOE

= 100 Developmental toxicity

–

rabbit Developmental LOAEL = 15 mg/kg/day, based on

decreased number of live fetuses, complete litter resorptions and increased

post

- implantation loss.

Cancer (oral, dermal, inhalation) Classification: ―Not likely to be Carcinogenic to Humans‖ based on the ca rcinogenicity 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 r elevant human exposures. NOAEL = no

- observed

adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members o f the human population (intraspecies). MOE = margin of exposure. LOC = level of concern.



### 4.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a ―naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.‖ The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal system s. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on th e available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA iss ued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and wate r, residential activity, and certain post

- applicationFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 22 of 45 

### agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Flutriafol was not among the group of 58 pesticide active ingredients on the initial list t o be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

- ins for all pesticide active ingredients.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

Based on structural similarity, HED concludes that the defluorinated, hydroxylated, and glucoside flutriafol metabolites identified in the plant and livestock metabolism studies are not likely to be more toxic than flutriafol. HED has previously reviewed toxicological data for T, triazole alanine (TA), triazole acetic acid (TAA), and triazole lactic acid (TLA) and concluded that the toxicological effects of T and TA/TAA/TLA are different from each other (D322215, M. Doherty et al. , 07

- Feb

- 2006). Based on these data and the flutriafol toxicological data, HED concludes that the toxicological effects of T and TA/T AA/TLA are

different from that of flutriafol.

5.1.1 Summary of Plant and Animal Metabolism Studies

Nature of the Residue

- Primary Crops: The petitioner submitted adequate apple, sugar beet, and rapeseed metabolism studies conducted with [triazole

- 3,5

- 14 

### C]flutriafol and [carbinol

14 

### C]flutriafol (1 × 0.10

- 0.12 lb ai/acre). The radiolabel position did not affect total radioactive residues (TRRs) or the metabolic profile for rapeseed (forage, pod, and mature seed; PHI = 0

- 21 days) or sugar beet tops (TRR s in root were too low for a comparison; PHI = 0

- 21 days); for apple (PHI = 64 days), TRRs were slightly higher following treatment with [triazole

- 3,5

- 14 

### C]flutriafol, but the resulting metabolic profiles did not vary with radiolabel position. Flutriafol ( 50

- 96% TRR) was the major residue identified in apple, rapeseed (foliage, pod, and seed), and sugar beet tops (TRR in roots too low for identification). Defluorinated flutriafol (12

- 14% TRR) and conjugated flutriafol (27

- 28% TRR) were identified at signif icant concentrations in rapeseed pod. All other identified/unknowns were ≤8% TRR (T, TA, and TAA were not identified). HED notes that the petitioner also submitted wheat and barley metabolism studies (foliar and seed treatment). Although these studies w ere found to be unacceptable due to numerous deficiencies, the resulting metabolic profiles were similar to that for apple, sugar beet, and rapeseed.

Based on these data, the HED Residues of Concern Knowledgebase Subcommittee (ROCKS)

concluded that the residues of concern in apple and dried soybean seed are flutriafol, T, TA, and TAA, and the residue of concern for tolerance enforcement is flutriafol per se (D355605, R. Daiss, 03

- Aug

- 08) . Defluorinated flutriafol and conjugated flutriafol were not inclu ded as residues of concern as apple and dried soybean seed do not possess a commodity similar to rapeseed pod (label prohibits feeding/foraging soybean forage/hay and use will be restricted to only soybean harvested for the dried seed). T, TA, and TAA wer e included as residues of concern as they were identified in the apple and soybean field trial studies and/or to be consistent with the other triazole fungicides.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 23 of 45 

### HED concludes that the previous decision regarding the residues of concern in apple and dried soybean seed may be translated to the requested fruit crops and to sugar beet (note the previous decision considered a sugar beet metabolism study). Adequate pea nut and cereal grain metabolism studies have not been submitted; however, the petitioner has submitted adequate metabolism data on three diverse crops and these data resulted in a similar metabolic profile. Based on the available data (including the rapes eed pod data), HED concludes that the residues of concern in peanut and cereal grains for tolerance enforcement is flutriafol per se and the residues of concern for risk assessment are flutriafol (free and conjugated), defluorinated flutriafol, T, TA, and TAA. The combined residues of flutriafol (free and conjugated) and defluorinated flutriafol may be estimated by multiplying the free flutriafol residue by 2.2. Table 5.1.4 is a summary of the residues of concern in the proposed/registered crops.

Natur e of the Residue

- Rotational Crops: The petitioner recently submitted a confined rotational crop study, which involved a single bare soil application of [carbinol

14 

### C]flutriafol or [triazole

- 3,5

- 14 

### C]flutriafol at 0.22 lb ai/acre with wheat, lettuce, or r adish planted 30, 120, and 365 days after application. Based on these data, HED concluded the following: (1) the residue of concern in rotational crops for tolerance enforcement is flutriafol per se ; (2) the

residues of concern for risk assessment in all rotational crops, excluding dried roughage feed commodities, are flutriafol (free and conjugated), M28, T, TA (free and conjugated), TAA, and TLA [combined flutriafol (free and conjugated) and M28 may be estimated by multiplying the free flutriafol residu e by 1.3x]; and (3) for the dried roughage feed commodities, the residues of concern for risk assessment will be same as that mentioned above, but with multiplication of the free flutriafol residues by 2.5x to account for the

combined residues of flutriafo l (free and conjugated), M28, and the uncharacterized residues in the post

- extraction solids (PES) for wheat straw samples collected from the [carbinol

14 

### C]flutriafol treated plots. Table 5.1.4 is a summary of the residues of concern in rotational

crops.

Nature of the Residue

- Poultry: Based on the poultry metabolism studies conducted with [triazole

- 3,5

- 14 

### C]flutriafol (13.9 ppm) and [carbinol

14 

### C]flutriafol (11.6 ppm), ROCKS

concluded that the residue of concern for tolerance enforcement was flutriafol per se and the residues of concern for risk assessment were flutriafol, T, TA, and TAA (D355605, R. Daiss, 03

- Aug

- 08) . Residues of TA and TAA were included as residues of concern due to their presence in feed commodities. M3 was excluded as a residue of concern since residues are expected to be negligible when normalized to the dietary burden at that time. HED noted that if the poultry dietary burden increased, then these conclusions would be revisited and poultry metabolism studies conducted as specifie d in OPPTS 860.1300 with [carbinol

14 

### C]flutriafol and [triazole

- 3,5

- 14 

### C]flutriafol may be required.

With inclusion of the residues of concern in rotational crops and the conclusions concerning the residues of concern in peanut and small grains, the resi due of concern in poultry for

tolerance enforcement remains as flutriafol per se , while the residues of concern for risk assessment are now flutriafol (free and conjugated), defluorinated flutriafol, M28, T, TA (free and conjugated), TAA, and TLA. Residue s of conjugated flutriafol, defluorinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concern due to their presence in feed commodities. Table 5.1.4 is a summary of the residues of concern in poultry.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 24 of 45 

### The poultry maximum reasonable dietary burdens (MRDBs) for tolerance enforcement/risk assessment as a result of all registered/proposed uses are 0.096/0.098 ppm (dietary burdens to flutriafol and the residues of concern identified as being toxicologically identical t o flutriafol). Based on these dietary burdens, HED concludes that the previously submitted poultry metabolism studies are adequate and the conclusions concerning the residues of concern in poultry summarized in the previous paragraph and in Table 5.1.4 ar e appropriate.

Nature of the Residue

- Ruminants: Based on a dairy cow metabolism study conducted with [triazole

- 3,5

- 14 

### C]flutriafol (2 ppm), the ROCKS concluded that the residue of concern

for tolerance enforcement is flutriafol per se and the residues of concern for risk assessment are flutriafol, M1B, T, TA, and TAA for the following reasons: (1) based on (a) the SAR analysis, which did not result in alerts for potential flutriafol metabolites without the triazole ring; (b) the rat metabolism study, which resulted in the identification of a metabolite without the triazole ring in urine and feces (M18; <1

- 8% of the administered dose); and (c) the fact that developmental toxicity demonstrated for many of the triazole fungicides, including flutriafol, is likely a result of the triazole ring, HED concludes that flutriafol metabolites without the triazole ring are not likely to be more toxic than parent (a [carbinol

14 

### C]flutriafol ruminant metabolism study has not been submitted); (2) based on the TRRs

from the [triazole

- 3,5

- 14 

### C]flutriafol dairy cow metabolism study (10x the MRDB at that time) and because the hen metabolism study resulted in higher TRRs following dosing with [triazole

- 3,5

- 14 

### C]flutriafol as compared to [carbinol

14 

### C]flutriafol, residues in al l ruminant commodities, excluding liver and kidney, are expected to be insignificant (TRRs from the [triazole

- 3,5

- 14 

### C] flutriafol ruminant metabolism study: liver

- 0.291 ppm; kidney

- 0.061 ppm; all other tissues ≤0.01 ppm; and milk

- ≤0.008 ppm (TRRs in milk appeared to plateau by day 4)); and (3) the ruminant feeding studies resulted in low flutriafol per se residues when normalized to 1x the MRDB at that time (liver ≤0.013 ppm; kidney ≤0.002 ppm; fat ≤0.002 ppm; muscle ≤0.0008 ppm; and milk <0.001 ppm) . Residues of TA and TAA were included as residues of concern due to their presence in feed commodities. HED noted that if the ruminant dietary burden increased, these conclusions will be revisited and ruminant metabolism studies conducted as specified i n OPPTS 860.1300 with [carbinol

14 

### C]flutriafol and [triazole

- 3,5

- 14 

### C]flutriafol may be required.

With inclusion of the residues of concern in rotational crops and the conclusions concerning the residues of concern in peanut and small grains, the residue o f concern in ruminants for

tolerance enforcement remains as flutriafol per se while the residues of concern for risk assessment are now flutriafol (free and conjugated), defluorinated flutriafol, M28, M1B, T, TA (free and conjugated), TAA, and TLA. Residu es of conjugated flutriafol, defluorinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concern due to their presence in feed commodities. Table 5.1.4 is a summary of the residues

of concern in ruminants.

The rumi nant dietary burden from only the roughage commodities associated with peanut, field corn, popcorn, and wheat are 5.82 ppm, 12.38 ppm, 5.82 ppm, and 52.80 ppm, respectively (dietary burdens to flutriafol and the residues of concern identified as being

toxi cologically identical to flutriafol). At these dietary burdens, HED concludes that points (2) and (3) above are no longer applicable; therefore, the currently available ruminant metabolism study is not adequate. Ruminant metabolism studies conducted as s pecified in OPPTS 860.1300 with [carbinol

14 

### C]flutriafol and [triazole

- 3,5

- 14 

### C]flutriafol are required prior to registration of flutriafol for use on peanut, field corn, popcorn, and wheat. HEDFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 25 of 45 

### notes that oat and barley field trial data are not available and these data are required for estimation of residues in barley, buckwheat, oat, rye, and teosinte. Based on the requested application scenario for these crops and the wheat field trial data, HED concludes that the requested ruminant metabolism studies w ill likely also be required for barley, buckwheat, oat, rye, and teosinte. For peanut, provided the petitioner prohibits the feeding of peanut hay to livestock, these ruminant metabolism studies will be unnecessary (feeding restrictions for

corn and small grains are not permitted).

With inclusion of the registered crops and the remaining proposed crops (including peanut with the feeding restriction), the MRDBs for tolerance enforcement/risk assessment for beef cattle, dairy cattle, and swine are 0.225/0.2 73 ppm, 0.273/0.305 ppm, and 0.061/0.064 ppm, respectively. Based on these dietary burdens, HED concludes that the previously submitted ruminant metabolism study is adequate and the conclusions concerning the residues of

concern in ruminants summarized ab ove and in Table 5.1.4 are appropriate.

5.1.2 Summary of Environmental Degradation

Flutriafol is expected to be persistent and moderately mobile in the environment, with its major routes of dissipation through biotic degradation. Flutriafol is expected to degrade with a half

- life of more than one year in the environment. Batch equilibrium data on flutriafol suggest that the compound will sorb to soil with moderate affinity, and display moderate mobility (Kd values range from 2.0 to 13.6). The compound does not volatilize significantly, with a partial vapor pressure of 4 x 10 - 7 

### Pa at 20 °C. Therefore, dissipation in the environment is expected to occur via runoff of dissolved residues, and sorption to eroding sediments. Flutriafol leachate is expected to persist in both aerobic and anaerobic soil compartments.

Flutriafol biodegrades with half

- lives of more than a year in both aerobic and anaerobic terrestrial and aquatic environments, and is expected to persist for years in both aerobic an d anaerobic environments. Additionally, flutriafol is stable to both hydrolysis and aquatic photolysis. Dissipation occurred with half

- lives of 106 to 13,566 days in terrestrial field studies, which is consistent with the submitted, laboratory

- derived da ta. Due to the length of the studies, and the persistence of flutriafol, major degradates were not detected in either laboratory or field studies. Minor degradates of flutriafol (which were only reported in two studies: a soil photolysis study and an ana erobic aquatic metabolism study) include: T, TAA, TA, 2,4’

- difluorobenzophenone, and CO 2



### .

5.1.3 Comparison of Metabolic Pathways

In rat metabolism studies, parent was isolated in only trace amounts in the urine and feces (<0.5% of the administered dos e) and more than 19 metabolites were isolated (<0.1

- 16% of the administered dose). In rats, the primary site for metabolism was the 2

- fluorophenyl ring. The initial metabolic step was probably epoxidation followed by either rearrangement to form the dihy drodiol isomers or to form hydroxy or dihydroxy metabolites. The hydroxyl groups on these primary metabolites may then be either conjugated with glucuronic acid or methylated. A second, minor route for metabolism of flutriafol was via the removal of the triazole ring to form

1

- ( 2

- fluorophenyl)

- 1

- (4

- fluorophenyl)

- ethandiol, which is then conjugated with glucuronic acid.

Flutriafol (free and conjugate d ) was the major residue identified in the apple, sugar beet, and rapeseed metabolism studies; defluorinate d flutriafol was also identified in rapeseed. TheFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 26 of 45 

### ruminant metabolism study resulted in TRRs ≤0.01 ppm in all samples, except for liver and kidney. The major residues identified in liver and kidney were flutriafol and M1B (4

- hydroxyflutriafol), with mino r amounts of M1D (4

- hydroxy

- 5

- methoxyflutriafol) also identified. The poultry metabolism study yielded sufficient radioactivity in all matrices for residue identification, with flutriafol and T being the major identified residues. An unknown, M3, was

ide ntified at significant concentrations following dosing with [carbinol

14 

### C]flutriaf ol; M5 (hydroxylated flutriafol ) was also identified, but at an insignificant concentration. The confined rotational crop study resulted in the identification of flutriafol (free and conjugated), TA (free and conjugated), TAA, and TLA along with M28, which was characterized as a glucoside of a flutriafol metabolite, possible a derivative hydroxylated on the phenyl ring.

5.1.4 Residues of Concern Summary and Rationale

Tabl e 5.1.4 is a summary of the residues of concern in primary crops, livestock, and rotational crops (see above for discussion concerning these decisions). Based on the indentified residues of concern and toxicological considerations, HED has determined that the following three dietary risk assessments are required when evaluating exposure to flutriafol: (1) T; (2) TA/TAA/TLA; and (3) flutriafol and the remaining residues of concern.

Defluorinated flutriafol was identified in the canola metabolism study ( pod without the seed

- 12

- 15% TRR (≤0.12 ppm); seed

- 3% TRR (≤0.04 ppm)) indicating that flutriafol may contribute to fluoride dietary exposure. HED has previously conducted dietary exposure analyses for fluoride residues from the insecticides cryolite a nd sulfuryl fluoride as well as from naturally occurring fluoride residues in food and water (D309014, M. Doherty, 12

- Oct

- 2004; D362183, M. Doherty,

6

- May

- 2009). For the following reasons, HED concludes that fluoride residues resulting from the applicatio n of flutriafol are insignificant and revisions to the previous fluoride dietary exposure analyses are unnecessary: (1) based on the identification of defluorinated flutriafol in only the canola metabolism study, HED concludes that defluorinated flutriafo l may be present in only soybean seed and peanut (defluorinated flutriafol was not identified in the apple, sugar beet, rotational crop, and livestock metabolism studies or in the environmental fate/degradation studies) and (2) the fluoride dietary exposur e analyses assumed a background fluoride residue of 0.496 ppm in soybean seed and peanut nutmeat commodities, which is significantly greater than what would be expected based on the canola metabolism study.

Table 5.1.4. Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance Enforcement.

Matrix Residues of Concern

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

flutriafol (free) peanut and cereal grains flutriafol (free and conjugated), defluorinated flutriafol, T, TA, and TAA; combined flutriafol (free and conjugated) and defluorinated flutriafol residues may be estimate by multiplying the free flutriafol residues by 2.2

rotational crops (excluding dried roughage feed commodities) flutriafol (free and conjugated), M28 3 , T, TA (free and conjugated), TAA, and TLA; combined flutriafol (free and conjugated) and M28 3 residue may be estimated by multiplying the free flutriafol residue by 1.3x

rotational crops (dried roughage feed commodities) same as that mentioned above but with multiplication of the free flutriafol residues by 2.5x to account for the combined residues of flutriafol (free and conjugated), M28 3 , and the uncharacterized residue s in the PES for wheat straw samples collected from the [carbinol

- 14C]flutriafol treated plots

poultry 1 flutriafol (free and conjugated), defluorinated flutriafol,

M28 3 , T, TA (free and conjugated), TAA, and TLA

ruminant 2 flutriafol (free and conjugated), defluorinated flutriafol,

M28 3 , M1B 3 , T, TA (free and conjugated), TAA, and TLA
1. HED notes that if the poultry dietary burdens increase, these conclusions will be revisited and poultry metabolism studie s conducted as specified in OPPTS 860.1300 with [carbinol

- 14C]flutriafol and [triazole

- 3,5

- 14C]flutriafol may be required. Residues of conjugated flutriafol,Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 27 of 45 defluorinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concern due to their presence in feed

commodities. 2. HED notes that if the ruminant dietary burden increases, these conclusions will be revisited and ruminant metabolism stud ies conducted as specified in OPPTS 860.1300 with [carbinol

- 14C]flutriafol and [triazole

- 3,5

- 1 4C]flutriafol may be required. Residues of conjugated flutriafol, defluorinated flutriafol, M28, TA (free and conjugated), TAA, and TLA are included as residues of concern due to their presen ce in feed

commodities. 3. M28 = glucoside of a flutriafol meta bolite, possible a derivative hydroxylated on the phenyl ring; M1B = 4

- hydroxyflutriafol.



### 5.2 Food Residue Profile

HED is not recommending for the proposed field corn, popcorn, and small grains registration due to several residue chemistry data deficiencies including issues concerning the nature/magnitude of the residue in ruminants at the dietary burdens associated wi th these crops. For a complete discussion of the residue chemistry data deficiencies associated with application of flutriafol to field corn, popcorn, and small grains see D388603 (T. Bloem, 16

- Jun

- 2011). The following text is a summary of the food resid ue profile for the remaining proposed crops (pome fruit, stone fruit, grape, imported banana, peanut, and sugar beet).

Magnitude of the Residue

- Primary Crops: Provided a revised Section B is submitted, the pome fruit, stone fruit, grape, banana (import tolerance), peanut, and sugar beet processing and/or field trial data are adequate and support the establishment of the HED

- recommended primary crop tolerances listed in Table 2.2.3 (revised Section F is requested).

Magnitude of the Residue

- Rotationa l Crops: Concurrent to the Section 3 registration being discussed here, HED reviewed residue data concerning the rotation of sweet corn, field corn, and cotton to soybean fields treated with flutriafol (application of flutriafol to soybeans is already

reg istered). Based on these data, HED concluded that the rotational crop tolerances listed in Table 2.2.3 should be established and the following rotational crop restrictions following application of flutriafol to soybean are appropriate (revised Sections B and F are requested): treated fields may be rotated to a labeled crop at any time or may be rotated to cotton, sweet corn, field corn, field corn grown for seed, and popcorn 180 days after application; rotation to any other crop is prohibited.

With eli mination of field corn, popcorn, and the small grains as primary crops (see paragraph at the beginning of Section 5.2), the only proposed crops which are rotated are peanut and sugar beet. Based on the submitted field corn, sweet corn, and cotton rotation al crop field trial data and the proposed peanut and sugar beet application scenarios, HED concludes the following concerning plant back intervals (PBIs) and residues in/on rotational crops (revised Sections B and F are requested):

Peanut

- Adequate fie ld rotational crop data conducted at the peanut application rate are not available; therefore, the label should be revised to indicate that only a labeled crop may be rotated following application of flutriafol to peanut.

Sugar Beet

- The application sc enario employed in the sweet corn, field corn, and cotton field rotational crop study are considered adequate to represent the magnitude of the residue following application of flutriafol to sugar beet. With the addition of sugar beet as a primary crop, t he following field rotational crop residue data conducted as specified in OPPTS 860.1900 should be

submitted: sweet corn

- NAFTA Growing Zones 10 (n=1) and 11 (n=1); cotton

- NAFTA Growing Zones 8 (n=4) and 10 (n=3). Based on the field rotational crop da ta, HED requests a revised Section B specifying the following rotational crop restrictions following application to sugar beet: treated fields may be rotated to a labeled crop at any time or may be rotated toFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 28 of 45 

### cotton, sweet corn, field corn, field corn gro wn for seed, and popcorn 180 days after application; rotation to any other crop is prohibited.

Magnitude of the Residue

- Poultry: Considering all proposed/registered crops, the poultry MRDBs for tolerance enforcement/risk assessment are 0.096/0.098 pp m (dietary burdens to flutriafol and the residues of concern identified as being toxicologically identical to flutriafol). Based on an adequate poultry feeding study and the current MRDB, residues in poultry commodities are expected to be ≤0.001 ppm. Bas ed on these estimates, HED concludes that the establishment of poultry tolerances and inclusion of poultry in the risk assessment are

unnecessary.

Magnitude of the Residue

- Ruminant: With elimination of field corn, popcorn, and the small grains (see p aragraph at the beginning of Section 5.2), the beef cattle, dairy cattle, and swine MRDBs to the remaining proposed crops and to the registered crops for tolerance enforcement/risk assessment are 0.225/0.273 ppm, 0.273/0.305 ppm, and 0.061/0.064 ppm,

respe ctively (dietary burdens to flutriafol and the residues of concern identified as being toxicologically identical to flutriafol). Based on an adequate feeding study and the current MRDBs, residues in all ruminant and hog commodities excluding liver are exp ected to be ≤0.003 ppm; residues in liver are expected to be ≤0.019 ppm (note that cattle, goat, hog, horse, and sheep liver tolerance are currently established at 0.02 ppm). Based on these estimates, HED concludes that the currently established ruminant and hog tolerances are adequate (no additional ruminant and hog tolerances are required). Submission of storage stability data demonstrating the stability of flutriafol, T, TA, and TAA in ruminant liver (4.6 months) are needed to validate

the ruminant fee ding study (D380493, T. Bloem, 16

- Jun

- 2011).

5.3 Drinking Water Residue Profile

EFED provided modeled ground [Pesticide Root Zone Model

- Groundwater (PRZM

- GW)] and surface [FQPA Index Reservoir Screening Tool (FIRST ver. 1.1.1)] estimated drinking water concentrations (EDWCs) for flutriafol per se (EFED memorandum; D383005, J. Wolf, 27

- Apr

2011; D390213, J. Wolf, 31

- May

- 2011). Table 5.3 is a summary of the flutriafol per se water estimates provided by EFED (bolded number s were used in the assessment). The water estimates were incorporated directly into the dietary exposure analysis vi a 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/wate r/

.

Table 5.3. Maximum Tier I Flutriafol EDWCs.

Model Application Rate EDWC (ppb)

Groundwater (PRZM

- GW) 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) apple (6 x 0.114 lbs ai/acre at 7 day intervals) 1 acute 48. 5

chronic 5.70

1 The initially proposed application rate for apple.



### 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).Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 29 of 45 

### Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM

- FCID TM 

### (ver. 2.03)

, which incorporates the food consumption data from the USDA CSFII (1994

- 1996 and 1998). HED is not recommending for the proposed field corn, popcorn, and small grains registration due to several residue chemistry data deficiencies including issues concerning the nature/magnitude of the residue in ruminants at the dietary burdens associated with these crops (for further discussion see D388603 (T. Bloem, 16

- Jun

2011)); these uses were not included in the analysis. The analysis did consider the registered crops, the remaining proposed crops, and residues in/on field corn, popcorn, and cotton as a

result of rotation to a t reated field.

The acute and chronic analyses assumed tolerance

- level residues, 100% crop treated, and modeled drinking water estimates. Since adequate processing studies have been submitted, which indicate that tolerances in/on apple juice, grape juic e, and dried prunes are unnecessary and since a raisin tolerance is being established, the DEEM TM 

### (ver 7.81) default processing

factors for these commodities were reduced to 1. The DEEM TM 

### (ver 7.81) default processing factors were retained for the remaining relevant commodities. In addition, since an adequate cottonseed processing study has not been submitted, the OPPTS 860.1520 default cottonseed oil processing factor was retained. The resulting acute (≤24% aPAD; females 13

- 49 years old were the most high ly exposed subgroup) and chronic (≤42% cPAD; all infants (<1 year old) were the most highly exposed subgroup) exposure estimates are not of concern to HED. Table 5.4 is a summary of the acute and chronic dietary (food and water) exposure and risk estimate s.

Table 5.4. Summary of Acute and Chronic Dietary (Food + Drinking Water) Exposure and Risk.

Population aPAD

(mg/kg/day) Exposure

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

(mg/kg/day) %cPAD

General U.S. Population

2.5 0.021798 <1

0.05 0.006197 12 All Infants (< 1 year old) 0.070570 2.8 0.021152 42

Children 1

- 2 years old 0.050188 2.0 0.016661 33

Children 3

- 5 years old 0.036759 1.5 0.012350 25

Children 6

- 12 years old 0.022167 <1 0.006793 14

Youth 13

- 19 years old 0.015224 <1 0.004121 8

Adults 20

- 49 years old 0.017447 <1 0.005043 10 Adults 50+ years old 0.016271 <1 0.005527 11

Females 13

- 49 years old 0.075 0.017880 24 0.005118 10

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 Residential Bystander Post

- application Inhalation

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for flutriafol at this time primarily. However, 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 FIFRA 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 is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation expos ure into the Agency's risk assessments. If new policies orFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 30 of 45 

### procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for flutriafol.

6.2 Spray Drift

Spray drift is always a potential sou rce of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for flutriafol. The Agenc y has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm ). On a chemical

- by

- chemical basis, the Agency is now requiring interim mitigation measures for ae rial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® 

### computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift

management pr actices to reduce off

- target drift w ith specific products with significant risks

associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhal ation exposure assessment was performed for flaggers

. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure sc enarios

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Because there are no residential uses for flutriafol, only food and water are inclu ded in the aggregate assessments. Since the dietary exposure analysis included the drinking water estimates, 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. A quantitative cancer aggregate risk assessment was not needed since there was no evidence of carcinogenicity.

Application o f flutriafol also results in exposure to T and its conjugated metabolites, which are considered to be toxicologically different from flutriafol. HED previously conducted an aggregate exposure analysis for these compounds, which resulted in aggregate expos ure less than HED’s level of concern (D388544, T. Bloem, 14

- Apr

- 2011). Dietary exposure analyses to T and its conjugated metabolites conducted in support of the proposed flutriafol uses did not result in an increase in the dietary exposure estimates incor porated into this most recent aggregate assessment (D388469, T. Morton, 27

- Apr

- 2011); therefore, a revised aggregate assessment is

unnecessary.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 31 of 45 

### 8.0 Cumulative Exposure/Risk Characterization

Flutriafol is a member of the triazole

- containing class of p esticides. 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 cons titute 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 in cluding 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

.

Flutriafol is a triazole

- derived pesticide. This class of compounds can form the common metabolite T and two triazole conjugates (TA and TAA). To support exist ing tolerances and to

establish new tolerances for triazole

- derivative pesticides, including flutriafol, U.S. EPA

conducted a human

- health risk assessment for exposure to T, TA, and TAA resulting from the use of all current and pending uses of any triazole

- derived fungicide. The risk assessment is a highly conservative, screening

- level evaluation in terms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary

and non

- dietary exposures (i.e., high

- end estimates of both dietary and non

- dietary exposures). In addition, the Agency retained the additional 10X FQPA SF for the protection of infants and children. The assessment includes evaluations of risks for various subgroups, including t hose comprised of infants and children. The Agency’s complete risk assessment is found in the propiconazole reregistration docket at http://www.regulations.gov

, Docket Identification (ID)

Number EPA

- HQ

- OPP

- 2005

- 049 7.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- and Intermediate

- Term Handler Risk

Flutriafol is a fungicide that can be used as a systemic eradicant and a protectant. Topguard ®


### Fungicide (EPA Reg # 67760

- 75) is already registered for use on apples and soybeans . The formulated product, an 11.8% (1.04 lb ai/gal) liquid formulation, is proposed for use on corn, grapes, peanuts, pome fruit ( crop group 11), stone fruit ( crop group 12), sugar beets, wheat, barley, tr iticale, buckwheat, oats, rye, and teosinte. An assessment for bananas was not performed since the petition was for an import tolerance only. The label allows for foliar applications via air and ground equipment. The label prohibits application via chem igation. The REI specified on the label is 12 hours.

Dermal and inhalation exposures/risks were estimated for handlers involved in mixing/loading activities for liquid formulations for aerial, groundboom and airblast equipment, applying sprays

via aerial , groundboom and airblast equipment and flagging. The flutriafol product labels directFlutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 32 of 45 

### mixers, loaders, applicators and other handlers to wear long

- sleeved shirt and long pants,

chemical

- resistant gloves, and shoes plus socks.

No chemical

- specific hand ler exposure data were submitted in support of this Section 3 registration. To assess handler exposures for regulatory actions when chemical

- specific monitoring data are not available, HED relies on the most scientifically reliable surrogate data

currentl y available from various sources such as PHED, AHETF, and ORETF. Some of this data, such as the industry task force data, is compensatory, subject to the data protection provisions of FIFRA. HED policy on use of surrogate data is described in more detail on the Agency's website ( http://www.epa.gov/pesticides/science/handler

- exposure

- data.html ).

Scenario

- specific surrogate exposure data, including their sources, are presented i n the ―Occupational Pesticide Handler Unit Exposure Surrogate Reference Table‖ ( http://www.epa.gov/pesticides/science/handler

- exposure

- table.pdf ).

Typically, HED completes short

- and intermediate

- term assessments for occupational scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate

- term scenarios. Based on use data and label

instr uctions, HED believes that occupational exposures may occur over a single day or up to weeks at a time for many use

- patterns and that intermittent exposure over several weeks may also occur. Some applicators may apply these products over a period of weeks , because they are commercial applicators who are completing multiple applications for multiple clients. Long

term exposures are not expected, therefore, a long

- term assessment was not conducted.

Table 9.1.2 presents the exposure/risks for short

- and i ntermediate

- term dermal and inhalation exposures at baseline. The combined dermal and inhalation exposure risks for mixer/loaders are not of concern (i.e., MOEs >100) at baseline for all scenarios except for mixers/loaders for aerial application to corn, wheat (spring and winter), barley, triticale, buckwheat, oats, rye, and teosinte. For these high

- acreage crops, mixer/loaders must wear protective gloves. Gloves are listed as PPE on the proposed label; therefore, HED does not have concerns for this scen ario.

HED has no data to assess exposures to pilots using open cockpits. The only data available are for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline atti re (long

- sleeve d shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves. With this level of protection, there are no risks of concern for applicators.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 33 of 45 Table 9.1.2. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Flutriafol.

All estimates are at b aseline (i.e., no gloves/respirator) except where noted

Exposure Scenario Crop or Target Dermal Unit Exposure 1 Inhalation Unit

Exposure 1 Application

Rate 2 Amount

Treated Daily 3 Dermal Inhalation Total

Baseline (except where noted) Baseline Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Mixer/Loader

Mixing/Loading Liquids for Aerial Applications corn, wheat (spring

and winter), barley, triticale, buckwheat, oats, rye and teosinte 0.22

0.000219 0.114 1200 0.11 71

0.0005 15,000 71

0.0376 (PPE gloves) 0.018 420 410

peanuts, stone fruit, sugar beets 0.22 0.000219 0.114 350 0.031 240 0.00015 51,000 240

pome fruit 0.22 0.000219 0.106 350 0.029 260 0.00014 55,000 260

grapes 0.22 0.000219 0.081 350 0.022 340 0.0001 72,000 340

Mixing/Loading Liq uids for

Groundboom Applications corn, wheat (spring

and winter), barley, triticale, buckwheat, oats, rye and teosinte 0.22 0.000219 0.114 200 0.018 430 0.000083 90,000 430

peanuts, sugar beets 0.22 0.000219 0.114 80 0.007 1,100 0.000033 230,000 1,100
Mixing/Loading Liquids for

Airblast Application s stone fruit 0.22 0.000219 0.114 40 0.0035 2,100 0.000017 450,000 2,100

pome fruit 0.22 0.000219 0.106 40 0.0033 2,300 0.000015 480,000 2,300

grapes 0.22 0.000219 0.081 40 0.0025 3,000 0.000012 630,000 3,000

Applicator

Applying Sprays

via Aerial Equipment corn, wheat (spring

and winter), barley, triticale, buckwheat, oats, rye and teosinte 0.005 0.000068 0.114 1200 0.0024 3,100 0.00016 48,000 2,900

peanuts, stone fruit, sugar beets 0.005 0.000068 0.114 350 0.0007 11,000 0.000045 170,000 10,000

pome fruit 0.005 0.000068 0.106 350 0.00065 12,000 0.000042 180,000 11,000

grapes 0.005 0.000068 0.081 350 0.0005 15,000 0.000032 230,000 14,000

Applying Sprays

via Groundboom Equipment corn, wheat (spring

and winter), barley, triticale, buckwheat, oats, rye and teosinte 0.0786 0.00034 0.114 200 0.0063 1,200 0.00013 58,000 1,200

peanuts 0.0786 0.00034 0.114 80 0.0025 3,000 0.000052 150,000 2,900Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 34 of 45 Table 9.1.2. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Flutriafol.

All estimates are at b aseline (i.e., no gloves/respirator) except where noted

Exposure Scenario Crop or Target Dermal Unit Exposure 1 Inhalation Unit

Exposure 1 Application

Rate 2 Amount

Treated Daily 3 Dermal Inhalation Total

Baseline (except where noted) Baseline Dose 4 MOE 5 Dose 6 MOE 7 MOE 8

Applying Sprays

via Airblast Equipment stone fruit 0.36 0.0045 0.114 40 0.0057 1,300 0.00034 22,000 1,200

pome fruit 0.36 0.0045 0.106 40 0.0053 1,400 0.00032 24,000 1,300

grapes 0.36 0.0045 0.081 40 0.0041 1,800 0.00024 31,000 1,700

Flagger

Flagging for Aerial Sprays Applications corn, peanuts, stone

fruit, sugar beets, wheat (spring and winter), barley, triticale, buckwheat, oats, rye and teosinte 0.011 0.00035 0.114 350 0.0015 4,900 0.00023 32,000 4,200

pome fruit 0.011 0.00035 0.106 350 0.0014 5,300 0.00022 35,000 4,600

grapes 0.011 0.00035 0.081 350 0.0011 6,900 0.00017 45,000 6,000

1 PHED/ORETF/AHETF (level of mitigation: Baseline and PPE (gloves).

2 Based on registered or proposed label (Reg. No. #67760

- 75).

3 Science Advisory Council for Exposure (ExpoSAC) Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (m g/kg) x Application Rate (lb ai/acre) x Amount Treated (A/day) x DAF (21%)/BW (60 kg).

5 Dermal MOE = Dermal NOAEL (7.5 mg/kg/day)/Dermal Dose (mg/kg/day).

6 Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre) x Amount Treated (A/day) /BW (60 kg).

7 Inhalation MOE = Inhalation NOAEL (7.5 mg/kg/day)/ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (mg/kg/day)/Dermal Dose + Inhalation Dose.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 35 of 45 

### 9.2 Short

- and Intermediate

- Term Post

- Application Risk

9.2.1 Dermal P ost

- Application Risk

In the case of flutriafol, there is a potential for postapplication dermal exposure to field workers following foliar applications of flutriafol to agricultural crops. Flutriafol is a fungicide that can be applied at all stages of growth. For example, the proposed product, Topguard ® 

### Fungicide, can be applied to grapes beginning with 6 to 10

- inch shoots up until 14 days prior to harvest. It can also be applied to pome fruit start ing at the green tip growth stage and/or the Pink Bud growth stage up until 14 day prior to harve st.

No post

- application data were submitted in support of this registration action; therefore, dermal exposures during post

- application activities were esti mated using dermal transfer coefficients from the Science Advisory Council for Exposure (ExpoSAC) Policy Number 3 ( http://www.epa.gov/pesticides/science/exposac_policy3.pdf ), summarize d in Table 9.2.1 below. This policy reflects adoption of all ARTF data. Use of the data in this policy requires compensation to the ARTF under FIFRA.

In addition to the transfer coefficients, the following assumptions were used:

Application Rates = 0.114 lb ai/A for corn, wheat (spring and winter), barley, triticale, buckwheat, oats, rye and teosinte, peanuts, stone fruit, sugar beets 0.106 lb ai/A for pome fruit 0.081 lb ai/A for grapes Exposure Duration = 8 hours per day Body Wei ght = 60 kg for adult female Dermal Absorption = 21%

The fraction of ai retained on foliage is assumed to be 20% (0.2) on the day of application (= %

DFR after initial treatment) for agricultural crops. This fraction is assumed to further dissipate at the rate of 10% (0.1) per day on following days.

The post

- application exposures associated with the proposed uses are summarized in Table 9.2.1. The resulting MOEs are greater than 100 on Day 0 (12 hours after application) for all crops and activities, e xcept for detasselling of corn and girdling/turning of grapes. For these high

- contact activities, an acceptable MOE (i.e., MOE > 100) is not reached until Day 5 after application. The high

- contact activities for grapes are only expected to occur for cult ivation of table grapes. The high

- contact activity for corn is only expected to occur for field corn or popcorn grown for

seed.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 36 of 45 Table 9.2.1. Summary of Occupational/Commercial Postapplication Risks for Flutriafol.

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) Application

Rate (lb ai/A) DFR 1

(ug/cm 2 ) Day 0

MOE 2 Day X at

which MOE ≥

LOC

Short

- and Intermediate

- term

Corn Hand weeding 70

0.114 0.26 15,000 0 Scouting (low crop height) 210 5,000 0 Scouting (high crop height) 1,100 950 0 Irrigation 1,900 550 0 Detasselling 17,600 60 5

Grapes Transplanting 230

0.081 0.18 6,400 0 Scouting, Hand pruning, Hand weeding, Propagating, Bird control, Trellis repair 640 2,300 0

Irrigation 1,900 780 0 Tying / Training, Hand harvesting, Leaf pulling 5,500 270 0

Tying / Training, Hand harvesting, Leaf pulling 10,100 150 0

Girdling, Turning 19,300 76 5

Peanuts Hand weeding 70

0.114 0.26 15,000 0 Scouting 210 5,000 0 Irrigation 1,900 550 0

Pome fruit (apple, crabapple, loquat, mayhaw, pear, oriental pear, quince) Hand weeding, Propping,

Orchard maintenance 100

0.11 0.24 11,000 0

Transplanting 230 4900 0 Scouting, Hand pruning, Training 580 1900 0

Hand harvesting 1,400 810 0 Thinning Fruit 3,600 310 0

Stone fruit (sweet cherries, tart cherries, apricot, nectarine, peach, plum, chicksaw plum, damson plum, Japanese plum plumcot, prune) Hand weeding, Propping,

Orchard maintenance 100

0.11 0.26 10,000 0

Transplanting 230 4,600 0 Scouting, Hand pruning, Training 580 1,800 0

Hand harvesting 1,400 750 0 Thinning Fruit 3,600 290 0

Sugar beet Hand weeding; Thinning (plants) 70

0.114 0.26 15,000 0 Scouting 210 5,000 0 Hand harvesting 1,100 950 0 Wheat (spring and winter), barley, triticale, buckwheat, oats, rye, and teosinte Hand weeding 70

0.114 0.26 15,000 0

Scouting 1,100 950 0

1. DFR = application rate (lb ai/A) x (1

- daily dissipation rate) t x 4.54E8 μg/lb x 24.7E

- 9 A/cm 2 x 20% DFR after initial treatment. 2. MOE = POD (NOAEL, 7.5 mg/kg/day) / Daily Dermal Dose

. Daily Dermal Dose = [DFR (μg/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day x 21% dermal absorption] body weight ( 60

- kg adult female).



### REI

Short

- and intermediate

- term post

- application risks were not a concern on Day 0 (12 hours following application) for all post

- application activities, except for 1) girdling/turning of table grapes, and 2) detasseling corn grown for seed. Risks were a conc ern until day 5 for table grape

post

- application activities and detasseling corn grown for seed. RD should ensure the appropriate REI is present on the label. In addition, under 40 CFR Part 158:1070, DFR data is required to further refine risk estimates.

For all other crops, the REI 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). Acute Toxicity Category III and IV chemicals via these routes are supported by a

12

- hour REI under the WPS.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 37 of 45 

### 9.2.2 Inhalation Post

- Application Risk

Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment was not performed for flutriafol at this time. However, there are multiple potential sources of post

- application inhalation exposure to in dividuals 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 o n issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meet ing.html ). The Agency is in the process of evaluatin g the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, then the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for flutriafol.

10.0 Referenc es

U.S. Environmental Protection Agency. 2002. Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity. January 14, 2002.

Memo, M. Doherty, D309014, 12

- Oct

- 2004. ―Correction to the Dietary Exposure Asses sment for Sulfuryl Fluoride and Fluoride Anion.‖

Memo, R. Daiss, D355605, 03

- Aug

- 2008. "Flutriafol. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS)"

Memo, M. Doherty et al. , D322215, 07

- Feb

- 2009. ―1,2,4

- Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health Aggregate Risk Assessment in Support of Reregistration and Registration Actions for Triazole

- derivative Fungicide Compounds.‖

Memo, T. Bloem, D362421, 11

- Mar

- 2009. ―Flutriafol. Enforcement Method Forwarded to FDA‖

Memo, T. Bloem, D340513, 11

- Mar

- 2009. ―Flutriafol. Section 3 Registration for Application of Flutriafol to Apple and Soybean. Summary of Analytical Chemistry and Residue Data.‖

Memo, M. Doherty, D362183, 06

- May

- 2009. ―Fluoride Chronic Dietary Exposure Analysis.‖

Memo, K. Lowe et al. , D372347, 16

- Dec

- 2009. ―Flutriafol. REVISED Human

- Health Risk Assessment for Proposed Uses on Apple and Soybean.‖

Memo, T. Bloem, D388544, 14

- Apr

- 2011. ― Common Triazole Metabolites. Updated Aggregate

Human

- Health Risk As sessment to Address Tolerance Petitions for Tetraconazole.‖

Memo, J. Wolf, D383005, 27

- Apr

- 2011. ―Tier 1 Drinking Water Assessment Proposed New Uses (R190) for Flutriafol for the establishment of tolerances for residue in field and pop corn,Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 38 of 45 

### grapes, peanu ts, pome fruit (Crop Group 11) stone fruit (Crop Group 12), sugar beets, and

wheat.‖

Memo, T. Morton, D388469, 27

- Apr

- 2011. ―Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The Amended Metconazole Sect ion 3 Registration to Add Uses on Tuberous and Corm Vegetables (Group 1C) and Bushberry Subgroup 13

- 07B.‖

Memo, T. Bloem, D388603, 16

- Jun

- 2011. ― Flutriafol in/on Bananas (imported), Field Corn, Grapes, Peanuts, Pome Fruit, Stone Fruit, Sugar Beets, Wheat, Barley, Buckwheat, Oats, Rye, Teosinte, and Triticale. Summ ary of Analytical Chemistry and Residue Data. ‖

Memo, T. Bloem, D380493, 16

- Jun

- 2011. ― Flutriafol. Section 3 Registration for Application of Flutriafol to Apple and Soybean. Review of Amendmen ts Dated 1

- October

- 2009, 1

- June

- 2010,

and 1

- July

- 2010 Submitted in Response to Residue Chemistry Deficiencies Identified in D340513 (T. Bloem, 11

- Mar

- 2009). ‖

Memo, T. Bloem, D383036, 16

- Jun

- 2011. ―Flutriafol. Acute and Chronic Dietary Exposure and

Risk Assessment for Application of Flutriafol to F ield Corn, Popcorn, Grapes, Peanuts, Pome Fruit, Stone Fruit, Sugar Beets, Wheat, Barley, Buckwheat, Oats, Rye, Teosinte, and Triticale. ―

Memo, K. Lowe, D383037, 20

- Sep

- 2011 . ― Flutriafol: Occupational and Res idential Exposure/Risk Assessment for Proposed Uses on corn, grapes, peanuts, pome fruit ( crop gr ou p 11), stone fruit ( crop gr ou p 12), sugar beets, wheat, barley, triticale, buckwheat, oats, rye and

teosinte.‖Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 39 of 45 

### Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food uses for flutriafol are in Table A.1

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

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

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

870.2600 Dermal Sensitization yes

yes

yes

yes

yes

yes yes

no

yes

yes

yes

yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent)

870.3200 21

- Day Dermal

870.3250 90

- Day Dermal

870.3465 90

- Day Inhalation yes

yes

yes

no

no yes

yes

yes

-

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

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent)

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

yes

yes

yes

yes yes

yes

yes

yes

yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations 870.5xxx Mutagenicity

— Other Genotoxic Effects yes

yes

yes

yes yes

yes

yes

yes 870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90

- Day Neurotoxicity (hen)

870.6 200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90

- Day Neurotoxicity Screening Battery (rat) 870.6300 Develop. Neurotoxicity no

no

yes

yes

no -

- yes

yes

- 870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity yes

yes

yes yes

yes

yes Special Studies for Ocular Effects

Acute Oral (rat) Subchronic Oral (rat)

Six

- month Oral (dog) no

no

no -

-

-Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 4 0 of 45 

### A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile

– Flutriafol.

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

870.1100 Acute oral (rat) 47090336 LD 50 = 1140 mg/kg (M); 1480 mg/kg (F) III

870.1100 Acute oral (mouse) 47090335 LD 50 = 365 mg/kg bw (M); 179 mg/kg bw (F) II

870.1200 Acute dermal (rat) 4786101 LD 50 >2000 mg/kg bw III

870.1300 Acute inhalation (rat) 47090338 LC 50 >5.20 mg/L IV

870.2400 Primary eye irritation (rabbit) 47090339 Minimally irritating III

870.2500 Primary dermal irritation

(rabbit) 47090341 Not a dermal irritant IV

870.2600 Dermal sensitization (mouse) 47090343 Not a sensitizer

-

Table A.2.2. 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 decr eased 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 th an 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)

U nacceptable/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.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 41 of 45 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

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;

nu merous 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

- implantati on 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). Reproduct ive NOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]).

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

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

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

870.3800 2

- gen. reproduction

and fertility effects (rat) 48196921, 48196922 (2009)

Acceptable/guideline

0, 30, 80, 150, 300, 1000

ppm 0, 1.8/2.2, 4.8/5.85, 9/10.8, 18.5/22.6, and 62.8/ 77.1 mg/kg bw/day [M/F] Parental/Systemic NOAEL = 150 ppm (9/10.8 mg/kg bw/day [M/F]). Parental/Systemic LOAEL = 300 ppm (18.2/22.6 mg/kg bw /day [M/F]) based upon increased relative liver weights, fatty deposits in the liver in both sexes as well as hepatocellular hypertropy in males. Reproductive NOAEL = 300 ppm (18.2/22.6 mg/kg bw/day [M/F]. Reproductive LOAEL was not observed. Offspring NOAEL = 150 ppm (9/10.8 mg/kg bw/day [M/F]). Offspring LOAEL = 300 ppm (18.5/22.6 mg/kg bw/day [M/F]) based upon increased pup mortality in the F1 pups at the first litter check and 0

- 4 postnatal days.

870.4100 Chronic toxicity (1

year; dog) 47090353 (1988)

Acceptable/guideline

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

- weight gains, and increased adrenal weights in the females.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 42 of 45 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

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

S9

- activation There were no marked increases in the mean number

of revertants/plate in any strain. There was no

evidence of induced mutant colonies over background.

870.5300 In Vitro Gene

Mutation assay in mouse lymphoma

cells 47090402 (1986)

Acceptable/guideline

0, 10, 33, 100, 333, or 1000 μg/mL (+S9, Trial 1); 0, 150, 300, 450, 600, or 750 μg/mL (

- S9, Trial 1); 0, 150, 300, 450, 600, 750, 900, 1050, or 1200 μg/mL (+S9, Trial 2); or 0, 200, 300, 400, 500, 600, 700, or 800 μg/mL (

- S9, Trial 2) There was a dose

- related increase in mutant

f requency (7.0

- 9.0x10
- 5 treated vs. 3.0x10

- 5 controls) and absolute mutant numbers (70

- 148 colonies/plate vs. 63 controls) at 100 μg/mL and above in Trial 1 and a marked increase in mutant frequency at 750 μg/mL (6.5x10

- 5 treated vs. 1.2x10

- 5 controls) in

T rial 2 attributable to severe cytotoxicity (2% relative survival). However, the increases in mutant frequency did not achieve the threshold value for a positive response (>10x10

- 5 ) in either trial and there

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

- activation.

870.5300 In Vitro Gene

Mutation assay in mouse lymphoma

cells 48196918 (2006)

Acceptable/guideline

0, 25, 50, 100, 200, 400 and 600 μg/mL (±S9, Trial 1); 0,
12.5, 25, 50, 100, 200, 300 or 400 μg/mL (

- S9, Trial 1); 0, 200, 300, 325, 350, 375, or 400 μg/mL (+S9, Trial 2) (

- S9, Trial 2) The mutagenicity criterion (threshold) of 126 colonies per 106 cells above the solvent control was not reached for any valid data at any test concentration, with or wi thout 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.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 43 of 45 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5375 In vitro Mammalian

Cytogenetics (Chromosomal Aberration Assay in Human Peripheral Blood Lymphocytes) 47090403 (1989)

Acceptable/guideline

0, 25, 125, or 250 μg/mL (+/

- S9) No significant increases in the numbers of cells with aberrations (excluding gaps) were observed in ei ther 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, mea n 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/Mammal

ian 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, a nd 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

g rip strength in males.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 44 of 45 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (rat) 47090414 (2004),

47090412 (2006)

Acceptable/guideline

5 or 250 mg/kg More than 78% of the dose was recovered in the bile and urine. Absorption was similar between sexes and between single and multiple dose regimes. Absorption is extensive. The dose was mostly eliminated within 48 hours. Only 0.04

- 0.05% of the

dose was fo und in the expired carbon dioxide. Most of the radioactivity was excreted in the bile (47

- 79% of the dose). The excretion profile was similar between sexes. In the blood, radioactivity partitioned into the red blood cells. In both sexes and all groups, concentrations of radioactivity were relatively high in whole blood, liver, and kidneys. Other organs with high concentrations included the adrenal glands, spleen, and pituitary. The distribution profiles were similar between species, dose level, and si ngle 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 on ly 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

t hen conjugated with glucuronic acid.

870.7600 In vivo dermal

penetration (rat) 47090415 (2006)

Acceptable/guideline

0.0 0 2, 0. 0 2

, or 0. 2 mg/cm 2
skin were tested (10 μl/cm 2

skin), and actual doses were

0.0 0 208, 0. 0 201, 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 μg/cm 2
dose groups. Absorption mechanisms were saturated at the high dose. The elimination half

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

.Flutriafol Human

- Health Risk Assessment DP#: 382902, D382945

Page 45 of 45 Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile

– Flutriafol.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7800 Immunotoxicity

(mice ) 48360301 (2011)

Classification: Pending

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

(0, 10.8, 49.9, 101.8 and

241.2 mg/kg/day [F] Preliminary NOAEL = 10.8 mg/kg /day

. Preliminary LOAEL = 49.9 mg/kg /day , based on statistically increased absolute and relative liver weights, and statistically significant increases in mean corpuscular volume.