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

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

DATE: March 27,2013

SUBJECT : Fluo-xastrobin

. Aggregate Human Health Risk Assessment for the Proposed · New Uses on Melon Subgroup 9A and Sorghum, Along with Establishment of Permanent Tolerances on Wheat, and Amendments to Es tablished Tolerances

. pn Mi l k and Milk Fat.

PC Code: 028869 DP Barcode: D405370, D409039 Decision No.: 465774 Registration Nos.: 66330-64, 66330-65 Petition No.: 2F8047, 2F8130 Regulatory Action: Section 3 Registration Case No.: NA Risk Assessment Type : Single ChemicaVAggregate TXRNo.: NA CAS No.: 361377-29-9 MRIDNo.: NA 40 CFR: § 180.609

FROM : Nancy Tsa ur, Chemist, Risk Assessor

# tJ!~--**-- -;J**  Mehe ret Negussie,**Chemist ~** **L+,fc·~--** Kristin Rury, Biologist Risk Assessment Branch 3 Health Effects Division (7509P)

THROUGH: Christine Olinger, Branch Ch i ef /} / 

# f 

# 4 / .

Risk Assessment Branch 3

## ~~ Health Effec ts Division (7509P)

TO: Heather Garvie/Shaja Joyner, RM #20 F ungicides Branch (FB) Registration Division (7505P) r:

. ...... , \. . .

I.

The Registration Division (RD) requested that the Health Effec ts Division (HED) provide an evaluation ofthe proposed new agricultural uses offluoxastrobin on melon subgroup 9A**and ~**  sorghum

. A summary of the findings and an assessment of human health risk resulting from**he** proposed and registered uses of fluoxastrobin are provided in this document. This assessment has incorporated the updated 2012 Residential Standard Operating Procedures (SOPs)

.

• ' The residue chemistry review and dietary risk assessment were conducted by Meheret**Negus~ie;** the occupational and residential exposure risk assessment was conducted 

### by Kristin**Rury ~**  an¢. th e aggregate human health risk assessment was conducted by Nancy Ts aur.

Page I of36

### Table of Contents

1

. 0 Executive Summary

.. ... . .. . ... .**~** 

### . . . . ... . . .. . . . . . . . . . . .. . . .. . . .. . . .. . . .. . . .. . . . . . ... .. .. . ... . ... . ... . . . . . ........ . . . . . .... . .... .. 4 

### 2.0 H E D Recommendations

. . .. . . .. . .. .. .. .. .. . . . .. .. . . .. . . .. .. .. .. ... . . ... . . . . . .. .. ... . .. ...... .. .... . . . . . .. .. .. . .. . ... .. .. ... . . . 6 2.1 

### Data D eficiencies

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

.. ... . .. .. .. . ... . ... .. . .. .. .. .. .. .. .. .. . ... . .. ... ...... .. .. . ... . ... .. ...... .. . . ........ . ...... 7 2.2.1 

### Enfo r cement Ana l ytical Method

........ . . ............. ... ..... .. ............ . .. . ....... . ... .. .. ... .. .. ... . ... . 7 2

. 2.2 

### Recommende d T olerances

. .. .. .. .. . .. . ... .. . ... .. .. . .. . .... . .... . ........................ . .. .. ... . .... . ........... 7 2

. 2.3 

### Revisions to Petit i oned-For Tolerances

.... .. .. .. .. .. .. .. .. . ... .. .. .. .. .. .. . . . ... .. ... .. .. .. . .... . ... ... . .. 8 2.2.4 

### Internat i onal H armonizat i on

. ... . ... . ...... . ... . ... .. ................. . ..................... ... .. .. ... .. ... . . . .. . 8 3

. 0 I ntroduction

. . .. . ... . . . . .... . . ... . .... . . . . . . . .. .. . . .. . ... . .......... . . .. . . .. .. . .. .. .. .. ... . . . . .. .. . . .... . ... .. .. .. .. ... .. .. .. . . .... . .. . 8 3.1 

### Chem i cal Identity

................................................................ . ................................ . ......... 8 3

. 2 

### PhysicaVChemica l Characteristics

.............. : .

................. . .. . ... .. . .. ... . .... . .. .. .. ... .. . ... .. ... .. .. . 9 3.3 

### Pesticide Use Pattern

. .. . ... . ... . .. . ... . ... . ...... . ... .. ......... . . . ..... .. ..... . ........... ... . . ... . ... . .................. 9 3.4 

### Anticipated Exposure Pathways

................................................................................. 10 3

. 5 

### C onsideration of E nvironmental Justice

. . .... . ..... .. .. .. ... . .. ... . .. .. .. .. .. .. .. .. .. ... .. .. . .. . . .... . ..... 1 0 4.0 H azard C haracterization and Dose

- Response Assessment

.. ... . .. .. .. .. ... . .. .. .... .. .... . .. . . . ...... . 11**~. 1**  

### S ummary of Toxicological Effects

.............................................................................. 1 1

_**.2** 

### Safety Factor for Infants and Children (FQPA Safety Factor)

.... . ............. .. .. ... .. .. .. 12

· -. 4.2.1 

### Completeness of the Tox i cology Database

.... . ... . ... . .... . . . .. . .. . . ...... ... .. .. .. .. .. ... .. .. . . ... .. .. 12

4.2

. 2 

### Evidence of Neurotoxicity

........................................................................................ 12 4.2

. 3 

### Evidence of Sensitivity/Susceptibility in the Developing or Y oung Animal..

...... 13 4.2.4 

### Residua l Uncertainty in t he E xposure Database

...................... .. .. ... .. . ... .. ... .. .. .. . . .. . 13 5

. 0 Dietary Exposure and Risk Assessment

.. . ... . . . .. .. .. ... . .. . ... .. .. . .. . . .. ... . ..... .. .. .... . . ... ....... . . .. .. .. . . . IS 5

. 1 

### Residues of Co ncern Summary and Rationale

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

. . 5

. 2 

### Food Residue Profi l e

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

' !

.. 

### 5

. 3 Water Residue Profile

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



## 5.4 Die t ary Risk Assessment

. ... .. ........ .. ...................................... ..... .. .. .. .. ... . ... . ................... 16 5.4.1 

### Descript i on of Residue Data Used in Dietary Assessment

.................**~** 

### .. . ... .. .. .. ... .. . 16 S.4

. 2 

### Acute Dietary Risk Assessmen t

......... .. ............... .. .. ... . . ... .. .. . ... .. .............................. . 17 5:4

. 3 

### Chronic Dietary Risk Assessment

.................................. . . . .............. . ....... . . . . .. .. .. . ..... 17 5.4.4 

### Cancer Dietary R i sk Assessment.

....................................................................... . .... 1 7 5

. 4.5 

### Summary Tab l e .

. ....................... . .. .. .. .. .. . .. .. .................... . ............. .. . . .. .. ... .. . ... .. ........... 17 6

. 0 "'- 

### Residential (Non-Occupational) Exposure/Risk Characterizat i on

. .. .... .. .. .. ... ..... . .. ... .. . .. 18 (). 1 Residen t ia l H andler Exposure

. .. .. . . .. .................. .. ......................... . .. . . ... . ... . ............... . . 18 6 .2 Post-Application Exposure

............... . ............. . .. . ...... .. ... . .. .. . ............ . ... . .............. . .... .. .. 19 6

. 3 Reside n tia l Bystander Post-App li cati o n Inha l ation Exposure

.. .. . . .. .. . .. . ................ . . 19 6

. 4 Spray D rift

.. .. .............................................. . . . .................................. . . . .......................... 20 7

. 0 Aggregate E xposure/Risk Characterization

.. .. .. .. . ..................... . .... ... .. .. .. .. . . . . ..... . .. . .. .. ...... 20



### ·. 7

. 1 Acu t e Aggregate Risk.

...... . ... . ................ .... ................. .. .. . ... . .. .. .... . ................................ 20



### 7

. 2 Short- T erm Agg r egate Risk

. ...... .. .. . ........................ . .......... .... ... . ... . .. . .. .................. . ..... 20

, 7.. 3 I ntermediate-Term A ggregate Risk

.......... . ...... .. ............... .. ............ . .......................... 2 1

J. .4 

### Chronic Aggregate Risk

.. .. ................... . ........ . .. .. ... .. .. .. .. . .. .. ............. . .................. .. ... . ... 2 1 7,. 5 Cancer Aggrega t e Risk

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

### 8.0 ._ ; Cumulative Exposure/Risk Characterization

.. . ...... .... .. ... . .. .......... .. ... . ... . ... .. .. .. ... .. .... ... . . .. 2 1**~** 

### O ccupational Exposure/Risk Characterization

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

### :,

.

Page 2 o f36Page 3 of 36



### 9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................... 22 9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ............. 23 9.2.1 Dermal Post

- Application Risk

................................ ................................ ............. 23 9.2.2 Restricted Entry Interval

................................ ................................ ..................... 24 9.2.3 Inhalation Post

- Application Risk

................................ ................................ ........ 24 10.0 References

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

................................ ................... 26 A.1 Toxicology Data Requirements

................................ ................................ ................... 26 A.2 Toxicity Profiles

................................ ................................ ................................ ............ 27 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 31 Appendix C. Review of Human Research

................................ ................................ ................ 33 Appendix D. International Residue Limit Status

................................ ................................ .... 33 Appendix E. Occupational Exposure/Risk Summary Tables

................................ ................ 34Page 4 of 36



### 1.0 Executive Summary

Fluoxastrobin is a strobilurin

- class fungicide that controls foliar fungal diseases and soilborne/seedling fungal diseases

. It works by interrupting mitochondrial respiration in plant

pathogenic fungi, thus inhibiting spore germination and mycelial growth.

In PP# 2F8047

, Arysta LifeScience North America, LLC (Arysta) has submitted a label amendment to add melon subgroup 9A an d sorghum to t he master label for Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330

- 64) , thus p etitioning for associated tolerances

. Fluoxastrobin 480 SC Fungicide is a suspension concentrate (SC) formulation containing 40.3% active ingredient (ai) by we ight (3.98 lb ai per gallon).

In reviewing the tolerances established under 40 CFR §180.609, HED has noted that the recommended tolerance of 0.09 ppm for wheat grain tolerance is not listed

. Due to submission of supplemental residue data , the tolerance o f wheat grain was increased to 0.15 ppm (DP397825, M. Negussie, 05/23/2012)

. Furthermore, the established tolerance for wheat bran at 0.15 ppm is no longer needed and should be revoked (the recommended tolerance of 0.15 ppm for wheat grain will cover expe cted residues in wheat bran). To support the recommended wheat grain tolerance of 0.15 ppm, Arysta has submitted another petition: PP#2F8130 (February 2013)

. Concurrent with this new petition (PP#2F8130) , Arysta has requested to change the following established tolerance s: 0.02 ppm to 0.03 ppm for milk, and 0.50 ppm to 0.75 ppm for milk, fat

. The established tolerance for milk is 0.02 ppm, which is below the combined LOQ (0.01 ppm for each analyte) of the milk method (0.03 ppm). Based on the maximum residues in milk (0.03 ppm) and an assumed 25X concentration factor, a tolerance of 0.75 ppm would be appropriate.

The most recent human health risk assessment , conducted for use on turf and ornamentals

, reported t he hazard characterization and toxicit y en dpoints for risk assessment (D P 404179, N. Tsaur, 11/13 /2012 ). T he hazard characterization and toxicity endpoints for risk assessment remain unchanged. A brief hazard characterization along with the salient features for the Food Quality Protection Act (FQPA) safety factor are summarized in this risk assessment

. Proposed Use Profile Fluoxastrobin 480 SC Fungicide may be applied as a foliar spray via groundboom, aircraft, chemigation, and handheld equipment. For melons, the maximum single application r ate is 5.7 fl oz/A (0.18 lb ai/A) and applications may be repeated on a 7

- day interval, up to a maximum seasonal application rate of 22.8 fl oz/A (0.72 lb ai/A) per year. For sorghum, the maximum single application rate is 4.0 fl oz/A (0.12 lb ai/A) and a pplications may be repeated on a 14

- day interval, up to a maximum seasonal application rate of 8 fl oz/A (0.26 lb ai/A) per year.

Exposure Profile Exposure pathways include dietary (food and drinking water), residential, and occupational
exposure sources. The existing residential uses result in non

- occupational exposure from handler and post

- application activities

. Non

- occupational e xposures to flu oxastrobin a re only expected for short

- term durations

. Dietary exposures are expected for chronic duration. Occupational handler and post

- application exposures are expected for short

- and intermediate

- term durationsPage 5 of 36



### only. The proposed label requires occ upational handlers to wear long pants, long sleeves, shoes, socks, and chemical resistant gloves.

Toxicity/Hazard The risk assessment for fluoxastrobin is based on a well

- characterized a nd complete toxicology database. Following repeated exposure , fluoxa strobin has mild or low toxicity in all tested species except for the dog. Repeated oral administration to dogs resulted in adverse liver toxicity at considerably lower doses than those noted in other species. Based on species sensitivity, the effects ob served in the dog were used as endpoints for risk assessment. In both the 90

- day and

one

- year oral feeding studies in dogs, the liver appeared to be the target organ. In dogs, mice, and rats

, the kidney was another target organ

.

There was no indication of an adverse effect attributable to a single dose

. Based on developmental toxicity studies (rat and rabbit) and a two

- generation rep roduction study (rat), there was neither increased susceptibility of pre

- / postnatal exposure to fluoxastrobin

, nor adverse effects on reproduction. Furthermore, were not seen in an acute neurotoxicity study in rats up to the limit dose of 2000 mg/kg/day. In a subchronic neurotoxicity study in rats , fluoxastrobin did
not elicit any neurotoxic effects. Repeated dose s tudies of fluoxastrobin in the database did not show immunotoxic effects in rats . Therefore, the data support a reduction of the FQPA safety factor to 1X. Results of genotoxicity testing were negative and there were no treatment

- related carcinogenicity f

indings in adequately performed carcinogenicity studies in rats and mice. Therefore, fluoxastrobin is classified as “not likely to be carcinogenic to humans.”

Dietary Exposure (Food and Water) and Risk Estimates The dietary exposure and risk estimate s ch anged slightly from the previous risk assessment. There was no indication of an adverse effect attributable to a single dose . Thus, an acute reference dose ( aRfD ) was not established, and an acute dietary exposure assessment was not conducted. A slightl y refined chronic dietary exposure assessment was performed for fluoxastrobin using tolerance

- level residues , average field trial residues, and 100% crop treated (CT). The estimated drinking water concentration ( EDWC ) of 137 μ g/L was incorporated directly into the dietary assessment . The results of the chronic dietary analysis for f ood and drinking water are below the HED’s level of concern (LOC) for all population subgroups. The dietary exposure for food and water is estimated at 3 0 % of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and 66 %, of the cPAD for all infants < 1 year old, the population subgroup with the highest estimated chronic dietary exposure to fluoxastrobin.

Residential Exposure and Risk Estimates Existing registered uses do not result in any residential handler or post

- application risk estimates of concern. The lowest and most protective s hort

- term residentia l handler (inhalation only) MOE is 7,300 based on a granular use on reside ntial turf. The lowest and most protective in cid ental oral post

- application MOE for children (1 to <2 years old) is 39 0 based on hand to mouth activities on turf treated with a liquid formulation of fluoxastrobin

. Aggregate Exposure Risk Estimates There is potential for short

- term aggregate exposure to fluoxastrobin via the dietary (which is considered background exposure) and residential (which is considered primary) pathways. AllPage 6 of 36



### aggregate MOEs are greater than 100, which indicates that exposure and risk estimates do not exceed HED’s LOC . The adult and children short

- term aggregate (dietary + residential ) MOEs

are 6 1 0 and 17 0, respectively. Since there are neither intermediate

- term nor chronic residential
exposure scenario s, the aggregate risk e stimates are expected to be equivalent to chronic dietary (food and drinking water) risk estimate

. Occupational Handler Exposures and Risk Estimates Based on the proposed uses, th ere is potential for short

- and intermediate

- term occupational
exposure to fluoxastrobin during handling activities (e.g. mixing, loading, application). There

are no risk estimates of concern without personal protective equipment (PPE); all short

- term handler risk estimates (inhalation only) resulted in MOEs ranging from 3,400 to 76,000; all intermediate

- term handler risk estimates (dermal + inhalation) resulted in MOEs ranging from 320 to 21,0 00.

Occupational Post

-

A pplication Exposures and Risk Estimates There is potential for short

- and intermediate

- term occupational exposure during post

- application activities. There is no short

- term dermal POD selected for fluoxastrobin. There are no inte rmediate

- term dermal post

- application risk estimates of concern on day 0 (12 hours after application); all scenarios resulted in MOEs greater than the LOC (100) and ranged from 1,400 to 55,000 on day 0. Based on a quantitative post

- application assessment, the 12

- hour restricted entry interval (REI) on the proposed label is acceptable for melons (subgroup 9A) and sorghum.

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

- cancer occupational post

- application inhalation exposure assessment was no t performed for fluoxastrobin at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for fluoxastrobin

.

2.0 HED Recommendations

Pend ing submission of a revised Section F

, t here are no issues that would preclude granting registration for the requested use s of fluoxastrobin on melon subgroup 9A and sorghum (grain, forage, and stover)

, o r establishment of the recommended tolerances for co mbined residues of fluoxastrobin and its Z

- isomer (See Table 2.2.3).

Note: Upon reviewing the tolerances established under 40 CFR §180.609, HED notes that the tolerance recommended under PP#9F7567 is not listed for wheat, grain (0. 15 ppm). Furthermore, t he established tolerance for milk (0.02 ppm) should be changed to the combined LOQ of the milk method (0.03 ppm) and the tolerance for milk, fat (0.50 ppm) should be changed to 0.75 ppm.

2.1 Data Deficiencies

The following changes are required prior to establishing a tolerance or allowing a registration :Page 7 of 36



### 875.2100 Turf Transferable Residues A TTR study is required for fluoxastrobin at this time since the incidental oral hand

- to

- mouth MOE for small children is less than 1,000 (MOE = 390, LOC = 100) base d on default values for the fraction of application rate available for transfer after a liquid application to turf (N. Tsaur, D406106, 10/25/2012).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Acceptable high performance liquid chromatography methods with tandem mass spectro metry detection ( LC/MS/MS ) are available for tolerance enforcement for plant commodities. Bayer AG method 00604 and confirmatory method 00946 have been adequately validated for the determination of residues o f fluoxastrobin and its Z

- isomer in/on plant commodities.

Acceptable LC/MS/MS methods are available for tolerance enforcement for livestock commodities. Bayer AG method 00691 and confirmatory method 00945 have been adequately validated for determination of fluoxastrobin, its Z

- isomer, and HEC 7154 in ruminant commodities.

Acceptable multiresidue methods test data were previously submitted for fluoxastrobin, its Z

isomer, and HEC 7154. The data indicate that the multiresidue methods are not adequate for tolerance enforcement for fluoxastrobin for plant or livestock commodities.

2.2.2 Recommended Tolerances

Table 2.2. 3. Tolerance Summary for Fluoxastrobin

Commodity Tolerance (ppm) Comments Correct Commodity Definition Established Proposed Recommended

40 CFR §180.609(a)(1) Melon, subgroup 9A

-- 1.5 1.5 Melon subgroup 9A Sorghum grain

-- 1.5 1.5 Sorghum, grain

Sorghum fodder

-- 4 5.0 Sorghum, fo rage. Recommended tolerance based on use of the OECD statistical calculation procedures.

Sorghum stover

-- 4 5.0 Sorghum, stover

. Recommended tolerance based on use of the OECD statistical calculation procedures. Wheat, grain

-- 0.15 0.15

Wheat, bran 0.15 None Revoke. The recommended tolerance on wheat, grain will cover expected residues in wheat bran.
Livestock Tolerances That Need to be Revised
Milk 0.02 0.03 0.03 Milk, fat 0.50 0.75 0.75Page 8 of 36



### 2.2.3 Revisions to Petitioned

- For Tolerances

The proposed tolerances must be modified for the following commodities: sorghum fodder, sorghum stover, milk, and milk fat. The recommended plant commodity tolerances are derived from use of the Organization of Economic Cooperation and Development (OECD) statistical calculation procedure s.

2.2. 4 International Harmonization

There are no Codex maximum residue limits (MRLs) established for fluoxastrobin . However, there are Canadian MRLs established on sorghum and wheat grain at 0.1 ppm, wheat bran at 0.15 ppm, milk at 0.02 ppm, and milk fat at 0.15 ppm. Furthermore, the Canadian tolerance expression is not harmonized with the US tolerance expression. F or plants and livestock, the Canadian tolerance expression does not include the Z

- isomer. An International Residue Limit Status sheet is attached as Appendix D

.

3.0 In troduction

Fluoxastrobin is the common name for the pesticidally active E

- isomer of [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime. The Z

- isomer of fluoxastrobin is typically present at much lower levels ( E:Z ratio of approximately 90:10). Additionally, the Z

- isomer of fluoxastrobin is considered to be a metabolite (photodegradate) of fluoxastrobin. The petitioner has requested that fluoxastrobin ( E

isomer only) be designated as the ai.

In PP# 2F8047

, Arysta requests the establishment of tolerance s for residues of the fungicide fluoxastrobin in/on the following raw agricultural commodit ies (RAC s ): melon subgroup 9A and sorghum (grain, fodder, and stover) . Furthermore, Arysta proposes a label amendment to add these crops to the master label for Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330

- 64). Fluo xastrobin 480 SC Fungicide is an SC formulation containing 40.3% a i by weight (3.98 lb ai per gallon).

3.1 Chemical Identity

Table 3.1 . Fluoxastrobin Nomenclature Compound

Common name f luoxastrobin Company experimental name HEC 5725Page 9 of 36

Table 3.1 . Fluoxastrobin Nomenclature IUPAC name ( E )

- {2

- [6

- (2

- chlorophenoxy)

- 5

- fluoropyrimidin

- 4

- yloxy]phenyl}(5,6

- dihydro

1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime
CAS name (1 E )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime CAS registry number 361377

- 29

- 9
Formula C 21 H 16 ClFN 4 O 5 End

- use product (EP) 4.0 lb ai/gal SC formulation (Fluoxastrobin 480 SC/EvitoTM 480 SC Fungicide 1 ; EPA Reg. No. 66330

- 64) Compound

Common name Fluoxastrobin Z

- isomer
Chemical name (1 Z )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime Compound

Common name HEC 7154
Chemical name 6

- (2

- chlorophenoxy)

- 5

- fluoro

- pyrimidinol



### 3.2 Physical/Chemical Characteristics

Fluoxastr obin has a low vapor pressure (4.2×10 - 1 2 

### mm Hg at 20 °C); therefore, inhalation due to chemical vaporization is unlikely. Fluoxastrobin has a log octanol/water partition coefficient (log P ow 

### ) of 2.85 and is considered relatively insoluble in water. Additionally, fluoxastrobin has a molecular weight of 458.8 g/mol ; therefore, the potential to cross biological barriers, such as the skin, is somewhat limited. More detailed physicochemical properties of fluoxastrobin are summarized in Appendix B

.

3.3 Pesticide Use Pattern

Fluoxastrobin is a strobilurin

- class fungici de that controls foliar fungal diseases and soilborne/seedling fungal diseases

. It works by interrupting mitochondrial respiration in plant

pathogenic fungi, thus inhibiting spore germination and mycelial growth. F luoxastrobin is currently registered for the following uses: field/sweet corn, field corn/sweet corn grown for seed, fr uiting vegetables, leaf petiole vegetables, low

- growing berries, peanuts, rice, soybeans, squash/cucumbers, tuberous and corm vegetables, wheat, and turf /ornamentals

.Page 10 of 36



### Arysta has submitted an amended label for Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330

- 64, also labeled under the trade name D isarm TM 480 SC Fungicide) to include use s on melon subgroup 9A and sorghum

. The newly proposed use pattern is presented in Table 3.3

.

Table 3.3 . Summary of Directions for Use of Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330

- 64) a
Applic ation Timing, Type, and Equip ment Single

Maximum Application Rate Maximum

Number of Applications
per Year Maximum

Annual Applic ation Rate PHI Use Directions and Limitations

days
Melons (S ubgroup 9A) Muskmelon, including hybrids and/or varieties of Cucumis melo (including true cantaloupe, cantaloupe, casaba, Santa Claus melon, crenshaw melon, honeydew melon, honey balls, Persian melon, golden pershaw melon, mango

melon, pineapple melon, snake melon, and other varieties and/or hybrids of ( Citr u llus spp.) Broadcast Foliar : g round, aerial, chemigation, or handheld 5.7 fl oz/A

0. 18 lb ai/A 4 22.8 fl oz/A 0.72 lb ai/A 1 Applications are to begin preventatively and continue as needed on a 7

- 14 day RTI. Do not apply to crops grown in a greenhouse. Do not tank mix with EC

- based insecticides. Sorghum Broadcast Foliar : g round, aerial, chemigation, or handheld 4.0 fl oz/A

0. 12 lb ai/A 2 8.0 fl oz/A 0.26 lb ai/A Forage: 14

Grain and Stover: 21 Applications are to begin

preventatively and continue as needed on a 14

- 21 day RTI.

a Not currently registered or approved for use in California.



### 3.4 Anticipated Exposure Pathways

Humans ma y be exposed to fluoxastrobin via food and drinking water because fluoxastrobin may be applied directly to growing crops

, and application may result in fluoxastrobin reaching surface and ground sources of drinking water. There are also residential uses of fluoxastrobin so there is 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 application. There is also a potenti al for post

- application exposure for workers re

- entering treated fields.

Several risk assessments have been previously prepared for the existing uses of fluoxastrobin. This risk assessment considers all of the aforementioned exposure pathways based on th e proposed new uses of fluoxastrobin, 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

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

- established
pr ocedures. In line with OPP policy, HED estimates risks to population subgroups fromPage 11 of 36



### 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 residen tial setting. Extensive data on food co nsumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), 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 and ethnic group . Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstanc es warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further c onsiderations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The fluoxastrobin hazard characterization is detailed in a previous risk assessment (DP 292422, S. Winfield, 01/24/2005). New toxicity data have not been submitted since the las t human health risk assessment ( DP404179, N. Tsaur, 11/13/2012 ) . All available toxicity studies are listed in Appendix A.

4.1 Summary of Toxicological Effects

Fluoxastrobin is a strobilurin fungicide analog (other registered strobilurin fungicides inclu de azoxystrobin, pyraclostrobin, and trifloxystrobin). The strobilurin biochemical mode of action consists of interaction with the ubiquinone binding site of the mitochondria in fungal cells, thereby preventing the trans fer of electrons to the cytochrome

. Interrupting the electron transport chain prevents oxidative phosphorylation, severely reducing the availability of adenosine triphosphate (ATP), the main energy currency of the cell. The energy shortage has several biochemical consequences including th e following: (1) breakdown of essential membrane potentials and concentration gradients ; and (2) inhibition of nucleic acid and protein biosynthesis; thus f

ungal spore germination, mycelial growth , and development of infection
structures are prevented . The available mammalian toxicity data do not demonstrate a similar mode of action as that on fungi

. Following repeated administration, in the rate, mouse, rabbit, and dog, fluoxastrobin has mild or low toxicity in all tested species except for the dog. Repeated oral administration to dogs elicited adverse liver toxicity at considerably lower doses than those noted in other species. Based on species sensitivity, the effects observed in the dog were used as endpoints for risk assessment. In both the 90

- day and one

- year oral feeding studies in dogs, the liver appeared to be the target
organ . In dogs, mice, and rats

, the kidney was another target organ.

N either increa sed susceptibility to pre

- / postnatal exposure to fluoxastrobin nor effects on reproduct ion were observed in developmental toxicity studies (rat and rabbit) or in a two

generation reproduction study (rat) . Furthermore, acute neurotoxic effects were not seen in ratsPage 12 of 36



### up to the limit dose of 2000 mg/kg/day. I n a subchronic neurotoxicity study in rats

, fluoxastrobin did not show any acute effects nor any neurotoxic effects compared to the control. Repeated dose studies of fluoxastrobi n in rats and mice did not show structural immunotoxic effects in rats

. Functional immunotoxicity was not obser ved in an immunotoxicity study of fluo x astrobin in rats. Results of genotoxicity testing were negative and there were no treatment

related increases in tumor incidence in adequately performed carcinogenicity studies in rats and mice. Therefore, fluoxastr obin is classified as “ not likely to be carcinogenic to humans. ”

Fluoxastrobin was extensively metabolize d as evidenced by the metabolic profiles in urine, feces, and bile along with the relative absence of the parent compound (except in the feces of rats given the high dose). The urinary metabolites were primarily the result of cleavage between the second and third rings of the parent compound. Bil iary metabolites were primarily products resulting fro m cleavage of rings 2, 3 and 4, and subsequent hydroxylation, methoxylation, and conjugation with glucuronic acid. The major metabolites, HEC5725

- E

- des

- chlorophenyl and HEC5725

- des

- chlorophenyl

- dioxazi ne

- OH

, were found in all excretion matrices.

Absorption, distribution, and metabolism were fully characterized in several rat metabolism studies using each of the three 14 

### C

- radiolabeled rings in fluoxastrobin. Following a single oral low or high dose, absorption was almost complete at a low dose with peak plasma concentrations being attained within 0.5 to 8 hours depending on the dose and label position. Fecal excretion

w as the major route of elimination (75

- 91% within 48 hours) while urinary excretion was a secondary route (11

- 20%). Elimination of the radioactivity via expired air was inconsequential (<0.1%)

, thereby confirming stability of the label. Bile duct cannulat ion experiments at a low dose revealed that nearly 100% of the fecal radioactivity was contributed by the bile in the form of hydroxylated, methylated, and conjugated products. In high

- dose groups, much of the fecal radioactivity (43

- 54% of administered d ose) was attributed to parent compound ( which suggests saturated absorption). Tissue/carcass burdens accounted for about 1% of the administered radioactivity at 48 hours post dose. Most of this radioactivity was associated with the liver and gastrointest inal tract

. Following an 8

- hour dermal application in a male mon key, absorption was negligible, and t he normali zed absorption value was 2.31%. This is consistent with the 21

- day dermal toxicity study where no effects were seen up to the limit dose of 1,0 00 mg/kg/day.

4. 2 Safety F actor for Infants and Children (FQPA Safety Factor)

The FQPA safety factor is reduced to 1X; consideration of the toxicology database leads to no additional concerns for infants and children

.

4. 2 .1 Completeness o f the Toxicolog y Database

The toxicological database for fluoxastrobin is complete

. The submitted toxicology studies are of good quality and provide sufficient information to determine whether fluoxastrobin poses a human health hazard. A subchronic inhalation toxicity study is not required for fluoxastrobin at this time (TXR0056388 , K. Rury , 08/01/2012 ).

4. 2 .2 Evidence of N eurotoxicityPage 13 of 36



### The available toxicity database for fluoxastrobin, which includes the ne urotoxicity screening batte ry , do es not show any evidence of neurotoxicity.

4. 2 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The available studies used to evaluate pre

- and post

- natal exposure susceptibility do not indicate increased sensitivity or su sceptibility in the developing or young animals to fluoxastrobin . These studies include the following: (1) a developmental toxicity stud y in rats , (2) a developmental toxicity stud y in rabbits, and (3) a two

- gene ration reproduction study in rat s.

4. 2 .4 Residual Uncertainty in the Exposure Datab ase
The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. The chronic dietary food exposure assessment was conservatively based on 100 % crop treated ( CT) assumptions, tolerance

- level residues

, average field trial residues, default processing factors, and conservative modeled ground and surface drinking water modeling estimates. New 2012 Residential SOPs we re used to assess post

- application exposure
to children including incide ntal oral exposure. The residential post

- application assessment assumes maximum application rates and conservative day zero hand

- to

- mouth activities. All of the exposure estimates are based on conservative high

- end assumptions an d are not likely to result in underestimated risk.

4. 3 Toxicity Endpoint s and Point s of D eparture Selections

There are no changes to the previous dose

- response assessment. A quantitative hazard estimate was not selected for the short

- term dermal exposur e scenario based on the lack of systemic and dermal toxicity in the 28

- day dermal toxicity study in the rat at the limit dose of 1000 mg/kg/day, and the absence of developmental or reproduction toxicity findings. The adverse liver findings (cholestasis) i n the 90

- day subchronic dog study were used as the endpoints for the following exposure scenarios: intermediate

- term dermal, short

- and intermediate

- term inhalation, and short

- and intermediate

- term incidental oral. Although long

- term dermal and inhalatio n exposures are not expected based on the proposed uses, the adverse liver findings (cholestasis) in the chronic toxicity dog study were used for setting the quan titative hazard estimate for chronic dietary exposure . Although acute exposure is expected, an acute quantitative hazard estimate was not established because an adverse effect attributable to a single exposure was not identified from the available database. A subchronic inhalation toxicity study is not req uired for fluoxastrobin at this time ( TXR0056388, K. Rury, 08/01/2012 ). Fluoxastrobin shows low acute toxicity via the oral, dermal, an d inhalation routes of exposure. It is a moderate eye irritant, and is neither a dermal irritant, nor a skin sensitizer.Page 14 of 36

Table 4.3. Summary of Toxicological Doses and Endpoints for Fluoxastrobin for Use in Dietary , Non

Occupational , and Occupational Human Health Risk Assessments a

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) and Females 13

- 49 years of age None: There is no indication of an adverse effect attributable to a single dose. An aRfD was not

established.

Chronic Dietary (All Populations) NOAEL =

1.5 mg/kg/day UF A = 10X

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

= 0.015 mg/kg/day

cPAD = 0.015 mg/kg/day Chronic toxicity dog

LOAEL = M/F 8.1/7.7 mg/kg/day based on body weight reductions and hepatocytomegaly and cytoplasmic changes associated with increased serum liver alkaline phosphatase indicative of cholestasis.

Incidental Oral Short

- Term (1

- 30 days) and Intermediate

Term (1

- 6 months) NOAEL =

3.0 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day based on dose

- related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver (cholestasis) in both sexes, and kidneys (in creased relative weights in females and degeneration of the proximal tubular epithelium in males). Dermal Short

Term (1

- 30 days) None: There were no systemic or dermal toxicity findings in a 28

- day dermal toxicity study in

the rat up to the limit dose (1000 mg/kg/day) and there were no developmental or neurotoxicity concerns raised in other studies.

Dermal Intermediate

Term (1

- 6

mo nths) NOAEL =

3.0 mg/kg/day

dermal absorption factor = 2.3% UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100

Occupational LOC for MOE = 100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day based on dose

- related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver (cholestasis) in both sexes, and kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).

Inhalation b Short

- Term (1

- 30 days) and Intermediate

Term (1

- 6 months) NOAEL =

3.0 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE = 100

Occupational LOC for MOE = 100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day based on dose

- related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver (cholestasis) in both sexes, and kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males). Cancer (oral, dermal, inhalat ion) Classification: “Not likely to be Carcinogenic to Humans.”

a 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 observe d adverse effect level. LOAEL = lowest observed adverse effect level.Page 15 of 36

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 expos ure. LOC = level of concern. b Toxicity by the oral route is assumed to be equivalent to the oral route. A subchronic inhalat ion toxicity study is not required for fluoxastrobin at this time ( TXR0056388, K. Rury, 08/01/2012 )

.



### 5.0 Dietary Exposure and Risk Assessment

5. 1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Fluoxastrobin and its Z

- isomer Fluoxastrobin and its Z

- isomer Rotational Crop

Livestock Ruminant Fluoxastrobin, its Z

- isomer, and its phenoxy

hydroxypyrimidine metabolite [6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinol] Fluoxastrobin, its Z

- isomer, and its phenoxy

hydroxypyrimidine metabolite [6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinol] Poultry

Drinking Water Fluoxastrobin and its Z

- isomer Not Applicable



### 5.2 Food Residue Profile

Adequate field trial data are available to support the proposed uses on melon subgroup 9A and sorghum. In the cantaloupe residue decline studies, combined residues of fluoxastrobin and its Z

- isomer generally declined with increasing sampling interval. In the so rghum residue decline studies, combined residues of fluoxastrobin and its Z

- isomer generally declined in forage and grain samples with increasing sampling interval, but residue decline was not consistent in stover samples.

An adequate p rocessing stud y was submitted for sorghum

. The data indicate that combined residues of fluoxastrobin and its Z

- isomer concentrate in AGF (37x ) . However, t he established tolerance for grain, aspirated grain f ractions (60 ppm) is sufficient

.

The available storage stability d ata for fluoxastrobin on the representative crops are adequate to support the storage durations and conditions of samples of melons and sorghum grain, forage, stover, and AGFs from the submitted crop field trials.

The available ruminant feeding study is a cceptable to support the proposed use of fluoxastrobin on sorghum

. The addition of sorghum grain and forage (beef and dairy only) to the dietary burden calculations for cattle increased the dietary burden for beef and dairy slightly and was lower for poul try and swine. The e xisting tolerances for livestock commodities are adequate.Page 16 of 36



### Available confined rotational crop data are adequate to satisfy data requirements and to delineate the nature of the residue in rotated crop commodities. The confined rotational crop studies indicate the potential for quantifiable residues of fluoxastrobi n in rotated crop commodities. HED previously concluded that the residues of concern for rotational crops for risk assessment and tolerance setting purposes are fluoxastrobin and its Z

- isomer.

5. 3 Water Residue Profile

Based on laboratory studies, fluoxastrobin persists in soils for several months to several years and is slightl y to moderately mobile in soil . Since aqueous photolysis is the major route of degradation for fluoxastrobin, the dissipation of this chemical in water is dependent on physi cal components of the water ( e.g. sediment loading, depth, etc.) which have an effect on sunlight penetration. A photolysis study performed in natural water/sediment systems indicates that the majority of applied fluoxastrobin adsorbs to sediment and no s oil metabolites are formed under natural conditions. Field studies indicate that fluoxas trobin persists for over a year; h owever, it was not observed to leach through soil.

In addition to evaluating the EDWCs from the proposed uses, EDWCs were r eevalu ate d for all existing uses with PRZM

- GW

, 1 

### which models continued use of fluoxastrobin over many years (DP403757, R. Bohaty, 02/05/2013)

. T he most conservative EDWC (137 μg/L ) wa s based on an existing turf use modeled with a 100 year simulation of 100 years o f repeated applications , using the highest s ingle maximum application rate and the highest yearly application rate

, and wa s used in the chronic dietary assessment.

Table 5.3 . Summary of Estimated Drinking Water Concentrations for Fluoxastrobin

Tier II Surface Water Model ( μg/L )

Scenario Melons Sorghum Turf Acute (1

- in

- 10 year peak) 48.7 7.0 24.8 Chronic (non

- cancer, 1

- in

- 10 year annual average) 7.9 4.6 18.6

Tier I Ground Water Model ( μg/L )

Scenario Melons Sorghum Turf Acute (peak c oncentration ) 47.1 a 15.3 a 146 a Chronic (p ost b reakthrough a verage c oncentration ) 44.2 a 14.3 a 137 a

a Extended weather file used; 100 year simulation with 100 years of repeated applications.



### 5. 4 Dietary Risk Assessment

5.4 .1 Description of Residue Data Used in Dietary Assessment

A partially refined chronic dietary exposure assessment was performed for fluoxastrobin. The assumptions include tolerance level residues, average field trial residues

, and 100% crop treated (CT ). Average field trial residues were used for m elon subgroup 9A, berry low growing

1 PRZM

- GW was recently (12/2012) approved for standard use in drinking water assessments as a Tier I and Tier II exposure tool.Page 17 of 36



### subgroup 13

- 07G, leaf petioles subgroup 4B, rice, squash/cucumber subgroup 9B, and vegetable fruiting group 8. Based on processing studies, the processing factors for tomato puree, potato chips, dried potato (granules/f lakes), and potato flour were reduced to 1. Separate tolerances were set for peanut oil and tomato paste; therefore, the processing factors for these commodities were set at 1 ( DP 289106 , W. Wassell, 01/25/2005 ). Default processing factors from the Dietar y Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) V ersion 7.81 were assumed except for where tolerances were established for processed commodities or when processing studies showed no concentration. Field trial data were translated from the representative commodities to the non

- representative commodities according to HED SOP 2000.1:”Guidance for Translation of Field Trial Data from Representative Commodities in the Crop Group Regulation to other Commodities in Each Cr op Group/Subgroup.” Th e estimated ground water post breakthrough average concentration of 137
μ g/L was incorporated directly into the dietary assessment

.

5. 4

. 2 Acute Dietary Risk Assessment

There was no indication of an adverse effect attributable to a single dose

. Thus, a n aRfD was not established, and an acute dietary exposure assessment was not conducted.

5. 4

. 3 Chronic Dietary Risk Assessment

A slight ly refined c hronic dietary (food and drinking water) exposure and risk assessment was conducted usi ng the D EEM

- FCID Version 3.16 . This model uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA)

. The results of the chronic dietary analysis for f ood and drinking water are below the Agency’s LOC for the general U.S population and all population subgroups. T he dietary (food and drinking wate r ) exposure is estimated at 3 0 % of the chronic Population Ad justed Dose (cPAD) for the general U.S. population and 66 %, of the cPAD for all infants <1 year old, the population subgroup with the highest estimated chronic dietary exposure to fluoxastrobin. The results of the chronic dietary exposure analys e s are rep orted in Table 5.2 .5

.

5.4 .4 Cancer Dietary Risk Assessment

Fluoxastrobin is classified as “not likely to be carcinogenic to hu mans;” therefore, cancer risk was no assessed

.

5

. 4

. 5 Summary Table

Table 5.2 .5 . Summary of Dietary Exposure and Risk for Fluoxastrobin ( c PAD = 0.015 mg/kg/day) a

Population Subgroup Chronic Dietary Exposure Estimates (Food and Drinking Water) mg/kg/day % cPAD General U.S. Population 0.004529 30 All Infants (< 1 year old) 0.009886 66Page 18 of 36

Table 5.2 .5 . Summary of Dietary Exposure and Risk for Fluoxastrobin ( c PAD = 0.015 mg/kg/day) a

Population Subgroup Chronic Dietary Exposure Estimates (Food and Drinking Water) mg/kg/day % cPAD

Children 1

- 2 years old 0.009516 63
Children 3

- 5 years old 0.007496 50
Children 6

- 12 years old 0.005052 34
Youth 13

- 19 years old 0.003514 23
Adults 20

- 49 years old 0.004226 28 Adults 50+ years old 0.003999 27
Females 13

- 49 years old 0.004118 28

a The population subgroup with the greatest exposure is in bold

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no propose d residential uses at this time. However, t he products currently registered for use on residential turf include granular and liquid formulations. R esidential handler and post

application assessment s were conducted to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body weight assumptions an d the results impact the human health aggregate risk assessment for fluoxastrobin ( DP405369, K. Rury, 02/25/2013)

.

6.1 Residential Handler Exposure

Residential h andler ex posure is expected to be short

- term

. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners. Since there are no toxicity findings for the short

- term dermal route of exposure up to the limit dose, the residential handler assessment only includes the inhalation route of exposure. A summary of the most protective short

- term risk estimate (inhalation only) for residential handlers is based on a granular application to turf and is detailed in Table 6.1

.

Table 6 .1. Residential Handler Non

- Cancer Exposure and Risk Estimates for Fluoxast robin

Exposure Scenario Level of

Concern Inhalation

Unit Exposure Maximum

Application Rate a Area Treated

or Amount Handled Daily b Inhalation

Dose c MOE d

m g/lb ai mg/kg/day Mixer/Loader/Applicator for Granular Application to Turf and Ornamentals
Hand Dispersal 100 0.38 0.0000719 lb ai/sq ft 1200

sq ft 0.00041 7,300

a Based on registered product label for Disarm G Fungicide ( EPA Reg. No. 66330

- 380 )

. b Based on HED’s SOPs: Lawns/Turf (January 2012). 0.023 A = 1000 ft 2

. c Inhalation Dose = Inhalation Unit Exposure ( m g/lb ai) × Application Rate (lb ai/acre or gal or square feet ) × Area Treated or Amo unt Handled (A or gallons or square feet /day) ÷ BW ( 80 kg). d Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). ST Inhalation NOAEL = 3 mg/kg/day. Level of concern = 100.Page 19 of 36



### 6.2 Post

- Application Exposure

Adults and children performing physical post

- application activities on turf (e.g. golfing, mowing) may receive dermal exposure to fluoxastrobin residues. Young children ( 1 to <2 years old ) may also receive incidental oral post

- application exposure to fluoxastrobin from treated turf.

Although residential dermal exposure is expected following the treatment of turf, short

- term dermal hazard was not identifi ed for fluoxastrobin. Therefore, a quantitative post

- application dermal risk assessment was not conducted. Regardless, short

- term incidental oral exposure and risk estimate s have been assessed for the physical activities of children 1 to <2 years old on turf

, following liquid and granular application of fluoxastrobin at maximum registered application
rates

. Intermediate

- term incidental oral exposure is not expected for post

- application activities to turf because residues are unlikely to persist for longe r than one month due to turf maintenance (e.g. mowing) and climate (e.g. rain).

Table 6.2 presents the most protective post

- application incidental oral MOE value calculated fo r liquid applications of fluoxastrobin to turf

. The p ost

- application risk estim ates is not of concern to HED (MOE = 39 0)

.

Table 6.2

. Short

- Term Residential Post

- Application Exposure and Risk Estimates for Fluoxastrobin on Turf a

Lifestage Post

- Application Exposure Scenario b Dose MOE c mg/kg/day Child 1 to < 2 year s old Hand to Mouth 0.00 77 390

a Based on registered product label for Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330

- 64); SC Liquid Formulation; 3.69 lb ai/gallon; max single application rate = 0.46 lb ai/A

. b Hand

- to

- Mouth Dose = hand residue loading (mg/cm 2 ) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm 2 )

× exposure time (1.5 hrs/day) × # of replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.5))^(Number of hand

- to

- mouth events per hour (13.9 events/hr) ÷ # of reple nishment intervals/hr)) ÷ body weight (11 kg).

c MOE = NOAEL ÷ Daily Dose (mg /kg/day)

. Incidental Oral NOAEL= 3. 0 mg/kg/day . Level of concern = 100.



### 6.3 Residential Bystander Post

- A pplication Inhalation Exposure

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

- application inhalation exposure assessment was not performed for fluoxastrobin at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (4.2 x 10 - 12 

### mm Hg at 20 °C), and the low proposed use rate (0.18 lb ai/A). 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 issue s related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 2 

### . 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 exposure into the Agency's risk assessments. If new policies or procedures are developed, th e Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for fluoxastrobin.

2 Available: http://www.epa.gov/scipoly/SAP/meetin gs/2009/120109meeting.htmlPage 20 of 36



### 6. 4 Spray Drift

Spray drift is always a potential source 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 method employed for fluoxastrobin

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices

, and Stat e 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 3 

### . 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 met hods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risk estimates 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 inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a

wor se case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider a nd aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For fluoxastrobin, potential exposures from food, drinking water, and residen tial scenarios were aggregated.

7.1 Acute Aggregate Risk

Acute exposures were not considered because an adverse effect attributable to a single dose was not identified.

7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to fluoxastrobin via the dietary (which is considered background exposure) and residential (which is considered primary) pathways. For adults, these pathways lead to exp osure via the oral (background) and inhalation (primary) routes. For children, these pathways lead to exposure via the oral (backg round) and incidental oral (primary)
routes. The most protective residential exposure risk estimates are included in the aggregate exposure assessment. The recommended residential exposure for use in the adult aggregate risk

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmPage 21 of 36



### a ssessment reflects dermal and inhalation exposure from hand dispersal of granulars to ornamentals (MOE = 7,300). The recommended residential exposure for use in the children 1<2 years old aggregate assessment reflects hand

- to

- mouth exposures from post

- app lication exposure to liquid applications to turf (MOE = 390). Aggregate MOEs are greater than 100, which indicates that exposure and risk do not exceed HED’s level of concern. The adult and children short

- term aggregate dietary and residential MOEs are 6 1 0 and 1 7 0, respectively.

Table 7.2. Short

- Te rm Aggregate Risk Calculations

Population NOAEL LOC 1 Max Allowable Exposure 2 Average

Food and Water Exposure Residential

Exposure 3 Total

Exposure 4 Aggregate

MOE (food, water, and residential) 5 mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day

Adult 3.0 100 0.030 0. 00 4529 0. 00041 0. 0049 39 61 0
Children 1

- 2 years old 3.0 100 0.030 0. 00951 6 0.0077 0. 01721 6 170

1 LOC = 100 ( based on inter

- and intra

- species uncertainty factors total ing 100X).
2 Maximum Allowab le Exposure (mg/kg/day) = NOAEL ÷ LOC.
3 Resident ial Exposure = Inhalation Only for adults, Incidental Oral Only for children ( See Table 6.3).
4 Total Exposure = Average Food and Water Exposure + Residential Exposure.
5 Aggregate MOE = NOAEL ÷ Total Exposure

. NOAEL = 3 mg/kg/day. LOC = 100.



### 7. 3 Intermediate

- Term Aggregate Risk

Intermediate

- term exposure is not expe cted for the adult or children residential exposure pathway. Therefore, the intermediate

- term aggregate risk would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.2 .5

.

7.4 Chronic Aggregate Risk

Chronic exposure is not expected for the adult residential (dermal and inhalation) exposure pathway. Therefore, the chronic aggregate risk would be equivalent to the chronic dietary exposure estimate . Refer to Section 5. 2

. 5

.

7.5 Cancer Aggregate Risk

Fluoxastrobin is classified as “not likely to be carcinogenic to humans;” therefore, an aggregate cancer assessment was not conducted.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fluoxastrobin and any other substances and fluoxastrobin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, there fore, EPA has not assumed that fluoxastrobin has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see thePage 22 of 36



### policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational handler and post

- application exposure may occu r by the dermal and inhalation routes of exposure only. For short

- term exposure, only inhalation exposures were assessed s ince there is no dermal hazard for the short

- term duration . For intermediate

- term exposures, combined (dermal + inhalation) exposure s were assessed

. The results of the occupational handler exposure and risk assessment indicate that short

- and intermediate

- term risk estimate s are not of concern (K

. Rury , DP 405369 , 02/2 5 /2013). Appendix E , Tables E .1 and E .2 summarize all assessed occu pational exposure and risk estimates.

9.1 Short

- and Intermediate

- Term Handler Risk

Based on the anticipated use patterns and current labeling, and types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: Mixing/Loading liquids for aerial, chemigation, and groundboom application ; Applying liquids with aerial and groundboom equipment; Flagging for aerial application; and Mixing/Loading/Applying with a mechanically pressurized handgun.

HED classifies exposur es from 1 to 30 days as short

- term and exposures from 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and th e cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for mult iple clients within a region). The area treated or amount handled is b ased on HED Exp oSAC Policy No. 9.1 (refer to Appendix E for these assumptions for each scenario).

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Expo sure Database ( PHED ) 1.1, the Agricultural Handlers Exposure Task Force ( AHETF ) database

, the Outdoor Residential Exposure Task Force (ORETF) database

, the Agricultural Re

- Entry Task Force (ARTF) , or other registrant

- submitted occupational exposure studies . Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) . The standard values recommended for use in predicting handler exposure that are use d in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler UnitPage 23 of 36



### Exposure Surrogate Reference Table 4 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the v arious sources, can be found at the Agency website 5



### . There are no risk estimates of concern at the baseline level of personal protective equipment (PPE); t he proposed l abel require s chemical

- resistant gloves as PPE

. A ll short

- term handler risk estimates (inhalation only) resulted in MOEs ranging from 3,400 to 76,000; all intermediate

- term handler risk estimates (dermal + inhalation) resulted in MOEs ranging from 320 to 21,000. Note that o nly engineering control (enclo sed cockpit) data are available to assess risks to handlers operating aircrafts.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers whe n appropriate, agricultural aviation has changed dramatically over the past two decades. According to the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultura l aviation has grown steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

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

- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators.

9.2 Short

- and Intermediate

- Term Post

- A pplication Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when wo rkers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- app lication exposure levels vary over time and depend on such things as the type of activity, th e nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- app lication exposure.

9.2.1 Dermal Post

- Application Risk

There is potential for short

- and intermediate

- term occupational exposure during post

- application activities. There is no short

- term dermal POD selected for fluoxastrobin. There are no

4 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf
5 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlPage 24 of 36



### intermediate

- term dermal post

- application risk estimates of concern on day 0 (12 hours after application); all scenarios resulted in MOEs greater than the LOC (100) and ranged fro m 1,400 to 55,000 on day 0.

9.2.2 Restricted Entry Interval

Fluoxastrobin i s classified as Toxicity Category I II via the dermal route. It is a moderate irritant to eyes, it is not irritating to the skin

, and it is not a skin sensitizer. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation

, and primary skin irrigation are assigned a 12

- hour REI

. Based on a quantitative post

application assessment, the 12

- hour restricted entry interval (REI) on the proposed label is acceptable for melons (subgroup 9A ) and sorghum.

9.2.3 Inhalation Post

- Application Risk

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

- application inhalation exposure

a ssessm ent was not performed for fluoxastrobin at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (4.2 x 10 - 12 

### mm Hg at 20 °C), and the low proposed use rate (0.18 lb ai/A) . However, there are multiple potential sources of post

application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that c ontain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final repo rt on March 2, 2010 6 

### . The Agency is in the process of evaluating 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 subs equently, the way to incorporate occupational post

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

- application inh al ation exposure assessment for fluoxastrobin

. Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure re sulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inh alation exposure scenarios.

10 .0 References

Bohaty, Rochelle. 0 5 /0 8 /2012. DP Barcode 401613 . “ Revised Drinking Water Assessment for Fluoxastrobin Use on Rice.”

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlPage 25 of 36



### Negussie, Meheret. 03/21/2013. DP Barcode 403571, 409039. “ Fluoxastrobin: Petition for the Establishment of Permanent Tolerances for Uses on Melon (Subgroup 9A), Sorghum

, and W heat. Amendments to Established Tolerances on Milk and Milk Fat. Summary of Analytical Chemistry and Residue Data. ”

Negussie, Meheret. 05/23/2012. DP Barcode 397825. “ F luoxastrobin . Supplemental Residue Data for Sweet Corn and Wheat. Response to Condition of Registration Requirements Specified Under DP#s 364445 and 367049. Summary of Analytical Chemistry and Residue Data. ”

Negussie, Meheret. 06/19/2012. DP Barcode 40 2506. “ Fluoxastrobin: Chronic Dietary (Food and Drinking Water) Exposure Assessments for the Section 3 Registration Action U se on Wheat Due to Submission of Supplemental data.”

Tsaur, Nancy. 06/27 /2012 . DP Barcode 393842 . “ Fluoxa strobin

. Human Health Risk Assessment for Proposed New Use on Rice Grain with Updated Residential Risk Estimates of All Existing Residential Uses. ”

Tsaur, Nancy. 10 / 25 /2012. DP Barcode 40610 6. “ Fluoxastrobin. Re sidential Exposure Assessment for a Proposed New U se on Turf and Ornamentals. ”Page 26 of 36



### A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The toxicology study requirements (40 CFR § 158. 500 ) for food use for fluoxastrobin are in Table A.1. Use of the new guideline number s does not imply that the new (1998) guideline protocols were used.

Table A.1. Satisfication of Fluoxastrobin Toxicology Data Requirements
Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

................................ ......................... 870.1200 Acute Dermal Toxicity

................................ .................... 870.1300 Acute Inhalation Toxicity

................................ ................ 870.2400 Primary Eye Irritation

................................ ...................... 870.2500 Primary Dermal Irritation

................................ ................ 870.2600 Dermal Sensitization

................................ ........................ yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)

................................ ................. 870.3150 Oral Subchronic (nonrodent)

................................ ........... 870.3200 21 /28

- Day Dermal

................................ ........................... 870.3250 90

- Day Dermal

................................ ................................ 870.3465 90

- Day Inhalation

................................ ............................ yes yes yes

no

no a 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 (rat)

................................ .............. - yes

- yes yes -

yes

- yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

....................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

.................. 870.5 375 Mutagenicity

— Structural Chromosomal Aberrations

..... 870.5385 Mutagenicity

— Other Genotoxic Effects

......................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen)

................................ . 870.6100b 90

- Day Neurotoxicity (hen)

................................ ............. 870.6200a Acute Neurotoxicity Screening Battery (rat)

................... 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

................. 870.6300 Develop. Neurotoxicity

................................ ................... no

no yes yes

no -

- yes yes

- 870.7485 General Metabolism

................................ ........................ 870.7600 Dermal Penetration

................................ .......................... 870.7800 Immunotoxicity

................................ ............................... yes yes yes yes

yes yes Special Studies for Ocular Effects

Acute Oral (rat)

................................ ............................. Subchronic Oral (rat)

................................ .................... Six

- month Oral (dog)

................................ .................... a A subchronic inhalation toxicity study is not required for fluoxastrobin at this time ( TXR0056388, K. Rury, 08/01/2012 ). The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data.Page 27 of 36



### A.2 Toxicity Profiles

Table A.2.1. Fluoxastrobin Acute Toxicity Profile

Guideline No. Study Type MRID Results Toxicity Category 870.1100 Acute oral

- rat 45865612 LD 50 >2000 mg/kg III 870.1200 Acute dermal

- rat 45865613 LD 50 >2000 mg/kg III 870.1300 Acute inhalation

- rat 45865618 LC 50 = 4.9 mg/L IV 870.2400 Acute eye irritation

- rabbit 45865620 moderate irritant III 870.2500 Acute dermal irritation

- rabbit 45865622 not an irritant IV 870.2600 Skin sensitization

- guinea pig 45865624 not a sensitizer

-

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 45865627 (1998)

acceptable/guideline M: 0, 125, 1000 or 8000 ppm (0, 8.7, 70.4 or 580.0 mg/kg/day) F: 0, 250, 2000 or 16000 ppm (0, 21.5, 162.9 or 1416.1 mg/kg/day) NOAEL = M: 70.4 mg/kg/day; F: 162.9 mg/kg/day LOAEL = M: 580.0 mg/kg/day based on reduced body weight gain and food intake, vacuolation in the zona fasciculate of the adrenal cortex, calculi in the urethra and kidney, and histological lesions in kidney, urinary bladder, and urethra. LOAEL = F: 1416.1 mg/kg/d ay based on increased liver weight (by 20%).

870.3100 90

- Day oral

toxicity (mouse) 45865626 (1998)

acceptable/non guideline 0, 450, 1800 or 7000 ppm M: 0, 81.1, 313.4 or 1303.7 mg/kg /day F: 0, 135.1, 539.2 or 2256.9 mg/kg/day NOAEL = 7000 ppm (M/F: 1304/2257 mg/kg/day) (highest dose tested); this dose was about the limit dose for a 90

- day oral toxicity study (1000 mg/kg/day).

870.3150 90

- Day oral

toxicity (dog) 45865629 (2001);

45 865628 (2001); 45865722 (2000) acceptable/guideline 4 beagle dogs/sex/dose (MRID 45865629): 0, 25, 50, 100, 800 or 2500 ppm M: 0, 0.7, 1.4, 3.0, 24.8 or 76.0 mg/kg/day F: 0, 0.7, 1.5, 3.0, 24.2 or 75.0 mg/kg/day NOAEL = M/F: 3.0 mg/kg/day (100 ppm) LOAEL = M/F 24.8/24.2 mg/kg/day (800 ppm) based on dose

- related red uctions in net body weight gain and food efficiency in addition to toxicity findings in the liver in both sexes (cholestasis) and in kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).

870.3200 21 /28

- Day dermal

toxicity (rat) 45865630 (2000)

acceptable/guideline 0, 100, 300 or 1000 mg/kg/day (6 hours/day, 5 days/week for the first three weeks; 7 days/week for the fourth week) NOAEL = 1000 mg/kg/day (the limit dose, for both systemic and dermal) LOA EL not identified.

870.3465 90

- Day inhalation

toxicity (rat) Waived (TXR 0056388)

.Page 28 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700a Prenatal

developmental in (rat) 45865631 (1997)

acceptable/guideline 0, 100, 300 or 1000 mg/kg/day Maternal NOAEL 1000 mg/kg/day (limit dose) LOAEL not identified. Developmental NOAEL 1000 mg/kg/day LOAEL not identified.

870.3700b Prenatal

developmental in (rabbit) 45865632 (1999)

acceptable/guideline 22 naturally mated female Himalayan rabbits/group by gavage: 0, 25, 100, 400 mg/kg/day Materna l NOAEL = 100 mg/kg/day LOAEL = 400 mg/kg/day based on cold ears, transient body weight loss, and decreased food consumption. Developmenta l NOAEL 400 mg/kg/day LOAEL not identified.

870.3800 Reproduction and

fertility effects (rat) 458 65633 (2001);

45865634 (2001) acceptable/guideline 0, 100, 1000 or 10000
ppm M: 0, 6.3, 70.0 or 665.0 mg/kg/day F: 0, 7.8, 84.7 or 825.4 mg/kg/day Parental Systemic NOAEL = M/F 70.0/84.7 mg/kg/day LOAEL = M/F 665.0/825.4 g/kg/day based on decreased premating body weight gain of the P

generation males and females and decreased premating absolute body weight of the F 1 males and females. Reproductive NOAEL = M/F > 665.0/825.4 mg/kg/day LOAEL not identified. Offspring NOAEL = M/F 70.0/84.7 mg/kg/day LOAEL = M/F 665.0/825.4 mg/kg/day based on decreased body weights, delayed preputial separation, and incomplete ossification in the F 1 and/or F 2 males and females.

870.4100b Chronic toxicity

(dog) 45865701 (2002);

45865722 (2000) acceptable/guideline 4 beagle dogs/sex/dose: 0, 25, 50, 250 or 1200
ppm M: 0, 0.8, 1.7, 8.1 or 34.9 mg/kg/day F: 0, 0.7, 1.5, 7.7 or 37.4 mg/kg/day NOAEL = M/F:1.7/1.5 mg/kg/day LOAEL = M/F:8.1/7.7 mg/kg/day based on body weight reductions and hepatocytomegaly and cytoplasmic changes associated with increased s erum liver alkaline phosphatase indicative of cholestasis.

870.4200b Carcinogenicity

(mouse) 45865702 (2001)

acceptable/guideline 0, 100, 700 or 4200 ppm M: 0, 18.5, 135.4 or 775.6 mg/kg/day F: 0, 29.5, 204.0 or 1265.1 mg/kg/day NOAEL = M/F: 775.6/1265.1 mg/kg/day LOAEL not identified. No evidence of carcinogenicity

.Page 29 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.4300 Carcinogenicity

(rat) 45865703 (2001)

acceptable/guideline M: 0, 40, 100, 1000 or 5000 ppm (0, 2.1, 5.2, 53.0 and 271.9 mg/kg/day) F: 0, 100, 500, 2500 or 12500 ppm (0, 6.9, 35.2, 181.3 and 1083.2 mg/kg/day) NOAEL = M/F: 53.0/181.3 mg/kg/day LOAEL = M/F: 271.9/1083.2 mg/kg/day based on decreased body weight, body weight gain, and food efficiency in both sexes, decreased spleen weight in males, and microscopi c lesions in the uterus of females. There is no evidence of carcinogenicity (ad hoc senior CARC member meeting on 10/25/2004).

Gene Mutation 870.5100 In vitro bacterial

reverse gene mutation 45865704 (1996)

acceptable/guideline plate incorporation: 16, 5 0, 158, 500, 1581 and 5000 μ g/plate; following preincubation: 10, 32, 100, 316, 1000 and 3162
μg /plate negative (considered non

- mutagenic in Salmonella typhimurium cultures treated up to cytotoxic/precipitating levels)

Gene Mutation 870.5100 In vitro bacterial

reverse gene mutation 45865705 (1998)

acceptable/guideline plate incorporation and following preincubation: 16, 50, 158, 500, 1581 and 5000 μg /plate Test substance: HEC 5725N (E:Z = 90:10%) negative (considered non

- mutagenic in this Salmonella t

yphimurium /microsome test)

Gene Mutation 870.5100 In vitro bacterial

reverse gene mutation 45865706 (2000)

unacceptable/guideline plate incorporation: 16, 50, 158, 500, 1581 and 5000 μg /plate; following preincubation: 100, 200, 400, 800, 1600 and 3200
μg / plate Test substance: HEC 5725

- phenoxy

- hydroxy

pyrimidine negative (considered non

- mutagenic in this Salmonella typhimurium /mammalian activation gene mutation assay)

Gene Mutation 870.5100 In vitro bacterial

reverse gene mutation 45865707 (2001)

acceptable/guideline plate incorporation: 16, 50, 158, 500, 1581 and 5000 μg /plate; following preincubation: 5, 16, 50, 158, 500 and 1581
μg /plate Test substance: HEC 5725

- phenoxy

- hydroxy

pyrimidine negative (considered non

- mutagenic in this Salmonella typ himurium /mammalian activation gene mutation assay)Page 30 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Gene Mutation 870.5100 In vitro bacterial

reverse gene mutation 45865708 (2 001)

unacceptable/guideline 16 to 5000 μg /plate (6 concentrations) Test substance: HEC 5725

- dihydroxy

pyrimidine negative (considered non

- mutagenic in this Salmonella typhimurium /mammalian activation gene mutation assay)

870.5300 In vitro

mammalian cell gene mutation test 45835709 (1997)

acceptable/guideline Negative. Test concentrations: 1 to 200 g/ml.

870.5375 In vitro

m ammalian chromosome aberration test 45835710 (1996)

acceptable/guideline Negative. Test concentrations: 0, 20,40,80,160, and 320 g/ml.

870.5395 In vivo

mouse micronucleus 45865711 (1999)

acceptable/guideline Negative. Test concentrations: 75,150 , and 3 0 0

m g/ kg/day

.

870.6200a Acute

neurotoxicity screening battery (rat) 45865712 (2001)

acceptable/guideline 12 rats/sex: 0, 200, 500 or 2000 mg/kg bw NOAEL (neurotoxic) 2000 mg/kg (limit dose) LOAEL not identified.

870.6200b Subchronic

neurotoxicity screening battery (rat) 45865713 (2002)

acceptable/guideline 12 rats/sex: 0, 200, 1000, 7500 ppm M: 0, 12.7, 59.5 or 473.9 mg/kg/day F: 0, 15.1, 71.7 or 582.4 mg/kg/day NOAEL (systemic and neurotoxic) = M/F: 473.9/582.4 mg/kg/day LOAEL not i dentified.Page 31 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.7485 Metabolism &

pharmacokinetics (rat) 45865714,

- 15,

- 20 (2002)

45865716,

- 17, 18,

- 19 (2001) acceptable/guideline 1, 3, or 5 mg/kg/day Orally administered 14 C

- fluoxastrobin was rapidly absorbed, and within 30 minutes peak plasma concentration was reached. Elimination and tissue/organ burden data showed that absorption via the GI tract nearly approached 100% of the administered dose. The absorbed dose was widel y distributed. Approximately 77% and 14% of the administered dose was eliminated in the feces and urine, respectively. Elimination via expired air was less than 0.3% of the administered dose. Overall elimination was >90% of the administered radioactivity a nd completed within 24 hours. Bile duct cannulation study showed that nearly 100% of the fecal radioactivity was contributed by the bile in the form of hydroxylation, methylation, and conjugation products. Fluoxatrobin was extensively metabolized primarily via hydroxylation and subsequent methylation, followed by gluxuronide or sulfate conjugation. No tissue accumulation was demonstrated, but liver and GI tract were found to be associated with more radioactivity (~0.42% and 0.44% of the administered dose, r espectively). Many metabolites were found, and the primary ones were glucuronide conjugates, methoxy

- OH

GA

- dioxazine

- OH and methoxy

- OH

- GA). Parent fluoxastrobin accounted for less than 3% of the administered dose.

870.7600 Dermal

penetration (monkey) 45911501/45911502

(2003) acceptable/nonguideline Following an 8

- hour dermal application in a male monkey, absorption was negligible (1.16% preliminary, 2.16% main). The normalized absorption value for the main study was 2.31%.

870.7800 Immunotoxicity

–

Subchronic Feeding Study (rat) 48692105 (2011)

acceptable/guideline 0, 125, 1000, or 8000 ppm (equivalent to 0, 10, 81, or 637 mg/kg/day) The systemic toxicity NOAEL is 8000 ppm (637 mg/kg/day) and the LOAEL is >8000 ppm (637 mg/kg/day). The immunotoxicity NOAEL is 8000 ppm (637 mg/kg/day) based on anti

- SRBC IgM ELISA results and the LOAEL is >8000 ppm (637 mg/kg/day).



### A ppendix B. Physical/Chemical Properties

Table B . Physico

- Chemical Properties

Parameter Value Reference Molecular Weight 458.8 g/mol Melting range 103

- 105 C MRID 45865525 pH 6.3 (1% in CIPAC

- D water) MRID 45865520 Water solubility (20°C) at 20 C : MRIDs 45865520, 45865525Page 32 of 36

Table B . Physico

- Chemical Properties

Parameter Value Reference 0.0019 g/L; 0.0024 g/L at pH 4 0.0023 g/L at pH 7 0.00227 g/L at pH 9

Solvent solubility (20°C to 25°C) at 20 C :

n

- heptane 0.05 g/L xylene 38 g/L dichloromethane >250 g/L 2

- propanol 6.7 g/L 1

- octanol 1.1 g/L polyethylenglycol 400 119 g/L
acetone >250 g/L ethyl acetate >250 g/L acetonitrile >250 g/L dimethylsulfoxide >250 g/L MRIDs 45865520, 45865525

Vapor pressure (25°C) 5.63 × 10 - 10 Pa (20 C) 4.2× 10 - 1 2 mm Hg (20 C) 8.72 × 10 - 10 Pa (25 C) MRID 45865525

Dissociation constant, pKa no dissociation constant at pH 4

- 9 MRID 45865303 Octanol/water partition coefficient, log K OW (25°C) 2.85 (20 C); P OW = 708 MRID 45865525
UV/visible absorption spectrum 19,358 L/mol cm at 250 nm MRID 45865303Page 33 of 36



### Appendix C. Review of Human Research

Studies reviewed for ethical conduct: MRID 44972201

– ORETF data PHED Surrogate Exposure Guide

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise PHED, ORETF

, and ARTF, have been determined to require a review of their ethical conduct and have received that review. In this assessment, ORETF data were used to assess loading/applying with a push type spreader (data from MRID 44972201 ) and PHED data were used to assess loading/applying with a belly grinder.

Studies reviewed by the Human Studies Review Board: None.

Appendix D. International Residue Limit Status

Table D.1. Fluoxastrobin Summary of US an d International Tolerances and Maximum Residue Limits
Residue Definition

US Canada Mexico b Codex
40 CFR 180.609: Plant : residues of fluoxastrobin, (1E)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidiny l]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, and its Z isomer, (1Z)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidiny l]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, calculated as the stoichiometric equivalent of fluoxastrobin. Livestock : residues of fluoxastrobin, (1E)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidiny l]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, its Z isomer, (1Z)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidiny l]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxim e, and its phenoxy

hydroxypyrimidine metabolite, 6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinol, calculated as the stoichiometric equivalent of fluoxastrobin

. Plant : (1E)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidiny l]oxy]phenyl](5, 6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime Livestock: (1E)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidiny l]oxy]phenyl](5, 6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, including the metabolite 6

- (2

- chlorophenoxy)

- 5

- f

luoro

4

- pyrimidinol None

Commodity a Toleranc e /Maximum Residue Limit
US Canada Mexico b Codex

ppm mg/kg Melon subgroup 9A 1.5 Sorghum, grain 1.5 0.1 sorghum Sorghum, forage 5.0 Sorghum, stover 5.0 Completed: M. Negussie; 02/21/2013

a Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. b Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Page 34 of 36



### Appendix E. Occupational Exposure/R isk Summary Tables

Table E. 1. Occupational Handler Short

- Term Non

- Cancer Exposure and Risk Estimates for Fluoxastrobin

Exposure Scenario Crop or Target Baseline Inhalation Unit Exposure a Maximum

Application Rate b Area

Treated or Amount Handled Daily c Inhalation

Dose d MOE e μg/lb ai mg/kg/day

Mixer/Loader at Baseline (No Respirator)

Mixing/Loading for Aerial Application Melon

(S ubgroup 9A) 0.219 0.18 lb ai/A 350 0.000173 17,000

Sorghum 0.219 0.12 lb ai/A 1200 0.000394 7,600
Mixing/Loading for Chemigation Application Melon (S ubgroup 9A) 0.219 0.18 lb ai/A 350 0.000173 17,000 Sorghum 0.219 0.12 lb ai/A 350 0.000115 26,000
Mixing/Loading for Groundboom Application Melon (S ubgroup 9A) 0.219 0.18 lb ai/A 80 0.0000394 76,000 Sorghum 0.219 0.12 lb ai/A 200 0.0000658 46,000 Applicator at Baseline (No Respirator)

Applying with Aerial Equipment Melon (S ubgroup 9A) 0.068 0.18 lb ai/A 350 0.0000535 56,000 Sorghum 0.068 0.12 lb ai/A 1200 0.000122 25,000
Applying with Groundboom Melon

(S ubgroup 9A) 0.34 0.18 lb ai/A 80 0.0000613 49,000 Sorghum 0.34 0.12 lb ai/A 200 0.000102 29,000 Flagger at Baseline (No Respirator)

Flagging for Aerial Application Melon (S ubgroup 9A) 0.35 0.18 lb ai/A 350 0.000276 11,000

Sorghum 0.35 0.12 lb ai/A 350 0.000184 16,000
Mixer/Loader/Applicator at Baseline (No Respirator) Mixing/Loading/Applying for Broadcast Application with Mechanically Pressurized Handgun Melon (S ubgroup 9A) 3.9 0.018 lb ai/gal 1000 0.000878 3,400

Mixing/Loading/Applying for Drench/Soil/Ground Directed Application with Mechanically Pressurized Handgun Melon

(S ubgroup 9A) 3.9 0.018 lb ai/gal 1000 0.000878 3,400

a Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation: Baseline. Aerial Application is in a cl osed system at baseline level (no PPE )

. b Based on registered or proposed label (Reg. No. 66330

- 64).

c Exposure Science Advisory Council Policy #9.1. d Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (80 kg).

e Inhalation MOE = Inhalation NOAEL (3.0 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

### FLUOXASTROBIN Human Health Risk Assessment DP No. D405370

Page 35 of 36 Table E .2. Occupational Handler Intermediate

- Term Non

- Cancer Exposure and Risk Estimates for Fluoxastrobin at Baseline

Exposure Scenario Crop or Target Dermal Unit Exposure a Inhalation

Unit Exposure a Maximum

Application Rate b Area

Treated or Amount Handled Daily c Dermal Inhalation Total

Dose d MOE e Dose f MOE g MOE h μg/lb ai mg/kg/day mg/kg/day
Mixer/Loader at Baseline
Mixing/Loading for Aerial Application Melon

(S ubgroup 9A) 220 0.219 0.18 lb ai/A 350 0.0040 750 0.000173 17,000 720 Sorghum 220 0.219 0.12 lb ai/A 1200 0.00911 330 0.000394 7,600 320

M ixing/Loading for Chemigation Application Melon (S ubgroup 9A) 220 0.219 0.18 lb ai/A 350 0.0040 750 0.000173 17,000 720 Sorghum 220 0.219 0.12 lb ai/A 350 0.00266 1,100 0.000115 26,000 1,100

Mixin g/Loading for Groundboom Application Melon (S ubgroup 9A) 220 0.219 0.18 lb ai/A 80 0.000911 3,300 0.0000394 76,000 3,200 Sorghum 220 0.219 0.12 lb ai/A 200 0.00152 2,000 0.0000658 46,000 1,900 Appli cator at Baseline
Applying with Aerial Equipment Melon (S ubgroup 9A) 5 0.068 0.18 lb ai/A 350 0.0000905 33,000 0.0000535 56,000 21,000 Sorghum 5 0.068 0.12 lb ai/A 1200 0.000207 14,000 0.000122 25,000 9,000
Apply ing with Groundboom Melon

(S ubgroup 9A) 78.6 0.34 0.18 lb ai/A 80 0.000325 9,200 0.0000613 49,000 7,700 Sorghum 78.6 0.34 0.12 lb ai/A 200 0.00054 5,500 0.000102 29,000 4,600 Flagger at Baseline
Flagging for Aerial Application Melon (S ubgroup 9A) 11 0.35 0.18 lb ai/A 350 0.000199 15,000 0.000276 11,000 6,300
Sorg hum 11 0.35 0.12 lb ai/A 350 0.000133 23,000 0.000184 16,000 9,400

Mixer/Loader/Applicator at Baseline Mixing/Loading/Applying for Broadcast Application with Mechanically Pressurized Handgun Melon

(S ubgroup 9A) 1,300 3.9 0.018 lb ai/gal 1,000 gal 0.00673 450 0.000878 3,400 400

Mixing/Loading/Applying for Drench/Soil/Ground Directed Application with Mechanically Pressurized Handgun Melon (subgroup 9A) 1,300 3.9 0.018 lb ai/gal 1,000 gal 0.00673 450 0.000878 3,400 400

a Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation: Base line. Aerial Application is in a closed system at baseline level of PPE. b Based on registered or proposed label (Reg. No. 66330

- 64).

c Exposure Science Advisory Council Policy #9.1.

### FLUOXASTROBIN Human Health Risk Assessment DP No. D405370

Page 36 of 36 d Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (80 kg).

e Dermal MOE = Dermal NOAEL (3.0 mg/kg/day) ÷ Dermal Dose (mg/kg/day). f Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80 kg).
g I nhalation MOE = Inhalation NOAEL (3.0 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). h Total MOE = NOAEL (3.0 mg/kg/day) ÷ Dermal Dose + Inhalation Dose.

Table E.3

. Occupational Post

- A pplication Non

- Cancer Intermediate

- Term Dermal Exposure and Risk Estimates for Fluoxastrobin

Crop Activities Transfer Coefficient DFR a Dermal Dose b MOE c

cm 2 /hr mg/kg/day

Cantaloupe, Watermelon Hand

- Set Irrigation 1900 0.505 0.00221 1,400

Hand Harvesting, Mechanically Assisted Harvesting, Turning 550 0.505 0.000639 4,700

Transplanting 230 0.505 0.000267 11,000
Scouting, Hand Weeding, Hand Pruning, Thinning Fruit 90 0.505 0.000105 29,000

Sorghum Scouting 210 0.337 0.000163 18,000
Hand Weeding 70 0.337 0.0000543 55,000

a DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day. b Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (80 kg).

c MOE = POD (mg/kg/day) / Da ily Dermal Dos e. Daily Dermal Dose = [DFR (μg/cm 2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal absorption factor (%)] BW (80 kg).