FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 1 of 43 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION

MEMORANDUM

DATE : February 28, 2011

SUBJECT: Fluoxastrobin. Human Health Risk Assessment for Proposed New Use on the

Squash/ Cucumber Subgroup 9B.

PC Code: 028869 DP Barcode: 379110
Decision No.: 433137 Re gistration No. : 66330

- 64
Petition No

. : 0F7726 Regulatory Action: Section 3 Registration
Risk A ss essment Type : Single Chemical/Aggregate Case No.: NA

T XR No.: NA CAS No.: 361377

- 29

- 9
MRID No

. : NA 40 CFR: 180.609

FROM: Nancy Tsaur, Chemist, Risk Assessor

Meheret Negussie, Chemist Cassi Walls, Biologist Kristin Rury, Biologist Whang Phang , Toxicologist
Risk Assessment Branch 3 Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief

Risk Assessment Branch 3

He alth Effects Division (7509P)

TO: Tony Kish /John Bazuin , Risk Manager Team 22

Fungicides Branch

R egistration Division (7505P)FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 2 of 43 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ........... 4
2.0 HED Recommendations

................................ ................................ ................................ .... 4
2.1 Data D eficiencies/Conditions of Registration

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

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

................................ ................................ ............... 5
2.2.2 International Harmonization

................................ ................................ ..................... 5
2.2.3 Recommended Tolerances

................................ ................................ ......................... 5
2.3 Label Recommendations

................................ ................................ ................................ 6
2.3.1 Recommendations from Residue Reviews

................................ ................................ 6
2.3.2 Recommendations from Occupational Assessment

................................ ................. 6
2.3.3 Recommendations from Residential Assessment

................................ ..................... 7
3.0 Introduction

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

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

................................ ................................ ............... 8
3.3 Pesticide Use Pattern

................................ ................................ ................................ ...... 8
3.4 Anticipated Exposure Pathways

................................ ................................ ................. 10
3.5 Consideration of Environmental Justice

................................ ................................ .... 10
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 11
4.1 Toxicology Studies Available for Analysis

................................ ................................ . 11
4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

............................. 11
4.3 Toxicological Effects

................................ ................................ ................................ .... 12
4.4 Sa fety Factor for Infants and Children (FQPA Safety Factor)

............................... 12
4.4.1 Completeness of the Toxicology Database

................................ .............................. 12
4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 13
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 13
4.4.4 Residual Uncertainty in the Exposure Database

................................ ................... 13
4.5 Toxicity Endpoint and Poin t of Departure Selections

................................ .............. 13
4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 14
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

..... 15
4.5.3 Cancer Classification and Risk Assessment Recommendation

............................ 15
4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

................................ ................................ ................................ ............................... 15
4.6 Endocrine Disruption

................................ ................................ ................................ ... 18
5.0 Diet ary Exposure and Risk Assessment

................................ ................................ ......... 19
5.1 Metabolite/Degradate Residue Profile

................................ ................................ ....... 19
5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ............. 19
5.1.2 Summary of Environmental Degradation

................................ .............................. 20
5.1.3 Comparison of Metabolic Pathways

................................ ................................ ....... 20
5.1.4 Residues of Concern Summary and Rationale

................................ ...................... 21
5.2 Food Residue Profile

................................ ................................ ................................ .... 21
5.3 Water Residue Profile

................................ ................................ ................................ .. 24
5.4 Di etary Risk Assessment

................................ ................................ .............................. 24
5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 24
5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 25FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 3 of 43 5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 25
5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 25
5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 25
5.4.6 Summary Table

................................ ................................ ................................ ......... 25
6.0 Resident ial (Non

- Occupational) Exposure/Risk Characterization

............................. 26
6.1 Residential Handler Exposure

................................ ................................ .................... 26
6.2 Post

- Application Exposure

................................ ................................ .......................... 27
6.3 Combined Exposure

................................ ................................ ................................ ..... 28
6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ 29
6.5 Spray Drift

................................ ................................ ................................ .................... 29
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 30
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 30
7.2 Shor t

- Term Aggregate Risk

................................ ................................ ........................ 30
7.3 Chronic Aggregate Risk

................................ ................................ .............................. 30
7.4 Cancer Aggregate Risk

................................ ................................ ................................ 31
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 31
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 31
9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................... 31
9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ............. 33
9.2.1 Dermal Post

- Application Risk

................................ ................................ ................. 33
9.2.2 Inhalation Post

- Application Risk

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

................................ ................ 35
A.1 Toxicology Data Requirements

................................ ................................ ................... 35
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 36 Appendix B. Metabolism Summary Table

................................ ................................ ............ 41 Appendix C. Physical/Chemical Properties

................................ ................................ ........... 42 Appendix D. Review of Human Research

................................ ................................ ............. 43 Appendix E. International Residue Limit Summary

................................ ........................... 43FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 4 of 43 1.0 Executive Summary

In PP# 0F7726

, Arysta LifeScience North America, LLC. (Arysta) petitioned for the
establishment of new tolerances for combined residues of the fungicide fluoxastrobin ( 1E )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- m ethyloxime and its Z

- isomer (1 Z

)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl) methanone O

- methyloxime in/on the following raw agricultural commodit ies (RAC s ):

Crop subgroup 9B Squash/Cucumbers

.................. 0.50 ppm

In conjunction with this petition, Arysta is requesting an amended registration of the 4 lb ai/gal suspension concentrate (SC) formulation of fluoxastrobin, FLUOXASTROBIN 480 SC Fungicide (EPA Reg. No. 66330

- 64) , to add use on the squash/cucumber subgroup 9B.

Pending submission of revised Section s B and F, and re solution of the deficiencies identified in
Section 2.1 , there are no residue chemistry issues that would preclude granting conditional registration for the requested uses of fluoxastrobin on the squash/cucumber subgroup 9B or establishment of permanent tol erances for combined residues of fluoxastrobin and its Z

- isomer.

The most recent human health risk assessment was conducted for uses on sweet corn, field corn/sweet corn grown for seed, and wheat; revised tolerances on peanut and refined peanut oil
based on a peanut processing study; and label revision allowing homeowner residential application to turf grasses (DP# 366179 , N

. Dodd, 0 8/13/ 2010 ). The hazard characterization and toxicity endpoints for risk assessment were reported in a 2005 risk assessment ( DP#292422, S. Winfield, 1/24/05). Since then, no new toxicology data have been submitted. The hazard characterization and toxicity endpoints for risk assessment remain unchanged since the 2005 risk

assessment

. The details of the hazard characterization and the rationale for toxicity endpoint selection will not be repeated in this risk assessment. However, the salient features will be summarized for these two topics and the F ood Q uality P rotection A ct (FQPA) safety factor.

A summary of the findings and an assessment of human health risk resulting from the proposed and registered uses of fluoxastrobin are provided in this document and its attachments. The residue chemistry data submitted in support of this petition we re reviewed by Meheret Negussie,
the dietary exposure assessment was completed by Cassi Walls, t he occupational/residential
assessment for food use on squash/cucumber subgroup 9B was conduct ed by Kristin Rury, and

t he toxicology evaluation was performed by Whang Phang. The drinking water ass essment was conducted by Rochelle Bohaty. The risk assessment was conducted by Nancy Tsaur

.

2.0 HED Recommendations

Pending submission of revised Sections B and F, HED recommend s for a conditional registration
and a permanent tolerance for the use of fluoxastrobin on the squash/cucumber subgroup 9B. Additional data are needed as a condition of registration as outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and the label modifications are
discussed i n Section 2.3.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 5 of 43 2.1 Data Deficiencies/Conditions of Registration

Data Deficiencies

Chemistry [860.1200 Directions for Use]

A revised Section B is needed to reflect the recommendations listed in Section 2.3.1.

Chemistry [ 860.1550 Proposed Tolerances ]

A revised Section F is needed to reflect the correc t commodity definition (Table 2.2.3 ).

Chemistry [ 860.1650 Submittal of Analytical Reference Standards ] Arysta must provide an a nalytical reference standard of the metabolite HEC 7154 to the
EPA National Pesticide Standards Repository

.

Toxicology [ 870.7800 Immunotoxicity] Additional information on the mouse subchronic immunotoxicity study is needed (for potential upgrade).

Conditions of Registration

Chemistry [860.1500 Crop Field Trials] To fulfill geographic distribution requirements, an additional cucumber field trial must be conducted in region 2.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

- isomer in plant commodities, and Bayer AG method 00691 and confirmatory method 00945 have been adequately validated for determination of fluoxastrobin, its Z

- isomer, and the metabolite HEC
7154 in ruminant commodities. Adequate method validation, concurrent method recoveries, independent laboratory validation data, and radiovalidation data are available.

2.2.2 International Harmonization

There are currently no establish ed Mexican, Canadian, or Codex maximum residue limits ( MRLs ) or tolerances for fluoxastrobin on the squash/cucumber subgroup 9B (see Appendix E ).

2.2.3 Recommended TolerancesFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 6 of 43 As shown in Table 2. 2.3 , the proposed tolerance commodity term has to be revise d in a revised
Section F to agree with the Agency’s Food and Feed Commodity Vocabulary.

Table 2. 2.3

. Tolerance Summary for Fluoxastrobin

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

40 CFR §180.609(a)(1)
Crop subgroup 9B Squash/Cucumbers -- 0.50 0.50 Squash/cucumber subgroup 9B

Note to PM: In accordance with HED’s Interim Guidance on Tolerance Expressions (S.

Knizner , 0 5/27/ 2 0 0 9 ), the tolerance expressions for fluoxastrobin should be revised as follows:

Under 40 CFR §180.609(a)(1) and §180.609(d): ―Tolerances are established for residues of fluoxastrobin, including is metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of (1 E )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime
and its Z

- isomer, (1 Z

)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyri midinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime.

Under 40 CFR §180.609(a)(2): ―Tolerances are established for residues of fluoxastrobin, including is metabolites and degradates, in or on the commodities in the table below.

Co mpliance with the tolerance levels specified below is to be determined by measuring only the sum of(1 E )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, its Z

- isomer, (1 Z )

- [2

- [[6

- (2

- chloro phenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, and the phenoxy

- hydroxypyrimidine metabolite, 6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinol, calculated as the stoichiometric equivalent of
fluoxastrobin.

2. 3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Chemistry [ 860.1200 Directions for Use ] The proposed use directions for squash/cucumber subgroup 9B should be revised to correct the application rate from a range of 0.09 to 0.16 lb ai /A to a range of 0.09 to 0.18
lb ai/A. The statement ―Do not apply more than 21.8 fl oz (0.68 lb ai) of EVITO® 480 SC per acre per year‖ should be revised to ―Do not apply more than 22.8 fl oz (0.72 lb ai/A ) of

EVITO® 480 SC per acre per year

. ‖ The propos ed use directions for squash/cucumber subgroup 9B should be revised to
include use of a non

- ionic surfactant (NIS).

2.3.2 Recommendations from Occupational AssessmentFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 7 of 43 None.

2.3.3 Recommendations f rom Residential Assessment

None.

3.0 In troduction

Fluoxastrobin is a strobilurin

- class fungicide ( also termed methoxyacrylates ) 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.

Fluoxastrobin is the accepted 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 fl uoxastrobin 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 (photo

- degradate) of fluoxastrobin. The petitioner has requested that fluoxastrobin ( E

- isomer only) be designated as the active ingredient (ai)

.

Arysta is petitioning for a tolerance for residues of fluoxastrobin on squash/cucumber subgroup 9B, and proposing the new use to be added to the currently registered label for

FLUOXASTROBIN 480 SC Fungicide (EPA Reg

. No. 66330

- 64 ). FLUOXASTROBIN 480 SC Fungicide consists of 40.3% ai at 4 lb ai/gal. FLUOXASTROBIN 480 SC Fungicide is the
master label which will serve as the basis for three different sub

- labels: EVITO ® 480 SC Fungicide for agricultural uses; DISARMTM 480 SC Fungicide (ABN: Armor Tech TM
DISARM TM 480 SC Fungicide) ; and FLUOXASTROBIN 480 SC Fungicide Seed Treatment

.

For the proposed squash/cucumber subgroup 9B, EVITO® 480 SC Fungicide is proposed for up to f our broadcast foliar applications at the rate of 0.16 lb ai/A/application for a maximum
seasonal application rate of 0.68 lb ai/A, with a 1

- day preharvest interval (PHI). For soilborne
disease control

, a rate of 0.16

- 0.24 fl oz/1000 row feet (0.005

- 0.075 lb ai/A) is proposed

. The

a pplications can be applied using ground or chemigation equipment. The restricted entry interval (REI) is 12 hours.

Currently r egistered fluoxastrobin uses include peanut, tuberous and corm vegetable subgroup 1C, leaf petiole v egetables subgroup 4B, fruiting vegetables group 8, and turf (DP#292422, S. Winfield, 0 1/24/ 20 05) ; field corn, soybeans, and the low

- growing berry subgroup 13

- 07G (DP#’s 356982 an d 357473, N. Dodd, 0 8/ 0 13/ 20 09); and sweet corn, field corn/sweet corn

grown for seed, and wheat (DP#366179, N. Dodd, 04/15/2010).

3.1 Chemical Identity

F l uoxastrobin is described in Table 3.1.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 8 of 43 Table 3.1 . Fluoxastrobin Nomenclature

Chemical Structure

Empirical Formula C 21 H 16 ClFN 4 O 5

Common name Fluoxastrobin Note: This name was originally approved for a mixture of the E

- and Z

- isomers (CAS # 193740

- 76

- 0) in April 2002. The definition of fluoxastrobin was changed
to mean the E

- isomer only in January 2003. This change was made based upon a request by the petiti oner. Company experimental name HEC 5725

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

End

- use product/EP F LUOXASTRO BIN 480 SC Fungicide (EPA Reg. No. 66330

- 64)/ EVITO® 480 SC Fungicide (EPA Reg. No. 66330

- 64) ; DISARMTM G Fungicide (EPA Reg. No.

66330

- 380) [ARN: Armor Tech TM DISARM TM 480 SC Fungicide]

Chemical Class Strobilurin, methoxyacrylates Known Impurities of

Concern None

3.2 Physical/Chemical Characteristics

Fluoxastrobin has a low vapor pressure (5.63 x 10 - 10 Pa at 20 °C); therefore, inhalation via chemical vaporization is unlikely. The physicochemical properties of fluoxastrobin are
summarized in Appendix C.

3.3 Pesticide Use Pattern

Arysta has submitted proposed use directions (Section B) for the 4 lb ai /gal SC formulation of fluoxastrobin ( EVITO® 480 SC Fungicide; EPA Reg. No. 66330

- 64) in/on the squash/cucumber subgroup 9B.

The proposed use directions for squash/cucumber subgroup 9B ar e presented in Table 3.3.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 9 of 43 Table 3.3. Summary of Directions for Use of Fluoxastrobin

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No .] Applic.

Rate Max.

No. Applic.

per Season Max.

Seasonal Applic.

Rate PHI Use Directions and Limitations

lb ai/A lb ai/A days Squash/Cucumber Subgroup 9B [Chayote; Chinese waxgourd (Chinese preserving melon); Cucumber; Gherkin; Gourd, edible (includes hyotan, cucuzza, hechima , Chinese okra, balsam apple, balsam pear, bitter melon, Chinese cucumber); Pumpkin; Squash, summer (includes crookneck squash, scallop squash, straightneck squash, vegetable marrow, and zucchini); and Squash, winter (includes butternut squash, calabaza, h ubbarb squash, acorn squash, and spaghetti squash)]

Foliar Disease
Control (alternaria blight, anthracnose, belly rot, cercospora leaf spot, downy mildew, gummy stem blight, microdomium blight, powdery mildew, target leaf spot) : Broadcast, Ground, Chemiga tion EVITO® 480 SC

Fungicide

4 lb fluoxastrobin per gallon

EPA Reg. No.
66330

- 64 0.09

-

0.16

(3

- 5.7 fl. oz/A)

4 0.68

(21.8 fl. oz/A) 1 Applications are to begin

preventatively and continue as
needed on a minimum 7

- 14 day interval. Use higher rates
when disease is severe. For belly

- rot control, the first application should me made at
the 1

- 3 leaf crop stage, and the second application 10

- 14 days later, or at vine tip

- over, whichever occurs first.

Soilborne Disease
Control (root rot) : Broadcast, Ground, Chemigation 0.005

- 0.0075
lb/1000
row feet

(0.16

- 0.24 fl.

oz/1000 row feet) Do not use the 0.24 fl oz/1000 row feet rate on rows spaced
narrower than 22 inches.
Do not use the 0.16 fl oz/1000 row feet rate on rows spaced
less than 15 inches.
For twin rows spaced 7.5

- 8‖ apart on 30 inch centers, use
the 0.16 fl oz/1000 row feet rate for 15‖ rows only.

The proposed use directions for squash/cucumbers include the following resistance management restriction: Alternate every application of the product wit h at least one application of another registered, non

- Group 11 fungicide. Do not make more than 4 applications of EVITO® 480 SC fungicide and or a Group 11 fungicide per season. Do not use EVITO® 480 SC for control of gummy stem blight where resistance t o Group 11 (Qol) fungicides exists.

The use directions submitted in Section B do not include application spray volumes, specifications for application via chemigation and adjuvant use. The registered label recommends a minimum spray volume of 10 gal/A fo r ground equipment. The registered label states that chemigation applications are to be made through sprinkler

- type irrigation systems only. The registered label does not specify adjuvant use in any tank

- mix partner.

The use directions submitted in Sect ion B prohibit use of EVITO® 480 SC to squash/cucumber subgroup 9B crops grown i n a greenhouse. In addition, the proposed label prohibits tank mix with emulsifiable concentrate (EC)

- based insecticides, or the following products: malathion, Kelthane®, Thio dan®, Phaser®, Lannate®, Lorsban®, M

- Pede®, or Botran®.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 10 of 43 The use directions submitted in Section B do not include rotational crop restrictions. The following crop restrictions appear on the registered label: 0

- day plantback interval (P BI ) for any

crop listed on the label; 30

- day PBI for root vegetables ( e.g. carrot, radish, sugar beet, and turnips), bulb vegetables ( e.g. onion and garlic), leafy greens subgroup ( e.g. lettuce and spinach),

Brassica vegetables ( e.g. broccoli, cauliflower, cabbage, and mustard greens), alfalfa, cotton, legume vegetables (dry and succulent peas and beans), cereal grains, and forage grasses; and a

12

- month PBI for all other crops.

3.4 Anticipated Exposure Pathways

The Registration Div ision has requested an assessment of human health risk to support the proposed new use of fluoxastrobin on squash/cucumber subgroup 9B. Humans may be exposed to fluoxastrobin in food and drinking water, since fluoxastrobin may be applied directly to growi ng crops and application may result in fluoxastrobin reaching surface and ground water sources of drinking water. There are also re sidential uses of fluoxastrobin; thus

, there is likely to be exposure in residential or non

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

- application exposure for workers re

- entering treated fields.

Several risk assessments have be en previously prepared for the existing uses of fluoxastrobin. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of fluoxastrobin, but also considers the existing uses as well, particularly for
the d ietary 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, "Fede ral 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 procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and a re used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models t hat consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 11 of 43 4.0 Hazard Characterization and Dose

- Response Assessment

References:

- HED/RAB3 F luoxastrobin H azard M eetings, October and November 2004.

- Fluoxastrobin: Human Health Risk Assessment for Proposed Uses on Peanuts, Tuberous and Corm Vegetables (Subgroup 1C), Leaf Petiole Vegetables (Subgroup 4B), Fruiting Vegetables (Group 8), Turf, and as a Seed Treatment on Potato (Seed Piece ), Peanut and Turf

. DP#292422, S arah Winfield, 01/24/ 20 05.

A detailed hazard characterization for fluoxastrobin is presented in a previous risk assessment (DP#292422, S. Winfield, 0 1/24/ 20 05). The available toxicity studies are listed in Appendix A. The salient features of toxicology for risk assessment are presented here.

Fluoxastrobin is considered a novel strobilurin analog (other strobilurin fungicides include azoxystrobin, dimoxyst robin, kresoxim

- methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, and trifloxystrobin).

The pesticidal biochemical mode of action of strobilurins consists of interaction with the ubiquinone binding site of the mitochondrial bc1 complex (complex III) in fungal cells, thereby preventing the oxidation of ubihydroquinone and the transfer of electrons to cytochrome c. Interrupting the electron transport chain in this way prevents oxidative phosph orylation, thus causing a severe reduction in the availability of adenosine triphosphate ( ATP ) , the main energy currency of the cell. The shortage of energy has a very wide range of biochemical consequences, such as the breakdown of essential membrane pote ntials and concentration gradients and the inhibition of nucleic acid and protein biosynthesis. Fungal spore germination, mycelial growth and the development of infection structures are thus prevented. The available mammalian toxicity data do not provide a clear set of results to demonstrate similar mode of action as that on
pests.

4.1 Toxicology Studies Available for Analysis

The submitted toxicology studies are of good quality and provide sufficient information to determine whether fluoxastrobin poses a human health hazard. Un der the current rules additional data on the mouse immunotoxicity study are needed to upgrade this study

.

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

Absorption, distribution, and metabolism were fully charac terized in several rat metabolism
studies using three 14 C

- radiolabeled rings in fluoxastrobin. 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 widely distributed. Approximately 77% and 14% of the administered dose was eliminated in the feces an d urine, respectively. Elimination via expired air was less than 0.3% of the administered dose. Overall elimination was >90% of the administered radioactivity and 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 wasFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 12 of 43 extensively metabolized primarily via hydroxylation and subseque nt methylation, followed by gluc uronide 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, respectively). 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.

Dermal Absorption

A dermal penetration study in monkey demonstrates that absorption was negligible f ollowing an

8

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

4.3 Toxicological Effects

Following repeated administration, fluoxastrobin has mild or low toxicity in all tested species,
and the most frequently finding was decrease in body weight and liver effects characterized by increased liver weights, hepatocellular hypertrophy. Kidney effects (tubular hypertrophy) were also found in several studies in both dogs and rodents. These effects wer e found to occur at much lower dose levels in dogs than other tested species (rats and rabbits). The findings of increased incidences in uterine adenocarcinoma and thyroid follicular cell adenoma in the rat chronic toxicity/carcinogenicity study were dete rmined to be unrelated to treatment. These observations, which were found within random occurrence in this strain of rats, are not treatment

- related and, therefore, are not indicative of possible endocrine disruption.

4.4 Safety F actor for Infants and Ch ildren (FQPA Safety Factor)

T he toxicology and exposure data and ha ve been evaluated and fluoxastrobin has been
determined to be safe for infants and children , supporting the reduction of the FQPA safety
factor to 1X.

4.4 .1 Completeness o f the Toxicology Database

The completeness of the toxicology database and rationale for reduction of FQPA safety factor has been discussed in Section 4.1. To reiterate the conclusion, the data on fluoxastrobin support the reduction of FQPA safety factor to 1X.

To address the issue of immunotoxicity data requirements as presented in the 40 CFR Part 158, the entire fluoxastrobin toxicity database was examined; the database of this chemical shows no indication that this chemical directly targets the immune system

. An immunotoxicity study in mouse is available; the results of this study show no apparent decrease on B

- cell activated, T

- cell mediated IgM response to sheep red blood cells (SRBC) at doses as high as 2383 mg/kg/day. However, this study has many defici encies including uncertainty in dietary test material intake, and the study is classified as unacceptable. At this time, HED does not believe that conducting an upgraded functional immunotoxicity study will result in a NOAEL less than that derive d for

cur rent risk assessment purposes ( cRfD of 0.015 mg/kg /day ) . Consequently, the existing dataFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 13 of 43 are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under the FQPA and a n additional factor for databa se uncertainty (UF DB ) is not
needed to ac count for lack of this study. H owever, the registrant should upgrade the study to meet the data requirement.

4.4.2 Evidence of N eurotoxicity

There is no indication in the toxicity data which include acute and subchronic neurotoxicity
studies that f

luoxastrobin is a neurotoxic chemical.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The database for evaluating in utero or postnatal susceptibility is adequate and includes develop mental toxicity studies in both rats and rabbits and a two

- generation reproduction study in the rat. The data provide no indication of increased susceptibility of rats or rabbits to pre

- and
post

- natal exposure to fluoxastrobin

.

4.4.4 Residual Uncertaint y in the Exposure Datab ase

The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. The d ietary food exposure assessment w as performed based on 100% crop treated ( CT ) assumptions and tolerance

- level residues. The Environmental Fate and Effects Division (E FED ) has provided conservative ground and surface water modeling estimates. The HED Residential SOPs are used to assess post

- application exposure to children as well as
incidental or al exposure of children (three to less than six years old) . These assessments will not underestimate the exposure and risks posed by fluoxastrobin.

4.5 Toxicity Endpoint and Point of D eparture Selections

As summarized in S ection 4 .3 , the fluoxastrobin d atabase indicates that among the tested species the dog is most sensitive to the adverse liver toxicity produced by fluoxastrobin. Therefore, the liver effects seen in the subchronic and chronic studies in dogs were selected for toxicity endpoints

, and th e corresponding NOAELs were chosen for the points of depart for risk assessment (Tables 4.5.4.1 & 4.5.4.2). An acute quantitative hazard estimate was not established because an adverse effect attributable to a single exposure was not identified from the a vailable database (although acute exposure is expected). No quantitative hazard estimate was selected for
the short

- term dermal exposure scenario based on lack of systemic or dermal toxicity in the

28

- day dermal toxicity study in the rat and the absence o f developmental / reproduction or

neuro toxicity findings. The adverse liver findings (cholestasis) in the 90

- day subchronic dog study were used to set endpoints for the intermediate

- term dermal, the short

- and
intermediate

- term inhalation, as well as the sh ort

- and intermediate

- term incidental oral exposure scenarios. The adverse liver findings (cholestasis) in the chronic toxicity dog study were used for setting the quantitative hazard estimate for the long

- term dermal and inhalation, as well as the
chroni c dietary exposure scenarios (although long

- term dermal and inhalation exposures are not expected based on the proposed uses).FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 14 of 43 4.5.1 Dose

- Response Assessment

Fluoxastrobin appears to have mild or low toxicity following repeated administration in all te sted species other than the dog. In both the 90

– day and 1

– year oral feeding dog studies, there was liver toxicity in the form of cholestasis as evidenced by hepatocytomegaly and cytoplasmic granular changes associated with increased liver weight and increased serum liver alkaline phosp h atase (ALP). In addition, several phase I and phase II liver drug metabolizing enzymes

were induced. Other toxicity in dogs included body weight loss or reduced gain, decreased food efficiency, and effects on kidneys in cluding increased relative weight in females and degeneration of proximal tubular epithelium in males. The no observed adverse effect level (NOAEL) of 1.5 milligrams/kilograms/day (mg/kg/day) in the 1

– year dog study was used for setting the chronic refere nce dose (RfD).

The liver appeared to be a target organ in other studies, as well, but the toxicolog ical relevance of liver findings in species other than the dog is questionable. For example, among the changes
noted in the treated animals were increased liver weight in the mouse and rat, and hypertrophy
and cytoplasmic changes in the mouse, but there were no increases in any of the serum liver enzymes including ALP.

In the 90

– day oral toxicity study in rats, the renal system in males was a target organ a s evidenced by increased kidney weight and histopathology findings in kidneys, urinary bladder, and urethra including the presence of calculi in the urethra and kidneys. In another rat study, there were markedly increased urinary pHs in males in addition t o increased urinary calcium excretion in the form of calcium oxalate crystals. Kidney changes were also seen in a 90

– day mouse feeding study with increased kidney weights and tubular hypertrophy in females. Following 90

– day administration in dogs, there wa s degeneration of the proximal tubular epithelium in males.

The adrenal glands seem to be another target organ in males of the 90

– day rat study where
vacuolation was seen in the zona fasciculata of the adrenal cortex. In another 30

– day rat feeding study, adrenal cortical cytomegaly with fine vacuolization was seen in all high dose males and the responses were comparable between the groups treated with the pure fluoxastrobin E

- or 2:1

E / Z

- isomers. The adrenal changes are not likely to be endocrine related e ffects.

In the rat and rabbit developmental toxicity studies and the 2

– generation reproduction rat study, there was no increased susceptibility to prenatal or postnatal exposure to fluoxastrobin and no effects on reproduction.

Fluoxastrobin is not acutely neurotoxic in rats up to a single high dose of 2,000 mg/kg/day or by repeated dietary feeding in the rat subchronic neurotoxicity screening study where the top dose was nearly half the limit dose of 1,000 mg/kg/day. Other studies in rats in cluding the subchronic,
chronic toxicity/carcinogenicity, 2

– generation reproduction, and developmental toxicity were
tested to or above the limit dose with no indication of clinical signs, histopathology or other signs of toxicity that could be attributed to neurotoxicity. Also, in both the 90

– day and 1

– year dog studies, neurologic examinations, including mental status/behavior, gait characteristics,FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 15 of 43 postural status and reactions, and spinal/cranial reflexes, were carried out and were found to be
within nor mal limits.

Fluoxastrobin is not immunotoxic based on repeated dosing studies in rats and mice. In the 90

– day oral toxicity rat study, there was no difference between the control and treated animals in spleen cell count, macrophage activities after PMA st imulation and plaque forming cell assay after challenge with sheep erythrocytes. Slight decreases were noted in IgG concentration in the high dose males but not females. An unacceptable subchronic immunotoxicity study in mice found no apparent decrease on B

- cell activated, T

- cell mediated IgM response to sheep red blood
cell s (SRBC) at doses as high as 2,383 mg/kg/day.

Fluoxastrobin and major metabolites were negative in a battery of genotoxicity tests. The carcinogenic potential of fluoxastrobin was adeq uately tested in rats and mice of both sexes. The
results demonstrated a lack of treatment

- related increase in tumor incidence in rats or mice.

T here was no mutagenicity concern and no structure activity relationship alert. It was concluded
that there w as no incidence of carcinogenicity for fluoxastrobin.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate
risk assessment must consider e xposures from three major routes: oral, dermal and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated as
follows: For short

- term aggregate exposure risk assessment

, the oral and inhalation routes can be c ombined ; and for intermediate

- and long

- term aggregate exposure risk assessments, the oral, dermal (oral equivalent) and inhalation routes can be combined because of the common toxicity endpoints (reduced body weight and liver toxicity) via these routes

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Fluoxastrobin and major metabolites were negative in a battery of genotoxicity tests. The carcinogenic potential of fluoxastrobin was adequately tested in rats and mice of both sexes. The

re sults demonstrated a lack of treatment

- related increase in tumor incidence in rats or mice.

T here was no mutagenicity concern and no structure activity relationship alert. It was concluded that there was no incidence of carcinogenicity for fluoxastrobin. F luoxastrobin is classified as

― not likely to be carcinogenic to humans

. ‖

4. 5

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

The summary of toxicological doses and endpoints for human health risk assessment are presented below in two separate tables: 1) Dietary and Non

- Occupational E xposures in Table
4.5.4.1 and 2) Occupational E xposures in Table 4.5.4.2

.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 16 of 43 Table 4 .5. 4

. 1

. Summar y of Toxicol ogical Doses and Endpoints for Fluoxastrobin for Use in Dietary and Non

Occupational Human Health Risk Assessments

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) None: There was no indication of an adverse effect attributable to a single dose. An aRfD was not

established.

Acute Dietary (Females 13

- 49 years of age) None: There was 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 = 10 X

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

= 0.015 mg/kg/day

cPAD = 0.015 mg/kg/day Chronic toxicity in the 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 = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for
MOE = 100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day (800 ppm) 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).

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 months) NOAEL =

3.0 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X

Dermal absorption
rate = 2.3% Residential

LOC for

MOE = 100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day (800 ppm) 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).

Dermal Long

- Term (> 6 months) NOAEL =

1.5 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X

Dermal absorption
rate = 2.3% Residential

LOC for

MOE = 100 Chronic toxicity in the 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.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 17 of 43 Table 4 .5. 4

. 1

. Summar y of Toxicol ogical Doses and Endpoints for Fluoxastrobin for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Inhalation
Short

- Term (1

- 30 days) NOAEL =

3.0 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for

MOE = 100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day (800 ppm) 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 degene ration of the proximal tubular epithelium in males).

Inhalation
Intermediate

Term (1

- 6 months) NOAEL =

3.0 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for

MOE = 100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day (800 ppm) 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 male s).

Inhalation Long

- Term (> 6 months) NOAEL =

1.5 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Residential

LOC for

MOE = 100 Chronic toxicity in the 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. Cancer (oral, dermal, inhalation) Classification: ―Not likely to be Carcinogenic to Humans

. ‖

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest o bserved adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = populati on adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5. 4 .2

. Summary of Toxicol ogical Doses and Endpoints for Fluoxastrobin for Use in Occupational

Human Heal th Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal Short

Term (1

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

- 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.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 18 of 43 Table 4.5. 4 .2

. Summary of Toxicol ogical Doses and Endpoints for Fluoxastrobin for Use in Occupational

Human Heal th Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal
Intermediate

Term (1

- 6 months) NOAEL =

3.0 mg/kg/day UF A = 10X

UF H = 10X FQPA SF =

1X

Dermal absorption
rate = 2.3% Occupational

LOC for MOE =

100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day (800 ppm) 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
Short

- Term (1

- 30 days) NOAEL =

3.0 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X Occupational

LOC for MOE =

100 90

- day subchronic dog

LOAEL = M/F 24.8/24.2 mg/kg/day (800 ppm) 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, inhalation) Classification: ―Not likely to be Carcinogenic to Humans

. ‖

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed ad verse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = us e of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Based on the available toxicity database and the Agency's current practices, the inhalation risk
for fluoxastrobin was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fung icide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). 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. If any new policies or procedures are developed, the Agency may
revisit the need for an inhalation toxicity study for fluoxastrobin and/or a reexamination of the inhalation toxicity risk assessment.

4.6 Endocrine Disruption

As required under FFDCA Section 408(p), EPA has developed the Endocrine Disruptor Screening Program ( EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced byFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 19 of 43 a ―naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.‖ The EDSP employs a two

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

Between Octobe r 2009 and February 2010, EPA i ssued test orders/data call

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

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

Fluoxastrobin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p)

, the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP orders/data call

- ins for all Registration Review cases, includ ing those for which EPA has already opened a Registration Review docket for a pesticide active ingredient.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screen ing battery, please visit our website: http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment

Reference s :

- Fluoxastrobin. Petition fo r the Establishment of Permanent Tolerances for Uses on Squash/Cucumber Subgroup 9B. Summary of Analytical Chemistry and Residue Data

. DP#380846, Meheret Negussie, 11/17/2010.

- Fluoxastrobin: Chronic Dietary (Food and Drinking Water) Exposure Assessments for the Section 3 Registration

Action use on Squash/Cucumber Subgroup 9B . DP#380847, Cassi Walls, 12/28/2010

.

- Drinking Water Assessment for Fluoxastrobin Use on Squash/Cucumber (crop subgroup 9B) and New In

- Furrow and Banded Uses on Tuberous and Corm Vegetables (crop subgroup 1C) as well as Peanut

. DP #s 379114 and
384377 , Rochelle Bohaty, 12/15/2010.

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants and livestock is adequately understood. In plants, the results of metabolism studies conducted on wheat, peanut, and tomato ind icate that metabolism of fluoxastrobin is similar in dissimilar crops. HED has concluded that t he residues of concern in plants for risk assessment and tolerance setting purposes a re fluoxastrobin and it s Z

- isomer. Acceptable metabolism studies on goats and laying hens are also available. The available data indicate that the metabolism in goats and hens is similar. Metabolism of fluoxastrobin was found to be more extensive in livestock than in plants, and metabolites consisting of single rings ( e.g.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 20 of 43 2

- c hlorophenol and 2

- cyanophenol) were observed in each of the livestock metabolism studies. HED has concluded that in livestock commodities, the residues of concern are fluoxastrobin, its

Z

- isomer, and the phenoxy

- hydroxypyrimidine metabolite (HEC 7154 ; 6

- ( 2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinol ) for risk assessment and tolerance setting purposes.

The nature of the residue in rotational crops is understood based on an adequate confined rotational crop study. HED has concluded that the residues of concern f or rotational crops for risk assessment and tolerance setting purposes are fluoxastrobin and its Z

- isomer. Adequate field rotational crop data are available which indicate that residues of fluoxastrobin and its Z

- isomer may accumulate in rotated crops. T he available data support the established tolerances for indirect or inadvertent residues established under 40 CFR 180.609(d), and indicate that the following rotational crop restrictions are appropriate for fluoxastrobin: a 0

- day plantback interval (PBI) for any crop listed on the label; a 30

- day PBI for the root vegetables subgroup ( e.g. carrot, radish, sugar beet, and turnip), bulb vegetables ( e.g. onion and garlic), leafy greens subgroup ( e.g. lettuce and spinach), Brassica vegetables ( e.g. broccoli, c auliflower, cabbage, and mustard greens), alfalfa, cotton, legume vegetables (dry and succulent peas and beans), cereal grains, and forage grasses; and a 12

- month PBI for all other crops.

5.1.2 Summary of Environmental Degradation

The environmental fate data indicate that the proposed use of fluoxastrobin as a foliar spray on agricultural crops could potentially lead to fluoxastrobin in drinking water. Although foliar interception may reduce the amount of fluoxastrobin available fo r runoff, it is believed that this chemical could reach surface waters through spray drift, penetration of the canopy to the soil surface at application, and foliar washoff followed by runoff. Fluoxastrobin did not seem to leach underground. It is very u nlikely that any degradate/metabolite of fluoxastrobin will persist in the environment for any extended period of time to reach surface water and/or leach into ground water at any considerable amount.

5.1.3 Comparison of Metabolic Pathways

For metabolism studies, fluoxastrobin rings are numbered as ring 1 (chlorophenyl ring), ring 2 (pyrimidine ring), ring 3 (methoxyiminotolyl ring), and ring 4 ( dioxazine ring).

Fluoxastrobin was extensively metabolized in the rat as evidenced by the extensive metabolic profiles from urine, feces, and bile, and the relative absence of parent compound (except in the feces of rats given the high dose). The urinary metabolites were primarily the result of cleavage between rings 2 and 3 of the parent compound. Biliary metabo lites were primarily products resulting from cleavage of rings 2, 3, and 4, and subsequent hydroxylation, methoxylation, and conjugation with glucuronic acid. HEC5725

- E

- des

- chlorophenyl and
HEC5725

- des

- chlorophenyl

- dioxazine

- OH were the major metabolites in all excretion matrices.

Some of the rat metabolites seem to be in common with metabolites in studies from the lactating goat ( e.g. HEC5725

- di

- OH and its dioxazine

- OH, HEC5725

- E

- des

- chlorophenyl and its derived ketone, dioxazine

- OH, and glycol, in addit ion to several dioxazine phenyl two ring metabolites) and laying hen ( e.g. several glucuronide conjugates of HEC5725

- including mono

- andFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 21 of 43 di

- OH

- GA, and oxime

- GA in addition to mono

- and bi

- ring fragments including
dioxazine

- oxime, 2

- cyanophenol, and salicy lic acid).

Fluoxastrobin was not extensively metabolized in some primary plants but was extensively metabolized in rotational crops, as evidenced by the extensive metabolic profiles and relative absence of parent compound. The major metabolic route of fl uoxastrobin in rotated crop matrices was hydroxylation, especially at the 4

- position of the chlorophenyl moiety to yield
HEC5725

- E

- 4

- hydroxyphenyl; conjugates of this metabolite were also observed. A second important metabolic route was cleavage of fluoxa strobin to yield HEC5725

- E

- des

- chlorophenyl, which was partly isomerized to the Z

- isomer. Cleavage of the ether bridge between the pyrimidine and methoxyiminotolyl rings of the parent compound was a minor metabolic route in rotational crops. Another mino r metabolic route was hydroxylation of the parent compound in the dioxazine ring, followed by oxidative cleavage and hydrolysis.

Fluoxastrobin was extensively metabolized in goats and hens, as evidenced by the extensive metabolic profiles and relative abs ence of parent compound, except in goat and poultry fat where a significant portion of the residue was identified as fluoxastrobin. Metabolites consisting of single rings ( e.g. 2

- chlorophenol) were observed in each of the livestock metabolism studies.

On e of the main metabolism pathways appears to be cleavage of the ether group in the pyrimidine moiety to form metabolites containing ring 1 and 2 ( e.g. HEC5725

- phenoxy

- hydroxypyrimidine) and containing only ring 1 ( e.g. 2

- chlorophenol).

5.1.4 Residues of C oncern Summary and Rationale

Table 5.1.4 summarizes the metabolites and degradates included in the risk assessment and the tolerance expression.

Table 5.1.4

. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expre ssion

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

F luoxastrobin residues on plants are mainly surface residues with only limited translocation within the plant. To support the newly proposed uses, Arysta has submitted field trials ofFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 22 of 43 fluoxastrobin on cucumber and summer squash. In the residue decline studies, combined
residues of fluoxastrobin and its Z

- isomer generally declined with increasing sampling interval.
The results from these studies are sum marized in Table 5.2.

For cucumbers, the number of field trials is not in accordance with OPPTS 860.1500. Six trials were conducted; however, the two field trials conducted in region 2 could not be counted as independent trials since both trials have the same address. One additional cucumber trial must be conducted in region 2.

Pending revision of the proposed use patterns and submission of the outstanding field trial data, the submitted field trial data will support the proposed tolerance of 0.5 ppm f or squash/cucumber subgroup 9B

.
The field trial data for cucumber and summer squash were separately entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on
Field Trial Data SOP to determine an appropriate tolerance level . The tolerance spreadsheet
recommends individual tolerances of 0. 25 ppm for cucumber and 0.5 ppm for summer squash. Because the minimum and maximum recommended tolerances differ by less than 5x, a crop

gro up tolerance is appropriate for squash/cucumber subgroup 9B. The recommended value is
0.5 ppm, the maximum of the recommended individual tolerances. The recommended tolerance level is the same as the level proposed by the petitioner (0.5 ppm).

Table 5.2. Summary of Residues f rom the Crop Field Trials with Fluoxastrobin

Crop Matrix Applic. Rate PHI Residues (ppm) 1

Mean Std.

Dev. HAFT 2 Min. Max. lb ai/A days

Cucumber (proposed use = 0.017 lb ai/A total application rate , 1

- day PHI )

RAC 3 0.68

- 0.71 1 0.09 0.04 0.17 0.04 0.18 Summer Squash (proposed use = 0.017 lb ai/A total application rate, 1

- day PHI )

RAC 3 0.68

- 0.71 1 0.08 0.05 0.16 0.01 0.18

1 Combined residues of fluoxastrobin and its Z

- isomer.

2 HA FT = H ighest average field trial

. 3 RAC = Raw agricultural commodity.

The submitted cucumber and summer squash field trial studies are acceptable and reflect the proposed use patterns. Samples were analyzed for residues of fluoxastrobin and its Z

- isomer using acceptable methods, and the studies are supported by adequate storage stability data.

Processed Food and Feed

HED does not require residue data for any processed commodities associated with squash/cucumber subgroup 9B

. Therefore, data requirements for processed food and feed are not relevant to this tolerance petition.

Meat, Milk, Poultry, and EggsFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 23 of 43 The potential exists for secondary residues to occur in some livestock commodities from registered uses

. There are no livestock feedstuff s associated with the proposed use s on squash/cucumber subgroup 9B

. The dietary burdens for fluoxastrobin residues in livestock diets will not be affected by the subject action; t herefore, data requirements pertaining to meat, milk, poultry, and eggs are not relevant to the proposed uses. The dietary burdens were previously calculated and estimated at 6.5 and 16.6 ppm for beef and dairy cattle, and 0.093 and 0.090 ppm for poultry and swine, respectively.

Field Accumulation in Rotational Crops

Availabl e confined rotational crop data are adequate to satisfy data requirements and to delineate the nature of the residue in rotated crop commodities.

A cceptable limited field rotational crop and extensive field rotational crop stud ies w ere previously revie wed

. Extensive field rotational crop studies reflecting a 1

- month PBI support the established indirect or inadvertent tolerances on alfalfa forage and hay; cotton gin byproducts; forage, fodder, and straw of cereal grains; grass forage and hay; and foliage of legume vegetables. These data support the established rotational crop restrictions on the master label (EPA Reg. No. 66330

- 64).

Adequate field rotational crop data are available, including a limited field rotational crop study
and an extensive field rot ational crop study

.

The limited field rotational crop study was conducted on the representative crops of mustard greens (leafy vegetable), turnips (root vegetable), and wheat (cereal grain). The primary crops each received four sp ray applications of fluoxastrobin at ~0.18 lb ai/A, for total application rates of ~0.72 lb ai/A. The limited field rotational crop data, which indicated no quantifiable residues
of fluoxastrobin and its Z

- isomer in mustard greens and turnip roots and top s at a 30

- day plant

back interval (PBI), are adequate to support the proposed 30

- day PBI for root and tuber vegetables, bulb vegetables, leafy vegetables, and Brassica

.

Based on the results of the limited field rotational crop stud y, the petitioner conducted extensive field rotational crop studies reflecting a 1

- month plant

- back interval on alfalfa, cereal grains, cotton, grass, and legume vegetables. Based on the extensive field rotational crop data,
toleranc es were established in 40 CFR §180.609 (d) for the indirect or inadvertent combined
residues of fluoxastrobin and its Z

- isomer in/on the following rotated crops: alfalfa forage at 0.050 ppm; alfalfa hay at 0.10 ppm; cotton gin byproducts at 0.020 ppm; fora ge, fodder and straw of cereal grain, group 16, at 0.10 ppm; grass forage at 0.10 ppm; grass hay at 0.50 ppm; and foliage of legume vegetable, group 7, at 0.05 ppm. The data indicated that a tolerance for residues in/on legume vegetables, crop group 6, wa s not needed. In addition, the following rotational crop restrictions were included on the master label (EPA Reg. No. 66330

- 64): ―Treated areas may be replanted immediately following harvest with any crop listed on this label. In addition, areas may be replanted with root vegetables subgroup ( e.g. carrot, radish, sugar beet, turnips), bulb vegetables ( e.g. onion and garlic), leafy greens subgroup ( e.g. lettuce, spinach), Brassica vegetables ( e.g. broccoli, cauliflower, cabbage, mustard greens), alfalfa, cotton, legume vegetables (dry and succulent peas and beans), cereal grains, and forage grassesFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 24 of 43 following a 30

- day plant

- back interval. For all other crops, do not plant back within one year of the last field application.‖

The field rotational crop data are adequate to support the established rotational crop restrictions on the master label (EPA Reg. No. 66330

- 64) and the indirect or inadvertent tolerances in 40 CFR §180.609 (d).

5.3 Water Residue Profile

Based on laborat ory 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 depen dent on physical 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 sedi ment and no soil 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.

Tier II EDWCs in surface water were estimated using PRZM/EXAMS while Tier I EDWCs in ground water were estimated using the SCI

- GROW Model. T he chronic Tier II EDWCs for the new use on squash/cucumbers are significantly lower (12 μg/L) than the exposures calculated based on the revised existing fluoxastrobin use on turf (5 3 μg/L). The estimated chronic drinking water concentration for fluoxastrobin (1

- in

- 10 year annual m ean) was based on a
revised calculation of an existing use on turf (4 applications at the rate of 0.55 lb ai/A/application
and a 7

- day application interval )

. The revised turf use provided the most conservative EDWC s

were used in this assessment (summarized in Table 5.3).

Table 5.3. Summary of Est imated Surface Water and Ground W ater Concentrations for Fluoxastrobin

Scenario Surface Water Conc., ppb a Ground W ater Conc., ppb b

Acute 60.7 0.23

Chronic (non

- cancer) 52.9 0.23

Chronic (cancer) 23.5 0.23

a From the Tier 1 First (FQPA Index Reservoir Screening Tool) model. Input parameters are based on the turf use (4 ground applications of 0.55 lb ai /A/application with a 7

- day interval), which generates the highest EDWCs.

b From the Tier 1 SCI

- GROW (Screening Concentration in Groundwater) model, also based on the turf use (4 ground applications of 0.55 lb ai/A/application with a 7

- day interval), assum ing a maximum use rate of 2.2 lb ai/A/year

.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A conservative chronic dietary exposure assessment was performed for fluoxastrobin. The assumptions included tolerance level residues and the 1

- in

- 10 year annual mean surface water EDWC for an existing turf use: 53 μ g/L (DP#379114, R. Bohaty, 12/15/2010). Based on processing studies, the processing factors for tomato puree, potato chips, dry potatoFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 25 of 43 (granules/fla kes), and potato flour were reduced to 1. Separate tolerances were set for peanut oil, wheat bran, and tomato paste; therefore, the processing factors for these commodities were set at 1. For all other processed commodities, DEEM version 7.81 default pro cessing factors were assumed.

5.4.2 Percent Crop Treated Used in Dietary Assessment

100% CT were used for all commoditi es included in the assessment.

5.4.3 Acute Dietary Risk Assessment

There was no indication of an adverse effect attributable to a single dose. An aRfD was not
established.

5.4.4 Chronic Dietary Risk Assessment

A c hronic dietary (food and drinking water) exposure and risk assessment was conducted using the Dietary Expo sure Evaluation Model (DEEM

- FCIDTM, Version 2.03), which use s food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. A conservative dietary exposure

assessment was performed for fluoxastrobin. The assumptions of this dietary assessment
included tolerance level residues and 100% CT. The EDWC for chronic exposure, the 1

- i n

- 10 year annual mean value of 53 ppb, was incorporated directly into the dietary assessment . Th e results of the chronic dietary (food and drinking water) analysis are below the Agency’s level of

concern for the general U.S. population and all population subgroups. T he dietary (food and drinking water) exposure is estimated at 22 % of the c hronic Pop ulation Adjusted Dose (cPAD) for the general U.S. population and 4 7 % of the cPAD for children 1

- 2 y ea rs old , the population subgroup with the highest estimated chronic dietary exposure to fluoxastrobin. The results of the chronic dietary exposure analys e s are reported in Table 5.4.6

.

5.4.5 Cancer Dietary Risk Assessment

Fluoxastrobin is classified as ―not likely to be carcinogenic to humans;‖ therefore, no cancer risk is expected.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary Exposure and Risk for Fluoxastrobin (PAD = 0.015 mg/kg/day)

.

Population Subgroup Chronic Dietary (Food Only) Chronic Dietary (Food and Drinking Water) Dietary Exposure % cPAD* Dietary Exposure % cPAD* mg/kg/day mg/kg/day
General U.S. Population 0.002154 14 0.003269 22

All Infants (< 1 year old) 0.001470 9.8 0.005125 34

Children 1

- 2 years old 0.005323 36 0.006979 47

Children 3

- 5 years old 0.004553 30 0.006103 41FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 26 of 43 Table 5.4.6. Summary of Dietary Exposure and Risk for Fluoxastrobin (PAD = 0.015 mg/kg/day)

.

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

Children 6

- 12 years old 0.003055 20 0.004125 28

Youth 13

- 19 years old 0.001914 13 0.002720 18

Adults 20

- 49 years old 0.001780 12 0.002821 19

Adults 50+ years old 0.001749 12 0.002844 19

Females 13

- 49 years old 0.001728 12 0.002765 18

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

References:

- Fluoxastrobin: Residential Exposure/Risk Assessment for proposed non food uses by residential handlers on turf

grasse s . DP#371251, Kristin Rury, 03/04/2010.

- Fluoxastrobin : Occupational and Residential Exposure Assessment for proposed agricu ltural uses of fluoxastrobin on Squash and Cucumber Crop Subgroup 9B (Chayote; Chinese waxgourd; Cucumber; Gherkin; Gourd, edible; Pumpkin; Squash, summer; and Squash, winter)

. DP# 380848

, K ristin Rury , 01/2 0 / 2010

.

- Occupational and Residential Exposure Asse ssment for Proposed Section 3 Registration of Fluoxastrobin on Peanuts, Leafy Vegetables, Fruiting Vegetables, Potatoes and Tuber Vegetables, Turf

. DP#289109, B arry O’Keefe, 12/09/2004.

Residential handlers may be exposed from loading and applying either a soluble concentrate (SC) or granular formulation of fluoxastrobin for spot treatment and/or broadcast control of
diseases on turf. Mixing, loading, and applying activities were all previously assessed for both
formulations . Because of the potent ial for application four times per year, exposure duration is expected to be short

- term and intermediate

- term. A short

- term dermal endpoint was not identified; therefore, only intermediate

- term dermal risks as well as short

- and intermediate

- term
inhalati on risks were assessed. The e stimated dermal and inhalation exposures were compared to the oral NOAEL of 3.0 mg/kg/day from a 90

- day subchronic feeding dog study

.

6.1 Residential Handler Exposure

Calculation inputs and results of previous the residential assessments are presented in Table 6 .1.
A combined MOE was calculated for intermediate

- term dermal and intermediate

- term inhalation exposures because the endpoints and point of departures were the same for both scenarios. Although a PoD from an oral study was used to assess residential handler inhalation risks for fluoxastrobin, HED does not believe this assessment is under

- protective of adult handlers. MOEs calculated for residential handlers were all > 140,000, thus providing an ample margi n of safety to account for any uncertainties in route

- to

- route extrapolation. Short

- term inhalation
risks were not of concern to HED. Intermediate

- term dermal, inhalation, and combined (intermediate

- term dermal + intermediate

- term inhalation) MOEs were n ot of concern to HED ( r esidential handler combined dermal + inhalation risks resulted in MOEs that ranged from 3,200 to 520,000 ).

Table 6.1. Short

- Term Residential Handler Exposure and Risk Estimates for Fluoxastrobin Use on Turf

. Exposure Scenario Dermal Inhalation Applic. Amount Dermal 3 Inhalation 4 TotalFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 27 of 43 Unit Exposure Unit

Exposure Rate 1 Treated or

Handled Daily 2 Dose 5 MOE 6 Dose 7 MOE 8 MOE 9
mg/kg/day mg/kg/day

Loader /Applicator

Loading/Applying Granulars via Push Type Spreader (ORETF) 0.67 0.00088 0.5 0.5 0.0000055 550,000 0.00000031 9,500,000 520,000

Loading/Applying Granulars via Belly Grinder or Similar (PHED) 10 0.062 0.5 0.5 0.000904 3,300 0.000022 140,000 3,200

1 Application rate is based on maximum values found in proposed label (EPA Reg. No. 66330

- 380).

2 Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values).

3 Dermal Unit Exposure PHED Baseline represents long pants, long sleeved shirts, no gloves, open mixing/loading. ORETF Baseline Dermal Exposure represents long pants and short sleeves.

4 PHED Baseline Inhalation Exposure represents no respiratory protec tion, open mixing/loading. ORETF Baseline Inhalation Exposure represents no respiratory protection, open mixing/loading.

5 Dermal Daily Dose (mg/kg/day) = (Unit Exposure (mg/lb ai) * dermal absorption (0.023) * Application rate * Area treated) / 70 kg.

6 MOE Baseline Dermal = NOAEL (3.0 mg/kg/day)/Dermal Dose

. 7 Inhalation Daily Dose (mg/kg/day) = (Inhalation unit exposure ( μ g/lb ai) * (1mg/1000 μ g) conversion*Application Rate*Area Treated)/body weight (70 kg)

. 8 MOE Baseline Inhalation = NOAEL (3.0 mg/k g/day)/Inhalation Dose

. 9 Combined Baseline Dermal + Inhalation MOE = NOAEL / (Baseline Dermal Dose + Baseline Inhalation Dose )

.

6.2 Post

- Application Exposure

There is potential for exposure to homeowners in residential settings from entering areas previously treated with fluoxastrobin, such as lawns where children might play, or recreational exposures on golf courses that could lead to exposures for adults and youths. As a result, risk assessments have been completed for residential post

- application scenarios.

The best data and methodology currently available were used in the fluoxastrobin residential
assessment. Since chemical

- specific data were unavailable, the Agency used the current approaches for residential assessment, many of which include recent upgrades to the SOPs. For example, for the hand

- to

- mouth calculations for children (three to less than six years old), a 5% transferability factor was applied to calculate residue levels appropriate for this exposure pathway. Overall, the Agency believes that the calculated risks represent screening level estimates. Estimates are thought to be conservative, even when measures of central tendency ( e.g. most tr ansfer coefficients) are used, because values that would be considered to be in the lower percentile aspect of any input parameter have not been used in the calculations. Maximum application rates have been used for all scenarios. Also, these risk estima tes assume no dissipation of residues after day zero, and do not account for the periodic growth and cutting of the grass. Actual residues should be considerably lower, and intermediate

- term exposures are therefore unlikely. Further, because a short

- term dermal toxicity endpoint was not identified, the
intermediate

- term endpoint was used for all dermal risk estimates, even though the residential exposure duration is believed to be mostly short

- term based on the use pattern.

U se of fluoxastrobin on turf m ay result in individuals of varying ages potentially being exposed from activities in areas that have been treated. Potential routes of exposure include dermal (adults and children) and incid ental oral ingestion (children t hree to less than six years old only). Since no acute hazard has been identified, an assessment of episodic granular ingestion was not
conducted. While it is assumed that most residential use will result in short

- term (1 to 30 days)FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 28 of 43 post

- application exposures, it is also believed that intermediate

- term exposures (> 30 days to 180 days) are possible, albeit unlikely.

The highest use rate was chosen for the assessment ( i.e. 0. 5 5 lb ai/A). A summary of the estimated exposures and risks, is presented below in Table 6.2. The algorithm s used to calculate the risk of each exposure scenario can be found in a previous risk assessment. Recreational exposures to turf are expected to be similar to, or in many cases less than, those evaluated in
Section 6 .1 Home Uses; therefore, a separate re creational exposure assessment was not included. Additionally, golf course exposures and risks were already assessed.

Table 6.2. Short

- and Int ermediate

- Term Residential Post

- A pplication Exposure and Risk Estimates for
Fluoxastrobin

Lifestage Post

- Application Exposure Scenario Dose 1 MOE 2 mg/kg/day

Adult Mowing Turf Dermal 0.000101 30,000

Golf Course Re

- Entry Dermal 0.000202 15,000 High Contact Dermal 0.00148 2,000

Child High Contact Dermal 0.00246 1,200

Treated Lawns Hand to Mouth (ST) 0.00821 370 Hand to Mouth (IT) 0.00390 770 Object to Mouth 0.00205 1500 Incidental Soil Ingestion 0.00002753 110,000

1 Dose calculated based on maximum a pplication rate values found on registered label (EPA Reg. No. 66330

- 3 79 ).

2 MOE Baseline Dermal = NOAEL (3.0 mg/kg/day)/Dermal Dose

.

6.3 Combined Exposure

HED combines risk values resulting from separate post

- application exposure scenarios when it is likely they can occur simultaneously based on the use

- pattern and the behavior associated with the exposed population. For post

- application exposure to children , HED generally combines the dermal and incidental oral (hand to mouth) exposures, but does not include additional exposure from soil ingestion, or mouthing ( i.e. object

- to

- mouth), since the hand

- to

- mouth exposure is considered to be a conservative upper

- bound estimate of oral post

- application exposure. For the

propos ed turf uses of fluoxastrobin, the total (dermal + incidental oral) post

- application MOE for
children resulted in an MOE of 2 8 0 and was not of concern to HED (MOE > 100). Table 6.3 presents a summary of the post

- application MOE estimates for adults and ch ildren.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 29 of 43 Table 6.3. Short

- and Intermediate

- Term Residential Exposures for the Fluoxastrobin Combined
Residential Risk Calculations

Population Handler Exposure 1

mg/kg/day Residential

Handler Total Exposure 3
mg/kg/day MOE Post

- Application Exposure 2
mg/kg/day Residential

Post

Application
Total Exposure 3
mg/kg/day MOE

Dermal Inhalation Dermal Inhalation Oral

Adult 0.000904 0.000022 0.000926 3200 0.00 148 NA NA 0.00148 2000

Child NA NA NA NA 0.00 246 NA 0.00821 0.01067 280

1 Handler exposure represents high end handler exposure, where the exposure duration is appropriate to assess

. 2 Post

- application exposure represents high end incidental oral exposure for the relevant exposure duration

. 3 F or adults, r esidential total exposure combines the highest dermal and inhalation exposure s (Table 6.1 and 6.2 ) , where applicable. For young children, total residential exposure combines high end post

- application incidental oral AND dermal

exposure , where applicable (Table 6.2 ). Handler exposures should not routinely be combined with post

- application exposures.

6.4 Residential Bystander Post

- A pplication Inhalation Exposure

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

- application inhalation exposure assessmen t was not performed for fluoxastrobin at this time . However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory P anel (SAP) in December 2009. The Agency received the

SAP ’ s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, d evelop policie s 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 put into place, the Agency may revisit the need for a quantitati ve post

- application inhalation exposure assessment
for fluoxastrobin

.

6. 5 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 lesse r extent, could also be a potential source of exposure from the ground a pplication method employed for fluoxastrobin

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

, and State Lead Agencies for pesticide regulation and o ther parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mi tigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast

, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks
associated with drift.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 30 of 43 It is noted that the 0. 5 5 lb ai/acre application rate for turf was modeled to estimate post

application residential exposure o f children three to less than six years old . As this rate is equal to agricultural application rates, this scenario is protective of any exposure of farm children via spray drift from agricultural fluoxastrobin applications.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are a dded 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 fluoxas trobin, potential exposures from food, drinking water, and residential 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

- and intermediate

- 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 exposure via the oral (background), and dermal and inhalation (primary) routes. For children, these pathways lead to exposure via the oral (background), and incidental oral and dermal (primary) routes. MOEs are greater than 100, which indicates that exposure and risk do not exceed HED’s level of concern.

Table 7.2

. Short

- and Intermediate Term Aggregate Risk Calculations

Population Short

- and Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult 3.0 100 0.030 0.003269 0.00 148 0.004749 630

Child ren 1

- 2 years old 3.0 100 0.030 0.006979 0.01067 0.017649 1 7 0

1 Indicate in this footnote the basis for the LOC (inter

- and intra

- species uncertainty factors total 100 X )

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

. 3 Residential Exposure = [Oral exposure + Dermal ex posure + Inhalation Exposure] (Table 6.3.1 ).

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

. 5 Aggregate MOE = [NOAE L / (Avg Food & Water Exposure + Residential Exposure)]

.

7.3 Chronic Aggregate RiskFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 31 of 43 There is potential chronic exposure via dietary (food and drinking water) exposure. Refer to
Section 5.4.4

.

7.4 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 ot her 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 mechan ism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to hav e a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Reference:

- Fluoxastrobin : Occupational and Residential Exposure Assessment for proposed agricultural uses of fluoxastrobin on Squash and Cucumber Crop Subgroup 9B (Chayote; Chinese waxgourd; Cucumber; Gherkin; Gourd, edible; Pumpkin; Squash, summer; and Squash, winter)

. DP# 380848

, Kristin Rury , 01/2 0 / 2010

.

9.1 Short

- and Intermediate

- Term Handler Risk

Fluoxastrobin can be applied to crop subgroup 9B using groundboom application equipment. Application methods, maximum application rates, and use sites are summarized in Table 3

. 3. Handler exposure is expected to be short

- or intermediate

- term based on information pro vided on proposed labels.

The quantitative exposure/risk assessment for occupational handlers is based on the following exposure scenarios:

Mixer/Loaders:

1. Mixing/loading liquid concentrate to support groundboom applications , and

Applicators:

2. Applying sprays with groundboom equipment

.

Summaries of the risks for occupational handlers are included in Table 9.1 . The maximum application rate for each exposure scenario is presented a s the worst

- case scenario. All handlerFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 32 of 43 scenarios resulted in MOEs greate r than the level of concern ( LOC = 100) at some level of risk mitigation.

Dermal

For all handler mixing, loading, and applying scenarios, t he intermediate

- term dermal risks do

not exceed HED ’s level of concern with baseline attire (i.e., long

- sleeve shirt, long pants, shoes, and socks) or baseline attire plus chemical resistant gloves. With baseline attire, the dermal MOE for mixer/loaders was 250, and the MOE for applicators was 17,000. With baseline attire plus chemical resistan t gloves, the dermal MOE for mixer/loaders was 31,000 and the MOE for applicators was 51,000.

Inhalation

The short

- and intermediate

- term inhalation risks to handlers do not exceed HED ’s level of

concern at baseline (no respirator) for any of the handler scenarios. With baseline attire (no respirator) the inhalation MOE for mixer loaders was 14,000 and the MOE for applicators was 22,000,000.

Combined

Combined dermal and inhalation risks do not exceed HED ’s level of concern with baseline attire or baseline attire plus chemical resistant gloves

. With baseline attire, the combined (dermal + inhalation) MOE for mixer/loaders was 240 and the MOE for applicators was 17,000. With baseline attire plus chemic al resistant gloves, the combined (dermal + inhalation) MOE was 9,500 for mixer/loaders and 51,000 for applicators.

Table 9.1. Short

- /Intermediate

- /Long

- Term Occupational Exposure and Risk Estimates for Fluoxastrobin

(baseline + dermal PPE: gloves only )

Dermal Unit Exposure 1 Inhalation Unit

Exposure 1 Application

Rate 2 Amount

Treated Daily 3 Dermal Inhalation Total

mg/lb ai mg/lb ai Dose 4 MOE 5 Dose 6 MOE 7 MOE 8 Mitigation Level Mitigation Level lb ai/A Acres mg/kg/day mg/kg/day

Mixer/Loader [ Mixing and Loading Liquid Formulation for Groundboom Application (PHED) ]

2.9 0.0012 0.16 80 0.012 250 0.0002194 14,000 250

baseline baseline baseline

0.023 0.0012 0.16 80 0.00010 30,000 0.0002194 14,000 9,400

gloves baseline gloves

Applicator [ Groundboom Application (PHED )]

0.041 0.00074 0.16 80 0.000172 17,000 0.000000135 22,000,000 17,000

baseline baseline baseline

0.014 0.00074 0.16 80 0.0000588 51,000 0.000000135 22,000,000 51,000

gloves baseline gloves

1 PHED/ORETF (level of mitigation: Baseline and Baseline+Gloves )

.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 33 of 43 2 Based on registered or proposed label (Reg. No. 66330

- 65 )

. 3 Exposure Science Advisory Council Policy No. 9.1

. 4 Dermal Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x A mount Treated (A/day) x DAF ( 2.3 %) / BW (kg)

. 5 Dermal MOE = Dermal NOAEL ( 3 mg/kg/day)/Dermal Dose (mg/kg/day)

. 6 Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x A mount Treated (A/day) /BW ( 70 kg)

. 7 Inhala tion MOE = Inhalation NOAEL ( 3 mg/kg/day)/ Inhalation Dose (mg/kg/day)

. 8 Total MOE = NOAEL ( 3 mg/kg/day)/Dermal Dose + Inhalation Dose

.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- A pplication Risk

The post

- application exposure associated with agricultural crops is summarized in Table 9.2

. Using HED default assumptions, maximum transfer coefficients, and surrogate DFR data, a ll scenarios resulted in MOEs greater than 100 on day 0 (12 hours after application) and

, therefore

, were not of concern to HED

.

Table 9.2

. Summary of Intermediate

- Term Occupational Post

- A pplication Risks for the Proposed New Use
of Fluoxastrobin on Squash/Cucumber Crop Subgroup 9B

Activities Foliage Development TC DFR Daily Dose Day 0 MOE

cm 2 /hr μg/cm 2 mg/kg/day

Intermediate

- Term

Irrigation, Scouting,

H and weeding Full 1500 0.3588416 0.0014 2,100

Hand Harvest ing, Leaf P ulling

, Hand P runing Low 2500 0.3588416 0.0024 1,2 00

Irrigation, Scouting, Thinning,
Hand W eeding Low 500 0.3588416 0.00047 6,400

1 Default DFR (μg/cm 2 ) = application rate (lb ai/A) x (1

- daily dissipation rate) t x 4.54E8 μg/lb x 2.47E

- 8 A/cm 2 x 20% DFR after initial treatment.

2 Daily Dermal Dose = [DFR (μg/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day x DA] x (body weight (70 kg)).

3 MOE = NOAEL/Daily Dose (Adult Dermal NOAEL = 3 mg/kg/day).

Restricted Entry Interval

Th e restricted entry interval (REI) is based on the acute toxicity of fluoxastrobin technical
material . Fluoxastrobin is classified as Toxicity Category III by the dermal route and for eye irritation potential and Toxicity Category IV for skin irritation potential

. Under the Worker Protection Standard for Agricultural Pesticides, active ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12

- hour REI. Therefore, the 12

- hour REI that appears on the proposed label is adequate.

9.2.2 Inhalation Post

- Application Risk

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

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

- application inhalation exposure to individuals performing post

-FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 34 of 43 application activities in previously tre ated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of e valuating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorpo rate 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 inhalation exposure assessment fo r fluoxastrobin.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 35 of 43 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

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

Table A.1. Satisfication of Fluoxastrobin Toxicology Data Requirements

Study Technical Required Satisfied

870.1100 Acute Oral Toxicity

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

................................ .................... 870.13 00 Acute Inhalation Toxicity

................................ ................ 870 .2400 Primary Eye Irritation

................................ ...................... 870.25 00 Primary Dermal Irritation

................................ ................ 870. 2600 Dermal Sensitization

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes 870.3 100 Oral Subchronic (rodent)

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

................................ ........... 870.3200 21

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

yes

yes CR 1

CR 2 yes

yes

yes

-

- 870.3700a Developmental Toxicity (rodent)

................................ ..... 870.3700b Developmental Toxicity (nonrodent)

............................... 870.3800 Reproduction

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

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent)

................................ ................ 870.4100b Chronic Toxicity (nonrodent)

................................ .......... 870.4200a Oncogenicity (rat)

................................ ............................ 870.4200b Oncogenicity (mouse)

................................ ...................... 870.4300 Chronic/ Oncogenicity

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

- yes

yes -

yes

- yes

yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

.................. 870.5xxx Mutagenicity

— Str uctural Chromosomal Aberrations

..... 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

yes

yes

yes yes

yes

yes

yes 870.6100a Acute Delayed Neurotoxicity (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neurotoxicity Screening Battery (rat)

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

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

no

yes

yes

no -

- yes

yes

- 870.7485 Gen eral Metabolism

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

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

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

yes

yes yes

yes

no * Special Studies for Ocular Effects

Acute Oral (rat)

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

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

- month Oral (dog)

................................ .................... CR 1 = Conditiona lly required; CR 2 = 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 assessme nts, including route to route extrapolation of toxicity data ; * = needs to be upgraded

.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 36 of 43 A.2 Toxicity Profile s

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/day 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 bw/day F: 0, 135.1, 539.2 or 2256.9 mg/kg/day NOAEL/LOAEL were not assigned. There was dose related increase of liver weight in both sexes and in kidney weight in females, in addition to other effects whose toxicological relevance was considered uncertain. Among these effects were increased hepatocellular hyper trophy with cytoplasmic changes in the high

- dose males and minimal to moderate kidney tubular hypertrophy in mid

- and high

dose females.

870.3150 90

- Day oral

toxicity (dog) 45865629 (2001);

45865628 (2001);
4586572 2 (2000)/ acceptable/guideline / 4 beag le 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 reductions 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 ).FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 37 of 43 Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3200 21/28

- Day dermal

toxicity (rat) 45865630 (2000) /

acceptable/guideline / 0, 100, 300 or 1000 mg/kg bw/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)
LOAEL not identified.

870.3700a Prenatal

developmental in (rat) 45865631 (1997) /

acceptable/guideline 0, 100, 300 or 1000 mg/kg bw/day Maternal NOAEL 1000 mg/kg bw/day (limit dose)
LOAEL not identified. Developmental NOAEL 1000 mg/kg bw/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) 45865633 (2001);

45865634 (2001) / acceptable/guideline / 0, 100, 1000 or 10000

ppm M: 0, 6.3, 70.0 or 665.0 mg/kg bw/day F: 0, 7.8, 84.7 or 825.4 mg/kg bw/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 bw/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 w ith increased serum liver alkaline phosphatase
indicative of cholestasis.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 38 of 43 Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

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 bw/day F: 0, 29.5, 204.0 or 1265.1 mg/kg bw /day NOAEL = M/F: 775.6/1265.1 mg/kg bw/day
LOAEL not identified. No evidence of carcinogenicity

.

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 microscopic
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, 50, 158, 500, 1581 and 5000 ug/plate; following preincubation: 10, 32, 100, 316, 1000 and 3162 ug/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 ug/plate
Test substance: HEC
5725N (E:Z = 90:10%) negative (considered non

- mutagenic in this Salmonella typhimurium /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 ug/plate; following preincubation: 100, 200, 400, 800, 1600 and 3200 ug/plate
Test substance: HEC
5725

- phenoxy

- hydroxy

pyrimidine negative (considered non

- mutag enic in this Salmonella typhimurium /mammalian activation gene mutation assay)FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 39 of 43 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 45865707 (2001) /

acceptable/guideline / plate incorporation: 16, 50, 158, 500, 1581 and 5000 ug/plate; following preincubation: 5, 16, 50, 158, 500 and 1581 ug/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 45865708 (2001) /

unacceptable/guideline / 16 to 5000 ug/plate (6 concentrations)

Test substance: HEC
5725

- dihydroxy

pyrimidine negative (considered non

- mutagenic in this Salmonella typhimurium /mammalian activation

gene m utation assay)

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/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 no t identified.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 40 of 43 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 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 (mouse) 45865726 (2001)

Unacceptable/guideline 0, 450, 1800, or 7000 ppm (equivalent to 0, 106.8, 367.3, and 1534.4 mg/kg/day for males and 0, 157.3, 659.6, and 2383.3 mg/kg/day for females) No clinical signs of toxicity or mortal ity were
found and no treatment

- related effects were found on body weight, food intake, or B

- cell activated, T

- cell mediated IgM response to

SRBC. How ever, the study is considered unacceptable because of uncertainty in dietary test material intake, failu re to report spleen weight of each mouse at necropsy, and failure of the laboratory to demon strate its capability in performing this type of assay.FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 41 of 43 A ppendix B. M etabolism Summary Table

Table B.1. Tabular Summary of Metabolites and Degradates

Company Name

Matrix Chemical Name Structure 1

Fluoxastrobin, E

- isomer [Parent]

Peanut hay Tomato fruit Wheat forage, hay, straw, and grain Rotated Swiss chard, turnip tops and roots, and wheat forage, hay, straw, and grain Goat milk, muscle, fat, liver, and kidney Hen egg, liver, muscle, and fat (1 E )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime

Fluoxastrobin, Z

- isomer [Isomer of parent, not pesticidally active, proposed for regulati on in plant and animal commodities]

Peanut hay Tomato fruit Wheat forage, hay, straw, and grain Rotated Swiss chard, turnip tops and roots, and wheat forage, hay, straw, and grain Goat fat and liver Hen egg, muscle, and fat (1 Z )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime

Phenoxy

- hydroxypyrimidine
metabolite [HEC7154] [Metabolite proposed for regulation in livestock commodities]

Peanut hay (glucose conjugate also identified) Wheat hay and straw Goat milk, muscle, fat, liver, and kidney Hen egg, liver, muscle, and fat 6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinolFLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 42 of 43 Appendix C. Physical/Chemical Properties

Table C . Physico

- Chemical Properties

Parameter Value Reference
Molecular Weight 458.8 amu

Melting range 103

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

- D water) MRID 45865520

Water solubility (20°C) at 20 C : 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 MRIDs 45865520, 45865525

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) 5.63x10 - 10 Pa (20 C)

8.72x10 - 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 45865303FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

Page 43 of 43 Appendix D. 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 ch emical. These studies, which comprise the Pesticide Handler Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF), 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 E. International Residue Limit Summary

Table E. Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition

US Canada Mexico 2 Code x 40 CFR 180.609
Plant: fluoxastrobin, (1 E )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime and its Z isomer, (1 Z )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime
Livestock: fluoxastrobin, (1E)

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

- 1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, its Z isomer, (1 Z )

- [2

- [[6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinyl]oxy]phenyl](5,6

- dihydro

1,4,2

- dioxazin

- 3

- yl)methanone O

- methyloxime, and its phenoxy

hydroxypyrimidine, 6

- (2

- chlorophenoxy)

- 5

- fluoro

- 4

- pyrimidinol None None None

Tolerance (ppm) /Maximum Residue Limit (mg/kg) Commodity 1 US Canada Mexico 2 Codex

Squash/cucumber subgroup 9B 0.5

Completed: M. Negussie; 09/23/2010

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purpos es.