FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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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 Registration No.: 66330-64

Petition No.: 0F7726 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical/Aggregate Case No.: NA

TXR 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

Health Effects Division (7509P)

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

Fungicides Branch

Registration Division (7505P)
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Table of Contents

1.0 Executive Summary........................................................................................................... 4

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

2.1 Data Deficiencies/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 Safety 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 Point 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 Dietary 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 Dietary 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 .............................................. 25
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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 Residential (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 Short-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 ........................................................... 43
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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-methyloxime and its Z-isomer (1Z)-[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 commodities (RACs):

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 Sections B and F, and resolution 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 tolerances 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, 08/13/2010). 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 Food Quality Protection Act (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 were reviewed by Meheret Negussie, 

the dietary exposure assessment was completed by Cassi Walls, the occupational/residential 

assessment for food use on squash/cucumber subgroup 9B was conducted by Kristin Rury, and 

the toxicology evaluation was performed by Whang Phang. The drinking water assessment 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 recommends 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 in Section 2.3.
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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 correct commodity definition (Table 2.2.3).

Chemistry [860.1650 Submittal of Analytical Reference Standards]

Arysta must provide an analytical 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 adequately 

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 established 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 Tolerances
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As shown in Table 2.2.3, the proposed tolerance commodity term has to be revised 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

Established Proposed Recommended Correct Commodity Definition

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, 05/27/2009), 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 (1E)-[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, (1Z)-[2-[[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]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. 

Compliance with the tolerance levels specified below is to be determined by measuring 

only the sum of(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, (1Z)-[2-[[6-(2-

chlorophenoxy)-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 proposed 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 Assessment
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None.

2.3.3 Recommendations from Residential Assessment

None.

3.0 Introduction

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 fluoxastrobin is typically present at much lower levels (E:Z

ratio of approximately 90:10). Additionally, the Z-isomer of fluoxastrobin is considered to be a 

metabolite (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 TechTM

DISARMTM 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 four 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 

applications can be applied using ground or chemigation equipment. The restricted entry interval 

(REI) is 12 hours.

Currently registered fluoxastrobin uses include peanut, tuberous and corm vegetable subgroup 

1C, leaf petiole vegetables subgroup 4B, fruiting vegetables group 8, and turf (DP#292422, S. 

Winfield, 01/24/2005); field corn, soybeans, and the low-growing berry subgroup 13-07G 

(DP#’s 356982 and 357473, N. Dodd, 08/013/2009); and sweet corn, field corn/sweet corn 

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

3.1 Chemical Identity

Fluoxastrobin is described in Table 3.1.
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Table 3.1. Fluoxastrobin Nomenclature

Chemical Structure

Empirical Formula C21H16ClFN4 O5 

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 petitioner.

Company experimental name HEC 5725

IUPAC name (E)-{2-[6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yloxy]phenyl}(5,6-dihydro1,4,2-dioxazin-3-yl)methanone O-methyloxime

CAS name (1E)-[2-[[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy]phenyl](5,6-dihydro1,4,2-dioxazin-3-yl)methanone O-methyloxime

CAS Registry Number 361377-29-9

End-use product/EP

FLUOXASTROBIN 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 TechTM DISARMTM 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 are presented in Table 3.3.

Cl

O

N N

F

O

O

O

N

N

O

CH3
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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, hubbarb 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, 

Chemigation

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 with 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 to 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 for 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 Section B prohibit use of EVITO® 480 SC to squash/cucumber 

subgroup 9B crops grown in a greenhouse. In addition, the proposed label prohibits tank mix 

with emulsifiable concentrate (EC)-based insecticides, or the following products: malathion, 

Kelthane®, Thiodan®, Phaser®, Lannate®, Lorsban®, M-Pede®, or Botran®.
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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 (PBI)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 Division 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 

growing crops and application may result in fluoxastrobin reaching surface and ground water 

sources of drinking water. There are also residential uses of fluoxastrobin; thus, there is likely to 

be exposure in residential or non-occupational settings. In an occupational setting, applicators 

may be exposed while handling the pesticide prior to application, as well as during application. 

There is a potential for post-application exposure for workers re-entering treated fields. 

Several risk assessments have been previously prepared for the existing uses of fluoxastrobin. 

This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed new uses of fluoxastrobin, but also considers the existing uses as well, particularly for 

the dietary exposure assessment. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and

for toddlers, youths, and adults entering or playing on treated areas 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 that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.
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4.0 Hazard Characterization and Dose-Response Assessment

References:

- HED/RAB3 Fluoxastrobin Hazard Meetings, 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, Sarah Winfield, 01/24/2005.

A detailed hazard characterization for fluoxastrobin is presented in a previous risk assessment 

(DP#292422, S. Winfield, 01/24/2005). 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, dimoxystrobin, 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 phosphorylation, 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 potentials 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. Under 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 characterized in several rat metabolism 

studies using three 14C-radiolabeled rings in fluoxastrobin. Orally administered 14Cfluoxastrobin 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 and 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 was 
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extensively metabolized primarily via hydroxylation and subsequent methylation, followed by 

glucuronide 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 following an 

8-hour dermal application 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 were 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 determined 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 Factor for Infants and Children (FQPA Safety Factor)

The toxicology and exposure data and have 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 of 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 deficiencies 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 derived for

current risk assessment purposes (cRfD of 0.015 mg/kg/day). Consequently, the existing data 
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are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of 

the requirements under the FQPA and an additional factor for database uncertainty (UFDB) is not 

needed to account for lack of this study. However, the registrant should upgrade the study to 

meet the data requirement.

4.4.2 Evidence of Neurotoxicity

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

studies that fluoxastrobin is a neurotoxic chemical.

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

The database for evaluating in utero or postnatal susceptibility is adequate and includes 

developmental 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 Uncertainty in the Exposure Database

The exposure databases are complete or are estimated based on data that reasonably account for 

potential exposures. The dietary food exposure assessment was performed based on 100% crop 

treated (CT) assumptions and tolerance-level residues. The Environmental Fate and Effects 

Division (EFED) 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 oral 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 Departure Selections

As summarized in Section 4.3, the fluoxastrobin database 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 the 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 available 

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 of developmental/reproduction or 

neurotoxicity 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 short- 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 

chronic dietary exposure scenarios (although long-term dermal and inhalation exposures are not 

expected based on the proposed uses). 
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4.5.1 Dose-Response Assessment

Fluoxastrobin appears to have mild or low toxicity following repeated administration in all tested 

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 

phosphatase (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 including 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 reference dose (RfD).

The liver appeared to be a target organ in other studies, as well, but the toxicological 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 as 

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 to 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 was 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 effects.

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 including 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, 
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postural status and reactions, and spinal/cranial reflexes, were carried out and were found to be 

within normal 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 stimulation 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 

cells (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 adequately tested in rats and mice of both sexes. The 

results demonstrated a lack of treatment-related increase in tumor incidence in rats or mice. 

There was no mutagenicity concern and no structure activity relationship alert. It was concluded 

that there was 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 exposures 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 combined; 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 

results demonstrated a lack of treatment-related increase in tumor incidence in rats or mice. 

There was no mutagenicity concern and no structure activity relationship alert. It was concluded 

that there was no incidence of carcinogenicity for fluoxastrobin. Fluoxastrobin 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 Exposures in Table 

4.5.4.1 and 2) Occupational Exposures in Table 4.5.4.2.
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Fluoxastrobin for Use in Dietary and NonOccupational 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

UFA = 10X

UFH = 10X

FQPA SF = 1X

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 

IntermediateTerm (1-6 

months)

NOAEL =

3.0 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

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 ShortTerm (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 

IntermediateTerm (1-6 

months)

NOAEL =

3.0 

mg/kg/day

UFA = 10X

UFH = 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

UFA = 10X

UFH = 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. 
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Fluoxastrobin for Use in Dietary and NonOccupational 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

UFA = 10X

UFH = 10X

FQPA SF = 1X

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).

Inhalation 

IntermediateTerm (1-6 

months)

NOAEL = 

3.0 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

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).

Inhalation 

Long-Term

(> 6 months)

NOAEL =

1.5 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

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 observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

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

of concern. N/A = not applicable.

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Fluoxastrobin for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (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.
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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Fluoxastrobin for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal 

IntermediateTerm (1-6 

months)

NOAEL = 

3.0 

mg/kg/day

UFA = 10X

UFH = 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

UFA = 10X

UFH = 10X

FQPA SF = 

1X

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 adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use 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, 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 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 by 
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a ―naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.‖ The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

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 Tier 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 October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and 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, including 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 screening battery, please visit our website: 

http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment 

References:

- Fluoxastrobin. Petition for 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 indicate that metabolism of 

fluoxastrobin is similar in dissimilar crops. HED has concluded that the residues of concern in 

plants for risk assessment and tolerance setting purposes are fluoxastrobin and its 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.
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2-chlorophenol 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 for 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. The 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, 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.

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 for 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 unlikely 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 metabolites 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 addition to several dioxazine phenyl two ring metabolites) 

and laying hen (e.g. several glucuronide conjugates of HEC5725- including mono- and 
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di-OH-GA, and oxime-GA in addition to mono- and bi-ring fragments including 

dioxazine-oxime, 2-cyanophenol, and salicylic 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 fluoxastrobin 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 fluoxastrobin 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 minor 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 absence 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. 

One 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 Concern 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 

Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Fluoxastrobin and its 

Z-isomer

Fluoxastrobin and its 

Z-isomer Rotational Crop

Livestock

Ruminant Fluoxastrobin, its Z-isomer, 

and its phenoxyhydroxypyrimidine metabolite 

[6-(2-chlorophenoxy)-5-

fluoro-4-pyrimidinol]

Fluoxastrobin, its Z-isomer, 

and its phenoxyhydroxypyrimidine metabolite 

[6-(2-chlorophenoxy)-5-

fluoro-4-pyrimidinol]

Poultry

Drinking Water Fluoxastrobin and its 

Z-isomer

Not Applicable

5.2 Food Residue Profile

Fluoxastrobin 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 of 
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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 summarized 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 for 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 

group 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 from 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 30.68-0.71 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 30.68-0.71 1 0.08 0.05 0.16 0.01 0.18

1 Combined residues of fluoxastrobin and its Z-isomer. 

2 HAFT = Highest 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 Eggs
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The potential exists for secondary residues to occur in some livestock commodities from 

registered uses. There are no livestock feedstuffs associated with the proposed uses on

squash/cucumber subgroup 9B. The dietary burdens for fluoxastrobin residues in livestock diets 

will not be affected by the subject action; therefore, 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

Available confined rotational crop data are adequate to satisfy data requirements and to delineate 

the nature of the residue in rotated crop commodities. 

Acceptable limited field rotational crop and extensive field rotational crop studies were

previously reviewed. 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 rotational 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 spray 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 tops at a 30-day plantback 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 study, 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, 

tolerances 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; forage, 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, was 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 grasses 
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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 laboratory studies, fluoxastrobin persists in soils for several months to several years 

and is slightly to moderately mobile in soil. Since aqueous photolysis is the major route of 

degradation for fluoxastrobin, the dissipation of this chemical in water is dependent on 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 sediment and no soil metabolites are formed under 

natural conditions. Field studies indicate that fluoxastrobin persists for over a year; however, 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. The 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 (53 μg/L). The estimated chronic 

drinking water concentration for fluoxastrobin (1-in-10 year annual mean) 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 EDWCs

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

Table 5.3. Summary of Estimated Surface Water and Ground Water Concentrations for Fluoxastrobin

Scenario Surface Water Conc., ppb a Ground Water 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), assuming 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 μg/L (DP#379114, R. Bohaty, 12/15/2010). Based on 

processing studies, the processing factors for tomato puree, potato chips, dry potato 
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(granules/flakes), 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 processing factors were 

assumed.

5.4.2 Percent Crop Treated Used in Dietary Assessment

100% CT were used for all commodities 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 chronic dietary (food and drinking water) exposure and risk assessment was conducted using 

the Dietary Exposure Evaluation Model (DEEM-FCIDTM, Version 2.03), which uses 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-in-10 

year annual mean value of 53 ppb, was incorporated directly into the dietary assessment. The 

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. The dietary (food and 

drinking water) exposure is estimated at 22% of the chronic Population Adjusted Dose (cPAD) 

for the general U.S. population and 47% of the cPAD for children 1-2 years old, the population 

subgroup with the highest estimated chronic dietary exposure to fluoxastrobin. The results of the 

chronic dietary exposure analyses 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 41
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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 

grasses. DP#371251, Kristin Rury, 03/04/2010.

- 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, 01/20/2010.

- Occupational and Residential Exposure Assessment for Proposed Section 3 Registration of Fluoxastrobin on 

Peanuts, Leafy Vegetables, Fruiting Vegetables, Potatoes and Tuber Vegetables, Turf. DP#289109, Barry

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 potential 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 

inhalation risks were assessed. The estimated 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 margin 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 not of concern to HED

(residential 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 3Inhalation 4 Total
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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 protection, 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 (μg/lb ai) * (1mg/1000 μg) conversion*Application Rate*Area 

Treated)/body weight (70 kg).

8 MOE Baseline Inhalation = NOAEL (3.0 mg/kg/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 transfer 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 estimates 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.

Use of fluoxastrobin on turf may 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 incidental oral ingestion (children three 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) 
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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. 0.55 lb ai/A). A summary of the 

estimated exposures and risks, is presented below in Table 6.2. The algorithms 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 recreational exposure assessment was not included. 

Additionally, golf course exposures and risks were already assessed.

Table 6.2. Short- and Intermediate-Term Residential Post-Application 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 application rate values found on registered label (EPA Reg. No. 66330-379).

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 

proposed turf uses of fluoxastrobin, the total (dermal + incidental oral) post-application MOE for 

children resulted in an MOE of 280 and was not of concern to HED (MOE > 100). Table 6.3 

presents a summary of the post-application MOE estimates for adults and children.
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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 

PostApplication

Total 

Exposure 3

mg/kg/day

MOE

Dermal Inhalation Dermal Inhalation Oral

Adult 0.000904 0.000022 0.000926 3200 0.00148 NA NA 0.00148 2000

Child NA NA NA NA 0.00246 NA 0.00821 0.01067 280

1Handler 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

For adults, residential total exposure combines the highest dermal and inhalation exposures (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-Application Inhalation Exposure

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

inhalation exposure assessment 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 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, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative 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 lesser extent, could also be a 

potential source of exposure from the ground application method employed for fluoxastrobin. 

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

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for 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.
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It is noted that the 0.55 lb ai/acre application rate for turf was modeled to estimate postapplication residential exposure of 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 added together and compared to quantitative 

estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. For fluoxastrobin, potential exposures from food, drinking water, and 

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 LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult 3.0 100 0.030 0.003269 0.00148 0.004749 630

Children

1-2 years old 3.0 100 0.030 0.006979 0.01067 0.017649 170

1

Indicate in this footnote the basis for the LOC (inter- and intra- species uncertainty factors total 100X).

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

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

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

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

7.3 Chronic Aggregate Risk
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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 other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that fluoxastrobin has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

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, 01/20/2010.

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 provided 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 as the worst-case scenario. All handler 
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scenarios resulted in MOEs greater than the level of concern (LOC = 100) at some level of risk 

mitigation. 

Dermal

For all handler mixing, loading, and applying scenarios, the 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 resistant 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 chemical 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 6MOE 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

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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 Amount 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 Amount Treated (A/day) 

/BW (70 kg).

7

Inhalation 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-Application 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, all 

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-Application 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/cm2

mg/kg/day

Intermediate-Term

Irrigation, Scouting,

Hand weeding Full 1500 0.3588416 0.0014 2,100

Hand Harvesting, Leaf Pulling,

Hand Pruning Low 2500 0.3588416 0.0024 1,200

Irrigation, Scouting, Thinning,

Hand Weeding Low 500 0.3588416 0.00047 6,400

1 Default DFR (μg/cm2

) = application rate (lb ai/A) x (1- daily dissipation rate) tx 4.54E8 μg/lb x 2.47E-8 A/cm2x 

20% DFR after initial treatment.

2 Daily Dermal Dose = [DFR (μg/cm2

) 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

The 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

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application activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

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 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 incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for fluoxastrobin.
FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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Appendix 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 ....................................................

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent).................................................

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

870.3200 21-Day Dermal ................................................................

870.3250 90-Day Dermal ................................................................

870.3465 90-Day Inhalation............................................................

yes

yes

yes

CR1

CR2

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—Structural Chromosomal Aberrations.....

870.5xxx Mutagenicity—Other Genotoxic Effects.........................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen).................................

870.6100b 90-Day Neurotoxicity (hen).............................................

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

870.6200b 90-Day Neurotoxicity Screening Battery (rat).................

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

no

no

yes

yes

no

-

-

yes

yes

-

870.7485 General Metabolism ........................................................

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

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

yes

yes

yes

yes

yes

no*

Special Studies for Ocular Effects

Acute Oral (rat).............................................................

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

Six-month Oral (dog)....................................................

CR1= Conditionally required; CR2= 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; * = needs to be upgraded.
FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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A.2 Toxicity Profiles

Table A.2.1. Fluoxastrobin Acute Toxicity Profile

Guideline No. Study Type MRID Results Toxicity 

Category

870.1100 Acute oral - rat 45865612 LD50 >2000 mg/kg III

870.1200 Acute dermal - rat 45865613 LD50 >2000 mg/kg III

870.1300 Acute inhalation - rat 45865618 LC50 = 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 

hypertrophy with cytoplasmic changes in the 

high-dose males and minimal to moderate 

kidney tubular hypertrophy in mid- and highdose females.

870.3150 90-Day oral 

toxicity (dog)

45865629 (2001); 

45865628 (2001); 

45865722 (2000)/ 

acceptable/guideline/ 

4 beagle dogs/sex/dose 

(MRID 45865629): 

0, 25, 50, 100, 800 or 

2500 ppm 

M: 0, 0.7, 1.4, 3.0, 24.8 or 

76.0 mg/kg/day

F: 0, 0.7, 1.5, 3.0, 24.2 or 

75.0 mg/kg/day

NOAEL = M/F: 3.0 mg/kg/day (100 ppm)

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

ppm) based on dose-related 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

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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

Maternal NOAEL = 100 mg/kg/day

LOAEL = 400 mg/kg/day based on cold ears, 

transient body weight loss, and decreased food 

consumption.

Developmental 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 Pgeneration males and females and decreased 

premating absolute body weight of the F1 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 F1

and/or F2 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 with 

increased serum liver alkaline phosphatase 

indicative of cholestasis.
FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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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-hydroxypyrimidine

negative (considered non-mutagenic in this 

Salmonella typhimurium/mammalian activation 

gene mutation assay)
FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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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-hydroxypyrimidine

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-dihydroxypyrimidine

negative (considered non-mutagenic in this 

Salmonella typhimurium/mammalian activation 

gene mutation 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 not identified.
FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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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 14C-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 and 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 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, respectively). Many 

metabolites were found, and the primary ones 

were glucuronide conjugates, methoxy-OHGA-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 mortality 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. However, the study is considered 

unacceptable because of uncertainty in dietary 

test material intake, failure to report spleen 

weight of each mouse at necropsy, and failure 

of the laboratory to demonstrate its capability 

in performing this type of assay. 
FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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Appendix B. Metabolism 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

(1E)-[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 regulation 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

(1Z)-[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-

pyrimidinol

Cl

O

N N

F

O

O

O

N

N

O

CH3

Cl

O

N N

F

O

O

O

N

N

O

CH3

Cl

O

N N

F

OH
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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 KOW

(25°C) 2.85 (20 C); POW = 708 MRID 45865525

UV/visible absorption spectrum 19,358 L/mol cm at 250 nm MRID 45865303
FLUOXASTROBIN Human Health Risk Assessment DP No. 379110

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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 chemical. 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 Mexico2 Codex

40 CFR 180.609

Plant: fluoxastrobin, (1E)-[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, (1Z)-[2-[[6-(2-

chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy]phenyl](5,6-dihydro1,4,2-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, (1Z)-[2-[[6-(2-

chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy]phenyl](5,6-dihydro1,4,2-dioxazin-3-yl)methanone O-methyloxime, and its phenoxyhydroxypyrimidine, 6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinol

None None None

Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity1 US Canada Mexico2 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 purposes.