UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

., 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: March 27,2013 

SUBJECT: Fluo-xastrobin. Aggregate Human Health Risk Assessment for the Proposed · 

New Uses on Melon Subgroup 9A and Sorghum, Along with Establishment of 

Permanent Tolerances on Wheat, and Amendments to Established Tolerances.pn 

Milk and Milk Fat. 

PC Code: 028869 DP Barcode: D405370, D409039 

Decision No.: 465774 Registration Nos.: 66330-64, 66330-65 

Petition No.: 2F8047, 2F8130 Regulatory Action: Section 3 Registration 

Case No.: NA Risk Assessment Type: Single ChemicaVAggregate 

TXRNo.: NA CAS No.: 361377-29-9 

MRIDNo.: NA 40 CFR: § 180.609 

FROM: Nancy Tsaur, Chemist, Risk Assessor tJ!~-----;J Meheret Negussie, Chemist~ L+,fc·~--

Kristin Rury, Biologist 

Risk Assessment Branch 3 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief /} / f 4 / . 

Risk 

Health 

Assessment 

Effects Division 

Branch 

(7509P) 

3 ~~ 

TO: Heather Garvie/Shaja Joyner, RM #20 

Fungicides Branch (FB) 

Registration Division (7505P) 

r: ....... , \. .. 

I. 

The Registration Division (RD) requested that the Health Effects Division (HED) provide an 

evaluation ofthe proposed new agricultural uses offluoxastrobin on melon subgroup 9A and ~ 

sorghum. A summary of the findings and an assessment of human health risk resulting from he 

proposed and registered uses of fluoxastrobin are provided in this document. This assessment 

has incorporated the updated 2012 Residential Standard Operating Procedures (SOPs). 

•' 

The residue chemistry review and dietary risk assessment were conducted by Meheret Negus~ie; 

the occupational and residential exposure risk assessment was conducted by Kristin Rury~ an¢. 

the aggregate human health risk assessment was conducted by Nancy Tsaur. 

Page I of36 
Table of Contents 

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

2.0 HED Recommendations ....................................................................................................... 6 

2.1 Data Deficiencies ..................................................................................................... ....... 6 

2.2 Tolerance Considerations ......................... .... ................................................................. 7 

2.2.1 Enforcement Analytical Method ....................................................................... ........ 7 

2.2.2 Recommended Tolerances ..... .... ... .... ........ ................................................................. 7 

2.2.3 Revisions to Petitioned-For Tolerances .................. ........ .......................................... 8 

2.2.4 International Harmonization ................................................................... .................. 8 

3.0 Introduction ........................................................................................................................... 8 

3.1 Chemical Identity ........................................................................................................... 8 

3.2 PhysicaVChemical Characteristics .............. : ..................... ............ ........ ............. .......... 9 

3.3 Pesticide Use Pattern ................................... ................................................................... 9 

3.4 Anticipated Exposure Pathways ................................................................................. 10 

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

4.0 Hazard Characterization and Dose-Response Assessment ............................................. 11 

~. 1 Summary of Toxicological Effects .............................................................................. 11 

_ .2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 12 

·-. 4.2.1 Completeness of the Toxicology Database ........ ................................ .... .................. 12 

4.2.2 Evidence of Neurotoxicity ........................................................................................ 12 

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

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

5.0 Dietary Exposure and Risk Assessment ............................................................................ IS 

5.1 Residues of Concern Summary and Rationale .......................................................... 15 

.. 5.2 Food Residue Profile .................................................................................................... 15 

'! .. 5.3 Water Residue Profile .................................................................................................. 16 

5.4 Dietary Risk Assessment .............................................................................................. 16 

5.4.1 Description of Residue Data Used in Dietary Assessment ................. ~ .................. 16 

S.4.2 Acute Dietary Risk Assessment ................................................ ............................... 17 

5:4.3 Chronic Dietary Risk Assessment ........................................................................... 17 

5.4.4 Cancer Dietary Risk Assessment. ............................................................................ 17 

5.4.5 Summary Table .............................. ........................................................................... 17 

6.0"'- Residential (Non-Occupational) Exposure/Risk Characterization ................................ 18 

().1 Residential Handler Exposure .................................................................................... 18 

6.2 Post-Application Exposure ........................................................................................ .. 19 

6.3 Residential Bystander Post-Application Inhalation Exposure ................................ 19 

6.4 Spray Drift .................................................................................................................... 20 

7.0 Aggregate Exposure/Risk Characterization ..................................................................... 20 

·. 7.1 Acute Aggregate Risk. .................................................................................................. 20 

7.2 Short-Term Aggregate Risk ......... ....................................................... ........................ 20 

, 7..3 Intermediate-Term Aggregate Risk ................... ........................................................ 21 

J..4 Chronic Aggregate Risk .... ................................................................................... ....... 21 

7,.5 Cancer Aggregate Risk ........................................................................ ........................ 21 

8.0._; Cumulative Exposure/Risk Characterization .................................................................. 21 

~ Occupational Exposure/Risk Characterization ............................................................... 22 :, . 

Page 2 of36 
Page 3 of 36

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 22

9.2 Short- and Intermediate-Term Post-Application Risk............................................. 23

9.2.1 Dermal Post-Application Risk ............................................................................. 23

9.2.2 Restricted Entry Interval ..................................................................................... 24

9.2.3 Inhalation Post-Application Risk ........................................................................ 24

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

Appendix A. Toxicology Profile and Executive Summaries...................................................26

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

A.2 Toxicity Profiles............................................................................................................ 27

Appendix B. Physical/Chemical Properties.............................................................................31

Appendix C. Review of Human Research ................................................................................33

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

Appendix E. Occupational Exposure/Risk Summary Tables ................................................34
Page 4 of 36

1.0 Executive Summary

Fluoxastrobin is a strobilurin-class fungicide that controls foliar fungal diseases and 

soilborne/seedling fungal diseases. It works by interrupting mitochondrial respiration in plantpathogenic fungi, thus inhibiting spore germination and mycelial growth.

In PP#2F8047, Arysta LifeScience North America, LLC (Arysta) has submitted a label 

amendment to add melon subgroup 9A and sorghum to the master label for Fluoxastrobin 480 

SC Fungicide (EPA Reg. No. 66330-64), thus petitioning for associated tolerances. 

Fluoxastrobin 480 SC Fungicide is a suspension concentrate (SC) formulation containing 40.3% 

active ingredient (ai) by weight (3.98 lb ai per gallon).

In reviewing the tolerances established under 40 CFR §180.609, HED has noted that the 

recommended tolerance of 0.09 ppm for wheat grain tolerance is not listed. Due to submission 

of supplemental residue data, the tolerance of wheat grain was increased to 0.15 ppm

(DP397825, M. Negussie, 05/23/2012). Furthermore, the established tolerance for wheat bran at 

0.15 ppm is no longer needed and should be revoked (the recommended tolerance of 0.15 ppm 

for wheat grain will cover expected residues in wheat bran). To support the recommended wheat 

grain tolerance of 0.15 ppm, Arysta has submitted another petition: PP#2F8130 (February 2013).

Concurrent with this new petition (PP#2F8130), Arysta has requested to change the following 

established tolerances: 0.02 ppm to 0.03 ppm for milk, and 0.50 ppm to 0.75 ppm for milk, fat. 

The established tolerance for milk is 0.02 ppm, which is below the combined LOQ (0.01 ppm for 

each analyte) of the milk method (0.03 ppm). Based on the maximum residues in milk (0.03 

ppm) and an assumed 25X concentration factor, a tolerance of 0.75 ppm would be appropriate. 

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

reported the hazard characterization and toxicity endpoints for risk assessment (DP404179, N. 

Tsaur, 11/13/2012). The hazard characterization and toxicity endpoints for risk assessment 

remain unchanged. A brief hazard characterization along with the salient features for the Food 

Quality Protection Act (FQPA) safety factor are summarized in this risk assessment.

Proposed Use Profile

Fluoxastrobin 480 SC Fungicide may be applied as a foliar spray via groundboom, aircraft, 

chemigation, and handheld equipment. For melons, the maximum single application rate is 5.7 fl 

oz/A (0.18 lb ai/A) and applications may be repeated on a 7-day interval, up to a maximum 

seasonal application rate of 22.8 fl oz/A (0.72 lb ai/A) per year. For sorghum, the maximum 

single application rate is 4.0 fl oz/A (0.12 lb ai/A) and applications may be repeated on a 14-day 

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

Exposure Profile

Exposure pathways include dietary (food and drinking water), residential, and occupational 

exposure sources. The existing residential uses result in non-occupational exposure from handler 

and post-application activities. Non-occupational exposures to fluoxastrobin are only expected 

for short-term durations. Dietary exposures are expected for chronic duration. Occupational 

handler and post-application exposures are expected for short- and intermediate-term durations 
Page 5 of 36

only. The proposed label requires occupational handlers to wear long pants, long sleeves, shoes, 

socks, and chemical resistant gloves.

Toxicity/Hazard

The risk assessment for fluoxastrobin is based on a well-characterized and complete toxicology 

database. Following repeated exposure, fluoxastrobin has mild or low toxicity in all tested 

species except for the dog. Repeated oral administration to dogs resulted in adverse liver toxicity 

at considerably lower doses than those noted in other species. Based on species sensitivity, the 

effects observed in the dog were used as endpoints for risk assessment. In both the 90-day and 

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

and rats, the kidney was another target organ.

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

developmental toxicity studies (rat and rabbit) and a two-generation reproduction study (rat), 

there was neither increased susceptibility of pre-/postnatal exposure to fluoxastrobin, nor adverse 

effects on reproduction. Furthermore, were not seen in an acute neurotoxicity study in rats up to 

the limit dose of 2000 mg/kg/day. In a subchronic neurotoxicity study in rats, fluoxastrobin did 

not elicit any neurotoxic effects. Repeated dose studies of fluoxastrobin in the database did not 

show immunotoxic effects in rats. Therefore, the data support a reduction of the FQPA safety 

factor to 1X. Results of genotoxicity testing were negative and there were no treatment-related 

carcinogenicity findings in adequately performed carcinogenicity studies in rats and mice. 

Therefore, fluoxastrobin is classified as “not likely to be carcinogenic to humans.”

Dietary Exposure (Food and Water) and Risk Estimates

The dietary exposure and risk estimates changed slightly from the previous risk assessment. 

There was no indication of an adverse effect attributable to a single dose. Thus, an acute 

reference dose (aRfD) was not established, and an acute dietary exposure assessment was not 

conducted. A slightly refined chronic dietary exposure assessment was performed for 

fluoxastrobin using tolerance-level residues, average field trial residues, and 100% crop treated

(CT). The estimated drinking water concentration (EDWC) of 137 μg/L was incorporated 

directly into the dietary assessment. The results of the chronic dietary analysis for food and 

drinking water are below the HED’s level of concern (LOC) for all population subgroups. The 

dietary exposure for food and water is estimated at 30% of the chronic Population Adjusted Dose 

(cPAD) for the general U.S. population and 66%, of the cPAD for all infants < 1 year old, the 

population subgroup with the highest estimated chronic dietary exposure to fluoxastrobin.

Residential Exposure and Risk Estimates

Existing registered uses do not result in any residential handler or post-application risk estimates 

of concern. The lowest and most protective short-term residential handler (inhalation only) 

MOE is 7,300 based on a granular use on residential turf. The lowest and most protective 

incidental oral post-application MOE for children (1 to <2 years old) is 390 based on hand to 

mouth activities on turf treated with a liquid formulation of fluoxastrobin.

Aggregate Exposure Risk Estimates

There is potential for short-term aggregate exposure to fluoxastrobin via the dietary (which is 

considered background exposure) and residential (which is considered primary) pathways. All
Page 6 of 36

aggregate MOEs are greater than 100, which indicates that exposure and risk estimates do not 

exceed HED’s LOC. The adult and children short-term aggregate (dietary + residential) MOEs 

are 610 and 170, respectively. Since there are neither intermediate-term nor chronic residential 

exposure scenarios, the aggregate risk estimates are expected to be equivalent to chronic dietary 

(food and drinking water) risk estimate.

Occupational Handler Exposures and Risk Estimates

Based on the proposed uses, there is potential for short- and intermediate-term occupational 

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

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

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

intermediate-term handler risk estimates (dermal + inhalation) resulted in MOEs ranging from 

320 to 21,000. 

Occupational Post-Application Exposures and Risk Estimates

There is potential for short- and intermediate-term occupational exposure during post-application 

activities. There is no short-term dermal POD selected for fluoxastrobin. There are no 

intermediate-term dermal post-application risk estimates of concern on day 0 (12 hours after 

application); all scenarios resulted in MOEs greater than the LOC (100) and ranged from 1,400 

to 55,000 on day 0. Based on a quantitative post-application assessment, the 12-hour restricted 

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

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for fluoxastrobin at this time. If new policies 

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

post-application inhalation exposure assessment for fluoxastrobin.

2.0 HED Recommendations

Pending submission of a revised Section F, there are no issues that would preclude granting 

registration for the requested uses of fluoxastrobin on melon subgroup 9A and sorghum (grain, 

forage, and stover), or establishment of the recommended tolerances for combined residues of 

fluoxastrobin and its Z-isomer (See Table 2.2.3).

Note: Upon reviewing the tolerances established under 40 CFR §180.609, HED notes that the 

tolerance recommended under PP#9F7567 is not listed for wheat, grain (0.15 ppm). 

Furthermore, the established tolerance for milk (0.02 ppm) should be changed to the combined 

LOQ of the milk method (0.03 ppm) and the tolerance for milk, fat (0.50 ppm) should be 

changed to 0.75 ppm.

2.1 Data Deficiencies

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

875.2100 Turf Transferable Residues

A TTR study is required for fluoxastrobin at this time since the incidental oral hand-to-mouth

MOE for small children is less than 1,000 (MOE = 390, LOC = 100) based on default values for 

the fraction of application rate available for transfer after a liquid application to turf (N. Tsaur, 

D406106, 10/25/2012).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Acceptable high performance liquid chromatography methods with tandem mass spectrometry

detection (LC/MS/MS) are available for tolerance enforcement for plant commodities. Bayer 

AG method 00604 and confirmatory method 00946 have been adequately validated for the 

determination of residues of fluoxastrobin and its Z-isomer in/on plant commodities.

Acceptable LC/MS/MS methods are available for tolerance enforcement for livestock 

commodities. Bayer AG method 00691 and confirmatory method 00945 have been adequately 

validated for determination of fluoxastrobin, its Z-isomer, and HEC 7154 in ruminant 

commodities.

Acceptable multiresidue methods test data were previously submitted for fluoxastrobin, its Zisomer, and HEC 7154. The data indicate that the multiresidue methods are not adequate for 

tolerance enforcement for fluoxastrobin for plant or livestock commodities.

2.2.2 Recommended Tolerances

Table 2.2.3. Tolerance Summary for Fluoxastrobin

Commodity

Tolerance (ppm) Comments

Established Proposed Recommended Correct Commodity Definition

40 CFR §180.609(a)(1)

Melon, subgroup 9A -- 1.5 1.5 Melon subgroup 9A

Sorghum grain -- 1.5 1.5 Sorghum, grain

Sorghum fodder -- 4 5.0

Sorghum, forage. Recommended 

tolerance based on use of the 

OECD statistical calculation 

procedures.

Sorghum stover -- 4 5.0

Sorghum, stover. Recommended 

tolerance based on use of the 

OECD statistical calculation 

procedures.

Wheat, grain -- 0.15 0.15

Wheat, bran 0.15 None

Revoke. The recommended 

tolerance on wheat, grain will 

cover expected residues in wheat 

bran.

Livestock Tolerances That Need to be Revised

Milk 0.02 0.03 0.03

Milk, fat 0.50 0.75 0.75
Page 8 of 36

2.2.3 Revisions to Petitioned-For Tolerances

The proposed tolerances must be modified for the following commodities: sorghum fodder, 

sorghum stover, milk, and milk fat. The recommended plant commodity tolerances are derived 

from use of the Organization of Economic Cooperation and Development (OECD) statistical 

calculation procedures.

2.2.4 International Harmonization

There are no Codex maximum residue limits (MRLs) established for fluoxastrobin. However, 

there are Canadian MRLs established on sorghum and wheat grain at 0.1 ppm, wheat bran at 

0.15 ppm, milk at 0.02 ppm, and milk fat at 0.15 ppm. Furthermore, the Canadian tolerance 

expression is not harmonized with the US tolerance expression. For plants and livestock, the 

Canadian tolerance expression does not include the Z-isomer. An International Residue Limit 

Status sheet is attached as Appendix D.

3.0 Introduction

Fluoxastrobin is the common name for the pesticidally active E-isomer of [2-[[6-(2-

chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy]phenyl](5,6-dihydro-1,4,2-dioxazin-3-yl)methanone 

O-methyloxime. The Z-isomer of fluoxastrobin is typically present at much lower levels (E:Z

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

metabolite (photodegradate) of fluoxastrobin. The petitioner has requested that fluoxastrobin (Eisomer only) be designated as the ai.

In PP#2F8047, Arysta requests the establishment of tolerances for residues of the fungicide 

fluoxastrobin in/on the following raw agricultural commodities (RACs): melon subgroup 9A and 

sorghum (grain, fodder, and stover). Furthermore, Arysta proposes a label amendment to add 

these crops to the master label for Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330-64). 

Fluoxastrobin 480 SC Fungicide is an SC formulation containing 40.3% ai by weight (3.98 lb ai 

per gallon).

3.1 Chemical Identity

Table 3.1. Fluoxastrobin Nomenclature

Compound

Common name fluoxastrobin 

Company experimental name HEC 5725

Cl

O

N N

F

O

O

O

N

N

O

CH3
Page 9 of 36

Table 3.1. Fluoxastrobin Nomenclature

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

Formula C21H16ClFN4 O5 

End-use product (EP) 4.0 lb ai/gal SC formulation (Fluoxastrobin 480 SC/EvitoTM 480 SC Fungicide1; 

EPA Reg. No. 66330-64) 

Compound

Common name Fluoxastrobin Z-isomer

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

Compound

Common name HEC 7154

Chemical name 6-(2-chlorophenoxy)-5-fluoro-pyrimidinol

3.2 Physical/Chemical Characteristics

Fluoxastrobin has a low vapor pressure (4.2×10-12 mm Hg at 20 °C); therefore, inhalation due to

chemical vaporization is unlikely. Fluoxastrobin has a log octanol/water partition coefficient 

(log Pow) of 2.85 and is considered relatively insoluble in water. Additionally, fluoxastrobin has 

a molecular weight of 458.8 g/mol; therefore, the potential to cross biological barriers, such as 

the skin, is somewhat limited. More detailed physicochemical properties of fluoxastrobin are 

summarized in Appendix B.

3.3 Pesticide Use Pattern

Fluoxastrobin is a strobilurin-class fungicide that controls foliar fungal diseases and 

soilborne/seedling fungal diseases. It works by interrupting mitochondrial respiration in plantpathogenic fungi, thus inhibiting spore germination and mycelial growth. Fluoxastrobin is 

currently registered for the following uses: field/sweet corn, field corn/sweet corn grown for 

seed, fruiting vegetables, leaf petiole vegetables, low-growing berries, peanuts, rice, soybeans, 

squash/cucumbers, tuberous and corm vegetables, wheat, and turf/ornamentals. 

Cl

O

N N

F

O

O

O

N

N

O

CH3

Cl

O

N N

F

OH
Page 10 of 36

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

66330-64, also labeled under the trade name DisarmTM 480 SC Fungicide) to include uses on

melon subgroup 9A and sorghum. The newly proposed use pattern is presented in Table 3.3.

Table 3.3. Summary of Directions for Use of Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330-64)a

Application

Timing, Type, 

and Equipment

Single 

Maximum 

Application 

Rate

Maximum 

Number of 

Applications

per Year

Maximum

Annual

Application

Rate

PHI

Use Directions and Limitations

days

Melons (Subgroup 9A)

Muskmelon, including hybrids and/or varieties of Cucumis melo (including true cantaloupe, cantaloupe, casaba, 

Santa Claus melon, crenshaw melon, honeydew melon, honey balls, Persian melon, golden pershaw melon, mango 

melon, pineapple melon, snake melon, and other varieties and/or hybrids of (Citrullus spp.)

Broadcast

Foliar: ground, 

aerial, 

chemigation, or 

handheld

5.7 fl oz/A

0.18 lb ai/A 4

22.8 fl oz/A

0.72 lb ai/A 1

Applications are to begin 

preventatively and continue as needed 

on a 7-14 day RTI. Do not apply to 

crops grown in a greenhouse. Do not 

tank mix with EC-based insecticides.

Sorghum

Broadcast

Foliar: ground, 

aerial, 

chemigation, or 

handheld

4.0 fl oz/A

0.12 lb ai/A 2

8.0 fl oz/A

0.26 lb ai/A

Forage: 14

Grain and 

Stover: 21

Applications are to begin 

preventatively and continue as needed 

on a 14-21 day RTI.

a Not currently registered or approved for use in California.

3.4 Anticipated Exposure Pathways

Humans may be exposed to fluoxastrobin via food and drinking water because fluoxastrobin may 

be applied directly to growing crops, and application may result in fluoxastrobin reaching surface 

and ground sources of drinking water. There are also residential uses of fluoxastrobin so there is 

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

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

application. There is also a 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 
Page 11 of 36

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

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

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

Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and 

are used in pesticide risk assessments for all registered food uses of a pesticide. These data are 

analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is 

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

performed when conditions or 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.

4.0 Hazard Characterization and Dose-Response Assessment

The fluoxastrobin hazard characterization is detailed in a previous risk assessment (DP292422, 

S. Winfield, 01/24/2005). New toxicity data have not been submitted since the last human health

risk assessment (DP404179, N. Tsaur, 11/13/2012). All available toxicity studies are listed in 

Appendix A.

4.1 Summary of Toxicological Effects

Fluoxastrobin is a strobilurin fungicide analog (other registered strobilurin fungicides include 

azoxystrobin, pyraclostrobin, and trifloxystrobin). The strobilurin biochemical mode of action 

consists of interaction with the ubiquinone binding site of the mitochondria in fungal cells, 

thereby preventing the transfer of electrons to the cytochrome. Interrupting the electron transport 

chain prevents oxidative phosphorylation, severely reducing the availability of adenosine 

triphosphate (ATP), the main energy currency of the cell. The energy shortage has several 

biochemical consequences including the following: (1) breakdown of essential membrane 

potentials and concentration gradients; and (2) inhibition of nucleic acid and protein 

biosynthesis; thus fungal spore germination, mycelial growth, and development of infection 

structures are prevented. The available mammalian toxicity data do not demonstrate a similar 

mode of action as that on fungi.

Following repeated administration, in the rate, mouse, rabbit, and dog, fluoxastrobin has mild or 

low toxicity in all tested species except for the dog. Repeated oral administration to dogs elicited

adverse liver toxicity at considerably lower doses than those noted in other species. Based on 

species sensitivity, the effects observed in the dog were used as endpoints for risk assessment. In 

both the 90-day and one-year oral feeding studies in dogs, the liver appeared to be the target 

organ. In dogs, mice, and rats, the kidney was another target organ.

Neither increased susceptibility to pre-/postnatal exposure to fluoxastrobin nor effects on 

reproduction were observed in developmental toxicity studies (rat and rabbit) or in a twogeneration reproduction study (rat). Furthermore, acute neurotoxic effects were not seen in rats 
Page 12 of 36

up to the limit dose of 2000 mg/kg/day. In a subchronic neurotoxicity study in rats, 

fluoxastrobin did not show any acute effects nor any neurotoxic effects compared to the control. 

Repeated dose studies of fluoxastrobin in rats and mice did not show structural immunotoxic 

effects in rats. Functional immunotoxicity was not observed in an immunotoxicity study of 

fluoxastrobin in rats. Results of genotoxicity testing were negative and there were no treatmentrelated increases in tumor incidence in adequately performed carcinogenicity studies in rats and 

mice. Therefore, fluoxastrobin is classified as “not likely to be carcinogenic to humans.”

Fluoxastrobin was extensively metabolized as evidenced by the metabolic profiles in urine, 

feces, and bile along with the relative absence of the parent compound (except in the feces of rats 

given the high dose). The urinary metabolites were primarily the result of cleavage between the 

second and third rings of the parent compound. Biliary metabolites were primarily products 

resulting from cleavage of rings 2, 3 and 4, and subsequent hydroxylation, methoxylation, and 

conjugation with glucuronic acid. The major metabolites, HEC5725-E-des-chlorophenyl and 

HEC5725-des-chlorophenyl-dioxazine-OH, were found in all excretion matrices. 

Absorption, distribution, and metabolism were fully characterized in several rat metabolism 

studies using each of the three 14C-radiolabeled rings in fluoxastrobin. Following a single oral 

low or high dose, absorption was almost complete at a low dose with peak plasma concentrations 

being attained within 0.5 to 8 hours depending on the dose and label position. Fecal excretion 

was the major route of elimination (75-91% within 48 hours) while urinary excretion was a 

secondary route (11-20%). Elimination of the radioactivity via expired air was inconsequential 

(<0.1%), thereby confirming stability of the label. Bile duct cannulation experiments at a low 

dose revealed that nearly 100% of the fecal radioactivity was contributed by the bile in the form 

of hydroxylated, methylated, and conjugated products. In high-dose groups, much of the fecal 

radioactivity (43-54% of administered dose) was attributed to parent compound (which suggests

saturated absorption). Tissue/carcass burdens accounted for about 1% of the administered 

radioactivity at 48 hours post dose. Most of this radioactivity was associated with the liver and 

gastrointestinal tract. Following an 8-hour dermal application in a male monkey, absorption was 

negligible, and the normalized absorption value was 2.31%. This is consistent with the 21-day 

dermal toxicity study where no effects were seen up to the limit dose of 1,000 mg/kg/day.

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

The FQPA safety factor is reduced to 1X; consideration of the toxicology database leads to no 

additional concerns for infants and children.

4.2.1 Completeness of the Toxicology Database

The toxicological database for fluoxastrobin is complete. The submitted toxicology studies are 

of good quality and provide sufficient information to determine whether fluoxastrobin poses a 

human health hazard. A subchronic inhalation toxicity study is not required for fluoxastrobin at 

this time (TXR0056388, K. Rury, 08/01/2012).

4.2.2 Evidence of Neurotoxicity
Page 13 of 36

The available toxicity database for fluoxastrobin, which includes the neurotoxicity screening 

battery, does not show any evidence of neurotoxicity.

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

The available studies used to evaluate pre- and post-natal exposure susceptibility do not indicate

increased sensitivity or susceptibility in the developing or young animals to fluoxastrobin. These 

studies include the following: (1) a developmental toxicity study in rats, (2) a developmental 

toxicity study in rabbits, and (3) a two-generation reproduction study in rats.

4.2.4 Residual Uncertainty in the Exposure Database

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

potential exposures. The chronic dietary food exposure assessment was conservatively based on 

100% crop treated (CT) assumptions, tolerance-level residues, average field trial residues, 

default processing factors, and conservative modeled ground and surface drinking water 

modeling estimates. New 2012 Residential SOPs were used to assess post-application exposure 

to children including incidental oral exposure. The residential post-application assessment 

assumes maximum application rates and conservative day zero hand-to-mouth activities. All of 

the exposure estimates are based on conservative high-end assumptions and are not likely to 

result in underestimated risk.

4.3 Toxicity Endpoints and Points of Departure Selections

There are no changes to the previous dose-response assessment. A quantitative hazard estimate 

was not selected for the short-term dermal exposure scenario based on the lack of systemic and 

dermal toxicity in the 28-day dermal toxicity study in the rat at the limit dose of 1000 mg/kg/day, 

and the absence of developmental or reproduction toxicity findings. The adverse liver findings 

(cholestasis) in the 90-day subchronic dog study were used as the endpoints for the following 

exposure scenarios: intermediate-term dermal, short- and intermediate-term inhalation, and 

short- and intermediate-term incidental oral. Although long-term dermal and inhalation 

exposures are not expected based on the proposed uses, the adverse liver findings (cholestasis) in 

the chronic toxicity dog study were used for setting the quantitative hazard estimate for chronic 

dietary exposure. Although acute exposure is expected, an acute quantitative hazard estimate 

was not established because an adverse effect attributable to a single exposure was not identified 

from the available database. A subchronic inhalation toxicity study is not required for 

fluoxastrobin at this time (TXR0056388, K. Rury, 08/01/2012). Fluoxastrobin shows low acute 

toxicity via the oral, dermal, and inhalation routes of exposure. It is a moderate eye irritant, and 

is neither a dermal irritant, nor a skin sensitizer.
Page 14 of 36

Table 4.3. Summary of Toxicological Doses and Endpoints for Fluoxastrobin for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessmentsa

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children) and 

Females 13-49 

years of age

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

established.

Chronic 

Dietary (All 

Populations)

NOAEL = 

1.5 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Chronic RfD 

= 0.015

mg/kg/day

cPAD = 

0.015 

mg/kg/day

Chronic toxicity dog

LOAEL = M/F 8.1/7.7 mg/kg/day based on 

body weight reductions and 

hepatocytomegaly and cytoplasmic changes 

associated with increased serum liver alkaline 

phosphatase indicative of cholestasis. 

Incidental Oral 

Short-Term 

(1-30 days) 

and 

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 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

dermal 

absorption 

factor = 

2.3%

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Occupational 

LOC for 

MOE = 100

90-day subchronic dog

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

on dose-related reductions in net body weight 

gain and food efficiency in addition to 

toxicity findings in the liver (cholestasis) in 

both sexes, and kidneys (increased relative 

weights in females and degeneration of the 

proximal tubular epithelium in males).

Inhalationb

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

Occupational 

LOC for 

MOE = 100

90-day subchronic dog

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

on dose-related reductions in net body weight 

gain and food efficiency in addition to 

toxicity findings in the liver (cholestasis) in 

both sexes, and kidneys (increased relative 

weights in females and degeneration of the 

proximal tubular epithelium in males).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans.”

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

and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant 

human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 
Page 15 of 36

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.

b Toxicity by the oral route is assumed to be equivalent to the oral route. A subchronic inhalation toxicity study is 

not required for fluoxastrobin at this time (TXR0056388, K. Rury, 08/01/2012).

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized 

in Table 5.1.

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

Expression

Matrix Residues included in

Risk Assessment

Residues included in

Tolerance Expression

Plants Primary Crop Fluoxastrobin and its

Z-isomer

Fluoxastrobin and its

Rotational Crop Z-isomer

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

Adequate field trial data are available to support the proposed uses on melon subgroup 9A and 

sorghum. In the cantaloupe residue decline studies, combined residues of fluoxastrobin and its 

Z-isomer generally declined with increasing sampling interval. In the sorghum residue decline 

studies, combined residues of fluoxastrobin and its Z-isomer generally declined in forage and 

grain samples with increasing sampling interval, but residue decline was not consistent in stover 

samples.

An adequate processing study was submitted for sorghum. The data indicate that combined 

residues of fluoxastrobin and its Z-isomer concentrate in AGF (37x). However, the established 

tolerance for grain, aspirated grain fractions (60 ppm) is sufficient.

The available storage stability data for fluoxastrobin on the representative crops are adequate to 

support the storage durations and conditions of samples of melons and sorghum grain, forage, 

stover, and AGFs from the submitted crop field trials.

The available ruminant feeding study is acceptable to support the proposed use of fluoxastrobin 

on sorghum. The addition of sorghum grain and forage (beef and dairy only) to the dietary 

burden calculations for cattle increased the dietary burden for beef and dairy slightly and was 

lower for poultry and swine. The existing tolerances for livestock commodities are adequate.
Page 16 of 36

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

the nature of the residue in rotated crop commodities. The confined rotational crop studies 

indicate the potential for quantifiable residues of fluoxastrobin in rotated crop commodities. 

HED previously concluded that the residues of concern for rotational crops for risk assessment 

and tolerance setting purposes are fluoxastrobin and its Z-isomer. 

5.3 Water Residue Profile

Based on laboratory studies, fluoxastrobin persists in soils for several months to several years

and is 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.

In addition to evaluating the EDWCs from the proposed uses, EDWCs were reevaluated for all 

existing uses with PRZM-GW,

1 which models continued use of fluoxastrobin over many years

(DP403757, R. Bohaty, 02/05/2013). The most conservative EDWC (137 μg/L) was based on an 

existing turf use modeled with a 100 year simulation of 100 years of repeated applications, using

the highest single maximum application rate and the highest yearly application rate, and was 

used in the chronic dietary assessment.

Table 5.3. Summary of Estimated Drinking Water Concentrations for Fluoxastrobin

Tier II Surface Water Model (μg/L)

Scenario Melons Sorghum Turf

Acute (1-in-10 year peak) 48.7 7.0 24.8

Chronic (non-cancer, 1-in-10 year annual average) 7.9 4.6 18.6

Tier I Ground Water Model (μg/L)

Scenario Melons Sorghum Turf

Acute (peak concentration) 47.1a15.3a146a

Chronic (post breakthrough average concentration) 44.2a14.3a137a

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

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A partially refined chronic dietary exposure assessment was performed for fluoxastrobin. The 

assumptions include tolerance level residues, average field trial residues, and 100% crop treated

(CT). Average field trial residues were used for melon subgroup 9A, berry low growing 

 

1

PRZM-GW was recently (12/2012) approved for standard use in drinking water assessments as a Tier I and Tier II 

exposure tool. 
Page 17 of 36

subgroup 13-07G, leaf petioles subgroup 4B, rice, squash/cucumber subgroup 9B, and vegetable 

fruiting group 8. Based on processing studies, the processing factors for tomato puree, potato

chips, dried potato (granules/flakes), and potato flour were reduced to 1. Separate tolerances 

were set for peanut oil and tomato paste; therefore, the processing factors for these commodities 

were set at 1 (DP289106, W. Wassell, 01/25/2005). Default processing factors from the Dietary 

Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID) 

Version 7.81 were assumed except for where tolerances were established for processed 

commodities or when processing studies showed no concentration. Field trial data were 

translated from the representative commodities to the non-representative commodities according 

to HED SOP 2000.1:”Guidance for Translation of Field Trial Data from Representative 

Commodities in the Crop Group Regulation to other Commodities in Each Crop 

Group/Subgroup.” The estimated ground water post breakthrough average concentration of 137 

μg/L was incorporated directly into the dietary assessment.

5.4.2 Acute Dietary Risk Assessment

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

established, and an acute dietary exposure assessment was not conducted.

5.4.3 Chronic Dietary Risk Assessment

A slightly refined chronic dietary (food and drinking water) exposure and risk assessment was

conducted using the DEEM-FCID Version 3.16. This model uses 2003-2008 food consumption 

data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). 

The results of the chronic dietary analysis for food and drinking water are below the Agency’s 

LOC for the general U.S population and all population subgroups. The dietary (food and 

drinking water) exposure is estimated at 30% of the chronic Population Adjusted Dose (cPAD) 

for the general U.S. population and 66%, of the cPAD for all infants <1 year old, the population 

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

chronic dietary exposure analyses are reported in Table 5.2.5.

5.4.4 Cancer Dietary Risk Assessment

Fluoxastrobin is classified as “not likely to be carcinogenic to humans;” therefore, cancer risk 

was no assessed. 

5.4.5 Summary Table

Table 5.2.5. Summary of Dietary Exposure and Risk for Fluoxastrobin (cPAD = 0.015 mg/kg/day)a

Population Subgroup

Chronic Dietary Exposure Estimates

(Food and Drinking Water)

mg/kg/day % cPAD

General U.S. Population 0.004529 30

All Infants (< 1 year old) 0.009886 66
Page 18 of 36

Table 5.2.5. Summary of Dietary Exposure and Risk for Fluoxastrobin (cPAD = 0.015 mg/kg/day)a

Population Subgroup

Chronic Dietary Exposure Estimates

(Food and Drinking Water)

mg/kg/day % cPAD

Children 1-2 years old 0.009516 63

Children 3-5 years old 0.007496 50

Children 6-12 years old 0.005052 34

Youth 13-19 years old 0.003514 23

Adults 20-49 years old 0.004226 28

Adults 50+ years old 0.003999 27

Females 13-49 years old 0.004118 28

a The population subgroup with the greatest exposure is in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time. However, the products currently registered 

for use on residential turf include granular and liquid formulations. Residential handler and postapplication assessments were conducted to reflect updates to HED’s 2012 Residential SOPs 

along with policy changes for body weight assumptions and the results impact the human health 

aggregate risk assessment for fluoxastrobin (DP405369, K. Rury, 02/25/2013).

6.1 Residential Handler Exposure

Residential handler exposure is expected to be short-term. Intermediate-term exposures are not 

likely because of the intermittent nature of applications by homeowners. Since there are no 

toxicity findings for the short-term dermal route of exposure up to the limit dose, the residential 

handler assessment only includes the inhalation route of exposure. A summary of the most 

protective short-term risk estimate (inhalation only) for residential handlers is based on a

granular application to turf and is detailed in Table 6.1.

Table 6.1. Residential Handler Non-Cancer Exposure and Risk Estimates for Fluoxastrobin

Exposure Scenario Level of 

Concern

Inhalation 

Unit 

Exposure 

Maximum 

Application 

Ratea

Area Treated 

or Amount 

Handled 

Dailyb

Inhalation

Dosec

MOEd

mg/lb ai mg/kg/day

Mixer/Loader/Applicator for Granular Application to Turf and Ornamentals

Hand Dispersal 100 0.38 0.0000719

lb ai/sq ft

1200

sq ft 0.00041 7,300

a Based on registered product label for Disarm G Fungicide (EPA Reg. No. 66330-380).

b Based on HED’s SOPs: Lawns/Turf (January 2012). 0.023 A = 1000 ft2.

c Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal or square feet) × Area 

Treated or Amount Handled (A or gallons or square feet/day) ÷ BW (80 kg).

d Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). ST Inhalation NOAEL = 3 

mg/kg/day. Level of concern = 100.
Page 19 of 36

6.2 Post-Application Exposure

Adults and children performing physical post-application activities on turf (e.g. golfing, mowing)

may receive dermal exposure to fluoxastrobin residues. Young children (1 to <2 years old) may 

also receive incidental oral post-application exposure to fluoxastrobin from treated turf.

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

dermal hazard was not identified for fluoxastrobin. Therefore, a quantitative post-application 

dermal risk assessment was not conducted. Regardless, short-term incidental oral exposure and 

risk estimates have been assessed for the physical activities of children 1 to <2 years old on turf, 

following liquid and granular application of fluoxastrobin at maximum registered application 

rates. Intermediate-term incidental oral exposure is not expected for post-application activities to 

turf because residues are unlikely to persist for longer than one month due to turf maintenance 

(e.g. mowing) and climate (e.g. rain).

Table 6.2 presents the most protective post-application incidental oral MOE value calculated for 

liquid applications of fluoxastrobin to turf. The post-application risk estimates is not of concern 

to HED (MOE = 390).

Table 6.2. Short-Term Residential Post-Application Exposure and Risk Estimates for Fluoxastrobin on 

Turfa

Lifestage Post-Application Exposure Scenariob Dose

MOEc

mg/kg/day

Child 1 to < 2 years old Hand to Mouth 0.0077 390

a Based on registered product label for Fluoxastrobin 480 SC Fungicide (EPA Reg. No. 66330-64); SC Liquid Formulation; 3.69 

lb ai/gallon; max single application rate = 0.46 lb ai/A.

b Hand-to-Mouth Dose = hand residue loading (mg/cm2) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm2) 

× exposure time (1.5 hrs/day) × # of replenishment intervals/hr (4 int/hr) × (1-((1-saliva extraction factor (0.5))^(Number of 

hand-to-mouth events per hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg).

c MOE = NOAEL ÷ Daily Dose (mg/kg/day). Incidental Oral NOAEL= 3.0 mg/kg/day. Level of concern = 100.

6.3 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for fluoxastrobin at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (4.2 x 10-12 mm Hg at 20 °C), and 

the low proposed use rate (0.18 lb ai/A). However, volatilization of pesticides may be a source 

of post-application inhalation exposure to individuals nearby pesticide applications. The Agency 

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

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

and received the SAP’s final report on March 2, 20102. The Agency is in the process of 

evaluating the SAP report and may, as appropriate, develop policies and procedures to identify 

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

the Agency's risk assessments. If new policies or procedures are developed, the Agency may 

revisit the need for a quantitative post-application inhalation exposure assessment for 

fluoxastrobin.

 

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Page 20 of 36

6.4 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

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

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and 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 information3. 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 risk estimates associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider 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-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 inhalation (primary) routes. For 

children, these pathways lead to exposure via the oral (background) and incidental oral (primary) 

routes. The most protective residential exposure risk estimates are included in the aggregate 

exposure assessment. The recommended residential exposure for use in the adult aggregate risk 

 

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

assessment reflects dermal and inhalation exposure from hand dispersal of granulars to 

ornamentals (MOE = 7,300). The recommended residential exposure for use in the children 1<2 

years old aggregate assessment reflects hand-to-mouth exposures from post-application exposure 

to liquid applications to turf (MOE = 390). Aggregate MOEs are greater than 100, which 

indicates that exposure and risk do not exceed HED’s level of concern. The adult and children 

short-term aggregate dietary and residential MOEs are 610 and 170, respectively.

Table 7.2. Short-Term Aggregate Risk Calculations

Population

NOAEL 

LOC1

Max 

Allowable 

Exposure2

Average 

Food and 

Water 

Exposure 

Residential 

Exposure3

Total 

Exposure4

Aggregate 

MOE (food, 

water, and 

residential)5

mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day

Adult 3.0 100 0.030 0.004529 0.00041 0.004939 610

Children

1-2 years old 3.0 100 0.030 0.009516 0.0077 0.017216 170

1 LOC = 100 (based on inter- and intra- species uncertainty factors totaling 100X).

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

3 Residential Exposure = Inhalation Only for adults, Incidental Oral Only for children (See Table 6.3).

4 Total Exposure = Average Food and Water Exposure + Residential Exposure.

5 Aggregate MOE = NOAEL ÷ Total Exposure. NOAEL = 3 mg/kg/day. LOC = 100.

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposure is not expected for the adult or children residential exposure 

pathway. Therefore, the intermediate-term aggregate risk would be equivalent to the chronic 

dietary exposure estimate. Refer to Section 5.2.5.

7.4 Chronic Aggregate Risk

Chronic exposure is not expected for the adult residential (dermal and inhalation) exposure 

pathway. Therefore, the chronic aggregate risk would be equivalent to the chronic dietary 

exposure estimate. Refer to Section 5.2.5.

7.5 Cancer Aggregate Risk

Fluoxastrobin is classified as “not likely to be carcinogenic to humans;” therefore, an aggregate 

cancer assessment was not conducted.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to fluoxastrobin and any other substances and fluoxastrobin does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, 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 
Page 22 of 36

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

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

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

9.0 Occupational Exposure/Risk Characterization

Occupational handler and post-application exposure may occur by the dermal and inhalation 

routes of exposure only. For short-term exposure, only inhalation exposures were assessed since 

there is no dermal hazard for the short-term duration. For intermediate-term exposures, 

combined (dermal + inhalation) exposures were assessed. The results of the occupational 

handler exposure and risk assessment indicate that short- and intermediate-term risk estimates

are not of concern (K. Rury, DP405369, 02/25/2013). Appendix E, Tables E.1 and E.2 

summarize all assessed occupational exposure and risk estimates.

9.1 Short- and Intermediate-Term Handler Risk

Based on the anticipated use patterns and current labeling, and types of equipment and 

techniques that can potentially be used, occupational handler exposure is expected from the 

proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is 

based on the following scenarios: 

Mixing/Loading liquids for aerial, chemigation, and groundboom application;

Applying liquids with aerial and groundboom equipment;

Flagging for aerial application; and

Mixing/Loading/Applying with a mechanically pressurized handgun.

HED classifies exposures from 1 to 30 days as short-term and exposures from 30 days to six 

months as intermediate-term. Exposure duration is determined by many things, including the 

exposed population, the use site, the pest pressure triggering the use of the pesticide, and the 

cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe 

that occupational handlers will not apply the same chemical every day for more than a onemonth time frame; however, there may be a large agribusiness and/or commercial applicators 

who may apply a product over a period of weeks (e.g., completing multiple applications for 

multiple clients within a region). The area treated or amount handled is based on HED 

ExpoSAC Policy No. 9.1 (refer to Appendix E for these assumptions for each scenario).

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handlers Exposure Task 

Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, the 

Agricultural Re-Entry Task Force (ARTF), or other registrant-submitted occupational exposure 

studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data 

protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The 

standard values recommended for use in predicting handler exposure that are used in this 

assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit 
Page 23 of 36

Exposure Surrogate Reference Table4”, which, along with additional information on HED policy 

on use of surrogate data, including descriptions of the various sources, can be found at the 

Agency website5.

There are no risk estimates of concern at the baseline level of personal protective equipment 

(PPE); the proposed label requires chemical-resistant gloves as PPE. All short-term handler risk 

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

handler risk estimates (dermal + inhalation) resulted in MOEs ranging from 320 to 21,000. Note 

that only engineering control (enclosed cockpit) data are available to assess risks to handlers 

operating aircrafts.

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for 

human flaggers when appropriate, agricultural aviation has changed dramatically over the past 

two decades. According to the 2012 National Agricultural Aviation Association (NAAA) survey 

of their membership, the use of GPS for swath guidance in agricultural aviation has grown 

steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial 

pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the 

most recent (2012) NAAA survey. The Agency will continue to monitor all available 

information sources to best assess and characterize the exposure potential for human flaggers in 

agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.

9.2 Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Dermal Post-Application Risk

There is potential for short- and intermediate-term occupational exposure during post-application 

activities. There is no short-term dermal POD selected for fluoxastrobin. There are no 

 

4 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

5 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Page 24 of 36

intermediate-term dermal post-application risk estimates of concern on day 0 (12 hours after 

application); all scenarios resulted in MOEs greater than the LOC (100) and ranged from 1,400 

to 55,000 on day 0.

9.2.2 Restricted Entry Interval

Fluoxastrobin is classified as Toxicity Category III via the dermal route. It is a moderate irritant 

to eyes, it is not irritating to the skin, and it is not a skin sensitizer. Typically, the REI specified 

on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 

156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye 

irritation, and primary skin irrigation are assigned a 12-hour REI. Based on a quantitative postapplication assessment, the 12-hour restricted entry interval (REI) on the proposed label is 

acceptable for melons (subgroup 9A) and sorghum.

9.2.3 Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for fluoxastrobin at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (4.2 x 10-12 mm Hg at 20 °C), and 

the low proposed use rate (0.18 lb ai/A). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

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

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

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

received the SAP’s final report on March 2, 20106. The Agency is in the process of evaluating 

the SAP report as well as available post-application inhalation exposure data generated by the 

ARTF and may, as appropriate, develop policies and procedures to identify the need for, and 

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.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

10.0 References

Bohaty, Rochelle. 05/08/2012. DP Barcode 401613. “Revised Drinking Water Assessment for 

Fluoxastrobin Use on Rice.”

 

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

Negussie, Meheret. 03/21/2013. DP Barcode 403571, 409039. “Fluoxastrobin: Petition for the 

Establishment of Permanent Tolerances for Uses on Melon (Subgroup 9A), Sorghum, 

and Wheat. Amendments to Established Tolerances on Milk and Milk Fat. Summary of 

Analytical Chemistry and Residue Data.”

Negussie, Meheret. 05/23/2012. DP Barcode 397825. “Fluoxastrobin. Supplemental Residue 

Data for Sweet Corn and Wheat. Response to Condition of Registration Requirements 

Specified Under DP#s 364445 and 367049. Summary of Analytical Chemistry and Residue 

Data.”

Negussie, Meheret. 06/19/2012. DP Barcode 402506. “Fluoxastrobin: Chronic Dietary (Food 

and Drinking Water) Exposure Assessments for the Section 3 Registration Action Use on 

Wheat Due to Submission of Supplemental data.”

Tsaur, Nancy. 06/27/2012. DP Barcode 393842. “Fluoxastrobin. Human Health Risk 

Assessment for Proposed New Use on Rice Grain with Updated Residential Risk Estimates 

of All Existing Residential Uses.”

Tsaur, Nancy. 10/25/2012. DP Barcode 406106. “Fluoxastrobin. Residential Exposure 

Assessment for a Proposed New Use on Turf and Ornamentals.”
Page 26 of 36

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The toxicology study requirements (40 CFR § 158.500) for food use for fluoxastrobin are in 

Table A.1. Use of the new guideline 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 21/28-Day Dermal ...........................................................

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

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

yes

yes

yes

no

noa

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent).....................................

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

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

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ................................................

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

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

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

870.4300 Chronic/Oncogenicity (rat)..............................................

- 

yes

-

yes

yes

-

yes

-

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.......................

870.5300 Mutagenicity—Gene Mutation - mammalian..................

870.5375 Mutagenicity—Structural Chromosomal Aberrations.....

870.5385 Mutagenicity—Other Genotoxic Effects.........................

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

no

no

yes

yes

no

-

-

yes

yes

-

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

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

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

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

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

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

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

a A subchronic inhalation toxicity study is not required for fluoxastrobin at this time (TXR0056388, K. Rury, 

08/01/2012). The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and 

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

extrapolation of toxicity data.
Page 27 of 36

A.2 Toxicity Profiles

Table A.2.1. Fluoxastrobin Acute Toxicity Profile

Guideline No. Study Type MRID Results Toxicity 

Category

870.1100 Acute oral - rat 45865612 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/nonguideline

0, 450, 1800 or 7000 ppm 

M: 0, 81.1, 313.4 or 

1303.7 mg/kg/day

F: 0, 135.1, 539.2 or 

2256.9 mg/kg/day

NOAEL = 7000 ppm (M/F: 1304/2257 

mg/kg/day) (highest dose tested); this dose was 

about the limit dose for a 90-day oral toxicity 

study (1000 mg/kg/day).

870.3150 90-Day oral 

toxicity (dog)

45865629 (2001); 

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).

870.3200 21/28-Day dermal 

toxicity (rat)

45865630 (2000)

acceptable/guideline

0, 100, 300 or 1000 

mg/kg/day (6 hours/day, 5 

days/week for the first 

three weeks; 7 days/week 

for the fourth week)

NOAEL = 1000 mg/kg/day (the limit dose, for 

both systemic and dermal)

LOAEL not identified.

870.3465 90-Day inhalation

toxicity (rat) Waived (TXR 0056388).
Page 28 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile

Guideline 

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

870.3700a Prenatal 

developmental in 

(rat)

45865631 (1997)

acceptable/guideline

0, 100, 300 or 1000 

mg/kg/day

Maternal NOAEL 1000 mg/kg/day (limit 

dose)

LOAEL not identified.

Developmental NOAEL 1000 mg/kg/day

LOAEL not identified.

870.3700b Prenatal 

developmental in 

(rabbit)

45865632 (1999)

acceptable/guideline

22 naturally mated female 

Himalayan rabbits/group 

by gavage: 0, 25, 100, 400 

mg/kg/day

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/day

F: 0, 7.8, 84.7 or 825.4 

mg/kg/day

Parental Systemic NOAEL = M/F 70.0/84.7 

mg/kg/day

LOAEL = M/F 665.0/825.4 g/kg/day based on 

decreased premating body weight gain of the 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/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.

870.4200b Carcinogenicity

(mouse)

45865702 (2001)

acceptable/guideline

0, 100, 700 or 4200 ppm

M: 0, 18.5, 135.4 or 775.6 

mg/kg/day

F: 0, 29.5, 204.0 or 1265.1 

mg/kg/day

NOAEL = M/F: 775.6/1265.1 mg/kg/day

LOAEL not identified.

No evidence of carcinogenicity.
Page 29 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile

Guideline 

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

870.4300 Carcinogenicity

(rat)

45865703 (2001)

acceptable/guideline

M: 0, 40, 100, 1000 or 

5000 ppm (0, 2.1, 5.2, 

53.0 and 271.9 

mg/kg/day)

F: 0, 100, 500, 2500 or 

12500 ppm (0, 6.9, 35.2, 

181.3 and 1083.2 

mg/kg/day)

NOAEL = M/F: 53.0/181.3 mg/kg/day

LOAEL = M/F: 271.9/1083.2 mg/kg/day based 

on decreased body weight, body weight gain, 

and food efficiency in both sexes, decreased 

spleen weight in males, and 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 μg/plate; following 

preincubation: 10, 32, 

100, 316, 1000 and 3162 

μg/plate

negative (considered non-mutagenic in 

Salmonella typhimurium cultures treated up to 

cytotoxic/precipitating levels)

Gene 

Mutation

870.5100

In vitro bacterial 

reverse gene 

mutation

45865705 (1998) 

acceptable/guideline

plate incorporation and 

following preincubation: 

16, 50, 158, 500, 1581 

and 5000 μg/plate

Test substance: HEC 

5725N (E:Z = 90:10%)

negative (considered non-mutagenic in this 

Salmonella 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 μg/plate; following 

preincubation: 100, 200, 

400, 800, 1600 and 3200 

μg/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

45865707 (2001)

acceptable/guideline

plate incorporation: 16, 

50, 158, 500, 1581 and 

5000 μg/plate; following 

preincubation: 5, 16, 50, 

158, 500 and 1581 

μg/plate

Test substance: HEC 

5725-phenoxy-hydroxypyrimidine

negative (considered non-mutagenic in this 

Salmonella typhimurium/mammalian activation 

gene mutation assay)
Page 30 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile

Guideline 

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

Gene 

Mutation

870.5100

In vitro bacterial 

reverse gene 

mutation

45865708 (2001)

unacceptable/guideline

16 to 5000 μg/plate (6 

concentrations)

Test substance: HEC 

5725-dihydroxypyrimidine

negative (considered non-mutagenic in this 

Salmonella typhimurium/mammalian activation 

gene mutation assay)

870.5300

In vitro

mammalian cell 

gene mutation test

45835709 (1997)

acceptable/guideline

Negative.

Test concentrations: 1 to 200 g/ml.

870.5375

In vitro

mammalian 

chromosome 

aberration test

45835710 (1996)

acceptable/guideline

Negative.

Test concentrations: 0, 20,40,80,160, and 320 

g/ml.

870.5395

In vivo 

mouse 

micronucleus

45865711 (1999)

acceptable/guideline

Negative.

Test concentrations: 75,150, and 300 

mg/kg/day.

870.6200a

Acute 

neurotoxicity 

screening battery 

(rat)

45865712 (2001)

acceptable/guideline

12 rats/sex: 0, 200, 500 or 

2000 mg/kg bw

NOAEL (neurotoxic) 2000 mg/kg (limit 

dose)

LOAEL not identified.

870.6200b

Subchronic 

neurotoxicity 

screening battery 

(rat)

45865713 (2002)

acceptable/guideline

12 rats/sex: 0, 200, 1000, 

7500 ppm

M: 0, 12.7, 59.5 or 473.9 

mg/kg/day

F: 0, 15.1, 71.7 or 582.4 

mg/kg/day

NOAEL (systemic and neurotoxic) = M/F: 

473.9/582.4 mg/kg/day

LOAEL not identified.
Page 31 of 36

Table A.2.2. Fluoxastrobin Subchronic, Chronic and Other Toxicity Profile

Guideline 

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

870.7485

Metabolism & 

pharmacokinetics 

(rat)

45865714,-15, -20 (2002)

45865716, -17, 18, -19 

(2001)

acceptable/guideline

1, 3, or 5 mg/kg/day

Orally administered 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 

(rat)

48692105 (2011)

acceptable/guideline

0, 125, 1000, or 8000 ppm 

(equivalent to 0, 10, 81, or 

637 mg/kg/day)

The systemic toxicity NOAEL is 8000 ppm 

(637 mg/kg/day) and the LOAEL is >8000 ppm 

(637 mg/kg/day).

The immunotoxicity NOAEL is 8000 ppm (637 

mg/kg/day) based on anti-SRBC IgM ELISA 

results and the LOAEL is >8000 ppm (637 

mg/kg/day).

Appendix B. Physical/Chemical Properties

Table B. Physico-Chemical Properties

Parameter Value Reference

Molecular Weight 458.8 g/mol

Melting range 103-105 C MRID 45865525

pH 6.3 (1% in CIPAC-D water) MRID 45865520

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

Table B. Physico-Chemical Properties

Parameter Value Reference

0.0019 g/L;

0.0024 g/L at pH 4

0.0023 g/L at pH 7

0.00227 g/L at pH 9

Solvent solubility (20°C to 25°C)

at 20 C:

n-heptane 0.05 g/L

xylene 38 g/L

dichloromethane >250 g/L

2-propanol 6.7 g/L

1-octanol 1.1 g/L

polyethylenglycol 400 119 g/L

acetone >250 g/L

ethyl acetate >250 g/L

acetonitrile >250 g/L

dimethylsulfoxide >250 g/L

MRIDs 45865520, 45865525

Vapor pressure (25°C)

5.63×10-10 Pa (20 C)

4.2×10-12 mm Hg (20 C)

8.72×10-10 Pa (25 C)

MRID 45865525

Dissociation constant, pKa no dissociation constant at pH 

4-9

MRID 45865303

Octanol/water partition coefficient, log 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
Page 33 of 36

Appendix C. Review of Human Research

Studies reviewed for ethical conduct:

MRID 44972201 – ORETF data 

PHED Surrogate Exposure Guide 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which comprise PHED, 

ORETF, and ARTF, have been determined to require a review of their ethical conduct and have 

received that review. In this assessment, ORETF data were used to assess loading/applying with 

a push type spreader (data from MRID 44972201) and PHED data were used to assess 

loading/applying with a belly grinder.

 

Studies reviewed by the Human Studies Review Board:

None.

Appendix D. International Residue Limit Status

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

Residue Definition

US Canada Mexicob Codex

40 CFR 180.609:

Plant: residues of 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, calculated as the 

stoichiometric equivalent of fluoxastrobin.

Livestock: residues of 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-dihydro-1,4,2-dioxazin-3-

yl)methanone O-methyloxime, and its phenoxyhydroxypyrimidine metabolite, 6-(2-chlorophenoxy)-5-

fluoro-4-pyrimidinol, calculated as the stoichiometric 

equivalent of fluoxastrobin.

Plant: (1E)-[2-[[6-(2-

chlorophenoxy)-5-fluoro-4-

pyrimidinyl]oxy]phenyl](5,

6-dihydro-1,4,2-dioxazin-3-

yl)methanone 

O-methyloxime

Livestock: (1E)-[2-[[6-(2-

chlorophenoxy)-5-fluoro-4-

pyrimidinyl]oxy]phenyl](5,

6-dihydro-1,4,2-dioxazin-3-

yl)methanone 

O-methyloxime,

including the metabolite 6-

(2-chlorophenoxy)-5-fluoro4-pyrimidinol

None

Commoditya

Tolerance/Maximum Residue Limit

US Canada Mexicob Codex

ppm mg/kg

Melon subgroup 9A 1.5

Sorghum, grain 1.5 0.1 sorghum

Sorghum, forage 5.0

Sorghum, stover 5.0

Completed: M. Negussie; 02/21/2013

a Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those 

proposed by the applicant.

b Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Page 34 of 36

Appendix E. Occupational Exposure/Risk Summary Tables

Table E.1. Occupational Handler Short-Term Non-Cancer Exposure and Risk Estimates for Fluoxastrobin

Exposure Scenario Crop or Target

Baseline 

Inhalation Unit 

Exposurea

Maximum

Application 

Rateb

Area 

Treated or 

Amount 

Handled 

Dailyc

Inhalation

Dosed

MOEe

μg/lb ai mg/kg/day

Mixer/Loader at Baseline (No Respirator)

Mixing/Loading for Aerial 

Application

Melon 

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

Sorghum 0.219 0.12 lb ai/A 1200 0.000394 7,600

Mixing/Loading for 

Chemigation Application

Melon 

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

Sorghum 0.219 0.12 lb ai/A 350 0.000115 26,000

Mixing/Loading for 

Groundboom Application

Melon 

(Subgroup 9A) 0.219 0.18 lb ai/A 80 0.0000394 76,000

Sorghum 0.219 0.12 lb ai/A 200 0.0000658 46,000

Applicator at Baseline (No Respirator)

Applying with 

Aerial Equipment

Melon 

(Subgroup 9A) 0.068 0.18 lb ai/A 350 0.0000535 56,000

Sorghum 0.068 0.12 lb ai/A 1200 0.000122 25,000

Applying with 

Groundboom

Melon 

(Subgroup 9A) 0.34 0.18 lb ai/A 80 0.0000613 49,000

Sorghum 0.34 0.12 lb ai/A 200 0.000102 29,000

Flagger at Baseline (No Respirator)

Flagging for 

Aerial Application

Melon 

(Subgroup 9A) 0.35 0.18 lb ai/A 350 0.000276 11,000

Sorghum 0.35 0.12 lb ai/A 350 0.000184 16,000

Mixer/Loader/Applicator at Baseline (No Respirator)

Mixing/Loading/Applying 

for Broadcast Application 

with Mechanically 

Pressurized Handgun

Melon 

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

Mixing/Loading/Applying 

for Drench/Soil/Ground 

Directed Application with 

Mechanically Pressurized 

Handgun

Melon 

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

a Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation: 

Baseline. Aerial Application is in a closed system at baseline level (no PPE). 

b Based on registered or proposed label (Reg. No. 66330-64).

c Exposure Science Advisory Council Policy #9.1.

d Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or 

gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (80 kg).

e Inhalation MOE = Inhalation NOAEL (3.0 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
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Table E.2. Occupational Handler Intermediate-Term Non-Cancer Exposure and Risk Estimates for Fluoxastrobin at Baseline

Exposure Scenario Crop or Target

Dermal 

Unit 

Exposurea

Inhalation 

Unit 

Exposurea

Maximum 

Application 

Rateb

Area 

Treated or 

Amount 

Handled 

Dailyc

Dermal Inhalation Total

Dosed

MOEe DosefMOEg MOEh

μg/lb ai mg/kg/day mg/kg/day

Mixer/Loader at Baseline

Mixing/Loading for Aerial 

Application

Melon 

(Subgroup 9A) 220 0.219 0.18 lb ai/A 350 0.0040 750 0.000173 17,000 720

Sorghum 220 0.219 0.12 lb ai/A 1200 0.00911 330 0.000394 7,600 320

Mixing/Loading for 

Chemigation Application

Melon 

(Subgroup 9A) 220 0.219 0.18 lb ai/A 350 0.0040 750 0.000173 17,000 720

Sorghum 220 0.219 0.12 lb ai/A 350 0.00266 1,100 0.000115 26,000 1,100

Mixing/Loading for 

Groundboom Application

Melon 

(Subgroup 9A) 220 0.219 0.18 lb ai/A 80 0.000911 3,300 0.0000394 76,000 3,200

Sorghum 220 0.219 0.12 lb ai/A 200 0.00152 2,000 0.0000658 46,000 1,900

Applicator at Baseline

Applying with 

Aerial Equipment

Melon 

(Subgroup 9A) 5 0.068 0.18 lb ai/A 350 0.0000905 33,000 0.0000535 56,000 21,000

Sorghum 5 0.068 0.12 lb ai/A 1200 0.000207 14,000 0.000122 25,000 9,000

Applying with 

Groundboom

Melon 

(Subgroup 9A) 78.6 0.34 0.18 lb ai/A 80 0.000325 9,200 0.0000613 49,000 7,700

Sorghum 78.6 0.34 0.12 lb ai/A 200 0.00054 5,500 0.000102 29,000 4,600

Flagger at Baseline

Flagging for 

Aerial Application

Melon 

(Subgroup 9A) 11 0.35 0.18 lb ai/A 350 0.000199 15,000 0.000276 11,000 6,300

Sorghum 11 0.35 0.12 lb ai/A 350 0.000133 23,000 0.000184 16,000 9,400

Mixer/Loader/Applicator at Baseline

Mixing/Loading/Applying for 

Broadcast Application with 

Mechanically Pressurized 

Handgun

Melon 

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

Mixing/Loading/Applying for 

Drench/Soil/Ground Directed 

Application with Mechanically 

Pressurized Handgun

Melon 

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

a Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation: Baseline. Aerial Application is in a closed system 

at baseline level of PPE. 

b Based on registered or proposed label (Reg. No. 66330-64).

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

DAF (%) ÷ BW (80 kg).

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

f Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or 

gal/day) ÷ BW (80 kg).

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

h Total MOE = NOAEL (3.0 mg/kg/day) ÷ Dermal Dose + Inhalation Dose.

Table E.3. Occupational Post-Application Non-Cancer Intermediate-Term Dermal Exposure and Risk Estimates for Fluoxastrobin

Crop Activities

Transfer 

Coefficient DFRa

Dermal Doseb

MOEc

cm

2

/hr mg/kg/day

Cantaloupe, 

Watermelon

Hand-Set Irrigation 1900 0.505 0.00221 1,400

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

Transplanting 230 0.505 0.000267 11,000

Scouting, Hand Weeding, Hand Pruning, Thinning Fruit 90 0.505 0.000105 29,000

Sorghum

Scouting 210 0.337 0.000163 18,000

Hand Weeding 70 0.337 0.0000543 55,000

a DFR = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day. 

b Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (80 kg).

c MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR (μg/cm2) × TC × 0.001 mg/μg × 8 hrs/day × dermal absorption factor (%)] BW (80 kg).