Page 3 of 70

5.4 Dietary Risk Assessment .................................................................................... 26

5.4.1 Description of Residue Data Used in Dietary Assessment .................... 26

5.4.2 Percent Crop Treated Used in Dietary Assessment............................... 26

5.4.3 Acute Dietary Risk Assessment ............................................................... 27

5.4.4 Chronic Dietary Risk Assessment ........................................................... 27

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................ 28

6.1 Handlers............................................................................................................... 28

6.2 Post-application Exposure.................................................................................. 29

6.2.1 Non-Occupational/Residential Exposure.............................................. 29

6.3 Combined Exposure............................................................................................ 31

6.4 Residential Bystander Post-application Inhalation Exposure ........................ 31

7.0 Aggregate Exposure/Risk Characterization................................................................. 32

7.1 Acute Aggregate Risk ......................................................................................... 32

7.2 Short- Term Aggregate Risk.............................................................................. 33

7.3 Intermediate-Term Aggregate Risk .................................................................. 35

7.4 Long-Term Aggregate Risk ............................................................................... 35

8.0 Cumulative Risk Characterization/Assessment............................................................... 35

9.0 Occupational Exposure/Risk Pathway.............................................................................. 36

 9.1 Handlers............................................................................................................... 36

9.2 Post-application Exposure and Risk ................................................................. 40

9.3 Inhalation Post-application Risk ....................................................................... 41

10.0 References........................................................................................................................ 41

Appendix A: Toxicology Assessment ....................................................................................... 43

A.1 Toxicology Data Requirements.......................................................................... 43

A.2 Toxicity Profiles................................................................................................... 45

A.3 Hazard Identification and Endpoint Selection................................................. 50

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49.............................. 50

A.3.2 Acute Reference Dose (aRfD) - General population, including infants 

and children......................................................................................................... 50

A.3.3 Chronic Reference Dose (cRfD) –all populations ................................ 51

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)............... 51

A.3.5 Dermal Absorption ................................................................................. 52

A.3.6 Dermal Exposure (Short and Intermediate-Term) for Children ....... 52

A.3.7 Dermal Exposure (Short-, Intermediate- and Long-Term) for Adults

52

A.3.8 Inhalation Exposure (Short- and Intermediate-Term) for Adults..... 53

A.3.9 Inhalation Exposure (Long-Term) for Adults...................................... 54

A.4 Executive Summaries.......................................................................................... 54

Appendix B. Physical/Chemical Properties............................................................................. 66

Appendix C. Residential Exposure/Risk Summary Table ..................................................... 67
Page 4 of 70

1.0 Executive Summary

Valent USA Corporation has requested the Section 3 registration of new uses for flumioxazin, 

the active ingredient in Valor Herbicide and Chateau Herbicide, in wheat, sunflower, safflower, 

flax, lentils and field peas. This document assesses the dietary and occupational exposures and 

risks that would result from the proposed uses of the herbicide, as well as the impact on 

aggregate exposure and risk.

Flumioxazin, 2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5,6,7-

tetrahydro-1H-isoindole-1,3(2H)-dione, is an herbicide of the N-phenylphthalimide class that is 

currently used for pre- and post-emergence control of susceptible weeds on a variety of fruits, 

vegetables, tree nuts, other agricultural crops, ornamentals, non-crop and bare-ground 

areas(recreational landscapes, apartment and office complexes, and schools), as well as in 

aquatic settings (bayous, canals, fresh water ponds, marshes, and water reservoirs). It is also 

registered on conifer reforestation sites, poplar/timber reforestation sites, and dormant warmseason turfgrass including golf courses and sod farms. Its mode of action is as an inhibitor of 

protoporphyrinogen oxidase. It is active against certain grasses, broadleaf weeds, and sedges

(including aquatic species). The end-use products being proposed are Valor Herbicide (EPA 

Reg. No. 59639-99, water dispersible granule), and Chateau WDG Herbicide (EPA Reg. No. 

59639-119, water dispersible granule), which are water dispersible granules (WDS) containing

51% flumioxazin by weight. The maximum single application rate proposed for field peas, flax, 

sunflower, lentils, and safflower is 0.09 lb ai/A per single application and for wheat is 0.06 lb 

ai/A. The recommended personal protective equipment (PPE) on the flumioxazin labels for 

handlers includes long-sleeved shirt and long pants, shoes plus socks, and chemical resistant 

gloves. The REI specified on the label is 12 hours. The proposed pre-harvest intervals are 5 or 

10 days.

Hazard Assessment: The toxicology database for flumioxazin is nearly complete as described in 

40 CFR, Part 158, except that HED requests an inhalation developmental study due to concerns 

for quantitative sensitivity of the fetus following both oral and dermal exposure. 

In general, the subchronic and chronic toxicity studies demonstrated that toxic effects associated 

with flumioxazin include anemia as well as effects on the liver and the cardiovascular system. 

Developmental effects were observed in developmental rat studies but not in developmental 

rabbit studies. Hematologic (hematopoietic) effects of anemia were noted in rats, consisting of 

alterations in hemoglobin parameters. Increased renal toxicity in male rats was also reported 

following chronic exposure. There is no evidence of neurotoxicity or immunotoxicity in the 

recently submitted guideline studies. 

Increased quantitative susceptibility was seen in the rat developmental toxicity studies. Fetal 

effects were observed in the absence of maternal toxicity. In addition, both increased qualitative 

and quantitative susceptibility were observed in the rat reproduction study. Severe fetal effects 

were observed at lower doses than milder parental effects. Although there was an increase in 

susceptibility, HED’s degree of concern for the susceptibility observed in the rat developmental 

and reproductive studies is low because the regulatory endpoints for flumioxazin are based on 
Page 5 of 70

clear NOAELs for developmental and offspring effects that are protective of the increased 

susceptibility seen in the developmental and reproduction studies, and there are no residual 

concerns for these effects. HED concluded that the 10x FQPA Safety Factor could be reduced to

1x for oral and dermal exposure. Flumioxazin is classified as “not likely to be carcinogenic to 

humans.”

Due to the inhalation developmental study data gap, the Agency is retaining a 10X database 

uncertainty factor (UFDB) for all inhalation exposure scenarios. Once these data have been 

received, the Agency will determine how the results affect the toxicology endpoints and 

uncertainty factors. 

Dietary Exposure: The acute and chronic dietary exposure analyses were based on conservative 

assumptions, including tolerance level residues, 100% crop treated (CT), and high-end estimated 

drinking water concentrations (EDWCs). The EDWCs based on the proposed uses are lower 

than those from a previously assessed aquatic use. The only population subgroup for which an 

acute dietary endpoint was selected was Females 13-49. The acute risk estimate for this 

subgroup is 68% of the aPAD, which is not of concern. The chronic risk estimates are below 

HED’s level of concern for all population subgroups. The risk estimate for the general U.S. 

population is 20% of the chronic PAD (cPAD). The population subgroup with the highest risk 

estimate is all infants (1 year old), which uses 54% of the cPAD.

Residential Exposure and Risk Estimates: Residential exposures are not anticipated from the 

proposed Section 3 uses; however, residential exposures are anticipated from currently registered 

uses on treated turf and gardens and trees. HED has revised its Residential Standard Operating 

Procedures (SOPs). This new guidance results in the need for an update of flumioxazin 

residential risk estimates. Exposures are expected for adults who apply flumioxazin-containing 

products and from post-application exposure to adults and children in residential areas previously 

treated with the chemical. Residential uses are anticipated to be short-term (i.e., 1 to 30 days) in 

duration. 

The following six short-term residential exposure scenarios for the use of flumioxazin on 

treated turf for liquid formulations were assessed: adult residential dermal and inhalation, and 

child dermal and hand-to-mouth transfer, object-to-mouth transfer, and exposure through soil

ingestion. 

Residential handler dermal and inhalation risk estimates for flumioxazin are not of concern to 

HED (i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) 

for these assessments). The combined handler dermal and inhalation risk estimates calculated 

using the Aggregate Risk Index (ARI) are not of concern to HED (i.e., ARIs are ≥ 1). The ARI 

approach was required to combine the dermal and inhalation routes of exposure because of the 

different levels of concern (LOCs).

Adult and child residential post-application dermal exposures also are not of concern to HED. 

For children 1 < 2 years old, the combined dermal and incidental oral risk estimates for the 
Page 6 of 70

identified residential uses are not of concern to HED (i.e., MOEs are ≥ 100, the LOC for these 

assessments). 

Aggregate Risk: The acute aggregate risk from exposure to flumioxazin is equivalent to the 

acute dietary risk. Acute dietary risk estimates are not of concern for the population subgroup 

Females 13-49, the only population subgroup for which an acute dietary endpoint was 

established. 

The short-term aggregate exposure assessment combines short-term residential (non-dietary) 

exposures with average dietary exposures (food and drinking water). Short-term aggregate risks 

estimated for adult females 13-49 years are not of concern to HED (i.e., ARIs are ≥ 1). Shortterm aggregate risk estimates (MOEs) for the most highly exposed population, children 1 < 2 

years old, are also not of concern to HED (i.e., MOEs are ≥ 100). The intermediate-term 

aggregate risk assessment is identical to the short-term assessment because the exposures and 

PODs are identical for both exposure durations. 

The chronic aggregate risk assessment for flumioxazin consists of risks resulting from exposure 

to residues in food and drinking water. As a result, the chronic aggregate risk assessment is 

equivalent to the chronic dietary risk assessment. All risk estimates are not of concern.

Occupational Exposure and Risk Estimates: Based on the proposed use pattern, both shortand intermediate-term exposure and risk assessments were conducted. These risk assessments 

addressed potential handler exposure, as well as exposure for those re-entering treated areas, 

including occupational workers who re-enter treated fields. 

Occupational handler exposures to flumioxazin may occur via the dermal and inhalation route 

and was assessed at the maximum label application rate for each crop. The short- and 

intermediate-term inhalation risk estimates for the occupational handler scenarios assessed are 

not of concern to HED (i.e., ARIs are ≥ 1) with baseline attire (i.e., single layer of clothing, no 

respirator), except for mixing/loading dry flowables for aerial applications at baseline. For this 

scenario, the ARI is greater than 1, and not of risk concern when engineering controls (closed 

systems) are applied. All post-application worker exposure scenarios assessed result in 

estimated risks that were not of concern [i.e., MOEs are > ≥100 on Day 0 (12 hours)] for all 

potential post-application activities.

Environmental Justice Considerations. 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.

1

” 

Review of Human Research: This risk assessment relies in part on data from studies in which 

adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, 

which comprise the Pesticide Handlers Exposure Database (PHED), the Agricultural Handler 

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

 

1

http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf.
Page 7 of 70

have been determined to require a review of their ethical conduct, have received that review, and 

have been determined to be ethical.

2.0 HED Recommendations

2.1 Data Deficiencies

Toxicology: 

The HASPOC concludes, based on a WOE approach, that a rat developmental inhalation toxicity 

study (Guideline No. 870.3700a), is required at this time. This study should include an 

evaluation of the respiratory tract and should follow the procedures described in Guideline No. 

870.3465. This approach considered the available hazard and exposure information for 

flumioxazin, including (1) the observed concern for the quantitative susceptibility of the 

developing fetus following both oral and dermal exposure; (2) the severity of the fetal effects 

(ventricular septal defects) observed in the oral and dermal developmental studies; (3) that the 

oral developmental toxicity studies only measure toxicity of flumioxazin after first-pass liver 

metabolism and do not address the concern for the potential for greater flumioxazin-induced 

toxicity to the developing fetus when directly entering the lung (via inhalation) and more rapidly 

entering the blood stream by bypassing the liver; and (4) the concern for the inhalation MOE of 

210 for mixing/loading DFs for application to field peas, flax, sunflowers, safflower, and lentils 

(and the inhalation MOE of 610 for the currently registered aquatic use). 

Residue Chemistry

Pending submission of a revised Section B and Section F and updated certificate(s) of analysis or 

new analytical reference standard(s), there are no residue chemistry issues that would preclude 

granting conditional registration for the requested use of flumioxazin on field pea, flax, lentils, 

sunflower, safflower, and wheat. The Analytical Reference Standard for flumioxazin will expire 

on 4/1/2012. An updated certificate of analysis or a new analytical reference standard must be 

provided to the EPA National Pesticide Standards Repository.

Occupational and Residential Exposure: 

In accordance with the updated Part 158 data requirements (2007), a turf transferable residue 

(TTR) study is required for all occupational (e.g., sod farms, golf courses, parks, and recreational 

areas) or residential turf uses. As part of the recent flumioxazin Section 3 turf assessment 

(Wang; 385849; 06/08/11) HED reviewed a waiver request for the submission of a TTR study 

(MRID No. 48131401). In that assessment, HED stated that TTR data was not required at that 

time but that such data may be needed for future exposure assessments. Since the time of that 

assessment, HED has revised it's Residential SOPs (Health Effects Division’s 2012 Standard 

Operating Procedures for Residential Pesticide Exposure Assessment). In the 2012 SOPs, HED 

analyzed all of the available TTR data and selected new liquid and granular default values for the 
Page 8 of 70

fraction of the application rate available for transfer after a turf application (FAR). This default is 

1% for formulations applied as liquids which is the case with flumioxazin. Of the available TTR 

studies submitted to the Agency, the maximum FAR value seen using a liquid product was 6.1% 

or 6.1 times higher than the default residue transfer value. Therefore, the HED has decided that a 

calculated MOE of approximately 10 times higher than the level of concern (e.g., an MOE > 

1,000 if the LOC = 100) using the default residue transfer values would provide an adequate 

margin of safety for any potentially higher residues seen in a chemical-specific TTR study. A 

TTR study is required for flumioxazin at this time since the lowest dermal MOEs for adults and 

children contacting treated turf are 180 and 290, respectively.

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are 

required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 

Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED analyzed a 

number of DFR studies and selected a new default value for the fraction of the application rate 

available to be dislodged after a foliar application (FAR). This default value is 25%. Of the 

analyzed DFR studies, the maximum FAR value seen was 89% or 3.6 times higher than the 

default residue transfer value. Therefore, a calculated MOE of approximately 4 times higher 

than the LOC (i.e., an MOE > 400 if the LOC = 100) using the default dislodged residue value 

would provide an adequate margin of safety for any potentially higher residues seen in a 

chemical-specific DFR study. A DFR study is required for flumioxazin at this time since the

lowest dermal residential post-application MOE for adults is 130.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate gas chromatography/nitrogen-phosphorus detection (GC/NPD) method, Valent 

Method RM30-A-1, is available for enforcing tolerances for residues of flumioxazin per se in/on 

plant commodities. The reported method limits of quantitation and detection (LOQ and LOD) 

for flumioxazin in/on plant commodities are 0.02 and 0.01 ppm, respectively. 

The requirements for multiresidue methods testing data for the metabolites 482-HA and APF

flumioxazin are fulfilled. The available data indicate that flumioxazin could not be recovered 

through application of the multiresidue protocols.

2.2.2 International Harmonization

There are no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for 

any of the proposed commodities in the current registration actions, therefore, there are no issues 

of international harmonization raised by this action.
Page 9 of 70

2.2.3 Recommended Tolerances

Table 2.2.3 summarizes the Section 3 proposed tolerances and the Agency’s final tolerance 

recommendations. Tolerances for residues in/on plant commodities are expressed in terms of 

residues of flumioxazin, including its metabolites and degradates, to be determined by measuring 

only flumioxazin.

Table 2.2.3. Tolerance Summary for Flumioxazin.

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments;

Correct Commodity Definition

Dried shelled pea and bean 

(except soybean), Crop 

Subgroup 6C, seed

0.1 0.07

Pea and bean, dried shelled, except 

soybean, subgroup 6C 

Bean, dry seed 0.05 Remove

Rapeseed, Crop Subgroup 

20A, seed 0.35 0.40 Rapeseed subgroup 20A

Rapeseed Crop Subgroup 

20A, meal 0.04 --

Residues in canola meal and oil will 

be covered by the recommended 

Rapeseed Crop Subgroup tolerance for rapeseed subgroup 20A.

20A, refined oil 0.02 --

Sunflower, Crop Subgroup 

20B, seed 0.5 0.50 Sunflower subgroup 20B

Sunflower, Crop Subgroup 

20B, meal 0.03 --

Residues in sunflower meal and oil 

will be covered by the recommended 

tolerance for rapeseed subgroup 20A. Sunflower, Crop Subgroup 

20B, refined oil 0.02 --

Wheat, forage 0.02 0.02

Wheat, hay 0.02 0.02

Wheat, grain 0.35 0.40

Wheat, straw 5 6.0

Grain, aspirated fraction 110 100 Grain, aspirated fractions

Wheat, bran 0.35 -- Residues in wheat bran, flour, germ, 

middlings, and shorts will be covered 

by the recommended tolerance for 

wheat grain.

Wheat, flour 0.05 --

Wheat, germ 0.35 --

Wheat, middlings 0.08 --

Wheat, shorts 0.11 --

Note to RD: In conjunction with the establishment of the proposed tolerance for pea and 

bean, dried shelled, except soybean, subgroup 6C, the tolerance for bean, dry seed should 

be removed.
Page 10 of 70

2.2.4 Revisions to Petitioned-For Tolerances

2.3 Label Recommendations

HED recommends the labels include engineering controls (closed system) mixer/loaders for 

aerial application of dry flowables to mitigate occupational exposure. HED will work with the 

Registration Division on these label modifications.

The following label revisions/clarifications are required:

The general label instructions regarding feeding/grazing restrictions should be omitted

from the label: Except for alfalfa, field corn, and almond hulls do not graze treated fields 

or feed treated forage or hay to livestock. EPA OPPTS 860.1000 guideline states that 

there are only three cases where a label restriction should be allowed: peanut hay, 

soybean forage, and soybean hay.

The stated pre-planting interval of “[7] 14 days” for preplant weed control in wheat 

should be clarified. The submitted data will support a minimum pre-planting interval of 

7 days.

3.0 Introduction

Flumioxazin is an herbicide of the N-phenylphthalimide class that is currently used for pre- and 

post-emergence control of susceptible weeds in a variety of crops and other use sites. Its mode 

of action in plants is as an inhibitor of protoporphyrinogen oxidase. It is active against certain 

grasses, broadleaf weeds, and sedges (including aquatic species).

3.1 Chemical Identity

The chemical structure and nomenclature of flumioxazin are presented in Table 3.1.

Table 3.1 Flumioxazin Nomenclature.

Compound

N

N

O

F

C

H2

O

O

HC C O
Page 11 of 70

Table 3.1 Flumioxazin Nomenclature.

Common Name Flumioxazin

IUPAC Name N-(7-fluoro-3,4-dihydro-3-oxo-4-prop-2-ynyl-2H-1,4-benzoxazin6-yl)cyclohex-1-ene-1,2-dicarboxamide

CAS Name 2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin6-yl]-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione

CAS Registry Number 103361-09-7

End-use Product (EP) Valor Herbicide (EPA Reg. No. 59639-99, water dispersible 

granule), and Chateau WDG Herbicide (EPA Reg. No. 59639-119, 

water dispersible granule)

3.2 Physical/Chemical Characteristics 

For this new use, Flumioxazin is formulated as a WDG with 51% active ingredient. Flumioxazin 

has a log octanol/water partition coefficient of 2.55 and a vapor pressure of 2.41 x 10-6 mm Hg at 

25o C. It has a water solubility of 1.079 g/L and there is no information available on solvent 

solubility. In the environment, flumioxazin photodegrades very rapidly in water and on soil 

(half-lives = 1 and 5.8 days, respectively). Flumioxazin is classified as having medium soil 

mobility potential. Its two major degradates (APF and THPA) are expected to be more mobile 

than the parent compound in the environment (Koc = 410 and 155, respectively). Flumioxazin is 

relatively volatile in water and on soil, and is not expected to bioaccumulate in fish (Kow = 355). 

See Appendix B for a listing of flumioxazin physical and chemical properties. 

3.3 Pesticide Use Pattern

Valent USA Corporation is proposing the use of the herbicide flumioxazin on field peas, flax, 

lentils, sunflower, safflower, and wheat. The end-use products being proposed for use on these 

sites are Valor Herbicide (EPA Reg. No. 59639-99) and Chateau Herbicide (EPA Reg. No. 

59639-119), which are water dispersible granules (WDG) containing 51% flumioxazin by 

weight. Flumioxazin is proposed for a single foliar application at a maximum seasonal rate of 

0.09 lb ai/A for field peas, flax, sunflower, safflower, lentils, and 0.06 lb ai/A for wheat. 

Applications are to be made using ground and aerial equipment. The proposed pre-harvest 

interval (PHI) are 5 or 10 days.

The use pattern for the proposed uses of flumioxazin is summarized in Table 3.2, below.

Table 3.2. Summary of Directions for Use of Flumioxazin.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No. 59639-

99, 59639-

119]

Applic. 

Rate (lb 

ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

REI Use Directions and 

Limitations

Field Peas, Flax, Sunflower, Safflower, Lentils

Ground and Water 0.09 lb 1 0.09 lb ai/A 12 hrs Application may be made 5 
Page 12 of 70

Table 3.2. Summary of Directions for Use of Flumioxazin.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[EPA Reg. 

No. 59639-

99, 59639-

119]

Applic. 

Rate (lb 

ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

REI Use Directions and 

Limitations

aerial Dispersible 

Granule

ai/A days prior to harvest. Do 

not apply to dry beans after 

beans begin to crack or 

have emerged.

Wheat

Ground and 

aerial

Water 

Dispersible 

Granule

0.06 lb 

ai/A 1 0.06 lb ai/A 12 hrs

Application may be made 

10 days prior to harvest. 

Wheat must be planted a 

minimum of 1” deep. Do 

not graze until wheat is 5” 

tall.

The personal protective equipment (PPE) requirements proposed on the Valor Herbicide and 

Chateau Herbicide label are: Applicators and other handlers must wear long-sleeved shirt and 

long pants, socks plus shoes, and chemical-resistant gloves.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of flumioxazin on field peas, flax, lentils, sunflower, safflower, and wheat. 

Humans may be exposed to flumioxazin in food and drinking water, since the proposed labels 

indicate that it may be applied directly to growing crops. Application may result in flumioxazin

reaching surface and ground water sources of drinking water, both of which can serve as sources 

of drinking water. It is also directly applied to surface water as an aquatic herbicide. There are 

residential uses of flumioxazin, so exposure to flumioxazin may occur in residential or nonoccupational settings. In an occupational setting, handlers may be exposed while handling the 

pesticide prior to application, as well as during application. There is also a potential for postapplication exposure for workers re-entering treated sites. 

Risk assessments have been completed for the existing uses of flumioxazin. This risk

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of flumioxazin, but also considers existing uses of flumioxazin, particularly in 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 
Page 13 of 70

to Address Environmental Justice in Minority Populations and Low-Income Populations2." As a 

part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups 

according to well-established procedures. In line with OPP policy, HED estimates risks to 

population subgroups from pesticide exposures that are based on patterns of that subgroup’s food 

and water consumption, and activities in and around the home that involve pesticide use in a 

residential setting. Extensive data on food consumption patterns are compiled by the USDA 

under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized 

by subgroups based on age, season of the year, ethnic group, and region of the country. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The available toxicology database is sufficient for assessing the toxicity and characterizing the 

hazard of flumioxazin. The available toxicology studies for flumioxazin are listed in Tables

A.2.a and A.2.b in Appendix A. The following toxicity studies have been submitted in support 

of registered and proposed uses of flumioxazin:

• Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, and 

dermal sensitization) 

• Subchronic oral toxicity studies (rat, mouse, and dog) 

• Dermal toxicity- rat (21-day dermal toxicity and dermal penetration) 

• Dermal developmental (rat)

• Oral developmental (rat and rabbit) and reproductive toxicity (rats) studies

• Chronic oral toxicity studies (rat and dog)

• Carcinogenicity studies (rat and mouse)

• Metabolism studies (rat) 

• Acute and subchronic neurotoxicity studies

• Immunotoxicity study

• Mutagenicity battery

• Special Study: Rat Developmental - Critical Time for Defects

 

2 Available: http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf
Page 14 of 70

While the toxicology database for flumioxazin is largely complete, additional data are required. 

An inhalation developmental study is needed to characterize more completely the potential for 

adverse effects associated with the inhalation route of exposure. For inhalation risk assessment, 

EPA is currently using the dose and endpoint from an oral rat developmental toxicity study with 

an estimated 100% default absorption factor (of oral absorption). Toxicity by the inhalation 

route was considered to be equivalent to toxicity by the oral route. However, in some cases 

toxicity via the inhalation route is higher than toxicity via the oral exposure, which results in an 

underestimation of risks from inhalation exposure. In addition, there may be a potential for 

portal of entry effects via the inhalation route, which would not be accounted for in the oral 

studies. As a result, an inhalation study is needed for a more accurate assessment of inhalation 

risks. EPA applied an additional database uncertainty factor to account for the missing study. 

Despite these missing studies, the toxicity database is considered to be adequate for the purposes

of dose and endpoint selection for the current risk assessment, and for characterizing toxic 

effects associated with flumioxazin. 

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

The absorption, distribution, metabolism and excretion (ADME) of flumioxazin was investigated 

in rats following single oral doses of radiolabeled flumioxazin. Metabolism studies in rats 

indicated that there was extensive biliary excretion following oral administration of flumioxazin. 

Gastrointestinal tract absorption of flumioxazin might amount to over 90% of the dose. Total 

recovery of radioactivity in feces and urine 7 days after dosing accounted for 97-101% of the 

dose in all test groups. It was noted that 4-5 times as much radioactivity is excreted in feces as in 

urine. Radioactivity excretion in urine was statistically significantly elevated in females (38.8-

42.8%, low dose; 22.9-23.4%, high dose) vs. males (28.1-30.8%, low dose; 12.8-13.0%, high 

dose). The highest levels of residues were found in blood cells (35.9-48.8 ppb, low dose and 

2823-3040 ppb, high dose), which were much higher than the plasma levels (0.5-0.7 ppb, low 

dose and 53-37 ppb, high dose). In addition to untransformed parent compound, analysis of 

feces and urine revealed up to 35 putative metabolites. Identified compounds amounted to 37.5-

46.1% of the dose at the low dose treatments and to 70.7-71.5% of the dose at the high dose.

4.2.1 Dermal Absorption

An acceptable dermal absorption study in rats is available for flumioxazin where dermal 

absorption was assessed using 2 different doses. Based on the results of the study, HED 

determined that an upper-bound estimate of 8% dermal absorption should be used for risk 

assessment purposes.

4.3 Toxicological Effects

Flumioxazin’s pesticidal mode of action is as an inhibitor of the enzyme protoporphyrinogen 

oxidase. In mammals, the inhibition of the enzyme can interfere with the porphyrin component

of heme. 

Flumioxazin has mild or low acute toxicity (Categories III or IV) when administered orally, 
Page 15 of 70

dermally, or by inhalation. It is not an eye or skin irritant, or a dermal sensitizer. 

Subchronic and chronic toxicity studies demonstrated that toxicity associated with flumioxazin 

includes anemia as well as effects on the liver and the cardiovascular system. Hematological

(hematopoietic) effects of anemia consisting of alterations in hemoglobin parameters were noted 

in rats. Increased renal toxicity in male rats was also reported following chronic exposure. 

Increased absolute and relative liver weights and/or increased alkaline phosphatase values were 

observed in dogs. 

Developmental effects were observed in developmental rat studies but not in developmental 

rabbit studies. The effects seen in the rat studies were fetal cardiovascular anomalies, especially 

ventricular septal defects. Flumioxazin was also administered dermally to rats in a 

developmental study, and the exposure resulted in similar cardiovascular anomalies, the most 

serious being ventricular septal defects. Although the same effects occurred by both dermal and 

oral routes in developmental studies, the oral effects were noted at 10 mg/kg/day and the dermal 

at 100 mg/kg/day. No systemic toxicity (or dermal irritation) was observed in a 21-day dermal 

study up to the limit dose of 1000 mg/kg/day. In a mechanistic oral developmental study in rats, 

a single dose of 400 mg/kg/day caused ventricular septal defects when administered on gestation 

day 12, but not when given on days 11, 13, 14 or 15. In the 2-generation reproduction study, 

systemic effects (clinical signs and mortality as well as a decrease in body weight/gain and food 

consumption) were noted at approximately 19 and 23 mg/kg/day in males and females, 

respectively; however, effects on the offspring (decrease in the number of live born and 

decreased pup body weights, decreased mating index, and testicular atrophy in F1 males) 

occurred at lower doses (approximately 13 and 15 mg/kg/day).

Increased quantitative susceptibility was observed in the rat developmental toxicity studies (oral 

and dermal) in which the effects on fetuses occurred at doses that did not cause maternal toxicity. 

In addition, both increased qualitative and quantitative susceptibility were observed in the rat 

reproduction study, in which offspring effects were observed at lower doses than those which 

caused parental/systemic toxicity, and in which the offspring effects were considered to be more 

severe. An additional rat developmental study was submitted in which a single dose of 400 

mg/kg/day was administered to pregnant rats on gestation days 11, 12, 13 or 14. The results of 

the study indicated that a single dose on gestation day 12 was the cause of the ventricular septal 

defect observed in the rat developmental toxicity studies.

Several mechanistic studies were submitted by the registrant to describe more fully the 

hematopoietic and fetal effects, and to determine the relationship between these effects. The 

registrant postulated that the anemia observed in rats leads to fetal anemia and subsequent fetal 

hypoxia, followed by suppressed liver function and a decrease in protein synthesis. The 

decreased protein synthesis was proposed to result in wavy ribs and changes in osmotic forces 

leading to edema observed in the fetus. Concurrently, the fetus would compensate for the 

anemia by pumping a greater volume of blood leading to the observed enlargement of the heart. 

The registrant further postulated that the ventricular septal defect was produced by mechanical 

distortion of the heart. The two other signs of developmental toxicity reported, growth 

retardation and fetal death, were also considered to be related to the hypoxia produced by the 

anemic condition in the fetus.
Page 16 of 70

After evaluating the data, the Agency concluded that the mechanistic studies were not 

sufficiently robust to support the registrant’s proposed mechanism of toxicity. However, as

doses and endpoints for risk assessment were chosen to be protective of the cardiovascular (acute 

dose and endpoint) and hematopoietic (chronic dose and endpoint) effects, the lack of a 

conclusion regarding the mechanism of toxicity does not result in the need for additional 

uncertainty factors.

There was no evidence (quantitative or qualitative) of susceptibility following in-utero oral 

exposure in rabbits. No developmental toxicity was seen at the highest dose tested, 3x the limit

dose. The absence of effects in rabbits was supported by literature studies indicating rabbits are 

less susceptible to the effects of protoporphyrinogen oxidase inhibitors.

Acute and subchronic neurotoxicity studies showed no evidence of neurotoxicity in male or 

female rats. There was no other evidence in any species tested to indicate neurotoxicity 

potential. Therefore, there is no concern for acute or chronic neurotoxicity resulting from 

exposure to flumioxazin. Similarly, the immunotoxicity study in rats suggests that this chemical 

does not directly target the immune system. Also, the toxicology database for flumioxazin does 

not show any evidence of treatment-related effects on the immune system.

In most of the available mutagenicity studies, flumioxazin was negative for mutagenicity; 

however, aberrations were seen in a chromosomal aberration assay (CHO cells). Based on the 

lack of evidence of carcinogenicity in mice and rats, flumioxazin is classified as “not likely to be 

carcinogenic to humans.”

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

HED recommends that the required 10x FQPA Safety Factor for the protection of infants and 

children be reduced to 1x for oral and dermal exposures, but be retained at 10X for inhalation 

exposures based on the following: 1) the toxicology database for flumioxazin is complete with 

regard to FQPA consideration, including the required developmental and reproductive toxicity 

studies; except for an inhalation developmental study to assess adult women of childbearing age; 

2) the required neurotoxicity studies have been submitted, are considered adequate; 3) although 

there is evidence of quantitative susceptibility in the rat developmental (oral and dermal) and 

reproduction studies, the endpoints and doses selected for oral and dermal risk assessment are 

protective for these effects; and 4) the dietary and drinking water assessments are conservative 

and based on upper-bound estimates of exposure. 

4.4.1 Completeness of the Toxicology Database

The toxicology database is complete for flumioxazin except for an inhalation developmental 

study to assess adult women of childbearing age exposed via inhalation exposure. The toxicity 

profile can be characterized for all effects, including potential developmental and reproductive 

toxicity, immunotoxicity and neurotoxicity. Acceptable studies for developmental toxicity in rats 

and rabbits, developmental immunotoxicity, 2-generation reproduction in rats, and neurotoxicity 
Page 17 of 70

are available.

In the absence of a route-specific inhalation developmental study, the Hazard and Science Policy 

Council (HASPOC) recommends that a 10X database uncertainty factor be applied only to assess 

risks for inhalation exposure scenarios for both occupational and residential use patterns

(D401671, May 31, 2012). The HASPOC concludes, based on a WOE approach, that a rat 

developmental inhalation toxicity study (Guideline No. 870.3700a), is required at this time

(D401671, May 31, 2012). This study should include an evaluation of the respiratory tract and 

should follow the procedures described in Guideline No. 870.3465. This approach considered the 

available hazard and exposure information for flumioxazin, including (1) the observed concern 

for the quantitative susceptibility of the developing fetus following both oral and dermal 

exposure; (2) the severity of the fetal effects (ventricular septal defects) observed in the oral and 

dermal developmental studies; (3) that the oral developmental toxicity studies only measure 

toxicity of flumioxazin after first-pass liver metabolism and do not address the concern for the 

potential for greater flumioxazin-induced toxicity to the developing fetus when directly entering 

the lung (via inhalation) and more rapidly entering the blood stream by bypassing the liver; and 

(4) the concern for the inhalation MOE of 210 for mixing/loading dry flowables for application 

to field peas, flax, sunflowers, safflower, and lentils (and the inhalation MOE of 610 for the 

currently registered aquatic use). 

 

4.4.2 Evidence of Neurotoxicity

There is no indication that flumioxazin is neurotoxic in the acute and subchronic neurotoxicity 

(SCN) studies. In addition, none of the acute, subchronic, chronic, developmental, or 

reproduction studies indicated that flumioxazin has an effect on the nervous system. 

Developmental effects (cardiovascular anomalies) were observed in the rat; however, these

effects are not related to developmental effects of the central or peripheral nervous systems. As 

a result, a DNT study is not required.

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

There is evidence of increased quantitative susceptibility of fetuses in the oral and dermal 

developmental rat studies, i.e., cardiovascular anomalies (ventricular septal defect) that occurred 

in the absence of maternal toxicity. Additionally, the rat reproduction study demonstrated 

evidence of qualitative and quantitative post-natal susceptibility because reproductive effects in 

offspring were observed at doses lower than those that caused parental/systemic toxicity, and 

because the reproductive effects in offspring were considered to be more severe than the 

parental/systemic effects.

Although increased susceptibility was seen in rats, HED concluded that there is a low concern 

and no residual uncertainties for pre- and/or postnatal toxicity because: 1) the developmental 

toxicity NOAELs/LOAELs are well characterized after oral and dermal exposure; 2) the 

offspring toxicity NOAEL and LOAEL are well characterized in the reproduction study; and 3) 

the doses and endpoints have been selected from the developmental and reproductive toxicity 
Page 18 of 70

studies for risk assessment for the relevant exposed populations, i.e., pregnant females and 

children, with the exception of the chronic dietary endpoint, for which a chronic study was 

chosen for endpoint selection. Thus, the regulatory endpoints for flumioxazin are protective of 

the increased susceptibility seen in the developmental and reproduction studies, and there are no 

residual concerns for these effects.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure database for flumioxazin is considered to be adequate for risk assessment. The 

exposure assessments are conservative. The acute and chronic dietary analysis was based on 

tolerance-level residues and 100% crop treated assumptions for all commodities. The field trials 

represent maximum application rates and minimum pre-harvest intervals (PHIs). The dietary 

drinking water assessment utilized water concentration values generated by model and associated 

modeling parameters which are designed to provide conservative, health protective, high-end 

estimates of water concentrations. For both the acute and chronic dietary exposure, actual 

exposures to flumioxazin will likely be lower than the estimated exposures. The residential 

exposure assessment incorporates similarly conservative assumptions in the assessment of postapplication exposure to children and in the incidental oral exposure assessment for children. 

However, an inhalation developmental toxicity study is required for a more accurate assessment 

of inhalation risks. Currently, an oral toxicity study (with a default 100% absorption factor) is 

being used to assess inhalation exposure. As a result, it is possible that route-to-route 

extrapolation will result in an underestimation of inhalation risks. However, based on the oral 

NOAEL used for inhalation risk assessment, the occupational and residential handler margins of 

exposure (MOEs) ranged from 21,000 to 17,000,000 and, therefore, are not a risk concern 

(MOE>1000), even with the additional 10X database uncertainty factor. HED concludes that the 

exposure estimates in this analysis are unlikely to underestimate actual exposure. 

4.5 Toxicity Endpoint and Point of Departure Selections

The available toxicity database was evaluated for endpoint selection for: 1) acute and chronic 

dietary risk assessments; 2) short-term residential exposures including dermal and incidental oral 

exposure for children and dermal and inhalation exposure for adults; and 3) for short- and 

intermediate-term occupational exposures via the dermal and inhalation routes. Although longterm dermal and inhalation doses and endpoints were considered and selected, there are no longterm exposures expected for these routes based on the existing and proposed use patterns.

4.5.1 Dose-Response Assessment

While the detailed description of the toxicity studies used for selecting toxicity endpoints and 

points of departure for various exposure scenarios are presented in Appendix A, the following 

outlines the dose-response assessment and a general description of the endpoint selection. A 
Page 19 of 70

summary of the endpoint and point of departure selections for flumioxazin is shown in Tables 

4.5.1 and 4.5.2. 

For acute dietary exposure, an acute reference dose (aRfD) of 0.03 mg/kg/day was selected for 

assessment of females 13-49 yrs, based on a NOAEL of 3 mg/kg/day in the rat developmental 

study. At the LOAEL of 10 mg/kg/day cardiovascular effects in fetuses, specifically ventricular 

septal defects were seen. The effects were observed after a single dose exposure in a dietary 

study and are considered appropriate for acute dietary exposure. No separate endpoint was 

identified for acute dietary exposure for the general population, including infants and children. 

For chronic dietary exposure, a chronic reference dose (cRfD) of 0.02 mg/kg/day was selected 

for assessment of all populations, based on a NOAEL of 2 mg/kg/day from a combined 

chronic/carcinogenicity study in rats. Increased chronic nephropathy in males and decreased 

hematological parameters in females were observed at the LOAEL of 18 mg/kg/day. Chronic 

mouse and dog studies were also considered for chronic dietary exposure; however, the chronic 

rat study provided the most sensitive endpoint for chronic dietary risk assessment.

For assessing risks from short and intermediate-term inhalation exposure, an oral NOAEL of 3 

mg/kg/day based on cardiovascular effects in fetuses seen at the LOAEL of 10 mg/kg/day in the 

rat developmental study was used. The short and intermediate-term dermal PODs for adults are 

also based on adverse cardiovascular effects in fetuses at 100 mg/kg/day (NOAEL of 30 

mg/kg/day) in a rat dermal developmental study. For children, short and intermediate-term 

dermal and incidental oral PODs were based on a NOAEL of 6.3 mg/kg/day for decreased pup 

body weight and testicular atrophy in F1 males observed at 12.7 mg/kg/day (LOAEL) in the rat 

2-Generation Reproduction Study. A dermal absorption factor of 8% was used. 

Long-term exposures (greater than 6 months) are not anticipated based on the existing use 

pattern. 

The level of concern (LOC) for the relevant dermal and incidental oral exposure scenarios is an 

MOE of less than 100, based on the standard uncertainty factors for intraspecies variation (10X) 

and interspecies extrapolation (10X). For inhalation exposure scenarios, a 10X database 

uncertainty factor is applied due to the lack of an inhalation developmental toxicity study. Thus, 

the LOC is MOEs less than 1000. 

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential residential exposures to a pesticide, an aggregate risk assessment must 

consider exposure from three major sources: food, drinking water and residential (oral, dermal 

and inhalation) exposure pathways. 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 has considered both the route and duration of exposure. For the purpose of 

occupational exposures, the dermal and inhalation exposures can be aggregated because the same 

endpoint, fetal effects, was selected for risk assessment. Likewise, children’s dermal and oral 

exposures can be aggregated because the same offspring effects are being used to assess dermal 
Page 20 of 70

and oral risks. Residential handlers’ dermal and inhalation risks can also be aggregated. 

Residential exposures should be combined with background exposure from food and water 

determined in the chronic dietary exposure assessment.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Based on the lack of evidence of carcinogenicity in mice and rats, flumioxazin is classified as 

“not likely to be carcinogenic to humans.” Therefore, there is no cancer risk associated with the 

existing or proposed uses of flumioxazin. 

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

Assessment

Tables 4.5.1 and 4.5.2 summarize the points of departure and toxicity endpoints used in the 

dietary and occupational human health risk assessments, respectively.

Table 4.5.1. Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure 

(POD) 

Uncertainty

/FQPA 

Safety 

Factors

RfD, PAD, Level of 

Concern for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

Females 13-49 

only

NOAEL = 3

mg/kg/day

UFA=10x

UFH=10x

FQPA 

SF=1x 

Acute RfD = Acute PAD

= 0.03 mg/kg/day

Oral Developmental and 

Supplemental Pre-natal Studies 

(Rat)

LOAEL = 10 mg/kg/day, based on 

cardiovascular effects in fetuses. 

Acute Dietary

General 

Population 

including infants 

and children

No appropriate toxicological effects attributable to a single exposure (dose) were observed in oral 

toxicity studies including maternal effects in developmental studies in rats and rabbits. Therefore, a 

dose and endpoint were not identified for this risk assessment. 

Chronic Dietary

all populations

NOAEL= 

2.0 

mg/kg/day

UFA=10x

UFH=10x

FQPA 

SF=1x

Chronic RfD = Chronic PAD

= 0.02 mg/kg/day

2-Year Chronic/Carcinogenicity 

Study (Rat)

LOAEL = 18 mg/kg/day, based on 

increased chronic nephropathy in 

males and decreased hematological 

parameters in females. 

Incidental Oral -

Short- (1-30 

days) and 

IntermediateTerm (1- 6 

months)

NOAEL= 

6.3 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF = 

1X

Residential LOC for

MOE < 100 2-Generation Reproduction Study 

(Rat)

LOAEL = 12.7 mg/kg/day, based on 

decreased pup body weight and 

testicular atrophy in F1 males. 

Dermal – NOAEL = UFA=10x Residential LOC for 2-Generation Reproduction Study 
Page 21 of 70

Table 4.5.1. Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure 

(POD) 

Uncertainty

/FQPA 

Safety 

Factors

RfD, PAD, Level of 

Concern for Risk 

Assessment

Study and Toxicological Effects

Children

Short- (1-30 

days) and 

IntermediateTerm (1-6 

months) 

6.3 

mg/kg/day

DAF = 8%

UFH=10x

FQPA SF = 

1X

MOE < 100 (Rat) LOAEL = 12.7 mg/kg/day, 

based on decreased pup body weight 

and testicular atrophy in F1 males. 

Dermal - Adults

(All durations)

NOAEL= 30 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF = 

1X

Residential LOC for

MOE < 100 Dermal Developmental Study (Rat)

LOAEL = 100 mg/kg/day, based on 

cardiovascular effects in fetuses.

Inhalation

Short- (1-30 

days) and 

IntermediateTerm (1 - 6 

months)

NOAEL = 3 

mg/kg/day

(IAF = 

100%)

UFA=10x

UFH=10x

FQPA SF = 

10X

(database 

UF)

Residential LOC for

MOE < 1000

Oral Developmental Study (Rat)

LOAEL = 10 mg/kg/day, based on 

cardiovascular effects in fetuses.

Inhalation 

Long-Term (> 6 

months) 

Inhalation

NOAEL= 2 

mg/kg/day

(IAF = 

100%)

UFA=10x

UFH=10x

FQPA SF = 

10X 

(database 

UF)

Residential LOC for

MOE < 1000

2-Year Chronic/Carcinogenicity 

Study (Rat)

LOAEL = 18 mg/kg/day, based on 

increased chronic nephropathy in 

males and decreased hematological 

parameters in females.

Cancer

(oral, dermal, 

inhalation)

“Not likely to be a carcinogenic to humans,” based on the lack of carcinogenicity in a 2-year rat 

study, an 18-month mouse study, and a battery of mutagenic studies. 

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

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

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

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

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

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

of concern. N/A = not applicable. DAF = dermal absorption factor. IAF = inhalation absorption factor. 

Table 4.5.2. Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Occupational Human 

Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern for Risk 

Assessment Study and Toxicological Effects

Dermal - All 

Durations

NOAEL= 

30 mg/kg/day UFA = 10X

UFH = 10X

Occupational LOC for

MOE < 100

Dermal Developmental Study in 

Rats

LOAEL = 100 mg/kg/day based on 

cardiovascular effects in fetuses.
Page 22 of 70

Table 4.5.2. Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Occupational Human 

Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern for Risk 

Assessment Study and Toxicological Effects

Inhalation 

Short- and 

IntermediateTerm (1- day up 

to 6 months)

NOAEL= 3.0 

mg/kg/day

(IAF = 100%)

UFA = 10X

UFH = 10X

UFDB = 10X

Occupational LOC for

MOE < 1000

Oral Developmental Study in Rats

LOAEL = 10 mg/kg/day based on 

cardiovascular effects in fetuses.

Inhalation 

Long-Term 

Inhalation (>6 

months)

NOAEL = 

2.0 

mg/kg/day

(IAF = 100%)

UFA = 10X

UFH = 10X

UFDB = 10X

Occupational LOC for

MOE < 1000

2-Year Chronic/Carcinogenicity 

Study (Rat)

LOAEL = 18 mg/kg/day, based on 

increased chronic nephropathy in 

males and decreased hematological 

parameters in females

Cancer (oral, 

dermal, 

inhalation)

“Not likely to be a carcinogenic to humans,” based on the lack of carcinogenicity in a 2-year rat study, 

an 18-month mouse study, and a battery of mutagenic studies. 

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty 

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

members of the human population (intraspecies), UFDB = database uncertainty factor for lack of inhalation 

developmental study. MOE = margin of exposure. LOC = level of concern. IAF = inhalation absorption factor.

4.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may 

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

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

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

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

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

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

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

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

such as food and water, residential activity, and certain post-application agricultural scenarios. 

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

Flumioxazin is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 
Page 23 of 70

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit EPA’s website: 

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

5.0 Dietary Exposure/Risk Characterization

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of flumioxazin residues in plants and animals is adequately understood based on 

acceptable soybean, peanut, corn, sugarcane, grape, hen, and goat metabolism studies. The 

nature of the residue in rotational crops is also understood based on studies conducted on carrots, 

lettuce, and wheat. In primary and rotated crops, the residue of concern is only the parent 

compound. For ruminants, the residues of concern are parent, 3-OH-flumioxazin, 4-OHflumioxazin, plus Metabolites B, C, and F. For poultry, the residues of concern are parent, 3-

OH-flumioxazin, 4-OH-flumioxazin, and 4-OH-S-53482-SA.

Plant Metabolism

Adequate plant metabolism studies are available depicting the uptake and metabolism of 

[

14C]flumioxazin following applications to soybean (preemergence), peanut (pre-emergence), 

corn (pre-emergence), sugarcane (directed to the lower 3 feet of plants), and grapes (directed to 

soil surface surrounding vines). Based on these studies, HED determined that the parent 

compound only is the residue of concern to be used in risk assessments and the tolerance 

expression for primary and rotated crops. The available data are adequate to support the uses 

proposed herein. 

Livestock Metabolism

Adequate ruminant and poultry metabolism studies are available depicting the metabolism of 

flumioxazin radiolabeled in either the phenyl or tetrahydrophthaloyl (THP) ring. The 

metabolism of flumioxazin is similar in both ruminants and poultry, involving the hydroxylation 

and reduction of the cyclohexene ring in the THP moiety, hydrolytic cleavage of the imide and 

amide linkages, and incorporation of sulfonic acid into the THP moiety. HED has determined 

that the residues of concern for ruminants should include parent, 3-OH-flumioxazin, 4-OHflumioxazin, and Metabolites B, C, and F. For poultry, the residues of concern are parent, 3-OHflumioxazin, 4-OH-flumioxazin, and 4-OH-S-53482-SA. 

5.1.2 Summary of Environmental Degradation
Page 24 of 70

Drinking Water Assessment for the Proposed Use of Flumioxazin as an Aquatic Herbicide, D357184, L. Liu, 

7/21/2010

In the environment, flumioxazin photodegrades very rapidly in water and on soil (half-lives = 1 

and 5.8 days, respectively). Flumioxazin is classified as having medium soil mobility potential. 

Its two major degradates (APF and THPA) are expected to be more mobile than the parent 

compound in the environment (Koc = 410 and 155, respectively). It has a log octanol/water 

partition coefficient of 2.55, and is not expected to bioaccumulate in fish. Flumioxazin has a 

vapor pressure of 2.41x10–6 mmHg, water solubility of 1.079 g/L, and an estimated Henry’s law 

constant of 6.2x10-7atm-m3/mol. Based upon its Henry’s law constant and vapor pressure, 

flumioxazin is relatively volatile in water and on soil. 

5.1.3 Comparison of Metabolic Pathways

The rat metabolism study is discussed in Section 4.2. Plant and animal metabolism studies are 

discussed in Section 5.1.1. 

The metabolic profile in plants is similar in soybean, peanut, corn, sugarcane, and grapes. 

Further, the metabolism in ruminants, and poultry is also similar. In plants, the unchanged 

parent compound is the major residue. In animals, the residues of concern for ruminants include 

parent, 3-OH-flumioxazin, 4-OH-flumioxazin, and Metabolites B, C, and F. For poultry, the 

residues of concern are parent, 3-OH-flumioxazin, 4-OH-flumioxazin, and 4-OH-S-53482-SA. 

In rats, metabolism studies indicated that there was extensive biliary excretion following oral 

administration of flumioxazin. In addition to untransformed parent compound, analysis of feces 

and urine revealed up to 35 putative metabolites. 

5.1.4 Residues of Concern Summary and Rationale

The residue of concern for both the tolerance expression and risk assessment in plants is 

flumioxazin. No livestock tolerances have been established. A tolerance for combined residues 

of flumioxazin and its metabolites APF (3-oxo-4-prop-2ynyl-6-amino-7-fluoro-3,4-dihydro-1,4-

benzoxazin) and 482-HA (N-(7-fluoro-3,4-dihdyro-3-oxo-4-prop-2-ynyl-2H-1,4-benzoxazin-6-

yl)cyclohex-1-ene-1-carboxamide-2-carboxylic acid) in freshwater fish. Flumioxazin and the 

metabolites 482-HA and APF are the residues of concern in drinking water. 

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Flumioxazin Flumioxazin 

Rotational Crop Flumioxazin Flumioxazin

Livestock

Ruminant Not Applicable Not Applicable 

Poultry Not Applicable Not Applicable 
Page 25 of 70

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Freshwater Fish Flumioxazin, APF, 482-HA Flumioxazin, APF, 482-HA

Drinking Water Flumioxazin, APF, 482-HA Flumioxazin

5.2 Food Residue Profile

Acceptable field trial data on canola, field pea, sunflower, and wheat were submitted reflecting 

the proposed use patterns for the 51% WG formulations; the submitted field pea data will 

support the proposed use on lentil. Spray adjuvants, including methylated seed oils (MSOs), 

non-ionic surfactants (NISs), and/or crop oil concentrates (COCs) were used in all trials. The 

maximum residues of flumioxazin were 0.25 ppm in/on canola, 0.065 ppm in/on dried pea, 0.34

ppm in/on sunflower seed, and 0.31 and 3.95 ppm in/on wheat grain and straw (foliar, harvestaid use pattern); residues of flumioxazin were below the LOQ (<0.02 ppm) in/on all samples of 

wheat forage and hay (pre-plant use pattern). 

The submitted canola, sunflower, and wheat processing studies, reflecting application at ~5x the 

maximum proposed seasonal application rates are adequate. The data indicate that residues of 

flumioxazin do not concentrate in canola oil or meal, sunflower oil or meal, or wheat bran, flour, 

middlings, shorts, or germ. Flumioxazin may concentrate in wheat aspirated grain fractions 

(AGF), with a processing factor of 308x. The available data indicate that tolerances are not 

needed for the regulated commodities of canola, sunflower, and wheat; however, a tolerance is 

needed for grain, aspirated fractions at 100 ppm. 

The previously submitted confined rotational crop study is adequate for the proposed uses on the 

requested crops. Based on the results of the confined accumulation study, HED concludes that 

the existing rotational crop plant back intervals (PBIs) are acceptable, and that field trials and 

tolerances are not necessary.

5.3 Water Residue Profile

Reference: Drinking Water Assessment for the proposed use of Flumioxazin as an Aquatic 

Herbicide, D357184, L. Liu, 7/21/2010.

For the dietary risk assessment, the Environmental Fate and Effects Division (EFED) provided 

high-end, conservative EDWCs based on the aquatic application rates of the herbicide, which 

are higher than the EDWC from the current proposed uses. These EDWCs included 

concentrations of flumioxazin and its major degradates (482-HA, APF, and THPA). The 

resulting values were 400 ppb (peak day-0) for acute exposure and of 142 ppb (30-days) for 

chronic exposure. Table 5.3 lists degradates identified and their relative concentrations. The 
Page 26 of 70

model and its description are available at the EPA internet site:

http://www.epa.gov/oppefed1/models/water/.

Table 5.3. Summary of Estimated Drinking Water Concentrations (EDWCs) 

(ppb) From the Subsurface Application of Flumioxazin as an Aquatic Herbicide

Compound Acute EWDC 

(Day 0)

ppb

Chronic EWDC at 

Days 30 and after1

ppb

Flumioxazin 400 10.4

482-HA - 21.6

APF - 110.1

THPA - 88.9

1

Total EEC = Flumioxazin + 482-HA + APF

5.4 Dietary Risk Assessment

Flumioxazin. Acute and Chronic Dietary (Food and Water) Exposure and Risk Assessments for the Proposed Uses 

on Field Pea, Flax, Lentil, Sunflower, Safflower, and Wheat Commodities. S. Piper. 8/12. D401806

Au unrefined and health protective acute and chronic dietary exposure and risk assessment was 

conducted for flumioxazin. High end modeled drinking water estimates were directly 

incorporated into the assessment. In order to assess short-term aggregate risk to flumioxazin, 

average dietary exposure estimates (i.e., food and drinking water) were calculated. 

5.4.1 Description of Residue Data Used in Dietary Assessment

The flumioxazin dietary exposure and risk assessment was conducted considering all supported 

food uses and drinking water. The assessment was conducted using the Dietary Exposure 

Evaluation Model DEEM-FCIDTM, Version 2.03, which incorporates consumption data from the 

U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (USDA’s 

CSFII), 1994-1996 and 1998. For all commodities the assessment used current tolerances. 

Drinking water information was incorporated directly into the dietary assessment using the acute 

and chronic EDWCs for the aquatic use of 400 ppb and 142 ppb, respectively. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments 

were conducted using conservative assumptions, 100% or all crops are treated with flumioxazin. 
Page 27 of 70

5.4.3 Acute Dietary Risk Assessment

An unrefined, acute dietary exposure assessment using tolerance levels, processing factors, and 

assuming 100% crop treated (CT) for the proposed commodities was conducted for the general 

U.S. population and various population subgroups. The estimated drinking water concentration 

of flumioxazin was provided by the Environmental Fate and Effects Division (EFED) and 

incorporated directly into the acute assessment. An estimated environmental concentrations 

(EECs) for flumioxazin and its major degradates (482-HA and APF) under the use as an aquatic 

herbicide of 400 ppb was estimated for acute exposure.

There were no appropriate toxicological effects attributable to a single exposure (dose) for the 

general population or any other population subgroups except females 13-49 years old; therefore,

these population subgroups were not included in this assessment. For food and drinking water, 

the acute dietary risk estimate is below HED’s level of concern (<100% of the acute population 

adjusted dose (aPAD)) at the 95th percentile of exposure. The acute dietary exposure estimate for 

females 13-49 years old is 0.020349 mg/kg/day (68% of the aPAD).

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary exposure and risk estimates are conservative since they assume that 100% of 

crops are treated, residues are present at tolerance levels, and empirical or default processing 

factors are used. The EECs for flumioxazin and its major degradates (482-HA and APF) under 

the use as an aquatic herbicide is 142 ppb. Combined chronic dietary exposure estimates for 

food and drinking water are well below HED’s level of concern. Using the DEEM-FCID 

software, dietary exposure is estimated at 0.003976 mg/kg/day for the general U.S. population, 

which is equivalent to 20% of the chronic Population Adjusted Dose (cPAD), and 0.010863

mg/kg/day, equivalent to 54% of the cPAD for all infants (< 1year old), the population subgroup 

with the highest estimated chronic dietary exposure to flumioxazin.

Table 5.2. Summary of Acute and Chronic Exposure and Risk Estimates for Flumioxazin

Population 

Subgroup

Acute Assessment (95th Percentile) Chronic Assessment

aPAD, 

mg/day

Exposure Estimate, 

mg/day

% 

aPAD

cPAD, 

mg/day

Exposure Estimate, 

mg/day

% cPAD

U.S. Population

N/A

0.02 0.003288 16

All infants 0.02 0.010257 51

Children 1-2 yrs 0.02 0.005231 26

Children 3-5 yrs 0.02 0.004875 24

Children 6-12 yrs 0.02 0.003333 17

Youth 13-19 yrs 0.02 0.002412 12

Adults 20-49 yrs 0.02 0.003015 15

Adults 50+ yrs 0.02 0.003171 16

Females 13-49 yrs 0.03 0.019736 66 0.02 0.003007 15
Page 28 of 70

As conservative, health-protective assumptions were made in both the acute and chronic dietary 

exposure analyses, actual dietary exposures and risks from flumioxazin are likely to be much 

lower than the values generated in the acute and chronic analyses. HED is confident that 

exposure to flumioxazin is not underestimated for the general U.S. population or any population 

subgroup.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The details regarding the assumptions and calculations used to evaluate residential exposure and 

risk are described in a separate memo (D391784, M. August 2012). However, unless otherwise 

stated, HED incorporated standard assumptions typically used for assessing residential exposure 

and risk.

Residential exposure to flumioxazin is not anticipated from the proposed Section 3 uses; 

however, residential exposure is anticipated from currently registered uses of the chemical. 

Exposures are expected for individuals (adults) who apply flumioxazin-containing products and 

from post-application exposure to adults and children in residential areas previously treated with 

the chemical. In accordance with FQPA, HED must consider and aggregate pesticide exposures 

and risks anticipated from food, drinking water, and residential exposures. An updated 

assessment of flumioxazin residential uses has been conducted for the purpose of assessing 

flumioxazin aggregate risk because of revisions to the Residential SOPs. 

There are currently registered uses of flumioxazin on several residential use sites, including turf, 

gardens and trees, and aquatic weeds, etc. Each of these existing residential use patterns has 

previously been assessed however; these residential uses have been reassessed to reflect the 

updates to residential exposure assessment in the Health Effects Division’s 2012 Standard 

Operating Procedures for Residential Pesticide Exposure Assessment. Specifically, the 

Lawn/Turf SOP and the Garden and Trees SOP have been utilized in this assessment. Some of 

the data included in these SOPs are proprietary and thus are subject to the data protection 

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

6.1 Handlers

The Agency uses the term “handlers” to describe those individuals who are involved in the 

pesticide application process. HED has determined that short-term dermal and inhalation 

exposure to residential handlers is likely during use of the following flumioxazin uses: the 

registered outdoor ornamental (garden and trees), and turf uses. 

Residential handler dermal and inhalation risk estimates for flumioxazin are not of concern to 

HED (i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) 

for these assessments). 
Page 29 of 70

HED’s level of concern for adult residential handlers is equal to an ARI of 1. The combined 

dermal and inhalation risk estimates (ARIs) to residential handlers for the identified residential 

outdoor (i.e., ARIs are ≥ 1). The lowest ARI is 5.5 from use of a belly grinder equipment to treat 

ornamentals (garden and tree). A summary of these results is presented in Appendix C of this 

document. 

 

6.2 Post-application Exposure

6.2.1 Non-Occupational/Residential Exposure

The Agency uses the term “post-application” to describe exposures to individuals that occur as a 

result of being in an environment that has been previously treated with a pesticide. Flumioxazin

can be used in areas frequented by the general population, including outdoor residential areas. 

As a result, HED anticipates post-application exposures from the residential use of flumioxazin. 

The same high end outdoor uses assessed for handlers were assessed for residential postapplication exposure assessment. Residential post-application risks are based on maximum 

application rates or values specified in the SOPs for Residential Exposure Assessment.

Short-term dermal and incidental oral exposure and risk estimates have been assessed for 

flumioxazin. Dermal and oral exposures were not combined as the toxicological effects from the 

dermal and oral routes of exposure are different. The scenarios, routes of exposure and 

lifestages assessed include:

Physical activities on turf: adults (dermal) and children 1 < 2 years old (dermal and 

incidental oral);

Mowing: adults (dermal) and children 11 < 16 years old (dermal);

Golfing: adults (dermal), children 11 < 16 years old (dermal), and children 6 < 11 years 

old (dermal); and

Gardens and Trees: adults (dermal) and children 6< 11 years old (dermal).

Based on the SOPs for Residential Exposure Assessment and the uses specified in the proposed 

labels, the following residential post-application exposure scenarios have been evaluated:

• Dermal Dose from pesticide residues on treated turf (adults and children)

• Oral Dose from hand-to-mouth activity from treated turf (children)

• Oral Dose from object-to-mouth activity from treated turf (children)

• Oral Dose from soil ingestion activity from treated turf (children)

Adult residential post-application dermal exposures assessed for the registered outdoor uses are 

not of concern to HED. The greatest estimated risk for adults corresponded to an MOE = 130 for 

post-application exposure in garden/ornamental gardens. For children 1 < 2 years old, the 

dermal and incidental oral risk estimates for the identified residential uses are not of concern to 

HED (i.e., MOEs are ≥ 100, the LOC for these assessments). The greatest estimated risk for 

children corresponds to a MOE of 290 for children <1 to 2 years old contacting treated turf. A

summary of these results is presented in Table 6.1 below. 
Page 30 of 70

Table 6.1 Short- and Intermediate-Term Residential Post-application Exposure and Risk Estimates for 

Flumioxazin.

Liquid Formulations

Lifestage Post-application Exposure Scenario Dosea MOEsb

Adult

Turf - sprays

Physical Activities on 

Turf 0.17 180

Mowing 0.0034 8,900

Golfing 0.013 2,300

Child 11 < 16 

years old

Mowing 0.0034 9,000

Golfing 0.013 2,300

Child 6 < 11 

years old Golfing 0.001 (g) 5,100

Child 1 < 2 

years old

Physical Activities on 

Turf 0.02 (g) 290

Hand to Mouth 0.0057 1,100

Object to Mouth 0.00017 36,000

Incidental Soil Ingestion 1.2E-05 510,000

Adult

Garden - sprays

0.238 130

Child 6 < 11 

years old 0.011 (g) 560

Adult

Tree – sprays

0.022 1,400

Child 6 < 11 

years old 0.001 (g) 6,100

a. Dermal Dose (mg/kg/day) = TTR (μg/cm2) x 0.001 (mg/μg) x short-term TC (cm2/hr) x ET (hr/day) x DAF (40%)

BW (kg) 

b. Dermal MOE = NOAEL (30 mg/kg/day for adults and 6.3 mg/kg/day with 8% dermal absorption factor for children / Dermal 

Dose (mg/kg/day)

c. Hand-to-Mouth Dose (mg/kg/day) = E = [HR * (FM * SAH) * (ET * N_Replen) * (1- (1- SE)

(Freq_Replen/N-Replen))]

d. Object-to-Mouth Dose (mg/kg/day) = E = [OR* CF1 * SAMO * (ET * N_Replen) * (1- (1- SEO)

(Freq_Replen/N_Replen))]

e. Soil Ingestion Dose (mg/kg/day) = E = SRt * SIgR * CF1

f. Oral MOE = NOAEL (6.3 mg/kg/day) / Oral Dose (mg/kg/day)

g. Dermal absorbed dose adjusted for 8% dermal absorption for comparison with oral NOAEL of 6.3 mg/kg/day for children.

A summary of the previously assessed short- and intermediate-term residential post-application 

risk estimates for the currently registered aquatic uses are included in Table 6.2. Using the 

SWIMODEL, all short- and intermediate-term residential post-application MOEs for swimmers 

are greater than 1000 (ranged from 2,300 to 190,000) and are not a concern to HED. (S. Wang, 

DP 358360, 4/20/09). 

Table 6.2 Recreational Swimmer Exposures and Risks

Exposed 

Person

Route of 

Exposure

Water 

Concentration 

(mg/L)

Dose 

(mg/kg/day)

NOAEL 

(mg/kg/day) MOEa

Child- 22 kg Oral 0.4 0.002727 6.3 2,300

Dermal 0.4 0.000417 6.3 with 8% DA 190,000

Adult- 60 kg Oral 0.4 0.001 6.3 6,300
Page 31 of 70

Table 6.2 Recreational Swimmer Exposures and Risks

Exposed 

Person

Route of 

Exposure

Water 

Concentration 

(mg/L)

Dose 

(mg/kg/day)

NOAEL 

(mg/kg/day) MOEa

Dermal 0.4 0.000357 30 84,000

a Oral MOE = NOAEL (6.3 mg/kg/day)/ dose (mg/kg/day)

 Dermal MOE = NOAEL (30 mg/kg/day for adults and 6.3 mg/kg/day with 8% dermal absorption factor for children)/ dose (mg/kg/day)

6.3 Combined Exposure

Table 6.3 below presents the combined risk estimates for the uses resulting in the highest 

potential for residential handler and post-application exposures. A summary of the high-end 

residential exposure estimates are provided in Table 6.3. The residential post-application 

exposure was selected for the adult females only and it was not combined with the residential 

handler exposure because individuals would not conduct both of these activities at the same time. 

Table 6.3. Combined Short- and Intermediate-Term Residential Exposures for the Flumioxazin Aggregate 

Assessment.

Population

Handler Exposure 

(mg/kg/day)1

Residential 

Handler Total 

Exposure 

(mg/kg/day)3

Post-application Exposure 

(mg/kg/day)2

Recommended Postapplication Exposure 

for Aggregate 

(mg/kg/day) Dermal Inhalation Dermal Inhalation Oral 3

Adult Female 0.054 0.0000058 0.054 0.238 N/A N/A 0.238

Child N/A N/A N/A 0.02 N/A 0.0057 0.026

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

exposure represents granular belly grinder for gardens and trees.

2

Post-application exposure represents high end dermal, inhalation and/or incidental oral exposure for the relevant exposure 

duration. Post-application exposure for adult females represents liquids for gardens. Post-application exposure for child 

represents Hand-To-Mouth exposure and risk

3 For adults, residential total exposure combines the highest dermal and inhalation exposures, where applicable. For young 

children, total residential exposure combines high-end post application incidental oral AND dermal exposure, where applicable. 

Handler exposures should not routinely be combined with post-application exposures. NOTE: The highest estimated total 

residential exposure (for adults and child populations) should be used as the basis of the aggregate assessments.

 

6.4 Residential Bystander Post-application Inhalation Exposure

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 flumioxazin. The 

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

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

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

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

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 
Page 32 of 70

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 air blast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

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, for which no risks of 

concern were identified, 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 flumioxazin 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.

While residential exposure to flumioxazin is not anticipated from the proposed Section 3 uses, it 

is anticipated from currently registered turf and ornamental uses of the chemical. As such, the 

short-term aggregate exposure and risk assessment of flumioxazin includes dietary (food and 

water) exposures anticipated from the proposed Section 3 uses and high end, non-dietary 

exposures anticipated from currently registered residential uses. 

 

For the purpose of residential exposures, the dermal and inhalation exposures can be aggregated 

because the same endpoint, fetal effects, was selected for risk assessment. Residential exposures 

should be combined with background exposure from food and water determined in the chronic 

dietary exposure assessment. Likewise, children’s dermal and oral exposures can be aggregated 

because the same offspring effects are being used to assess dermal and oral risks. 

7.1 Acute Aggregate Risk

Acute aggregate risks result from exposure to residues in food and drinking water alone. As a 

result, the acute aggregate risk assessment is equivalent to the acute dietary risk assessment

discussed in Section 5.2.1, above. The risk estimate for the population subgroup Females 13-49

years old, the only subgroup for which an acute dietary endpoint was established, is not of 

concern. 

 
Page 33 of 70

7.2 Short- Term Aggregate Risk

The short- term aggregate exposure assessment includes exposures anticipated to occur from one 

to thirty days from dietary (food and water) and non-dietary, residential exposures from current 

and pending uses of flumioxazin. In order to aggregate short-term residential uses with dietary 

exposure, it was necessary to calculate average dietary exposure. Risk estimates (MOEs) were 

calculated by comparison of the short-term oral NOAEL to average dietary exposures for all 

populations. 

HED combines risk values resulting from separate residential exposure scenarios when it is 

likely they can occur simultaneously based on the use-pattern and the behavior associated with 

the exposed population. Residential handler and post-application scenarios should generally not 

be combined. Although there is potential for the same individual (i.e. adult) to apply a pesticide 

in and around the home and be exposed by reentering a treated area (i.e. home lawn or golf 

course) in the same day, this is an unlikely exposure scenario, especially day after day for up to 

30 days. Combining both of these exposure scenarios would also be inappropriate because of the 

conservative nature of each individual assessment. Therefore, HED used the worst case 

residential scenario for adults, which was the adult (dermal) post-application exposure (MOE 

=130) for liquid formulations applied to turf. 

The combined residential exposure for children is based on post-application dermal and oral 

exposure for treated turf. In the case of oral exposure for children, hand to mouth exposure 

represents the worst case scenario. Therefore it is HED’s policy not to combine object-to–mouth 

or soil ingestion with the hand-to-mouth exposure value as combining scenarios would be 

inappropriate because of the conservative nature of each individual assessment. 

Different methodologies were used for the presentation of short-term aggregate risk for adults 

and children. An ARI approach was required to estimate short-term adult aggregate risk because 

there are different LOCs for adult dermal and inhalation exposures, 100 and 1,000, respectively. 

For short-term child aggregate risk, the combined MOE approach was used because the endpoint 

of concern (decreased pup weight) and the levels of concern (LOC) are the same. 

Please refer to the residential assessment, Section 6.3, for a discussion regarding the exposures 

that are likely to be combined. 

Short-term aggregate risk estimates (ARIs) for adult females (13-49 yrs) (to protect for potential 

fetal effects), are not of concern to HED (i.e., ARIs are ≥ 1). Table 7.1, below, summarizes the 

results from the short-term aggregate for adults. 

Short-term aggregate risk estimates (MOEs) for the most highly exposed child population, 

children 1< 2 years old, is also not of concern to HED (i.e, MOEs are ≥ 100). Table 7.2, below, 

summarizes the results from the short-term aggregate assessment of children 1 < 2 years old.

Table 7.1 Short-Term Adult Aggregate Risk Calculations1

Population Short -Term Exposure Scenario
Page 34 of 70

Dietary

Exposure2

Dermal Residential 

Exposure3

Inhalation Residential 

Exposure4

Aggregate ARI

(food, water, 

and 

residential)5 MOE ARI MOE ARI MOE ARI

Adult Female

13-49 yrs 997 9.9 130 1.3 510,00 510 1.15

1. An ARI less than 1 is of concern to HED (ARI = Aggregate Risk Index.)

2. MOE dietary = [(short-term oral NOAEL)/(average dietary exposure)]. ARI dietary = [(MOE dietary)/(MOE 

target)]. Short-term oral NOAEL is 3 mg/kg/day to protect for fetal effects in pregnant women. Average dietary 

exposure is 0.003007 mg/kg/day for Adults 13-49 years old (See Table 5.2). The MOE target is 100. 

3. MOE dermal = [(short-term dermal NOAEL)/(high end dermal residential exposure)]. ARI dermal = [(MOE 

dermal)/(MOE target)]. Short-term dermal NOAEL is 30 mg/kg/day. The target MOE is 100. See Table 6.3 for 

residential exposure values used in aggregate assessment.

4. MOE inhalation = [(short- term inhalation NOAEL)/(high end inhalation residential exposure)]. ARI inhalation = 

[(MOE inhalation)/(MOE target)]. Short-term inhalation NOAEL is 3 mg/kg/day. The target MOE is 1,000. See 

Table 6.3 for residential exposure values used in aggregate assessment.

5. ARI Aggregate = 1/[(1/ARI dietary) + (1/ARI dermal) + (1/ARI inhalation)]
Page 35 of 70

Table 7.2 Short-Term Child Aggregate Risk Calculations

Population

Short-Term Exposure Scenario

LOC for 

Aggregate 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure3

MOE

Dermal 

Residential 

Exposure4

MOE

Inhalation 

Residential 

Exposure5

Aggregate 

MOE (food, 

water, and 

residential)6

Child 1 < 2 

Years Old 100 614 1,100 242 NA 150

1. LOC is an MOE = 100 (10X inter- and intra- species uncertainty factors totaling 100). 

2. MOE dietary = [(short-term oral NOAEL)/(average dietary exposure)]. Short-term oral NOAEL is 6.3 

mg/kg/day. Average dietary exposure is 0.010257 for children <1 years old (See Table 5.2).

3. MOE oral = [(short- term incidental oral NOAEL)/(high end residential incidental oral exposure)]. Short-term 

incidental oral NOAEL is 6.3 mg/kg/day. Residential incidental oral exposure is 0.0057 mg/kg/day. See Table 6.3 

for source of residential exposure values used in aggregate assessment.

4. MOE dermal = [(short-term dermal NOAEL)/(high end dermal absorbed dose residential exposure)]. Short-term 

dermal NOAEL is 6.3 mg/kg/day, with 8% dermal absorption factor (i.e., 0.026 mg/kg/day as dermal absorbed 

dose). See Table 6.3 for source of residential exposure values used in aggregate assessment.

5. NA = Not applicable 

6. MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal)]

7.3 Intermediate-Term Aggregate Risk

The intermediate aggregate is identical to the short-term aggregate assessment because the same 

points of departure were chosen for short-term and intermediate-term exposures; therefore, risks 

are the same for all durations of exposure.

7.4 Long-Term Aggregate Risk

The chronic aggregate risk assessment consists of risks resulting from exposure to residues in 

food, drinking water, and residues resulting from long term exposure through residential 

applications. However, there are no residential uses that would result in long-term exposure to 

any population subgroup. As a result, chronic aggregate risk consists of risks resulting from 

exposure to residues in food and drinking water alone. The chronic dietary exposure analysis 

included both food and drinking water, so the chronic aggregate risk assessment is equivalent to 

the chronic dietary risk assessment discussed in Section 5.4.4, above. All risk estimates are not

of concern. 

8.0 Cumulative Risk Characterization/Assessment

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information concerning the 

cumulative effects” of a particular pesticide’s residues and “other substances that have a 

common mechanism of toxicity.”
Page 36 of 70

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 flumioxazin and any other substances, and flumioxazin does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this regulatory action, therefore, 

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

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

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

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

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

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

9.0 Occupational Exposure/Risk Pathway

Reference: Flumioxazin: Occupational and Residential Exposure Assessment for A Proposed 

Use on Field Peas, Flax, Lentils, Sunflower, Safflower, and Wheat. D391784, M. Hawkins, 

August 2012.

HED has determined that there is the potential for both occupational handler and post-application 

exposure to occur from the proposed Section 3 uses of flumioxazin. 

9.1 Handlers

Occupational exposure is expected for handlers who apply flumioxazin products for the proposed 

Section 3 uses. Both dermal and inhalation exposures are expected. Handler exposure is 

expected to be short-and intermediate-term based on information provided on the proposed 

labels. Long-term exposures (greater than 6 months) are not anticipated based on the existing use 

pattern. As the same endpoint and dose were selected for both short- and intermediate-term 

durations, HED only calculated short-term handler exposures and risks, which are protective of 

intermediate-term exposure and risk. Typical assumptions regarding the acres treated and the 

length of a work day were used to derive the exposure estimates, along with a body weight of 69 

kg, and assuming the maximum application rate for each scenario. 

Chemical-specific data were not submitted to the Agency in support of the Section 3 application. 

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 Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, 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 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 Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 
Page 37 of 70

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

A quantitative exposure/risk assessment was developed for occupational handlers based on the 

following exposure scenarios:

Mixer/Loader

Mixing/loading dry flowables for aerial applications

Mixing/loading dry flowables for groundboom applications

Applicator

Applying sprays for aerial applications

Applying sprays for groundboom applications

Flagger

Flagging for aerial spray applications

The handler exposure estimates in this assessment are based on a central tendency estimate of unit 

exposure and an upper-percentile assumption for the application rate, and are assumed to be 

representative of high-end exposures. The uncertainties associated with this assessment stem 

from the use of surrogate exposure data (e.g., differences in use scenario and data confidence), 

and assumptions regarding the amount of chemical handled. The estimated exposures are 

believed to be reasonable high-end estimates based on observations from field studies and 

professional judgment.

All Section 3 occupational handler scenarios assessed are not of concern to HED (i.e., ARIs are 

≥ 1) with baseline attire (i.e., single layer of clothing, no respirator), except for mixing/loading 

dry flowables for aerial applications at baseline. For this scenario, the ARI is greater than 1, and 

not of risk concern when engineering controls (closed systems) are applied. Table 9.1 presents a 

summary of the short- and intermediate-term occupational handler exposures and risks from the 

Section 3 proposed uses. 
Page 38 of 70

Table 9.1 Short-/Intermediate-Term Occupational Handler Exposure and Risk Estimates for Flumioxazin. 

Exposure Scenario Crop or Target

Dermal Unit 

Exposure (ug/lb ai)a

Inhalation Unit 

Exposure (ug/lb ai)b Maximum 

Application 

Rateb

Area 

Treated or 

Amount 

Handled 

Dailyc

Dermal Inhalation Total

Mitigation Level Mitigation Level Dose 

(mg/kg/day)d MOEe Dose (mg/kg/day)f MOEg ARIh

Mixer/Loader

Mixing/Loading Dry 

Flowable for Aerial 

Applications

Field Peas,

Flax, 

Sunflower, 

Safflower, 

Lentils

51.6 8.96 0.09 1200 0.081 370 0.014 210 0.2i

6

j

Mixing/Loading Dry 

Flowable for Aerial 

Applications

Wheat

51.6 8.96 0.06 1200 0.054 560 0.0093 320 0.3

Mixing/Loading Dry 

Flowable for Groundboom 

Applications

Field Peas,

Flax, 

Sunflower, 

Safflower, 

Lentils

51.6 8.96 0.09 200 0.013 2,200 0.0023 1,300 1.2

Mixing/Loading Dry 

Flowable for Groundboom 

Applications

Wheat

51.6 8.96 0.06 200 0.009 3,300 0.0016 1,900 1.8

Applicator

Applying Sprays via 

Aerial Equipment 

(Engineering Controls)k

Field Peas,

Flax, 

Sunflower, 

Safflower, 

Lentils

5 0.068 0.09 1200 0.0078 3,800 0.00011 28,000 3,400

Applying Sprays via 

Aerial Equipment 

(Engineering Controls)k

Wheat 5 0.068 0.06 1200 0.0052 5,800 0.000071 42,000 5,100

Applying Sprays via 

Groundboom Equipment

Field Peas,

Flax, 

Sunflower, 

Safflower, 

Lentils

16.1 0.34

0.09 200 0.0042 7,100

0.000089

34,000 23

Applying Sprays via 

Groundboom Equipment Wheat 16.1 0.34 0.06 200 0.0028 11,000 0.000059 51,000 34
Page 39 of 70

Table 9.1 Short-/Intermediate-Term Occupational Handler Exposure and Risk Estimates for Flumioxazin. 

Exposure Scenario Crop or Target

Dermal Unit 

Exposure (ug/lb ai)a

Inhalation Unit 

Exposure (ug/lb ai)b Maximum 

Application 

Rateb

Area 

Treated or 

Amount 

Handled 

Dailyc

Dermal Inhalation Total

Mitigation Level Mitigation Level Dose 

(mg/kg/day)d MOEe Dose (mg/kg/day)f MOEg ARIh

Flagger

Flagging for Aerial 

Sprays Applications

Field Peas,

Flax, 

Sunflower, 

Safflower, 

Lentils

12 0.35 0.09 350 0.0055 5,500 0.00016 19,000 14

Flagging for Aerial 

Sprays Applications

Wheat

12 0.35 0.06 350 0.0037 8,200 0.00011 28,000 21

a. PHED/ORETF (level of mitigation: single layer of PPE, gloves).

b. Based on proposed label (Reg. No. 59639-99, 59639-119).

c. Exposure Science Advisory Council Policy #9.1.

d. Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount 

Handled (A or gal/day) x DAF (%) / BW (kg).

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

f. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or 

Amount Handled (A or gal/day) / BW (kg).

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

h. ARI = 1/(1/RIdermal)+ (1/RIinhalation).

i. Level of mitigation: single layer of PPE, gloves, no respirator 

j. Level of mitigation: engineering controls for dermal and inhalation; ARI does not exceed 1 until engineering controls are used.

k. Enclosed cockpits are expected to be used for aerial application.

 
Page 40 of 70

9.2 Post-application Exposure and Risk

HED has determined that there is the potential for post-application dermal exposure to 

flumioxazin following application to the proposed Section 3 uses. Post-application exposure 

may occur when workers enter previously treated areas to perform job functions. Re-entry 

workers are expected to experience short-term exposure to flumioxazin while performing postapplication activities such as scouting and irrigation. 

Chemical-specific dislodgeable foliar residue (DFR) studies for flumioxazin are not available. It 

is the policy of HED to use the best available data to assess post-application exposure. Sources 

of generic post-application data, used as surrogate data in the absence of chemical-specific data, 

are derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies, and, as 

proprietary data, are subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting post-application exposure that are used in this assessment, 

known as “transfer coefficients”, are presented in the “Science Advisory Council for Exposure 

(ExpoSAC) Policy 3” (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, 

along with additional information about the ARTF data, can be found at 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

The results of the post-application exposure and risk assessment indicate that MOEs > 100 are 

achieved on Day 0 (12 hours) for all potential post-application activities and, therefore, are not of 

concern. The post-application activity scenarios along with respective TCs and risk estimates for 

short -term MOEs are summarized in Table 9.2. 

Table 9.2: Summary of Occupational/Commercial Post-application Risks for Flumioxazin.

Crop/Site Activities DFR Day 0 MOE (a) 

Day X at which MOE ≥ LOC

of 100

Short-term and Intermediate-term

Field Peas Scouting 0.252 930 N/A

Field Peas Hand Set Irrigation 0.252 540 N/A

Flax Scouting 0.252 930 N/A

Lentils Scouting 0.252 930 N/A

Lentils Hand Set Irrigation 0.252 540 N/A

Safflower Hand Weeding 0.252 15,000 N/A

Safflower Scouting 0.252 930 N/A

Safflower Hand Set Irrigation 0.252 540 N/A

Sunflower Scouting 0.252 11,000 N/A

Wheat Hand Weeding 0.168 22,000 N/A

Wheat Scouting 0.168 1,400 N/A

DFR = Dislodgeable Foliar Residue

(a) LOC for dermal MOE is > 100. 
Page 41 of 70

9.3 Inhalation Post-application Risk

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

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

inhalation toxicity (Toxicity Category IV), low vapor pressure (2.41 x 10-6 mmHg at 25o C), 

and the low proposed use rate (0.09 lb ai/A). However, there are multiple potential sources of 

post-application inhalation exposure to individuals performing post-application activities in 

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

resuspension of dusts and/or particulates that 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, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

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

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

post-application inhalation exposure assessment for flumioxazin.

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

Flumioxazin: Occupational and Residential Exposure Assessment for A Proposed Use on Field 

Peas, Flax, Lentils, Sunflower, Safflower, and Wheat. M. August 2012. 

Acute and Chronic Dietary (Food and Water) Exposure and Risk Assessments for the Proposed 

Uses on Field Pea, Flax, Lentil, Sunflower, Safflower, and Wheat Commodities. S. 8/12. 

D401806

Flumioxazin. Petition for the Establishment of Permanent Tolerances for Use on Field Pea, Flax, 

Lentil, Sunflower, Safflower, and Wheat Commodities. Summary of Analytical Chemistry and 

Residue Data, D391781, S. 8/2012. 
Page 42 of 70

Drinking Water Assessment for a Section 3 New Use for Flumioxazin End-Use Products 

Chateau WDG and Valor WDG Applications to Wheat, Sunflower, Safflower, Flax, Lentils, and 

Field Peas, D392618, L.Liu, 3/21/2012.

Drinking Water Assessment for the proposed use of Flumioxazin as an Aquatic Herbicide, 

D357184, J. Stone, 7/21/2010.

Flumioxazin. Human Health Risk Assessment for the Proposed Uses on Turfgrass and Forest 

Sites. D380073, D. Dotson, K. Middleton, S. Wang, M. Collantes, 6/8/2011

Flumioxazin. Human Health Risk Assessment for a Proposed Aquatic Use. PC Code: 129034, 

Petition No: 8E7438, DP Barcode: D379028, B. Hanson, 7/14/2010
Page 43 of 70

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for flumioxazin are in the table below. Use of 

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

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity .....................................

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

no

no

yes

yes

yes

no

no

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

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

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

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

yes

yes

yes

1

yes

yes

1

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial ...

870.5375 Mutagenicity—Gene Mutation – CHO cells

870.5395 Mutagenicity— In vivo rat bone marrow.....

870.5550 Mutagenicity—Other Genotoxic EffectsUDS assay.......................................................................

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

870.6300 Developmental Neurotox .............................

no

no

yes

yes

no

-

-

yes

yes

-
Page 44 of 70

Test Technical

Required Satisfied

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

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

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

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

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

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

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

no -

1 Requirements for 870.4100a and 870.4200a are satisfied by the receipt of an 

acceptable/guideline combined chronic/carcinogenicity study in rats (870.4300.)
Page 45 of 70

A.2 Toxicity Profiles

Table A.2.a. Acute Toxicity Profile for Flumioxazin

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

870.1100 Acute oral [rat] 42684911 LD50>5000 mg/kg 

M & F

IV

870.1200 Acute dermal [rat] 42684913 LD50>2000 mg/kg III

870.1300 Acute inhalation [rat] 42684915 LC50 =3.93 mg/L IV

870.2400 Acute eye irritation [rabbit] 42684917 Not an ocular irritant III

870.2500 Acute dermal irritation [rabbit] 42684917 Non-irritating IV

870.2600 Skin sensitization [guinea pig] 42684921 Non-sensitizer N/A
Page 46 of 70

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity - rat

42684923

dose levels: 0, 2.3, 20.7, 

69.7, and 243.5 

mg/kg/day (M)

and 0, 2.2, 21.7, 71.5, and 

229.6 mg/kg/day (F)

NOAEL = 69.7 (M), 71.5 (F) mg/kg/day

LOAEL = 243.5 (M), 229.6 (F) mg/kg/day based on a 

decrease in MCV both sexes; increase in platelets F 

only.

870.3100 90-Day oral 

toxicity - rat

42683922

dose levels: 0, 1.9, 19.3, 

65.0, and 196.7 

mg/kg/day (M) and 0, 2.2, 

22.4, 72.9, and

218.4 mg/kg/day (F)

NOAEL = 65.0 (M), 72.9 (F) mg/kg/day LOAEL = 

196.7 (M), 218.4 (F) mg/kg/day based on hematology 

changes.

870.3100 90-Day oral 

toxicity - mouse

MRID unknown (referred 

to in 79-week study, 

MRID 44295018)

dose levels: 0, 143, 429, 

or 1429 (M & F) 

mg/kg/day

NOAEL = 429 mg/kg/day

LOAEL = 1429 mg/kg/day based on increased liver 

weight in males.

870.3100 4-Week oral 

toxicity - mouse

44307301 (see MRID 

44295018 DER#2)

dose levels: 0, 151.5, 

419.9 or 1366.5 (M) and 

0, 164.5, 481.6 or 1698.3 

(F) mg/kg/day 

NOAEL = 151.5 (M), 164.5 (F) mg/kg/day

LOAEL = 419.9 (M), 481.6 (F) mg/kg/day based on 

increased absolute &/or relative liver weights in M & F.

870.3150 90-Day capsule -

dog

42684924

dose levels of 0, 10, 100, 

or 1000 mg/kg/day

NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on dose dependent 

increase in total cholesterol, phospholipid & alkaline 

phosphatase activity.

870.3200 21-Day dermal 

toxicity - rat

44295016

dose levels: 1, 100, 300, 

or 1000 mg/kg/day

NOAEL = mg/kg/day: 1000 (LIMIT DOSE)

LOAEL = mg/kg/day: >1000 based on no effects.

870.3465 28-Day inhalation 

toxicity (species)

Not Required

870.3700a Pre-natal 

developmental - rat 

(oral)

(1)42684930 (pilot study); 

42684925 (main study); 

(2) 42884006

dose levels: 0, 1, 3, 10 and 

30 mg/kg/day

Maternal NOAEL = 30 mg/kg/day (HDT)

LOAEL = >30 mg/kg/day (HDT)

Developmental NOAEL = 3 mg/kg/day

LOAEL = 10 mg/kg/day based on cardiovascular effects 

(especially ventricular septal defects).

870.3700a Pre-natal 

developmental - rat

(dermal)

42684929 (pilot); 

42684926 (main study)

dose levels: 0, 30, 100,

and 300 mg/kg/day

Maternal NOAEL = 300 mg/kg/day (HDT)

LOAEL = >300 mg/kg/day (HDT)

Developmental NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on cardiovascular 

effects (especially ventricular septal defects).
Page 47 of 70

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Pre-natal 

developmental - rat 

(inhalation)

Data Gap

870.3700b Pre-natal 

developmental -

rabbit (oral)

42684927 (range-finding); 

42684928 (main study)

dose levels: 0, 300, 1000, 

or 3000 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL = 3000 mg/kg/day (HDT) based on decrease in 

body weight and food consumption during dosing

Developmental NOAEL = 3000 mg/kg/day (HDT) 

LOAEL = >3000 mg/kg/day

870.3800 Reproduction and 

fertility effects -

rat)

42684934 and 42684936 

(pilot studies); 42684935 

(main study)

dose levels: 0, 3.2, 6.3, 

12.7, and 18.9 mg/kg/day 

(M) and 0, 3.8, 7.6, 15. 1, 

and 22.7 mg/kg/day (F)

Parental/Systemic NOAEL = 12.7 (M), 15.1 (F) 

mg/kg/day; LOAEL = 18.9 (M), 22.7 (F) mg/kg/day 

based on increase in clinical signs (red substance in 

vagina) and increased female mortality as well as 

decreased body weight, body weight gain and food 

consumption.

Reproductive NOAEL = 18.9 (HDT) (M), 22.7 (HDT) 

(F) mg/kg/day; LOAEL = >18.9 (HDT) (M), >22.7 

(HDT) (F) mg/kg/day

Offspring NOAEL = 6.3 (M), 7.6 (F) mg/kg/day; 

LOAEL = 12.7 (M), 15.1 (F) mg/kg/day based on a 

decrease in the number of liveborn, a decrease in pup 

body weight, a decrease in the mating index, and 

testicular atrophy of F1 males.

870.4100b 12-Month capsule -

dog

44295017

dose levels: 0, 10, 100 or 

1000 mg/kg/day

NOAEL = 100 mg/kg/day (M & F)

LOAEL = 1000 mg/kg/day (M &F), (LIMIT DOSE) 

based on the following for males and females: increased 

absolute and relative liver weights; 300% increase in 

alkaline phosphatase values

870.4200b Carcinogenicity -

mouse

44295018

dose levels: 0, 31.1, 314.9 

or 754.1 mg/kg/day in 

males and 0, 36.6, 346.4, 

or 859.1 mg/kg/day in 

females 

NOAEL = 754.1 (M), 859.1 (F) mg/kg/day (LIMIT 

DOSE); LOAEL = no systemic effects at LIMIT DOSE 

in males or females

No evidence of carcinogenicity

870.4300 Combined chronic 

carcinogenicity -

rat

44295028

dose levels: 0, 1.8, 18.0, 

and 36.5 mg/kg/day in 

male rats and 0, 2.2, 21.8, 

and 43.6 mg/kg/day in 

female rats

NOAEL = 1.8 (M), 2.2 (F) mg/kg/day

LOAEL = 18.0 (M), 21.8 (F) mg/kg/day based on 

increased chronic nephropathy in males and decreased 

hematological parameters in females (Hgb, MCV, MCH 

and MCHC).

No evidence of carcinogenicity
Page 48 of 70

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Gene 

Mutation

870.5100

Gene mutation in S. 

typhimurium and E. 

coli

42684938

dose levels: with or 

without metabolic 

activation to 0, 50, 100, 

200, 500, 1000, or 2000 

μg/plate

Neither cytotoxic nor mutagenic up to 2000 μg/plate. 

There were reproducible increases in revertant colonies 

of S. typhimurium strains TA1538 and TA98 in S9 

activated phases of the preliminary cytotoxicity and both 

mutation assays. [Results are considered to be 

equivocal.]

Gene 

Mutation

870.5375

Gene mutation in 

Chinese hamster 

ovary cells

42684939

nonactivated levels, 30, 

100, 200, and 500 μM 

(11, 35, 70, and 177 

μg/mL, respectively)

Precipitation at 200 μM. Cytotoxicity at 500 μM. 

Positive +S9 100 μM and negative at 30-500 μM -S9. 

Aberrations were chromatid breaks and exchanges.

870.5395 In vivo rat bone 

marrow

42684940

dose levels: 1250, 2500, 

or 5000 mg/kg

Negative in male (up to 5000 mg/kg) and female rats (up 

to 4400 mg/kg) when tested orally.

870.5550 UDS assay 42684941

dose levels: by oral 

gavage to 5000 mg/kg or 

12 hours post exposure to 

1250 or 2500 mg/kg

Negative up to 5000 mg/kg.
Page 49 of 70

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200a Acute neurotoxicity 

screening battery

48402405

acceptable/guideline

0, 200, 700 or 2000 mg/kg 

bw

NOAEL = 2000 mg/kg/day (M & F)

LOAEL = >2000 mg/kg/day (M &F), (LIMIT DOSE) 

no signs of neurotoxicity 

870.6200b Subchronic 

neurotoxicity 

screening battery

48651401

acceptable/guideline

0, 500, 1500, or 4500 ppm 

(equivalent to 0, 37/41, 

110/124, 323/358 mg/kg 

bw/day for males/females)

NOAEL = 500 ppm (equivalent to 37/41 mg/kg bw/day

for males/females, respectively)

LOAEL = 1500 ppm (equivalent to 110/124 mg/kg 

bw/day for males/females, respectively), based on signs 

of anemia [decreased hemoglobin and hematocrit, mean 

corpuscular volume (MCV), mean corpuscular 

hemoglobin (MCH)]. 

N OAEL= 4500 ppm for neurotoxicity (HDT)

870.6300 Developmental 

neurotoxicity

Not required.

870.7485 Metabolism and 

pharmacokinetics -

rat (oral)

42684943

single oral dose of 1 

mg/kg or 100 mg/kg,

Gastrointestinal tract absorption >90% at 1 mg/kg and 

up to 50% at 100 mg/kg. At least 97% recovery in feces 

and urine 7 days after dosing. Highest levels of residues 

(36-49 ppb) in blood cells at low dose and 2800-3000 

ppm at high dose (RBC levels > plasma). In addition to 

untransformed parent, 7 metabolites identified in urine 

and feces (38-46% for low dose and about 71% at high 

dose). 

870.7600 Dermal penetration 

- rat

42684944

dose levels: 200 or 800 

mg/kg bw 

Females dosed with 200 or 800 mg/kg bw. Dermal 

absorption for 200 and 800 mg/kg was 3.9% and 8.0%, 

respectively, by 48 hours after initiation of treatment for 

6 hours. Blood levels at 6-24 hours after dermal dosing 

with 200 mg/kg were similar to those obtained at 2-6 

hours after oral dosing with 1 mg/kg. Blood levels at 6-

24 hours after dermal dosing with 800 mg/kg were 

similar to those obtained at 2-6 hours after oral dosing 

with 30 mg/kg.

870.7800 Immunotoxicity 48402407 and 48402408

acceptable/guideline

0 (control), 500, 1500, or 

4500 ppm (0, 44, 127, and 

375 mg/kg bw/day, 

respectively)

NOAEL = 500 ppm (equivalent to 42 mg/kg bw/day)

LOAEL = 1500 ppm (equivalent to 126 mg/kg bw/day), 

based on signs of anemia (decreased hemoglobin and 

hematocrit). 

Under conditions of this study, the immunotoxicity 

NOAEL for anti-SRBC PFC response is 4500 ppm (375 

mg/kg/day), the highest dose tested; a LOAEL was not 

established.
Page 50 of 70

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Nonguideline Special Study -

Rat

Developmental: 

Critical Time for 

Defects

42694931, 42684932

single dose:400 mg/kg bw

Pregnant females were administered 400 mg/kg by 

gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 

12 administration showed: largest incidence of 

embryonic death, lowest fetal body weights and greatest 

incidence of ventricular septal defects.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Pre-natal Developmental Toxicity Study - Rat

MRID Nos.: 42684930 (pilot study); 42684925 (main study); and 42884006, 42694931, and 

42684932 (studies demonstrating critical time to effects).

Executive Summary: See Appendix A

Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day, Endpoint = cardiovascular 

effects, specifically ventricular septal defects in fetuses, seen at the LOAEL of 10 mg/kg/day

Uncertainty Factor(s): 100X [10 interspecies; 10X intraspecies].

Comments about Study/Endpoint/Uncertainty Factors: The endpoint selected is appropriate 

because the critical effect, cardiovascular abnormalities observed in fetuses, has been 

demonstrated to be the result of a single dose, with dosing on gestation day 12 being the most 

critical time period for the effect. The application of the endpoint and dose to the population of 

potentially pregnant females is protective of fetal effects. A clear NOAEL and LOAEL were 

identified for the fetal abnormalities; therefore, no additional uncertainty factors (other than the 

standard 10x for interspecies extrapolation and 10x for intraspecies variability) are needed. 

Furthermore, the FQPA factor has been reduced to 1x. Therefore, the acute reference dose (RfD) 

and acute population adjusted dose (PAD) are calculated as follows:

Acute RfD = Acute PAD = 3 mg/kg/day (NOAEL) = 0.03 mg/kg/day

 100 (UF)

A.3.2 Acute Reference Dose (aRfD) - General population, including infants and 

children

No appropriate endpoints were selected because no toxic effects that could result from a single 

dose and that were relevant to the general population (including infants and children) were 

identified in the database.
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A.3.3 Chronic Reference Dose (cRfD) –all populations

Study Selected: Combined chronic carcinogenicity - rat

MRID No.: 44295028

Executive Summary: See Appendix A

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/day, Endpoint = increased 

chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, 

MCH, and MCHC) seen at the LOAEL of 18 mg/kg/day.

Uncertainty Factor(s): 100X [10 interspecies; 10X intraspecies].

Comments about Study/Endpoint/Uncertainty Factors: The duration and route of exposure 

in the rat study are applicable to the chronic dietary route (oral) and duration of exposure (long 

term to lifetime). In addition, the rat is the most sensitive species. In the one-year dog study, 

liver effects were observed at the LOAEL of 1000 mg/kg/day, with a NOAEL of 100 mg/kg/day. 

In the carcinogenicity study in the mouse, no systemic effects were seen at the highest dose 

tested. Finally, the NOAEL selected from the rat study is the lowest observed in the submitted 

studies, and is protective of all other effects, including the offspring effects in the reproductive 

toxicity study. As the FQPA factor has been reduced to 1x, and there are no other uncertainty 

factors needed, the standard 100x (10x for interspecies extrapolation and 10x for intraspecies 

variability) UF has been applied to attain the chronic RfD and PAD, which are equivalent.

Chronic RfD = Chronic PAD = 2 mg/kg/day (NOAEL) = 0.02 mg/kg/day

 100 (UF) 

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: Reproduction and fertility effects - rat

MRID No.: 42684934 and 42684936 (pilot studies); 42684935 (main study)

Executive Summary: See Appendix A

Dose and Endpoint for Risk Assessment: NOAEL = 6.3 mg/kg/day, Endpoint = decreased 

live born pups and decreased pup body weight, and testicular atrophy in F1 males seen at the 

LOAEL of 12.7 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The endpoint and dose have been 

selected from an oral study, which is appropriate for assessing the incidental oral pathway of 

exposure. In addition, the endpoint, offspring effects in a reproduction study, is relevant for the 

exposed population (infants and children) and, therefore, the risk assessment will be protective 
Page 52 of 70

for the qualitative and quantitative susceptibility observed in the reproduction study. As the 

FQPA factor has been reduced to 1x, and a clear NOAEL and LOAEL were identified in the 

study, the standard UFs of 100x (10x for interspecies extrapolation and 10x for intraspecies 

variability) define the level of concern (LOC) for risk assessment as a MOE of less than 100 for 

residential exposure and risk assessments.

A.3.5 Dermal Absorption

Study Selected: Dermal penetration - rat

MRID No.: 42684944

Dermal absorption following application of 200 and 800 mg/kg was 3.9% and 8.0%, 

respectively, by 48 hours after initiation of treatment for 6 hours. Blood levels at 6-24 hours 

after dermal dosing with 200 mg/kg were similar to those obtained at 2-6 hours after oral dosing 

with 1 mg/kg. Blood levels at 6-24 hours after dermal dosing with 800 mg/kg were similar to 

those obtained at 2-6 hours after oral dosing with 30 mg/kg. For the purpose of risk assessment, 

an upper-bound estimate of 8% dermal absorption should be used.

A.3.6 Dermal Exposure (Short and Intermediate-Term) for Children

Study Selected: Reproduction and fertility effects - Rat

MRID No.: 42684934 and 42684936 (pilot studies); 42684935 (main study)

Dose and Endpoint for Risk Assessment: NOAEL = 6.3 mg/kg/day, Endpoint = decreased live 

born pups and decreased pup body weight, and testicular atrophy in F1 males seen at the LOAEL 

of 12.7 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The endpoint and dose have been 

selected from the oral reproductive toxicity study in the rat. The route-specific dermal study was 

not appropriate because reproductive parameters were not measured in the dermal study in rats. 

In addition, the endpoint, offspring effects in a reproduction study, is relevant for the exposed 

population (infants and children) and, therefore, the risk assessment will be protective for the 

qualitative and quantitative susceptibility observed in the reproduction study. As the FQPA 

factor has been reduced to 1x, and a clear NOAEL and LOAEL were identified in the study, the 

standard UFs of 100x (10x for interspecies extrapolation and 10x for intraspecies variability) 

define the LOC for risk assessment as an MOE of less than 100 for residential exposure and risk 

assessment. The 8% dermal absorption value should be used for route-to-route extrapolation, 

i.e., an oral study is used for dermal risk assessment.

A.3.7 Dermal Exposure (Short-, Intermediate- and Long-Term) for Adults

Study Selected: Dermal Developmental Study (Rat)
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MRID No.: 42684929 (pilot); 42684926 (main study)

Dose and Endpoint for Risk Assessment: Dermal NOAEL = 30 mg/kg/day, Endpoint = 

cardiovascular effects, specifically ventricular septal defects, in fetuses observed at the LOAEL 

of 100 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for dermal risk 

assessment because the most critical toxic effect, ventricular septal defect in fetuses, was 

evaluated following exposure via the dermal route. This study is appropriate for all durations 

because of the developmental toxicity concerns. The oral NOAEL selected for chronic dietary 

risk assessment is typically used to assess long-term dermal risk. However, for flumioxazin, the 

developmental NOAEL was selected for all dermal exposures, including long-term, because the 

use of the oral NOAEL of 2.0 mg/kg/day (chronic RfD) with an 8% dermal absorption factor 

yielded a dermal equivalent dose of 25 mg/kg/day (2.0/0.08 = 25), which is comparable to the 

selected dermal NOAEL of 30 mg/kg/day.

As the FQPA factor has been reduced to 1x, and a clear NOAEL and LOAEL were identified in 

the study, the standard UFs of 100x (10x for interspecies extrapolation and 10x for intraspecies 

variability) define the LOC for risk assessment as an MOE of less than 100 for both residential 

and occupational exposure and risk assessment.

A.3.8 Inhalation Exposure (Short- and Intermediate-Term) for Adults

Study Selected: Oral Developmental Study (Rat)

MRID No.: 42684930 (pilot study); 42684925 (main study); 42884006

Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day, Endpoint = cardiovascular 

effects, specifically ventricular septal defects, in fetuses seen at the LOAEL of 10 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: In the absence of an inhalation study with 

flumioxazin, HED selected the endpoint from an oral study. The developmental study was 

considered to be the most appropriate for both short- and intermediate-term exposure, and the 

selection of the endpoint ensures the risk assessment is protective of potential developmental 

effects. The selection of the developmental effects allows for aggregation of dermal and 

inhalation exposure for both residential and occupational scenarios. As an oral study was 

selected for the inhalation route, an inhalation absorption factor of 100% should be applied for

risk assessment.

Because the FQPA factor has been reduced to 1x, and a clear NOAEL and LOAEL were 

identified in the study, the standard UFs of 100x (10x for interspecies extrapolation and 10x for 

intraspecies variability) define the LOC for risk assessment as an MOE of less than 100 for both 

residential and occupational exposure and risk assessment.
Page 54 of 70

A.3.9 Inhalation Exposure (Long-Term) for Adults

Study Selected: 2-Year Chronic/Carcinogenicity Study (Rat)

MRID No.: 44295028

Dose and Endpoint for Risk Assessment: NOAEL = 2 mg/kg/day, Endpoint = increased chronic 

nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH, 

and MCHC) seen at the LOAEL of 18 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: In the absence of an inhalation study for 

flumioxazin, HED selected an oral study. The duration of exposure in the chronic rat study is 

applicable to long-term durations of exposure. In addition, the rat is the most sensitive species. 

In the one-year dog study, liver effects were observed at the LOAEL of 1000 mg/kg/day, with a 

NOAEL of 100 mg/kg/day. In the carcinogenicity study in the mouse, no systemic effects were 

seen at the highest dose tested. Furthermore, the selected NOAEL is the lowest observed in the 

submitted studies, and is protective of all other effects, including the offspring effects in the 

reproductive toxicity study. As a route-specific inhalation study is not available, an inhalation 

absorption factor of 100% should be used for risk assessment purposes. Finally, because the 

FQPA factor has been reduced to 1x, and a clear NOAEL and LOAEL were identified in the 

study, the standard UFs of 100x (10x for interspecies extrapolation and 10x for intraspecies 

variability) define the LOC for risk assessment as an MOE of less than 100 for both residential 

and occupational exposure and risk assessment.

A.4 Executive Summaries 

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a 13-week subchronic feeding study S-53482 Technical (98.4% purity) was administered to 

Crj:CD(SD) rats from Charles River Japan (12/sex/dose level) for a period of 13 weeks in the 

diet at dose levels of 0, 30, 300, 1000 or 3000 ppm (approximately 0, 2.3, 20.7, 69.7, and 243.5 

mg/kg b.w./day, respectively in males and 0, 2.2, 21.7, 71.5, and 229.6 mg/kg b.w./day, 

respectively in females). Mean body weight gains by week 13 were statistically significantly 

smaller than in controls at 3000 ppm (amounting to 83-89% of controls) in both sexes. 

Hematology parameters and bone marrow examination were consistent with anemia and bone 

marrow response in both sexes. In males there were statistically significant decreases in 

hemoglobin (by 8.2%), hematocrit (by 8.4%), MCH (by 9.4%) at 3000 ppm and of MCV at 1000 

ppm (by 3.8%) and at 3000 ppm (by 9.9%). In addition, reticulocytes were statistically 

significantly increased from 0.9% to 1.7% at the 3000 ppm level. There were also statistically

significant changes in bone marrow parameters: erythroblasts were increased from 0.4 to 7.8 per 

100 WBC and the granulocyte/erythroblast ratio was decreased from 1.7 to 1.0 in 3000 ppm rats. 

In females there were statistically significant decreases at 3000 ppm in erythrocyte count (by 

11.2%), hemoglobin (by 25.5%), hematocrit (by 25.1%), MCH (by 15.9%), and MCV (by 
Page 55 of 70

15.3%). Reticulocytes were statistically significantly increased vs controls from 1.2% to 3.1% at 

the 3000 ppm level. Additionally, statistically significant changes in bone marrow parameters 

were: erythroblasts were up from 0.4 to 31.3 per 100 WBC and the granulocyte/erythroblast ratio 

was decreased from 1.7 to 0.4 in 3000 ppm rats. Absolute and relative spleen weights were 

elevated in both sexes at 3000 ppm. Microscopic pathology examination revealed 

extramedullary hematopoiesis in spleens in 8/12 males and in all females at 3000 ppm. The 

LOAEL = 3000 ppm (mg/kg/day: males = 243.5, females = 229.6) and is based on doserelated findings in hematology (statistically significant decrease in MCV in both sexes at 

3000 ppm [mg/kg/day: males = 243.5, females = 229.6] and statistically significant increases 

in platelets at 3000 ppm [mg/kg/day: 229.6] in females). The NOAEL = 1000 ppm 

(mg/kg/day: males = 69.7, females = 71.5)

This study is classified as Core Supplementary. This study does not satisfy the requirement 

(82-1) for a subchronic oral toxicity study in rodents. This study may be upgraded to Core

Minimum if the following additional information is provided and is judged to be acceptable: (1) 

Data to support the stability of the test material in the prepared diets under the condition of 

storage between the time of preparation and use; (2) Clinical chemistry data for individual males 

(only summary tables were available); (3) Individual gross pathology data for all animals except 

the 1000 and 3000 ppm males (summary tables and individual data for 1000 and 3000 ppm 

males were available).

In a subchronic feeding study, S-53482 Technical (94.8%) was administered to male and female 

Crj:CD Sprague-Dawley rats (16/sex/group) at dietary levels of 0, 30, 300, 1000, and 3000 ppm 

(approximate doses of 0, 1.9, 19.3, 65.0, and 196.7 mg/kg/day for males, and 0, 2.2, 22.4, 72.9, 

and 218.4 mg/kg/day for females) for 90 days. Dose-related changes in hematology parameters 

and histopathology, associated with anemia, were seen in females at 300 ppm and above and in 

males at 1000 ppm and above. In females, decreases (p<0.05) in MCV (3%) and MCH (3%) and 

increased extramedullary hematopoiesis in spleen (1/10 vs 0/10 in controls) were observed at 

300 ppm. At 3000 ppm, decreases (p<0.05) in MCV (18%), MCH (25%), MCHC (9%) and 

other hematology parameters were coupled to increased reticulocyte count (up to 3.9%) and 

extramedullary hematopoiesis in spleen (10/10) and liver (5/10). In males, decreases (p<0.05) in 

MCV (6%) and MCH (7%) and increased extramedullary hematopoiesis in spleen (1/10 vs 0/10 

in controls) were observed at 1000 ppm. At 3000 ppm, decreases (p<0.05) in MCV (11%), 

MCH (14%), MCHC (9%) were coupled to increased reticulocyte count (up to 1.4) and 

extramedullary hematopoiesis in the spleen (6/10). LOAEL = 3000 ppm (196.7 mg/kg/day for 

males and 218.4 mg/kg/day for females) are based on dose-related alterations in 

hematology parameters and histologic alterations associated with anemia. NOAEL = 1000 

ppm (65.0 mg/kg/day for males and 72.9 mg/kg/day for females). This study is Core 

Minimum and satisfies the requirement (82-1) for a subchronic oral toxicity study in rats.

870.3150 90-Day Oral Toxicity – Dog

S-53482 Technical was administered to beagle dogs of both sexes for a period of 13 weeks via 

gelatin capsules at dose levels of 0, 10, 100, or 1000 mg/kg/day. Clinical chemistry parameters 
Page 56 of 70

showed dose-related increases in total cholesterol, phospholipid and alkaline phosphatase, which 

became statistically significant in 1000 mg/kg/day males (cholesterol, phospholipid) cr females 

(alkaline phophatase). In addition, at 1000 mg/kg/day, treatment-related effects in male and 

female dogs included increased liver weights, gross hepatic lesions (rounded margin and 

enlargement) and microscopic hepatic lesions (proliferation and dilatation of bile duct and 

smooth endoplasmic reticulum in hepatocytes and increased fibrous tissue around the 

centrilobular veins). LOEL: 100 mg/kg/day (based on dose dependent increases in dosedependent increases in total cholesterol, and phospholipid levels and alkaline phosphatase

activity). NOEL: 10 mg/kg/day. CORE Classification: Supplementary. The study is 

upgradeable pending submission of stability data in the used diet.

A.4.2 Pre-natal Developmental Toxicity

870.3700a Pre-natal Developmental Toxicity Study – Rat

Executive Summary: In an oral developmental toxicity study, the test substance, S-54382 

(94.8% purity), was administered once daily by gavage to pregnant female Scl:SD (SpragueDawley) rats on days 6-15 of gestation (with the day of mating defined as gestation Day 0) at 

dose levels of 0, 1, 3, 1 0 and 30 mg/kg/day. The rats were observed for signs of toxicity; body 

weight and food consumption values were recorded. On day 20 of gestation, the rats were 

sacrificed and necropsied; gravid uterine weights were recorded. The uteri were examined, 

implantation sites were counted, and the numbers of corpora lutea were determined. The fetuses

were removed, weighed, sexed, and examined for external anomalies. They were then processed 

for visceral or skeletal evaluation.

There were no treatment-related effects on maternal mortality, clinical observations, body 

weight, food consumption or gross pathology data. Maternal LOAEL = Not determined; 

Maternal NOAEL = 30 mg/kg/day. At the 30 mg/kg/day dose level, a treatment-related 

increase in fetal death (5.6% resorptions in control versus 20.4% at the high-dose), a 21% 

decrease in mean live litter size, and a decrease in male (14.3%) and female (15.2%) fetal body 

weights were noted as compared to control. A dose and treatment-related increase in the 

incidence of fetuses with cardiovascular abnormalities, particularly ventricular septal defect, was 

observed. Ventricular septal defect was noted in the following numbers of fetuses (litters) for the

control, 1, 3, 10 and 30 mg/kg/day dose groups, respectively: 2(2), l(l), 2(2), 6(6), and 26(12); 

combined cardiovascular abnormalities were noted with the following distribution: 8(6), 7(6), 

10(8), 13(9), and 36(14). These findings were both statistically significant at 30 mg/kg/day, and 

the increased incidence of cardiovascular abnormalities was judged to be biologically significant 

at 10 mg/kg/day. Appropriate historical control data submitted by the performing laboratory 

support and confirm these conclusions. Also at the 30 mg/kg/day dose level, significantly 

increased incidences of wavy ribs (27 fetuses, representing 12 of 18 litters) and curvature of the 

scapula (10 fetuses in 4 litters) and a significant 4-7% decrease in the number of ossified 

sacrococcygeal vertebral bodies as compared to control were attributed to treatment. 

Developmental LOAEL = 10 mg/kg/day; Developmental NOAEL = 3 mg/kg/day, based on a 

biologically significant increase in cardiovascular abnormalities, particularly ventricular septal 
Page 57 of 70

defect; at 30 mg/kg/day, statistical significance was achieved for these observations and the

following additional findings were noted: increased resorptions and decreased number of viable 

fetuses, decreased fetal body weight, increased abnormalities of the ribs (wavy) and scapula 

(curvature), and decreased numbers of ossified sacrococcygeal vertebral bodies.

The above findings were generally similar to those observed in the dermal developmental 

toxicity study in rats conducted with S-53482 (MRID No. 42684926, Teratology Study of S53482 Administered Dermally to Rats, performed by Sumitomo Chemical Co. Ltd., for Valent 

U.S.A. Corporation, project No. 2018, March 14, 1991). In that study, a dose- and treatmentrelated increase in the incidence of cardiovascular abnormalities, particularly ventricular septal 

defect, was noted for fetuses of dams treated by 6-hour dermal exposure to the test substance on

days 6-15 of gestation. CORE CLASSIFICATION: not acceptable/guideline; does not satisfy 

the requirement (83-3) for an oral developmental toxicity (teratology) study in rats; this 

study can be upgraded to acceptable following the receipt of the following acceptable individual 

fetal observation data: body weight, external observations, visceral findings, and skeletal 

findings.

Executive Summary: In a dermal developmental toxicity study, the test substance, S-54382 

(94.8% purity), was administered by 6-hour daily dermal application to pregnant female Scl: SD 

(Sprague-Dawley) rats on days 6-15 of gestation (with the day of mating defined as gestation 

Day 0) at dose levels of 0, 30, 100, and 300 mg/kg/day. The rats were observed for signs of 

toxicity; body weight and food consumption values were recorded. On day 20 of gestation, the 

rats were sacrificed and necropsied; gravid uterine weights were recorded. The uteri were 

examined, implantation sites were counted, and the numbers of corpora lutea were determined. 

The fetuses were removed, weighed, sexed, and examined for external anomalies. They were 

then processed for visceral or skeletal evaluation. There were no systemic treatment-related 

effects on maternal mortality, clinical observation, body weight, food consumption, or gross 

pathology data. Maternal LOAEL = not determined; Maternal NOAEL= 300 mg/kg/day.

A dose- and treatment-related increase in the incidence of fetuses with cardiovascular 

abnormalities, particularly ventricular septal defect, was observed. Ventricular septal defect was 

noted in the following numbers of fetuses (litters) for the control, 30, 100, and 300 mg/kg/day 

dose groups, respectively: l(l), l(l), 2(2), and 13(9); combined cardiovascular abnormalities were 

noted with the following distribution: 5(5), 4(4), 10(7), and 19(9). These findings were both 

statistically significant at 300 mg/kg/day, and the increased incidence of cardiovascular 

abnormalities was judged to be biologically significant at 100 mg/kg/day. Appropriate historical 

control data submitted by the performing laboratory support and confirm these conclusions. At 

the 300 mg/kg/day dose level, an increase in fetal death (40.7% resorptions as compared to 6.0% 

in controls), a 40% decrease in live litter size, and a 6-9% decrease in fetal body weights were 

attributed to treatment. t the same dose level, significantly increased incidences of wavy ribs (18 

fetuses, representing 10 of 17 litters) and a 3.4% decrease in the mean number of ossified 

sacrococcygeal vertebral bodies were attributed to treatment. Developmental LOAEL = 100 

mg/kg/day; Developmental NOAEL = 30 mg/kg/day, based on a biologically significant 

increase in cardiovascular abnormalities, particularly ventricular septal defect; at 300 mg/kg/day, 

statistical significance was achieved for these observations and the following additional findings 

were noted: increased resorptions and decreased number of viable fetuses, decreased fetal body 
Page 58 of 70

weight, increased abnormalities of the ribs (wavy), and decreased numbers of ossified 

sacrococcygeal vertebral bodies. The above findings were generally similar to those observed in 

the oral developmental toxicity study in rats conducted with S-53482 (MRID No. 42684925, 

Teratology Study of 6 S-53482 Administered Orally to Rats, performed by Sumitomo Chemical 

Co. Ltd., for Valent U.S.A. Corporation, project No. 1759, August 28, 1990). In that study, a 

dose- and treatment-related increase in the incidence of cardiovascular abnormalities, 

particularly ventricular septal defect, was noted for fetuses of dams treated on days 6-15 of 

gestation. CORE CLASSIFICATION: not acceptable/guideline; does not satisfy the 

requirement (83-3) for a dermal developmental toxicity (teratology) study in rats; this study 

can be upgraded to acceptable following the receipt of the following acceptable individual fetal 

observation data: body weight, external observations, visceral findings, and skeletal findings.

870.3700b Pre-natal Developmental Toxicity Study – Rabbit

Executive Summary: In a developmental toxicity study, New Zealand White rabbits received V53482 (94.8% purity) daily via gavage at doses of 0, 300, 1000, or 3000 mg/kg/day on 

gestational days (GDs) 7-19, inclusively. Group mean body weight gain (kg) during dosing 

(gestation days 7-19) were as follows (0, 300, 1000 or 3000 mg/kg/day): 0.17, 0.18, 0.14 and 

0.05 (p<0.05). Group mean food consumption (g/kg/day) during dosing were as follows: 42.9, 

42.1, 39.4 and 35.7 (p<0.05). No other parameters (maternal or developmental) were considered 

to have been affected by test article administration. Maternal LOAEL = 3000 mg/kg/day 

based on decreased body weight and food consumption mostly during the dosing period 

Maternal NOAEL = 1000 mg/kg/day. Developmental LOAEL = not determined 

Developmental NOAEL = 3000 mg/kg/day This study is considered to be 

acceptable/guideline and meets the requirements to fulfill 83-3 for a developmental toxicity 

study in rabbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

Executive Summary: In a two-generation reproduction study, Sprague-Dawley rats were fed V53482 (94.8% purity) in the diet at dosage levels of 0, 50, 100, 200 or 300 ppm (during 

premating, at least 0, 3.2, 6.3, 12.7, and 18.9 mg/kg/day in males and 0, 3.8, 7.6, 15. 1, and 22.7 

mg/kg/day in females, respectively). There were no definitive clinical signs attributed to test 

article administration in males of either generation. In F0 females only, there was an increase 

(p<0.01) in the incidence of "red substance in vagina" only at 300 ppm (9/25 versus 0-1/27-30 

for the other 4 groups). The mortality in the F1 females was as follows for 0, 50, 100, 200 or 

300 ppm: 0, 1, 0, 0 and 5 (p<0.01). Group mean body weight gains were less than control 

(p<0.05 or 0.01) in F1 males and females during the first week of premating. During gestation, 

F0 and F1 females had lower body weight gain (p<0.01) during the last 5 days and for the entire 

period of gestation(28-31% decrease in gain). There was a decrease in food consumption in 300 

ppm females of both generations: F0, 65-84% of control during lactation (p<0.05 or 0.01); F1, 

92-95% of controls during gestation (p<0.05 or 0.01); and F1, 78-89% of control during lactation 

(p<0.05 or 0.01). The incidence of grossly observable yellow livers was increased in 300 ppm 
Page 59 of 70

F1 females that died (p<0.01, 3/30 versus 0/30 for controls). There was a decrease (p<0.01) in 

absolute only testis and epididymides weights in 300 ppm F1 males (not F0). [Study authors 

excluded all rats with small organs from the analysis.] No definitive histopathological changes 

were attributed to test article administration. There was the suggestion of 

atrophied/hypoplastic/hypospermia of the testes and/or epididymides in both generations of 300 

ppm males (of 30 males examined in 0 and 300 ppm groups, the treated group had no more than 

one finding more than the control group). Tissues from the 100 and 200 ppm (and most of the 50 

ppm) groups were not evaluated. In F1 300 ppm females that died, liver lobular necrosis and 

bile stasis was observed (2-3/4 examined). Systemic LOAEL = 300 ppm (mg/kg/day: males = 

18.9, females = 22.7) based on increased clinical signs (F0 females); increased mortality (Fl 

females), gross and histopathology findings in the liver (Fl females); decreased body 

weight/weight gain (F0 and Fl females during gestation, Fl males during the early portion 

of premating); and decreased food consumption (F0 and Fl females during lactation). 

Systemic NOAEL = 200 ppm (mg/kg/day: males = 12.7, females = 15.1) In both generations, 

the following reproductive parameters were affected primarily at 300 ppm and to a lesser extent 

at 200 ppm: females with liveborn (300 ppm, 16/21 for Fl pups and 16/18 for F2 pups; control, 

23/23 and 23/23); mean number of live pups/litter on day one of lactation (300 ppm 7/9; control, 

14/16); mean pup weight on lactation day one (300 ppm, 5.7/5.6 g; 200 ppm, 6.1/6.1; control, 

6.9/6.4). Reproduction/Offspring LOAEL = 200 ppm (mg/kg/day: males = 12.7, females = 

15.1) based on decreased number of females with liveborn and mean number of pups/litter 

on lactation day 1, decreased pup body weight, testicular atrophy in F1 males and 

decreased mating index. Reproduction/Offspring NOAEL = 100 ppm (mg/kg/day: males = 

6.3, females = 7.6). This study is classified acceptable/guideline and meets the requirements of 

83-4 for a two generation reproductive toxicity study in rats.

A.4.4 Chronic Toxicity/Carcinogenicity

870.4200a Chronic Toxicity/Carcinogenicity Study – Rat

In a combined chronic/oncogenicity study (MRID 44295028), flumioxazin (technical, 94.8% a.i., 

S-53482) was administered in the diet for up to 24 months to 74 Crj CD (SD) rats/sex/dose at 

levels of 0, 50, 500, and 1000 ppm (equivalent to 0, 1.8, 18.0, and 36.5 mg/kg/day in male rats 

and 0, 2.2, 21.8, and 43.6 mg/kg/day in female rats). At approximately 52 and 78 weeks 10-14 

rats per group were terminated and all remaining animals were terminated at approximately 104 

weeks. Survival rates, clinical observations, clinical chemistry, ophthalmoscopic, urinalysis, and 

gross pathologic parameters were unaffected by treatment with S-53482. Minor changes (2-

15%) in hematological parameters (hemoglobin, MCV, MCH, MCHC) in the mid and high-dose 

females were consistent with a chronic mild anemia. The presence of circulating erythroblasts in 

peripheral blood, reticulocytosis, decreased bone marrow Myeloid/Erythroid ratio (949%, 

p<0.05) and splenic extramedullary hematopoiesis (8/10 treated; 6/10 controls, p<0.05) are 

consistent with a severe stress on erythropoiesis similar to what might be observed in chronic 

iron deficiency. However, the relatively moderate decreases in hemoglobin and lack of 

progression to a more severe type of anemia such as aplastic anemia or pancytopenia indicate 

successful compensatory erythropoiesis. Histopathological changes of the kidney indicative of 
Page 60 of 70

slight to mild chronic nephropathy was found at the final necropsy in the 500 (18.0 mg/kg/day) 

and 1000 (36.5 mg/kg/dah) ppm male groups (26-27/33 treated vs 13/31 controls, p<0.01). The 

chronic LOAEL is 500 ppm (equivalent to 18.0 and 21.8 mg/kg/day in males and females, 

respectively) based upon decreased hemoglobin, MCV, MCH and MCHC in females and 

increased incidence of chronic nephropathy in males. The chronic NOAEL is 50 ppm 

(equivalent to 1.8 and 2.2 g/kg/day in males and females, respectively). Under the conditions 

of this study, there was no evidence of carcinogenic potential. Dosing was considered adequate 

due to hematological and histopathological changes observed in the mid- and high-dose animals. 

This study is classified as acceptable (§83-5; 870.4300) and satisfies the guideline requirements 

for a combined chronic toxicity study and a carcinogenicity study in rats.

870.4200b Carcinogenicity (feeding) – Mouse

In a mouse oncogenicity study (MRID 44295018), flumioxazin technical, 94.8% a.i. (S-53482) 

was administered in the diet for 78 weeks to 51 CD-1 mice/sex/dose at levels of 0, 300, 3000 or 

7000 ppm which is equivalent to dietary levels of 0, 31.1, 314.9 or 754.1 mg/kg/day in males and 

0, 36.6, 346.4,or 859.1 mg/kg/day in females, respectively. An additional 15 mice/sex/dose were 

used to provide samples for hematological examination, pathology and histopathology. These 

animals were terminated at 53 weeks. All remaining animals were sacrificed at 79 weeks of the 

study. Survival rates, clinical observations, body weights, feed consumption, organ weights, 

gross pathology and hematological parameters were unaffected by treatment with S-53482. No 

clinical chemistry was performed. There were statistically significant increases in malignant 

lymphoma/leukemia in mid-dose males (6/15 treated; 1/14 controls, p<0.05) and increases in 

pulmonary adenoma in mid-dose females (5/51 treated; 0/50 control, p<0.05), these tumor 

incidences were comparable to historical controls and did not exhibit dose-dependency. The 

LOAEL was not observed. The chronic NOAEL is > 7000 ppm which is equivalent to 754.1 and 

859.1 mg/kg/day in male and female mice, respectively. Under the conditions of this study, 

there was no evidence of carcinogenic potential. Dosing was considered adequate because the 

highest dose of 7000 ppm represented a "limit dose". This study is classified as acceptable (§83-

2b; 870.4200) and satisfies the guideline requirements for a carcinogenicity study in mice.

A.4.5 Neurotoxicity

Acute Neurotoxicity Study

In an acute neurotoxicity study (MRID 48402405), groups of 6 week old Crl:CD(SD) rats

(12/sex/dose) were given a single oral dose of Flumioxazin TG (99.6 % a.i., Lot no. 080839G) in 

0.5% methylcellulose at doses of 0, 200, 700 or 2000 mg/kg bw and observed for 14 days. 

Neurobehavioral assessment (functional observational battery and motor activity testing) was

performed in 12 animals/sex/group 8 hours following dose administration and on study days 7 

and 14. At study termination, 6 animals/sex in the control and 2000 mg/kg bw/groups were 

euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 6

animals/sex in the control and 2000 mg/kg bw/groups were subjected to histopathological 

evaluation of brain and peripheral nervous system tissues. 
Page 61 of 70

Significant (p<0.05 or p<0.0l) increases in mean brain width were observed in a somewhat dosedependent manner for males in all test substance-treated groups, however, these mean values 

were generally within the mean brain width in the historical control database. The brain width in 

males in the 2000 mg/kg group was above the range of male brain widths in the historical control 

data base. Although, it appears that there was a dose-related effect on mean brain width in males 

in this study, there was close similarity in widths between the 200, 700 and 2000 mg/kg groups.

The brain widths relative to brain weights were unaffected and no histologic correlates were 

evident. The mean brain weight for the 2000 mg/kg group females was statistically lower than 

for the control group; however, all individual animal data were within the historical control

range, no effects on brain length or width were evident, and no histologic correlates were noted. 

These brain measurements differences were not considered evidence of a test substance relatedeffect.

Based on the effects seen in this study, the LOAEL for is >2000 mg/kg bw. The NOAEL is 

2000 mg/kg bw.

This neurotoxicity study is classified as acceptable/guideline and satisfies the guideline 

requirement for an acute neurotoxicity study in rats (870.6200; OECD 424). The sensitivity of 

the test system was confirmed by the incorporation of positive control data.

Subchronic Neurotoxicity Study

In a subchronic (90-day) neurotoxicity study (MRID 48651401) Flumioxazin (99.6% a.i., 

batch/lot # 080839G) was administered to12 Crl:CD(SD rats/sex/group at dose levels of 0, 500, 

1500, or 4500 ppm (equivalent to 0, 37/41, 110/124, 323/358 mg/kg bw/day for males/females) 

for 13 weeks. Neurobehavioral assessment (functional observational battery and motor activity 

testing) was performed in12 animals/sex/group during pretest and at study Weeks 3, 7, 12. At 

study termination, all surviving animals were euthanized and perfused in situ for 

neuropathological examination. Of the perfused animals, 6 animals/sex in the control and 4500 

ppm groups were subjected to histopathological evaluation of brain and peripheral nervous 

system tissues. 

All animals survived to the scheduled necropsy, except one female in the 4500 ppm group which 

was euthanized in extremis on Day 70 due to moribund conditions not related to test substance 

treatment. In surviving animals, there were no test substance-related clinical signs observed at 

any dietary dose level in either males or females.

No adverse, treatment-related effects were observed on survival, clinical signs, mean body 

weights, body weight gains, and food consumption at any dietary concentration level in males 

and females. In addition, no compound-related alterations were observed in gross histopathology 

observations, brain weights and measurements or microscopic neurohistopathology findings at 

4500 ppm males and females.
Page 62 of 70

In males, there were treatment-related effects on hemoglobin, hematocrit, mean corpuscular 

volume (MCV) and mean corpuscular hemoglobin (MCH). Hemoglobin and hematocrit were 

significantly decreased by 6% (p≤0.01) in the 1500 ppm male group and by 13% and 10%

(p≤0.01), respectively, at 4500 ppm males at Week 13. Significant (p≤0.05 or p≤0.01) decreases 

in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were noted in the 

500 ppm, 1500 ppm, and 4500 ppm groups. However, the lower MCV (49.2 fL) and MCH (17.1 

pg) values were within the range of the WIL historical control data of 48.3-70.9 fL for MCV and 

16.9-21.5 pg for MCH. Therefore, these significant decreases in the 500 ppm male group were 

considered not adverse effects. Increased reticulocyte values (94-97%, p≤0.01) were noted in the 

4500 ppm males when compared to the controls at Week 13. The alterations in the hematology 

parameters were consistent with a regenerative microcytic, hypochromic anemia.

Similarly, in the females, treatment-related effects were noted in the following hematologic 

parameters: hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular 

hemoglobin (MCH) and MCHC at dietary concentration levels of 1500 ppm and 4500 ppm at 

Week 13. At 1500 ppm, hemoglobin and hematocrit were decreased by 8% and 5%, respectively, 

when compared to the controls. Also, significant decreases in hemoglobin (23 %, p≤0.01) and 

hematocrit (16 %, p≤0.01) values were observed in the 4500 ppm females group. There were 

significant higher reticulocyte counts (171%-186%, p≤0.01) and platelet counts (24%, p≤0.01)

and lower absolute cell count in the 4500 ppm female group when compared to controls. 

Significantly (p≤0.05 or p≤0.01) lower absolute lymphocyte count and white blood cell were 

noted in the 500 and 1500 ppm female group, and a higher red blood cell count in the 1500 ppm 

group. These results indicated that females and males exhibited a similar characteristic anemia 

due to exposure to the test substance. This hematotoxicity effect of Flumioxazin has been 

observed in earlier studies. 

The neurological test measures (FOB and motor activity) and neurohistopathology examinations 

in this study showed no Flumioxazin-related neurotoxic effects in rats exposed to dietary 

concentration ranging up to 4500 ppm.

Based on the results of this study, the NOAEL for subchronic neurotoxicity was 4500 ppm 

for males (equivalent to 323 mg/kg/day) and females (equivalent to 358 mg/kg/day). The 

systemic toxicity LOAEL for Flumioxazin is 1500 ppm (equivalent to 110/124 mg/kg 

bw/day for males/females, respectively), based on signs of anemia [decreased hemoglobin 

and hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH)]. 

The NOAEL for systemic toxicity is 500 ppm (equivalent to 37/41 mg/kg bw/day for 

males/females, respectively).

The study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.6200b; OECD 424) for a subchronic neurotoxicity study in rats.
Page 63 of 70

A.4.6 Metabolism

870.7485 Metabolism – Rat

Executive Summary: In a metabolism study, [phenyl-U-’4C)S-53482 was administered to 

Sprague-Dawley rats (5/sex/dose) as a single oral dose of 1 mg/kg or 100 mg/kg or as a single 

oral dose of 1 mg/kg following a 14-day pretreatment with unlabeled 5-53482 at 1 mg/kg/day. 

C.I. tract absorption of S-53482 may amount to over 90% of the dose at 1 mg/kg and to about 

50% at 100 mg/kg. Total recovery of radioactivity in feces and urine, 7 days after dosing, 

accounted for 96.5- 100.7% of the dose in all test groups. Radioactivity excretion in urine was 

statistically significantly elevated in females (38.8-42.8%, low dose; 22.9- 23.4%, high dose) vs. 

males (28.1-30.8%, low dose; 12.8-13.0%, high dose). Highest levels of residues were found in 

blood cells (35.9-48.8 ppb, low dose and 2823-3040 ppb, high dose), which were much higher 

than the plasma levels (0.5-0.7 ppb, low dose and 53-37 ppb, high dose). TLC analysis of feces 

and urine revealed up to 35 putative metabolites. In addition to untransformed parent compound, 

7 metabolites were identified in urine and feces. Identified compounds amounted to 37.5-46.1% 

of the dose at the low dose treatments and to 70.7-71.5% of the dose at the high dose. The study 

is classified as Core Supplementary Data. This study does not satisfy at present the requirement, 

§ 85-1 for metabolism study in rats. However, this study an be ungraded to Minimum if 

information (as detailed in p. 13 of the DER) clarifying discrepancies between listed Rfs and 

apparent TLC mobilities of standards, in addition to information on the type of TLC used, is 

provided by the Registrant and is judged to be acceptable by the Agency.

870.7600 Dermal Absorption – Rat

Executive Summary: In a dermal absorption study. 24 male Sprague-Dawley (CD)/dose group 

received (PhenylUHC)S53482 by the dermal route at levels of 0.02, 0.20, or 1.0 mg/rat (0.002, 

0.020 and 0.100 mg/cm2) as a suspension of 50 WDC formulation in water. Four rats/per dose 

level were sacrificed for assessment of dermal absorption after 0.5, 1, 2, 4, 10, and 24 hours of 

exposure. At 0.02 mg/rat absorption ranged from 0.48% of the dose at 0.5 hours to 5.46% by 26 

hours. In addition, at 24 hours the sum of material remaining in skin plus material absorbed 

amounted to 8.4% of the dose at 10 hours and to 18.5% of the dose at 24 hours. At 0.2 mg/rat 

(0.02 mg/cm), absorption ranged from 0.007% of the dose at 0.5 hours to 0.74% at 24 hours. In 

addition, the sum of material remaining in skin plus material absorbed amounted to .2% of the 

dose at 10 hours and to 2.3% of the dose at 24 hours. At 1.0 mg/rat (0.02 mg/cm2), absorption 

ranged from 0.006% of the dose at 0.5 hours to 0.47% at 24 hours. In addition, the sum of 

material remaining in skin plus material absorbed amounted to 1.4% of the dose at 10 hours and 

to 2.4% of the dose at 24 hours. The study is classified as Core Minimum Data (Acceptable) and 

satisfies the requirement (85-2) for a dermal absorption study in rats.

A.4.7. Immunotoxicity Study—Subchronic Rat

In an immunotoxicity study (MRID 48402408) Flumioxazin (99.6%, Lot No. 080839G) was 

administered in the diet to two groups (T-cell dependent antibody response (TDAR) and 
Page 64 of 70

hematology) of female Crl:CD(SD) rats at concentrations of 0 (control), 500, 1500, or 4500 ppm 

for 28 consecutive days (Day 0 –28). Test substance doses were equivalent to 0, 44, 127, and 

375 mg/kg bw/day, respectively, for the TDAR groups (10 females/dose) and 0, 42, 126, and 371 

mg/kg bw/day, respectively, for the hematology groups (5 females/dose). On Day 24, animals in 

the TDAR groups were immunized with a suspension of sheep red blood cells (SRBC) by 

intravenous injection (2x108SRBC/animal, 0.5 mL/animal dose volume). Animals in the 

positive control group received an intraperitoneal injection of cyclophosphamide on Days 24-27 

at a dose of 50 mg/kg bw (10 mL/kg bw dose volume). All animals were evaluated for mortality, 

clinical signs, body weight changes, food consumption, water consumption, and gross pathology. 

Animals in the TDAR groups were evaluated for immunotoxicity by a splenic IgM antibody 

plaque-forming cell (PFC) assay; spleen and thymus weights were determined at necropsy. 

Animals in the hematology groups were evaluated for hematological parameters.

There were no effects of test substance treatment on mortality, clinical signs, body weight, food 

consumption, water consumption, or gross pathology. Mean corpuscular volume and mean 

corpuscular hemoglobin values were significantly decreased in the 1500 and 4500 ppm groups. 

In the 4500 ppm group, mean hemoglobin, mean corpuscular hemoglobin concentration, and 

mean hematocrit values also were significantly decreased; and mean white blood cell, absolute 

and percent reticulocyte, absolute neutrophil, and absolute lymphocyte counts were significantly 

increased. 

The systemic toxicity LOAEL for Flumioxazin in female rats is 1500 ppm (equivalent to 

126 mg/kg bw/day), based on signs of anemia (decreased hemoglobin and hematocrit). The 

NOAEL for systemic toxicity is 500 ppm (equivalent to 42 mg/kg bw/day).

There were no effects of test substance treatment on absolute or relative thymus weights. 

Significantly increased mean absolute and relative spleen weights were observed in the 4500 

ppm group; however, there were no effects of test substance treatment on mean spleen cell 

numbers, or on the IgM antibody-forming cell (AFC) response as evaluated by AFC/106spleen 

cells (specific activity), or AFC/spleen (total activity) in the PFC assay. 

The Natural Killer (NK) cells activity assay was not performed in this study. The toxicology 

database for flumioxazin demonstrated that toxic effects were associated with anemia as well as 

effects on the liver and cardiovascular system. There was no evidence that suggested this 

chemical directly targets the immune system. Under HED guidance, NK cells activity assay is 

not required at this time.

Under conditions of this study, the immunotoxicity NOAEL for anti-SRBC PFC response is 

4500 ppm (375 mg/kg/day), the highest dose tested; a LOAEL was not established. 

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in rats. 
Page 65 of 70

In an immunotoxicity study (MRID 48402408) Flumioxazin (99.6%, Lot No. 080839G) was 

administered in the diet to two groups (T-cell dependent antibody response (TDAR) and 

hematology) of female Crl:CD(SD) rats at concentrations of 0 (control), 500, 1500, or 4500 ppm 

for 28 consecutive days (Day 0 –28). Test substance doses were equivalent to 0, 44, 127, and 

375 mg/kg bw/day, respectively, for the TDAR groups (10 females/dose) and 0, 42, 126, and 371 

mg/kg bw/day, respectively, for the hematology groups (5 females/dose). On Day 24, animals in 

the TDAR groups were immunized with a suspension of sheep red blood cells (SRBC) by 

intravenous injection (2x108SRBC/animal, 0.5 mL/animal dose volume). Animals in the 

positive control group received an intraperitoneal injection of cyclophosphamide on Days 24-27 

at a dose of 50 mg/kg bw (10 mL/kg bw dose volume). All animals were evaluated for mortality, 

clinical signs, body weight changes, food consumption, water consumption, and gross pathology. 

Animals in the TDAR groups were evaluated for immunotoxicity by a splenic IgM antibody 

plaque-forming cell (PFC) assay; spleen and thymus weights were determined at necropsy. 

Animals in the hematology groups were evaluated for hematological parameters.

There were no effects of test substance treatment on mortality, clinical signs, body weight, food 

consumption, water consumption, or gross pathology. Mean corpuscular volume and mean 

corpuscular hemoglobin values were significantly decreased in the 1500 and 4500 ppm groups. 

In the 4500 ppm group, mean hemoglobin, mean corpuscular hemoglobin concentration, and 

mean hematocrit values also were significantly decreased; and mean white blood cell, absolute 

and percent reticulocyte, absolute neutrophil, and absolute lymphocyte counts were significantly 

increased. 

The systemic toxicity LOAEL for Flumioxazin in female rats is 1500 ppm (equivalent to 

126 mg/kg bw/day), based on signs of anemia (decreased hemoglobin and hematocrit). The 

NOAEL for systemic toxicity is 500 ppm (equivalent to 42 mg/kg bw/day).

There were no effects of test substance treatment on absolute or relative thymus weights. 

Significantly increased mean absolute and relative spleen weights were observed in the 4500 

ppm group; however, there were no effects of test substance treatment on mean spleen cell 

numbers, or on the IgM antibody-forming cell (AFC) response as evaluated by AFC/106spleen 

cells (specific activity), or AFC/spleen (total activity) in the PFC assay. 

The Natural Killer (NK) cells activity assay was not performed in this study. The toxicology 

database for flumioxazin demonstrated that toxic effects were associated with anemia as well as 

effects on the liver and cardiovascular system. There was no evidence that suggested this 

chemical directly targets the immune system. Under HED guidance, NK cells activity assay is 

not required at this time.

Under conditions of this study, the immunotoxicity NOAEL for anti-SRBC PFC response is 

4500 ppm (375 mg/kg/day), the highest dose tested; a LOAEL was not established. 

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in rats. 
Page 66 of 70

Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of Flumioxazin. 

Parameter Value Reference

Melting point/range 202-204°C EPA Fact Sheet for 

Flumioxazin issued April 

12, 2001 pH 7.29 at 25°C

Density 1.51 g/mL at 20°C

Water solubility 1.079 g/L at 25°C 

Solvent solubility Not available

Vapor pressure 2.41x10-6 mm Hg

Dissociation constant, pKa None

Octanol/water partition coefficient, 

Log(KOW)

2.55 at 20°C

UV/visible absorption spectrum λ218, ε = 14700 (pH 1.9)

λ216, ε = 43600 (pH 6.8)

λ216 ε = 51200 (pH 10.0)

MRID No. 44295004
Page 67 of 70

Table 4.1.1, lists the updated assessment of currently registered residential handler exposures and 

risk estimates. The updated exposure and risk estimates for all residential handler use pattern 

scenarios result in dermal risk estimates that are greater than or equal to 100 and therefore do not 

exceed HED’s LOC and inhalation risk estimates that are greater than or equal to 1000 and 

therefore do not exceed HED’s LOC.

Appendix C. Residential Exposure/Risk Summary Table

A summary of flumioxazin residential handler exposure/risk is presented in Table C.1 below. 

Table C.1. Residential Flumioxazin Handler Short-and Intermediate-Term Exposure and 

Risk

Use Site Equip. 

Types

App. 

Rate (a)

Area

Treated or 

Amount 

Handled 

Daily (b)

Route of 

Exposure

Dose 

(mg/kg/day)

(c,d)

MOE(e) ARI(f)

Outdoor

Ornamentals 

(Gardens and 

Trees) 

WDG 

Formulations

Hose-End 

Sprayer

0.0000073 1200 ft2

Dermal 0.0074 4,100

41

Inhalation 0.00000018 17,000,000

Backpack 

Sprayer

Dermal 0.0088 3,400

13

Inhalation 0.00014 21,000

ManuallyPressurized 

Handwand,

Dermal 0.0088 3,400

13

Inhalation 0.00014 21,000

Sprinkler 

Can

Dermal 0.0074 4,100

41

Inhalation 0.00000018 17,000,000

Ornamentals 

(Gardens and 

Trees) 

Granular

Formulations

Push Type 

Spreader

0.0000087 1200 ft2

Dermal

0.00012 240,000

1,900

Inhalation 0.00000039 7,600,000

Belly 

Grinder

Dermal

0.054 550

5.5

Inhalation 0.0000058 510,000

spoon

Dermal

0.00094 32,000

130

Inhalation

0.000013 230,000

cup

Dermal 0.000017 1,800,000

1,400

Inhalation

0.000002 1,500,000

Hand Dermal 10
Page 68 of 70

Table C.1. Residential Flumioxazin Handler Short-and Intermediate-Term Exposure and 

Risk

Use Site Equip. 

Types

App. 

Rate (a)

Area

Treated or 

Amount 

Handled 

Daily (b)

Route of 

Exposure

Dose 

(mg/kg/day)

(c,d)

MOE(e) ARI(f)

Dispersal 0.024 1,200

Inhalation

0.000057 52,000

Shaker Can

Dermal 0.000017 1,800,000

1,400

Inhalation 0.000002 1,500,000

Turf (Lawns, 

Ornamentals, 

Outdoor 

Premises, 

Recreational 

Areas)

Manually 

Pressurized 

Handwand

0.38 

(lb ai/A)

0.023 A

Dermal

0.0087 3,400

13

Inhalation

0.00014 22,000

Hose-End 

Sprayer 

Dermal

0.0017 18,000

150

Inhalation 0.0000028 1,100,000

Backpack 

Sprayer

Dermal

0.0087 3,400

13

Inhalation

0.00014

22,000

Sprinkling 

Can 1,000 ft2

Dermal

0.0017 18,000

150

Inhalation 0.0000028 1,100,000

a) Based on registered gardens and trees labels (lb ai/A converted to lb ai/sq. ft); turf labels (lb ai/A) 

b) Exposure Science Advisory Council Policy #9.1 and 2011 Residential SOPs

c) Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount 

handled (gallons) * dermal absorption factor (100 %) / body weight (80 kg).

d) Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) * application rate (lb ai/gallon) * amount 

handled (gallons) * inhalation absorption (100%) / body weight (80 kg). 

e) Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day); Inhalation MOE = 

PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). Dermal Level of concern = 100, 

Inhalation Level of Concern = 1,000 (Adult)

f) Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal 

exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral 

exposure))
Page 69 of 70

Table C.2: Short-Term Residential Handler Exposure and Risk Estimates for Flumioxazin.

Exposure Scenario Target MOE Maximum 

Application Ratea

Area Treated 

or Amount 

Handled 

Dailyb

Dermal Inhalation

Dose 

(mg/kg/day)c MOE d Dose (mg/kg/day)e MOEf ARIg

Gardens and Trees – WDG Formulations

Mixer/Loader/Applicator

Mixing/Loading/Applying WDG 

with Manually Pressurized 

Handwand

100

0.0000073 1200 ft2 0.0088 3,400 0.00014 21,000 13

Mixing/Loading/Applying WDG 

with Hose-end Sprayer 100 0.0000073

1200 ft20.0074 4,100 0.00000018 17,000,000 41

Mixing/Loading/Applying WDG 

with Backpack Sprayer 100 0.0000073 1200 ft2 0.0088 3,400 0.00014 21,000 13

Mixing/Loading/Applying WDG 

with Sprinkler Can 100 0.0000073 1200 ft2

0.0074 4,100 0.00000018 17,000,000 41

Gardens and Trees – Granular Formulations

Mixer/Loader/Applicator

Applying Granule with Push Type 

Spreader 100 0.0000087 1200 ft2

0.00012 240,000 0.00000039 7,600,000 1,900

Applying Granule with Belly Grinder

100 0.0000087 1200 ft20.054 550 0.0000058 510,000 5.5

Applying Granule with Spoon 

100 0.0000087 1200 ft20.00094 32,000 0.000013 230,000 130

Applying Granule with Cup 

100 0.0000087 1200 ft20.000017 1,800,000 0.000002 1,500,000 1,400

Applying Granule with Hand 

Dispersal 100 0.0000087 1200 ft2

0.024 1,200 0.000057 52,000 10

Applying Granule with Shaker Can 100

0.0000087 1200ft20.000017 1,800,000

0.000002

1,500,000 1,400

Turf 

Mixer/Loader/Applicator

Mixing/Loading/Applying WDG

with Manually Pressurized 

Handwand 100 0.38 0.023 acres 0.0087 3,400 0.00014 22,000 13

Mixing/Loading/Applying WDG 

with Hose-end Sprayer

100

0.38 0.023 acres 0.0017 18,000 0.0000028 1,100,000 150

Mixing/Loading/Applying WDG 

with Backpack Sprayer 100 0.38 0.023 acres 0.0087 3,400 0.00014

22,000

13
Page 70 of 70

Table C.2: Short-Term Residential Handler Exposure and Risk Estimates for Flumioxazin.

Exposure Scenario Target MOE Maximum 

Application Ratea

Area Treated 

or Amount 

Handled 

Dailyb

Dermal Inhalation

Dose 

(mg/kg/day)c MOE d Dose (mg/kg/day)e MOEf ARIg

Mixing/Loading/Applying WDG 

with Sprinkler Can 100

0.38 1,000 ft20.0017 18,000 0.0000028 1,100,000 150

a. Based on registered gardens and trees labels (lb ai/A converted to lb ai/sq. ft); turf labels (lb ai/A) 

b. Exposure Science Advisory Council Policy #9.1.

c. Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or 

gal) x Area Treated or Amount Handled (A or gallons/day) x DAF (%) / BW (kg).

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

e. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre 

or gal) x Area Treated or Amount Handled (A or gallons/day) / BW (kg).

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

g. ARI = 1/(1/RIdermal)+ (1/RIinhalation)

Note: 1000 sq ft per day is calculated to be equivalent to 0.023 acres (1000 sq ft/day ) x (43,560 sq ft/1 acre) = 0.023 

acres/day