UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC 20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE: 1/07/10

SUBJECT: Flumioxazin. Human Health Risk Assessment for the Proposed Aquatic Use and 

Proposed Food Uses on Cucurbit Vegetables, Leaf Petioles, and Hops. 

PC Code: 129034 DP Num: D359142

Decision No.: 402046 Registration No.: 59639-161, 59639-99, 59639-119

Petition Nos.: 8F7438, 8E7462 Regulatory Action: Section 3 Registration

Risk Assess Type: Single Chemical Aggregate Case No.: NA

TXR No.: NA CAS No.: 103361-09-7

MRID No.: NA 40 CFR: §180.568

FROM: W. Cutchin, Acting Senior Branch Scientist 

Alternative Risk Integration and Assessment (ARIA) Team

Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)

Registration Division (RD; 7505P)

THROUGH: Christina Swartz, Chief

Risk Assessment Branch II (RABII)

Health Effects Division (HED; 7509P)

TO: L. Nolan / D. Rosenblatt

RIMUERB/RD (7505P)
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ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged with estimating 

the risk to human health from exposure to pesticides. RD of OPP has requested that ARIA 

evaluate hazard and exposure data and conduct dietary, occupational, residential and aggregate 

exposure assessments, as needed, to estimate the risk to human health that will result from 

proposed and currently registered uses of the active ingredient flumioxazin. 

Valent has submitted a petition to establish a tolerance as a result of the aquatic uses of

flumioxazin, formulated as a 51% water-dispersible granular (WDG) formulation, in freshwater 

fish. The Interregional Research Project No. 4 (IR-4) has also submitted petitions to establish 

tolerances as a result of the uses of flumioxazin, formulated as two 51% WDG formulations

in/on cucurbit vegetables, leaf petioles, and hops. In this document, ARIA has conducted an 

assessment of the human exposure and risks resulting from these proposed uses and all currently 

registered uses. The overall risk assessment, dietary risk assessment, and residue chemistry

assessment were provided by W. Cutchin, the water exposure assessment by L. Liu 

(Environmental Fate and Effects Division (EFED)) and the occupational exposure assessments

by M. Dow (ARIA) and S. Wang (HED, Risk Assessment Branch II (RABII)). 
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TABLE OF CONTENTS

1.0 EXECUTIVE SUMMARY .................................................................................................... 5

2.0 INGREDIENT PROFILE.............................................................................................. 12

2.1 Summary of Proposed Uses............................................................................................ 13

2.2 Structure and Nomenclature ......................................................................................... 14

2.3 Physical and Chemical Properties:................................................................................ 14

3.0 HAZARD CHARACTERIZATION.................................................................................. 15

3.1 Hazard and Dose-Response Characterization.............................................................. 15

3.1.1 Database Summary............................................................................................. 15

3.1.1.1 Studies available and considered................................................................... 15

3.1.1.2 Mode of action, metabolism, toxicokinetic data........................................... 15

3.1.1.3 Sufficiency of studies/data.............................................................................. 15

3.1.2 Toxicological Effects........................................................................................... 16

3.1.3 Dose-response ...................................................................................................... 17

3.1.4 FQPA.................................................................................................................... 18

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)........................................ 18

3.3 FQPA Considerations..................................................................................................... 18

3.3.1 Adequacy of the Toxicity Database ................................................................... 18

3.3.2 Evidence of Neurotoxicity .................................................................................. 18

3.3.3 Developmental Toxicity Studies......................................................................... 19

3.3.4 Reproductive Toxicity Study ............................................................................. 19

3.3.5 Additional Information from Literature Sources............................................ 19

3.3.6 Pre-and/or Post-natal Toxicity........................................................................... 19

3.3.6.1 Determination of Susceptibility ..................................................................... 19

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties............................ 20

3.3.7 Recommendation for a Developmental Neurotoxicity Study.......................... 20

3.4 FQPA Safety Factor for Infants and Children............................................................. 20

3.5 Hazard Identification and Toxicity Endpoint Selection.............................................. 21

3.5.1 Acute Reference Dose (aRfD) - Females age 13-49 .............................................. 21

3.5.2 Acute Reference Dose (aRfD) - General Population........................................ 22

3.5.3 Chronic Reference Dose (cRfD)......................................................................... 22

3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term)........................... 22

3.5.5 Dermal Absorption ............................................................................................. 23

3.5.6(b) Dermal Exposure (Short-, Intermediate- and Long-Term) for Adults...... 23

3.5.7 Inhalation Exposure (Short- and Intermediate-Term) ................................... 24

3.5.8 Inhalation Exposure (Long-Term).................................................................... 25

3.5.9 Level of Concern for Margin of Exposure........................................................ 25

3.5.10 Recommendation for Aggregate Exposure Risk Assessments........................ 26

3.5.11 Classification of Carcinogenic Potential ........................................................... 26

3.6 Endocrine Disruption ..................................................................................................... 28

4.0 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA ........................... 29

5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION .......................................... 29

5.1 Pesticide Metabolism and Environmental Degradation.............................................. 29

5.1.1 Metabolism in Primary Crops and Livestock Commodities........................... 29

5.1.2 Metabolism in Rotational Crops........................................................................ 29
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5.1.3 Analytical Methodology...................................................................................... 30

5.1.4 Multiresidue Methods......................................................................................... 31

5.1.5 Storage Stability.................................................................................................. 31

5.1.6 Magnitude of the Residue................................................................................... 31

5.1.7 Magnitude of the Residue in Meat, Milk, Poultry, and Eggs.......................... 32

5.1.8 Confined and Field Rotational Crops............................................................... 32

5.1.9 Pesticide Metabolites and Degradates of Concern........................................... 33

5.1.10 Drinking Water Residue Profile........................................................................ 33

5.2 Dietary Exposure and Risk ............................................................................................ 34

5.2.1 Acute Dietary Exposure/Risk............................................................................. 34

5.2.2 Chronic Dietary Exposure/Risk......................................................................... 34

5.2.3 Cancer Dietary Risk ........................................................................................... 35

6.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION ........................................................................................................... 35

6.1 Other (Spray Drift, etc.)................................................................................................. 39

7.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ....... 39

7.1 Acute Aggregate Risk ..................................................................................................... 39

7.2 Short- and Intermediate-Term Aggregate Risk........................................................... 40

7.3 Chronic Aggregate Risk ................................................................................................. 42

7.4 Cancer Risk ..................................................................................................................... 42

8.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT ............................ 42

9.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY.................................................. 42

9.1 Short-/Intermediate-/Long-Term Handler Risk .......................................................... 43

9.2 Short-/Intermediate-/Long-Term Post-application Risk............................................. 51

9.3 Restricted Entry Interval (REI) .................................................................................... 52

10.0 TOLERANCE SUMMARY........................................................................................... 52

11.0 DATA NEEDS AND LABEL RECOMMENDATIONS............................................. 53

11.1 Toxicology........................................................................................................................ 53

11.2 Residue Chemistry.......................................................................................................... 54

11.3 Occupational and Residential Exposure....................................................................... 54

12.0 REFERENCES................................................................................................................ 54

Appendix A: Toxicology Assessment ....................................................................................... 56

A.1 Toxicology Data Requirements...................................................................................... 56

A.2 Toxicity Profiles............................................................................................................... 57

A.3 Data Requirements ......................................................................................................... 61

Appendix B: Metabolism Assessment...................................................................................... 64

Appendix C: Review of Human Research ............................................................................... 64
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1.0 EXECUTIVE SUMMARY

Background

This document is a human health risk assessment to support an aquatic use (PP#: 8F7438) and 

Section 3 requests for crop uses (PP#: 8E7462) and for the establishment of permanent 

flumioxazin tolerances in/on freshwater fish, cucurbit vegetables, leaf petioles, and hops. 

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 (Group 

14) that is currently used for pre- and post-emergence control of susceptible weeds in a variety of 

fruit, vegetable and other field crops. Its mode of action is as an inhibitor of protoporphyrinogen 

oxidase (PPO); it is active against certain grasses, broadleaf weeds, and sedges (including 

aquatic species). 

The most recent human health risk assessment for flumioxazin was conducted in conjunction 

with a request for the establishment of tolerances for residues on field corn (PP#: 7F7243, DP 

Num: D342248, B. Hanson, 4/8/08).

This document includes revised dietary (food and drinking water), non-occupational,

occupational (handler and post-application), residue chemistry, and aggregate assessments.

Proposed Uses

The registrant, Valent, proposes a use of Clipper Herbicide (EPA Reg. No 59639-161), a 

WDG formulation containing flumioxazin at 51%, for management of aquatic weeds in bayous, 

canals, fresh water ponds, lakes, marshes and reservoirs. The proposed maximum rates are 

0.3825 lb ai/A for surface and aerial applications, and 8.62 lb ai/A for subsurface application.

IR-4 is seeking the registration of flumioxazin on cucurbit vegetables, leaf petioles, and hops. 

The end-use products (EPs) relevant to this registration request are ValorTM Herbicide (EPA Reg. 

No. 59639-99) and ChateauTM Herbicide (EPA Reg. No. 59639-119). The products are WDG 

formulations containing 51% flumioxazin. Valor and Chateau are proposed for uses with ground 

equipment for a pre-emergence or pre-transplant application and followed by a second 

application to row middles at a total of 0.25 lb ai/A on cucurbit vegetables; for a pre-transplant 

soil application at 0.094-0.188 lb ai/A on leaf petioles; and for 0.375 lb ai/A with a 30-day preharvest interval (PHI) on hops.

Toxicology and Dose-Response

The toxicology database for flumioxazin is not complete because several studies newly required 

in accordance with the 12/2007 update of the Part 158 Guidelines for toxicology have not yet 

been submitted. These include rat acute and subchronic neurotoxicity studies, as well as an 

immunotoxicity study. Despite these missing studies, the toxicity database is considered to be 

adequate for the purpose of dose and endpoint selection for the current risk assessment, and for 

characterizing toxic effects associated with flumioxazin.
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Flumioxazin has mild or no acute toxicity (categories III or IV) when administered orally, 

dermally, or by inhalation. It has little or no toxicity with respect to eye or skin irritation

(categories III or IV). In addition, flumioxazin is not a dermal sensitizer. Subchronic and 

chronic toxicity studies demonstrated that toxicity associated with flumioxazin include anemia, 

and effects on the liver and the cardiovascular system. Developmental effects were observed in 

developmental rat studies but not in developmental rabbit studies. These effects were fetal 

cardiovascular anomalies, especially ventricular septal defects.

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. Increased absolute and relative liver weights and/or increased alkaline 

phosphatase values were observed in dogs. Flumioxazin administered orally and dermally to rats 

in developmental studies resulted in cardiovascular anomalies, the most serious being ventricular 

septal defects. The same effects occurred by both dermal and oral routes of administration, with 

the oral being observed at 10 and the dermal at 100 mg/kg/day. A mechanistic oral 

developmental study in rats indicated that a single dose of 400 mg/kg caused the ventricular 

septal defects when administered on gestation day 12, but not when given on days 11 or 13 or 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). Based on the lack of evidence of carcinogenicity in mice and rats, flumioxazin is 

classified as “not likely to be carcinogenic to humans.”

The endpoint selected for acute dietary risk assessment was based on the cardiovascular effects,

ventricular septal defects in fetuses, observed in oral developmental and supplemental pre-natal 

studies in rats. The endpoint is only applicable to females of childbearing age (i.e., females 13-

49). No acute dietary endpoint (i.e., toxic effect resulting from a single dose) applicable to the

general population or any other population subgroups was identified in the submitted studies. 

The endpoint selected for chronic dietary risk assessment for all population subgroups was 

increased chronic nephropathy in males and decreased hematological parameters in females 

observed in a 2-year chronic/carcinogenicity study in rats. This endpoint and dose are the lowest 

of any long-term studies submitted for flumioxazin, and are also protective of the offspring 

effects seen in the 2-generation reproduction study.

A no observable adverse effects level (NOAEL) of 30.0 mg/kg/day was selected from a rat 

dermal developmental toxicity study for short- and intermediate-term dermal risk assessments

for adults potentially exposed to flumioxazin. The NOAEL was based on a biologically 

significant increase in cardiovascular abnormalities, particularly ventricular septal defects

observed at the lowest observed adverse effects level (LOAEL) of 100 mg/kg/day. Since the 

dermal endpoint and dose were selected from a dermal study, an absorption factor was not used 

in the dermal assessments. However, for children potentially exposed to flumioxazin via the 
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dermal route, the offspring effects in the rat reproduction study were chosen for risk assessment, 

and a dermal absorption factor was used to account for route-to-route extrapolation.

For both short- and intermediate-term incidental oral exposure and risk assessments, the endpoint 

and dose were selected from the reproductive toxicity study in rat, based on the 

offspring/reproductive effects, including decreased live born pups and decreased pup body 

weights observed at the LOAEL of 12.7 mg/kg/day. The dose for risk assessment was the 

NOAEL of 6.3 mg/kg/day. The study was considered to be the most appropriate for the route of 

exposure (oral), the duration, short- and intermediate-term, and because the endpoint is relevant 

for the potentially exposed population, children.

For short-term inhalation exposure, a NOAEL of 3.0 mg/kg/day was selected from an oral 

developmental study in rats, based on a biologically significant increase in cardiovascular 

abnormalities, particularly ventricular septal defects, at the LOAEL of 10 mg/kg/day. For 

intermediate-term inhalation exposure, a NOAEL of 2.0 mg/kg/day was selected from a 2-year 

chronic rat study, based on increased chronic nephropathy in males, and decreased hematological 

parameters in females, observed at the LOAEL of 18 mg/kg/day. Since the doses and endpoints 

for inhalation risk assessments were selected from oral studies, a 100% inhalation absorption 

factor was used for risk assessment.

Both qualitative and quantitative susceptibility were observed in the rat developmental toxicity

studies, in which the effects on fetuses occurred at doses which did not cause maternal toxicity. 

In addition, 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. 

Although there were both qualitative and quantitative susceptibility, HED concluded the 10X 

FQPA Safety Factor could be removed (reduced to1X). This conclusion was based on the low 

degree of concern for the observed susceptibility because the observed effects were adequately 

characterized and the doses and endpoints selected for risk assessment are sufficiently protective 

of the fetal/offspring susceptibility. In addition, there were no concerns for neurotoxicity based 

on the submitted data, and a developmental neurotoxicity study is not required. Although there 

are missing studies, including acute and subchronic neurotoxicity and immunotoxicity studies, 

there is no evidence in the submitted data to indicate flumioxazin directly impacts the nervous 

system or the immune system. Finally, the exposure assessment is conservative, and therefore 

potential risks to infants and children have not been underestimated.

Since the FQPA factor was reduced to 1X, and there were no other database uncertainty factors 

retained for missing data or the lack of a NOAEL, the level of concern (LOC) for both residential 

and occupational exposure and risk is margin of exposure (MOE) of 100, based on the standard

10X uncertainty factors retained for interspecies extrapolation and intraspecies variability.

Endocrine Disruptor Screening Program (EDSP)

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for endocrine 

testing for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 
Page 8 of 64

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, and 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. 

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

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

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

Residue Chemistry

With the exception of the aquatic use and the need for a restriction on the use of adjuvants, the 

proposed application labels are acceptable. Based on occupational exposure concerns associated 

with the aquatic use, ARIA/HED recommends that the water depth for subsurface application 

should not go beyond 7 feet (a 7 foot deep water column requires 7.55 lb ai/A/application). 

Updated labels are required.

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

previously submitted studies. In primary and rotated crops, the residue of concern is the parent 

compound, flumioxazin. For ruminants, the residues of concern are parent, 3-OH-flumioxazin, 

4-OH-flumioxazin, 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. For purposes of this petition, 

ARIA has waived the requirement for a fish metabolism study and has concluded that the 

residues of concern in fish include flumioxazin and its major degradates in water, APF and 482-

HA.

For tolerance enforcement in fish tissues, Valent has submitted a liquid chromatography with 

tandem mass spectroscopy/mass spectroscopy detector (LC-MS/MS) method (GPL-MTH-066) 

for determining residues of flumioxazin, APF and 482-HA. The validated limit of quantitation 

(LOQ) is 0.01 ppm for each analyte in fish. This method has undergone a successful 

independent laboratory validation (ILV) trial and appears to be acceptable for data collection and 

tolerance enforcement; however, additional information/data are required before the method can 

be recommended as an enforcement method (See Sec. 11, below). In addition, FDA multiresidue 

testing data are required for the metabolite/degradates 482-HA and APF, and reference standards 

must be provided for the EPA National Pesticide Standards Repository.

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

Method RM-30-A-1, is available for enforcing tolerances for residues of flumioxazin per se

in/on plant commodities. The reported method LOQ and limits of detection (LOD) for 

flumioxazin in/on plant commodities are 0.02 and 0.01 ppm, respectively.
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Acceptable data collection methods were used in the submitted studies based on acceptable 

concurrent method recoveries.

The submitted fish residue study is adequate and supports the proposed aquatic use. Residues of 

flumioxazin, APF and 482-HA were determined in the water and edible fish tissues over a 28-

day period of exposure to residues at 2x the application rate. Total flumioxazin residues were 

highest at the earliest sampling interval (4 hours), ranging from 0.85-2.52 ppm. Total residues 

declined rapidly by Day 3 and then remained relatively steady up to Day 28 (0.063-0.204 ppm). 

Total flumioxazin residues did not bioaccumulate over the 28 day study. When extrapolated to 

reflect the 1x use rate, the estimated total residues would support the proposed 1.5 ppm tolerance 

for residues in freshwater fish. Because applications to flowing water, intertidal or estuarine 

areas and to water used for crawfish farming are prohibited, residue data and tolerances are not 

required for shellfish or saltwater fishes.

The submitted residue data for cucumber and summer squash are adequate. In addition, residue 

field trial data on cantaloupe, the representative crop for muskmelon subgroup 9A were 

submitted previously in support of the tolerance using the same use pattern. The data indicate 

that a tolerance for residues on cucurbits should be established at 0.03 ppm. ARIA recommends 

for the proposed flumioxazin tolerance on cucurbit vegetables, group 9, at 0.03 ppm. 

Concurrently, with the establishment of the tolerance on cucurbit vegetables, the existing 

tolerance on muskmelon subgroup 9A should be removed.

The submitted residue data for celery are adequate. Since celery is the representative crop for 

leaf petioles, subgroup 4B, the data is adequate to support the requested tolerance. ARIA 

recommends for the proposed flumioxazin tolerance on leaf petioles, subgroup 4B, at 0.02 ppm.

The submitted residue data for hops are adequate. Following Agency policy, a tolerance of 0.05 

ppm would be appropriate on hops. ARIA recommends for a tolerance of 0.05 ppm for the 

residues of flumioxazin on hops. A revised Section F is required. 

However, since adjuvants were not used in the submitted residue field trials, the labels should 

prohibit such uses on cucurbit vegetables, leaf petioles, and hops.

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

requested field corn commodities. Based on the results of the confined accumulation study, the 

existing rotational crop plantback intervals (PBIs) are acceptable and rotational crop field trials 

and tolerances are not necessary.

Dietary Risk (Food and Drinking Water)

The drinking water residues for flumioxazin (flumioxazin, 482-HA, and APF) used in the dietary

risk assessment were provided by EFED and incorporated directly into the dietary assessments

The estimated drinking water concentration (EDWC) for flumioxazin residues (used in both the 

acute and chronic dietary analyses) was 0.048 ppm.
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The acute dietary exposure analysis for flumioxazin is an unrefined assessment, assuming 100% 

crop treated and tolerance level residues, upper bound estimates of potential drinking water 

residues, and using DEEM default processing factors (Version 7.81) for processed 

commodities (with the exception of tomato, which used the empirical processing factor of 1x). 

The acute dietary endpoint is applicable only to the population subgroup females 13- 49 years 

old. An acute dietary endpoint for the general population, including infants and children was not 

identified. The estimated acute dietary exposure (food and drinking water) for females 13-49 

years old occupies 9% of the aPAD and does not exceed ARIA’s level of concern.

Similarly, the chronic dietary exposure analysis for flumioxazin is an unrefined assessment, with 

the same food residue and drinking water assumptions as the acute analysis. The chronic dietary

endpoint applies to all population subgroups, including infants and children. The estimated 

chronic dietary exposure (food and water) from flumioxazin does not exceed ARIA’s level of 

concern for any population subgroup. Food and water exposure occupies 7% of the cPAD for 

the US population and 19% of the cPAD for all infants (<1 year old), the subgroup with the 

highest exposure. 

Non-Occupational and Residential Risk

Flumioxazin is not registered for use by homeowners for weed control in residential areas. 

However, HED recently reviewed a proposed use of BroadStarTM Herbicide for use by

commercial applicators for control of weeds on walkways, parking lots and non-grassy areas in 

home landscapes. Although the product is not intended for use by homeowners, HED assumed 

homeowners could buy the product if available in garden centers and other retail outlets.

Therefore, residential handlers were assessed for both dermal and inhalation exposure, and the 

risks were not of concern (i.e., MOEs were significantly greater than the level of concern, and 

MOE of 100). No postapplication scenarios were assessed because children and adults are not 

expected to come into contact with flumioxazin following application to parking lots, walkways, 

and non-grassy areas.

There is also the potential for non-occupational exposure associated with swimming in treated 

water for recreational purposes. ARIA used the standard approach used for assessing exposure 

and risk for recreational swimmers. The exposure estimates are considered to be reasonable 

high-end estimates based on observations from chemical-specific field studies and professional 

judgment. Swimmer assessments based on the proposed use pattern indicated that all MOEs are 

above the level of concern, with MOEs ranging from 2,300 to 84,000. 

Aggregate Risk

When aggregating exposures and risks from various sources, ARIA has considered both the route 

and duration of exposure. Potential residential exposure scenarios include adult and child 

swimmers, and adult handlers applying flumioxazin for weed control. When these short-term 

exposures were combined with background (chronic) dietary exposure from food and drinking 

water, aggregate risks were not of concern, with MOEs ranging from 900 to 1300. The lowest 

MOE was associated with children’s combined exposure from the diet (food and water) and from 
Page 11 of 64

swimming in water treated with flumioxazin. ARIA notes that both the adult and children’s 

short-term aggregate risk assessments are conservative based on the use of the SWIMMODEL to 

determine potential exposure from recreational swimming. Acute and chronic aggregate risks 

are the same as dietary risks which incorporated exposure from both food and drinking water. 

These risks were not of concern.

Occupational Exposure and Risk

Based on the product use information, there is a potential for occupational exposure from 

handling (mixing/loading/applying) flumioxazin for the aquatic uses. A MOE of 100 or more is 

sufficient to protect occupational pesticide handlers. Except for the short-term total MOE for the 

subsurface application (MOE = 94), all short-term total MOEs and intermediate-term dermal & 

inhalation MOEs for the handlers performing the proposed uses on aquatic weeds are greater 

than 100 (110 ~ 43,000) and therefore, the risks do not exceed HED’s level of concern. The rate 

of 8.62 lb ai/A results a short-term total MOE of 94 when assessed using baseline protection plus 

gloves as required on the label. The short-term total MOE calculated for the next highest 

application rate (7.55 lb ai/A) used in the subsurface application is 110. Based on this result and 

given the serious nature of the toxicological endpoint, ARIA/HED recommends that the water 

depth for subsurface application shall not go beyond 7 feet; an updated label is required.

Workers may also be exposed to flumioxazin during mixing, loading, and application activities 

associated with agricultural crops. Occupational handler assessments indicate that all MOEs are 

above the levels of concern at the baseline level (total MOEs = 210 to 4,400). The postapplication MOEs for commodities were not determined because the exposures to flumioxazin 

for workers performing post-application activities on these commodities are expected to be 

negligible. The 12-hour restricted entry interval (REI) appearing on the label is appropriate for 

this chemical.

Environmental Justice

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

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

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

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

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

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

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

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

and exposure assessments are performed when conditions or circumstances warrant. Whenever 
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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.

Cumulative Exposure and Risk

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 tolerance action, therefore, 

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

substances.

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 (listed in Appendix C) have 

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

Additional Data Needs and Recommendations

Pending the resolution of the requirements listed in Section 11, ARIA recommends in favor of 

establishing the tolerances as listed in Table 10.0.

2.0 INGREDIENT PROFILE

Flumioxazin is an herbicide of the N-phenylphthalimide class (Group 14) that is currently used 

for pre- and post-emergence control of susceptible weeds in a variety of fruit, vegetable and 

other field crops. Its mode of action is as an inhibitor of protoporphyrinogen oxidase (PPO); it is 

active against certain grasses, broadleaf weeds, and sedges. Tolerances are currently established 

for residues of flumioxazin in/on various plant commodities, at levels ranging from 0.02 to 0.70 

ppm (40 CFR §180.568[a]). Temporary tolerances associated with a Section 18 emergency

exemption have also been established on alfalfa forage and hay at 0.13 and 0.45 ppm, 

respectively (40 CFR 180.568[b]).

Valent and IR-4, wish to amend the product labels for ValorTM Herbicide, ChateauTM Herbicide, 

and Clipper Herbicide. The products are WDG formulations containing flumioxazin at 51% to 

incorporate new aquatic uses and uses on cucurbit vegetable, leaf petioles, and hops. The 

nomenclature and physicochemical properties of flumioxazin are presented below in Tables 2.2

and 2.3.
Page 13 of 64

2.1 Summary of Proposed Uses

Table 2.1. Summary of Proposed Use Pattern of Flumioxazin. 

Applic. Timing, 

Type, and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. 

No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

RTI 1 PHI

(days)

Use Directions and 

Limitations

Aquatic Weeds and Algae

Surface 

application---

broad spray 

using backpack 

or handgun 

sprayer, airboat, 

or other 

equipment ClipperTM

51% WDG 

[59639-161]

0.3825 2 0.765 28 NA

Treat up to half of the water 

body and wait 10 to 14 days

before treating the remaining 

area. Do not re-treat the same 

section of water within 28

days of application.

Aerial 

application---

helicopter, 

airplane

0.3825 2 0.765 28 NA

Subsurface 

application---

hoses trailing 

behind a boat

8.62 

(8 foot 

deep 

water 

column)

2 17.24 28 NA

Cucurbit Vegetables Group 9

Ground 

equipment

ValorTM

51% WDG 

[59639-99]

ChateauTM

51% WDG 

[59639-119]

0.125 2 0.250

21±2 after 

transplant

28±2 after 

emergence

NS2

Fist shielded application to 

row middles 14±2 before crop 

emergence or transplant. 

Apply at 10-40 gal/A.

Leaf Petioles Subgroup 4B

Ground 

equipment

ValorTM

51% WDG 

[59639-99]

ChateauTM

51% WDG 

[59639-119]

0.094-

0.188 1 0.094-0.188 NA NS

Apply to soil surface before 

transplant. Apply at 20-40 

gal/A.

Hops

Ground 

equipment

ValorTM

51% WDG 

[59639-99]

ChateauTM

51% WDG 

[59639-119]

0.375 2 0.750 30±3 30±3

Apply to lower 30in of plant 

extending to 18in from row. 

Apply at 10-40 gal/A.

1

 Retreatment Interval. 

2

 NS = not specified.
Page 14 of 64

Conclusion: Based on occupational exposure and risk concerns, ARIA recommends that the 

water depth for subsurface application shall not go beyond 7 feet (a 7 foot deep water column 

requires 7.55 lb ai/A/application to achieve the desired 400 ppb water concentration). An 

updated aquatic application label is required. In addition, since adjuvants were not used in the 

submitted residue field trials, the labels should prohibit such uses on cucurbit vegetables, leaf 

petioles, and hops; updated labels are required.

2.2 Structure and Nomenclature

Table 2.2. Flumioxazin Nomenclature.

Compound

N

N

O

F

C

H2

O

O

HC C O

Common name Flumioxazin

Company experimental name VC-1152

IUPAC name N-(7-fluoro-3,4-dihydro-3-oxo-4-prop-2-ynyl-2H-1,4-benzoxazin-6-yl)cyclohex1-ene-1,2-dicarboxamide

CAS name 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

CAS registry number 103361-09-7

End-use product (EP) ValorTM Herbicide (EPA Reg. No 59639-99), ChateauTM Herbicide (EPA Reg. No 59639-

199), and Clipper Herbicide (EPA Reg. No 59639-161). All products are WDG 

formulations containing 51% flumioxazin.

2.3 Physical and Chemical Properties:

Table 2.3. 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 (25°C) 1079 mg/L 

Solvent solubility Not available

Vapor pressure 2.41 x10-6 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)

λ216ε = 51200 (pH 10.0),

MRID No. 44295004
Page 15 of 64

3.0 HAZARD CHARACTERIZATION

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

3.1.1.1 Studies available and considered

The following toxicity studies have been submitted in support of registered and proposed uses of 

flumioxazin:

Acute- oral, dermal, inhalation, eye irritation, dermal irritation, skin sensitization;

Subchronic- Dermal 21-day rat; Oral 28-day mouse, oral 90-day rat, oral 90-day dog;

Chronic- Oral dog and rat;

Carcinogenicity- Rat and mouse;

Reproductive/developmental- Oral Pre-natal developmental rat, oral pre-natal developmental 

rabbit, dermal pre-natal developmental rat, 2-generation reproduction rat;

Other- Mutagenicity screens, metabolism and pharmacokinetic studies, dermal penetration rat, 

and a Special Study: Rat Developmental: Critical Time for Defects.

3.1.1.2 Mode of action, metabolism, toxicokinetic data

Flumioxazin is an herbicide of the N-phenylphthalimide class (Group 14) that is currently used 

for pre- and post-emergence control of susceptible weeds in a variety of fruit, vegetable and 

other field crops. Its mode of action is as an inhibitor of the enzyme PPO; it is active against 

certain grasses, broadleaf weeds, and sedges. In mammals, the inhibition of the enzyme can 

interfere with porphyrin component of heme.

Metabolism studies in rats indicated that there was extensive biliary excretion following oral 

administration of flumioxazin. It is noted that 4-5 times more radioactivity is excreted in feces 

than 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). 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). 

3.1.1.3 Sufficiency of studies/data

The toxicology database for flumioxazin is not complete because several studies newly required 

in accordance with the 12/2007 update of the Part 158 Guidelines for toxicology have not yet 

been submitted. These include acute and subchronic neurotoxicity studies, as well as an 

immunotoxicity study. Despite these missing studies, the toxicity database is considered to be 

adequate for the purpose of assessment of susceptibility, dose and endpoint selection for the 

current risk assessment, and for characterizing toxic effects associated with flumioxazin.
Page 16 of 64

3.1.2 Toxicological Effects

The toxicity profile of flumioxazin may be found in Appendix A. In general, the subchronic and 

chronic toxicity studies demonstrated that toxic effects associated with flumioxazin include 

anemia, and 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.

Acute Toxicity: Flumioxazin has mild or no acute toxicity (categories III or IV) when 

administered orally, dermally, or by inhalation. It is also classified as Toxicity Category III or 

IV for primary eye and skin irritation. Flumioxazin is not a dermal sensitizer.

Reproductive and Developmental Toxicity: The pre- and post-natal toxicity database for 

flumioxazin includes the rat and rabbit developmental toxicity studies and the two-generation 

reproduction toxicity study in rats. There is quantitative evidence of increased susceptibility of 

rat fetuses to in-utero exposure to flumioxazin in the oral and dermal developmental studies. In 

both studies, there was an increased incidence in fetal cardiovascular anomalies (especially

ventricular septal defects). In the oral study, no maternal effects were seen at the highest dose 

tested (30 mg/kg/day); however, the effects in the fetuses were observed at 10 mg/kg/day. In the 

dermal study, no maternal effects were noted at the highest dose tested (300 mg/kg/day) but the 

effects in fetuses were observed at 100 mg/kg/day. In the 2-generation rat reproduction study, 

parental effects (red substance in vagina and increased mortality in females as well as decreases 

in male and female body weights, body weight gains and food consumption) were noted at 18.9 

mg/kg/day in males at the highest dose tested (HDT) and 22.7 mg/kg/day in females (HDT). The 

observed reproduction/offspring effects were a decrease in the number of liveborn, a decrease in 

pup body weights, and a decrease in mating index at 12.7 mg/kg/day for males and 15.1 

mg/kg/day for females. In addition, testicular atrophy was observed in the F1 males at 12.7 

mg/kg/day.

The effects observed in the fetuses and offspring in the developmental and reproductive toxicity

studies occurred at lower doses than those which caused maternal and/or parental effects, which 

is considered to be evidence of an increase in quantitative susceptibility. 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 (GDs) 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.

A number of mechanistic studies were submitted by the Registrant to further describe 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. 
Page 17 of 64

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.

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

robust to support the registrant’s proposed mechanism of toxicity. However, since 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 HDT (3x the limit-dose). The 

absence of effects in rabbits was supported by literature studies indicating rabbits are less 

susceptible to the effects of PPO inhibitors.

Neurotoxicity: HED concluded there is no concern for neurotoxicity resulting from exposure to 

flumioxazin. None of the acute, subchronic, chronic, developmental or reproduction studies 

indicated an effect on the nervous systems. Based on the lack of concern for neurotoxicity, HED 

concluded a developmental toxicity study (DNT) was not required. Nonetheless, the acute and 

chronic neurotoxicity studies are now required for all pesticide active ingredients, in accordance 

with 40 CFR, Part 158 (Updated, 12/2007).

Carcinogenicity: In accordance with the 1999 Proposed Guidelines for Carcinogen Risk 

Assessment, HED determined that flumioxazin was “not likely to be a human carcinogen.” 

Flumioxazin did not induce significant increases in any tumor type in either rats or mice under 

the conditions of the studies and it did not induce any mutagenic activity in the required battery

of mutgenicity studies. 

3.1.3 Dose-response

Ventricular septal defects in the rat oral and dermal developmental toxicity studies were seen in 

the absence of maternal toxicity. Therefore to be protective of potential developmental effects

from exposure to pregnant females, the adults’ dermal and inhalation risk assessments were 

based on these effects. In addition, since the developmental effect was demonstrated to occur on 

gestation day 12, it was considered to be a single-dose effect and served as the basis for the acute 

dietary risk assessment for females 13-49. In addition, offspring effects observed in the rat 

reproductive toxicity study (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) served as the basis for assessing potential risks to children from dermal 

and incidental oral exposure. No acute dietary endpoint was identified in the database for 

children or the general population.

Based on the submitted studies, the rat appeared to be the most sensitive species, and the risk 

assessments (all durations and routes of exposure) were based on effects observed in rats. Long-
Page 18 of 64

term dosing in the chronic/carcinogenicity study did not yield evidence of carcinogenicity. 

However, after long-term dosing, effects on blood parameters and the kidney were observed and

these effects were used for risk assessment purposes. The dose of 2 mg/kg/day selected from the 

chronic rat study for chronic dietary risk assessment was the lowest dose observed in the toxicity 

database.

3.1.4 FQPA

HED evaluated the toxicology data base of flumioxazin and determined that it was adequate to 

characterize the potential for pre-natal or post-natal risks to infants and children, despite the 

previously mentioned data gaps (i.e., acute and subchronic neurotoxicity, immunotoxicity). The 

scientific quality of the flumioxazin database is relatively high, and the toxicity profile can be 

characterized for most effects, including potential carcinogenic, mutagenic and 

developmental/reproductive.

3.2 Absorption, Distribution, Metabolism, Excretion (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. 

G.I. tract absorption of flumioxazin may amount to over 90% of the dose. 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. It was noted that 4-5 times more radioactivity is excreted in feces than 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). 

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). Thin layer chromatography 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.

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

The submitted toxicology studies are considered adequate to support a determination of the need 

for additional uncertainty factors to account for potential pre- and postnatal susceptibility.

3.3.2 Evidence of Neurotoxicity

No neurotoxicity studies are available for flumioxazin. However, none of the acute, subchronic, 

chronic, developmental or reproduction studies indicated an effect on the nervous system. HED

concluded that there is no concern for neurotoxicity resulting from exposure to flumioxazin. In

accordance with the updated Part 158 Toxicology Data Requirements, 12/2007, acute and 
Page 19 of 64

subchronic neurotoxicity studies must be submitted.

3.3.3 Developmental Toxicity Studies

Acceptable gavage developmental toxicity studies are available in both the rat and rabbit, and in 

addition a dermal developmental toxicity study in the rat was submitted. In the rat 

developmental studies, developmental effects, including cardiovascular abnormalities, were 

observed in fetuses at doses which did not cause maternal toxicity. In the oral study, maternal 

doses of 30 mg/kg did not result in maternal toxicity, whereas the developmental LOAEL was 10 

mg/kg/day, with a NOAEL of 3 mg/kg/day. In the dermal study, no maternal effects were 

observed at dermal doses of up to 300 mg/kg/day, whereas the developmental LOAEL was 100 

mg/kg/day, with a NOAEL of 30 mg/kg/day. A special study was conducted which 

demonstrated that the developmental effects were most prominent when dosing with flumioxazin 

occurred on gestation day 12. In the rabbit developmental study, maternal effects were limited to 

decreased body weight and food consumption at the high dose of 3000 mg/kg/day, with no 

developmental/fetal effects (i.e., developmental LOAEL not determined).

3.3.4 Reproductive Toxicity Study

In the rat reproductive toxicity study, reproductive effects in the offspring were observed at 

lower doses than those which caused effects in the parental animals. The systemic/parental 

LOAEL was 18.9/22.7 mg/kg/day (males/females) based on increased clinical signs, increased 

mortality and liver effects, and decreased food consumption during lactation in females; and

decreased body weight/weight gain in males and females. The systemic/parental NOAEL for 

these effects was 12.7/15.1 mg/kg/day (males/females). Reproductive parameters were affected 

in both generations of offspring. These effects were more pronounced at the 18.9/22.7 

mg/kg/day dose level, and were observed to a lesser extent at the next lowest dose, the LOAEL 

of 12.7/15.1 mg/kg/day (males/females). Reproductive/offspring effects were 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. The reproductive/offspring 

NOAEL was 6.3/7.6 mg/kg/day (males/females).

3.3.5 Additional Information from Literature Sources

No additional literature sources were consulted in conjunction with evaluating the currently 

proposed agricultural and aquatic uses. 

3.3.6 Pre-and/or Post-natal Toxicity

3.3.6.1 Determination of Susceptibility

Based upon the oral as well as the dermal developmental rat studies, due to cardiovascular 

anomalies (ventricular septal defect) which occurred at doses which did not cause maternal 

toxicity, there is evidence of increased qualitative and quantitative susceptibility of fetuses. The 

rat reproduction study demonstrated evidence of qualitative and quantitative post-natal 
Page 20 of 64

susceptibility because reproductive effects in offspring were observed at doses lower than those 

which cause parental/systemic toxicity, and were also considered to be more severe than the 

parental/systemic effects.

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties

Since there is evidence of increased qualitative and quantitative susceptibility of the young 

following exposure to flumioxazin in the oral and dermal developmental toxicity studies in the 

rat and in the rat reproduction study, a degree of concern analysis was performed to: 1) 

determine the level of concern for the effects observed when considered in the context of all 

available toxicity data; and 2) identify any residual concerns after establishing toxicity endpoints 

and traditional uncertainty factors to be used in the risk assessment. If residual concerns are 

identified, HED examines whether these residual concerns can be addressed by a special FQPA 

safety factor and, if so, the size of the factor needed.

While the toxicity database is not complete, due to the lack of neurotoxicity and immunotoxicity

studies, the database is adequate for the purpose of evaluating susceptibility. There was no 

evidence in any of the submitted studies that flumioxazin affects the nervous system or directly 

targets the immune system. 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 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.

3.3.7 Recommendation for a Developmental Neurotoxicity Study

There was no evidence of neurotoxicity in any of the submitted studies, including chronic (rat, 

mouse or dog), 90 day (rat, mouse or dog), 4 week (mouse), 21-day rat dermal, 2-generation rat 

reproduction and developmental (oral rat, dermal rat or oral rabbit). In addition, the

developmental effects observed in the rat, cardiovascular anomalies, are not related to 

developmental effects of the central or peripheral nervous systems. Therefore, a DNT study is 

not required.

3.4 FQPA Safety Factor for Infants and Children

HED recommends the 10X FQPA Safety Factor (as required by the Food Quality Protection Act) 

be reduced to 1X (i.e., removed) for all population subgroups for all exposure durations in 

assessing the risk posed by flumioxazin. Although increased prenatal and postnatal qualitative 

and quantitative susceptibility were seen in rats, there is low concern for this susceptibility and 

no residual uncertainties for pre- and/or post-natal toxicity because:

1) The only missing toxicity data for flumioxazin are the newly required neurotoxicity and 

immunotoxicity studies; however, no additional uncertainty factor is needed in the absence of 

these studies because there is no evidence in the available studies indicating that flumioxazin 
Page 21 of 64

targets the nervous system or the immune system. Further, HED has concluded a developmental 

neurotoxicity study is not required.

2) Although increased prenatal and postnatal qualitative and quantitative susceptibility was seen 

in rats, HED concluded that there is a low concern and no residual uncertainties for pre- and/or 

postnatal toxicity because the developmental toxicity NOAELs/LOAELs are well characterized 

after oral and dermal exposure; the offspring toxicity NOAEL and LOAEL are well 

characterized; and the doses and endpoints have been selected from the developmental and 

reproductive toxicity 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.

3) The exposure assessment is conservative, based on tolerance-level residues in food and 

drinking water and upper-bound estimates of potential residential/aggregate exposure; therefore, 

the potential risk for infants and children will not be underestimated.

3.5 Hazard Identification and Toxicity Endpoint Selection

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

dietary risk assessments; residential exposures including dermal and incidental oral exposure for 

children and dermal and inhalation exposure for adults; and for occupational exposures via the 

dermal and inhalation routes. HED notes that although long-term dermal and inhalation doses 

and endpoints were considered and selected, there are no long-term exposures expected for these 

routes based on the existing and proposed use patterns.

3.5.1 Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Pre-natal Developmental Toxicity Study - Rat

MRID Nos.: 42684930 (pilot study); 42684925 (main study); 42884006; 42694931 and

42684932

(studies demonstrating critical time to effects).

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: 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 and 

acute population adjusted dose are calculated as follows:

Acute RfD = Acute PAD = 3 mg/kg/day (NOAEL) = 0.03 mg/kg/day
Page 22 of 64

 100 (UF)

3.5.2 Acute Reference Dose (aRfD) - General Population

No appropriate endpoints were selected because there were no toxic effects relevant to the 

general population (including infants and children) identified in the database which could result 

from a single dose.

3.5.3 Chronic Reference Dose (cRfD) 

Study Selected: Combined chronic carcinogenicity - rat

MRID No.: 44295028

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.

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 (long term to lifetime) 

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. 

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. Since 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 reference dose and population adjusted 

dose, which are equivalent.

Chronic RfD = Chronic PAD = 2 mg/kg/day (NOAEL) = 0.02 mg/kg/day

 100 (UF) 

3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: Reproduction and fertility effects - rat

MRID No.: 42684934 and 42684936 (pilot studies); 42684935 (main study)

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 reproductive study, is relevant for the 
Page 23 of 64

exposed population (infants and children) and therefore the risk assessment will be protective for 

the qualitative and quantitative susceptibility observed in the reproductive study. Since 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 100 for residential exposure and 

risk assessments.

3.5.5 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.

3.5.6(a) Dermal Exposure (Short, 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 reproductive 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 reproductive study. Since 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 100 for residential exposure and risk 

assessments.

3.5.6(b) Dermal Exposure (Short-, Intermediate- and Long-Term) for Adults

Study Selected: Dermal Developmental Study (Rat)
Page 24 of 64

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, since 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 essentially comparable to the 

selected dermal NOAEL of 30 mg/kg/day.

Since 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 100 for both 

residential and occupational exposure and risk assessments.

3.5.7 Inhalation Exposure (Short- and Intermediate-Term)

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 because the duration is relevant for short-term exposure, 

and because selection of the endpoint from the study ensures the risk assessment is protective of 

potential developmental effects. Furthermore, although the selection of the dose and endpoint 

are considered to be conservative for short- and intermediate-term exposure durations, the 

selection of the developmental effects allows for aggregation of dermal and inhalation exposure 

for both residential and occupational scenarios. Since an oral study was selected for the 

inhalation route, an inhalation absorption factor of 100% should be applied during 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 100 for both 

residential and occupational exposure and risk assessments.
Page 25 of 64

3.5.8 Inhalation Exposure (Long-Term)

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 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. Since 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 100 for both residential and 

occupational exposure and risk assessments.

3.5.9 Level of Concern for Margin of Exposure

Table 3.5.9 Summary of Levels of Concern for Risk Assessment.

 Duration 

Route

Short-Term Intermediate-Term Long-Term

Occupational (Worker) Exposure

Dermal 100 100 N/A

Inhalation 100 100 N/A

Residential (Non-Dietary) Exposure

Oral 100 100 N/A

Dermal 100 100 N/A

Inhalation 100 100 N/A

For Occupational Exposure: A MOE of 100 is required. This is based on the

conventional uncertainty factor of 100X (10X for intraspecies extrapolation and 10X for

interspecies variation).
Page 26 of 64

For Residential Exposure: A MOE of 100 is required. This is based on the conventional

uncertainty factor of 100X (10X for intraspecies extrapolation and 10X for interspecies

variation).

3.5.10 Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk 

assessment must consider exposures 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 associated with swimming in treated water can 

be aggregated due to the same offspring effects being used to assess dermal and oral risks. 

Residential handlers’ dermal and inhalation risks can also be aggregated, as can adults’ postapplication exposure from swimming. These combined occupational and residential exposures 

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

dietary exposure assessment.

3.5.11 Classification of Carcinogenic Potential

HED classified flumioxazin as “not likely to be a carcinogen to humans;” therefore, there is no 

cancer risk associated with the existing or proposed uses of flumioxazin. 

3.5.12 Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Human 

Risk Assessments

Table 3.5.12a 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

There were no appropriate toxicological effects attributable to a single exposure (dose) 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 
Page 27 of 64

Table 3.5.12a 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

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

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 – Children

Short- (1-30 days) 

and IntermediateTerm (1-6 months) 

NOAEL = 6.3 

mg/kg/day

DAF = 8%

UFA=10x

UFH=10x

FQPA SF = 

1X

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 - Adults

(All durations)

NOAEL= 30

mg/kg/day

UFA=10x

UFH=10x

FQPA SF = 

1X

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

(inhalation 

absorption 

rate = 100%)

UFA=10x

UFH=10x

FQPA SF = 

1X

LOC for MOE = 100 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

(inhalation 

absorption 

rate = 100%)

UFA=10x

UFH=10x

FQPA SF = 

1X

LOC for MOE = 100 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 carcinogen for 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 (intraspecies). UFH = potential variation in 

sensitivity among members of the human population (interspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. NA = not applicable.

Table 3.5.12b 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 LOC for MOE = 100

Dermal Developmental Study in Rats

LOAEL = 100 mg/kg/day based on 

cardiovascular effects in fetuses.
Page 28 of 64

Table 3.5.12b 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 Shortand IntermediateTerm (1- day up 

to 6 months)

NOAEL= 3.0 

mg/kg/day

(inhalation 

absorption rate 

= 100%)

UFA = 10X

UFH = 10X LOC for MOE = 100

Oral Developmental Study in Rats

LOAEL = 10 mg/kg/day based on 

cardiovascular effects in fetuses.

Inhalation LongTerm Inhalation 

(>6 months)

NOAEL = 2.0 

mg/kg/day

(inhalation 

absorption rate 

= 100%)

UFA = 10X

UFH = 10X LOC for MOE = 100

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 carcinogen for 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 (intraspecies). UFH = potential variation in 

sensitivity among members of the human population (interspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. NA = not applicable.

3.6 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 is issuing 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 
Page 29 of 64

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

pesticide active ingredients. 

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

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

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

4.0 PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

There are no new public health data or pesticide epidemiology data to report at this time.

5.0 DIETARY EXPOSURE/RISK CHARACTERIZATION

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops and Livestock Commodities.

The nature of the residue has been adequately delineated for both plant and animal commodities. 

In plants, the major metabolic pathway is hydrolysis of the imide moiety to produce the 

metabolites THPA and APF. The THPA is then hydrated to produce 1-OH-HPA. The residue of 

concern in plants, for both tolerance expression and risk assessment purposes, is the parent 

compound only.

The results of the ruminant and poultry metabolism studies with both phenyl- and THP-labeled 

flumioxazin show that the major metabolic pathways are hydrolysis of the imide moiety, 

hydroxylation of the cyclohexene ring, and the equivalent of addition of sulfonic acid to the 

alkene function. The residues of concern in ruminants for risk assessments are the parent, 3-OHflumioxazin, 4-OH-flumioxazin, and metabolites B, C, and F. In poultry, the residues of concern 

are parent, 3-OH-flumioxazin, 4-OH-flumioxazin, and 4-OH-S-53482-SA (PP#: 1F06296, DP

Num: D284045, W. Drew, 5/24/04). For purposes of this petition, ARIA/HED has waived the 

requirement for a fish metabolism study and has concluded that the residues of concern in fish 

include flumioxazin and its major degradates in water, APF and 482-HA.

5.1.2 Metabolism in Rotational Crops

The previously submitted confined rotational crop study (DP Num: D259593, D. Dotson, 

3/12/01) is adequate for the proposed uses on the requested field corn commodities. Following 

an application of [14C]flumioxazin at 0.96 lb ai/A, total radioactive residues (TRR) were 0.004-

0.057 ppm in RACs from representative rotational crops planted 30 days post-treatment (60 days 

for lettuce, because of phytotoxicity). Extraction and analysis of plant samples with TRRs >0.01 

ppm indicated that the majority of extractable 14C-residues were comprised of unknown polar 

components each present at ≤0.015 ppm. Low levels of flumioxazin (≤0.003 ppm) were detected 

in carrot tops and wheat chaff and straw, along with trace amounts (<0.001 ppm) of the 

metabolites 482-HA, IMOXA, and 482-CA.
Page 30 of 64

HED has concluded that the residue of concern in rotational crops is the parent compound only. 

Based on the results of the confined accumulation study, HED concluded that the existing 

rotational crop PBIs are acceptable, and that field trials and tolerances in rotated crops are not 

necessary.

5.1.3 Analytical Methodology

An adequate GC/NPD method is available for enforcing tolerances of flumioxazin in plant 

commodities (MRID No. 43935509, Valent Residue Method #RM-30A-1, Determination of 

Flumioxazin Residues in Crops, J. Garbus, 1/8/96). This method has undergone a successful ILV

trial and a successful PMV trial by the Agency. The reported method LOQ and LOD for 

flumioxazin are 0.020 and 0.010 ppm, respectively.

For tolerance enforcement in fish tissues, Valent has submitted a LC-MS/MS method (GPLMTH-066) for determining residues of flumioxazin, APF and 482-HA. For this method, residues 

are extracted with acetonitrile (ACN) and aqueous ACN, each containing either 1% formic acid 

for extraction of parent and APF or 1% ammonium hydroxide for extraction of 482-HA. 

Extracted residues are diluted with water and analyzed directly by LC-MS/MS using external 

standards for quantitation. The validated LOQ is 0.01 ppm for each analyte in fish. This method 

has undergone a successful ILV trial and appears to be acceptable for enforcing tolerances; 

however, additional information/data are required before the method can be recommended as an 

enforcement method (See Sec. 11, below).

Residues of flumioxazin in/on cucumber, summer squash, and celery were quantified by

GC/NPD. The harvested RAC samples were analyzed by Cornell Analytical Laboratory using 

the Method, Residue Analysis of Flumioxazin on Cucumber by GC/NPD Detection, Version #6,

adapted and modified from Determination of Flumioxazin Residues in Crops; Residue Method 

RM-30A-1. Valent USA Corporation (Revised January 1996). Residues were extracted with 

acetone:water (4:1, v:v). The residues were partitioned into dichloromethane (DCM), 

concentrated to dryness, and further purified by partitioning in hexane/ACN. The residues in the 

ACN phase were evaporated to dryness, re-dissolved in hexane:ethyl acetate (2:1, v:v), and 

cleaned up on a Florisil column eluted with hexane:ethyl acetate (2:1, v:v). The residues were 

evaporated to dryness, re-constituted in acetone, and analyzed by GC/NPD. The LLMV for 

residues of flumioxazin in/on cucumbers, summer squash celery was 0.02 ppm. The analytical 

method was adequate for data collection purposes

Residues of flumioxazin in/on hops RAC samples (dried cones) were quantified by GC/MSD

using Valent method RM-30A-3, Determination of Flumioxazin Residues in Crops, modified by

the analytical laboratory, IR-4 Western Region Leader Laboratory, University of California, 

Department of Environmental Toxicology, Davis, CA. The residues were partitioned into DCM, 

concentrated to dryness, re-dissolved in hexane:ethyl acetate (2:1, v:v), and cleaned up on a 

Florisil column eluted with hexane:ethyl acetate (2:1, v:v). The residues were evaporated to 

dryness, re-dissolved in hexane:ethyl acetate (1:1, v:v) and further purified on a tandem NH2

carbon SPE column eluted with hexane:ethyl acetate (1:1, v:v). The residues in the eluate were 

evaporated to dryness, re-constituted in acetone, and analyzed by GC/MSD in the selective ion 
Page 31 of 64

monitoring (SIM) mode. The LLMV for residues of flumioxazin on hops samples was 0.02 

ppm. The analytical method was adequate for data collection purposes

Residues of flumioxazin and its two hydroxy metabolites (3-OH-flumioxazin and 4-OHflumioxazin) were determined in milk and tissues using two related liquid chromatography with 

tandem mass spectroscopy/mass spectroscopy (LC/MS/MS) methods, Valent Methods RM30MK for milk and RM-30T for tissues. Recoveries from milk, cream and skim milk averaged 

84-92% (± 1-9%) for flumioxazin, 89-95% (± 8-11%) for 3-OH-flumioxazin, and 84-93% (± 6-

10%) for 4-OH-flumioxazin. Recoveries from tissues averaged 77-88% (± 3-12%) for 

flumioxazin, 85-102% (± 12-25%) for 3-OH-flumioxazin, and 96-102% (± 17-20%) for 4-OHflumioxazin. For both methods, the validated LOQ is 0.02 ppm for each analyte, and the 

reported LOD is 0.01 ppm. 

5.1.4 Multiresidue Methods

Data depicting the analysis of flumioxazin through FDA Multiresidue Protocols were submitted 

and will be forwarded to FDA for review. The multiresidue method testing data indicate that 

flumioxazin is not recovered through Sections 304 and 402 of PAM, Vol. I (DP Num: D259493, 

D. Dotson, 3/12/01). However, analytical reference standards and multiresidue method testing 

data are not available for APF and 482-HA.

5.1.5 Storage Stability

During the fish magnitude of residue study, tissue samples were stored frozen for 8-14 days prior 

to extraction for analysis. As samples were stored frozen for <30 days prior to extraction and 

analysis, storage stability data is not required to support the fish residue study. The available 

storage stability data are adequate and support the sample storage durations incurred in the 

cucumber, summer squash, celery, and hop field trials. 

5.1.6 Magnitude of the Residue

Fish

The submitted fish residue study is adequate and supports the proposed aquatic use. Juvenile 

bluegill sunfishes (Lepomis macrochirus) and channel catfish (Ictalurus punctatus) were treated 

under static water conditions with flumioxazin at an initial concentration of 800 ppb (2x 

maximum proposed rate), and residues of flumioxazin, APF and 482-HA were determined in the 

water and edible fish tissues over a 28-day period of exposure. In edible fish tissues, the 

distribution and decline of residues were similar for both test species, although residue levels 

were generally higher in catfish than in bluegills. Total flumioxazin residues were highest at the 

earliest sampling interval (4 hours) in both catfish (2.52 ppm) and bluegills (0.85 ppm). Total 

residues declined rapidly by Day 3 and then remained relatively steady up to Day 28 in both 

bluegills (0.063-0.075 ppm) and catfish (0.098-0.204 ppm). At the earliest sampling interval, 

total residues in both species were comprised primarily of parent (55-65%) and 482-HA (34-

45%), with trace amounts of APF (<1%), but by Day 28, total residues were distributed equally 
Page 32 of 64

between parent (38-39%), 482-HA (26-27%) and APF (34-39%). Total flumioxazin residues did 

not bioaccumulate in either test species over the 28 day study. When extrapolated to reflect the 

1x use rate, the estimated total residues in bluegills (0.43 ppm) and catfish (1.26 ppm) would 

support the proposed 1.5 ppm tolerances for freshwater fish. Because applications are prohibited 

to flowing water, intertidal or estuarine areas and to water used for crawfish farming, residue 

data and tolerances are not required for shellfish or saltwater fishes.

Plants

The submitted residue data for cucumber and summer squash are adequate. In addition, residue 

field trial data on cantaloupe, the representative crop for muskmelon subgroup 9A were 

submitted previously in support of the tolerance using the same use pattern. The only cucurbit 

vegetable residue data set containing quantifiable residues is cucumber. The data indicate that a 

tolerance for residues on cucurbits should be established at 0.03 ppm. ARIA recommends for 

the proposed flumioxazin tolerance on cucurbit vegetables, group 9 at 0.03 ppm. Concurrently, 

with the establishment of the tolerance on cucurbit vegetables, the existing tolerance on 

muskmelon subgroup 9A should be removed.

The submitted residue data for celery are adequate. No residues of flumioxazin above the LOQ 

of 0.02 ppm were found on celery. Since celery is the representative crop for leaf petioles, 

subgroup 4B, the data is adequate to support the requested tolerance. ARIA recommends for the 

proposed flumioxazin tolerance on leaf petioles, subgroup 4B, at 0.02 ppm.

The submitted residue data for hops are adequate. The submitted data is adequate to support a 

tolerance on hops. However, the proposed tolerance was calculated with the MRL spreadsheet 

using half the LLMV value. Following Agency policy, using the LLMV value in place of the 

residue result lower than LOQ, the MRL spreadsheet indicates a tolerance of 0.05 ppm would be 

appropriate. ARIA recommends for a tolerance of 0.05 ppm for the residues of flumioxazin on 

hops. A revised Section F is required. 

Since adjuvants were not used in the submitted residue field trials, the labels should prohibit such 

uses on cucurbit vegetables, leaf petioles, and hops.

There are no processed food or feed items of regulable interest associated with the raw 

agricultural commodities in the current petitions.

5.1.7 Magnitude of the Residue in Meat, Milk, Poultry, and Eggs

None of the commodities in this petition, fish, cucurbit vegetables, leaf petioles, and hops are 

associated with livestock feed items of regulable interest. ARIA concludes that tolerances for 

meat, milk, poultry, and eggs are not required for the purpose of this petition.

5.1.8 Confined and Field Rotational Crops

Current label directions for both 51% WDG formulations of flumioxazin specify the following 

general rotational crop restriction: Do not plant any crop except cotton, peanut, soybean and 
Page 33 of 64

sugarcane earlier than 30 days after application of flumioxazin. In addition, the labels also 

specify a variety of PBIs for different field crops depending on the application rate. For the 

highest use rate on any rotated crop (0.38 lb ai/A), the specified PBIs are 9 months for cotton, 

field corn, peanut, rice, sorghum, soybean, sunflower, tobacco and wheat, and 18 months for all 

other field crops. 

5.1.9 Pesticide Metabolites and Degradates of Concern

Table 5.1.9. 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 Flumioxazin; 3-OHflumioxazin, 4-OHflumioxazin, and metabolites 

B, C, and F.

Not Applicable*

Swine Flumioxazin; 3-OHflumioxazin, 4-OHflumioxazin, and metabolites 

B, C, and F.

Not Applicable*

Poultry Flumioxazin and 3-OHflumioxazin, 4-OHflumioxazin, and 4-OH-S53482-SA. Not Applicable*

Drinking Water Flumioxazin, 482-HA and 

APF

Not Applicable

* Tolerances have not been required for livestock commodities to date.

5.1.10 Drinking Water Residue Profile

The EDWC for flumioxazin residues (flumioxazin, 482-HA, and APF) used in this dietary risk 

assessment was obtained from EFED’s environmental risk assessment for flumioxazin, Drinking 

Water Assessment for: (1) IR-4 Registration for Flumioxazin to be used on Asparagus, Dry Bean, 

Bushberry Subgroup 13B, Fruiting Vegetable Subgroup 8, Melon Subgroup 9A, Okra and Tree 

Nut Subgroup 14; and (2) Section 3 Registration for Use on Field Corn and Alfalfa; DP Num:

D336195, D342249, and D331732; L. Liu; 9/25/07. The hydrolysis study for flumioxazin 

indicates that flumioxazin forms the metabolite 482-HA, which can further hydrolyze to the 

metabolites APF and THPA. The rates of the two hydrolytic reactions are very pH dependent, 

but flumioxazin (parent compound) is not very stable at any likely environmental pH. Data also 

indicates that THPA and APF are likely to be very mobile. Although THPA can comprise a 

major portion of the total residue in water, it does not possess the phenyl ring and is thus 
Page 34 of 64

considered significantly less toxic than parent, APF, and 482-HA. Thus, THPA has not been 

included in the residue of concern for drinking water. Therefore, parent flumioxazin and the 

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

flumioxazin residues (used in both the acute and chronic dietary analyses) was 0.048 ppm, the 

concentration in groundwater as estimated by the SCI-GROW model. SCI-GROW is an 

empirical model for predicting pesticide levels in groundwater; the value from SCI-GROW is 

considered an upper bound concentration estimate, and thus conservative. In order to be 

conservative with the estimates, the groundwater EDWC (0.048 ppm), which is greater than the 

surface water EDWC (0.034 ppm), was used in both dietary analyses. Table 5.1.10 summarizes 

the drinking water concentrations provided by EFED. The model and its description are 

available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.

Table 5.1.10. EDWCs for Flumioxazin and its Degradates in Surface Water and 

Groundwater at pH 7. 1

Compound Average 56-Day 

Conc. in Surface 

Water

Peak Conc. in 

Surface Water

Conc. in 

Groundwater

Flumioxazin negligible 1.03 ppb negligible

482-HA 4.84 ppb 6.87 ppb 45.27 ppb

APF 12.85 ppb 26.46 ppb 2.66 ppb

THPA 19.50 ppb 27.67 ppb 182.28 ppb

1 Total EDWC = Flumioxazin + 482-HA + APF

5.2 Dietary Exposure and Risk

5.2.1 Acute Dietary Exposure/Risk

The analysis summarized in Table 5.2.2 (below) is based on tolerance-level residues in all RACs 

(modified by DEEM processing factors, Version 7.81, for processed commodities), and 100% 

CT assumptions. Dietary exposure via drinking water was also included in this assessment. 

Even with the conservative assumptions utilized, the risk estimate is well below ARIA’s level of 

concern. The only population subgroup analyzed is females 13-49 (only subgroup with an 

identified acute dietary endpoint), which has an exposure estimate of 0.002734 mg/kg/day at the 

95th percentile, and utilizes 9% of the aPAD.

5.2.2 Chronic Dietary Exposure/Risk

The analysis summarized in Table 5.2.2 (below) are based on tolerance-level residues in all 

RACs (modified by DEEM processing factors, Version 7.81, for processed commodities), and 

100% CT assumptions. Dietary exposure via drinking water was also included in these 

assessments. Even with the conservative assumptions utilized, the risk estimates are well below 

ARIA’s level of concern. The most highly exposed population subgroup is all infants <1, which 

has an exposure estimate of 0.003761 mg/kg/day, and utilizes 19% of the cPAD.

 
Page 35 of 64

TABLE 5.2.2. Summary of Dietary Exposure and Risk for Flumioxazin. 

Population Subgroup1

DEEM Acute Dietary Analysis,

95th Percentile

DEEM Chronic Dietary Analysis

aPAD 

(mg/kg)

Exposure 

(mg/kg/day)

% aPAD cPAD 

(mg/kg/day)

Exposure 

(mg/kg/day)

% cPAD

General U.S. Population

NA 2

0.02 0.001307 7

All Infants (< 1 year old) 0.02 0.003761 19

Children 1-2 years old 0.02 0.002289 11

Children 3-5 years old 0.02 0.002120 11

Children 6-12 years old 0.02 0.001433 7

Youth 13-19 years old 0.02 0.000980 5

Adults 20-49 years old 0.02 0.001165 6

Adults 50+ years old 0.02 0.001225 6

Females 13-49 years old 0.03 0.002734 9 0.02 0.001165 6

1 Values for the population with the highest risk for each type of risk assessment are bolded. 

2 NA = Not Applicable; no acute dietary endpoint was identified for these population subgroups

5.2.3 Cancer Dietary Risk

HED classified flumioxazin as “not likely to be a human carcinogen.” Therefore, quantification 

of human cancer risk was not necessary. 

6.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION

HED has reviewed two proposed use patterns that could potentially result in residential (nonoccupational) exposure. First, a new use site, to include walkways, parking lots and non-grassy 

areas around residential dwellings was assessed for residential handlers. Although the product is 

not intended for use by homeowners, the label does not specifically prohibit use by residential 

handlers. However, based on the use sites, no postapplication exposure for adults or children 

was expected or assessed. Residential handler risks were not of concern (refer to the 8/11/09 S.

Oonnithan memo for details (DP Num: D362611). The results of the handler exposure and risk 

assessment are presented below, in Table 6.1.

Table 6.1 Short-term Risk to Homeowners From the Use of BroadStar Granules on Non-crop Areas 

Within Residential Settings 1
Page 36 of 64

Exposure 

Scenario 

Appl. 

rate, lb 

AI/A 

Dermal 

unit exp. 

(mg AI /lb)

Inhal. 

unit exp. 

(mg AI/lb)

Dermal 

dose 

(mg/kg/day) 2/

Dermal MOE

Inhal. dose 

(mg/kg/ 

day) 2/

Inhal. MOE

Total 

MOE 3

Applying granules 

with push-type 

spreader 4

0.375 0.67 0.00088

0.00209/

14,000

2.75E-06/

1 x 106

14,000 

Applying granules 

with a hand 

shaker 5

0.375 3.5 0.045

0.01094/

2700

1.41E-04/

21,000

2,400

1. Inputs used for the exposure and MOE calculations are : (1) area treated per day = 0.5 Acres (from HED's 

ExpoSAC Policy No. 12, (2) body wt. of handlers, (3) Inhalation absorp., (4) short-term dermal NOAEL, (5) shortterm inhalation NOAEL. 

2. Dermal dose (mg/kg/day) = (appl. rate * area treated/day * dermal unit exp.) / body wt. Inhalation exposure 

(mg/kg/day) = (appl. rate * area treated/day * inhalation unit exp. * inhalation absorption rate) / body wt.

3. Total MOE = 1 / [(1/dermal MOE) + (1/inhal. MOE)]. Dermal MOE = dermal NOAEL / dermal exposure. 

Inhalation MOE = inhalation NOAEL/ inhalation exposure. The short-term dermal and inhalation MOEs were 

combined because of the common endpoints (i.e., developmental effects) for both exposure routes. 

4. The unit exposures (geometric means) represent homeowners applying granules with push-type drop/rotary 

spreader while wearing T-shirt and shorts (ORETF Study No. OMA 003, 2003). 

5. The unit exposures are for homeowners applying granules with a shaker can (S. Recore, D296625, 5/6/04). The 

area treated/day with a shaker-can was taken as 0.5 Acres, which is on the higher side. 

In conjunction with the proposed use for control of aquatic weeds, there is a potential for nonoccupational/residential post-application exposure to treated water for recreational purposes (i.e., 

swimming) because there is no post-application holding restriction against such use. 

HED used the SWIMODEL to assess short-term post-application exposures/risks for children 

and adults exposed to flumioxazin-treated water. The SWIMODEL uses well-accepted 

screening exposure assessment equations to calculate the total worst-case exposure for swimmers 

expressed as a mass-based intake value (mg/event). 

The formula the model uses to calculate the dermal dose of the swimmer is as follows:

ADR = CW * SA * ET * Kp * CF1

Where:

ADR = Absorbed Dose Rate (mg/day)

CW = Concentration of ai in pool water (mg/L)

SA = Surface Area exposed (cm2)

ET = Exposure Time (hours/day)

Kp = permeability coefficient (cm/hr)

CF1 = volume unit Conversion Factor (L/1,000 cm3)

Dermally absorbed dose rate, normalized to body weight, is calculated as:

ADRnorm = ADR / BW

Where:
Page 37 of 64

ADRnorm = Absorbed Dose Rate, normalized to body weight (mg/kg/day)

BW = Body Weight (kg)

The formula used to calculate incidental oral dose is as follows:

PDR = CW * IgR * ET

Where:

PDR = Potential Dose Rate (mg/day)

CW = Concentration of ai in pool water (mg/L)

IgR = Ingestion Rate of pool water (L/hour)

ET = Exposure Time (hours/day)

Potential dose rates, normalized to body weight, are calculated as:

PDRnorm = PDR / BW

Where:

PDRnorm = Potential Dose Rate, normalized to body weight (mg/kg/day)

BW = Body Weight (kg)

The assumptions and factors used in the risk calculations are consistent with current EPA policy

for completing residential exposure assessments (SOPs for Residential Exposure Assessment). 

The SWIMODEL was applied incorporating the assumptions and factors of the SOPs for 

Residential Exposure Assessments. The values used in the assessment include:

 It is assumed that 100% of the application concentration is available in the water for 

dermal contact. This is believed to be a reasonable assumption because biocides are 

typically maintained in water at specified levels.

 For subsequent days after application, it may be assumed that the pesticide will not 

dissipate because it is usually desirable to maintain a specified level of biocide in the 

water.

 The skin surface area of adults is assumed to be 21,000 cm2cited in the Residential 

SOPs. This is the 95th percentile value for females (EPA Exposure Factors Handbook, 

1997).

 The body weight for children is assumed to be 22 kg as cited in the Residential SOPs. 

This is a mean value for 6 year old children.

 The skin surface area for children is assumed to be 9,000 cm2as cited in the Residential 

SOPs. This is the 90th percentile value for male and female children.

 The exposure time is assumed to be 3 hours per day. This is the 90th percentile value for 

time spent swimming in a freshwater pool. (EPA Child Specific Exposure Factors 

Handbook, 2002).
Page 38 of 64

 The body weight for adult short-term exposures is assumed to be 60 kg (due to the use of 

a developmental endpoint in the risk assessment).

 Post-application risks are based on maximum application rates specific on the label. The 

maximum concentration of 0.4 mg/liter (400 ppb) was used to assess exposures.

 Post-application inhalation exposure was not required as the active ingredient 

flumioxazin has a vapor pressure less than 10-6 mm Hg and is non-volatile, thus exposure 

is negligible and was not calculated.

 The permeability coefficient of flumioxazin (Kp) is 0.00085 cm/hr.

 The assumed mean inhalation rates are 1.7 m3/hour for adults and 1.2 m3/hour for 

children, based on a moderate activity level (U.S. EPA, 1996). These rates were not 

needed in the present assessment due to the low vapor pressure noted above.

 The assumed mean ingestion rate for adult and children swimmers is 0.05 L/hour (U.S 

EPA, 1989; Dang 1996) and as cited in the Residential SOP.

All short-term post-application MOEs are greater than 100 and therefore are not of concern. 

HED notes that the children’s exposures were assessed using the NOAEL and endpoint from the 

reproductive toxicity study, in which offspring effects were observed. For adults, however, HED 

used the oral and developmental NOAELs and endpoints for risk assessment, in order to be 

protective of potential fetal effects. In addition, the use of the developmental effects observed 

via the dermal and oral routes allowed for combining exposure and risk from both routes of 

exposure. HED notes that the SWIMODEL provides an upper-bound assessment for exposure 

associated with aquatic weed control, since it is representative of potential exposure to 

competitive swimmers in pools. A summary of the MOEs is presented in Table 6.2.

Table 6.2. Flumioxazin Recreational Swimmer Exposures and Risks.

Exposed 

Person

Route of 

Exposure

Water 

Concentration 

(mg/L)

Dose 

(mg/kg/day)

NOAEL 

(mg/kg/day) MOE

Child- 22 kg Oral 0.4 0.002727 6.3 2,300

Dermal 0.4 0.000417 6.3 15,000

Adult- 60 kg Oral 0.4 0.001 3 3,000

Dermal 0.4 0.000357 30 84,000

For children’s exposures, the NOAEL and endpoint were selected from the reproductive study in rats. No additional corrections 

were made for dermal absorption, based on the use of the permeability coefficient. MOE = NOAEL/Dose

For adult exposure, the NOAELs were selected from route-specific studies, the dermal and oral developmental toxicity studies in 

rats. MOE = NOAEL/Dose. 

The exposures calculated using the SWIMODEL are based on some central tendency (i.e., 

ingestion rate, body weight) and some upper-percentile assumptions (i.e., exposure duration, 

application rate, surface area), and are assumed to be representative of high-end exposure. The 

uncertainties associated with this assessment stem from the assumptions regarding dissipation of 

chemical residue in the water, and the use of an assumed permeability coefficient. The dose 

estimates are considered to be reasonable high-end estimates based on observations from 

chemical-specific field studies and professional judgment. A MOE of 100 or more is sufficient 
Page 39 of 64

to protect swimmers. Swimmer assessments indicate that all MOEs are above the levels of 

concern, with MOEs ranging from 3,000 to 84,000. 

6.1 Other (Spray Drift, etc.)

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. On a chemical by chemical basis, the Agency is now requiring interim 

mitigation measures for aerial applications that must be placed on product labels/labeling. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risks associated with drift.

7.0 AGGREGATE RISK ASSESSMENTS AND 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, and also determines which scenarios are likely to co-occur. 

Flumioxazin exposures can occur through food and drinking water (all populations), swimming 

in treated waters (adults and children), and, potentially, applying (handler only) a granular 

formulation around residences (adults only). In the current risk assessment, HED considered 

both the handler and postapplication (swimmer) assessments to be very conservative; in addition, 

HED concluded that co-occurrence of these exposure scenarios is unlikely. Therefore, shortterm aggregate assessments were conducted for food and water plus handlers, and food and 

water plus swimmers (see below).

7.1 Acute Aggregate Risk

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

general population; therefore, a dose and endpoint were not identified for this risk assessment. 

The aPAD for females 13-49 years was 0.03 mg/kg/day. The aggregate acute risk is equivalent 

to the dietary (food and water) risk shown in Section 5.2.1; acute aggregate risk is below the 

level of concern.
Page 40 of 64

7.2 Short- and Intermediate-Term Aggregate Risk

Intermediate-term aggregate risks were not calculated, since endpoints for short- and 

intermediate-term risk assessments were the same, and since residential exposure durations are 

expected to be short-term in nature. For calculating short-term aggregate risks for adults 

(residential handler and swimming), the 1/MOE approach was used because a route-specific 

study was used to select the endpoint for dermal risk assessment (developmental dermal toxicity

study, fetal cardiovascular abnormalities). For children’s risks from swimming, both the dermal 

and oral routes were assessed based on an endpoint selected from an oral study (offspring effects 

in the reproductive toxicity), so the exposures were simply combined, along with the 

contribution from food and water. The specific equations and calculations used are described 

below:

Residential Handlers Aggregate Exposure and Risk

Aggregate MOE = ________________1_______________ 

 1/MOEDermal + 1/MOEInhalation + Dietary

Where the dermal MOE was presented in Table 6.1, and the MOE for Inhalation + 

dietary exposure was calculated as follows:

MOEInhalation + Dietary = ___________Oral NOAEL________

 Inhalation Exp. + Dietary Exposure

Chronic dietary exposure for the general US population was used, since it was 

higher than the other adult subpopulations (Table 5.2.2, 0.001307 mg/kg/day)

MOEInhalation + Dietary = ______ 3 ___ = 2070

0.000141 + 0.001307

Aggregate MOE = ______1______

1/2700 + 1/2070

 = 1170 (1200 after rounding)

Adult Swimmers Aggregate Exposure and Risk

Aggregate MOE = ________________1_______________ 

 1/MOEDermal + 1/MOE Oral + Dietary

Where the dermal MOE was presented in Table 6.2 and the MOE for oral + dietary
Page 41 of 64

exposure was calculated as follows:

MOE Oral + Dietary = ___________Oral NOAEL________

 Oral Exposure + Dietary Exposure

Chronic dietary exposure for the general US population was used, since it was 

higher than the other adult subpopulations (Table 5.2.2, 0.001307 mg/kg/day)

MOE Oral + Dietary = ______ 3 ___ = 1300

 0.001 + 0.001307

Aggregate MOE = ______1________

1/84,000 + 1/1300

 = 1280 (1300 after rounding)

Children Swimmers Aggregate Exposure and Risk

Aggregate Exposure = Oral Dose + Dermal Dose + Chronic Dietary Exposure

= 0. 002727 +0.000417 + 0.003761

= 0.006905 mg/kg/day

Where Oral and Dermal Doses were taken from Table 6.2, and the chronic dietary

exposure for all infants, the highest exposed subpopulation, was taken from Table 5.2.2.

Aggregate MOE = ____NOAEL______

Aggregate Exposure

Aggregate MOE = ____6.3_mg/kg/day__ = 912 (900 after rounding)

 0.006905 mg/kg/day

Both adults’ and children’s short-term aggregate exposure and risk are below HED’s level of 

concern, since combined exposure through dietary (food + water) and residential (handlers and 

postapplication swimmers) resulted in MOEs greater than 100, ranging from a minimum of 900 

for children swimmers to 1300 for adult swimmers. The residential aggregate exposure 

assessment is conservative and health protective, since upper-bound estimates of both residential 

and dietary exposure were used to calculate aggregate exposure and risk.
Page 42 of 64

7.3 Chronic Aggregate Risk

Because there are no long-term (chronic) exposures associated with the residential pathway, the 

chronic aggregate risk is equivalent to chronic dietary (food plus water) risk. Refer to section 

5.2.2 for the chronic aggregate risk estimates, which are not of concern.

7.4 Cancer Risk

HED classified flumioxazin as "not likely” to be a human carcinogen. Therefore, there is no 

cancer risk associated with flumioxazin exposure.

8.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

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 tolerance 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

Based on the product use information, there is a potential for occupational exposure from 

handling (mixing/loading/applying) flumioxazin for the aquatic uses:

 Mixing/Loading Dry Flowable for Aerial Applications (Scenario 1)

 Applying Sprays with Helicopter or Fix-Wing Airplane (Scenario 2)

 Flagging during Aerial Applications (Scenario 3)

 Mixing/Loading Dry Flowable for Boom Mounted Airboat Application (Scenario 4)

 Applying Sprays with Boom Mounted Airboat (Scenario 5)

 Mixing/Loading/Applying for Sprays with Boom Mounted Airboat (Scenario 6)

 Mixing/Loading/Applying for Sprays with Low Pressure Handwand Sprayer (Scenario 7)

 Mixing/Loading/Applying for Sprays with Backpack Sprayer (Scenario 8)

 Mixing/Loading/Applying for Sprays with Right of Way Sprayer (Scenario 9)

 Mixing/Loading/Applying for Sub-Surface Application---hoses trailing behind a boat 

(Scenario 10)
Page 43 of 64

Based upon the proposed new use patterns for cucurbit vegetables, leaf petiole vegetables, and 

hops, the methods of application are by ground-boom sprayer which includes hooded or directed 

sprays. The most highly exposed occupational pesticide handlers for these uses are:

 Mixing/Loaders using open pour loading of granules

 Applicators using open-cab, ground-boom sprayers. 

It should be noted that HED and RD do not have study data regarding the loading of water 

dispersible granules, per se. However, the data for loaders using open-pour loading of dry

flowable (DF) formulation are considered appropriate surrogates. 

9.1 Short-/Intermediate-/Long-Term Handler Risk

Aquatic Uses

Equations/Calculations

The following equations were used to calculate handler exposure and risk:

Dermal Dose (mg/kg/day) = Rate (lb ai/A) x UE (mg/lb ai) x Acres Treated (A/day)

BW (kg)

Inhalation Dose (mg/kg/day) = Rate (lb ai/acre) x UE (mg/lb ai) x Acres Treated (A/day)

 BW (kg)

Where:

Rate (Application Rate) = Maximum application rate on product label (lb 

ai/acre)

UE (Unit Exposure) = Exposure value derived from August 1998 PHED 

Surrogate Exposure Table (mg/lb ai handled)

Acres Treated = Maximum number of acres treated per day

(acres/day)

 BW = Body weight (kg)

Dermal MOE = NOAEL (30 mg/kg/day) 

(Short- & Intermediate-Term) Dermal Dose (mg/kg/day)

Short-Term Inhalation MOE = NOAEL (3 mg/kg/day) 

 Inhalation Dose (mg/kg/day)

Intermediate-Term Inhalation MOE = NOAEL (2 mg/kg/day) 

 Inhalation Dose (mg/kg/day)

Short-Term Total MOE = ________________1________________ 
Page 44 of 64

 (1/ Dermal MOE) + (1/ Inhalation MOE)

 

Application Rate

The maximum application rates given in the label were used for all exposure assessments. The 

maximum rates are 0.3825 lb ai/A for surface & aerial applications, and 8.62 lb ai/A (note: an 8 

foot deep water column requires this rate to achieve a desired 400 ppb water concentration, and a 

7 foot deep water column requires 7.55 lb ai/A to achieve a desired 400 ppb water concentration) 

for subsurface application.

Area or the Amount Treated

Based on HED’s Exposure Science Advisory Council Policy Number 9.1, and the values used in 

a previous assessment (DP Num: D316596, T. Dole, 2005), the following acres per day treated 

were assumed:

 350 acres/day for aerial applications;

 10 acres/day for surface applications (DP Num: D316596, T. Dole, 2005); and

 30 acres/day for subsurface application (DP Num: D316596, T. Dole, 2005).

Body Weight

The female body weight (60 kg) was used for all assessments because: (1) NOAELs are 

identified from a developmental study with fetal effects, or (2) it produces a more conservative 

exposure estimate which can be protective to all workers (both females and males).

Exposure Frequency

No data on the number of exposure days per year was provided. For this risk assessment, HED

assumes that most handlers would be exposed for less than 30 days per year (short-term 

exposure). However, commercial pesticide handlers could be exposed for more than 30 days but 

less than 6 months (intermediate-term exposure). Long-term exposure is not expected.

Unit Exposures

Based on the PHED Version 1.1 as presented in the August 1998 PHED Surrogate Exposure 

Guide, the unit exposures used in the handlers’ exposure/risk assessment are: 

 Dermal unit exposure for mixing/loading dry flowables = 0.066 mg/lb ai

 Inhalation unit exposure for mixing/loading dry flowables = 0.77 μg/lb ai

 Dermal unit exposure for applying with helicopter or airplane = 0.0050 mg/lb ai

 Inhalation unit exposure for applying with helicopter or airplane = 0.068 μg/lb ai

 Dermal unit exposure for flagging = 0.011 mg/lb ai

 Inhalation unit exposure for flagging = 0.35 μg/lb ai
Page 45 of 64

 Dermal unit exposure for applying with airboat-boom = 0.014 mg/lb ai

 Inhalation unit exposure for applying with airboat-boom = 0.74 μg/lb ai

 Dermal unit exposure for mixing/loading/applying with airboat-boom = 0.37 mg/lb ai

 Inhalation unit exposure for mixing/loading/applying with airboat-boom = 1.3 μg/lb ai

 Dermal unit exposure for mixing/loading/applying with low-pressure handwand sprayer 

= 0.43 mg/lb ai (gloves) 

 Inhalation unit exposure for mixing/loading/applying with low-pressure handwand 

sprayer = 30 μg/lb ai

 Dermal unit exposure for mixing/loading/applying with backpack sprayer = 2.5 mg/lb ai 

(gloves)

 Inhalation unit exposure for mixing/loading/applying with backpack sprayer = 30 μg/lb ai

 Dermal unit exposure for mixing/loading/applying with right-of-way sprayer = 1.3 mg/lb 

ai

 Inhalation unit exposure for mixing/loading/applying with right-of-way sprayer = 3.9 

μg/lb ai

 Dermal unit exposure for mixing/loading/applying for subsurface application = 0.066 

mg/lb ai

 Inhalation unit exposure for mixing/loading/applying for subsurface application = 0.77 

μg/lb ai

PHED was designed by a task force of representatives from the U.S. EPA, Health Canada, the 

California Department of Pesticide Regulation, and member companies of the American Crop 

Protection Association. PHED is a software system consisting of two parts–a database of 

measured exposure values for workers involved in the handling of pesticides under actual field 

conditions and a set of computer algorithms used to subset and statistically summarize the 

selected data. Currently, the database contains values for over 1,700 monitored individuals (i.e., 

replicates).

Users select criteria to subset the PHED database to reflect the exposure scenario being 

evaluated. The subsetting algorithms in PHED are based on the central assumption that the 

magnitude of handler exposures to pesticides is primarily a function of activity (e.g., 

mixing/loading, applying), formulation type (e.g., wettable powders, granulars), application 

method (e.g., aerial, ground-boom), and clothing scenarios (e.g., gloves, double layer clothing).

Once the data for a given exposure scenario have been selected, the data are normalized (i.e., 

divided by) by the amount of pesticide handled resulting in standard unit exposures (milligrams 

of exposure per pound of active ingredient handled). Following normalization, the data are 

statistically summarized. The distribution of exposure values for each body part (e.g., chest, 

upper arm) is categorized as normal, lognormal, or “other” (i.e., neither normal nor lognormal). 

A central tendency value is then selected from the distribution of the exposure values for each 

body part. These values are the arithmetic mean for normal distributions, the geometric mean for 

lognormal distributions, and the median for all “other” distributions. Once selected, the central 

tendency values for each body part are composited into a “best fit” exposure” value representing 

the entire body.
Page 46 of 64

There are three basic risk mitigation approaches considered appropriate for controlling 

occupational exposures. These include administrative controls, the use of personal protective 

equipment or PPE, and the use of engineering controls. Occupational handler exposure 

assessments are often completed by HED using baseline, PPE, and engineering controls. [Note: 

Administrative controls available generally involve altering application rates for handler 

exposure scenarios. These are typically not utilized for completing handler exposure 

assessments.] The baseline clothing level scenario for occupational exposure scenarios is 

generally an individual wearing long pants, a long-sleeved shirt, no chemical resistant gloves, 

and no respirator. The first level of mitigation generally applied is PPE. PPE may involve the 

use of an additional layer of clothing, chemical-resistant gloves, and a respirator. The next level 

of mitigation considered in the risk assessment process is the use of appropriate engineering 

controls which, by design, attempt to eliminate the possibility of human exposure. Examples of 

commonly used engineering controls include enclosed tractor cabs and cockpits, closed 

mixing/loading/transfer systems, and water-soluble packets.

Except for scenarios 7, 8, & 10, the handler exposure/risk were evaluated at baseline level 

(handlers wearing long pants, a long-sleeved shirt, no gloves, and no respirator). For all 

scenarios except sub-surface use, mitigation controls (i.e. PPE and engineering controls) were 

not needed for the MOE to be greater than or equal to the level of concern (MOE = 100).

Handlers’ Exposure and Risk

Except for the short-term total MOE for the subsurface application (MOE = 94), all short-term 

total MOEs and intermediate-term dermal & inhalation MOEs for the handlers performing the 

proposed uses on aquatic weeds are greater than 100 (110 ~ 43,000) and therefore, the risks do 

not exceed HED’s level of concern. The short-term total MOE calculated for the next highest 

application rate (7.55 lb ai/A) used in the subsurface application is 110. Based on this result and 

given the serious nature of the toxicological endpoint, HED recommends that the water depth for 

subsurface application shall not go beyond 7 feet (a 7 foot deep water column requires 7.55 lb 

ai/A to achieve desired 400 ppb water concentration, while an 8 foot deep water column requires 

8.62 lb ai/A to achieve desired 400 ppb water concentration). The rate of 8.62 lb ai/A results a 

short-term total MOE of 94 when assessed using baseline protection plus gloves as required on 

the label. 

Summaries of the exposures/risks for flumioxazin occupational handlers are presented in Tables 

9.1.a and 9.1.b. 

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 that amount of chemical handled. The estimated exposures are 

believed to be reasonable high-end estimates based on observations from field studies and 

professional judgment.
Table 9.1.a. Non-Cancer Short-Term Risk for Flumioxazin Handlers for Aquatic Uses.

Exposure Scenario 

(Scenario #)

Mitigation 

Levela

Dermal 

Unit 

Exposureb

(mg/lb ai)

Inhalation 

Unit 

Exposurec 

(μg/lb ai)

Crop Application 

Rate

(lb ai/A)

Amount 

Treatedd

(A/day)

Daily

Dermal

Dosee

(mg/kg/day)

Daily

Inhalation

Dosef

(mg/kg/day)

Dermal 

MOEg

Inhalation 

MOEh

Total

MOEi 

Mixer/Loader

Dry Flowables for 

Aerial Application (1) Baseline 0.066 0.77

Aquatic 

Weeds

0.3825 350 0.1473 0.00172 204 1,744 180

Dry Flowables for 

Airboat Application (4) Baseline 0.066 0.77

Aquatic 

Weeds 0.3825 10 <0.1473 <0.00172 >204 >1,744 >180

Applicator

Sprays with Helicopter/ 

Fix-Wing Airplane (2) En. Control 0.0050 0.068 Aquatic Weeds 0.3825 350 0.0112 0.00015 2,679 20,000 2,400

Sprays with Boom 

Mounted Airboat (5) Baseline 0.014 0.74 Aquatic Weeds 0.3825 10 0.00089 0.000047 33,708 63,830 22,000

Mixer/Loader/Applicator

Sprays with Boom 

Mounted Airboat (6) Baseline 0.37 1.3

Aquatic 

Weeds 0.3825 10 0.0236 0.000083 1,271 36,145 1,200

Sprays with Low-Press 

Handwand (7)

Baseline + 

gloves 0.43 30

Aquatic 

Weeds 0.3825 10 <0.1594 0.0019 >188 >1,579 >170

Sprays with Back Pack

Sprayer (8)

Baseline + 

gloves 2.5 30

Aquatic 

Weeds 0.3825 10 0.1594 0.0019 188 1,579 170

Sprays with Right-ofWay (9) Baseline 1.3 3.9

Aquatic 

Weeds 0.3825 10 <0.1594 <0.0019 >188 >1,579 >170

Sub-Surface 

Application (10)

Baseline + 

gloves 0.066 0.77

Aquatic 

Weeds

8.62

7.55

30

0.2845

0.2492

0.0033

0.0029

105

120

909

1034

94

110

Flagger

Flagging during 

Aerial Application (3) Baseline 0.011 0.35 Aquatic 

Weeds 0.3825 350 0.0245 0.00078 1,224 3,846 930

a Baseline consists of long-sleeve shirt, long pants, shoes, and socks and no respirator. PPE consists of long-sleeve shirt, long pants, shoes, socks, chemical-resistant gloves, and no respirator.

b Baseline Dermal Unit Exposure represents long pants, long sleeved shirt, no gloves, open mixing/loading, and open cab tractors, as appropriate. 

c Baseline Inhalation Exposure represents no respiratory protection, open mixing/loading, and open cab tractors, as appropriate. 

d Daily acres treated values are from EPA estimates of acreage that could be treated or volume handled in a single day for each exposure scenario of concern, based on the application method 

and formulation/packaging type; and also based on values used in D 316596 (T. Dole 2005).

e Daily dermal dose (mg/kg/d) = unit dermal exposure (mg/lb ai) * application rate (lb ai/acre) * daily acres treated / body weight (60 kg).

f Daily inhalation dose (mg/kg/d) = unit exposure (μg/lb ai) * (1mg/1000 μg) conversion * application rate (lb ai/acre) * daily acres treated / body weight (60 kg).

g Dermal MOE = NOAEL (30 mg/kg/d) / daily dermal dose. UF = 100. 

h Inhalation MOE = NOAEL (3 mg/kg/d) / daily inhalation dose. UF = 100.

i Total MOE = 1 / 1 / Dermal MOE + 1/ Inhalation MOE. UF = 100.
Page 48 of 64

Table 9.1.b. Non-Cancer Intermediate-Term Risk for Flumioxazin Handlers for Aquatic Uses.

Exposure Scenario 

(Scenario #)

Mitigation 

Levela

Dermal 

Unit 

Exposureb

(mg/lb ai)

Inhalation 

Unit 

Exposurec 

(μg/lb ai)

Crop Application 

Rate

(lb ai/A)

Amount 

Treatedd

(A/day)

Daily

Dermal

Dosee

(mg/kg/day)

Daily

Inhalation

Dosef

(mg/kg/day)

Dermal 

MOEg

Inhalation 

MOEh

Total

MOEi 

Mixer/Loader

Dry Flowables for 

Aerial Application (1) Baseline 0.066 0.77

Aquatic 

Weeds

0.3825 350 0.1473 0.00172 200 1,200 NA

Dry Flowables for 

Airboat Application (4) Baseline 0.066 0.77

Aquatic 

Weeds 0.3825 10 <0.1473 <0.00172 >200 >1,200 NA

Applicator

Sprays with Helicopter/ 

Fix-Wing Airplane (2) En. Control 0.0050 0.068 Aquatic Weeds 0.3825 350 0.0112 0.00015 2,700 13,000 NA

Sprays with Boom 

Mounted Airboat (5) Baseline 0.014 0.74 Aquatic Weeds 0.3825 10 0.00089 0.000047 34,000 43,000 NA

Mixer/Loader/Applicator

Sprays with Boom 

Mounted Airboat (6) Baseline 0.37 1.3

Aquatic 

Weeds 0.3825 10 0.0236 0.000083 1,300 24,000 NA

Sprays with Low-Press 

Handwand (7)

Baseline + 

gloves 0.43 30

Aquatic 

Weeds 0.3825 10 <0.1594 0.0019 >190 >1,100 NA

Sprays with Back Pack

Sprayer (8)

Baseline + 

gloves 2.5 30

Aquatic 

Weeds 0.3825 10 0.1594 0.0019 190 1,100 NA

Sprays with Right-ofWay (9) Baseline 1.3 3.9

Aquatic 

Weeds 0.3825 10 <0.1594 <0.0019 >190 >1,100 NA

Sprays for Sub-Surface 

Application (10) Baseline 0.066 0.77

Aquatic 

Weeds

8.62

7.55

30

0.2845

0.2492

0.0033

0.0029

110

120

610

690

NA

Flagger

Flagging during 

Aerial Application (3) Baseline 0.011 0.35 Aquatic 

Weeds 0.3825 350 0.0245 0.00078 1,200 2,600 NA

a Baseline consists of long-sleeve shirt, long pants, shoes, and socks and no respirator. PPE consists of long-sleeve shirt, long pants, shoes, socks, chemical-resistant gloves, and no respirator.

b Baseline Dermal Unit Exposure represents long pants, long sleeved shirt, no gloves, open mixing/loading, and open cab tractors, as appropriate. 

c Baseline Inhalation Exposure represents no respiratory protection, open mixing/loading, and open cab tractors, as appropriate. 

d Daily acres treated values are from EPA estimates of acreage that could be treated or volume handled in a single day for each exposure scenario of concern, based on the application method 

and formulation/packaging type; and also based on values used in D 316596 (T. Dole 2005).

e Daily dermal dose (mg/kg/d) = unit dermal exposure (mg/lb ai) * application rate (lb ai/acre) * daily acres treated/body weight (60 kg).

f Daily inhalation dose (mg/kg/d) = unit exposure (μg/lb ai) * (1mg/1000 μg) conversion * application rate (lb ai/acre) * daily acres treated / body weight (60 kg).

g Dermal MOE = NOAEL (30 mg/kg/d) / daily dermal dose. UF = 100. 

h Inhalation MOE = NOAEL (2 mg/kg/d) / daily inhalation dose. UF = 100.

i Total MOE is not applicable since the intermediate-term dermal and inhalation NOAELs are based on different toxicological endpoints.
Cucumber Vegetables, Leaf Petioles, and Hops

ARIA/RD believes handlers will be exposed to short-term duration exposures (1-30 days). 

Depending on crop, there are one or two applications per year as described in the proposed 

supplemental product labels and the IR-4 submission. ARIA/RD expects that ground applications 

will be conducted by private, (i.e., grower) applicators. Particularly for ground applications, 

private (i.e., grower) applicators may perform all functions, that is, mix, load and apply the 

material. Standard HED procedure directs that although the same individual may perform all 

those tasks, they shall be assessed separately. The available exposure data for combined 

mixer/loader/applicator scenarios are limited in comparison to the monitoring of these two 

activities separately. These exposure scenarios are outlined in the Pesticide Handler Exposure 

Database (PHED) Surrogate Exposure Guide (August 1998). HED has adopted a methodology

to present the exposure and risk estimates separately for the job functions in some scenarios and 

to present them as combined in other cases. Most exposure scenarios for hand-held equipment 

(such as hand wands, backpack sprayers, and push-type granular spreaders) are assessed as a 

combined job function. With these types of hand held operations, all handling activities are 

assumed to be conducted by the same individual. The available monitoring data support this and 

HED presents them in this way. Conversely, for equipment types such as fixed-wing aircraft, 

groundboom tractors, or air-blast sprayers, the applicator exposures are assessed and presented 

separately from those of the mixers and loaders. By separating the two job functions, HED 

determines the most appropriate levels of personal protective equipment (PPE) for each aspect of 

the job without requiring an applicator to wear unnecessary PPE that might be required for a 

mixer/loader (e.g., chemical resistant gloves may only be necessary during the pouring of a 

liquid formulation). 

No chemical specific data were available with which to assess potential exposure to pesticide 

handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data 

available in the PHED (v. 1.1, 1998). For pesticide handlers, it is HED standard practice to 

present estimates of dermal exposure for “baseline” that is, for workers wearing a single layer of 

work clothing consisting of a long sleeved shirt, long pants, shoes plus socks and no protective 

gloves as well as for “baseline” and the use of protective gloves or other PPE as might be 

necessary. PPE for the two products was discussed earlier. 

The toxicological endpoints used herein for risk assessment are listed in Table 3.5.12b, above.

A short-term duration (1 - 30 days) dermal toxicological endpoint was identified from a dermal 

developmental study in the rat. The NOAEL is 30.0 mg ai/kg bw/day and the effects seen were 

cardiovascular effects, especially ventricular septal defects in fetuses. The level of concern for 

occupational exposures is for MOE < 100. Since the toxicological endpoint was identified from 

a dermal study, dermal exposure is not corrected for dermal absorption. Also, since the effects 

were identified from a developmental study with fetal toxicological effects, a 60 kg body weight 

is used to calculate average daily exposure. 

The short-term inhalation toxicological NOAEL is 3.0 mg ai/kg bw/day. The endpoint was 

identified from an oral developmental study in the rat. The effects seen were the same as those 

noted in the dermal study (i.e., cardiovascular effects, especially ventricular septal defects in 
Page 50 of 64

fetuses). Since the toxic effects were identified from a developmental study with fetal effects, a 

60 kg bw is used to calculate exposure. HED and RD assume 100 % absorption via the 

inhalation route of exposure. MOEs are calculated separately and as “combined” MOEs. The 

dermal and inhalation NOAELs are different, therefore, the combined MOE is calculated as 

1/(1/MOEdermal + 1/MOEinhalation).

Flumioxazin is classified as "not likely" to be a human carcinogen based on the lack of 

carcinogenicity in a 2-year rat study, an 18-month mouse study, and a battery of mutagenic 

studies. Therefore there is no cancer risk for flumioxazin. 

Table 9.1.c. Summary of Exposure & Risk for Occupational Handlers Applying Flumioxazin 

Unit Exposure1

mg ai/lb handled

Applic. Rate2

lb ai/unit

Units Treated

3 Avg. Daily Exposure4

mg ai/kg bw/day

MOE5 Combined

MOE6

Mixer/Loader Using Open Pour Loading of Dry Flowable (Hops)

Dermal:

SLNoGlove 0.066

SLWithGlove 0.066

Inhal. 0.00077

0.375 

lb ai/A

40 

A/day

Dermal:

SLNoGlove 0.0165

SLWithGlove 0.0165

Inhal. 0.00019

1,818

1,818

15,789

1,630

1,630

Mixer/Loader Using Open Pour Loading of Dry Flowable (Leaf Petiole)

Dermal:

SLNoGlove 0.066

SLWithGlove 0.066

Inhal. 0.00077

0.188 

lb ai/A

200

A/day

Dermal:

SLNoGlove 0.0414

SLWithGlove 0.0414

Inhal. 0.000483

725

725

6,211

649

649

Applicator Using Open-cab Ground-boom Sprayer

Dermal:

SLNoGlove 0.014 

SLWithGlove 0.014

Inhal. 0.00074

0.375 

lb ai/A

40

A/day

Dermal:

SLNoGlove 0.0035

SLWithGlove 0.0035

Inhal. 0.00019

8,571

8,571

15,789

5,555

5,555

Applicator Using Open-cab Ground-boom Sprayer

Dermal:

SLNoGlove 0.014 

SLWithGlove 0.014

Inhal. 0.00074

0.188 

lb ai/A

200

A/day

Dermal:

SLNoGlove 0.0088

SLWithGlove 0.0088

Inhal. 0.000464 

3,409

3,409

6,465

2,233

2,233

1. Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”, Estimates of Worker Exposure from The 

Pesticide Handler Exposure Database Version 1.1, August 1998. Inhal. = Inhalation. Units = mg ai/pound of active ingredient 

handled

2. Applic. Rate. = Taken from the proposed draft labels

3. Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; SOP No. 9.1. Science Advisory 

Council for Exposure; Revised 5 July 2000; 

4. Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units Treated  Body Weight (60 kg since NOAELs are 

identified from a developmental study with fetal effects).

5. MOE = Margin of Exposure = No Observed Adverse Effect Level (NOAEL)  ADD. NOAEL = 30.0 mg ai/kg bw/day for 

short-term dermal; 3.0 mg ai/kg bw/day for short-term inhalation).

6. Combined MOE = 1 ÷ (1 ÷ MOEDermal + 1 ÷ MOEInhalation)

Conclusion: A MOE of 100 is adequate to protect occupational pesticide handlers from

exposures to flumioxazin. Except for the short-term total MOE for the subsurface application 

(MOE = 94; application rate for 8 foot deep water column = 8.62 lb ai/A), all short-term total 

MOEs and intermediate-term dermal & inhalation MOEs for handlers performing the proposed 

uses on aquatic weeds and terrestrial crops are greater than 100 and therefore, the risks do not 

exceed ARIA/HED’s level of concern. The short-term total MOE calculated for the next highest 
Page 51 of 64

aquatic application rate of 7.55 lb ai/A (the application rate for 7 foot deep water column in the 

subsurface application) is 110. Based on this result and given the serious nature of the 

toxicological endpoint, HED recommends that the water depth for subsurface application shall 

not go beyond 7 feet. Pending the receipt of an updated aquatic application label, the proposed 

new uses do not exceed ARIA/HEDs level of concern. 

9.2 Short-/Intermediate-/Long-Term Post-application Risk

Occupational post-application exposures are not expected for the proposed aquatic uses.

It is possible for agricultural workers to have post-application exposures to pesticide residues 

during the course of typical terrestrial agricultural activities. HED in conjunction with the 

Agricultural Re-entry Task Force (ARTF) has identified a number of post-application 

agricultural activities that may occur and which may result in post-application exposures to 

pesticide residues. HED has also identified Transfer Coefficients (TC) (cm2/hr) relative to the 

various activities which express the amount of foliar contact over time, during each of the 

activities identified. For the proposed new crop use sites, the highest appropriate TC is 1,500 

cm2/hr which results from "scouting" (i.e., crop advisors) in peanut, leaf petiole vegetables and 

cucurbit vegetables. The TC for scouting hops in the earlier parts of the season is 1,300 cm2/hr. 

One might typically expect high exposures in late season hops, however, the directions for 

application to hops indicates application to the hop yard floor for sucker control and are made 

earlier in the season. Therefore, as a “screening” level assessment, RD herein uses a TC of 1,500 

cm2/hr.

The TCs used in this assessment are from an interim TC Standard Operating Procedure (SOP) 

developed by HED’s ExpoSAC using proprietary data from the ARTF database (SOP # 3.1). It 

is the intention of HED’s ExpoSAC that this SOP will be periodically updated to incorporate 

additional information about agricultural practices in crops and new data on transfer coefficients. 

Much of this information will originate from exposure studies currently being conducted by the 

ARTF, from further analysis of studies already submitted to the Agency, and from studies in the 

published scientific literature.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED assumes 20 % of the 

application rate is available as DFR on day zero after application. This is adapted from the 

ExpoSAC SOP No. 003 (7 May 1998 - Revised 7 August 2000). 

The following convention may be used to estimate post-application exposure. 

Average Daily Dose (ADD) (mg ai/kg bw/day) = DFR μg/cm2* TC cm2/hr * hr/day * 0.001 

mg/μg * 1/60 kg bw 

and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20% available as dislodgeable 

residue * (1-D)t* 4.54 x 108μg/lb * 2.47 x 10-8 A/cm2 . 
Page 52 of 64

0.188 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 μg/lb * 2.47 x10-8 A/cm2 = 0.42 μg/cm2, therefore,

0.42 μg/cm2* 1,500 cm2/hr * 8 hr/day * 0.001 mg/μg  60 kg bw = 0.084 mg/kg bw/day.

MOE = NOAEL  ADD then 30 mg/kg bw/day  0.084 mg/kg bw/day = 357.

0.375 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 μg/lb * 2.47 x10-8 A/cm2 = 0.84 μg/cm2, therefore,

0.84 μg/cm2* 1,500 cm2/hr * 8 hr/day * 0.001 mg/μg  60 kg bw = 0.168 mg/kg bw/day.

MOE = NOAEL  ADD then 30 mg/kg bw/day  0.168 mg/kg bw/day = 178.

Conclusion: A MOE of 100 is adequate to protect agricultural workers from post-application 

exposures. Since the estimated MOEs are > 100, the proposed uses do not exceed ARIA’s level 

of concern.

9.3 Restricted Entry Interval (REI)

Flumioxazin is classified in Acute Toxicity Category III for acute dermal toxicity and for eye 

irritation. It is classified in Acute Toxicity Category IV for acute inhalation toxicity and for 

dermal irritation. It is not a dermal sensitizer.

The interim worker protection standard (WPS) REI of 12 hours is adequate to protect agricultural 

workers from postapplication exposures to flumioxazin. The product labels both list 12 hour 

REIs. 

10.0 TOLERANCE SUMMARY

Flumioxazin tolerances are established under 40 CFR §180.568. Tolerances for residues in/on 

plant commodities are listed in 40 CFR §180.568[a] and are expressed in terms of flumioxazin 

per se. Tolerances ranging from 0.02 to 0.70 ppm have been established in/on the commodities 

of almonds, cotton, pome fruits (group 11), stone fruits (group 12), garlic, grape, onion, peanut, 

peppermint, pistachio, shallot, soybean, spearmint, strawberry, sugarcane, and tuberous/corm 

vegetables (subgroup 1C). Time-limited tolerances in/on alfalfa forage and hay, with a 12/31/09 

expiration date, are also listed in 40 CFR §180.568[b]. No tolerances have been established in 

meat, milk, poultry, or eggs.

HED/ARIA notes that the residue definition for the tolerance expression for CFR § 180.568 (a) 

General should be as follows: “Tolerances are established for residues of flumioxazin, including 

its metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only flumioxazin, 2-[7-fluoro-
Page 53 of 64

3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5,6,7-tetrahydro-1H-isoindole1,3(2H)-dione.”

HED/ARIA notes that once the analytical method deficiencies have been resolved for fish, the 

residue definition for the tolerance expression for fish should be as follows: “Tolerances are 

established for residues of flumioxazin, including its metabolites and degradates, in or on the 

commodities in the table below. Compliance with the tolerance levels specified below is to be 

determined by measuring only the sum of 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, 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), calculated as the stoichiometric equivalent of flumioxazin, in or 

on the commodity.”

There are no Codex, Canadian or Mexican MRLs for flumioxazin; therefore, there are no issues 

of international harmonization raised by this action.

Table 10.0. Tolerance Summary for Flumioxazin.

Commodity

Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments;

Correct Commodity Definition

Fish, freshwater 1.5 1.5

Cucurbit vegetables, group 

9

0.03 0.03

Leaf petioles, subgroup 4B 0.02 0.02

Hops, dried cones 0.07 0.05

Melon subgroup 9A 0.02 remove

With the establishment of the 

tolerance on cucurbit vegetables, the 

existing tolerance on muskmelon 

subgroup 9A should be removed.

11.0 DATA NEEDS AND LABEL RECOMMENDATIONS

11.1 Toxicology

The following toxicology studies should be submitted as a condition of registration –

 870.7800 Immunotoxicity – in accordance with the 12/2007 updated Part 158 Toxicology

Data Requirements, an immunotoxicity study is required.

 870.6200 Neurotoxicity – in accordance with the 12/2007 updated Part 158 Toxicology

Data Requirements, acute and subchronic neurotoxicity studies are required. 
Page 54 of 64

11.2 Residue Chemistry

The following residue chemistry deficiencies must be resolved prior to establishment of the 

tolerance for residues in fish:

 An updated aquatic application label is required (see Section 11.3 below).

 The labels should prohibit the use of adjuvants on cucurbit vegetables, leaf petioles, and 

hops. Updated labels are required.

 A confirmatory method is required for the proposed enforcement method for fish (GPLMTH-066).

 FDA multiresidue method testing data are required for 482-HA and APF.

 Reference standards for 482-HA and APF must be submitted to the EPA National 

Pesticide Standards Repository.

The following should be submitted to support the recommended tolerance for residues in hops:

 A revised Section F is required for a tolerance of 0.05 ppm for the residues of 

flumioxazin on hops.

11.3 Occupational and Residential Exposure

ARIA/HED recommends that the water depth for subsurface application should not go beyond 7 

feet (a 7 foot deep water column requires 7.55 lb ai/A/application to achieve desired 400 ppb 

water concentration). An updated aquatic application label is required.

12.0 REFERENCES

Dietary Exposure Memorandum

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

Petition Proposing Tolerances for Residues of Flumioxazin on Fish, Cucurbit Vegetables, Leaf 

Petioles, and Hops. DP Num: D367978, W. Cutchin, 8/11/09.

Drinking Water Memorandum

Section 3 Registration for Use on Field Corn and Alfalfa. DP Num: D336195, D342249, 

D331732; L. Liu; 9/25/07.

Product Chemistry Memorandum

EPA Fact Sheet for Flumioxazin.
Page 55 of 64

Residue Chemistry Data Reviews

Flumioxazin. Petition for the Establishment of Permanent Tolerances on Cucurbit 

Vegetables, Leaf Petioles, and Hops. Summary of Analytical Chemistry and Residue Data. 

PP#8E7462, DP Num: D359142, W. Cutchin, 12/14/09

Occupational and Residential Exposure Memorandum

Flumioxazin - Occupational Exposure/Risk Assessment for the Proposed Uses of 

Flumioxazin on Cucurbit Vegetables (Crop Group 9), Leaf Petiole Vegetables (Crop Group 

4B), Hops, and Peanut. DP Num: D359690, M. Dow, 1/5/09.

Flumioxazin: Occupational and Residential Exposure/Risk Assessment of Flumioxazin for 

Section 3 Registration of a New Use on Aquatic Weeds. DP Num: D358360, S. Wang, 

4/20/09.

Flumioxazin: Occupational and Residential Exposure Assessment for the Registration of 

New Uses for BroadStar Herbicide. DP Num: D362611, S. Oonnithan, 8/11/09.

Flumioxazin: Addendum to the Residential Exposure Assessment of Flumioxazin for Seciotn 

3 Registration of a New Use on Aquatic Weeds. DP Num: D372257, C. Swartz, 12/14/09.
Page 56 of 64

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for flumioxazin are in Table A.1. 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

yes1

yes

yes1

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 Effects- UDS 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 Develop. Neuro .............................................................

no

no

yes

yes

no

-

-

no

no

-

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

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

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

yes

yes

yes

yes

yes

no

Special Studies for Ocular Effects

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

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

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

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 57 of 64

A.2 Toxicity Profiles

Table A.2.1 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 58 of 64

Table A.2.2 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.

870.3250 90-Day dermal 

toxicity (species)

Study Not Submitted

870.3465 90-Day inhalation 

toxicity (species)

Study Not Submitted

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).
Page 59 of 64

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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).

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

870.4100a Chronic toxicity 

(species)

[ ] NOAEL = [ ] mg/kg/day

LOAEL = [ ] mg/kg/day based on [ ].

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 60 of 64

Table A.2.2 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 61 of 64

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200a Acute neurotoxicity 

screening battery

Data Gap

870.6200b Subchronic 

neurotoxicity 

screening battery

Data Gap

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 b.w. 

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 Data Gap

NonguidelineSpecial 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 Data Requirements

Guideline Number: 870.6200

Study Title: Neurotoxicity Battery (Acute and Subchronic Studies)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of 

a pesticide (food and non-food uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential adverse 

effects on the nervous system from exposure to pesticide chemicals. The Agency believes that the 
Page 62 of 64

Guideline Number: 870.6200

Study Title: Neurotoxicity Battery (Acute and Subchronic Studies)

guideline studies are inadequate in their assessment of behavioral effects and do not use optimal methods 

to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize 

these potential effects more fully, a battery of more sensitive testing is required. The objective of this 

neurotoxicity battery testing is to evaluate the incidence and severity of the functional and/or behavioral 

effects, the level of motor activity, and the histopathology of the nervous system. The acute neurotoxicity

study is required to detect possible effects resulting from a single exposure. The subchronic neurotoxicity

study is intended to detect possible effects resulting from repeated or long-term exposures.

Practical Utility of the Data

How will the data be used?

The acute and subchronic neurotoxicity studies provide critical scientific information needed to 

characterize potential hazard to the human population on the nervous system from pesticide exposure. 

These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including 

sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system 

For example, animal studies with organophosphorous chemicals have shown neurotoxicity to be the 

primary toxic endpoints (e.g., cholinesterase inhibition) of concerns in rodents and non-rodents. These 

animal studies can be used to select endpoints and doses for use in risk assessment of all exposure 

scenarios and are considered a primary data source for reliable reference dose calculation. The Agency 

has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., 

organophosphates and carbamates) where neurotoxicity was the most sensitive endpoint of concern.

How could the data impact the Agency's future decision-making?

If the acute or subchronic neurotoxicity studies show that flumioxazin poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessments for flumioxazin

may need to be revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied when conducting 

a risk assessment using the currently available studies.

Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of 

a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and 

is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., 

suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system 

to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies 

assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential 

immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ 

weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential 

immunotoxic effects. 

Practical Utility of the Data

How will the data be used?
Page 63 of 64

Guideline Number: 870.7800

Study Title: Immunotoxicity

These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure 

scenarios and are considered a primary data source for reliable reference dose calculation. For example, 

animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive 

manifestations of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive, and 

endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for 

tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than 

that given in the interim decision’s conclusion, the risk assessments for the test material may need to be 

revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied for conducting a 

risk assessment from the available studies.
Page 64 of 64

Appendix B: Metabolism Assessment

Not included.

Appendix C: Review of Human Research

No MRID - PHED Surrogate Exposure Guide