UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

Date: 12/19/2012 

SUBJECT: Flumioxazin. Human Health Risk Assessment for the Proposed Uses on 

Artichoke) Cabbage, Olive) Pomegranate, and Prickly Pear Cactus. 

PC Code: 129034 

Decision No.: 460336 

Petition No.: 1F7886 

DP Barcode: 0398750 

Registration No.: 100-727 

Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Case No.: 7244 

Aggregate 

TXRNo.: NA 

MRID Nos.: NA 

FROM: 

CAS No.: 103361-09-7 

40 CFR: § 180.568 

SheilaPiper,Chemist 

Deborah Smegal, MPH, 

6~~ 

xi~lo~ .G ~e_ ~ kl · J\ lr . Monica Hawkins, Ph.D., MPH. Environmental Health Scientist J~~ 

Risk Assessment Branch VI 

Health Effects Division (7509P) 

THROUGH: 

Risk 

Christine 

Health 

Assessment 

Effects 

Olinger, 

Division 

Branch 

Acting 

(7509P) 

VI 

Branch Chi~f \1-/ 

1 ~ 

• 

TO: Andrew Ertman, Barbara Madden RM05 

Risk Integration, Minor Use, and Emergency Response Branch 

Registration Division (7505P) 

Page 1 of 57 
1.0 

2.0 

Table of Contents 

Executive Summary ......................................................................... ~······~·······-········-··-········ 4 

HED Recommendations ..... 0# .......................................................................................... - .... 7 

2.1 Data Deficiencies ••••••-•••••••••uoo._,,,,,,.,.,,,,,.,.,,,,,,n•••••n•••••••••••••••_.,,,,, .. ,,,,, ... ,,.,,,_,,_,,, 7 

2.2 Tolerance Considerations-.. n··-·····•-••••••••••••••••••••••••···························•••············· 8 

2.2.1 Enforcement Analytical Method nooon••··-·····························-·····H·····-····· ......... 8 

2.2.2 International Harmonizationn•~•••••n•••· .. -···· .. ····•"•''''''"'"''"'''''"'""""'""'"""'''' ......... 8 

2.2.3 Recommended Tolerances .................. _._,,_,,,,,_, .................................................. 8 

2.2.4 Revisions to Petitioned-For Tolerances ............. H ............................ u ..... 9 

2.3 Label Recommendatiom ...................................................................................... 9 

3.0 lntroduction .................. - .................................. - ......................................... _ ••.•..•.•..••••........... 9 

3.1 Chemical1dentity ......................................... _,., •• """'""'"'''"" ............................................... 9 

3.2 Physical/Chemical Characteristic.s ................... H ..... u ..... -.. ..................................................... 10 

3.3 

3.4 

3.5 

Pesticide Use Pattern ......................... ~ ..••. .., ........ u ... n ... ~ .. -·.-· .. ···-···••• .. ·•• ... •• .. •• ... 10 

Anticipated Exposure Patbways .................................. ~ .................................... n 11 

Consideration of Environmental Justice ............................................. - ..... - ........ 12 

4.0 Hazard Characterization and Dose~ Response Assessment ....... ., ........... ~·-·-·"·'""''"'"'12 

5.0 

4.1 Toxicology Studies Available for Analysis •..... -······-··-··-··-··-·-············-·······12 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)···········-···-·· 13 

4.2.1 Dermal Absorption ............................................................................................... 13 

4.3 Toxicological Effects .................................................................................... ~ ............ l4 

4.4 Safety Factor for Infants and Children (FQPA Safety Faetor).···-·········-·····15 

4.4.1 Completeness of tbe T oxieology Database·-························ .. ························-- 16 

4.4.2 Eviden« of Neurotoxicity .. _ ............................................................. ~ ............... ~ 16 

4.5 

4.5.1 

4.5.2 

4.5.3 

4.5.4 

4.4.3 Evidence of Sensitivity/Susceptibility in tbe Developing or Young 

Animal .......... - ................... ~ ................ - ..... - ................................................. ~········· 16 

4.4.4 Residual Uncertainty in tbe Exposure J)atabase ••.•.•.•.......•.........•....•.•• 17 

Toxicity Endpoint and Point of Departure Selections-. ................................... 17 

Dose-Response Assessment ........... - ...................... - .............. u ........................... 17 

Recommendation for Combining Routes of Exposure for Risk Assessment. IS 

Cancer Classification and Risk Assessment Re.;ommendation ............... _ ..... 19 

Summary of Points of Departure and Toxicity Endpoints Used in Human 

Risk Asses..~ent .................................................. ~ ................. - ...... - ..... - ..... - ..... - ............. 19 

llietury 

5.1 

5.1.2 

5.1.3 

5.1.4 

5.2 

5.3 

Exposure!R.isk Characterization .................... ~ ...... H ............. _ ...... u ..................... 21 

Metabolite/Degradate Residue Profile ••••..•• H .................................. - ..... H ...... - ... 11 

5.1.1 Summary of Plant and Animal Metabolism Studies -·•m-•••••••••····-··· 21 

Summary of Environmental Degradation···················-·········-·-·············-······ 21 

Compari!on of Metabolic Pathways._ ... , .......................................... H .................. 22 

Residues of Concern Summary and Rationale ................................................... 23 

Food R.esidue Profile.-................................................................................... .,., ..... 23 

Water Residue Profile ......................................................................................... 14 

Page2 of 57 
5.4 Dietary Risk Assessment ....................................................•..........•...••..•••...•••..•• 24 

5.4.1 Description of Residue Data Used in Dietary Assessment .............................. 25 

5.4.2 Percent Crop Treated Used in Dietary Assessment ......................................... 25 

5.4.3 Acute Dietary Risk Assessment ......................................................................... 25 

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

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................ 26 

6.1 Combined Exposure ............................................................................................ 27 

6.2 Residential Bystander Post-application Inhalation Exposure ........................ 27 

7.0 Aggregate Exposure/Risk Characterization ................................................................. 28 

7.1 Acute Aggregate Risk ......................................................................................... 28 

7.2 Short- Term Aggregate Risk .................................................................................. 29 

7.3 Intermediate-Term Aggregate Risk ...................................................................... 3I 

7.4 Long-Term Aggregate Risk ................................................................................... 3I 

8.0 Cumulative Risk Characterization/Assessment ............................................................... 3I 

9.0 Occupational Exposure/Risk Pathway .............................................................................. 32 

___ 9.I Handlers .................................................................................................................... 32 

9.2 Post-application Exposure and Risk ................................................................. 39 

9.3 Inhalation Post-application Risk ....................................................................... 39 

10.0 References ........................................................................................................................ 40 

Appendix A: Toxicology Assessment ....................................................................................... 41 

A.I Toxicology Data Requirements .......................................................................... 41 

A.2 Toxicity Profiles ...................................................................................................... 43 

A.3 Hazard Identification and Endpoint Selection ................................................. 48 

A.3.1 Acute Reference Dose (aRID)- Females age 13-49 .............................. 48 

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

and children ......................................................................................................... 48 

A.3.3 Chronic Reference Dose (cRID) -all populations ................................ 49 

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term) ............... 49 

A.3.5 Dermal Absorption •..........................................................................•••.•• 50 

A.3.6 Dermal Exposure (Short and Intermediate-Term) for Children ....... 50 

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

50 

A.3.8 Inhalation Exposure (Short- and Intermediate-Term) for Adults ..... 51 

A.3.9 Inhalation Exposure (Long-Term) for Adults ••..•..••..••.•••......•...•.......... 52 

Appendix B. Physical/Chemical Properties ............................................................................. 52 

Appendix C. Residential Exposure/Risk Summary Table ..................................................... 54 

Page 3 of 57 
1.0 Executive Summary 

Valent USA Corporation and IR-4 (The Interregional Research Project No.4) has requested the 

Section 3 registration of new uses for flumioxazin, the active ingredient in Valornt: Herbicide 

(EPA Reg. No, 59639-99) and Chateau Herbicide (EPA Reg. No. 59639-119), in artichol«; 

cabbage, olive, pomegranate, and prickly pear cactus. This document assesses the dietary and 

occupational exposures and risks that would result from the proposed uses of the herbicide, as 

well as the impact on aggregate exposure and risk. 

Fl urn ioxazin, 2-[ 7 -fluoro-3 ,4-dihydro-3-oxo-4-(2 -propyny 1)-2H-1 , 4-benzoxazio-6-yl]-4,5,6, 7-

tetrahydro-lH-isoindole-1,3(211)-dione, is an herbicide of the N-phenylphthalimide class that is 

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

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

(recreationallandscapt;:s, apartment and office complexes, and schools)} as well as in aquatic 

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

on conifer reforestation sites, poplar/timber reforestation sites, and dormant warm-season 

turfgrass including golf courses and sod farms. Its mode of action is as an inhibitor of 

protopnrphyrinogen oxidase. It is active against certain grasses, broadleafweeds, and sedges 

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

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

119, water dispersible granule), which are formulated as a water dispersible granule (WDS) 

containing 51% flumioxazln by weight. The maximum single application rate proposed for 

olive, pomegranate, and prickly pear cactus is 0.38 lb ai/A, artichoke is 0.19lb ai/A, and cabbage 

and Chinese cabbage are 0.13 lb ail A. The recommended personal protective equipment (PPE) 

on the flumioxazin labels for handlers includes long-sleeved shirt and long pants, shoes plus 

socks, and chemical resistant gloves. The REI specified on the label is 12 hours. The proposed 

pre-harvest intervals are 5 or I 0 days. 

Ha7.ard Assessment: The toxicology database for flumioxazin is nearly complete as described in 

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

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

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

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

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

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

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

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

recently submitted guideline studies. 

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

effects V.'ere observed in the absence of maternal toxicity. In addition, lxlth increased qualitative 

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

were observed at lower doses than milder parental effects. Although there was an in"'-rease in 

susceptibility. HE D'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 

Page4 of 57 
clear NOAELs for developmental and offspring effects that are protective of the increased 

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

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

lx for oral and dermal exposure. Flumioxazin is classified as "not likely to be carcinogenic to 

humans." 

Due to the inhalation developmental study data gap, the Agency is retaining a 1 OX database 

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

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

uncertainty factors. 

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

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

drinking water concentrations (EDWCs) based on the aquatic use offlumioxazin. The EDWCs 

based on the proposed uses and application rates are lower than those from a previously assessed 

aquatic use. The only population subgroup for which an acute dietary endpoint was selected was 

Females 13-49 years. The acute risk estimate for this subgroup is 75% of the aPAD at the 95th 

percentile of exposure, which is not of concern. The chronic risk estimates are below HED' s 

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

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

all infants (I year old), which uses 44% of the cPAD. 

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

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

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

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

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

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

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

duration. 

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

HED (i.e., MOEs are 2': 100 for dermal and 2': 1,000 for inhalation, the levels of concern (LOC) 

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

using the Aggregate Risk Index (ARI) are not of concern to HED (i.e., ARls are 2': 1). The ARI 

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

different levels of concern (LOCs). 

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

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

identified residential uses are not of concern to HED (i.e., MOEs are 2': 100, the LOC for these 

assessments). 

Page 5 of 57 
Aggregate Risk: The acute aggregate risk from exposure to fl.umioxazin is equivalent to the 

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

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

established. 

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

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

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

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

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

PODs are identical for both exposure durations. 

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

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

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

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

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

including occupational workers who re-enter treated fields. 

Occupational handler exposures to fl.umioxazin may occur via the dermal and inhalation route 

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

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

not of concern to RED (i.e., ARis are~ 1) with baseline attire (i.e., single layer of clothing, no 

respirator), except for mixing/loading dry flowables for aerial groundboom and chemigation 

applications at baseline. For these scenarios, the ARl is greater than 1, and not of risk concern 

when a NIOSR approved dust mist respirator (PFS) or organic vapor (PFlO) respirator is worn. 

Furthermore, there are potential occupational combined dermal and inhalation exposure risk 

estimates of concern (i.e., ARls < 1) for mixing/loading dry flowables for commercial and onfann impregnation of dry bulk fertilizers when the recommended PPE on the label is worn. 

An assessment of occupational post-application exposure to flumioxazin was not conducted 

because the proposed applications to prickly pear cactus, artichoke, cabbage, and Chinese 

cabbage are made directly to the soil as pre-plant or pre-emergent applications. 

Environmental Justice Considerations. Potential areas of environmental justice concerns, to 

the extent possible, were considered in this human-health risk assessment, in accordance with 

U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations.1

" 

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

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

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

1 http://www .hss.energy.gov/nuclearsafety/env/ guidance/justice/eo 12898 ,pd£ 

Page 6 of 57 
Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF) 

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

have been determined to be ethical. 

2.0 HED Recommendations 

2.1 Data Deficiencies 

Toxicology: 

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

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

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

870.3465. The HASPOC considered the available hazard and exposure information for 

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

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

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

oral developmental toxicity studies only measure toxicity offlumioxazin after first-pass liver 

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

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

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

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

(and the inhalation MOE of610 for the currently registered aquatic use). 

Residue Chemistry 

Pending submission of a revised Section F there are no residue chemistry issues that would 

preclude granting a Section 3 registration for flumioxazin and for the recommended tolerances 

on the proposed commodities. 

Occupational and Residential Exposure: 

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

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

areas) or residential turf uses. Flumioxazin does not meet the criteria for a data waiver. In the 

absence of chemical-specific TIR data, conservative default assumptions were used in this 

assessment. 

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

required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. Flumioxazin does not meet the criteria for a data waiver. In the 

absence of chemical-specific DFR data, conservative default assumptions were used in this 

assessment. 

Page 7 of 57 
2.2 Tolerance Considerations 

2.2.1 Enforcement Analytical Method 

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

Method RM30-A-l, is available for enforcing tolerances for residues of flumioxazin per se inion 

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

for flumioxazin inion plant commodities are 0.02 and 0.01 ppm, respectively. 

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

and the available data indicate that flumioxazin could not be recovered through application of the 

FDA multiresidue protocols. 

2.2.2 International Harmonization 

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

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

of international hannonization raised by this action. 

2.2.3 Recommended Tolerances 

Table 2.2.3 summarizes the Section 3 proposed tolerances and the HED's final tolerance 

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

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

only flumioxazin. 

Table 2.2.3'. Tolerance· Summary for Flumioxazin 

Commodity . Proposed liED Comments (correct ·, Tolerance Recommended oommodity definition) 

(ppm) Telerance (ppm) 

Artichoke 0.02 0.02 

Cabbage 0.02 0.02 

Chinese Cabbage 0.02 0.02 

Olive 0.02 0.02 

Pomegranate 0.02 0.02 

Prickly pear cactus, fruit 0.1 0.07 

Prickly pear cactus, pads 0.05 0.06 

Page 8 of 57 

. . 
2.2.4 Revisions to Petitioned~ For Tolerances 

The proposed tolerances are only different for prickly pear cactus from those recommended by 

HED. HED selected the highest residues from cactus data at two use rates and multiple PHis. 

The registrant should submit a revised Section F in which the proposed tolerances are the same 

as those recommended by HED. 

2.3 Label Recommendations 

HED recommends the proposed labels be revised to require a NIOSH approved dust mist 

respirator in addition to the labeled PPE (baseline plus chemical~resistant gloves) to mitigate the 

occupational inhalation risk estimates. HED will work with the Registration Division on these 

label modifications. 

3.0 Introduction 

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

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

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

grasses, broadleafweeds, and sedges (including aquatic species). 

3.1 Chemical Identity 

The chemical structure and nomenclature offlumioxazin are presented in Table 3.1. 

Table 3.1 Flumioxazin Nomenclature. 

Compound 

Common Name 

IUPACName 

Flumioxazin 

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

Page 9 of 57 
Table 3.1 Flumioxazin Nomenclature. 

CAS Name 2-[7 • fluoro-3 ,4-dihyrlro-3-ox<>-4-(2-propynyl)-2H-l ,4-benzoxazin6-vl]-4,5 6, 7-tetrahyrlro-IH-isoindole-1 ,3(iH)-dione 

CAS Registry Number 103361-09-7 

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

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

water dispersible granule) 

3.2 Physical/Chemical Characteristics 

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

has a log octanol/water partition coefficient of2.55 and a vapor pressure of2.41 x 10"" 1nm Hg at 

25• C. It has a water solubility of L079 !liL and is soluble in common organic solvents. In tbe 

environment, tlumioxazin pbotodegrades very rapidly in water and on soil (half-lives= 1 and 5.8 

da}'S, respectively). Flumioxazin is classified as having medium soil mobility potential. Its two 

major degradates (APF and THPA) are expected to be more mobile tban the parent compound in 

the environment (Koc = 410 and 155, respectively). Flumioxazin is relatively volatile in water 

and on soil, and is not expe<..-ted to bioaccumulate in fish (Kow = 355). See Appendix B for a 

listing of flumioxazin physical and cbemical properties. 

3.3 Pesticide Use Pattern 

Valent USA Corporation is proposing the use of the herbicide flunrloxazin on artichoke, 

cabbage) Chine.se cabbage, olive, pomegranate~ and prickly pear cactus, The end-use products 

being proposed fur use on these sites are Valor Herbicide (EPA Reg, Ko. 59639-99) and Chateau 

Herbicide (EPA Reg. Ko, 59639-119, water dispersible granule), which are formulated as a 

water digpersible granule (\VTIG) containing 51% flumioxazin by weight The maximum single 

application rete proposed for olive, pomegranate, and prickly pear cactus is 0381b ail A, 

artichoke is 0.19lb ail A, and cabbage and Chinese cabbage are 0.13 lb ail A, Applications are to 

be made using ground and aerial equipment. The proposed pre-harvest intervals (PHis) are none 

or 60 days. 

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

Table 3 

______ ' 2 ' .... Summary ofDireetioos for __ .... Proposed Use5 nfFlumioxaz~n. ____ .... 

Formulation : Max. Applic. [EPAR'Il. ' Applic. Max. No. ' Sd50naJ ! Timing, Type, No. 59639- Rare (lb Applic. per Applit. Rate i and Equip. 99, 59639~ aVA) Season 

119] (lb aVA) 

Prickly Pear Cactus ______ .... 

' Ground, 

i 

0.38lb ai/A ' Water ChemJgation, ' 0.38 lb (L91lb Dispersible ' 1 Dry Bulk Granule ai/A ai/ton 

Fertilizer fertilizer) 

Page JO of 57 

PHI 

60 day-s 

Use Direct! ons: aud 

Limita ..... 

________ , 

Apply as a 

preemCTgcncen 

postemergence 

"' Wld 

application. 

Apply as a unifo onn 

broadcast awr u:-ation to the 
Table 3.2. Summary of Directions for Proposed Uses of Flumioxazln. 

Formulation Max. Applic. [EPA Reg. Applic. Max. No. Seasonal Use Dfreetions and Timing, Type, No. 59639- Rate (lb Applic. per Applic. Rate Pm Limitations and Equip. 99, 59639- ail A) Season 

119] Qb au A) 

plantation floor or as a 

uniform band directed at 

the base of the agave. Do 

not apply over the top of 

crop or allow spray to 

come in contact with crop 

as a result of application or 

drift. Use a minimum of 

15 gallons of spray solution 

I per acre. 

Olive, Pomegranate 

Apply after bud break 

through final harvest using 

Ground Water 0.38 lb ai/A shielded application 

Chemigation, Dispersible 0.38 lb I (1.911b 60 days equipment if the applicator 

Dry Bulk Granule ail A ai/ton can ensure the spray drift 

Fertilizer fertilizer) will not come into contact 

with non-target vegetation, 

crop fruit and/or foliage. 

Artichoke 

Ground, aerial O.I9lb ail A Apply as a pre-plant 

""d Water 0.191b (1.911b application for 

Chemigation, Dispersible ail A I ai/ton None preemergence control of 

Dry Bulk Granule fertilizer) weeds. 

Fertilizer 

Cabbage, Chinese Cabbage 

All applications must be 

Ground 0.13 lb ail A made with shielded or 

Cbemigation, 

Water 0.13lb (1.91 lb hooded equipment in row 

Dry Bulk Dispersible ail A I ai/ton None middles between raised 

Fertilizer Granule fertilizer) plastic mulched beds. Do 

not apply after crops are 

transplanted. 

3.4 Anticipated Exposure Pathways 

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

proposed new use offlumioxazin on artichoke, cabbage, olive, pomegranate, and prickly pear 

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

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

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

serve as sources of drinking water. It is also directly applied to surface water as an aquatic 

herbicide. There are residential uses offlumioxazin, so exposure to :flumioxazin may occur in 

residential or non-occupational settings. In an occupational setting, handlers may be exposed 

while handling the pesticide prior to application, as well as during application. There is also a 

Page 11 of 57 
potential for post-application exposure for workers re-entering treated sites. 

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

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

uses of flumioxazin, but also considers existing uses of flumioxazin, particularly in the dietary 

exposure assessment. 

3.S Consideration of Environmental Justice 

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

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

to Address Environmental Justice in Minority Populations and Low-Income Populations2

." As a 

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

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

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

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

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

Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANESIWWEIA) from 2003-2008 and are used in pesticide risk assessments for all 

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

on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

cunently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment 

4.1 Toxicology Studies Available for Analysis 

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

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

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

of registered and proposed uses offlum.ioxazin: 

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

dermal sensitization) 

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

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

• Dermal developmental (rat) 

2 Available: http://www.eh.doe.gov/oepalguidance/justiceleo 12898.pdf 

Page 12 of 57 
• Oral developmental (rat and rabbit) and reproductive toxicity (rats) studies 

• Chronic oral toxicity studies (rat and dog) 

• Carcinogenicity studies (rat and mouse) 

• Metabolism studies (rat) 

• Acute and subchronic neurotoxicity studies 

• Immunotoxicity study 

• Mutagenicity battery 

• Special Study: Rat Developmental - Critical Time for Defects 

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

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

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

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

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

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

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

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

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

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

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

Despite this missing study, the toxicity database is considered to be adequate for the purposes of 

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

associated with flumioxazin. 

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

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

in rats following single oral doses of radio labeled flumioxazin. Metabolism studies in rats 

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

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

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

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

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

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

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

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

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

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

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

4.2.1 Dermal Absorption 

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

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

Page 13 of 57 
determined that an upper-bound estimate of8% dennal abSOI]ltion should be used for risk 

assessment purposes. 

4.3 Toxieologieal Effects 

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

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

of heme. 

Flumioxazin has mild or low a<:ute toxicity (Categories III or IV) when edministered orally, 

dennally, or by inhalation. [tis not an CJ"e or skin irritant, or a dermal sensitizer. 

Subchronic and chronic toxicity studies demonstrated that toxicity associated with flumioxazin 

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

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

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

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

observed in dogs. 

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

rabbit studies. The effects seen in the rat studies were fetal cardiova'lcular anomalies, especially 

ventricular septal defects. Flumioxazin was a1so administered dermally to rats in a 

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

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

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

at I 00 mg!kg/day. No systemic toxicity (or dermal irritation) was observed in a 21-day dermal 

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

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

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

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

consumption) were noted at approximately 19 and 23 mglkg!day in males and females, 

respectively; however, effects on the offspring ( decrea'le in the nwnber of live born and 

decreased pup body weights, decreased mating index, and testicular atrophy in F 1 males) 

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

Increased quantitative susceptibility was observed in the rat developmenta1 toxicity studies (oral 

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

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

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

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

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

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

the study iedicated that a single dose on gestation day 12 wns the cause of the ventricular septal 

defect observed in the rat developmental toxicity studies. 

Page 14 of 57 
Several mechanistic studies were submitted by the registrant to describe more fully the 

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

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

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

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

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

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

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

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

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

anemic condition in the fetus. 

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

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

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

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

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

uncertainty factors. 

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

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

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

less susceptible to the effects of protoporphyrinogen oxidase inhibitors. 

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

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

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

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

does not directly target the inunune system. Also, the toxicology database for flurnioxazin does 

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

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

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

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

carcinogenic to humans." 

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

HED recommends that the required 1 Ox FQPA Safety Factor for the protection of infants and 

children be reduced to lx for oral and dermal exposures, but be retained at lOX for inhalation 

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

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

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

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

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

Page 15 of 57 
reproduction studies, the endpoints and doses selected for oral and dennal risk assessment are 

protective for these effects; anrl4) the dietary and drinking water assessments are conservative 

and based on upper~bound estimates of exposure. 

4.4.1 Completeness of the Toxicology Database 

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

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

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

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

and rabbits, developmentallmmWlotoxicity, 2~generation reproduction in rats, and neurotoxicity 

are available. 

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

Council (HASPOC) recommends that a 1 OX database uncertainty fuctor be applied only to assess 

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

{D401671, May 31, 2012). The HASPOC concludes, based on a Weight of Evidence (WOE) 

approach, that a rat developmental inhalation toxicity study (Guideline No. 870.3700a), is 

required at this time (0401671, May 31, 2012). This study should include an evaluation of the 

respiratory tract and should follow the procedures described in Guideline No. 870.3465. This 

approach considered the available hazard and exposure information for flurnioxazin, including 

(1) the observed concern for the quantitative susceptibility of the developing fetus following both 

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

in the oral and dermal developmental studies; (3) that the oral developmental toxicity studies 

only measure toxicity of tlumioxazin after first-pass liver metabolism and do not address the 

concern for the potential for greater flumioxazin~induced toxicity to the developing fetus when 

directly entering the lung (via inhalation) and more rapidly entering the blood stream by 

bypassing the liver; and (4) the concern for inhalation MOEs ofless than 1000. 

4.4.2 Evidence of Neurotoxicity 

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

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

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

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

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

a result, a DNT study is not required. 

4.4.3 •;vidence of Sensitivity /Susceptibility in the Developing or Young Animal 

There is evidence of increased quantitative susceptibility offetuses in the oral and dennal 

developmental rat studies, i.e., cardiovascular ano:malies (ventricular septal defect) that occurred 

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

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

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

Page 16 of 57 
because the reproductive effects in offspring were considered to be more severe than the 

parentaVsystemic effects. 

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

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

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

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

the doses and endpoints have been selected from the developmental and reproductive toxicity 

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

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

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

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

residual concerns for these effects. 

4.4.4 Residual Uncertainty in the Exposure Database 

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

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

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

represent maximum application rates and minimwn pre-harvest intervals (PHis). The dietary 

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

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

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

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

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

HED concludes that the exposure estimates in this analysis are unlikely to underestimate actual 

exposure. 

4.5 Toxicity Endpoint and Point of Departure Selections 

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

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

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

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

4.5.1 Dose-Response Assessment 

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

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

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

Page 17 of 57 
summary of the endpoint and point of departure selections for flumioxazin is shovm in Tables 

4.5.1 and 4.5.2. 

For acute dietary exposure, an acute reference dose (aRID) of0.03 mglkg/day was selected for 

assessment of females 13-49 yrs, based on a NOAEL of3 mglkg!day in the rat developmental 

stedy. At the LOAEL of 10 mglkg/day cardiovascular effects in fetuses, specifically ventricular 

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

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

identified for acute dietary exposure for the general population, incl\lding infimts and children. 

For chronic dietary exposure, a chronic reference dose ( cRJD) of 0.02 mglkg!day was selected 

for assessment of all populations, based on a KOAEL of2 mgikg/day from a combined 

chronicJcarcinogenicity study in rats. Increased chronic nephropathy in males and decreased 

hematological parameters in fentales were observed at the LOAEL of 18 mglkg/day. Chronic 

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

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

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

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

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

also based on edverse cardiovascular effects in fetuses at 100 mg/kg/day (KOAEL of30 

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

derntal and incidental oral PODs were based on a NOAEL of 6.3 mglkg!day for decreased pup 

hedy weight and testicular atrophy in Fl males observed at 12.7 mglkg/day (LOAEL) in the rat 

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

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

pattern. 

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

MOE of less than I 00, based on the st3ndard uncertainty factors for intraspecies variation (I OX) 

and interspecies extrapolation (1 OX). For inhalation exposure scenarios, a I OX database 

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

the LOC is MO Es less than I 000. 

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment 

~'hen there are potential residential exposures to a pesticide~ an aggregate risk assessment must 

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

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 :-<OAEL or PAD), or 

the risks themselves can be aggregated. When aggregating exposures and risks from various 

sources, HED has considered both the route and duration of exposure. For the purpose of 

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

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

exposures can be aggregated because the same offspring effects are being used to assess detnlal 

Page 18 of 57 
and oral risks. Residential handlers' dermal and inhalation risks can also be aggregated with 

food and water, since the points of departure are all based on the same oral toxicity study. 

4.5.3 Cancer Classification and Risk Assessment Recommendation 

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

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

existing or proposed uses of flumioxazin. 

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

Assessment 

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

dietary and occupational human health risk assessments, respectively. 

Table 4.5.1. Summary ofToxi~logical Doses and Endpoints for Flnmioxazin for Use in Dietary and NonOccol!_ational Human Health Risk Assessments . ·.,· .. < 

Exposure/ Point of Uncertainty ~,P~,Levelof Study and Toxicological Effects 

Scenario Departure IFQPA .. Concern for Risk .. :o• .. ; 

. : . ·- (PQD) Safety Assessment ' i~ .. .. -~; Facton . . • -~ 

.. 

Acute Dietary NOAEL=3 UFA=IOx Acute RID = Acute PAD Oral Developmental and Females 13-49 UF..r=IOx 

only mglkg/day FQPA = 0.03 mglkg/day Supplemental Pre-natal Studies 

SF=1x (Rat) 

LOAEL = 10 mglkg/day, based on 

cardiovascular effects in fetuses. 

Acute Dietary No appropriate toxicological effects attributable to a single exposure (dose) were obsetved in oral 

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

Population dose and endpoint were not identified for this risk assessment. 

including infants 

and children 

Chronic Dietary NOAEL= UFA=10x Chronic RID = Chronic PAD 2-Year Chronic/Carcinogenicity all populations 2.0 UFH=10x 

mglkg/day FQPA = 0.02 rug/kg/day Study (Rat) 

SF=lx LOAEL = 18 mglkg/day, based on 

increased chronic nephropathy in 

males and decreased hematological 

parameters in females. 

Incidental Oral - NOAEL= UFA=IOx Residential LOC for 2-Generation Reproduction Study Short- (1-30 6.3 UF..r=IOx MOE< 100 

days) and mglkg/day FQPA SF= (Rat) 

Intermediate- IX LOAEL = 12.7 mglkg/day, based on 

Term (1- 6 decreased pup body weight and 

months) testicular atrophy in F 1 males. 

Dermal- NOAEL- UFA-10x Residential LOC for 2-Generation Reproduction Study Children 6.3 UFJF10x MOE< 100 

Shon- (1-30 mglkglday FQPA SF= (Rat) LOAEL = 12.7 mglkg/day, 

days) and lX based on decreased pup body weight 

Page 19 of 57 
Table 4.5.1. Summary of Toxicological Doses and Endpoints for FlumioDZio for Use in Dietary and NoaOccupational Human Health Risk Assessments . Exposure/ Point of Uncertainty RID, PAD, Level of Study aad Toxicolocical Eflect!l 

Scenario Departure IFQPA Concero for Risk 

(POD) Safety Atsessment 

Facton r -. ,. ?'< 

Intennediate- DAF=8% and testicular atrophy in F l males. 

Tenn (l-6 

months) 

Dermal - Adults NOAEL=30 UFA=lOx Residential LOC for Dermal Developmental Study (Rat) (All durations) mglkglday UFfF IOx MOE< 100 

FQPA SF = LOAEL = 100 mglkglday, based on 

IX cardiovascular effects in fetuses. 

Inhalation NOAEL=3 UFA=lOx Residential LOC for Oral Developmental Study (Rat) Short- (1-30 mglkglday1 UFH=IOx. MOE< 1000 

days) and FQPASF = WAEL = 10 mglkglday, based on 

Intennediate- lOX cardiovascular effects in fetuses. 

Term (1- 6 (database 

months) UF) 

Inhalation NOAEL=2 UFA=IOx Residential LOC for 2-Yeax Chronic/Carcinogenicity Long-Tenn (> 6 mglkglday1 UFtrlOx MOE< 1000 

months) FQPA SF = Study (Rat) 

Inhalation lOX WAEL = 18 mglkglday, based on 

(database 

increased chronic nephropathy in 

UF) males and decreased hematological 

parameters in females. 

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

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

inhalation) 

Pomt ofDeparture (POD) =A data pomt or an estimated pomt that rs denved from observed dose-response data and 

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

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

WlCertainty factor. UF A= extrapolation from animal to human (interspecies). UFH =potential variation in 

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

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

of concern. N/A = not applicable. DAF = dermal absorption factor. 1Inhalation toxicity assumed to be equivalent to 

oral toxicity. 

Table 4.5.2. Summary of Toxicological Doses and Eadpoints for Flumioxazin for Use in Occupatioaal Human 

Health Risk Assessments . . Exposure/ Point of Uncertainty Level of Concern for Risk Study and Toxicological 

Scenario Departure Facton Assessment Effects 

Dermal Developmental Study 

in Rats 

Dermal -All NOAEL= UFA = lOX Occupational LOC for WAEL = 100 mglkglday 

Durations 30 mglkglday UFH = 10X MOE< 100 based on cardiovascular effects 

in fetuses. 

Inhalation UFA =lOX Oral Developmental Study in 

Short- and NOAEL=3.0 Rats 

Intermediate- mglkglday1 UFH= l OX Occupational LOC for WAEL = 10 mglkglday based 

Term (1- day up 

UF0 s= lOX MOE< 1000 

on cardiovascular effects in 

to 6 months) fetuses. 

Page 20 of 57 
.. 

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

Health Risk Assessments .. w 

Exposure! PoiJltof Uncertainty ,. Level of Concern for Risk , Study and Toxicological ... : 

"Effects ·• · -. Scenario Departure Factors .As&essment . -

2-Year 

Inhalation NOAEL= UFA =lOX 

Chronic/Carcinogenicity Study 

(Rat) 

Long-Term 2.0 UFH =lOX Occupational LOC for LOAEL = 18 mglkwday, based 

Inhalation (>6 mglkwday1 UFDB =lOX MOE< 1000 on increased chronic 

months) nephropathy in males and 

decreased hematological 

parameters in females 

Cancer (oral, "Not likely to be a carcinogenic to humans," based on the lack of carcinogenicity in a 2-year rat dermal, 

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

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

factor. UF A= extrapolation from animal to human (interspecies). UFR =potential variation in sensitivity among 

members of the human population (intraspecies), UFos =database uncertBintr, factor for lack of inhalation 

developmental study. MOE= margin of exposure. LOC =level of concern. Inhalation toxicity assumed to be 

equivalent to oral toxicity. 

5.0 Dietary Exposure/Risk Characterization 

Source: Flumioxazin. Petition for the Section 3 Registration and Establishment of Tolerances for uses on 

Artichoke, Cabbage, Olive, Pomegranate, and Prickly Pear Cactus. Summary of Analytical Chemistry 

and Residue Chemistry Data. S. Piper. 11/12. 0406070 

5.1 Metabolite/Degradate Residue Proflle 

5.1.1 Summary of Plant and Animal Metabolism Studies 

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

acceptable soybean, peanut, com, sugarcane, grapes, ruminant, and poultry metabolism studies. 

The residue of concern for plants is only the parent compound. The residues of concern for 

ruminants should include parent, 3-0H-flumioxazin, 4-0H-flumioxazin, and Metabolites B, C, 

and F. For poultry, the residues of concern are parent, 3-0H-flwnioxazin, 4-0H-flwnioxazin, 

and 4-0H-S-53482-SA. 

Plant Metabolism 

Page 21 of 57 
Adequate plant metabolism studies are available depicting the uptake and metabnlism of 

rt 4CJtlumioxazin following applications to soybean (preemergence), peanut (pre-emergence)~ 

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

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

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

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

proposed herein. 

Livestock Metabnlism 

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

flumioxazin radiolabeled in either the phenyl or tetrahydrophtbaloyl (TI!P) ring. The 

metabolism of flumioxazln ls similar in both ruminants and poultry, involving the hydroxylation 

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

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

that the residues of concern for ruminants should include parent, 3-0H-flumioxazin, 4-0Hflumioxazin, and Metabolites B, C, and F. For poultry, the residues of concern are parent, 3-0Hflumioxazin, 4-0H-flumioxazin, and 4-0H-S-53482-SA. 

5.1.2 Summary of Environmental Degradation 

Drinking Water Assessment for the Proposed Use of Flumioxazin as an Aquatic Herbicide, 

D357184, L. Liu, 7/2112010 

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

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

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

compound in the environment (Koc 410 and 155, respectively). Flumioxazin has a vapor 

pressure of2.41x!o·• mmHg, water solubility of 1.079 giL, and an estimated Henry's law 

constant of 6.2xl0~7 atm·m3/mol. Based upon its Henry's law constant and vapor pressure, 

flumioxa;dn is relatively volatile in water and on soiL 

5.1.3 Comparison of Metabolic Pathways 

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

discussed in Section 5.1.1. 

The metabolic profile in plants is similar in soybean, peanut; com, sugarcane, and grapes, 

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

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

parent, 3-0H-tlumioxazin, 4-0H-flumioxazin, and Metabolites B, C, and F. For poultry, the 

residues of ccncem are parent, 3-0H-flumioxazin, 4-0H-flumioxazin, and 4-0H-S-53482-SA. 

Page 22 of 57 
In rats, metabolism studies indicated that there vvas extensive biliary excretion following oral 

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

and urine revealed up to 35 putative metabolites. 

5.1.4 Residues of Concern Summary and Rationale 

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

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

offlumioxazin and its metabolites APF (3-oxo-4-prop-2ynyl-6-amino-7-fluoro-3A-dihydro-1Abenzoxazin) and 482-HA (N-(7 -fluoro-3A-dihdyro-3-oxo-4-prop-2-ynyl-2H-1, 4-benzoxazin-6-

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

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

Tabl~ s.i4 Summary of Met~liteo and Degradates to be ineiiuJ~ in the Risk ~i~ Assessment and Tolef11nce Expre~sion . · , ·.~ · '·"'· ·· :, · . '· · · <;:;! 1~,,; 

~sidues included in Risk "d . >_ lud d . . ""':~· 

Matrix · Res1 ues me e m 

Assessment Tolerance Expression 

Plants Primary Crop Flumioxazin Flwnioxazin 

Rotational Crop Flumioxazin Flwnioxazin 

Livestock Ruminant Not Applicable Not Applicable 

Poultry Not Applicable Not Applicable 

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

Drinking Water Flumioxazin, APF, 482-HA Flumioxazin 

5.2 Food Residue Profile 

Acceptable field trial data on artichoke, cabbage, olive, pomegranate and prickly pear cactus 

were submitted reflecting the proposed use patterns for the 51% WG formulations. The field 

trial data did not include an adjuvant in the spray mixture. The maximum residues of 

flumioxazin were <0.02 ppm inion artichoke, cabbage, olives, pomegranate and 0.037 ppm inion 

prickly pear cactus fruit. 

The Interregional Research Project No. 4 (IR-4) has submitted a processing study on olives. In 

one trial conducted inCA, two broadcast exaggerated rate (5X) applications offlumioxa.zin were 

made to the orchard floor at a 60-day interval at rates from 1.83-1.85 lb ail A. Olive samples 

(fruit with pits) were harvested at 56 days after the last application and were processed into olive 

oil according to normal commercial practice. Olive oil samples from the 5X treated plot showed 

residues offlumioxazin that were each below LOQ <0.02 ppm. A separate tolerance for olive oil 

is not needed. 

Page 23 of 57 
The previously submitted confmed rotational crop study is adequate for the proposed uses on the 

requested commodities. 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 plantback intervals (PBis) are acceptable, and that 

field trials and tolerances in rotated crops are not necessary. 

5.3 Water Residue Profile 

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

Herbicide, D357184, L. Liu, 7/2112010 (updated L. Liu 3/2 1/12, D392618). 

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

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

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

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

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

chronic exposure. Table 5.3 lists degradates identified and their relative concentrations. The 

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

http://www.epa.gov/oppefed 1 /models/water/. 

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

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

Compound AcuteEWDC Chronic EWDC at 

(Day 0) Days 30 and after1 

ppb ppb 

Flumioxazin 400 10.4 

482-HA - 21.6 

APF - 110.1 

THPA - 88.9 

1 Total EDWC = Flumioxazin + 482-HA + APF 

5.4 Dietary Risk Assessment 

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

the Proposed Uses on Artichoke, Cabbage, .Olive, Pomegranate, and Prickly Pear Cactus. R. 

Duncan. 11/12. D406069 

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

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

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

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

Page 24 of 57 
5.4.1 Description of Residue Data Used in Dietary Assessment 

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

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

Evaluation Model DEEM-FCID, Version 3.16 which uses food consumption data from the U.S. 

Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANESIWWEIA) from 2003-2008. For all commodities the assessment used 

current tolerances. Drinking water infonnation was incorporated directly into the dietary 

assessment using the acute and chronic EDWCs for the aquatic use of 400 ppb and 142 ppb, 

respectively. 

5.4.2 Percent Crop Treated Used in Dietary Assessment 

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

were conducted using conservative assumptions, and that 100% of all crops are treated with 

flumioxazin. 

5.4.3 Acute Dietary Risk Assessment 

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

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

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

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

incorporated directly into the acute assessment. An estimated drinking water concentration 

(EDWC) for flwnioxazin and its major degradates (482-HA and APF) under the use as an 

aquatic herbicide of 400 ppb was estimated for acute exposure. 

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

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

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

the acute dietary risk estimate is below RED's level of concern [<100% of the acute population 

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

females 13-49 years old is 0.022607 mg/kg/day (75% of the aPAD). 

5.4.4 Chronic Dietary Risk Assessment 

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

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

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

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

for food and drinking water are well below RED's level of concern. Using the DEEM-FCID 

software, dietary exposure is estimated at 0.00392 mg/kg/day for the general U.S. population, 

which is equivalent to 20% of the chronic Population Adjusted Dose (cPAD), and 0.008753 

mg/kg/day, equivalent to 44% of the cPAD for all infants(< lyear old), the population subgroup 

with the highest estimated chronic dietary exposure to flwnioxazin. 

Page 25 of 57 
I 

'Table 5.2. Summary of Dietary Exposure and Risk for F1umioxazin. 

" 

DEEM Acute Dietary Analysis, DEEM Chronic Dietary Analysis 

Population Subgroup1 ~Percentile 

' 

aPAD Exposure % I cPAD Exposure %cPAD 

' (melkl!l (maik..lday) aPAD (ml!ikll/day) (m.ikelday) ,, 

General U.S. Population 0.02 0"003932 20 

All Infants ( < I year old) NA' 0.02 0"008753 44 

Children 1-2 vears old 0.02 0.006811 34 

Children 3-5 years old ' 0.02 0,005959 30 f 

Children 6-12 years old O.o2 0.004253 21 

Youth 13-19 years old 0.02 0.003116 16 

Adults 20-49 vcars old 0.02 0"003715 19 

:1 0.02 0"003633 18 li :: Adult<; 50+ years old 

' 

Females 13-49 years old 0.03 o o226o1 I 15 0.02 0.003692 19 

Valnes for the populaf:!on wtth the highellt nsk for each type ofnsk a&SeSSlllellt are balded. 

t NA Xot Applicable; no acute dietary endpoint was identified for lhese population subgroups 

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

exposure analyses~ actual dietary exposures and risks from flumioxnzin are likely to be much 

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

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

subgroup, 

6.0 Residential (Non·Occupatinnal) Exposure/Risk Characterix,ation 

:! 

' 

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

ho\\--ever, residential exposure is anticipated from currently registered uses of lhe chemicaL 

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

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

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

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

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

flumioxazin aggregate risk because of revisions to the Residential SOPs. 

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

risk are described in a separate memo (D406669, M. Hav.tins November 2012, and D391784. 

M. August 2012). However, unless otherwise stated, RED incorporated s!llndard assumptions 

typically used for assessing residential exposure and risk. 

Page26 of 57 
Residential handler dennal and inhalation risk estimates for flumioxazin are not of concern to 

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

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

using the Aggregate Risk Index (ARI) are not of concern to HED (i.e., AR!s are "' I). The ARI 

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

different levels of concern (LOCs). The lowest ARl is 5.5 from use of a belly grinder equipment 

to 1reat ornamentals (garden and tree). A summary of these results is presented in Appendix C of 

this document. 

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

For children 1 < 2 years old, the combined dennal and incidental oral risk estimates for the 

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

assessments). 

6.1 Combined Exposure 

Table 6.1 below presents the combined risk estimates for the uses resulting in the highest 

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

residential exposure estimates are provided in Table 6.1. The residential post-application 

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

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

Table 6.1. Combined Short- and Intermediate-Term Residential Exposures for the Flumioxazin Aggregate 

Assessment. 

Handler Exposure Residential Post-application Exposure Recommended Post- <mof<o/d~v\' Handler Total m•ik•idav>' application Exposure Population Exposure for Aggregate Dermal Inhalation {mo/ko/dav\' Dermal Inhalation Oral (ml!ik2fd;y)' 

Adult Female 0.054 0.0000058 0.054 0.238 NIA N/A 0.238 

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

Handler exposure represents high-end handler exposure, where the appropnate duranon IS appropnate to assess. Handler 

exposure represents granular belly grinder for gardens and trees. 2

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

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

represents Hand-To-Mouth exposure and risk 3 For adults, residential total exposure combines the highest dermal and inhalation exposures, where applicable. For young 

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

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

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

6.2 Residential Bystander Post-application Inhalation Exposure 

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

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

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

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

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

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

Page 27 of 57 
http://www.epa.gov/opp{)OOO!/factsheets!spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures fur aerial applications thai must be placed 

on product lahels/laheling. The Agency hes conspleted its evaluation of the new dstabase 

submitted by the Spray Drift Task Foree, 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, orcherd air blast and ground hydraulic methods. 

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

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

associated wilh drift. 

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

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

exposure assessment was performed for flaggers. This exposure scenario, for which no risks of 

concern were identified, is representative of a worse case inhalation (drift) exposure and may be 

considered protective of most outdoor agricultural and commercial post-application inhalation 

exposure scenarios. 

7.0 Aggregate Exposnre/Rlsk Characterization 

In accordance \vith the FQPA. HED must consider and aggregate flumioxazin pesticide 

exposures and risks from three mqjor sources: food, drinking water, and residential exposures. 

In an aggregate assessment~ exposures from relevant sources are added together and compared to 

quantitative estimates ofhezard (e.g., a NOAEL or PAD), or the risks themselves can he 

aggregated. 'When aggregating exposures and risks from various sources. HED considers both 

the route and duration of exposure. 

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

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

short-term aggregate exposure and risk assessment of flumiox:azin includes dietary (food and 

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

exposures anticipated from currently registered residential uses. 

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

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

should he combined with background exposure from fuud and waler determined in the chronic 

dietary exposure assessment. Likewise, children's dennal and oral exposures can be aggregated 

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

7.1 Aeute Aggregate Risk 

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

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

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

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

Page 28 of 57 
concern. 

7.2 Short- Term Aggregate Risk 

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

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

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

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

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

populations. 

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

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

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

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

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

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

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

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

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

~130) for liquid formulations applied to turf. 

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

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

represents the worst case scenario. Therefore it is RED's policy not to combine object-to-mouth 

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

inappropriate because of the conservative nature of each individual assessment. 

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

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

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

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

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

Please refer to the residential assessment, Section 6.1, for a discussion regarding the exposures 

that are likely to be combined. 

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

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

results from the short -term aggregate for adults. 

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

children 1 < 2 years old, is also not of concern to HED (i.e, MOEs are 2:: 1 00). Table 7.2, below, 

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

Page 29 of 57 
Table 7.1 Short-Term Adult Aggregate Risk Estimates1 !. 

Short-Term Exposure Scenario -

Dietary Dermal Residential Inhalation Residential Aggregate ARI 

Population ~ Exposare1 Exposure from Exposure from Belly (food, water, 

Garden Sprays3 Grinder• and 

MOE ARI MOE ARI MOE ARI residential)5 

Adult Female 812 8.1 130 1.3 510,00 510 1.12 13-49 yrs 

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

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

target)]. Short-term oral NOAEL is 3 mglkglday to protect for fetal effec.ts in pregnant women. Average dietary 

exposure is 0.003692 mg/kglday for Adults 13-49 years old (See Table 5.2). The MOE target is 100. 

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

handlers of from garden spray treatment. ARI dermal= [(MOE dermal)/(MOE target)]. Short-term dermal NOAEL 

is 30 mglkglday. The target MOE is I 00. See Table 6.1 for residential exposure values used in aggregate 

a.!isessment. 

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

exposure represents granular belly grinder for ga..rdell.'l and trees. ARI inhalation = [(MOE inhalation)/(MOE target)]. 

Short-term inhalation NOAEL is 3 mglkglday. The target MOE is 1,000. See Table 6.3 for residential exposure 

values used in aggregate a.!isessment. 

S. ARI Aggregate= 1/[(1/ARI dietary) + (1/ARI dermal)+ (1/ARI inhalation)] 

Page 30 of 57 
PopUlation 

Child 1 < 2 

Years Old 100 720 

Exposure 

from Turf 

Treatmenf 

1,100 242 NA 

I. LOC is an MOE= I 00 (I OX inter- and intra- species uncertainty factors totaling 1 00). 

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

mglkg/day. Average dietary exposure is 0.008753 for children <I years old (See Table 5.2). 

182 

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

incidental o111l NOAEL is 6.3 mg/kg/day. Residential incidental oral exposure is 0.0057 mglkglday. See Table 6.1 

for source of residential exposure values used in aggregate assessment. 

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

dermal NOAEL is 6.1 mg/kg/day, with 8% dermal absorption factor (i.e., 0.026 mglkglday as dermal absorbed 

dose). See Table 6.1 for source of residential exposure values used in aggregate assessment. 

5. NA = Not applicable 

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

7.3 Intermediate-Term Aggregate Risk 

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

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

are the same for aU durations of exposure. 

7.4 Long-Term Aggregate Risk 

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

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

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

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

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

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

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

of concern. 

8.0 Cumulative Risk Characterization/Assessment 

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

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

Page 31 of 57 
cumulative effects" of a particular pesticide's residues and "other substances that have a 

common mechanism of toxicity." 

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

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

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

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

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

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

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

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

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

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

9.0 Occupational Exposure/Risk Pathway 

Reference: Flumioxazin: Occupational and Residential Exposure Assessment for a Proposed 

Use on Artichoke, Cabbage, Chinese Cabbage, Olive, Pomegranate, and Prickly 

Pear Cactus D406669, M. Hawkins, November 2012. 

HED has determined that there is the potential for occupational handler exposure to occur from 

the proposed Section 3 uses of flumioxazin. Occupational post-application exposure is not 

expected because the proposed applications to prickly pear cactus, artichoke, cabbage, and 

Chinese cabbage are made pre-plant or pre-emergent and olives and pomegranates are applied 

via shielded equipment in a way that does not result in foliage being treated. 

9.1 Handlers 

Occupational exposure is expected for handlers who apply flwnioxazin products for the proposed 

Section 3 uses. Both dermal and inhalation exposures are expected. Handler exposure is 

expected to be short-and intermediate-term based on information provided on the proposed 

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

pattern. As the same endpoint and dose were selected for both short- and intermediate-term 

durations, HED only calculated short-term handler exposures and risks, which are protective of 

intermediate-term exposure and risk. Typical assumptions regarding the acres treated and the 

length of a work day were used to derive the exposure estimates, along with a body weight of 69 

kg, and assuming the maximum application rate for each scenario. 

Chemical-specific data were not submitted to the Agency in support of the Section 3 application. 

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

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

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1 ), the Agricultural Handler 

Exposure Task Force (AHETF) database, or other registrant-submitted occupational exposure 

Page 32 of 57 
studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data 

protection provisions of FIFRA. The standard values recommended for use in predicting handler 

exposure that are used in this assessment, known as "unit exposures", are outlined in the 

"Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" 

(http://www.epa.gov/oppOOOOllsciencelhandler-exposure-table.pdf), whic~ along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html. 

A quantitative exposure/risk assessment was developed for occupational handlers based on the 

following exposure scenarios: 

Mixer/Loader 

• Mixing/loading dry flowables for aerial applications 

• Mixing/loading dry flowables for groundboom applications 

• Mixing/loading dry flowables for chemigation 

• Impregnating dry flowables onto dry bulk fertilizer in commercial settings 

• Impregnating dry flowables onto dry bulk fertilizer on-fann 

Applicator 

• Applying sprays for aerial applications 

• Applying sprays for groundboom applications 

• Applying sprays for chemigation 

• Applying impregnated dry bulk fertilizer with commercial equipment 

• Applying impregnated dry bulk fertilizer with grower-owned equipment 

Flagger 

• Flagging for aerial spray applications 

The handler exposure estimates in this assessment are based on a central tendency estimate of unit 

exposure and an upper-percentile assumption for the application rate, and are assumed to be 

representative of high-end exposures. The uncertainties associated with this assessment stem 

from the use of surrogate exposure data (e.g., differences in use scenario and data confidence), 

and assumptions regarding the amount of chemical handled. The estimated exposures are 

believed to be reasonable high-end estimates based on observations from field studies and 

professional judgment. 

All dermal handler scenarios do not exceed HED' s LOC (MOEs ~1 00) when wearing labeled 

PPE (baseline plus chemical resistant gloves). AU inhalation handler scenarios do not exceed 

HED's LOC (MOEs ~1000) when wearing PPE except for mixing/loading dry flowables for 

aerial applications for artichoke and mixing/loading dry flowables for groundboom applications 

for prickly pear cactus, olive, and pomegranate when the recommended PPE on the label is worn. 

Page 33 of 57 
The combined short- and intermediate-term inhalation risk estimates for the occupational handler 

scenarios assessed are not of concern to HED (i.e., ARis are 2': 1) with baseJine attire (i.e .• single 

layer of clothing, no respirator), except for mixing/loading dry flowables for aerial groundboom 

and chernigation applications at baseline. For these scenarios. the ARl is greater than l, and not 

of risk concern when a NIOSH approved dust mist respirator (PF5) or organic vapor (!'FlO) 

respirator is worn. Table 9.1 presents a summary of the short- and intermediate-term 

occupational handler exposures and risks from the Section 3 proposed uses. 

Table 9.2 presents the exposure/risk estimates for short- and intermediate-term dermal and 

inhalation exposures for dry bulk fertilizer applications. 'Ihe combined detmal and inhalation 

exposure risk estimates are not of concern (i.e., ARis > 1) for all scenarios, except the folloV¥ing: 

• Mixing/loading dry flowables for commercial impregnation of dry bulk fertilizers7 risk 

estimates of concern using sunogate closed rnixing/1oading exposure data and assuming 

960 tons treated daily. 

• Mixing/loading dry flov.'ables for on-farm impregnation of dry bulk fertilizers for prickly 

pear cactus, olives, and pomegranate ~ risk estimates of concern using surrogate 

exposure data and assuming I 60 acres and 80 acres treated daily. 

• Mixinglloeding dry flowables for on-farm impregnation of dry bulk fertilizers for 

artichoke using surrogate exposure data and assuming 160 acres treated daily. 

The estimate for amount of dry bulk fertilizer treated is based on use data submitted previously 

for another chemical and is the best data currently available to HED. Chemical-specific use data 

could he submitted to refme the assessment. 

Page 34 of 57 
Table 9.1 Short-/Intermediate-Term Occupational Handler Exposure and Risk Estimates for Flumioxazin. 

Dermal Unit Inhalation Unit Maximu Area Dermal Inhalation Total Exposure (ugllb ai)" Exposure (ugllb ai)" m Treated or 

Exposure Scenario Crop or Target Mitigation Level Mitigation Level Applicat Amount 

ion Handled Dose MOEe Dose MOE8 ARih 

Rateb Daily• (mglkglday)d (mglkglday)' 

Mixer/Loader 

Mixing/Loading Dry 1.792 

Flowable for Aerial Artichoke 51.6 8.96 (SLw/G + 0.19 350 0.0497 600 0.00864 350 0.33; Applications t.:V PF5R) 

Mixing/Loading Dry Prickly Pear 0.896 0.00172 Cactus, Olive, 51.6 8.96 1.1 Flowable for Chemigation and (SLw/G + 0.38 350 0.0994 300 (SL w/G + 170 0.16; 

(SL w/G + PFIO R) Applications Pomegrante PFIOR) PFlO R) 

Mixing/Loading Dry 51.6 8.96 1.792 0.00172 

Plowable for Chemigation Artichoke (SLw/G + 0. 19 350 0.0497 600 (SLw/G+PF5 350 0.33; t.:V 

Applications ' PF5 R) R) 

Mixing/Loading Dry Cabbage, and 51.6 8.96 1.792 0.00118 

Plowable for Chemigation Chinese (SLw/G+ 0.13 350 0.0341 880 (SL w/G + PFS 510 0.48; 1.9i 

Applications Caobage PF5 R) R) 

Mixing/Loading Dry Pricltly Pear 1.792 

Cactus, Olive, 51.6 8.96 

Plowable for Ground boom and (Baseline + 0.38 80 0.0228 1,300 0.00394 760 0.7i 2.9i Applications Pomegranate PF5R) 

Mixing/Loading Dry 

Flowable for Ground boom Artichoke 

51.6 8.96 0.19 80 0.0114 2,600 0.00197 1,500 1.4; Applications 

Mixing/Loading Dry Cabbage, and 

Flowable for Ground boom Chinese 

51.6 8.96 0.13 80 0.00778 3,900 0.00135 2,200 2.1i Applications Cabbage 

" ~ ~ '".;7 J; Applicator !.i' •. 

Applying Sprays via Aerial 5 

(Engineering Equipment Artichoke Controls)k 0.068 0.19 350 0.00483 6,200 0.0000655 46,000 26 

Applying Sprays via Prickly Pear 

Groundboom Equipment Cactus, Olive, 

Page 35 of 57 
Table 9.1 Short-/Intermediate-Term Occupational Handler Exposure and Risk Estimates for Flumioxazin. 

Dermal Unit Inhalation Unit Maximu Area Dermal Inhalation Total Exposure (ugllb ai)" Exposure (ugllb ai)" m Treated or 

Exposure Scenario Crop or Target Mitigation Level Mitigation Level Applicat Amount 

ion Handled Dose MOEe Dose MOE8 ARI" 

Rateb Daily (mglkglday)d (mglkglday)r 

Pomegranate 16.1 0.34 0.38 80 0.00709 4,200 0.000149 20,000 14' 

Applying Sprays via 

Groundboom Equipment Artichoke 16.1 0.34 O.I9 80 0.00355 8,500 40,000 27; 

0.0000749 

Applying Sprays via. Cabbage, and 

Oroundboom Equipment Chinese I6.1 0.34 0.13 80 0.00242 12,000 0.0000513 58,000 3~ 

Cabbage . Flagger -.- :!} ;. ·,,, 

Flagging for Aerial Sprays 

Applications Artichoke 12 

0.35 0.19 350 O.Oll6 2,600 0.000338 8,900 6.6 

.. a. PHED/AHETF (level of mitigation: smgle layer ofPPE, gloves). SL w/G ,. smgle layer w/glove; PFS R = PF5 Resprrator; PFlO R= PFIO Respirator 

b. Based on proposed label (Reg. No. 59639-99, 59639-119). 

c. Exposure Science Advisory Council Policy #9 .1. 

d. Dermal Dose = Dermal Unit Exposure (ugllb ai) x Conversion Factor (0.001 mglug) x Application Rate (lb ai!acre or gal) x Area Treated or AmoUCit 

Handled (A or gaVday) x DAF (%) I BW (kg). 

e. Dermal MOE = Dermal NOAEL (mg/kglday)!Dermal Dose (mglkglday). 

f. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb aVacre or gal) x Area Treated or 

Amount Handled (A or gaVday) I BW (kg). 

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

h. ARI = 1/(1/RLtem.Ll+ (1/RI;IIhalalioJ· 

i. Level of mitigation: single layer ofPPE, gloves, no respirator. 

j. Level of mitigation: single layer ofPPE, gloves, NIOSH approved dust mist respirator for dermal and inhalation; ARI exceeds 1. 

Enclosed cockpits are expected to be used for aerial application 

Page 36 of 57 
Table 9.1. Short-/Intermediate-Term Occupational Exposure aod Risk Estimates for Dn: Bulk Fertilizer Use ofFiumioxazin. 

Dennal Unit Inhalation Unit Amount Dose (mglkglday)4

•

5 MOE6

•

7 

Exposure Scenario Exposure Exposure Application Treat~ ARJ' Rate2 Dennal Inhalation (ugllb ai)1 (ugllb ai)1 Daily Dennal Inhalation (LOC = (LOC= 

100) 1000) 

... ~..,~.., .. 

Commercial 

Impregnation of 9.8 (closed 0.24 (closed 1.91 lb 960 tons 0.261 0.00638 110 470 0.33 (closed system) Dry Bulk system) system) ailton 

Fertilizers 

On-fann SLw/G + SLw/G+ Impregnation of l60A SLw/G: PF5R: 660 380 SLw/G: PF5 R: Dry Bulk SL w/G + PF5 R: 0.38lb 0.0455 0.00158 0.36 1.5 Fertilizers SL w/G: 51.6 

(Prickly Pear 1.792 ail A SL w/G+ SLw/G+ 

Cactus, Olive, 80A SL w/G: PF5 R: 1,300 760 SLw/G: PF5 R: 

Pomegranate) 0.0228 0.00079 0.72 2.9 

On-farm SLw/G: SL w/G + SLw/G: SLw/G+ 

Impregnation of l60A 0.0228 PF5R: 1,300 760 0.72 PF5 R: 

Dry Bulk SL w/G: 51.6 SLw/G: 8.96 0.191b 0.00079 2.9 ail A Fertilizers 80A SLw/G: SLw/G: 2,600 1,500 SLw/G: 

(Artichoke) 0.0114 0.00197 1.4 

On· farm SLw/G: SLw/G: SLw/G: Impregnation of 160 A 0.0155 0.0027 1,900 1,100 1 Dry Bulk SL w/G: 51.6 SLw/G: 8.96 0.131b 

Fertilizers ail A SLw/G: SLw/G: SLw/G: (Cabbage, and 80A 0.00778 0.00135 3,900 2,200 2.1 Chinese Cabbage) 

AIPJiutor . 

Commercial 320 SLw/G: SLw/G: 2,400 1,400 SLw/G: 

Impregnation of 0.0127 0.00212 1.3 

Dry Bulk 160 SLw/G: SLw/G: 4,700 2,800 SLw/G: 

Fertilizers SLw/G: 0.38lb 0.00635 0.00106 2.6 

On·fann 

SLw/G: 7.2 1.2 a.i/A SLw/G: SLw/G: SL w/G: 

Impregnation of 160 0.00635 0.00106 4,700 2,800 2.6 

Dry Bulk 80 SLw/G: SLw/G: 9,500 5,700 SLw/G: 

Fertilizers 0.00317 0.000529 5.4 I " .. Based on Occupational Pestrcrde Handler Urut Exposure Surrogate Reference Table " (September 26, 20 11 ), mcludes data from 

PHED/ORETF/AHETF. Closed mixing/loading assumed for commercial impregnation of dry bulk fertilizer. Open mixing/loading assumed for on-fann 

Page 37 of 51 
impregnation of dry bulk fertilizer. Exposure values for granular application via open cab solid broadcast spreader used as surrogate for application of 

impregnated dry bulk fertiliz:er. SL w/G"' single layer w/glove; PF5 R= l'F5 Respirator. 

'Based on proposed labels for flmnioxazio (Reg. No. 5903(}..99, 59639-119)-

3 Exposure Science Advisory Council Policy #9.1 and industry information. 4

Dermal Dose= Dennal Unit Exposure (ug!Jb ai) x CF (0.001 mg/ug) x Application Rate (tb ai/acre or lb ai!ton) x Area Treated or Amount Handled 

(Nday or ton,;day) i BW (69 kg). 

'Dermal MOE= Dennal NOAEL (30 mglkglday)JDcnnal Dose (mglkglday). 

6 lnhalation Ilose"" Inhalation Unit Exposure (ugllb ai) x CF (0.001 mglug) x Application Rate (lb ail acre or lb ai/ton) x Area Treated or Amount 

Handled (Alday or tons/day) /BW (69 kg). 

7 Inhalation MOE= Inhalation NOAEL (3 mgikg/day)/ Inhalation Dose (mglkg!day} 11 ARI {Aggregated Risk lndex} = 1! ((1 +Dermal Risk Index)+ (l .,. (Inhalation Risk Index) 

Page 38 of 57 
9.2 Post-appli<:ation Exposure and Risk 

For flumioxazin, based on the proposed use, short- and intermediate-term post-application 

exposure is not expected because: (1) proposed applications to prickly pear cactus, artichoke, 

cabbage, and Chinese cabbage are made pre-plant or pre-emergent and olives and pomegranates 

are applied via shielded equipment in a way that does not result in foliage being treated. 

Restricted Entry Interval 

The REI specified on the proposed label is based on the acute toxicity of flumioxazin. 

Flumioxazin is classified as Toxicity Category III via the dermal route and Toxicity 

Category IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 

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

irritation and primary skin irritation are assigned a 12-hour REI. Therefore, the [156 

subpart K] Worker Protection Statement interim REI of 12 hours is adequate. 

r.~tf4•i 

9.3 Inhalation Post-appli<:ation Risk 

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

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

inhalation toxicity (Toxicity Category IV) and the low proposed use rate (0.38, 0.19, and 0.13 lb 

ail A). However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory 

Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 

(http://www .epa.gov/scipoly/SAP/meetings/2009/120 I 09meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

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

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

post-application inhalation exposure assessment for flumioxazin. 

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

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

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

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

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

inhalation exposure scenarios. 

Page 39 of 57 
10.0 Eteferenees 

Flumioxazin. Human Health Risk Assessment for the Proposed Uses on Wheat, Sunflower, 

Safflower, Flax, Lentils and Field Peas. D. Smegal, S. Piper, M. Hawkins, August 8, 2012. 

D391419 

Flumioxazin: Occupational and Residential Exposure Assessment for A Proposed Use on 

Artichoke, Cabbage, Chinese Cabbage, Olive, Pomegnmate, and Prickly Pear Cactus. D, 

406669. M. Hawkins November 2012. 

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

Uses on Artichoke, Cabbage, Olive, Pomegranate, and Prickly Pear Cactus. R. Duncan. 11112. 

])406069 

Flumioxazin. Petition for the Section 3 Registration and Establishment of Tolerances for uses on 

Artichoke, Cabbage, Olive, Pomegranate, and Prickly Pear Cactus. Summary of Analytical 

Chemistry and Residue Cbamistry Data. S. Piper. 11112. D406070 

Drinking Water Assessment for a Section 3 New Use for Flumioxazin End-Use Products 

Chateau WDG and Valor WDG Applications to Wheat, Sunflower, Safflower, Flax, Lentils, and 

Field Peas, D392618, L.Liu, 3/21!2012. 

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

D357184,J. Stone, 712112010. 

Flumioxazin. Human Health Risk Assessment for the Proposed Uses on Turf grass and Forest 

Sites. D380073, D. Dotson, K. Middleton, S. Wang, M. Collantes, 618/2011 

Flumioxazin. Human Health Risk Assessment for a Proposed Aquatic Use, PC Code: 129034, 

Petition No' 8E7438, DP Barcode: D379028, B. Hanson, 7/14/2010 

Page 40 of 57 
Appendix A: Toxicology Assessment 

A.l Toxicology Data Requirements 

The requirements (40 CFR 158.340) for food use for flumioxazin are in the table below. Use of 

the new guideline numbers does not imply that the new (1998) guideline protocols were used. 

.,,,-. ,~:, _,_ --· ~ 

Test -, .. ,'tc -f-' = '<:(._ -~~~:<" 1-t ~·- Technical • ~ ,,\,;rr _,. 

}~i~ .. I• -~ ·.' ,; r,-cc' ~'¥' ...... ' ·~ Required Satisfied 

870.1100 Acute Oral Toxicity ..................................... yes yes 

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

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

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

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

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

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

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

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

870.3250 90-Day Dermal ............................................. no no 

870.3465 90-Day Inhalation ........................................ no no 

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

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

870.3800 Reproduction ................................................ yes yes 

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

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

870.4200a Oncogenicity (rat) ........................................ yes yes1 

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

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

870.5100 Mutagenicity-Gene Mutation - bacterial ... yes yes 

870.5375 Mutagenicity-Gene Mutation- CHO cells yes yes 

870.5395 Mutagenicity-In vivo rat bone marrow ..... yes yes 

870.5550 Mutagenicity-Other Genotoxic EffectsUDS assay ....................................................................... 

yes yes 

870.6100a Acute Delayed Neurotox. (hen) ................... no - 870.61 OOb 90-Day Neurotoxicity (hen) ......................... no - 870.6200a Acute Neurotox. Screening Battery (rat) ...... yes yes 870.6200b 90-Day Neuro. Screening Battery (rat) ........ yes 

870.6300 Developmental Neurotox ............................. yes 

no -

Page 41 of 57 
Test Technical 

Required 

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

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

870.7800 lnununotOXlClty ............................................ yes 

Special Studies for Ocular Effects no 

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

Sub chronic Oral (rat) .................................... 

Six-month Oral (dog) .................................... . . ReqUirements for 870.41 OOa and 870.4200a are satisfied by the rece1pt of an 

acceptable/guideline combined chronic/carcinogenicity study in rats (870.4300.) 

Page 42 of 57 

Satisfied 

yes 

yes 

yes 

-
A.l T oxi~ity Profiles 

Table A.2.a. Acute Toxicity Profile for Flumiou,zin ..,_ - .. ~ 

. · - c,c l ~ ' 

GuideliDe No.,.., StudyTyp~ 

-, "' ~(s) r rc· Res Us .-r.: " I* , ..... ~ u ~ '; Toxicity C~t~ory 

870.1100 Acute oral [rat] 42684911 LDso>SOOO mglkg IV 

M&F 

870.1200 Acute dermal [rat] 42684913 LD5o>2000 mg/kg m 

870.1300 Acute inhalation [rat] 42684915 LC.so -3.93 mg!L IV 

870.2400 Acute eye iiTitation [rabbit] 42684917 Not an ocular irritant m 

870.2500 Acute dermal irritation [rabbit) 42684917 Non-irritating IV 

870.2600 Skin sensitization [guinea pig] 42684921 Non-sensitizer N/A 

Page 43 of 57 
,, 

Table A.l.b. Subebronie, Chronic and Other Toxicity Profile 

- Guideline Study Type ' MRID No. (year)! Results 

No. Claulfication IDoses r, 

870.3100 90-Day oral 42684923 NOAEL = 69.7 (M), 71.5 (F) mg/kglday 

toxicity • rat dose levels: 0, 2.3, 20.7, LOAEL = 243.5 (M), 229.6 (F) mg/kglday based on a 

69.7, and 243.5 decrease in MCV both sexes; increase in platelets F 

mg/kglday (M) only. and 0, 2.2, 21.7, 71.5, and 

229.6 mglkglday (F) 

870.3 100 90-Dayoral 42683922 NOAEL = 65.0 (M), 72.9 (F) mg/kglday LOAEL= 

toxicity - rat dose levels: 0, 1.9, 19.3, 196.7 (M), 218.4 (F) mg/kglday based on hematology 65.0, and 196.7 changes. mg/kglday (M) and 0, 2.2, 

22.4, 72.9, and 

218.4 mglkg/day (F) 

870.3100 90-Day oral MR1D unknown (referred NOAEL = 429 mg/kglday 

toxicity • mouse to in 79-week study, LOAEL = 1429 mglkglday based on increased liver 

MRID 44295018) weight in males. 

dose levels: 0, 143, 429, 

or 1429 (M & F) 

rnglkglday 

870.3100 4-Week oral 44307301 (see MRID NOAEL = 1 51.5 (M), 164.5 (F) mg./kg/day 

toxicity - mouse 44295018 DER#2) LOAEL = 419.9 (M), 481.6 (F) mg/kglday based on 

dose levels: 0, 151.5, increased absolute &/or relative liver weights in M & F. 

419.9 or 1366.5 (M) and 

0, 164.5, 481.6 or 1698.3 

(F) m_glkglday 

870.3150 90-Day capsule - 42684924 NOAEL = 10 mg/kglday dog 

dose levels of 0, 10, 100, LOAEL = 100 mg/kglday based on dose dependent 

or 1000 mg./kg/day increase in total cholesterol, phospholipid & alkaline 

phosphatase activity. 

870.3200 21-Day dermal 44295016 NOAEL = mglkglday: 1000 (LIMIT DOSE) 

toxicity - rat dose levels: 1, 100, 300, 

LOAEL = mg./kg/day:> 1000 based on no effects. 

or 1 000 mg/kglday 

870.3465 28-Day inhalation Not Required 

toxicity (species) 

870.3700a Pre-natal (1)42684930 (pilot study); Maternal NOAEL = 30 mglkglday (HDT) 

developmental - rat 42684925 (main study); LOAEL = > 30 mg/kglday (HDT) 

(oral) (2) 42884006 Developmental NOAEL = 3 mg/kglday 

LOAEL = 10 mg./kg/day based on cardiovascular effects 

dose levels: 0, 1, 3, 10 and (especially ventricular septal defects). 30 mg./kg/day 

870.3700a Pre-natal 42684929 (pilot); Maternal NOAEL = 300 mg./kg/day (HOT) developmental - rat 42684926 (main study) LOAEL = >300 mg./kg/day (HDT) (dermal) dose levels: 0, 3 0, 100, Developmental NOAEL = 30 mg/kglday 

and 300 mglkglday LOAEL = 100 mglkglday based on cardiovascular 

effects (especially ventricular septal defects). 

Page 44 of 57 
Table A.2.b. 

GuideliJle 

No. 

870.3700a 

870.3700b 

870.3800 

870.4100b 

870.4200b 

870.4300 

Subcllronic, Chronic: a~d Other Toxicity Profile 

Study Type MRID No. (year)/ 

Claui1lcatioo /Doses 

Pre-natal Data Gap 

developmental - rat 

(inhalation) 

Pre-natal 

developmentalrabbit (oral) 

Reproduction and 

fertility effects -

rat) 

42684927 (range-finding); 

42684928 (main study) 

dose levels: 0, 300, I 000, 

or 3000 mg/kg/day 

42684934 and 42684936 

(pilot studies); 42684935 

(main study) 

dose levels: 0, 3.2, 6.3, 

12.7, and 18.9 mg/kglday 

(M) and 0, 3.8, 7.6, 15. 1, 

and 22.7 m.g/kg/day (F) 

12-Month capsule- 44295017 

dog 

Carcinogenicity -

mouse 

Combined chronic 

carcinogenicity -

rat 

dose levels: 0, 10, 100 or 

1000 mg/kg/day 

44295018 

dose levels: 0, 31.1, 314.9 

or 754.1 mglkglday in 

males and 0, 36.6, 346.4, 

or 859.1 mg/kg/day in 

females 

44295028 

dose levels: 0, 1.8, 18.0, 

and 36.5 mg/kglday in 

male rats and 0, 2.2, 21.8, 

and 43.6 mglkglday in 

female rats 

Page 45 of 57 

Resula ; 

·~ 

Maternal NOAEL = I 000 mglkg/day 

LOAEL = 3000 mg/kglday (HDT) based on decrease in 

body weight and food consumption during dosing 

Developmental NOAEL = 3000 mg/kglday (HOT) 

LOAEL = >3000 mglkg/day 

Parental/Systemic NOAEL = 12.7 (M), 15.I (F) 

mglkglday; LOAEL = 18.9 (M), 22.7 (F) mglkglday 

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 (HOT) 

(F) mg/kglday; LOAEL = > 18.9 (HDT) (M), >22.7 

(HDT) (F) mg/kg/day 

Oflspring NOAEL = 6.3 (M), 7.6 (F) mglkglday; 

LOAEL = 12.7 (M), 15.1 (F) mg/kglday based on a 

decrease in the number of liveborn, a decrease in pup 

body weight, a decrease in the mating index, and 

testicular atrophy ofFI males. 

NOAEL- 100 mg/kg/day (M & F) 

LOAEL = 1000 mglkg/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 

NOAEL = 754.1 (M), 859.1 (F)mglkglday (LIMIT 

DOSE); LOAEL = no systemic effects at LIMIT DOSE 

in males or females 

No evidence of carcinogenicity 

NOAEL = 1.8 (M), 2.2 (F) mglkglday 

LOAEL = 18.0 (M), 21.8 (F) mglkglday based on 

increased chronic nephropathy in males and decreased 

bematological parameters in females (Hgb, MCV, MCH 

andMCHC). 

No evideaee of carcinogenicity 
Table A.l.b. Subehronic, Cbroaic and Other Toxicity Profile . I 

Guideline Study Type MRID No. (year)/ Results 

No. Classification /Doses 

Gene Gene mutation in S. 42684938 Neither cytotoxic nor mutagenic up to 2000 JJ.g/plate. 

Mutation typhimUTium and E. dose levels: with or 

There were reproducible increases in revertant colonies 

870.5100 coli without metabolic of S. typhimurium strains TA 153 8 and TA98 in S9 

activation to 0, 50, 100, activated phases of the preliminary cytotoxicity and both 

200, 500, 1000,or2000 mutation assays. [Results are considered to be 

,!lg/plate equivocal.] 

Gene Gene mutation in 42684939 Precipitation at ~00 ,liM. Cytotoxicity at 500 JJ.M. 

Mutation Chinese hamster nonactivated levels, 30, Positive +S9 ~100 J.I.M and negative at 30-500 )lM -89. 

870.5375 ovary cells 100, 200, and 500 J.1M Aberrations were chromatid breaks and exchanges. 

(11, 35, 70, and 177 

JJ.g/mL, respectively) 

870.5395 In v;vo rat bone 42684940 Negative in male (up to 5000 mglkg) and female rats (up 

marrow dose Levels: 1250,2500, to 4400 mglkg) when test«! orally. 

or 5000 mglkg 

870.5550 UDS assay 42684941 Negative up to 5000 mglkg. 

dose levels: by oral 

gavage to 5000 mglkg or 

12 hoUIS post exposure to 

1250 or 2500 mglkg 

Page 46 of 57 
Table A.l.b. 

Guideline 

No. 

870.6200a 

870.6200b 

870.6300 

870.7485 

870.7600 

870.7800 

Subc:bronic:, Chronic: and Otber Toxicity Profile 

Study Type MRID No. (year)/ 

Classification /Doses 

Acute neurotoxicity 48402405 

screening battery 

Subchronic 

neurotoxicity 

screening battery 

Developmental 

neurotoxicity 

Metabolism and 

pharmacokinetics -

rat (oral) 

Dennal penetration 

-rat 

Immunotoxicity 

acceptable/guideline 

0, 200, 700 or 2000 mglkg 

bw 

48651401 

acceptable/guideline 

0, 500, 1500, or 4500 ppm 

(equivalent to 0, 37/41, 

110/124, 323/358 mg/kg 

bw/day for males/females) 

Not required. 

42684943 

single oral dose of 1 

mglkg or I 00 mglkg, 

42684944 

dose levels: 200 or 800 

mglkgbw 

48402407 and 48402408 

acceptable/guideline 

0 (control), 500, 1500, or 

4500 ppm (0, 44, 127, and 

375 mglkg bw/day, 

respectively) 

Page 47 of 57 

._, . 

NOAEL = 2000 mglkglday (M & F) 

LOAEL = >2000 mglkglday (M &F), (LIMIT DOSE) 

no signs of neurotoxicity 

NOAEL = 500 ppm (equivalent to 37/41 mglkg bw/day 

for males/females, respectively) 

LOAEL = 1500 ppm (equivalent to 110/124 mglkg 

bw/day for males/females, respectively), based on signs 

of anemia [decreased hemoglobin and hematocrit. mean 

corpuscular volume (MCV), mean corpuscular 

hemoglobin (MCH)J. 

N OAEL= 4500 ppm for neW'otoxicity (HD1) 

Gastrointestinal tract absorption >900/o at 1 mg/kg and 

up to 50% at 100 mglkg. 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 

untransfcnmed parent, 7 metabolites identified in urine 

and feces (38-46% for low dose and about 7 [%at high 

dose). 

Females dosed with 200 or 800 mglkg bw. Dermal 

absorption for 200 and 800 mg/kg was 3.9% and 8.00/o, 

respectively, by 48 hours after initiation of treatment for 

6 hours. Blood levels at 6-24 hoW's 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 hoW's after dermal dosing with 800 mg/kg were 

similar to those obtained at 2-6 hours after oral dosing 

with 30 mglkg. 

NOAEL = 500 ppm (equivalent to 42 mglkg bw/day) 

LOAEL = 1500 ppm (equivalent to 126 mglkg bw/day), 

based on signs of anemia (decreased hemoglobin and 

hematocrit). 

Under conditions of this study, the immwtotoxicity 

NOAEL for anti-SRBC PFC response is 4500 ppm (375 

mglkg/day), the highest dose tested; a LOAEL was not 

established. 
Table~l.b. Subcbronie, Chronic and Otber Toxicity Profile •· 

Guideline Study Type MRID No. (yeJJr)/ : Results 

No. Clauification /Doses 

Non- Special Study - 42694931,42684932 Pregnant females were administered 400 mglkg by guideline Rat single dose:400 m~g bw gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 

Developmental: 12 administration showed: largest incidence of 

Critical Time for embryonic death, lowest fetal body weights and greatest 

Defects incidence of ventricular septal defects. 

A.3 Hazard Identification and Endpoint Selection 

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

Study Selected: Pre-natal Developmental Toxicity Study- Rat 

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

42684932 (studies demonstrating critical time to effects). 

Executive Summary: See Appendix A 

Dose and Endpoint for Risk Assessment: NOAEL = 3 mglkglday, Endpoint = cardiovascular 

effects, specifically ventricular septal defects in fe~es, seen at the LOAEL of 10 mglkglday 

Uncertainty Factor(s): lOOX [10 interspecies; lOX intraspecies]. 

Comments about Study/Endpoint/Uncertainty Factors: The endpoint selected is appropriate 

because the critical effect, cardiovascular abnormalities observed in fetuses, has been 

demonstrated to be the result of a single dose, with dosing on gestation day 12 being the most 

critical time period for the effect. The application of the endpoint and dose to the population of 

potentially pregnant females is protective of fetal effects. A clear NOAEL and LOAEL were 

identified for the fetal abnormalities; therefore, no additional uncertainty factors (other than the 

standard 1 Ox for interspecies extrapolation and 1 Ox for intraspecies variability) are needed. 

Furthermore, the FQPA factor has been reduced to lx. Therefore, the acute reference dose (RID) 

and acute population adjusted dose (PAD) are calculated as follows: 

Acute RID= Acute PAD= 3 mg!kg/day (NOAELl = 0.03 mglkg/day 

100 (UF) 

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

children 

No appropriate endpoints were selected because no toxic effects that could result from a single 

dose and that were relevant to the general population (including infants and children) were 

identified in the database. 

Page48 of 57 
A.3.3 Chronic Reference Dose ( cRID) --1111 populations 

Study Selected: Combined chronic carcinogenicity - rat 

MRID No.: 44295028 

Executive Summary: See Appendix A 

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/day, Endpoint= increased 

chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, 

MCH, and MCHC) seen at the LOAEL of 18 mg/kg/day. 

Uncertainty Factor(s): IOOX [10 interspecies; lOX intraspecies]. 

Comments about Study/Endpoint/Uncertainty Factors: The duration and route of exposure 

in the rat study are applicable to the chronic dietary route (oral) and duration of exposure (long 

term to lifetime). In addition, the mt is the most sensitive species. In the one-year dog study, 

liver effects were observed at the LOAEL of 1000 mg/kg/day, with a NOAEL of 100 mg/kg/day. 

In the carcinogenicity study in the mouse, no systemic effects were seen at the highest dose 

tested. Finally, the NOAEL selected from the rat study is the lowest observed in the submitted 

studies, and is protective of all other effects, including the offspring effects in the reproductive 

toxicity study. As the FQPA factor has been reduced to lx, and there are no other uncertainty 

factors needed, the standard lOOx (lOx for interspecies extrapolation and lOx for intraspecies 

variability) UF has been applied to attain the chronic RID and PAD, which are equivalent. 

A.3.4 

Chronic RID~ Chronic PAD~ 2 mg(kgiday (NOAEL) ~ 0.02 mglkg/day 

100 (UF) 

Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: Reproduction and fertility effects - rat 

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

Executive Summ.an: See Appendix A 

Dose and Endpoint Cor Risk Assessment: NOAEL ~ 6.3 mg/kg/day, Endpoint~ decreased 

live born pups and decreased pup body weight, and testicular atrophy in Fl males seen at the 

LOAEL of 12.7 mg/kg/day. 

Comments about Study/Endpoint!Uncertaintv Factors: The endpoint and dose have been 

selected from an oral study, which is appropriate for assessing the incidental oral pathway of 

exposure. In addition, the endpoint, offspring effects in a reproduction study, is relevant for the 

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

Page 49 of 57 
for the qualitative and quantitative susceptibility observed in the reproduction study. As the 

FQPA factor has been reduced to lx, and a clear NOAEL and LOAEL were identified in the 

study, the standard UF s of I OOx (1 Ox for interspecies extrapolation and I Ox for lntraspecies 

variability) define the level of concern (LOC) for risk assessment as a MOE ofless than 100 for 

residential exposure and risk assessments, 

A.3.S Dermal Absorption 

Stody Selected: Dennal penetration - rat 

MRID No.: 42684944 

Dermal absorption following application of200 and 800 mg/kg was 3.9% and 8.0%, 

respectively, by 48 hours after initiation of treatment for 6 hours. Blond levels at 6-24 hours 

after dermal dosing with 200 mg!kg were sin:rilar 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 mglkg were similar to 

those obtained at 2-6 hours after oral dosiog with 3 0 mg/kg. For the purpose of risk assessment, 

an upper·lxYund estimate of8% dennal absorption should be used. 

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

Sllldy Selected: Reproduction and fertility effects - Rat 

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

Dose and Endpoint for Risk Asses.sment: NOAH-~ 6.3 mglkg!day, Endpoint~ decreased live 

born pups and decreased pup body weight, and testicular atrophy in Fl males seen at the LO AEL 

of 12.7 mglkg!day. 

Comments about;!tudy/Endpoint!Uncertainty)'actors: The endpoint and dose have boeo 

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. 

rn addition, the endpoint, offspring effects in a reproduction study, is relevant for the exposed 

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

qualitative and quantitative susceptibility observed in the reproduction stody. As tbe FQPA 

factor has been reduced to lx, and a clearNOAEL and LOAEL were iden:rified in tbe study, tbe 

standard UFs of 1 OOx (lOx for interspecies extrapolation and lOx for intraspeeies variability) 

define the LOC for risk assessment as an MOE of less than 100 for residential exposure and risk 

assessment. The 8% dermal absorption value should be used for route~ to-route extrapolation, 

i.e.~ an oral study is used for dermal risk assessment. 

A.3. 7 Dermal Exposure (Short-, Intermediate- and Long-Term) for Adults 

Studv Selected: Dennal Developmental Study (Rat) 

Page 50 of 57 
MRID No.: 42684929 (pilot); 42684926 (main study) 

Dose and Endpoint for Risk Assessment: Dennal NOAEL ~ 30 mg/kg/day, Endpoint~ 

cardiovascular effects, specifically ventricular septal defects, in fetuses observed at the LOAEL 

of 100 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for dermal risk 

assessment because the most critical toxic effect, ventricular septal defect in fetuses, was 

evaluated following exposure via the dermal route. This study is appropriate for all durations 

because of the developmental toxicity concerns. The oral NOAEL selected for chronic dietary 

risk assessment is typically used to assess long-term dermal risk. However, for flumioxazin, the 

developmental NOAEL was selected for all dermal exposures, including long-term, because the 

use of the oral NOAEL of2.0 mglkg/day (chronic RID) with an 8% dermal absorption factor 

yielded a dermal equivalent dose of25 mg/kg/day (2.0/0.08 ~ 25), which is comparable to the 

selected dermal NOAEL of30 mg/kg/day. 

As the FQPA factor has been reduc¢ to lx, and a clear NOAEL and LOAEL were identified in 

the study, the standard UFs of I OOx (lOx for interspecies extrapolation and lOx for intraspecies 

variability) defme the LOC for risk assessment as an MOE of less than 100 for both residential 

and occupational exposure and risk assessment. 

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

Study Selected: Oral Developmental Study (Rat) 

MRlD No.: 42684930 (pilot study); 42684925 (main study); 42884006 

Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day, Endpoint= cardiovascular 

effects, specifically ventricular septal defects, in fetuses seen at the LOAEL of 10 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: In the absence of an inhalation study with 

flumioxazin, HED selected the endpoint from an oral study. The developmental study was 

considered to be the most appropriate for both short- and intermediate-term exposure, and the 

selection of the endpoint ensures the risk assessment is protective of potential developmental 

effects. The selection of the developmental effects allows for aggregation of dermal and 

inhalation exposure for both residential and occupational scenarios. As an oral study was 

selected for the inhalation route, an inhalation absorption factor of 100% should be applied for 

risk assessment. 

Because the FQPA factor has been reduced to lx, and a clear NOAEL and LOAEL were 

identified in the study, the standard UFs of lOOx (lOx for interspecies extrapolation and lOx for 

intraspecies variability) define the LOC for risk assessment as an MOE of less than 100 for both 

residential and occupational exposure and risk assessment. 

Page 51 of 57 
A-3.9 Inhalation Exposure (Long-Term) for Adults 

Study Selected: 2-Year ChroniciCaxcinogenicity Study (Rat) 

MRID No.: 44295028 

Dose and Endpoint for Risk Assessment: NOAEL ~ 2 mg!kglday, Endpoint~ increased chronic 

nephrcpathy in males and decreased hematological parameters in females (Hgb, MCV, MCH, 

and MCHC) seen at the LOAEL of 18 mg/kglday . 

. Comments.ili:>out Study/EndgoinVUn~,::rtaintv Factors: In the absence of an inhalation study for 

flumioxazin~ HED selected an oral study. The duration of exposure in the chronic rat study is 

applicable to long-term durations of exposure. In addition. the rat is the most sensitive species. 

!n the one-year dog study, liver effects were observed at the LOAEL of 1000 rnl!lkg/day, with a 

NOAEL of 100 mg!kglday. In the carcinogenicity study in the mouse, no systemic effects were 

seen at the highest dose rested. Furthennore, the selected NOAEL is the lowest observed in the 

submitted studies, and is protective of all other effects, including the ofiSpring effects in the 

reproductive toxicity study. As a route-specific inhalation study is not available, an inhalation 

absorption fuctor of I 00% should be used for risk assessment purposes. Finally, because the 

FQPA factor bas been reduced to lx, and a clear NOAEL and LOAEL were identified in the 

study, the standard UFs of IOOx (lOx for interspecies extrapolation and !Ox for intraspeeies 

variability) define the LOC for risk assessment as an MOE of less than 100 for both residential 

and occupational exposure and risk assessment. 

A,4 Executive Summaries 

See previous flumioxazin risk assessment Flumioxazin. Human Health Risk Asse.<Jsment for 

the Proposed Uses on Wheat, Sunflower, Safflower, Flax, Lentils and Field Peas. D. Smegal, S. 

Piper, M. Hawkins, August 8, 2012. D391419 

App<lndix B. Physicai!Chemical Prop<lrties 

Page 52 of 57 
Table B.l. Physicochemical Properties of Flumioxazin. 

Parameter Value Reference 

Octanol/water partition coefficient, 2.55 at 20"C 

Log(Kowl 

UV /visible absorption spectrwn "-z1s, s 14700 (pl:l l.9) MRID No. 44295004 

~16> s = 436og f~Ii 6.8) ~16 s = 51200 H 10.0) 

Page 53 of 57 
Table 4.1.1, lists the updated assessment of currently registered residential handler exposures and 

risk estimates. The updated exposure and risk estimates for all residential handler use pattern 

scenarios result in dermal risk estimates that are greater than or equal to 1 00 and therefore do not 

exceed HED's LOC and inhalation risk estimates that are greater than or equal to 1000 and 

therefore do not exceed HED's WC. 

Appendix C. Residential Exposure/Risk Summary Table 

A summary of flumioxazin residential handler exposure/risk is presented in Table C. I below. 

Table C.l. Residential Flumioxazin Handler Short-and Intermediate-Term Exposure and 

Risk 

Area 

Equip. App. Treated or Route of Dose 

Use Site Rate (a) Amouut (mglkg/day) MOEC•> .uu<t> 

Types Handled Exposure (c,d) 

Daity(b) 

Outdoor 

I Dermal 0.0074 4, 100 I Hose-End _J 41 Sprayer Inhalation 0.00000018 17,000,000 

Ornamentals Backpack Dermal 0.0088 I 3,400 

13 (Gardens and Sprayer Inhalation 0.00014 21,000 Trees) 0.0000073 1200 ftl Manually- Dermal 0.0088 3,400 

WDG Pressurized 13 

Formulations Handwand, Inhalation 0.00014 21,000 

Sprinkler Dermal 0.0074 4,100 I 

__j 41 Can Inhalation 0.00000018 17,000,000 

' Dermal 

Push Type 0.00012 I 240,000 

1,900 Spreader Inhalation 

0.00000039 7,600,000 

r Dermal 

Belly 0.054 550 I 5.5 

Ornamentals Grinder 

(Gardens and Inhalation 

0.0000058 510,000 

Trees) 0.0000087 1200 if Dermal 0.00094 I 32,000 Granular spoon i - 130 

Formulations Inhalation 

0.000013 230,000 

Dermal 

0.000017 1,800,000 

cup 1,400 

Inhalation 

0.000002 1,500,000 -

Hand Dermal w I 

Page 54 of 57 
Table C.l. Residential Flumioxazin Handler Short·and Intermediate-Term Exposure and 

Risk 

Area 

Equip. App. Treated or Route of Dose 

Use Site Rate (a) Amount (mg/kglday) MOE<e> ARJ<I) Types Handled E~posure (e,d) 

Daily (b) I 

Dispersal 0.024 1,200 

Inhalation 0.000057 52,000 

Dermal 0.000017 1,800,000 Shaker Can 1,400 

Inhalation 0.000002 1,500,000 

Dermal 

Manually 0.0087 3,400 Pressurized 13 

Handwand 

Inhalation 

0.023A 0.00014 22,000 

Dermal 

Turf (Lawns, Hose-End 0.0017 18,000 

Sprayer 150 

Ornamentals, 

Outdoor 0.38 Inhalation 0.0000028 1,100,000 

Premises, (lb a.i/A) 

Recreational 

Areas) Backpack 

Dermal 0.0087 3,400 

Sprayer 13 

Inhalation 0.00014 22,000 

Dermal 

Sprinkling 1,000 ftl 0.0017 18,000 

Can 150 

Inhalation 0.0000028 1,100,000 

a) Based on registered gardens and trees labels (lb wA converted to lb ai/sq. ft); turf labels (lb ail A) 

b) Exposure Science Advisory Council Policy #9.1 and 20 II Residential SOPs 

c) Dermal Dose (mglkglday) =daily unit exposure (mgllb ai) *application rate (lb ai/gallon) • amount 

handled (gallons) • dermal absorption factor ( 100 %) I body weight (80 kg). 

d) Inhalation Dose (mglkglday) =daily unit exposure (mg!lb ai) • application rate (lb ail gallon) • amount 

handled (gallons) • inhalation absorption (100%) I body weight (80 kg). 

e) Dennal MOE= PoD (BMDL10 of96.3 (mglkglday) I Daily dermal dose (mglkg/day); Inhalation MOE= 

PoD (BMDLI SD of 3.1 mg/kglday) I Daily inhalation dose (mglkglday). Dermal Level of concern= 100, 

Inhalation Level of Concern= 1,000 (Adult) 

f) Aggregate Risk Index (ARI) = 11 ((1/estimated MOE for adult dennal exposure/ LOC for adult dermal 

exposure)+ (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral 

exposure)) 

Page 55 of 57 
Table C.l: Short-Term Residential Handler Exposure and Risk Estimates for Flumionzin. 

Area Treated Dermal Inhalation 

Target MOE MaJ.! mum or Amount Exposure Scenario Dose Application Rate• Handled Dose MOEd MOEr ARJI 

Dailyb (mg/kg/dayt (mg/kg/day)" 

Gardens and Trees- WDG Formulations . ...!:. .l - Mixer/Loader/ Applicator 

Mixing/Loading/Applying WDG 

with Manually Pressurized 100 0.0088 3,400 0.00014 21,000 13 1200 ftl Hand wand 0.0000073 

Mixing/Loading! Applying WDG 1200 ttl 0.0074 4,100 0.00000018 17,000,000 41 with Hose-end Sprayer 100 0.0000073 

Mixing/Loading! Applying WDG 

1200 ftl 0.0088 3,400 0.00014 21,000 13 with Backpack Sprayer 100 0.0000073 

!Mixing/Loading! Applying WDG 100 0.0000073 1200 ftl 0.0074 4,100 0.00000018 17,000,000 41 with Sprinkler Can 

~' Gardens and Trees- Granular Formulations _.. 

Mixer/Loader/ Applicator 

Applying Granule with Push Type 

Spreader 100 0.0000087 1200 ftl 0.00012 240,000 0.00000039 7,600,000 1,900 

Applying Granule with Belly Grinder 

100 0.0000087 1200 If 0.054 550 0.0000058 510,000 5.5 

Applying Granule with Spoon 100 0.0000087 1200 ftl 0.00094 32,000 0.000013 230,000 130 

Applying Granule with Cup 100 0.0000087 1200 ftl 0.000017 1,800,000 0.000002 1,500,000 1,400 

jA.pplying Granule with Hand 

Dispersal 100 0.0000087 1200 If 0.024 1,200 0.000057 52,000 lO 

Applying Granule with She.ker Can 100 0.0000087 1200tf 0.000017 1,800,000 

0.000002 

1,500,000 1,400 

'"tf,!- ·:.'" ~i~~- ~ ·: ~· ~ ; .. ~: ~ 

'<" 

' I;.{ ., 

~~- ·- y • 

..... .. ~ Turf -'- · oi" '~ ~ 

Mixer/Loader/ Applicator 

Mixing/Loading! Applying WDG 

with Manually Pressurized 

Hand wand 100 0.38 0.023 acres 0.0087 3,400 0.00014 22,000 13 

Mixing/Loading! Applying WDG 0.38 0.023 acres 0.0017 18,000 0.0000028 1,100,000 ISO with Hose-end Sprayer 

100 

Mixing/Loading! Applying WDG 

3,400 0.00014 22,000 with Backpack Sprayer 100 0.38 0.023 acres 0.0087 13 

Page 56 of 57 
Table C.2: Short-Term Residential Handler Exposure and Risk Estimates for Flumioxazin. 

Area Treated Dermal Inhalation 

Exposure Scenario Target MOE Maximum or Amount 

Application Rate" Handled Dose MOEd Do,. MOE' 

Dailyb (mglkglday)" (mglkg!day)" 

Mixing/Loading/Applying WDG 0.38 1,000 w 0.0017 18,000 0.0000028 1,100,000 with Sprinkler Can 100 

a.. Based on reg:tstered gardens and trees labels {lb ail A converted to lb ai/sq. ft), turf labels (lb ail A) 

b. Exposure Science Advisory Council Policy #9.1. 

c. Dermal Dose= Dermal Unit Exposure {ugllb ai) x Conversion Factor (0.001 mglug) x Application Rate (lb ail acre or 

gal) x Area Treated or Amount Handled (A or gallons/day) x DAF (%)I BW (kg). 

d. Dermal MOE= Dermal NOAEL (mg/kglday) I Dermal Dose (mg/kglday). 

e. Inhalation Dose= Inhalation Unit Exposure (ugllb ai) x Conversion Factor (0.001 mg!ug) x Application Rate {lb IIi/acre 

or gal) x Area Treated or Amount Handled (A or gallons/day) IBW (kg). 

f. Inhalation MOE= Inhalation NOAEL (mglkglday) I Inhalation Dose (mglkglday). 

g. ARI = 11(l/R1dermol)+ (l/RI;nhol.WJ 

Note: 1000 sq ft per day is calculated to be equivalent to 0.023 acres (1000 sq ft/day) x {43,560 sq ft/1 acre)= 0.023 

acres/day 

Page 57 of 57 

ARI' 

150