### 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 Case No.: 7244 RiskAssessment Type: Single Chemical Aggregate TXRNo.: NA MRID Nos.: NA

FROM: CAS No.: 103361-09-7 40 CFR: §180.568

Deborah Smegal, MPH,

# xi~lo**~** 

# . G**~e_ ~**  SheilaPiper,Chemist

### 6~~ 

# kl · J\ 

## lr

. Monica Hawkins, Ph.D., MPH. Environmental Health Scientist

### J~~ Risk Assessment Branch VI Health Effects Division (7509P) THROUGH: Christine Olinger, Acting Branch

### Chi~f 1

### ~ Risk Assessment Branch VI 

## \1-/ Health Effects Division (7509P) • TO: AndrewErtman, Barbara Madden RM05 Risk Integration, MinorUse, and Emergency Response Branch Registration Division (7505P)

Page 1 of57

### 1.0 

### 2.0 

## Table ofContents

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

### EnvironmentalJustice

.............................................- .....- ........ 

### 12 4.0 Hazard Characterization and**Dose~**

### Response Assessment

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### 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 oftbe Toxieology Database·-························

..························-- 16 4.4.2 Eviden« 

### ofNeurotoxicity

.._.............................................................**~**

### ...............**~** 

### 16

4.5 

### 4.5.1 

### 4.5.2 

### 4.5.3 4.5.4 4.4.3 Evidence ofSensitivity/Susceptibility in 

### tbe Developing or Young Animal

..........- ...................**~**

### ................- .....- .................................................**~·········** 

### 16 

### 4.4.4 Residual Uncertainty in

### tbeExposure J)atabase••.•.•.•.......•.........•....•.•• 17 Toxicity Endpoint and Point ofDeparture Selections-.

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

...........- ......................- .............. u ........................... 

### 17 Recommendation for Combining Routes of

### Exposure for RiskAssessment. 

### 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

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### ......H

............. _ ...... u ..................... 

### 21 Metabolite/Degradate Residue Profile••••..•• H

.................................. - ..... H

...... - ... 

### 11 

### 5.1.1 Summary ofPlant and Animal Metabolism Studies -·•m-•••••••••····-··· 

### 21 Summary ofEnvironmental Degradation···················-·········-·-·············-······ 21 Compari!on ofMetabolic Pathways._

...,..........................................H

..................

### 22 Residues ofConcern Summary and Rationale

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

....................................................................................,.,..... 23 Water Residue Profile

......................................................................................... 14 

### Page2 of57

### 5.4 Dietary RiskAssessment ....................................................•..........•...••..•••...•••..•• 24 5.4.1 Description ofResidue Data Used in Dietary Assessment

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

......................................... 25 5.4.3 Acute Dietary RiskAssessment

......................................................................... 25 5.4.4 Chronic Dietary RiskAssessment

..................................................................... 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 of57

### 1.0 Executive Summary 

### Valent USA Corporation and IR-4 (The Interregional Research Project No.4) has requested the Section 3 registration ofnew 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 ofthe herbicide, as well 

### as the impact on aggregate 

### exposure and risk. Fl

### urnioxazin, 2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propyny1)-2H-1 , 4-benzoxazio-6-yl]-4,5,6,7- tetrahydro-lH-isoindole-1,3(211)-dione, is an herbicide ofthe N-phenylphthalimide class that is currently used for pre- and post--emergence control ofsusceptible weeds on a variety offruits, 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 golfcourses and 

### sod 

### farms. Its mode ofaction 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 I0 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 ofthe 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 indevelopmental rat studies but not 

### in developmental rabbit studies. Hematologic (hematopoietic) effects ofanemia were noted inrats. 

### consisting of alterations in

### hemoglobin parameters. Increased renal toxicity in male rats was 

### also reported following chronic exposure. There is no evidence ofneurotoxicity or immunotoxicity in the 

### recently submitted guideline studies. Increased quantitative susceptibility was seen in the rat developmental toxicity studies. Fetal effects V.'ere observed inthe absence ofmaternal 

### 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. HED's degree ofconcern for the susceptibility observed 

### in the rat 

### developmental and reproductive studies is low because the regulatory endpoints for flumioxazin are 

### based on Page4 of57clear NOAELs for developmental and offspring effects that are protective ofthe 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 (UFDB) for all inhalation exposure scenarios. Once these data have been received, the Agency will determine how the results affect the toxicology endpoints and uncertainty factors. Dietary Exposure: The acute and chronic dietary exposure analyses were based on conservative assumptions, including tolerance level residues, 100% crop treated (CT), and high-end estimated drinking water concentrations (EDWCs) based onthe 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% ofthe aPAD atthe 95th percentile ofexposure, which is not ofconcern. The chronic risk estimates are below HED's level ofconcern for all population subgroups. The risk estimate for the general U.S. population is 20% ofthe chronic PAD (cPAD). The population subgroup with the highest risk estimate is all infants 

### (I year old), which uses 44% ofthe 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 turfand 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 ofconcern to HED (i.e., MOEs are 

### 2': 100 for dermal and 

### 2': 1,000 for inhalation, the levels ofconcern (LOC) for these assessments). The combined handler dermal and inhalation risk estimates calculated using the Aggregate Risk Index (ARI) are not ofconcern to HED (i.e., ARls are 

### 2': 1). The ARI approach was required to combine the dermal and inhalation routes ofexposure because ofthe different levels ofconcern (LOCs). Adult and child residential post-application dermal exposures also are not ofconcern to HED. For children 1 < 2 years old, the combined dermal and incidental oral risk estimates for the identified residential uses are not ofconcern to HED (i.e., MOEs are 

### 2': 100, the LOC for these assessments).

Page 5 of57Aggregate Risk: The acute aggregate risk from exposure to fl.umioxazin is equivalentto the acute dietary risk. Acute dietary risk estimates are not ofconcern for thepopulation subgroup Females 13-49, the onlypopulation 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 ofconcern 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 ofconcern to RED (i.e., MOEs**are~** 100). The intermediate-term aggregate risk assessment is identical to the short-term assessment beca use the exposures and PODs are identical for both exposure durations. The chronic aggregate risk assessment for flumioxazin consists ofrisks 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 ofconcern. Occupational Exposure and RiskEstimates: Based on the proposed use pattern, both short

and 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 ofconcern to RED (i.e., ARis**are~** 1) with baseline attire 

### (i.e., single layer ofclothing, no respirator), except for mixing/loading dry flowables for aerial groundboom and chemigation applications atbaseline. Forthese scenarios, the ARl is greater than 1, andnot ofrisk 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 ofconcern (i.e., ARls 

### < 1) for mixing/loading dry flowables for commercial and onfann impregnation ofdrybulk fertilizers whenthe recommend ed PPE on the label is worn. An assessment ofoccupational post-a pplication 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 ofenvironmentaljustice concerns, to the extentpossible, were considered in this human-healthrisk assessment, inaccordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice inMinority Populations and Low-Income Populations. 1"
Review ofHuman 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 Pes ticide Handlers Exposure Database (PRED), the Agricultural Handler

1 http:// www.hss.energy.gov /nuclearsafety /env /guidance/justice/eo12898,pd£ Page 6 of57Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF) have been determined to require a review oftheir 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 ofthe 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 ofthe developing fetus following both oral and dermal exposure; (2) the severity ofthe 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 ofa 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 turftransferable residue (TIR) study is required for all occupational (e.g., sod fanns, golfcourses, parks, and recreational areas) or residential turfuses. Flumioxazin does not meetthe criteria for a data waiver. In the absence ofchemical-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. Inthe absence ofchemical-specific DFR data, conservative default assumptions were used in this assessment. Page 7 of57

### 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 offlumioxazin

### per se inion plant commodities. The reported method limits ofquantitation and detection (LOQ and LOD) for flumioxazin inion plant commodities are 0.02 and 0.01 ppm, respectively. Datadepicting the analysis offlumioxazin through FDA Multiresidue Protocols were submitt ed and the available dataindicate thatflumioxazin could notberecovered through application ofthe FDA multiresidue protocols.


### 2.2.2 International Harmonization There are no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for any ofthe proposed commodities in the current registration actions; therefore, there are no iss ues ofinternational hannonizationraised 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 offlumioxazin, including its metabolites and degradates, to be determined by measuring only flumioxazin.


### Table2.2.3'

. 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 of57 

# . .

### 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 ofthe N-phenylphthalimide class that is currently used for pre- and post-emergence control of susceptible weeds 

### in a variety ofcrops and other use sites. Its mode ofaction in plants is as an inhibitor ofprotoporphyrinogen 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 of57

### 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 vaporpressure 

### 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 infish (Kow = 

### 355). See Appendix B for a listing offlumioxazin physical and cbemical properties. 

### 3.3 Pesticide Use Pattern Valent USA Corporation is proposing the use ofthe 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 

### of57 PHI

60 day-s Use Direct!ons: aud 

# ..... Limita

________, Apply as a preemCTgcncen postemergence "' Wld application. onn Apply as a unifo u:-ation to the broadcast awrTable 3.2. Summary ofDirections for Proposed Uses ofFlumioxazln. 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 ofthe agave. Do not apply over the top of crop or allow spray to come in contact with crop as a result ofapplication or drift. Use a minimum of 15 gallons ofspray solution Iper acre. Olive, Pomegranate Apply after budbreak through final harvest using Ground Water 0.38 lb ai/A shielded application Chemigation, Dispersible 0.38 lb I (1.911b 60 days equipment ifthe 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 ofhuman 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 ofdrinking water, both ofwhich can serve as sources ofdrinking 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 of57

### 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 ofthe aforementioned exposure pathways based onthe proposed new uses offlumioxazin, but also considers existing uses offlumioxazin, particularly in the dietary exposure assessment. 

### 3.S 

### Consideration ofEnvironmental Justice Potential areas ofenvironmentalj ustice concerns, to 

### the extent possible, were considered 

### in this humanhealth risk assessment, in accordance withU.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations2

. " 

### As a part ofevery pesticide risk assessment, OPP considers a large variety ofconsumer subgroups according 

### to well-established procedures. In line 

### with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based onpatterns ofthat 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 ofAgriculture'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 ofa pesticide. These data are analyzed and categorized by subgroups based onage 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 inAppendix A. The following toxicity studies have been submittedin support ofregistered andproposed 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/ justiceleo12898.pdf 

### Page 12 of57

### • 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 ofexposure. 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 (oforal 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 ofrisks from inhalation exposure. In 

### addition, there may be a potential for portal ofentry 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 ofinhalation 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) offlumioxazin was 

### investigated in rats following single oral doses ofradiolabeled flumioxazin. Metabolism studies in 

### rats indicated that there was extensive biliary excretion following oral administration offlumioxazin. Gastrointestinal tract absorption offlumioxazin might amount to over 90% ofthe dose. Total recovery ofradioactivity in feces and urine 7 days after dosing accounted for 97-101% ofthe 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 ofresidues 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% ofthe dose at the low dose treatments and to 70.7-71.5% ofthe 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 ofthe study, HED Page 13 of57determined that an upper-bound estimate of8% dennal abSOI]ltion should be used for risk 

### assessment purposes. 4.3 Toxieologieal Effects Flumioxazin's pesticidal mode ofaction is as an inhibitor ofthe enzyme protoporphyrinogen 

### oxidase. In mammals, the 

### inhibition ofthe enzyme can interfere with 

### the porphyrin component ofheme. 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 ofanemia consisting ofalterations 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 

### I00 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 andmortality 

### 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 onthe offspring (decrea'le in 

### the nwnber oflive 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, bothincreased qualitative 

### and quantitative susceptibility were observed intherat 

### 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 

### of400 mg!kg/day 

### was administered 

### to pregnantrats on gestation days 

### 11, 12, 13 or 

### 14. The results of the study iedicatedthat 

### a single dose 

### on gestation day 

### 12 wns the 

### cause ofthe ventricular septal 

### defect observed in the rat 

### developmental toxicity 

### studies.



### Page 14 of57Several 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 ofblood leading to the observed enlargement ofthe heart. The registrant further postulated that the ventricular septal defect was produced by mechanical distortion ofthe heart. The two other signs ofdevelopmental 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 oftoxicity. However, as doses and endpoints for risk assessment were chosen to be protective ofthe cardiovascular (acute dose and endpoint) and hematopoietic (chronic dose and endpoint) effects, the lack ofa conclusion regarding the mechanism oftoxicity 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 ofeffects in rabbits was supported by literature studies indicating rabbits are less susceptible to the effects ofprotoporphyrinogen oxidase inhibitors. Acute and subchronic neurotoxicity studies showed no evidence ofneurotoxicity 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 oftreatment-related effects on the immune system. In most ofthe available mutagenicity studies, flurnioxazin was negative for mutagenicity; however, aberrations were seen in a chromosomal aberration assay (CHO cells). Based on the lack ofevidence ofcarcinogenicity 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 thatthe required 1Ox FQPA Safety Factor for the protection ofinfants 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 ofchildbearing age; 2) the required neurotoxicity studies have been submitted, are considered adequate; 3) although there is evidence ofquantitative susceptibility in the rat developmental (oral and dermal) and Page 15 of57

### 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 ofexposure. 4.4.1 Completeness ofthe Toxicology Database 

### The toxicology database is complete for flumioxazin except for an inhalation developmental study to 

### assess adult women ofchildbearing 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 ofa 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 ofEvidence (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 ofthe 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 ofthe developing fetus following both oral and dermal exposure; (2) 

### the severity ofthe fetal effects (ventricular septal defects) observed in the oral and dermal developmental studies; (3) 

### that the oral 

### developmental toxicity studies only measure toxicity oftlumioxazin 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 ofNeurotoxicity 

### There is no indication that 

### flumioxazin is neurotoxic in the acute and subchronic neurotoxicity (SCN) studies. In 

### addition, none ofthe 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 ofthe 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 ofincreased quantitative susceptibility offetuses 

### in the oral 

### and dennal developmental rat studies, i.e., cardiovascular ano:malies (ventricular septal defect) that occurred in the absence ofmaternal toxicity. Additionally, the 

### rat reproduction study 

### demonstrated evidence ofqualitative 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 

### of57because 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 ofthe 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 ofwater 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 ofpostapplication 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 ofDeparture 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 ofthe toxicity studies used for selecting toxicity endpoints and points ofdeparture for various exposure scenarios are presented in Appendix A, the following outlines the dose-response assessment and a general description ofthe endpoint selection. A 

### Page 17 of57

### summary ofthe endpoint and point ofdeparture 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 offemales 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) of0.02 

### mglkg!day was selected for 

### assessment ofall 

### 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 of3 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 of6.3 

### 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 

### of8% was used. 

### Long-term exposures (greater than 6 

### months) are not anticipated based on the existing use pattern. The 

### level ofconcern (LOC) for the

### relevant dennal and incidental 

### oral exposure scenarios 

### is 

### an MOE ofless than 

### I00, based on the st3ndard uncertainty factors for 

### intraspecies variation 

### (IOX) and interspecies extrapolation (1 

### OX). For inhalation exposure scenarios, a IOX database uncertainty factor is applied due 

### to the lack ofan inhalation developmental toxicity study. Thus) the LOC is MOEs less than I

### 000.

4.5.2 

### Recommendation 

### for Combining 

### Routes ofExposure 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 ofhazard (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 ofexposure. 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 of57and oral risks. Residential handlers' dermal and inhalationrisks can also be aggregated with food and water, since the points ofdeparture are all based on the same oral toxicity study.


### 4.5.3 Cancer Classification and Risk Assessment Recommendation Based onthe lack ofevidence ofcarcinogenicity 

### 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 offlumioxazin.


### 4.5.4 Summary ofPoints ofDeparture and Toxicity Endpoints Used in 

### HumanRisk Assessment Tables 4.5.1 and 4.5.2 summarize the points ofdeparture and toxicity endpoints used inthe dietary and occupational humanhealthrisk assessments, respectively.

Table4.5.1. Summary**ofToxi~logical** Doses and Endpoints for Flnmioxazin for Use inDietary 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 andchildren 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, basedon 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, basedon Term (1- 6 decreasedpup 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 ondecreased pup body weight Page 

### 19 of57Table 4.5.1. Summary ofToxicological Doses and Endpoints for FlumioDZio for Use in Dietary and NoaOccupational Human Health RiskAssessments 

# . Exposure/ Pointof Uncertainty RID, PAD,Level of Study aad Toxicolocical Eflect!l Scenario Departure IFQPA Concero for Risk (POD) Safety Atsessment 

### r -. ,. ?'< Facton 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 FQ PA SF = LOAEL 

### = 100 mglkglday, based on IX cardiovascular effects infetuses. Inhala tion NOAEL=3 UF A=lOx Residential LOC for Oral Developmental Study (Rat) Short- (1-30 mglkglday 1 UFH= IOx. MOE< 1000 days) and FQPASF = WAEL = 10 mglkglday, based on Intennediate- lOX cardiovasculareffects in fetuses. Term (1- 6 (database months) UF) Inhalation NOAEL=2 UFA = IOx Residential LOC for 2-Yeax Chronic/Carcinogenicity Long-Tenn (> 6 mglkglday 1 UFtrlOx MOE< 1000 months) FQPA SF = Study (Rat ) Inhalation lOX WAEL = 18 mglkglday, based on (data base increased chronic nephropathy in UF) males anddecreased hematological parameters in females. Cancer "Not likely to be a carcinogenic tohumans," based onthe lack ofcarcinogenicityin a 2-yearrat (oral, dermal, study, an 18-month mouse study, and a battery ofmutagenic 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 ofextrapolation 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 ofthehuman population (intraspecies). FQPA SF=FQPA Safety Factor

. PAD = population adjusted dose (a = acute, c =chronic). RID=reference dose

. MOE= maxgin ofexposure. LOC =level ofconcern. N/A = not applicable. DAF = dermal absorption factor

. 1Inhalationtoxicity assumed to be equivalent to oral toxicity

.
Table 4.5.2. Summary ofToxicological Doses and Eadpoints for Flumioxazin for Use in Occupatioaal Human Health Risk Assessments 

# . . Exposure/ Point of Uncertainty Level ofConcern for Risk Study and Toxicological Scenario Departure Facton Assessment Effects Dermal Developmental Stud y in Rats Dermal -All NOAEL= UFA = lOX Occupational LOC for WAEL = 100 mglkglday Durations 30 mglkglday UFH = 10X MOE< 100 based oncardiovascular effects in fetuses.

Inhalation UFA =lOX Oral Developmental Study in Short- and NOAEL=3.0 Rats Intermediate- mglkglday 1 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 of57

# ..

Table4.5.2. SummaryofToxicological Doses and Endpoints for Flumioxazln for Use in OccupationalHuman Health RiskAssessments 

### .. w Exposure! PoiJltof Uncertainty ,. Level ofConcern for Risk , Study andToxicological 

# ... : "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 mglkwday 1 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 onthe lack ofcarcinogenicity in a 2-year rat dermal, inhalation) study, an 18-month mouse study, and a battery ofmutagenic 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 ofthe human population (intraspecies), UFos =database uncertBintr, factor for lack ofinhalation developmental study. MOE= margin ofexposure. LOC =level ofconcern. Inhalation toxicity assumed to be equivalentto oral toxicity.



### 5.0 Dietary Exposure/RiskCharacterization
Source: Flumioxazin. Petition for the Section 3 Registration and Establishment ofTolerances for uses on Artichoke, Cabbage, Olive, Pomegranate, and Prickly Pear Cactus. Summary ofAnalytical Chemistry and Residue Chemistry Data. S. Piper. 11/12. 0406070 

### 5.1 Metabolite/Degradate Residue Proflle
5.1.1 Summary ofPlant and AnimalMetabolism Studies The nature offlwnioxazin residues inplants and animals is adequately understood based on acceptable soybean, peanut, com, sugarcane, grapes, ruminant, andpoultry metabolism studies. The residue ofconcern for plants is only the parent compound. The residues ofconcern for ruminants should include parent, 3-0H-flumioxazin, 4-0H-flumioxazin, and Metabolites B, C, and F. For poultry, the residues ofconcern are parent, 3-0H-flwnioxazin, 4-0H-flwnioxazin, and4-0H-S-53482-SA. Plant Metabolism

Page 21 of57

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

# rt4

### CJtlumioxazin following applications to soybean (preemergence), peanut**(pre-emergence)~** 

### corn (pre-emergence), sugarcane (directed to 

### the lower 3 feet ofplants), and grapes (directed to 

### soil surface surrounding vines). Based on these studies, HED determined that the parent compound only is the residue ofconcern 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 offlumioxazln ls similar in both ruminants and poultry, involving the 

### hydroxylation and reduction ofthe cyclohexene ring in the THP moiety, bydrolytie cleavage ofthe imide and amide linkages, and incorporation ofsuUbnic acid into the THP moiety. HED 

### has determined 

### that the residues ofconcern for 

### ruminants should include parent, 3-0H-flumioxazin, 4-0Hflumioxazin, and 

### Metabolites B, C, and F. For poultry, the residues ofconcern are parent, 3-0Hflumioxazin, 4-0H-flumioxazin, and 4-0H-S-53482-SA.


### 5.1.2 Summary ofEnvironmental 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 ofMetabolic 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 ofconcern for ruminants incJude parent, 3-0H-tlumioxazin, 4-0H-flumioxazin, and Metabolites B, C, and F. For poultry, the residues ofccncem are parent, 3-0H-flumioxazin, 4-0H-flumioxazin, and 

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

Page 22 

### of

### 57In rats, metabolism studies indicated that there vvas extensive biliary excretion following oral administration offlumioxazin. In addition to untransformed parent compound, analysis offeces and urine revealed up to 35 putative metabolites. 

### 5.1.4 Residues ofConcern Summary and Rationale The residue ofconcern for boththe tolerance expression andrisk assessment 

### inplants is flurnioxazin. No livestock tolerances have been established. A tolerance for combinedresidues 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 arethe residues ofconcern 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

. >_ 

## l ud 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 

### FoodResidue Profile Acceptable field trial data onartichoke, 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 maximumresidues of flumioxazin were <0.02 ppm inion artichoke, cabbage, olives, pomegranate and 0.037 ppm inion prickly pearcactus fruit. The Interregional Research ProjectNo. 4 (IR-4) has submitted a processing study onolives. In one trial conducted inCA, two broadcast exaggerated rate (5X) applications offlumioxa.zin were made to the orchard floor at a 60-day interval atrates 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 of57The previously submitted confmed rotational crop study is adequate for the proposed uses on the requested commodities. HED has concluded thatthe residue ofconcern 

### in rotational crops is the parent compound only. Based onthe results ofthe confined accumulation study, HED concluded thatthe existingrotational cropplantback intervals (PBis) are acceptable, and that field trials and tolerances inrotated crops are notnecessary. 

### 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). Forthe dietaryrisk assessment, the Environmental Fate and Effects Division (EFED) provided high-end, conservative EDWCs based onthe aquatic application rates ofthe herbicide, which are higher than the EDWC from the currentproposeduses. These EDWCs included concentrations offlumioxazin 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 ofEstimated Drinking Water Concentrations (EDWCs) (ppb) From the Subsurface Application ofFlumioxazin as anAquatic 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 1Total EDWC 

## =Flumioxazin 

### + 482-HA

### + APF


### 5.4 Dietary RiskAssessment Flumioxazin. Acute and Chronic Dietary (Food and Water) Exposure and Risk Assessments for the Proposed Uses onArtichoke, Cabbage,

. Olive, Pomegranate, and Prickly Pear Cactus

. 

### R. Duncan. 11 / 12. D406069 Au unrefined 

### andhealthprotective 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 of57

### 5.4.1 Description ofResidue 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 ofAgriculture'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 of400 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% ofall 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 offlumioxazin 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) underthe use as an aquatic herbicide of400 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 belowRED's level ofconcern [<100% ofthe acute population adjusted dose (aPAD)] at the 95th percentile ofexposure. The acute dietary exposure estimate for females 13-49 years old is 0.022607 mg/kg/day (75% ofthe 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 ofconcern. 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% ofthe chronic Population Adjusted Dose (cPAD), and 0.008753 mg/kg/day, equivalent to 44% ofthe cPAD for all infants(< lyear old), the population subgroup withthe highest estimated chronic dietary exposure to flwnioxazin. Page 25 of57I 'Table 5.2. Summary ofDietary Exposure and Risk for F1umioxazin.
" DEEMAcute Dietary Analysis, DEEM Chronic Dietary Analysis Population Subgroup 1**~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 ofrevisions 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 of57Residential handler dennal and inhalation risk estimates for flumioxazin are not ofconcern to HED (i.e., MOEs are"' 100 for dermal and"' 1,000 for inhalation, the levels ofconcern (LOC) for these assessments). The combined handler dermal and inhalation risk estimates calculated using the Aggregate Risk Index (ARI) are not ofconcern to HED (i.e., AR!s are "' I). The ARI approach was required to combine the dennal and inhalationroutes ofexposure because ofthe different levels ofconcern (LOCs). The lowest ARl is 5.5 from use ofa belly grinder equipment to 1reat ornamentals (garden and tree). A summary ofthese results is presented in Appendix C of this document. Adult and childresidential post-application dennal exposures also are not ofconcern to HED. For children 1 < 2 years old, the combined dennal and incidental oral risk estimates for the identified residential uses are not ofconcern to HED (i.e., MOEs**are~** 100, the LOC for these assessments). 

### 6.1 Combined Exposure Table 6.1 belowpresents the combined risk estimates for the uses resulting in the highest potential for residential handler and post-application exposures. A summary ofthe 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 ofthese 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. 2Post-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 3For 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 ofthe aggregate assessments.


### 6.2 Residential Bystander Post-application Inhalation Exposure Spray drift is always a potential source ofexposure 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 ofexposure 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 of57

### http://www.epa.gov/opp{)OOO!/factsheets!spraydrift.htm). On a chemical by chemical basis, the Agency isnowrequiring interim mitigation measures fur aerial applications 

### thai mustbe placed 

### on product lahels/laheling. The Agency hes 

### conspleted its evaluation ofthe 

### new dstabase submitted by the Spray 

### Drift Task Foree, a 

### membership ofU.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 ofpesticide 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 ofa worse case inhalation (drift) 

### exposure and may be considered protective ofmost 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 ofexposure. While residential exposure to 

### flumioxazin is 

### not anticipated from the proposed Section 3 uses, 

### it is anticipated 

### from currently registered turfand ornamental uses ofthe chemical. As such, the 

### short-term aggregate exposure and risk assessment offlumiox: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 ofresidential 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 of57concern.


### 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 offlumioxazin. 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 ofthe 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 ofthese exposure scenarios would also be inappropriate because ofthe conservative nature ofeach 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 oforal 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 ofthe conservative nature ofeach 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 ofconcern (decreased pup weight) and the levels ofconcern (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 ofconcern 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 ofconcern to HED (i.e, MOEs are 

### 2:: 100). Table 7.2, below, summarizes the results from the short-term aggregate assessment ofchildren 1 

### < 2 years old.
Page 29 of 57Table 7.1 Short-TermAdultAggregate Risk Estimates1 !

. Short-Term Exposure Scenario 

## - Dietary Dermal Residential Inhalation Residential Aggregate ARI Population**~** Exposare 1 Exposure from Exposure from Belly (food, water, Garden Sprays 3 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. AnARI less than l 1 s ofconcernto HED (ARI = Aggrega te Risk Index.) 2. MOE dietary = [(short-term oralNOAEL)/(average dietary exposure)]. ARI dietary= [(MOE dietary) /(MOE target)]. Short-term oralNOAEL is 3 mglkglday to protect for fetal effec

. ts inpregnant women. Average dietary exposure is 0.003692 mg/kglday for Adults 13-49 years old (See Table 5

.2). The MOEtarget is 100. 3. MOE dermal = [(short-term dermal NOAEL)/(high end dermalresidential exposure)]. Highestexposure for adult handlers offrom garden spray treatment. ARI dermal= [(MOE dermal)/(MOE target)]. Short-term dermal NOAEL is 30 mglkglday. The target MOE is I00. 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 f o

r ga..rdell.'l and trees
. ARI inhalation = [(MOE inhalation)/(MOE target)]. Short-term inhalation NOAEL is 3 mglkglday. The targetMOE 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 of57PopUlation

Child 1 

### < 2 Years Old 100 720 Exposure 

### from Turf 

### Treatmenf 1,100 242 NA I. LOC is an MOE= I00 (IOX 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 ofresidential exposure values used in aggregate assessment. 4. MOE dermal= [(short-term dermal NOAEL)/(high enddermal 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 ofresidential exposure values used in aggregate assessment. 5. NA = Not applicable 6. MOE Aggregate= 1/[(1/MOE dietary) + (1/MOEoral)+ (1/MOE dermal)]


### 7.3 Intermediate-Term Aggregate Risk
The intermediate aggregate is identical to the short-term aggregate assessment because the same points ofdeparture were chosen for short-term andintermediate-term exposures; therefore, risks 

### are the same for aU durations ofexposure.


### 7.4 Long-Term Aggregate Risk
The chronic aggregate risk assessment consists ofrisks 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 wouldresult in long-term exposure to any population subgroup. As a result, chronic aggregate risk consists ofrisks 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 equivalentto the chronic dietary risk assessment discussed in Section 

### 5.4.4, above. 

### All risk estimates are not ofconcern.


### 8.0 Cumulative Risk Characterization/Assessment
Section408(b)(2)(D)(v) ofthe FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information concerning the
Page 

### 31 of57

### cumulative effects" ofa particular pest icide's residues and "other substances that have a common mechanism oftoxicity." Unlike otherpesticides for whichEPA has 

### followed a cumulative risk approach based on a common mechanism oftoxicity, EPA has not made a common mechanism oftoxicity 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 ofthis regulatory action, therefore, EPA 

### has not assumed that flumioxazin has 

### a common mechanism oftoxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism oftoxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office ofPesticide 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 Assessmen t for a Proposed Use onArtichoke, 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 offlumioxazin. 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 intermedia te-term exposure and risk. Typical assumptions regarding the acres treated and the length ofa work daywere used to derive the exposure estimates, along with a body weight of69 kg, and assuming the maximum application rate for each scenario. Chemical

-specific data were not submitted to the Agency 

### in support ofthe Section 3 application. 

### It is the policy ofHED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence ofchemical-specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1 ), the Agricultural Handler Exposure Task Force (AHETF) database, orotherregistrant-submitted occupational exposure Page 32 of57studies. Some ofthese data areproprietary (e.g., AHETF data), and subject to the data protection provisions ofFIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unitexposures", are outlined inthe "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/oppOOOOllsciencelhandler-exposure-table.pdf),**whic~** along with additional information onHEDpolicy onuse ofsurrogate data, including descriptions ofthe 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 onthe 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 incommercial 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 inthis assessment are based on a central tendency estimate ofunit exposure and anupper-percentile assumption for the application rate, and are assumed to be representative ofhigh-end exposures. The uncertainties associated with this assessment stem from the use ofsurrogate exposure data (e.g., differences in use scenario and data confidence), and assumptions regarding the amount ofchemical handled. The estimated exposures are believed to bereasonable high-end estimates based onobservations from field studies and professionaljudgment.

All dermal handler scenarios do notexceedHED's LOC (MOEs**~1** 00) when wearing labeled PPE (baseline plus chemical resistant gloves). AU inhalationhandler 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 whenthe recommended PPE onthe label is worn. Page 33 of57

### The combined short- and intermediate-term inhalation risk estimates for the occupational handler scenarios assessed are not ofconcern to 

### HED (i.e., ARis are 2': 

### 1) with baseJine attire (i.e.• 

### single layer ofclothing, 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 ofrisk concern when a NIOSH approved dust mist respirator (PF5) or organic vapor (!'FlO) 

### respirator is worn. Table 9.1 presents a summary ofthe 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 ofconcern (i.e., ARis > 

### 1) for all scenarios, except the folloV¥ing:

• Mixing/loading dry 

### flowables for commercial impregnation ofdry 

### bulk fertilizers7 risk estimates ofconcern using sunogate closed rnixing/1oading exposure data 

### and assuming 960 tons treated daily. • Mixing/loading dry 

### flov.'ables for on-farm impregnation ofdry 

### bulk fertilizers for prickly pear cactus, olives, and pomegranate**~** risk 

### estimates ofconcern using surrogate exposure data and assuming I60 acres and 

### 80 acres treated daily. • Mixinglloeding dry 

### flowables for on-farm impregnation ofdry bulk 

### fertilizers for artichoke using surrogate 

### exposure data 

### and assuming 160 acres treated daily. 

### The estimate for amount ofdry 

### bulk fertilizer treated is based onuse 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 of57Table 9.1 Short-/Intermediate-Term Occupational Handler Exposure and Risk Estimates for Flumioxazin. Dermal Unit Inhalation Unit Maximu Area Der mal Inhalation Total Exposure (ugllb ai)" Exposure (ugllb ai)" m Treated or Exposure Scenario Crop orTarget Mitigation Level Mitigation Level Applicat Amount ion Handled Dose MOEe Dose MOE 8 ARih Rate b 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; t.:V Applications PF5R) Mixing/Loading Dry Prick ly 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 0.034 1 880 (SL w/G + PFS 510 0

.48; 1.9i Applications Caobage PF5 R) R) Mi xing/Loading Dry Pricltly Pear 1.792 Cactus, Olive, 51.6 8.96 Plowable for Groundboom and (Baseline + 0

.38 80 0.0228 1,300 0.00394 760 0.7i 2.9i Applications Pomegranate PF5R) Mixing/Loading Dry Flowable for Groundboom Artichoke 51.6 8.96 0

. 19 80 0

.0 114 2,600 0.00 197 1,500 1.4; Applications Mixing/Loading Dry Cabbage, and Flowable for Groundboom 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 of57Table 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 Ex posure Scenario Crop orTar get Mitigation Level Mitigation Level Applicat Amount ion Handled Dose MOEe Dose MOE8 ARI" Rateb Daily (mglkglday)d (mglkglday)r Pomegranat e 16.1 0.34 0

.38 80 0.00709 4,200 0.000149 20,000 14' Applying Sprays via Groundboom Equipment Artichok e 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 ofmitigation: smgle layer ofPPE, gloves). SLw/G ,. smgle layer w/glove; PFS R = PF5 Resprrator; PFlO R= PFIO Respirator b. Based onproposed 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. DermalMOE = Dermal NOAEL (mg/kglday)!Dermal Dose (mglkglday). f. Inhalation Dose = Inhalation UnitExposure (ug/lb ai) x ConversionFactor (0.001 mg/ug) x Application Rate (lb aVacre or gal) x AreaTreated 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/RLt em.Ll+ (1/RI; IIhalalioJ· i. Level ofmitigation: single layer ofPPE, gloves, no respirator. j. Level of mitigation: single layer ofPPE, gloves, NIOSH approved dust mistrespirator for dermal and inhalation; ARI exceeds 1. Enclosed cockpits are expected to beused for aerial application

Page 36 of57Table 9.1. Short-/Intermediate-Term OccupationalExposure aod RiskEstimates for Dn: BulkFertilizer 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 syst em) 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 ailA 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: DryBulk 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), mcl udes data from PHED/ORETF /AHETF. Closed mixing/ loading assumed for commercial impregnation ofdry bulk fertilizer. Open mixing/loading assumed for on-fann Page 37 of

### 51impregnation ofdry 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 orAmount Handled (Nday or ton,;day) i BW(69 kg). 'Dermal MOE= DennalNOAEL (30 mglkglday)JDcnnal Dose (mglkglday). 6 lnhalation Ilose"" Inhalation Unit Exposure (ugllb ai) x CF (0.001 mglug) x Application Rate (lb ailacre or lb ai/ton) x Area Treated orAmount 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 of57

### 9.2 Post-appli<:ation Exposure and Risk Forflumioxazin, based on the proposed use, short- and intermediate-termpost-application exposure is notexpected because: (1)proposed applications topricklypearcactus, artichoke, cabbage, and Chinese cabbage are made pre-plant orpre-emergent and olives andpomegranates are applied via shielded equipment 

### in a way that does notresult in foliage being treated. Restricted EntryInterval The REI specified onthe proposed label is based onthe acute toxicity offlumioxazin. Flumioxazinis classified as Toxicity Category III viathe dermal route and Toxicity Category IV for skinirritationpotential. 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 Statementinterim REI of 12 hours is adequate.**r.~tf4•i** 

### 9.3 Inhalation Post-appli<:ation Risk Based onthe Agency•s currentpractices, a quantitative post-applicationinhalation exposure assessment was notperformed for flumioxazin at this time primarily because ofthe low acute inhalation toxicity (Toxicity Category IV) and the lowproposeduse rate (0.38, 0.19, and 0.13 lb 

### ail A). However, there are multiple potential sources ofpost-application inhalation exposure to individuals performingpost-application activities 

### inpreviously treated fields. These potential sources include volatilization ofpesticides and resuspension ofdusts and/or particulates that contain pesticides. The Agency soughtexpert advice and input on issues related to volatilization ofpesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, andreceived the SAP's final report onMarch 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120I09meeting.html)

. The Agency is 

### inthe process ofevaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry TaskForce and may, as appropriate, develop policies andprocedures, to identify the need for and, subsequently, the wayto incorporate occupational post-application inhalation exposure into the Agency's risk assessments. 

### Ifnewpolicies 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, aninhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application ofpesticides outdoors is likely to result in higher exposurethanpost-application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective ofmost occupational post-application inhalation exposure scenarios.
Page 39 of57

### 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 ofTolerances for uses on Artichoke, Cabbage, Olive, Pomegranate, and Prickly Pear Cactus. Summary ofAnalytical Chemistry and Residue Cbamistry Data. S. Piper. 11112. D406070 

### Drinking Water Assessment for a Section 3New 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 ofFlumioxazin as an Aquatic Herbicidej D357184,J. Stone, 712112010. Flumioxazin. Human Health Risk Assessment forthe Proposed Uses on Turf grass andForest 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 of57

### Appendix A: Toxicology Assessment A.l 

### Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for flumioxazin are inthe 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 yes 1 

### 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 

# - 870.61OOb 90-DayNeurotoxicity (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 of57

### 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)

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

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

....................................



# . . ReqUirements for 870.41OOa and 870.4200a are satisfied by the rece1pt ofan acceptable/guideline combined chronic/carcinogenicity study inrats (870.4300.)

Page 42 of57 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 of57, , Table A.l.b. Subebronie, Chronic and Other ToxicityProfile



### - Guideline Study Type ' MRIDNo. (year)! Results No. ClaulficationIDoses 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/kgldaybased 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 = 151.5 (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 intotal 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 onno 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 DevelopmentalNOAEL= 3 mg/kglday LOAEL

### = 10 mg./kg/day based on cardiovascular effects dose levels: 0, 1, 3, 10 and (especially ventricular septal def ects). 30 mg./kg/ day 870.3700a Pre-natal 42684929 (pilot); Maternal NOAEL 

### =300 mg./kg/day (HOT) developmental

- rat 42684926 (main study) LOAEL 

### =>3 00 mg./kg/day (HDT) (dermal) dose levels: 0, 30, 100, Developmental NOAEL = 30 mg/kglday and 300 mglkglday LOAEL = 100 mglkglday based on cardiovascular effects (especially ventricular septal defects). Page 44 of57Table 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-nataldevelopmentalrabbit (oral) Reproduction and fertility effects

- rat) 42684927 (range-finding); 42684928 (main study) dose levels: 0, 300, I000, 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 1000mg/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 of57 Resula ;**·~**

MaternalNOAEL = 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 inclinical 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 numberofliveborn, a decrease inpup body weight, a decrease inthe mating index, and testicular atrophy ofFI males. NOAEL- 100 mg/kg/day (M & F) LOAEL = 1000 mglkg/day (M &F), (LIMITDOSE) based onthe 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 ofcarcinogenicity

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 ofcarcinogenicityTable A.l.b. Subehronic, Cbroaic and Other ToxicityProfile 

# . I Guideline Study Type MRID No. (year)/ Results No. Classification /Doses Gene Gene mutation inS. 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 ofS. typhimurium strains TA1538 andTA98 in S9 activation to 0, 50, 100, activated phases ofthe 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 Chinesehamster 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 5000mglkg or 12 hoUIS postexposureto 1250 or2500 mglkg



### Page 46 of57Table 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, or4500 ppm (equivalent to 0, 37/41, 110/124, 323/358 mg/kg bw/day for males/females)
Notrequired.
42684943 single oral dose of 1 mglkg or I00 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 of57 ._, . NOAEL = 2000 mglkglday (M & F) LOAEL = >2000 mglkglday (M&F), (LIMIT DOSE) no signs ofneurotoxicity

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 ofanemia [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 1mg/kg and up to 50% at 100 mglkg. At least 97% recovery in feces and urine 7 days after dosing. Highest levels ofresidues (36-49 ppb) in blood cells at low dose and 2800-3000 ppm at high dose (RBC levels >plasma). Inaddition to untransfcnmed parent, 7 metabolites identified in urine and feces (38-46% for low dose and about 7 [%athigh 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 oftreatment 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 1mg/kg. Blood levels at 6- 24 hoW's after dermal dosing with 800 mg/kg were similar tothose obtained at2-6 hours after oral dosing with 30 mglkg. NOAEL = 500 ppm (equivalent to42 mglkg bw/day) LOAEL = 1500 ppm (equivalent to 126 mglkg bw/day), based on signs ofanemia (decreased hemoglobin and hematocrit). Under conditions ofthis 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 OtberToxicityProfile •· Guideline Study Type MRID No. (yeJJr)/ : Results No. Clauification/Doses Non- Special Study

- 42694931,42684932 Pregnant females were administered400 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 ofventricular 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 timeto effects). Executive Summary: See Appendix A Dose and Endpoint for RiskAssessment: NOAEL 

### = 3 mglkglday, Endpoint = cardiovascular effects, specifica lly 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 theresult ofa single dose, with dosing on gesta tion day 12 beingthe most critical timeperiod for the effect. The application ofthe endpoint and dose to the population of potentiallypregnant females isprotective offetal effects. A clearNOAEL andLOAEL 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 beenreduced 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 AcuteReference Dose (aRID) -General population, includinginfants 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 of57A.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 RiskAssessment: 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 ofexposure in the rat study are applicable to the chronic dietary route (oral) and duration ofexposure (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 atthe highest dose tested. Finally, the NOAEL selected from the rat study is the lowest observed in the submitted studies, and is protective ofall 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 RiskAssessment: 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 of57

### for the qualitative and quantitative susceptibility observed in 

### the reproduction study. As the FQPA factor 

### has beenreduced to lx, 

### and a clear NOAEL and LOAEL were identified in the study, the standard 

### UFs of 

### IOOx (1Ox for interspecies extrapolation and 

### IOx for lntraspecies variability) define the level ofconcern (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 oftreatment 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 30 mg/kg. 

### For the 

### purpose ofrisk 

### 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 LOAEL 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 intbe 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 ofless 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 of57MRID 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 assessmentbecause 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 ofthe 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 ofthe 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 IOOx (lOx for interspecies extrapolation and lOx for intraspecies variability) defme the LOC for risk assessment as an MOE ofless 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 ofan 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 ofthe endpoint ensures the risk assessment is protective ofpotential developmental effects. The selection ofthe developmental effects allows for aggregation ofdermal 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 ofless than 100 for both residential and occupational exposure and risk assessment.

Page 51 of57

### A-3.9 Inhalation Exposure (Long-Term) for Adults Study Selected: 2-Year ChroniciCaxcinogenicity Study (Rat) MRIDNo.: 

### 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 ofan inhalation study for**flumioxazin~** HED 

### selected an oral study. 

### The duration ofexposure in 

### the chronic rat study is 

### applicable to long-term durations ofexposure. 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 ofall other effects, including the ofiSpring effects in 

### the reproductive toxicity study. As a route-specific inhalation study is not available, an inhalation absorption fuctor 

### ofI00% 

### 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 inthe study, the standard UFs of IOOx (lOx for interspecies extrapolation and !Ox for intraspeeies variability) define the LOC for risk assessment as an MOE ofless 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 of57

### Table B.l. Physicochemical Properties ofFlumioxazin. 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 of57Table 4

. 1

. 1, lists the updated assessment ofcurrently registered residential handler exposures and risk estimat es. The updated exposure and risk estimates for all residential handler use pattern scenarios result 

### indermal risk estima tes that are greater

### than or equal to 100 and therefore do not exceed HED' s LOC and inhalation risk estimates that are greater than orequal 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 HandlerShort-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-En d _J 41 Sprayer Inhalation 0.000000 18 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 0.000000 18 17,000,000 

# ' Dermal 0

.00012 

# I 240 ,000 PushType 1,900 Spreader Inhalation 0.00000039 7,600,000 r Dermal 0.054 550 Belly 

# 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 of57

### Table C.l. Residential Flumioxazin Handler Short·and Intermediate-TermExposure 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) 

# I Dail y (b) 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 onregistered gardens and trees labels (lb wA converted to lb ai/sq. ft); turflabels (lb ail A) b) Exposure Science Advisory Council Policy#9.1 and 20II 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 unitexposure (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 (BMDLISD of3.1 mg/kglday) I Daily inhalation dose (mglkglday). Dermal Level ofconcern= 100, Inhalation Level ofConcern= 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 of57Table C.l: Short-Term Residential Handler Exposure and Risk Estimates for Flumionzin. Area Treated Dermal Inhalation TargetMOE MaJ.!mum or Amount Dose Exposure Scenario Application Rate• Handled Dose MOEd MOEr ARJI Dailyb (mg/kg/dayt (mg/kg/day)" Gardens and Trees- WDG Formulations 

### . ...!:. .l 

## - Mixer/Loade r/

Applicator Mixing/Loading/Applying WDG 0.0088 3,400 0.00014 21,000 13 with Manually Pressurized 100 1200ftl 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 1200ftl 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 13 with Backpack Sprayer 100 0.38 0.023 acres 0.0087 

### Page 

### 56 of57Table 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), turflabels (lb ailA) 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 of57 ARI'

150