Page 3 of 70

5.4 Dietary Risk Assessment

................................ ................................ .................... 26

5.4.1 Description of Residue Data Used in Dietary Assessment

.................... 26

5.4.2 Percent Crop Treated Used in Dietary Assessment

............................... 26

5.4.3 Acute Dietary Risk Assessment

................................ ............................... 27

5.4.4 Chronic Dietary Risk Assessment

................................ ........................... 27

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ 28

6.1 Handlers

................................ ................................ ................................ ............... 28

6.2 Post

- application Exposure

................................ ................................ .................. 29

6.2.1 Non

- Occupational/Residential Exposure

................................ .............. 29

6.3 Combined Exposure

................................ ................................ ............................ 31

6.4 Residential Bystander Post

- application Inhalation Exposure

........................ 31

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ . 32

7.1 Acute Aggregate Risk

................................ ................................ ......................... 32

7.2 Short

- Term Aggregate Risk

................................ ................................ .............. 33

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ .. 35

7.4 Long

- Term Aggregate Risk

................................ ................................ ............... 35

8.0 Cumulative Risk Characterization/Assessment

................................ ............................... 35 9.0 Occupational Exposure/Risk Path way

................................ ................................ .............. 36

9.1 Handlers

................................ ................................ ................................ ............... 36

9.2 Post

- application Exposure and Risk

................................ ................................ . 40

9.3 Inhalation Post

- application Risk

................................ ................................ ....... 41

10.0 References

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

................................ ................................ ....................... 43

A.1 Toxicology Data Requirements

................................ ................................ .......... 43

A.2 Toxicity Profiles

................................ ................................ ................................ ... 45

A.3 Hazard Identification and Endp oint Selection

................................ ................. 50

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

.............................. 50

A.3.2 Acute Reference Dose (aRfD)

- General population, inc luding infants

and children

................................ ................................ ................................ ......... 50

A.3.3 Chronic Reference Dose (cRfD)

– all populations

................................ 51

A.3.4 Incidental Oral Exposure (Short

- and Inte rmediate

- Term)

............... 51

A.3.5 Dermal Absorption

................................ ................................ ................. 52

A.3.6 Dermal Exposure (Short and Intermediate

- Term) for Children

....... 52

A.3.7 Dermal Exposure (Short

- , Intermediate

- and Long

- Term) for Adults

52

A.3.8 Inhalation Exposure (Short

- and Intermediate

- Term) for Adults

..... 53

A.3.9 Inhalation Exposure (Long

- Term) for Adults

................................ ...... 54

A.4 Executive Summaries

................................ ................................ .......................... 54 Appe ndix B. Physical/Chemical Properties

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

................................ ..................... 67Page 4 of 70

1.0 Executive Summary

Valent USA Corporation ha s requested the Section 3 registration of new uses for flumioxazin, the active ingredient in Valor Herbicide and Chateau Herbicide, in w heat, sunflower, safflower, flax, lentils and field peas. T his document assesses the dietary and occupational exposures and

risks t hat would result f

rom the proposed uses of the herbicide , as well as the impact on aggregate exposure and risk

.

Flumioxazin, 2

- [7

- fluoro

- 3,4

- dihydro

- 3

- oxo

- 4

- (2

- propynyl)

- 2 H

- 1,4

- benzoxazin

- 6

- yl]

- 4,5,6,7

- tetrahydro

- 1 H

- isoindole

- 1,3(2 H )

- dione, is an herbicid e of the N

- phenylphthalimide class that is currently used for pre

- and post

- emergence control of susceptible weeds o n a variety of fruit s
, vegetable s, tree nuts, other agricultural crops
, ornamentals, non

- crop and bare

- ground

areas (recreational landscapes, apartment and office complexes, and schools) , as well as in aquatic settings (bayous, canals, fresh water ponds, marshes, and water reservoirs)

. It is also registered on conifer reforestation sites, poplar/timber reforestation sites, and dormant warm

sea son turfgrass including golf courses and sod farms. Its mode of action is as an inhibitor of protoporphyrinogen oxidase . I t is active against certain grasses, broadleaf weeds, and sedges (including aquatic species)

. The end

- use product s being proposed a re Valor Herbicide (EPA Reg. No. 59639

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

59639

- 119, water dispersible granule ) , which are water dispersible granule s (WDS) containing 51% flumioxazin by weight. The maximum single appli cation rate proposed for field peas, flax, sunflower, lentils, and safflower is 0.09 lb ai/A per single ap plication and for wheat is 0.06 lb

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

handlers includes long

- sle eved shirt and long pants, shoes plus socks, and chemical resistant gloves . The REI specified on the label is 12 hours. The proposed p re

- harvest intervals are 5 or 10 days.

Hazard Assessment: T he tox icology database for flumioxazin is nearly complete a s described in 40 CFR, Part 158, except that HED requests an inhalation developmental study due to concerns for quant it ative sensitivity of the fetus following both oral and dermal exposure.

In general, the s ubchronic and chronic toxicity studies demo nstrated that toxic effects associated

with flumioxazin include anemia a s well as effects on the liver and the cardiovascular system. Developmental effects were observed in developmental rat studies but not in developmental rabbit studies. Hematologic (h ematopoietic) effects of anemia were noted in rats, consisting of alterations in hemoglobin parameters. Increased renal toxicity in male rats was also reported following chronic exposure. There is no evidence of neurotoxicity or immunotoxicity in the

rece ntly submitted guideline studies.

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

effects were observed in the absence of maternal toxicity. In addition, both increased qualitative and quantitative susce ptibility w ere observed in the rat reproduction study

. S evere fetal effects

were observed at lower doses than milder parental effects. Although there was an increase in susceptibility, HED’s degree of concern for the susceptibility observed in the rat de velopmental and reproductive studies is low because the regulatory endpoints for flumioxazin are based onPage 5 of 70

clear NOAELs for developmental and offspring effects that are protective of the increased susceptibility seen in the developmental and reproduction st udies, and there are no residual

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

1 x for oral and dermal exposure

. F lumioxazin is classified as “not likely to be carcinogenic to

humans.”

Due to the inhalatio n developmental study data gap, the Agency is retaining a 10X database uncertainty factor (UF DB ) for all inhalation exposure scenarios. Once these data have been received, the Agency will determine how the results affect the toxicology endpoints and

uncert ainty factors.

Dietary Exposure : T he acute and chronic dietary exposure analyses were based on conservative assumptions , including tolerance level residues, 100% crop treated (CT)

, and high

- end estimated drinking water concentrations ( EDWCs )

. The EDW Cs based on the proposed uses are lower than those from a previously assessed aquatic use. The only population subgroup for which an acute dietary endpoint was selected was Females 13

- 49. The acute risk estimate for this subgroup is 6 8 % of the aPAD

, whic h is not of concern

. The c hronic risk estimates are below HED’s level of concern for all population subgroups. The risk estimate for the general U.S. population is 20 % of the chronic PAD (cPAD). The population subgroup with the highest risk

estimate is a ll i nfants (1 year old)

, which uses 5 4 % of the c PAD.

Residential Exposure and Risk Estimates : Residential exposures are not anticipated from the proposed Section 3 uses; however, residential exposure s are anticipated from currently registered

uses on treated turf and gardens and trees

. HED has revised its Residential Standard Operating Procedures (SOPs). This new guidance results in the need for an update of flumioxazin

residential risk estimates. Exposures are expected for adults who apply flumio xazin

- containing products and from post

- application exposure to adults and children in residential areas previously

treated with the chemical. Residential uses are anticipated to be short

- term (i.e., 1 to 30 days) in

duration.

The following six short

- t erm residential exposure scenarios for the use of flumioxazin on

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

child dermal and hand

- to

- mouth transfer, object

- to

- mouth transfer, and exposure through soil ingestion

.

Residential handler dermal and inhalation risk estimates for flumioxazin are not of concern to HED (i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) for these assessments). The combined handler dermal a nd inhalation risk estimates calculated using the Aggregate Risk Index (ARI) are not of concern to HED (i.e., ARIs are ≥ 1). The ARI approach was required to combine the dermal and inhalation routes of exposure because of the different levels of concern ( LOCs).

Adult and child residential post

- application dermal exposures also are not of concern to HED. For children 1 < 2 years old, the combined dermal and incidental oral risk estimates for thePage 6 of 70

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

Aggregate Risk: The acute aggregate risk from exposure to flumioxazin is equivalent to the acute dietary risk. Acute d ietary risk estimates are not of concern for the population subgroup

Females 13

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

established.

The short

- term aggregate exposure assessment combines short

- term residential (non

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

- term aggregate risks

estimated for adult females 13

- 49 years are not of concern to HED (i. e., ARIs are ≥ 1). Short

term aggregate risk estimates (MOEs) for the most highly exposed population, children 1 < 2 years old, are also not of concern to HED (i.e., MOEs are ≥ 100). The intermediate

- term aggregate risk assessment is identical to the sho rt

- term assessment because the exposures and PODs are identical for both exposure durations.

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

to residues in food and drinking water

. As a result, the chroni c aggregate risk assessment is equivalent to the chronic dietary risk assessment . All risk estimates are not of concern.

Occupational Exposure and Risk Estimates : Based on the proposed use pattern, both short

and intermediate

- term exposure and risk ass essments 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.

Occup ational handler exposures to flumioxazin may occur via the dermal and inhalation rout e and was assessed at the maximum label application rate for each crop

. The short

- and

intermediate

- term inhalation risk estimates for the occupational handler scenarios assessed are not of concern to HED (i.e., AR Is are ≥ 1 ) with baseline attire ( i.e ., single layer of clothing, no respirator)

, except for mixing/loading dry flowables for aerial applications at baseline

. For this scenario, the ARI is greater than 1 , and not of risk concern when engineering controls ( closed systems) are applied. All post

- application worker exposure scenarios assessed result in estimated risks that were not of concern [i.e., MOEs are > ≥ 100 on Day 0 (12 hours)] for all potential post

- application activities.

Environmental Justice Cons iderations

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

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Popul ations and Low

- Income Populations

. 1 ”

Review of Human Research : This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Pestic ide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF)

1 http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf

.Page 7 of 70

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

have been determined to be ethical.

2.0 HED Recommendations

2.1 Data Deficiencies

Toxicology:

The HASPOC concludes, based on a WOE approach, that a rat developmental inhalation toxicity study (Guideline No. 870.3700a), is required at this time. This study should include an evaluation of the respiratory tract and should follow the procedures described in Guideline No. 870.3465. This approach considered the available hazard and exposure information for flumioxazin, including (1) the observed concern for the q uantitative susceptibility of the developing fetus following both oral and dermal exposure; (2) the severity of the fetal effects ( ventricular septal defects ) observed in the oral and dermal developmental studies; (3) that the oral developmental toxicity s tudies only measure toxicity of flumioxazin after first

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

- induced toxicity to the developing fetus when directly entering the lung (via inhalation) and more rapidl y entering the blood stream by bypassing the liver; and (4) the concern for the inhalation MOE of 210 for mixing/loading DFs for application to field peas, flax, sunflowers, safflower, and lentils (and the inhalation MOE of 610 for the currently registered aquatic use).

Residue Chemistry

Pending submission of a revised Section B and Section F and updated certificate ( s ) of analysis or new analytical reference standard ( s ), t here are no residue chemistry issues that would preclude

g ranting conditional registration for the requested use of flumioxazin o n field pea, flax, lentils, sunflower, safflower, and wheat

. T he Analytical Reference Standard for flumioxazin will expire

on 4/1/2012 . An updated certificate of analysis or a new analytical reference st andard must be provided to the EPA National Pesticide Standards Repository.

Occupational and Residential Exposure:

In accordance with the updated Part 158 data requirements (2007), a turf transferable residue (TTR) study is required for all occupation al (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses. As part of the recent flumioxazin Section 3 turf assessment (Wang; 385849; 06/08/11) HED reviewed a waiver request for the submission of a TTR study (MRID No. 4813 1401). In that assessment, HED stated that TTR data was not required at that time but that such data may be needed for future exposure assessments. Since the time of that assessment, HED has revised it's Residential SOPs ( Health Effects Division’s 2012 S tandard Operating Procedures for Residential Pesticide Exposure Assessment ). In the 2012 SOPs, HED analyzed all of the available TTR data and selected new liquid and granular default values for thePage 8 of 70

fraction of the application rate available for transfer a fter a turf application (F AR ). This default is 1% for formulations applied as liquids which is the case with flumioxazin. Of the available TTR studies submitted to the Agency, the maximum F AR value seen using a liquid product was 6.1% or 6.1 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 10 times higher than the level of concern (e.g., an MOE > 1,000 if the LOC = 100) using the default residue transfer values would provide an ad equate margin of safety for any potentially higher residues seen in a chemical

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

children contacting treated turf are 180 and 290 , respectiv ely.

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 post

application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessmen t , HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a fo liar application (F AR ). This default value is 25%. Of the analyzed DFR studies, the maximum F AR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, a calculated MOE of approximately 4 times higher than the LOC (i.e ., an MOE > 400 if the LOC = 100) using the default dislodged residue value would provide an adequate margin of safety for any potentially higher residues seen in a

chemical

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

lowest dermal residential post

- application MOE for adults is 130

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate gas chromatography/nitrogen

- phosphorus detection (GC/NPD) method, Valent

Method RM30

- A

- 1, is available for en forcing tolerances for residues of flumioxazin per se in/on plant commodities. The reported method limits of quantitation and detection (LOQ and LOD) for flumioxazin in/on plant commodities are 0.02 and 0.01 ppm, respectively.

Th e requirements for mult iresidue methods testing data for the metabolites 482

- HA and APF

flumioxazin are fulfilled. The available data indicate that flumioxazin could not be recovered through application of the multiresidue protocols.

2.2.2 International Harmonization

There ar e no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for any of the proposed commodities in the current registration actions, therefore, there are no issues of international harmonization raised by this action.Page 9 of 70

2.2.3 Recommended Tolerances

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

recommendations. Tolerances for residues in/on plant commodities are expressed in terms of residues of flumioxazin, including its metabolites and degrada tes, to be determined by measuring only flumioxazin.

Table 2.2.3 . Tolerance Summary for Flumioxazin.

Commodity Established/Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition

Dried shelled pea and bean (except soybean), Crop Subgroup 6C, seed 0.1 0.07 Pea and bean, dried shelled, except soybean, subgroup 6C

Bean, dry seed 0.05 Remove

Rapeseed, Crop Subgroup 20A, seed 0.35 0.40 Rapeseed subgroup 20A

Rapeseed Crop Subgroup 20A, meal 0.04

-- Residues in canola meal and oil will be covered by the recommended tolerance for rapeseed subgroup 20A. Rapeseed Crop Subgroup 20A, refined oil 0.02

--

Sunflower, Crop Subgroup 20B, seed 0.5 0.50 Sunflower subgroup 20B

Sunflower, Crop Subgroup 20B, meal 0.03

-- Residues in sunflower meal and oil will be covered by the recommended tolerance for rapeseed subgroup 20A. Sunflower, Crop Subgroup 20B, refined oil 0.02

--

Wheat, forage 0.02 0.02

Wheat, hay 0.02 0.02

Wheat, grain 0.35 0.40

Wheat, straw 5 6.0

Grain, as pirated fraction 110 100 Grain, aspirated fractions

Wheat, bran 0.35

-- Residues in wheat bran, flour, germ, middlings, and shorts will be covered by the recommended tolerance for wheat grain. Wheat, flour 0.05

-- Wheat, germ 0.35

-- Wheat, middlings 0.08

-- Wheat, shorts 0.11

--

Note to RD : In conjunction with the establishment of the proposed tolerance for pea and bean, dried shelled, except soybean, subgroup 6C , the tolerance for bean, dry seed should

be removed.Page 10 of 70

2.2.4 Revisions to Peti tioned

- For Tolerances

2.3 Label Recommendations

HED recommends the labels include engineering controls (closed system ) mixer/loaders for aerial application of dry flowables to mitigate occupational exposure. HED will work with the Registration Division on these label modifications.

The following label revisions/clarifications are required:

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

from the label : Except for alfalfa, field corn, and almond hulls do not gra ze treated fields or feed treated forage or hay to livestock. EPA OPPTS 860.1000 guideline states that there are only three cases where a label restriction should be allowed: peanut hay, soybean forage, and soybean hay.

The stated pre

- planting interval o f “[7] 14 days” for preplant weed control in wheat

should be clarified . The submitted data will support a minimum pre

- planting interval of 7 days.

3 .0 I ntroduction

Flumioxazi n is an herbicide of the N

- phenylphthalimide class that is currently used for pre

- and
post

- emergence control of susceptible weeds in a variety of crops and other use sites

. Its mode

of action in plants is as an inhibitor of protoporphyrinogen oxidase . I t is active against certain grasses, broadleaf weeds, and sedges (including a quatic species)

.

3.1 Chemical Identity

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

Table 3.1 Flumioxazin Nomenclature.

CompoundPage 11 of 70

Table 3.1 Flumioxazin Nomenclature.

Common N ame Flumioxazin

IUPAC N ame N

- (7

- fluoro

- 3,4

- dihydro

- 3

- oxo

- 4

- prop

- 2

- y nyl

- 2 H

- 1,4

- benzoxazin

6

- yl)cyclohex

- 1

- ene

- 1,2

- dicarboxamide

CAS N ame 2

- [7

- fluoro

- 3,4

- dihydro

- 3

- oxo

- 4

- (2

- propynyl)

- 2 H

- 1,4

- benzoxazin

6

- yl]

- 4,5,6,7

- tetrahydro

- 1 H

- isoindole

- 1,3(2 H

)

- dione

CAS R egistry N umber 103361

- 09

- 7

End

- use P roduct (EP) Valor Herbicide (EPA Reg. No. 59639

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

- 119, water dispersible granule )

3.2 Physical/Chemical Characteristics

For this new use, Flumioxazin is formulated as a WDG with 5 1% active ingredient

. Flumioxazin has a log octanol/water partition coefficient of 2.55 and a vapor pressure of 2.41 x 10

- 6 mm Hg at

25 o C. It has a water solubility of 1.079 g/L and there is no information available on solvent solubility. In the environment, flumioxazin p hotodegrades very rapidly in water and on soil (half

- lives = 1 and 5.8 days, respectively). Flumioxazin is classified as having medium soil mobility potential. Its two major degradates (APF and THPA) are expected to be more mobile than the parent compou nd in the environment (Koc = 410 and 155, respectively). Flumioxazin is relatively volatile in water and on soil, and is not expected to bioaccumulate in fish (Kow = 355 ). See Appendix B for a listing of flumioxazin physical and chemical properties.

3.3 Pesticide Use Pattern

Valent USA Corporation is proposing the use of the herbicide flumioxazin on field peas, flax, lentils, sunflower, safflower, and wheat. The end

- use products being proposed for use on these

sites are Valor Herbicide (EPA Reg. No. 59639

- 99) and Chateau Herbicide (EPA Reg. No.

59639

- 119) , which are water dispersible granule s (WDG) containing 51 % flumioxazin by weight

. Flumiox a zin is proposed for a single foliar application at a maximum seasonal rate of

0.09 lb ai/A for f

ield p eas
, f

lax, s unflower, s afflower, l entils, and 0.06 l b ai/A for wheat. Applications are to be made using ground and aerial equipment. The proposed pre

- harvest interval (PHI) are 5 or 10 days.

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

Table 3. 2 . Summary of Directions for Use of Flumioxazin

.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg.

No. 59639

- 99, 59639

- 119 ] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic. Rate (lb ai/A) REI Use Directions and

Limitations

Field Peas, Flax, Sunflower, Safflower, Lentils

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

Table 3. 2 . Summary of Directions for Use of Flumioxazin

.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg.

No. 59639

- 99, 59639

- 119 ] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic. Rate (lb ai/A) REI Use Directions and

Limitations

aerial Dispersible

Granule ai/A days prior to harvest. Do not apply to dry beans after beans begin t o crack or have emerged.

Wheat

Ground and

aerial Water

Dispersible

Granule 0.06 lb

ai/A 1 0.06 lb ai/A 12 hrs Application may be made 10 days prior to harvest. Wheat must be planted a minimum of 1” deep. Do not graze until wheat is 5”

tall.

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

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

- sleeved shirt and long pants, socks plus shoes, and chemical

- resistant gloves.

3.4 Anticipated E xposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of flumioxazin on field peas, flax, lentils, sunflower, safflower, and wheat

. Humans may be exposed to flumioxazin in food and dri nking water, since the proposed labels indicate that it may be applied directly to growing crops. Application may result in flumioxazin reaching surface and ground water sources of drinking water, both of which can serve as sources of drinking water. It is also directly applied to surface water as an aquatic herbicide. There are

residential uses of flumioxazin , so exposure to flumioxazin may occur in residential or non

occupational settings. In an occupational setting, handlers may be exposed while hand ling the pesticide prior to application, as well as during application. There is also a potential for post

application exposure for workers re

- entering treated sites.

Risk assessments have been completed for the existing uses of flumioxazin . This risk assessment considers all of the aforementioned exposure pathways based on the proposed new

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

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal ActionsPage 13 of 70

to Address Environmental Justice in Minority Populations and Low

- Income Populations 2

. " As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide expo sures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA

under the Cont inuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticid e products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas
post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertis e 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 T oxicology Studies Available for Analysis

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

hazard of flumioxazin

. The available toxicology studies for flumioxazin are listed in Table s A. 2.a and A.2.b in App endix A

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

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

• Subchronic oral toxici ty studies (rat, mouse, and dog)

• Dermal toxicity

- rat (21

- day dermal toxicity and dermal penetration)

• Dermal developmental (rat)

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

• Chronic oral toxicity studies (rat and dog)

• Carc inogenicity studies (rat and mouse)

• Metabolism studies (rat)

• Acute and subchronic neurotoxicity studies

• Immunotoxicity study

• Mutagenicity battery

• Special Study: Rat Developmental

- Critical Time for Defects

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

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

. A n inhalation developmental study is needed to characterize more completely the potential for adverse effects associated with the inhalation route of exposure. For inhalation risk assessment,

EPA is curr ently using the dose and endpoint from an oral rat developmental toxicity study with an estimated 100% default absorption factor (of oral absorption). Toxicity by the inhalation route was considered to be equivalent to toxicity by the oral route. However , in some cases toxicity via the inhalation route is higher than toxicity via the oral exposure, which results in an underestimation of risks from inhalation exposure. In addition, there may be a potential for portal of entry effects via the inhalation ro ute, which would not be accounted for in the oral studies. As a result, an inhalation study is needed for a more accurate assessment of inhalation

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

.

Desp ite these missing studies, the toxicity database is considered to be adequate for the purpose s of dose and endpoint selection for the current risk assessment, and for characterizing toxic

effects associated with flumioxazin.

4 .2 Absorption, Distribution , Metabolism, & Elimination (ADME)

The absorption, distribution, metabolism and excretion (ADME) of flumioxazin was investigated in rats following single oral doses of radiolabeled flumioxazin. Metabolism studies in rats

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

Gastrointestinal tract absorption of flumioxazin m ight amount to over 90% of the dose. Total recovery of radioactivity in feces and urine 7 days after dosing accounted for 9 7

- 10 1 % of the

d ose in all test groups. It was noted that 4

- 5 times as much radioactivity is excreted in feces a s 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 h ighest levels of residues were found in blood cells (35.9

- 48.8 ppb, low dose and

2823

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

- 0.7 ppb, low

dose and 53

- 37 ppb, high dose). In addition to untransformed parent compound, a nalysis of feces and urine revealed up to 35 putative metabolites. Identified compounds amounted to 37.5

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

- 71.5% of the dose at the high dose.

4 .2.1 Dermal Absorption

A n acceptable dermal absorption study in rats is available for flumioxazin where dermal absorption was assessed using 2 different doses . B ased on the results of the study, HED

determined that an upper

- bound estimate of 8% dermal absorption sh ould be used for risk
assessment purposes

.

4 .3 Toxicological Effects

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

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

of heme.

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

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

Subchronic and chronic toxicity studies demonstrated that to xicity associated with flumioxazin includes anemia as well as effects on the liver and the cardiovascular system. Hematologic al (hematopoietic) effects of anemia consisting of alterations in hemoglobin parameters were noted

in rats. Increased renal toxic ity in male rats was also reported following chronic exposure. Increased absolute and relative liver weights and/or increased alkaline phosphatase values were observed in dogs.

Developmental effects were observed in developmental rat studies but not in developmental rabbit studies. The effects seen in the rat studies were fetal cardiovascular anomalies, especially ventricular septal defects. Flumioxazin was also administered dermally to rats in a developmental study, and the exposure resulted in simil ar cardiovascular anomalies, the most serious being ventricular septal defects. Although the same effects occurred by both dermal and oral routes in developmental studies, the oral effects were noted at 10 mg/kg/day and the dermal at 100 mg/kg/day. N o sy stemic toxicity (or dermal irritation) was observed in a 21

- day dermal study up to the limit dose of 1000 mg/kg/day

. In a mechanistic oral developmental study in rats, a single dose of 400 mg/kg/day caused ventricular septal defects when administered on g estation day 12, but not when given on days 11, 13, 14 or 15. In the 2

- generation reproduction study, systemic effects (clinical signs and mortality as well as a decrease in body weight/gain and food consumption) were noted at approximately 19 and 23 mg/k g/day in males and females, respectively; however, effects on the offspring (decrease in the number of live born and decreased pup body weights, decreased mating index, and testicular atrophy in F1 males) occurred at lower doses (approximately 13 and 15 mg /kg/day).

Increased quantitative susceptibility was observed in the rat developmental toxicity studies (oral and dermal) in which the effects on fetuses occurred at doses that did not cause maternal toxicity. In addition, both increased qualitative and quantitative susceptibili ty w ere observed in the rat reproduction study, in which offspring effects were observed at lower doses than those which caused parental/systemic toxicity, and in which the offspring effects were considered to be more

severe. An a dditional rat developmental study was submitted in which a single dose of 400 mg/kg/day was administered to pregnant rats on gestation days 11, 12, 13 or 14. The results of the study indicated that a single dose on gestation day 12 was the cause of the ve ntricular septal defect observed in the rat developmental toxicity studies.

Several mechanistic studies were submitted by the r egistrant 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 a nd changes in osmotic forces leading to edema observed in the fetus. Concurrently, the fetus would compensate for the anemia by pumping a greater volume of blood leading to the observed enlargement of the heart.

The r egistrant further postulated that the ventricular septal defect was produced by mechanical distortion of the heart. The two other signs of developmental toxicity reported, growth

retardation and fetal death

, were also considered to be related to the hypoxia produced by the

anemic condition i n the fetus.Page 16 of 70

After evaluating the data, the Agency concluded that the mechanistic studies were not sufficiently robust to support the registrant’s proposed mechanism of toxicity. However, a s doses and endpoints for risk assessment were chosen to be prote ctive of the cardiovascular (acute dose and endpoint) and hematopoietic (chronic dose and endpoint) effects, the lack of a conclusion regarding the mechanism of toxicity does not result in the need for additional uncertainty factors.

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

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

dose . The absence of effects in rabbits was supported by literature studies indicati ng rabbits are less susceptible to the effects of protoporphyrinogen oxidase inhibitors.

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

female rats. There was no other evidence in any species tested to indicate neurotoxicity potential. Therefore, there is no concern for acute or chronic neurotoxicity resulting from
exposure to flumioxazin . Similarly, t he immunotoxicity study in rats suggests that this chemical does not directly target the immune system. Also, t he toxicology database for flumioxazin does not show any evidence of treatment

- related effects on the immune system.

In most of the available mutagenicity studies, flumioxazin was negative for mutagenicity ; h owever, aberrations were seen in a chromosomal aberration assay (CHO cells). Based on the lack of evidence of carcinogenicity in mice and rats, flumioxazin is classified as “not likely to be carcinogenic to humans.”

4 .4 Safety F actor for Infants and Children (FQPA Safety Factor)

HED recommends tha t the required 10 x FQPA S afety F actor for the protection of infants and

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

exposures based on the following: 1) the toxicology database for flumioxazin is complete with regard to FQPA consideration, including the required developmental and reproductive toxicity studies; except for an inhalation developmental study to assess adult women of childbearing age ; 2) the required neurotoxicity studie s have been submitted, a re considered adequate; 3) although there is evidence of quantitative susceptibility in the rat developmental (oral and dermal) and reproduction studies

, the endpoints and doses selected for oral and dermal risk assessment are protective for these effect s ; and 4) the dietary and drinking water assessments are conservative

and based on upper

- bound estimates of exposure.

4 .4.1 Completeness of the Toxicology Database

The toxicology database is complete for flumioxazin except for an inhalation developmen tal study to assess adult women of childbearing age exposed via inhalation exposure . The toxicity profile can be characterized for all effects, including potential developmental and reproductive toxicity, immunotoxicity and neurotoxicity. Acceptable studi es for developmental toxicity in rats and rabbits, developmental immunotoxicity, 2

- generation reproduction in rats, and neurotoxicityPage 17 of 70

are available.

I n the absence of a route

- specific inhalation developmental study, the Hazard and Science Policy

Council ( HASPOC) recommends that a 10X database uncertainty factor be applied only to as sess risks for inhalation exposure scenarios for both occupational and residential use patterns (D 401671 , May 31, 2012)

. The HASPOC concludes, based on a WOE approach, that a r at developmental inhalation toxicity study (Guideline No. 870.3700a), is required at this time (D 401671 , May 31, 2012)

. This study should include an evaluation of the respiratory tract and should follow the procedures described in Guideline No. 870.3465. This approach considered the available hazard and exposure information for flumioxazin, including (1) the observed concern for the quantitative susceptibility of the developing fetus following both oral and dermal exposure; (2) the severity of the fetal ef fects ( ventricular septal defects ) observed in the oral and dermal developmental studies; (3) that the oral developmental toxicity studies only measure toxicity of flumioxazin after first

- pass liver metabolism and do not address the concern for the potenti al for greater flumioxazin

- induced toxicity to the developing fetus when directly entering the lung (via inhalation) and more rapidly entering the blood stream by bypassing the liver; and (4) the concern for the inhalation MOE of 210 for mixing/loading dry flowables for application to field peas, flax, sunflowers, safflower, and lentils (and the inhalation MOE of 610 for the currently registered aquatic use).

4 .4.2 Evidence of Neurotoxicity

T here is no indication that flumioxazin is neurotoxic i n the acute and subchronic neurotoxicity (SCN) stud ies

. In addition, none of the acute, subchronic, chronic, developmental

, or reproduction studies indicated that flumioxazin has an effect on the nervous system. Developmental effects (cardiovascular ano malies) were observed in the rat; however, the se effects are not related to developmental effects of the central or peripheral nervous systems. As

a result , a DNT study is not required.

4 .4.3 Evidence of Sensitivity/Susceptibility in the Developing or Y oung Animal

T here is evidence of increased quantitative susceptibility of fetuses in the oral and dermal developmental rat studies , i.e., cardiovascular anomalies (ventricular septal defect) that occurred in the absence of maternal toxicity

. Additionally , t he rat reproduction study demonstrated evidence of qualitative and quantitative post

- natal susceptibility because reproductive effects in offspring were observed at doses lower than those that cause d parental/systemic toxicity, and because the reproduct ive effects in offspring were considered to be more severe than the parental/systemic effects.

Although increased susceptibility was seen in rats, HED concluded that there is a low concern and no residual uncertainties for pre

- and/or postnatal toxicity b ecause: 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 t he developmental and reproductive toxicityPage 18 of 70

studies for risk assessment for the relevant exposed populations, i.e., pregnant females and children, with the exception of the chronic dietary endpoint, for which a chronic study was chosen for endpoint selectio n. 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 Databa se

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

. The acute and chronic dietary analysis was based on

tolerance

- level residues and 100% crop treated assumptions for all c ommodities. T he field trials represent maximum application rates and minimum pre

- harvest intervals ( PHIs )

. T he dietary drinking water assessment utilized water concentration values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high

- end

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

exposure s to flumioxazin will likely be lower than the estimated exposures

. The residential

exposure assessmen t incorporates similarly conservative assumptions in the assessment of post

application exposure to children and in the incidental oral exposure assessment for children. However, an inhalation developmental toxicity study is required for a more accurate a ssessment of inhalation risks. Currently, an oral toxicity study (with a default 100% absorption factor) is being used to assess inhalation exposure. As a result, it is possible that route

- to

- route extrapolation will result in an underestimation of inhal ation risks. However, based on the oral NOAEL used for inhalation risk assessment, the occupational and residential handler m argins of

e xposure (MOEs) ranged from 21 ,000 to 17,000,000 and, therefore, are not a risk concern ( MOE >100 0 ) , even with the addit ional 10X database uncertainty factor

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

4 .5 Toxicity Endpoint and Point of Departure Selections

The available toxicity database was evaluated for endpoint selection for : 1) acute and chronic dietary risk assessments; 2) short

- term residential exposures including dermal and incidental oral exposure for children and dermal and inhalation exposure for adults; and 3) for short

- and

intermediate

- term o ccupational exposures via the dermal and inhalation routes. A lthough long

term dermal and inhalation doses and endpoints were considered and selected, there are no long

term exposures expected for these routes based on the existing and proposed use patter ns.

4 .5.1 Dose

- Response Assessment

While the detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A , the following

outlines the dose

- respons e assessment and a general description of the endpoint selection. APage 19 of 70

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

4.5.1 and 4.5.2.

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

assessment of f

emales 13

- 49 yrs , based on a NOAEL of 3 mg/kg/day in the rat developmental study. At the LOAEL of 10 mg/kg/day cardiovascular effects in fetuses

, specifically ventricular septal defects were seen. The effects were observ ed after a single dose exposure in a dietary study and are considered appropriate for acute dietary exposure. No separate endpoint was identified for acute dietary exposure for the general population, including infants and children.

For chronic dieta ry exposure, a chronic reference dose (cRfD) of 0.02 mg/kg/day was selected for assessment of all populations, based on a NOAEL of 2 mg/kg/day from a combined chronic/carcinogenicity study in rats. I ncreased chronic nephropathy in males and decreased

hema tological parameters in females were observed at the LOAEL of 18 mg/kg/day. Chronic mouse and dog studies were also considered for chronic dietary exposure; however, the chronic rat study provided the most sensitive endpoint for chronic dietary risk asses sment.

For assessing risks from short and intermediate

- term inhalation exposure, an oral NOAEL of 3 mg/kg/day based on cardiovascular effects i n fetuses seen at the LOAEL of 10 mg/kg/day in the rat developmental study was used. The short and intermediate

- term dermal PODs for adults are also based on adverse cardiovascular effects in fetuses at 100 mg/kg/day (NOAEL of 30 mg/kg/day) in a rat dermal developmental study. For children, short and intermediate

- term
dermal and incidental oral PODs were based on a NOAEL of 6.3 mg/kg/day for decreased pup body weight and testicular atrophy in F1 males observed at 12.7 mg/kg/day (LOAEL) in the rat

2

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

- term exposures (greater than 6 month s) are not anticipated based on the existing use
pattern.

The level of concern (LOC) for the relevant dermal and incidental oral exposure scenarios is an MOE of less than 100, based on the standard uncertainty factors for intraspecies variation (10X)

an d interspecies extrapolation (10X). For inhalation exposure scenarios, a 10X database uncertainty factor is applied due to the lack of an inhalation developmental toxicity study. Thus,

the LOC is MOEs less than 1000.

4 .5.2 Recommendation for Combinin g Routes of Exposure for Risk Assessment

When there are potential residential exposures to a pesticide, an aggregate risk as sessment must consider exposure from three major sources: food, drinking water and residential (oral, dermal and inhalation) exposu re pathways. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from vari ous sources, HED has considered both the route and duration of exposure. For the purpose of occupational exposures, the dermal and inhalation exposures can be aggregated because the same endpoint, fetal effects, was selected for risk assessment. Likewise , children’s dermal and oral exposures can be aggregated because the same offspring effects are being used to assess dermalPage 20 of 70

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

R esidential exposures should be combined with background exposure from food and water determined in the chronic dietary exposure assessment.

4 .5.3 Cancer Classification and Risk Assessment Recommendation

Based on the lack of evidence of carcinogenicity in mice and rats, flumioxazin is classi fied as “not likely to be carcinogenic to humans.” Therefore, there is no cancer risk associated with the existing or proposed uses of flumioxazin.

4 .5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Tables 4.5.1 and 4.5.2 summarize the points of departure and toxicity endpoints used in the dietary and occupational human health risk assessments, respectively.

Table 4 .5. 1

. Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Dietary and Non

Occ upational Human Health Risk Assessments Exposure/

Scenario Point of

Departure (POD) Uncertainty

/FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary

Females 13

- 49 only NOAEL = 3

mg/kg/day UF A =10x

UF H =10x FQPA

SF=1x Acute RfD = Acute PAD

= 0.03 mg/kg/day Oral Developmental and Supplemental Pre

- natal Studies (Rat) LOAEL = 10 mg/kg/day, based on

cardiovascular effects in fetuses.

Acute Dietary

General Population including infants

and child ren N o appropriate toxicological effects attributable to a single exposure (dose) were observed in oral

toxicity studies including maternal effects in developmental studies in rats and rabbits. Therefore, a dose and endpoint were not identified for this r isk assessment.

Chronic Dietary all populations NOAEL=

2.0 mg/kg/day UF A =10x

UF H =10x FQPA

SF=1x Chronic RfD = Chronic PAD

= 0.02 mg/kg/day 2

- Year Chronic/Carcinogenicity Study (Rat) LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in

male s and decreased hematological parameters in females.

Incidental Oral

- Short

- (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL=

6.3 mg/kg/day UF A =10x

UF H =10x FQPA SF =

1X Residential LOC for

MOE < 100 2

- Generation Reproduction Study (Rat)

LOAEL = 12.7 mg/kg/day, based on decreased pup body weight and testicular atrophy in F1 males.

Dermal

– NOAEL = UF A =10x Residential LOC for 2

- Generation Reproduction StudyPage 21 of 70

Table 4 .5. 1

. Summary of Toxicological Doses and Endpoints for Flumioxazin for Use in Dietary and Non

Occ upational Human Health Risk Assessments Exposure/

Scenario Point of

Departure (POD) Uncertainty

/FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Children

Short

- (1

- 30 days) and

Intermediate

Term (1

- 6 months) 6.3

mg/kg/day

DAF = 8% UF H =10x

FQPA SF =

1X MOE < 100 (Rat) LOAEL = 12.7 mg/kg/day, based on decreased pup body weight and testicular atrophy in F1 males.

Dermal

- Adults (All durations) NOAEL= 30

mg/kg/day UF A =10x

UF H =10x FQPA SF =

1X Residential LOC for

MOE < 100 Dermal Developmental Study (Rat) LOAEL = 100 mg/kg/day, based on

cardiovascular effects in fetuses.

Inhalation

Short

- (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL = 3

mg/kg/day (IAF = 100%) UF A =10x

UF H =10x FQPA SF =

1 0 X (database UF) Residential LOC fo r

MOE < 100 0 Oral Developmental Study (Rat) LOAEL = 10 mg/kg/day, based on

cardiovascular effects in fetuses.

Inhalation Long

- Term (> 6 months)

Inhalation NOAEL= 2

mg/kg/day (IAF = 100%) UF A =10x

UF H =10x FQPA SF =

1 0 X (database UF) Residential LOC for

MO E < 100 0 2

- Year Chronic/Carcinogenicity Study (Rat) LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males and decreased hematological parameters in females.

Cancer (oral, dermal, inhalation) “Not likely to be a carcinogen ic to humans,” b ased on the lack of carcinogenicity in a 2

- year rat

study, an 18

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

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

- response data and

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from anima l to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of expo sure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor. IAF = inhalation absorption factor.

Table 4 .5. 2

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

Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern for Risk

Assessment Study and Toxicological Effects

Dermal

- All

Durations NOAEL=

30 mg/kg/day UF A = 10X

UF H = 10X Occupational LOC for

MOE < 100 Dermal Developmental Study in

Rats LOAEL = 100 mg/kg/day based on

cardiovascular effects in fetuses.Page 22 of 70

Table 4 .5. 2

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

Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern for Risk

Assessment Study and Toxicological Effects

Inhalation

Short

- and

Intermediate

Term (1

- day up to 6 months) NOAEL= 3.0

mg/kg/day (IAF = 100%) UF A = 10X

UF H = 10X

UF DB = 10X Occupational LOC for

MOE < 100 0 Oral Developmenta l Study in Rats LOAEL = 10 mg/kg/day based on

cardiovascular effects in fetuses.

Inhalation Long

- Term Inhalation (>6 months) NOAEL =

2.0 mg/kg/day (IAF = 100%) UF A = 10X

UF H = 10X

UF DB = 10X Occupational LOC for

MOE < 100 0 2

- Year Chronic/Carcinogenicit y Study (Rat) LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males and decreased hematological parameters in females Cancer (oral, dermal, inhalation) “Not likely to be a carcinogen ic to humans,” based on the lack of carcinogenicity in a 2

- year rat study,

an 18

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

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

factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies)

, UF DB = database uncertainty factor for lack of inhalation developmental study . MOE = margin of exposure. LOC = level of concern. IAF = inhalation absorption factor.

4 .6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

determinations. Tier 1 co nsists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine rel ated effects caused by the substance, and

establish a dose

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

Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 5 8 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post

- application agricultural scenarios.

This list should not be construed as a list of known or likely endocrine disruptors. Flumioxazin is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pe sticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

- ins for all pesticide active ingredients.Page 23 of 70

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidel ines and the Tier 1 screening battery, please visit EPA’s website: http://www.epa.gov/endo/.

5.0 Dietary Exposure/Risk Characterization

5.1 Metabolite/Degradate Residue Profile

5.1.1 Sum mary of Plant and Animal Metabolism Studies

The nature of flumioxazin residues in plants and animals is adequately understood based on acceptable soybean, peanut, corn, sugarcane, grape, hen, and goat metabolism studies. The

nature of the residue in rota tional crops is also understood based on studies conducted on carrots, lettuce, and wheat. In primary and rotated crops, the residue of concern is only the parent compound. For ruminants, the residues of concern are parent, 3

- OH

- flumioxazin, 4

- OH

flumiox azin, plus Metabolites B, C, and F. For poultry, the residues of concern are parent, 3

- OH

- flumioxazin, 4

- OH

- flumioxazin, and 4

- OH

- S

- 53482

- SA.

Plant Metabolism

Adequate plant metabolism studies are available depicting the uptake and metabolism of [ 14 C]flumioxazin following applications to soybean (preemergence), peanut (pre

- emergence), corn (pre

- emergence), sugarcane (directed to the lower 3 feet of plants), and grapes (directed to soil surface surrounding vines). Based on these stu dies, HED determined that the parent compound only is the residue of concern to be used in risk assessments and the tolerance expression for primary and rotated crops. The available data are adequate to support the uses proposed herein.

Livestock Meta bolism

Adequate ruminant and poultry metabolism studies are available depicting the metabolism of flumioxazin radiolabeled in either the phenyl or tetrahydrophthaloyl (THP) ring. The metabolism of flumioxazin is similar in both ruminants and poultry, inv olving the hydroxylation and reduction of the cyclohexene ring in the THP moiety, hydrolytic cleavage of the imide and amide linkages, and incorporation of sulfonic acid into the THP moiety. HED has determined

that the residues of concern for ruminants sh ould include parent, 3

- OH

- flumioxazin, 4

- OH

flumioxazin, and Metabolites B, C, and F. For poultry, the residues of concern are parent, 3

- OH

flumioxazin, 4

- OH

- flumioxazin, and 4

- OH

- S

- 53482

- SA.

5.1.2 Summary of Environmental DegradationPage 24 of 70

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

7/21/2010

In the environment, flumioxazin photodegrades very rapidly in water and on soil (half

- lives = 1 and 5.8 days, respectively). Flumioxazin is classified a s having medium soil mobility potential. Its two major degradates (APF and THPA) are expected to be more mobile than the parent compound in the environment (Koc = 410 and 155, respectively). It has a log octanol/water partition coefficient of 2.55 , and is not expected to bioaccumulate in fish. Flumioxazin has a vapor pressure of 2.41 x10
– 6 mmHg, water solubility of 1.079 g/L , and an estimated Henry’s law

constant of 6.2 x10 - 7 atm

- m3/mol. Based upon its Henry’s law constant and vapor pressure,

flumioxazin is relatively volatile in water and on soil.

5.1.3 Comparison of Metabolic Pathways

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

discussed in Section 5.1.1.

The metabolic profile in plants is simila r in soybean, peanut, corn, sugarcane, and grapes. Further, the metabolism in ruminants, and poultry is also similar. In plants, the unchanged parent compound is the major residue . I n animals, the residues of concern for ruminants include parent, 3

- OH

- f

lumioxazin, 4

- OH

- flumioxazin, and Metabolites B, C, and F. For poultry, the residues of concern are parent, 3

- OH

- flumioxazin, 4

- OH

- flumioxazin, and 4

- OH

- S

- 53482

- SA.

In rats, m etabolism studies indicated that there was extensive biliary excretion follo wing oral

administration of flumioxazin. In addition to untransformed parent compound, a nalysis of feces and urine revealed up to 35 putative metabolites.

5.1.4 Residues of Concern Summary and Rationale

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

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

of flumioxazin and its metabolites APF (3

- oxo

- 4

- prop

- 2ynyl

- 6

- amino

- 7

- fluoro

- 3,4

- dihydro

- 1,4

- benzoxazin) and 482

- HA (N

- ( 7

- fluoro

- 3,4

- dihdyro

- 3

- oxo

- 4

- prop

- 2

- ynyl

- 2H

- 1,4

- benzoxazin

- 6

- yl)cyclohex

- 1

- ene

- 1

- carboxamide

- 2

- carboxylic acid) in freshwater fish. F lumioxazin and the

metabolites 482

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

Table 5.1.4 Summary of Me tabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop F lumioxazin F lumioxazin

Rotational Crop Flumioxazin Flum ioxazin

Livestock Ruminant Not Applicable Not Applicable

Poultry Not Applicable Not ApplicablePage 25 of 70

Table 5.1.4 Summary of Me tabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Freshwater Fish Flumioxazin, APF, 482

- HA Flumioxazin, APF, 482

- HA

Drinking Water Flumioxazin, APF, 482

- HA Flumioxazin

5.2 Food Residue Profile

Acce ptable field trial data on canola, field pea, sunflower, and wheat were submitted reflecting the proposed use patterns for the 51% WG formulation s; the submitted field pea data will support the proposed use on lentil. Spray adjuvants, including methylated seed oil s (MSO s ),

non

- ionic surfactant s (NIS s ), and/or crop oil concentrates (COC s ) were used in all trials. The

maximum residues of flumioxazin were 0. 25 ppm in/on canola, 0.06 5 ppm in/on dried pea, 0. 34 ppm in/on sunflower seed, and 0.3 1 and 3. 95 ppm i n/on wheat grain and straw (foliar, harvest

aid use pattern); r esidues of flumioxazin were below the LOQ (<0.02 ppm) in/on all samples of wheat forage and hay (pre

- plant use pattern).

T he submitted canola, sunflower, and wheat processing studies, reflec ting application at ~5x the maximum proposed seasonal application rates are adequate

. The data indicate that residues of

flumioxazin do not concentrate in canola oil or meal, sunflower oil or meal, or wheat bran, flour, middlings, shorts, or germ. F lumio xazin may concentrate in wheat aspirated grain fractions (AGF), with a processing factor of 308x. T he available data indicate that tolerances are not needed for the regulated commodities of canola, sunflower, and wheat; however

, a tolerance is needed for g rain, aspirated fractions at 100 ppm.

The previously submitted confined rotational crop study is adequate for the proposed uses on the requested crops. Based on the results of the confined accumulation study, HED concludes that the existing rotational c rop plant back intervals (PBIs) are acceptable, and that field trials and tolerances are not necessary.

5.3 Water Residue Profile

Reference: Drinking Water Assessment for the proposed use of Flumioxazin as an Aquatic Herbicide, D357184, L. Liu , 7/21/20 10.

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

- end, conservative EDWCs based on the aquatic application rates of the herbicide , which are higher than the EDWC from the current proposed uses . These EDWCs included

concentrations of flumioxazin and its major degradates (482

- HA, APF

, and THPA) . The resulting values were 400 pp b ( peak day

- 0) for acute exposure and of 142 pp b (30

- days) for chronic exposure

. Table 5.3 lists degradates identified and thei r relative concentrations. ThePage 26 of 70

model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5.3

. Summary of Estimated Drinking Water Conce ntrations ( E DW Cs ) (ppb) From the Subsurface Application of Flumioxazin as an Aquatic Herbicide Compound Acute E WD C (Day 0) ppb Chronic E WD C at

Days 30 and after 1

ppb

Flumioxazin 400 10.4

482

- HA

- 21.6

APF

- 110.1

THPA

- 88.9

1 Total E E C = Flumioxazin + 482

- HA + APF

5.4 Dietary Risk Assessment

Flumioxazin. Acute and Chronic Dietary (Food and Water) Exposure and Risk Assessments for the Proposed Uses on Field Pea, Flax, Lentil, Sunflower, Safflower, and Wheat Commodities. S. Piper. 8 /12. D401806

A u un refined and health protective acute and chronic dietary exposure and risk assessment was

conducted for flumioxazin

. High end modeled drinking water estimates were directly incorporated into the assessment. In order to assess short

- term aggregate risk to flumioxazin

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

5.4.1 Description of Residue Data Used in Dietary Assessment

The flumioxazin dietary exposure and risk assessment was conducted considering all suppor ted food uses and drinking water. The assessment was conducted using the Dietary Exposure

Evaluation Model DEEM

- FCIDTM, Version 2.03 , which incorporates consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals ( USDA’s

CS FII ) , 1994

- 1996 and 1998. For all commodities the assessment used current tolerances

. Drin king water information was incorporated directly into the dietary assessment using the acute and chronic EDWCs for the aquatic use of 400 ppb and 142 ppb, respectively

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using conservative assumptions

, 100% or all crops are treated with flumioxazin.Page 27 of 70

5.4.3 Acute Dietary Risk Assessment

An unrefined, acute dietary exposure assessment using tol erance levels, processing factors, and assuming 100% crop treated (CT) for the proposed commodities was conducted for the general U.S. population and various population subgroups . The estimated drinking water concentration of flumioxazin was provided by t he Environmental Fate and Effects Division (EFED) and incorporated directly into the acute assessment. An estimated environmental concentrations (EECs) for flumioxazin and its major degradates (482

- HA and APF) under the use as an aquatic

herbicide of 400 ppb was estimated for acute exposure.

There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population or any other population subgroups except females 13

- 49 years old ; therefore

, these population subgrou ps were not included in this assessment. For food and drinking water, the acute dietary risk estimate is below HED’s level of concern (<100% of the acute population adjusted dose (aPAD)) at the 95 th percentile of exposure. The acute dietary exposure estim ate for

females 13

- 49 years old is 0.0 20349 mg/kg/day ( 68 % of the aPAD)

.

5.4.4 Chronic Dietary Risk Assessment

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

, residues are present at t olerance levels, and empirical or default processing

factors are used. The EECs for flumioxazin and its major degradates (482

- HA and APF) under the use as an aquatic herbicide is 142 ppb. C ombined chronic diet ary exposure estimates for food and drinking water are well below HED’s level of concern. Using the DEEM

- FCID software, dietary exposure is estimated at 0.0 03976 mg/kg/day for the general U.S. population, which is equivalent to 20 % of the chronic Populati on Adjusted Dose (cPAD), and 0.01 0863 mg/kg/day, equivalent to 54 % of the cPAD for all infants (< 1year old ) , the population subgroup with the highest estimated chronic dietary exposure to flumioxazin

.

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

Population Subgroup Acute Assessment (95 th Percentile) Chronic Assessment

aPAD, mg/day Exposure Estimate,

mg/day %

aPAD cPAD,

mg/day Exposure Estimate,

mg/day % cP AD

U.S. Population

N/A 0.02 0.003288 16

All infan ts 0.02 0.010257 51

Children 1

- 2 yrs 0.02 0.005231 26

Children 3

- 5 yrs 0.02 0.004875 24

Children 6

- 12 yrs 0.02 0.003333 17

Youth 13

- 19 yrs 0.02 0.002412 12

Adults 20

- 49 yrs 0.02 0.003015 15 Adults 50+ yrs 0.02 0.003171 16

Females 13

- 49 yrs 0. 0 3 0.01 9736 66 0.02 0.00 3007 15Page 28 of 70

As conservative, health

- protective assumptions were made in both the acute and chronic dietary exposure analyses, a ctual dietary exposures and risks from f lumioxazin are likely to b e much lower than the values generated in the acute and chronic analyses. HED is confident that exposure to flumioxazin is not underestimated for the general U.S. population or any population subgroup.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

The details regarding t he assumptions and calculations used to evaluate residential exposure and risk are described in a separate memo ( D391784, M. August 2012). However, unless otherwise stated, HED incorporated standard assumptions typically used for assessing residential exp osure and risk.

Residential exposure to flumioxazin is not anticipated from the proposed Section 3 uses; however, residential exposure is anticipated from currently registered uses of the chemical. Exposures are expected for individuals (adults) who appl y flumioxazin

- containing products and from post

- application exposure to adults and children in residential areas previously treated with the chemical. In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks anticipated from food, drinking water, and residential exposures. An updated

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

flumioxazin aggregate risk because of revision s to the Residential SOPs.

T here are currently register ed uses of flumioxazin on several residential use si tes, including turf

, gardens and trees, and aquatic weeds , etc. Each of these existing residential use patterns has previously been assessed however ; these residential uses have been reassessed to reflec t the updates to residential exposure assessment in the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment

. Specifically, the

Lawn/Turf SOP and the Garden and Trees SOP have been utilized in this ass essment. S ome of

the data included in these SOP s are proprietary and thus are subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)

.

6.1 Handlers

The Agency uses the term “handlers” to describe th ose individuals who are involved in the pesti cide application process. HED has determined that short

- term dermal and inhalation exposure to residential handlers is likely during use of the following flumioxazin uses: the registered outdoor ornamental (ga rden and trees) , and turf uses.

Residential handler dermal and inhalation risk estimates for flumioxazin are not of concern to HED (i.e., MOEs are ≥ 100 for dermal and ≥ 1,000 for inhalation, the levels of concern (LOC) for these assessments).Page 29 of 70

HED’s level of concern for adult residential handlers is eq ual to an ARI of 1. The combined dermal and inhalation risk estimates (ARIs) to residential handlers for the identified residential outdoor (i.e., ARIs are ≥ 1). The lowest ARI is 5.5 from use of a b el ly grinder equipment to treat

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

document.

6.2 Post

- application Exposure

6.2.1 Non

- Occupational /Re sidential Exposure

The Agency uses the term “ post

- application ” to describe exposures to individuals that occur as a result of being in an environment that has been previ ously treated with a pesticide. Flumioxazin can be used in areas frequented by the general population, including outdoor residential areas.

As a resul t, HED anticipates post

- application exposures from the residential use of flumioxazin

. The same high end outdoor uses assessed for handlers were assessed for residential post

application exposure assessment. Residential post

- application risks are based o n maximum application rates o r values specified in the SOPs f or Residential Exposure Assessment.

Short

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

flumioxazin. Dermal and oral exposures were not combined as the toxi cological effects from the dermal and oral routes of exposure are different . The scenarios, routes of exposure and lifestages assessed include:

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

Mowi ng: adults (dermal) and children 11 < 16 years old (dermal); Golfing: adults (dermal), children 11 < 16 years old (dermal), and children 6 < 11 years old (dermal); and Gardens and Trees: adults (dermal) and children 6< 11 years old (dermal).

Based on th e SOPs for Residential Exposure Assessment and the uses specified in the proposed labels, the following residential post

- application exposure scenarios have been evaluated:

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

• Oral Dos e from hand

- to

- mouth activity from treated turf (children)

• Oral Dose from object

- to

- mouth activity from treated turf (children)

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

Adult residential post

- application dermal exposures assesse d for the registered outdoor uses are not of concern to HED. The greatest estimated risk for adults corresponded to an MOE = 130 for
post

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

dermal and incidental oral risk estimates for the identified residential uses are not of concern to HED (i.e., MOEs are ≥ 1 00, the LOC for these assessments). The greatest estimated risk for children corresponds to a MOE of 290 for children <1 to 2 years old contacting treated turf. A summary of these results is presented in Table 6.1 below.Page 30 of 70

Table 6.1 Short

- and Intermediate

- Term Residential Post

- application Exposure a nd Risk Estimates for

Flumioxazin.

Liquid Formulations
Lifestage Post

- application Exposure Scenario Dose a MO Es b

Adult

Turf

- sprays Physical Activities on

Turf 0.17 180

Mowing 0.0034 8,900
Golfing 0.013 2,300

Child 11 < 16 years old Mowing 0.0034 9,000
Golfing 0.013 2,300

Child 6 < 11 years old Golfing 0.0 01 (g) 5

, 1 00

Child 1 < 2 years old Physi cal Activities on

Turf 0. 02 (g) 290

Hand to Mouth 0.0057 1,100
Object to Mouth 0.00017 36,000
Incidental Soil Ingestion 1.2E

- 05 510,000

Adult

Garden

- sprays 0.238 130

Child 6 < 11 years old 0. 011 (g) 560

Adult

Tree

– sprays 0.022 1,400

Child 6 < 11 years old 0.0 01 (g) 6,100

a

. Dermal Dose (mg/kg/day) = TTR (μg/cm 2 ) x 0.001 (mg/μg) x short

- term TC (cm 2 /hr) x ET (hr/day) x DAF (40%) BW (kg)

b

. Dermal MOE = NOAEL (3 0 mg/kg/day for adults and 6.3 mg/kg/day with 8% dermal absorption fac tor for children / Dermal Dose (mg/kg/day)

c

. Hand

- to

- Mouth Dose (mg/kg/day) = E = [HR * ( F M * SA H ) * (ET * N_Replen) * (1

- (1

- SE ) (Freq_Replen/N

- Replen) )]

d . Object

- to

- Mouth Dose (mg/kg/day) = E = [OR* CF1 * SAM O * (ET * N_Replen) * (1

- (1

- SE O ) (Freq_Re plen/N_Replen) )]

e

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

f

. Oral MOE = NOAEL (6.3 mg/kg/day) / Oral Dose (mg/kg/day) g. Dermal absorbed dose adjusted for 8% dermal absorption for comparison with oral NOAEL of 6.3 mg/kg/day for children

.

A summary of the previously assessed short

- and intermediate

- term residential post

- application risk estimates for the currently registered aquatic uses are included in Table 6.2. Using the SWIMODEL, a ll short

- and intermediate

- term residential post

- app lication MOEs for swimmers are greater than 100 0 (ranged from 2,300 to 190 ,000) and are not a concern to HED. (S. Wang, DP 358360, 4/20/09).

Table 6.2 Recreational Swimmer Exposures and Risks

Exposed

Person Route of

Exposure Water

Concentration (mg/L) Dose

(mg/kg/day) NOAEL

(mg/kg/day) MOE a

Child

- 22 kg Oral 0. 4 0.002727 6.3 2,300

Dermal 0. 4 0.000417 6.3 with 8% DA 190,000

Adult

- 6 0 kg Oral 0. 4 0.001 6.3 6,300Page 31 of 70

Table 6.2 Recreational Swimmer Exposures and Risks

Exposed

Person Route of

Exposure Water

Concentration (mg/L) Dose

(mg/kg/day) NOAEL

(mg/kg/day) MOE a

Dermal 0. 4 0.000357 30 84,000

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

6.3 Combined Exposure

Table 6. 3 below presents the combined risk estimates for the uses resulting in the highes t potential for residential handler and post

- application exposures. A summary of the high

- end residential exposure estimates are provided in Table 6. 3 . The residential post

- application exposure was selected for the adult females only and it was not combi ned with the residential handler exposure because individuals would not conduct both of these activities at the same time.

Table 6. 3

. Combined Short

- and Intermediate

- Term Residential Exposures for the Flumioxazin Aggregate

Assessment.

Population Ha ndler Exposure

(mg/kg/day) 1 Residential

Handler Total Exposure (mg/kg/day) 3 Post

- application Exposure

(mg/kg/day) 2 Recommended Post

application Exposure for Aggregate (mg/kg/day) 3 Dermal Inhalation Dermal Inhalation Oral

Adult Female 0.0 5 4 0.0000 0 5 8 0 .05 4 0.238 N/A N/A 0.238

Child N/A N/A N/A 0. 02 N/A 0.0057 0. 02 6

1 Handler exposure represents high

- end handler exposure, where the appropriate duration is appropriate to assess. Handler exposure represents granular belly grinder for gardens and trees.

2 P ost

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

duration. Post

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

- application exposure for child

represents Hand

- To

- Mouth exposure and risk

3 For adults, residential total exposure combines the highest d ermal and inhalation exposures , where applicable. For young children, total residential exposure combines high

- end post application incidental oral AND de rmal e xposure, where applicable

. Handler exposures should not routinely be combined with post

- application exposures. NOTE: The highest estimated total residential exposure (for adults and child populations) should be used as the basis of the aggregate assessme nts.

6.4 Residential Bystander Post

- application Inhalation Exposure

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, coul d also be a potential source of exposure from the ground application method employed for flumioxazin . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to d evelop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and isPage 32 of 70

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard air blast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift

manag ement practices to reduce off

- target drift with specific products with significant risks

associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neigh boring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario , for which no risks of concern were identified, is representative of a worse case inhalation (drift) exposure and may be considered pr otective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate flumioxazin pesticide exposures and risks fro m three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

While residential exposure to flumioxazin is not anticipated from the proposed Section 3 uses, it is anticipated from currently registered turf and ornamental uses of the chemical. As such, the

short

- term aggregate exposure and risk assessment of flumioxazin includes dietary (food and water) exposures anticipated from the proposed Section 3 uses and high end, non

- dietary

exposures anticipated from currently registered residential uses.

For the purpose of residential exposures, the dermal and inhalation exposures can be aggregated because the same endpoint, fetal effects, was selected for risk assessment. R esidential exposures should be combined with background exposure from food and water determined in the chronic dietary exposure assessment. Likewise, children’s dermal and oral exposures can be aggregated

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

7.1 Acute Aggregate Risk

Acute aggregate risk s 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 ri sk estimate for the population subgroup Females 13

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

concern

.Page 33 of 70

7.2 Short

- Term Aggregate Risk

The short

- term aggregate exposure assessm ent includes exposures anticipated to occur from one to thirty days from dietary (food and water) and non

- dietary, residential exposures from current and pending uses of flumioxazin. In order to aggregate short

- term residential uses with dietary

exposure, it was necessary to calculate average dietary exposure. Risk estimates (MOEs) were calculated by comparison of the short

- term oral NOAEL to average dietary exposures for all populations

.

HED combines risk values resulting from separate residential exp osure 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 poten tial for the same individual (i.e. adult) to apply a pesticide in and around the home and be exposed by reentering a treated area (i.e. home lawn or golf course) in the same day, this is an unlikely exposure scenario, especially day after day for up to

30 days. Combining both of these exposure scenarios would also be inappropriate because of the conservative nature of each individual assessment. Therefore, HED used the worst case residential scenario for adults, which was the adult (dermal) post

- applicati on exposure (MOE

= 130) for liquid formulations applied to turf.

The combined residential exposure for children is based on post

- application dermal and oral

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

rep resents the worst case scenario. Therefore it is HED’s policy not to combine object

- to

– mouth or soil ingestion with the hand

- to

- mouth exposure value as combining scenarios would be inappropriate because of the conservative nature of each individual assess ment.

Different methodologies were used for the presentation of short

- term aggregate risk for adults and children. An ARI approach was required to estimate short

- term adult aggregate risk because

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

For short

- term child aggregate risk, the combined MOE approach was used because the endpoint of concern (decreased pup weight) and the levels of concern (LOC) are the same.

Please refer to the residential assess ment, Section 6. 3 , for a discussion regarding the exposures that are likely to be combined.

Short

- term aggregate risk estimates (ARIs) for adult females (13

- 49 yrs) (to protect for potential fetal effects), are not of concern to HED (i.e., ARIs are ≥ 1). Table 7.1, below, summarizes the

results from the short

- term aggregate for adults.

Short

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

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

summarizes the results from the short

- term aggregate assessment of children 1 < 2 years old.

Table 7.1 Short

- Term Adult Aggregate Risk Calculations 1

Population Short

- Term Exposure Sce narioPage 34 of 70 Dietary Exposure 2 Dermal Residential

Exposure 3 Inhalation Residential Exposure 4 Aggregate ARI

(food, water,

and residential) 5 MOE ARI MOE ARI MOE ARI
Adult Female

13

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

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

2. MOE di etary = [(short

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

- term oral NOAEL is 3 mg/kg/day to protect for fetal effects in pregnant women. Average dietary exposure is 0.003007 mg/kg/day for Adults 13

- 49 years old (See Table 5.2). The MOE target is 100.

3. MOE dermal = [(short

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

- term dermal NOAEL is 30 mg/kg/day

. The target MOE is 100. See Table 6.3 for residential exposure values used in aggregate assessment

. 4. MOE inhalation = [(short

- term inhalation NOAEL)/(high end inhalation residential exposure)]. ARI inhalation = [(MOE inhalation)/(MOE tar get)]. Short

- term inhalation NOAEL is 3 mg/kg/day

. The target MOE is 1,000. See

Table 6.3 for residential exposure values used in aggregate assessment

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

Table 7.2 Short

- Te rm Child Aggregate Risk Calculations

Population Short

- Term Exposure Scenario

LOC for Aggregate

Risk 1 Dietary

MOE 2 M OE Oral

Residential Exposure 3 M OE

Dermal

Residential Exposure 4 M OE

Inhalation

Residential Exposure 5 Aggregate

MOE (food, water, and

resi dential) 6

Child 1 < 2

Years Old 1 00 614 1, 1 00 2 42 NA 1 5 0

1. LOC is an MOE = 100 ( 10X inter

- and intra

- species uncertainty factors totaling 100 ).

2. MOE dietary = [( short

- term oral NOAEL )/( average dietary exposure)]. Short

- term oral NOAEL is 6.3 mg/ kg/day. Average dietary exposure is 0.010257 for children < 1 years old (See Table 5.2).

3. MOE oral = [(short

- term incidental oral NOAEL)/( high end residential incidental oral exposure)]. Short

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

for source of residential exposure values used in aggregate assessment

. 4. MOE dermal = [(short

- term dermal NOAEL)/(high end dermal absorbed dose residential exposure)]. Short

- term
dermal NOAE L is 6.3 mg/kg/day, with 8% dermal absorption factor (i.e., 0.02 6 mg/kg/day as dermal absorbed dose) . See Table 6.3 for source of residential exposure values used in aggregate assessment

. 5. NA = Not applicable

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

7.3 Intermediate

- Term Aggregate Risk

The inte rmediate aggregate is identical to the short

- term aggregate assessment because the same points of departure were chosen for short

- term and intermediate

- term exposures; theref ore, risks are the same for all durations of exposure.

7. 4 Long

- Term Aggregate Risk

The chronic aggregate risk assessment consists of risks resulting from exposure to residues in food, drinking water, and residues resulting from long term exposure through residential applications. However, there are no residential uses that would result in long

- term exposure to any population subgroup. As a result , chronic aggregate risk consists of risks resulting from
exposure t o residues in food and drinking water alone. The chronic dietary exposure analysis included both food and drinking water , so the chronic aggregate risk assessment is equivalent to

the chronic dietary risk assessment discussed in Section 5. 4

. 4 , above . All risk estimates are not
of concern.

8.0 Cumulative Risk Characterization/Assessment

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “ available information concerning the cumulative effects” of a particular pesticide ’ s residues and “ other substances that have a common mechanism of toxicity.”Page 36 of 70

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to flu mioxazin and any other substances

, and flu mioxazin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this regulatory action, therefore,

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

substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have
a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

Reference: Flumioxazin : Occupational and Residential Exposure Assessment for A Proposed Use on Field Peas, Flax, Lentils, Sunflower, Safflower, and Wheat. D 391784, M. Hawkins

, August 2012

.

HED has determined that there is the potential for both occupational handler and post

- application exposure to occur from the proposed Section 3 uses of f lumioxazin

.

9.1 Handlers

Occupational exposure is expected for handlers who apply f lumioxazin 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

label s. 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, HE D only calculated short

- term handler exposures and risks, which are protective of

intermediate

- term exposure and risk. Typical assumptions regarding the acres treated and the length of a work day were used to derive the exposure estimates, along with a bo dy weight of 69 kg, and assuming the maximum application rate for each scenario.

Chemical

- specific data were not submitted to the Agency in support of the Section 3 application

. It is the policy of HED to use the best available data to assess handler e xposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposu re Task Force (AHETF) database , or other reg istrant

- submitted occupational exposure studies. Some of these data are proprietary ( e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this a ssessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf), which, along with additional information on HED policy on u se of surrogate data, including descriptions of thePage 37 of 70

various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html

.

A quantitative exposure/r isk assessment was developed for occupational handlers based on the following exposure scenarios:

Mixer/Loader Mixing/loading dry flowables for aerial applications Mixing/loading dry flowables for groundboom applications

Applicator Applying sprays for ae rial applications Applying sprays for groundboom applications

Flagger Flagging for aerial spray applications

Th e handler exposure estimates in this assessment are based on a central tendency estimate of unit exposure and an upper

- percentile assumption f or the application rate, and are assumed to be representative of high

- end exposures. The uncertainties associated with this assessment stem from the use of surrogate exposure data (e.g., differences in use scenario and data confidence), and assumptions re garding th e amount of chemical handled. The estimated exposures are believed to be reasonable high

- end estimates based on observations from field studies and professional judgment.

All Section 3 occupational handler scenarios assessed are not of concern to HED (i.e., ARIs are
≥ 1 ) with baseline attire ( i.e ., single layer of clothing, no respirator)

, except for mixing/loading dry flowables for aerial applications at baseline

. For this scenario, the ARI is greater than 1 , and

not of risk concern when engineering controls (closed systems) are applied. Table 9.1 presents a summary of the short

- and intermediate

- term occupational handler exposures and risks from the Section 3 proposed uses.Page 38 of 70

Table 9.1 Short

- /Intermediate

- Term Occupational Handler Exposure and Risk Estima tes for Flumioxazin

.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) a Inhalation Unit

Exposure (ug/lb ai) b Maximum

Application

Rate b Area

Treated or

Amount

Handled Daily c Dermal Inhalation Total

Mitigation Level Mitigation Level Do se (mg/kg/day) d MOE e Dose (mg/kg/day) f MOE g ARI h

Mixer/Loader

Mixing/Loading Dry

Flowable for Aerial Applications Field Peas, Flax, Sunflower, Safflower,

Lentils 51.6 8.96 0.09 1200 0.081 370 0.014 210 0.2 i 6 j

Mixing/Loading Dry

Flowable for Aeria l Applications Wheat

51.6 8.96 0.06 1200 0.054 560 0.0093 320 0.3

Mixing/Loading Dry

Flowable for Groundboom Applications Field Peas, Flax, Sunflower, Safflower,

Lentils 51.6 8.96 0.09 200 0.013 2,200 0.0023 1,300 1.2

Mixing/Loading Dry

Flowable for Groundboom Applications Wheat

51.6 8.96 0.06 200 0.009 3,300 0.0016 1,900 1.8

Applicator

Applying Sprays via Aerial Equipment (Engineering Controls) k Field Peas, Flax, Sunflower, Safflower,

Lentils 5 0.068 0.09 1200 0.0078 3,800 0.00011 28 ,000 3,400

Applying Sprays via Aerial Equipment (Engineering Controls) k Wheat 5 0.068 0.06 1200 0.0052 5,800 0.000071 42,000 5,100

Applying Sprays via Groundboom Equipment Field Peas, Flax, Sunflower, Safflower,

Lentils 16.1 0.34 0.09 200 0.0042 7,100 0.000089 34,000 23

Applying Sprays via Groundboom Equipment Wheat 16.1 0.34 0.06 200 0.0028 11,000 0.000059 51,000 34Page 39 of 70

Table 9.1 Short

- /Intermediate

- Term Occupational Handler Exposure and Risk Estima tes for Flumioxazin

.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) a Inhalation Unit

Exposure (ug/lb ai) b Maximum

Application

Rate b Area

Treated or

Amount

Handled Daily c Dermal Inhalation Total

Mitigation Level Mitigation Level Do se (mg/kg/day) d MOE e Dose (mg/kg/day) f MOE g ARI h

Flagger

Flagging for Aerial Sprays Applications Field Peas, Flax, Sunflower, Safflower,

Lentils 12 0.35 0.09 350 0.0055 5,500 0.00016 19,000 14

Flagging for Aerial Sprays Applications Wheat

12 0.35 0.06 350 0.0037 8,200 0.00011 28,000 21

a. PHED/ORETF (level of mitigation: single layer of PPE, gloves)

. b. Based on proposed label (Reg. No. 59639

- 99, 59639

- 119).

c. Ex posure Science Advisory Council Policy #9.1.

d. Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) x DAF (%) / BW (kg).

e. Dermal MOE = Dermal NOA EL (mg/kg/day)/Dermal Dose (mg/kg/day).

f. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal ) x Area Treated or Amount Handled (A or gal/day) / BW (kg).

g. Inhalation MOE = Inhalation NO AEL (mg/kg/day)/ Inhalation Dose (mg/kg/day).

h. ARI = 1/(1/RI dermal )+ (1/RI inhalation )

. i. Level of mitigation: single layer of PPE, gloves, no respirator j. Level of mitigation: engineering controls for dermal and inhalation; ARI does not exceed 1 until eng ineering controls are used.

k. Enclosed cockpits are expected to be used for aerial application

.Page 40 of 70

9.2 Post

- application Exposure and Risk

HED has determined that there is the potential for post

- application dermal exposure to flumioxazin following application to the proposed S ection 3 uses. Post

- application exposure may occur when workers enter previously treated areas to perform job functions. Re

- entry workers are expected to experience short

- term exposure to flumioxazin while performing post

application activities such as s couting and irrigation.

Chemical

- specific dislodgeable foliar residue (DFR) studies for flumioxazin are not available. It is the policy of HED to use the best available data to assess post

- application exposure. Sources of generic post

- application data, used as surrogate data in the absence of chemical

- specific data, are derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values

re commended for use in predicting post

- application exposure that are used in this assessment, known as “transfer coefficients”, are presented in the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” ( http://www.epa.gov/pesticides/science/exposac_policy3.pdf ), which, along with additional information about the ARTF data, can be found at http://www.epa. gov/pesticides/science/post

- app

- exposure

- data.html

.

The results of the post

- application exposure and risk assessment indicate that MOEs > 100 are achieved on Day 0 (12 hours) for all potential post

- application activities and, therefore, are not of

concer n. The post

- application activity scenarios along with respective TCs and risk estimates for

short

- term MOEs are summarized in Table 9.2.

Table 9.2 : Summary of Occupational/Commer cial Post

- application Risks for Flumioxazin

.

Crop/Site Activities DFR Day 0 MOE (a) Day X at which MOE ≥ LOC

of 100

Short

- term and Intermediate

- term

Field Peas Scouting 0.252 930 N/A

Field Peas Hand Set Irrigation 0.252 540 N/A

Flax Scouting 0.252 930 N/A

Lentils Scouting 0.252 930 N/A

Lentils Hand Set Irrigation 0. 252 540 N/A

Safflower Hand Weeding 0.252 15,000 N/A

Safflower Scouting 0.252 930 N/A

Safflower Hand Set Irrigation 0.252 540 N/A

Sunflower Scouting 0.252 11,000 N/A

Wheat Hand Weeding 0.168 22,000 N/A

Wheat Scouting 0.168 1,400 N/A
DFR = Dislodgeab le Foliar Residue (a) LOC for dermal MOE is > 100.Page 41 of 70

9. 3 Inhalation Post

- application Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for flumioxazin at this time primarily becau se of the low acute

inhalatio n toxicity ( Toxicity Category I V ), low vapor pressure ( 2

. 41 x 10

- 6 mmHg at 25o C), and the low proposed use rate (0. 09 lb ai/A). However, there are multiple potential sources of
post

- application inhalation exposure to individ uals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on iss ues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational
post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures ar e put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for flumioxazin

.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an i nhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that the se handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10.0 References

Flumioxazin : Occupational and Residential Exposure Assessment for A Proposed Use on Field Peas, Flax, Lent ils, Sunflower, Safflower, and Wheat. M. August 2012.

Acute and Chronic Dietary (Food and Water) Exposure and Risk Assessments for the Proposed Uses on Field Pea, Flax, Lentil, Sunflower, Safflower, and Wheat Commodities. S. 8 /12.

D401806

Flumioxazi n. Petition for the Establishment of Permanent Tolerances for Use on Field Pea, Flax, Lentil, Sunflower, Safflower, and Wheat Commodities. Summary of Analyt ical Chemistry and Residue Data, D391781, S. 8 /2012.Page 42 of 70

Drinking Water Assessment for a Section 3 New Use for Flumioxazin End

- Use Products Chateau WDG and Valor WDG Applications to Wheat, Sunflower, Safflower, Flax, Lentils, and

Field Peas , D392618, L.Liu, 3/21/2012.

Drinking Water Assessment for the proposed use of Flumioxazin as an Aquatic Herbicid e, D357184, J. Stone, 7/21/2010.

Flumioxazin. Human Health Risk Assessment for the Proposed Uses on Turfgrass and Forest

Sites. D380073, D. Dotson, K. Middleton, S. Wang, M. Collantes, 6/8/ 20 11

Flumioxazin. Human Health Risk Assessment for a Proposed Aquatic Use

. PC Code: 1290 34

, Petition No: 8 E7 4 3 8 , DP Barcode: D3 79028, B. Hanson, 7/14/2010Page 43 of 70

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for flumioxazin are in the t able below

. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ..... 870.1200 Acute Dermal Toxicity

................................ . 870. 1300 Acute Inhalation Toxicity

............................ 870.2400 Primary Eye Irritation

................................ .. 870.2500 Primary Dermal Irritation

............................. 870.2600 Dermal Sensitization

................................ .... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

............................. 870.3150 Oral Subchron ic (nonrodent)

....................... 870.3200 21

- Day Dermal

................................ ............. 870.3250 90

- Day Dermal

................................ ............. 870.3465 90

- Day Inhalation

................................ ........ yes

yes

yes

no

no yes

yes

yes

no

no

870.3700a Developmental Toxicity (rodent)

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

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

................................ ................ y es

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

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

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

................................ .. 870.4300 Chronic/Oncogenicity

................................ .. yes

yes

yes

yes

yes yes 1

yes

yes 1

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

... 870.5375 Mutagenicity

— Gene Mutation

– CHO cells 870.5395 Mutagenicity

— In vivo rat bone marrow

..... 870.5550 Mutagenicity

— Other Genotoxic Effects

UDS assay

................................ ................................ ....... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute De layed Neurotox. (hen)

................... 870.6100b 90

- Day Neurotoxicity (hen)

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

...... 870.6200b 90

- Day Neuro. Screening Battery (rat)

........ 870.6300 Develop mental Neuro tox

............................. no

no

yes

yes

no -

-

yes

yes

-Page 44 of 70 Test Technical

Required Satisfied

870.7485 General Meta bolism

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

................................ ...... 870.7 8 00 Immunotoxicity

................................ ............ y es

yes

yes yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

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

................................ .... Six

- month Oral (dog)

................................ .... no

-

1 Requirements for 870.4100a and 870.4200a are satisfied b y the receipt of an acceptable/guideline combined chronic/carcinogenicity study in rats (870.4300.)Page 45 of 70

A.2 T oxicity Profiles

Table A. 2.a. Acute Toxicity Profile for Flumioxazin

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acu te oral [rat] 42684911 LD 50 >5000 mg/kg

M & F IV

870.1200 Acute dermal [rat] 42684913 LD 50 >2000 mg/kg III

870.1300 Acute inhalation [rat] 42684915 LC 50 =3.93 mg/L IV

870.2400 Acute eye irritation [rabbit] 42684917 Not an ocular irritant III

870.2500 Ac ute dermal irritation [rabbit] 42684917 Non

- irritating IV

870.2600 Skin sensitization [guinea pig] 42684921 Non

- sensitizer N/APage 46 of 70

Table A.2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Dose s Results

870.3100 90

- Day oral

toxicity

- rat 42684923

dose levels: 0, 2.3, 20.7, 69.7, and 243.5 mg/kg/day (M) and 0, 2.2, 21.7, 71.5, and 229.6 mg/kg/day (F) NOAEL = 69.7 (M), 71.5 (F) mg/kg/day

LOAEL = 243.5 (M), 229.6 (F) mg/kg/day based on a

decre ase in MCV both sexes; increase in platelets F only.

870.3100 90

- Day oral

toxicity

- rat 42683922

dose levels: 0, 1.9, 19.3, 65.0, and 196.7 mg/kg/day (M) and 0, 2.2, 22.4, 72.9, and

218.4 mg/kg/day (F) NOAEL = 65.0 (M), 72.9 (F) mg/kg/day LOAEL =

196 .7 (M), 218.4 (F) mg/kg/day based on hematology changes.

870.3100 90

- Day oral

toxicity

- mouse MRID unknown (referred

to in 79

- week study, MRID 44295018)

dose levels: 0, 143, 429, or 1429 (M & F) mg/kg/day NOAEL = 429 mg/kg/day LOAEL = 1429 mg/kg/day b ased on increased liver weight in males.

870.3100 4

- Week oral

toxicity

- mouse 44307301 (see MRID

44295018 DER#2)

dose levels: 0, 151.5, 419.9 or 1366.5 (M) and 0, 164.5, 481.6 or 1698.3 (F) mg/kg/day NOAEL = 151.5 (M), 164.5 (F) mg/kg/day

LOAEL = 419.9 (M), 481.6 (F) mg/kg/day based on increased absolute &/or relative liver weights in M & F.

870.3150 90

- Day capsule

-

dog 42684924

dose levels of 0, 10, 100, or 1000 mg/kg/day NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on dose dependent

increase in total cholesterol, phospholipid & alkaline phosphatase activity.

870.3200 21

- Day dermal

toxicity

- rat 44295016

dose levels: 1, 100, 300, or 1000 mg/kg/day NOAEL = mg/kg/day: 1000 (LIMIT DOSE) LOAEL = mg/kg/day: >1000 based on no effects.

870.3465 28

- Day inhalation

toxicity (species) Not Required

870.3700a Pre

- natal

developmental

- rat (oral) (1)42684930 (pilot study);

42684925 (main study); (2) 42884006

dose levels: 0, 1, 3, 10 and 30 mg/kg/day Maternal NOAEL = 30 mg/kg/day (HDT) LOAEL = >30 mg /kg/day (HDT) Developmental NOAEL = 3 mg/kg/day LOAEL = 10 mg/kg/day based on cardiovascular effects (especially ventricular septal defects).

870.3700a Pre

- natal

developmental

- rat (dermal) 42684929 (pilot);

42684926 (main study)

dose levels: 0, 30, 100, and 300 mg/kg/day Maternal NOAEL = 300 mg/kg/day (HDT) LOAEL = >300 mg/kg/day (HDT) Developmental NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day based on cardiovascular effects (especially ventricular septal defects).Page 47 of 70

Table A.2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Dose s Results

870.3700a Pre

- natal

developmental

- ra t ( inhalation ) Data Gap

870.3700b Pre

- natal

developmental

- rabbit (oral) 42684927 (range

- finding);

42684928 (main study)

dose levels: 0, 300, 1000, or 3000 mg/kg/day Maternal NOAEL = 1000 mg/kg/day LOAEL = 3000 mg/kg/day (HDT) based on decrease in

bo dy weight and food consumption during dosing Developmental NOAEL = 3000 mg/kg/day (HDT) LOAEL = >3000 mg/kg/day

870.3800 Reproduction and

fertility effects

- rat ) 42684934 and 42684936

(pilot studies); 42684935 (main study)

dose levels: 0, 3.2, 6.3,

12. 7, and 18.9 mg/kg/day (M) and 0, 3.8, 7.6, 15. 1, and 22.7 mg/kg/day (F) Parental/Systemic NOAEL = 12.7 (M), 15.1 (F) mg/kg/day; LOAEL = 18.9 (M), 22.7 (F) mg/kg/day based on increase in clinical signs (red substance in vagina) and increased female mortal ity as well as decreased body weight, body weight gain and food consumption. Reproductive NOAEL = 18.9 (HDT) (M), 22.7 (HDT) (F) mg/kg/day; LOAEL = >18.9 (HDT) (M), >22.7 (HDT) (F) mg/kg/day Offspring NOAEL = 6.3 (M), 7.6 (F) mg/kg/day; LOAEL = 12.7 (M), 15.1 (F) mg/kg/day based on a decrease in the number of liveborn, a decrease in pup body weight, a decrease in the mating index, and testicular atrophy of F1 males

.

870.4100b 12

- Month capsule

-

dog 44295017

dose levels: 0, 10, 100 or 1000 mg/kg/day NOAE L = 100 mg/kg/day (M & F) LOAEL = 1000 mg/kg/day (M &F), (LIMIT DOSE) based on the following for males and females: increased absolute and relative liver weights; 300% increase in alkaline phosphatase values

870.4200b Carcinogenicity

-

mouse 44295018

dos e levels: 0, 31.1, 314.9 or 754.1 mg/kg/day in males and 0, 36.6, 346.4, or 859.1 mg/kg/day in

females NOAEL = 754.1 (M), 859.1 (F) mg/kg/day (LIMIT DOSE); LOAEL = no systemic effects at LIMIT DOSE

in males or females No evidence of carcinogenicity

870.4 300 Combined chronic

carcinogenicity

- rat 44295028

dose levels: 0, 1.8, 18.0, and 36.5 mg/kg/day in male rats and 0, 2.2, 21.8, and 43.6 mg/kg/day in

female rats NOAEL = 1.8 (M), 2.2 (F) mg/kg/day LOAEL = 18.0 (M), 21.8 (F) mg/kg/day based on

increased c hronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC). No evidence of carcinogenicityPage 48 of 70

Table A.2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Dose s Results

Gene

Mutation

870.5100 Gene mutation in S.

typhimurium and E.

coli 42684938

dose levels: with or

without metabolic

acti vation to 0, 50, 100, 200, 500, 1000, or 2000 μg/plate Neither cytotoxic nor mutagenic up to 2000 μg/plate. There were reproducible increases in revertant colonies

of S. typhimurium strains TA1538 and TA98 in S9 activated phases of the preliminary cytotox icity and both mutation assays. [Results are considered to be equivocal.]

Gene

Mutation

870.5375 Gene mutation in

Chinese hamster ovary cells 42684939

nonactivated levels, 30, 100, 200, and 500 μM (11, 35, 70, and 177 μg/mL, respectively) Precipitation at 200 μM. Cytotoxicity at 500 μM.

Positive +S9 100 μM and negative at 30

- 500 μM

- S9. Aberrations were chromatid breaks and exchanges.

870.5395 In vivo rat bone

marrow 42684940

dose levels: 1250, 2500, or 5000 mg/kg Negative in male (up to 5000 mg/k g) and female rats (up to 4400 mg/kg) when tested orally.

870.5550 UDS assay 42684941

dose levels: by oral gavage to 5000 mg/kg or 12 hours post exposure to 1250 or 2500 mg/kg Negative up to 5000 mg/kg.Page 49 of 70

Table A.2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Dose s Results

870.6200a Acute neurotoxicity

screening battery 48402405

acceptable/guideline

0, 200, 700 or 2000 mg/kg

bw NOAEL = 20 00 mg/kg/day (M & F)

LOAEL = >2 000 mg/kg/day (M &F), (LIMIT DOSE) no signs of neurotoxicity

870.6200b Subchronic

neurotoxicity screening battery 48651401

acceptable/guideline

0, 500, 1500, or 4500 ppm (equivalent to 0, 37/41, 110/124, 323/358 mg/kg bw/day for males/females) NOAEL = 500 ppm (equivalent to 37/41 mg/kg bw/day for males/females, respectively ) LOAEL = 1500 ppm (equivalent to 110/124 mg/kg bw/day for males/females, respect ively), based on signs of anemia [decreased hemoglobin and hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH)]

.

N OAEL= 4500 ppm for neurotoxicity (HDT)

870.6300 Developmental

neurotoxicity Not required.

870.7485 Metabo lism and

pharmacokinetics

- rat (oral) 42684943

single oral dose of 1 mg/kg or 100 mg/kg, Gastrointestinal tract absorption >90% at 1 mg/kg and up to 50% at 100 mg/kg. At least 97% recovery in feces and urine 7 days after dosing. Highest levels of residu es (36

- 49 ppb) in blood cells at low dose and 2800

- 3000 ppm at high dose (RBC levels > plasma). In addition to untransformed parent, 7 metabolites identified in urine and feces (38

- 46% for low dose and about 71% at high dose).

870.7600 Dermal penetrat ion

- rat 42684944

dose levels: 200 or 800 mg/kg bw Females dosed with 200 or 800 mg/kg bw. Dermal absorption for 200 and 800 mg/kg was 3.9% and 8.0%, respectively, by 48 hours after initiation of treatment for

6 hours. Blood levels at 6

- 24 hours aft er dermal dosing with 200 mg/kg were similar to those obtained at 2

- 6 hours after oral dosing with 1 mg/kg. Blood levels at 6

- 24 hours after dermal dosing with 800 mg/kg were

similar to those obtained at 2

- 6 hours after oral dosing with 30 mg/kg.

870.780 0 Immunotoxicity 48402407 and 48402408

acceptable/guideline

0 (control), 500, 1500, or 4500 ppm (0, 44, 127, and 375 mg/kg bw/day, respectively) NOAEL = 500 ppm (equivalent to 42 mg/kg bw/day ) LOAEL = 1500 ppm (equivalent to 126 mg/kg bw/day), based on sig ns of anemia (decreased hemoglobin and hematocrit).

Under conditions of this study, the immunotoxicity

NOAEL for anti

- SRBC PFC response is 4500 ppm (375 mg/kg/day), the highest dose tested; a LOAEL was not

established.Page 50 of 70

Table A.2 .b. Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Dose s Results

Non

guideline Special Study

-

Rat Developmental:

Critical Time for

Defects 42694931, 42684932

single dose:400 mg/kg bw Pregnant females were administered 400 mg/kg by gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 12 administration showed: largest incidence of embryonic death, l owest fetal body weights and greatest incidence of ventricular septal defects.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

Study Selected : Pre

- natal Developmental Toxicity Study

- Rat

MRID No s. : 42684930 (pilot study) ; 42684925 (main study) ; and 42884006

, 42694931

, and

42684932 (studies demonstrating critical time to effects). Executive Summary : See Appendix A

Dose and Endpoint for Risk Assessment : NOAEL = 3 mg/kg/day, Endpoint = cardiovas cular effects, specifically ventricular septal defects in fetuses, seen at the LOAEL of 10 mg/kg/day Uncertainty Factor(s): 100X [10 interspecies; 10X intraspecies].

Comments about Study/Endpoint/Uncertainty Factors : The endpoint selected is appropriate because the critical effect, cardiovascular abnormalities observed in fetuses, has been demonstrated to be the result of a single dose, with dosing on gestation day 12 being the most critical time period for the effect. The application of the endpoint and dose to the population of potentially pregnant females is protective of fetal effects. A clear NOAEL and LOAEL were identified for the fetal abnormalities; therefore

, no additional uncertainty factors (other than the

standard 10 x for interspecies extrapo lation and 10 x for intraspecies variability) are needed. Furthermore, the FQPA factor has been reduced to 1 x . Therefore, the acute reference dose (RfD) and acute population adjusted dose (PAD) are calculated as follows:

Acute RfD = Acute PAD = 3 mg/kg/d ay (NOAEL) = 0.03 mg/kg/day 100 (UF)

A.3.2 Acute Reference Dose (aRfD)

- General population, including infants and

children

No appropriate endpoints were selected because no toxic effects that could result from a single

dose and that were relevant to the general population (including infants and children) were identified in the database.Page 51 of 70

A.3.3 Chronic Reference Dose (cRfD)

– all populations

Study Selected : Combined chronic carcinogenicity

- rat
MRID No. : 44295028 Executive Summary : See Appendix A Dose and Endpoint for Risk Assessment : NOAEL = 2.0 mg/kg/day, Endpoint = increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH, and MCHC) seen at the LOAEL of 18 mg/kg/day. Uncertainty Factor(s): 100X [10 interspecies; 10X intraspecies].

Comments about Study/Endpoint/Uncertainty Factors : The duration and route of exposure in the rat study are applicable to the chronic dietary route (oral) and duration of expo sure (long term to lifetime). In addition, the rat is the most sensitive species . I n 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 systemi c effects were seen at the highest dose tested. Finally, the NOAEL selected from the rat study is the lowest observed in the submitted studies, and is protective of all other effects, including the offspring effects in the reproductive toxicity study

. As the FQPA factor has been reduced to 1 x , and there are no other uncertainty factors needed, the standard 100 x (10 x for interspecies extrapolation and 10 x for intraspecies variability) UF has been applied to attain the chronic RfD and PAD , which are equival ent.

Chronic RfD = Chronic PAD = 2 mg/kg/day (NOAEL) = 0.02 mg/kg/day 100 (UF)

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Study Selected : Reproduction and fertility effects

- rat

MRID No. : 42684934 and 42684936 (pilot studies); 42684935 (main study)
Executive Summary : See Appendix A Dose and Endpoint for Risk Assessment : NOAEL = 6.3 mg/kg/day, Endpoint = decreased live born pups and decreased pup body weight, and testicula r atrophy in F1 males seen at the LOAEL of 12.7 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : The endpoint and dose have been selected from an oral study, which is appropriate for assessing the incidental oral pathway of exposure. In ad dition

, the endpoint, offspring effects in a reproducti on study, is relevant for the exposed population (infants and children) and

, therefore

, the risk assessment will be protectivePage 52 of 70

for the qualitative and quantitative susceptibility observed in the reprod ucti on study. As the FQPA factor has been reduced to 1 x , and a clear NOAEL and LOAEL were identified in the study, the standard UFs of 100 x (10 x for interspecies extrapolation and 10 x for intraspecies variability) define the level of concern ( LOC ) for ris k assessment as a MOE of less than 100 for residential exposure and risk assessments.

A.3.5 Dermal Absorption

Study Selected : Dermal penetration

- rat

MRID No. : 42684944

Dermal absorption following application of 200 and 800 mg/kg was 3.9% and 8.0%,

r espectively, by 48 hours after initiation of treatment for 6 hours. Blood levels at 6

- 24 hours after dermal dosing with 200 mg/kg were similar to those obtained at 2

- 6 hours after oral dosing with 1 mg/kg. Blood levels at 6

- 24 hours after dermal dosing w ith 800 mg/kg were similar to

those obtained at 2

- 6 hours after oral dosing with 30 mg/kg. For the purpose of risk assessment,

an upper

- bound estimate of 8% dermal absorption should be used.

A.3.6 Dermal Exposure (Short and Intermediate

- Term) for Childre n

Study Selected : Reproduction and fertility effects

- R at

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

Dose and Endpoint for Risk Assessment : NOAEL = 6.3 mg/kg/day, Endpoint = decreased live born pups and decreased pup body weight, and testicular atrophy in F1 males seen at the LOAEL of 12.7 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : The endpoint and dose have been selected from the oral reproductive toxicity study in the rat . T he route

- specific dermal study was not appropriate because reproductive parameters were not measured in the dermal study in rats.

In addition

, the endpoint, offspring effects in a reproducti on study, is relevant for the exposed population (infants and children) and

, therefore

, th e risk assessment will be protective for the qualitative and quantitative susceptibility observed in the reproducti on study. As the FQPA

factor has been reduced to 1 x , and a clear NOAEL and LOAEL were identified in the study, the

standard UFs of 100 x (10 x for interspecies extrapolation and 10 x for intraspecies variability)

define the LOC for risk assessment as an MOE of less than 100 for residential exposure and risk

assessment. The 8% dermal absorption value should be used for route

- to

- route extrapolatio n, i.e., an oral study is used for dermal risk assessment.

A.3.7 Dermal Exposure (Short

- , Intermediate

- and Long

- Term) for Adults

Study Selected : Dermal Developmental Study (Rat)Page 53 of 70

MRID No. : 42684929 (pilot); 42684926 (main study)

Dose and Endpoint for Risk Assessment : Dermal NOAEL = 30 mg/kg/day, Endpoint = cardiovascular effects, specifically ventricular septal defects, in fetuses observed at the LOAEL of 100 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : The study is appropriate for dermal risk assessment because the most critical toxic effect, ventricular septal defect in fetuses, was evaluated following exposure via the dermal route. This study is appropriate for all durations because of the developmental toxicity concerns. The o ral 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, becaus e the

use of the oral NOAEL of 2. 0 mg/kg/day (chronic RfD) with an 8% dermal absorption factor yielded a dermal equivalent dose of 25 mg/kg/day (2.0/0.08 = 25), which is comparable to the selected dermal NOAEL of 30 mg/kg/day.

As the FQPA factor has been reduced to 1 x , and a clear NOAEL and LOAEL were identified in the study, the standard UFs of 100 x (10 x for interspecies extrapolation and 10 x for intraspecies variability) define the LOC for risk assessment as an MOE of less than 100 for both residential and occupational exposure and risk assessment.

A.3.8 Inhalation Exposure (Short

- and Intermediate

- Term) for Adults

Study Selected : Oral Developmental Study (Rat)

MRID No. : 42684930 (pilot study); 42684925 (main study); 42884006

Dose and Endpoint for Risk Assessment : NOAEL = 3 mg/kg/ day, Endpoint = cardiovascular effects, specifically ventricular septal defects, in fetuses seen at the LOAEL of 10 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : In the absence of an inhalation study with flumioxazin, HED selected the en dpoint from an oral study. The developmental study was considered to be the most appropriate for both short

- and intermediate

- term exposure, and the selection of the endpoint ensures the risk assessment is protective of potential developmental

effects. T he selection of the developmental effects allows for aggregation of dermal and inhalation exposure for both residential and occupational scenarios. As an oral study was selected for the inhalation route, an inhalation absorption factor of 100% should be a pplied for

risk assessment.

Because the FQPA factor has been reduced to 1 x , and a clear NOAEL and LOAEL were identified in the study, the standard UFs of 100 x (10 x for interspecies extrapolation and 10 x for intraspecies variability) define the LOC for ris k assessment as an MOE of less than 100 for both residential and occupational exposure and risk assessment.Page 54 of 70

A.3.9 Inhalation Exposure (Long

- Term) for Adults

Study Selected : 2

- Year Chronic/Carcinogenicity Study (Rat)

MRID No. : 44295028

Dose and Endpoin t for Risk Assessment : NOAEL = 2 mg/kg/day, Endpoint = increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH, and MCHC) seen at the LOAEL of 18 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : In the absence of an inhalation study for flumioxazin, HED selected an oral study. The duration of exposure in the chronic rat study is applicable to long

- term durations of exposure. In addition, the rat is the most sensitive species

. I n the one

- year dog study, liver effects were observed at the LOAEL of 1000 mg/kg/day, with a NOAEL of 100 mg/kg/day. In the carcinogenicity study in the mouse, no systemic effects were seen at the highest dose tested. Furthermore, the selected NOAEL is the lowest obse rved in the submitted studies, and is protective of all other effects, including the offspring effects in the reproductive toxicity study. As a route

- specific inhalation study is not available, an inhalation absorption factor of 100% should be used for ri sk assessment purposes. Finally, because the FQPA factor has been reduced to 1 x , and a clear NOAEL and LOAEL were identified in the study, the standard UFs of 100 x (10 x for interspecies extrapolation and 10 x for intraspecies variability) define the LOC fo r risk assessment as an MOE of less than 100 for both residential and occupational exposure and risk assessment.

A.4 Executive Summaries

A. 4 .1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

– Rat

In a 13

- week subchronic feeding study S

- 53482 Techn ical (98.4% purity) was administered to Crj:CD(SD) rats from Charles River Japan (12/sex/dose level) for a period of 13 weeks in the diet at dose levels of 0, 30, 300, 1000 or 3000 ppm (approximately 0, 2.3, 20.7, 69.7, and 243.5 mg/kg b.w./day, respective ly in males and 0, 2.2, 21.7, 71.5, and 229.6 mg/kg b.w./day, respectively in females). Mean body weight gains by week 13 were statistically significantly smaller than in controls at 3000 ppm (amounting to 83

- 89% of controls) in both sexes. Hematology pa rameters and bone marrow examination were consistent with anemia and bone marrow response in both sexes. In males there were statistically significant decreases in hemoglobin (by 8.2%), hematocrit (by 8.4%), MCH (by 9.4%) at 3000 ppm and of MCV at 1000

pp m (by 3.8%) and at 3000 ppm (by 9.9%). In addition, reticulocytes were statistically significantly increased from 0.9% to 1.7% at the 3000 ppm level. There were also statistically significant changes in bone marrow parameters: erythroblasts were increase d from 0.4 to 7.8 per 100 WBC and the granulocyte/erythroblast ratio was decreased from 1.7 to 1.0 in 3000 ppm rats. In females there were statistically significant decreases at 3000 ppm in erythrocyte count (by 11.2%), hemoglobin (by 25.5%), hematocrit ( by 25.1%), MCH (by 15.9%), and MCV (byPage 55 of 70

15.3%). Reticulocytes were statistically significantly increased vs controls from 1.2% to 3.1% at the 3000 ppm level. Additionally, statistically significant changes in bone marrow parameters were: erythroblasts were up from 0.4 to 31.3 per 100 WBC and the granulocyte/erythroblast ratio was decreased from 1.7 to 0.4 in 3000 ppm rats. Absolute and relative spleen weights were elevated in both sexes at 3000 ppm. Microscopic pathology examination revealed extramedullary hematopoiesis in spleens in 8/12 males and in all females at 3000 ppm. The LOAEL = 3000 ppm (mg/kg/day: males = 243.5, females = 229.6) and is based on dose

related findings in hematology (statistically significant decrease in MCV in both sexes at 3000 p pm [mg/kg/day: males = 243.5, females = 229.6] and statistically significant increases in platelets at 3000 ppm [mg/kg/day: 229.6] in females). The NOAEL = 1000 ppm (mg/kg/day: males = 69.7, females = 71.5)

This study is classified as Core Supplementary

. This study does not satisfy the requirement (82

- 1) for a subchronic oral toxicity study in rodents. This study may be upgraded to Core

Minimum if the following additional information is provided and is judged to be acceptable: (1) Data to support the st ability of the test material in the prepared diets under the condition of storage between the time of preparation and use; (2) Clinical chemistry data for individual males (only summary tables were available); (3) Individual gross pathology data for all an imals except the 1000 and 3000 ppm males (summary tables and individual data for 1000 and 3000 ppm males were available).

In a subchronic feeding study, S

- 53482 Technical (94.8%) was administered to male and female Crj:CD Sprague

- Dawley rats (16/sex/group ) at dietary levels of 0, 30, 300, 1000, and 3000 ppm (approximate doses of 0, 1.9, 19.3, 65.0, and 196.7 mg/kg/day for males, and 0, 2.2, 22.4, 72.9, and 218.4 mg/kg/day for females) for 90 days. Dose

- related changes in hematology parameters and histopat hology, associated with anemia, were seen in females at 300 ppm and above and in males at 1000 ppm and above. In females, decreases (p<0.05) in MCV (3%) and MCH (3%) and increased extramedullary hematopoiesis in spleen (1/10 vs 0/10 in controls) were obse rved at 300 ppm. At 3000 ppm, decreases (p<0.05) in MCV (18%), MCH (25%), MCHC (9%) and other hematology parameters were coupled to increased reticulocyte count (up to 3.9%) and extramedullary hematopoiesis in spleen (10/10) and liver (5/10). In males, d ecreases (p<0.05) in MCV (6%) and MCH (7%) and increased extramedullary hematopoiesis in spleen (1/10 vs 0/10 in controls) were observed at 1000 ppm. At 3000 ppm, decreases (p<0.05) in MCV (11%), MCH (14%), MCHC (9%) were coupled to increased reticulocyte count (up to 1.4) and extramedullary hematopoiesis in the spleen (6/10). LOAEL = 3000 ppm (196.7 mg/kg/day for males and 218.4 mg/kg/day for females) are based on dose

- related alterations in hematology parameters and histologic alterations associated wit h anemia. NOAEL = 1000 ppm (65.0 mg/kg/day for males and 72.9 mg/kg/day for females). This study is Core

Minimum and satisfies the requirement (82

- 1) for a subchronic oral toxicity study in rats.

870.3150 90

- Day Oral Toxicity

– Dog

S

- 53482 Technical w as administered to beagle dogs of both sexes for a period of 13 weeks via gelatin capsules at dose levels of 0, 10, 100, or 1000 mg/kg/day. Clinical chemistry parametersPage 56 of 70

showed dose

- related increases in total cholesterol, phospholipid and alkaline phosph atase, which became statistically significant in 1000 mg/kg/day males (cholesterol, phospholipid) cr females (alkaline phophatase). In addition, at 1000 mg/kg/day, treatment

- related effects in male and

female dogs included increased liver weights, gross h epatic lesions (rounded margin and enlargement) and microscopic hepatic lesions (proliferation and dilatation of bile duct and smooth endoplasmic reticulum in hepatocytes and increased fibrous tissue around the centrilobular veins). LOEL: 100 mg/kg/day (b ased on dose dependent increases in dose

dependent increases in total cholesterol, and phospholipid levels and alkaline phosphatase activity). NOEL: 10 mg/kg/day. CORE Classification: Supplementary. The study is upgradeable pending submission of stabili ty data in the used diet.

A. 4 .2 Pre

- natal Developmental Toxicity

870.3700a Pre

- natal Developmental Toxicity Study

– Rat

Executive Summary: In an oral developmental toxicity study, the test substance, S

- 54382 (94.8% purity), was administered once daily by gavage to pregnant female Scl:SD (Sprague

Dawley) rats on days 6

- 15 of gestation (with the day of mating defined as gestation Day 0) at dose levels of 0, 1, 3, 1 0 and 30 mg/kg/day. The rats were observed for signs of toxicity; body weight and food co nsumption values were recorded. On day 20 of gestation, the rats were sacrificed and necropsied; gravid uterine weights were recorded. The uteri were examined, implantation sites were counted, and the numbers of corpora lutea were determined. The fetuses were removed, weighed, sexed, and examined for external anomalies. They were then processed

for visceral or skeletal evaluation.

There were no treatment

- related effects on maternal mortality, clinical observations, body weight, food consumption or gross pathology data. Maternal LOAEL = Not determined;

Maternal NOAEL = 30 mg/kg/day. At the 30 mg/kg/day dose level, a treatment

- related increase in fetal death (5.6% resorptions in control versus 20.4% at the high

- dose), a 21%

decrease in mean live litter s ize, and a decrease in male (14.3%) and female (15.2%) fetal body weights were noted as compared to control. A dose and treatment

- related increase in the

incidence of fetuses with cardiovascular abnormalities, particularly ventricular septal defect, was

o bserved. Ventricular septal defect was noted in the following numbers of fetuses (litters) for the control, 1, 3, 10 and 30 mg/kg/day dose groups, respectively: 2(2), l(l), 2(2), 6(6), and 26(12);

combined cardiovascular abnormalities were noted with the following distribution: 8(6), 7(6), 10(8), 13(9), and 36(14). These findings were both statistically significant at 30 mg/kg/day, and

the increased incidence of cardiovascular abnormalities was judged to be biologically significant at 10 mg/kg/day. Appr opriate historical control data submitted by the performing laboratory support and confirm these conclusions. Also at the 30 mg/kg/day dose level, significantly increased incidences of wavy ribs (27 fetuses, representing 12 of 18 litters) and curvature of the scapula (10 fetuses in 4 litters) and a significant 4

- 7% decrease in the number of ossified sacrococcygeal vertebral bodies as compared to control were attributed to treatment. Developmental LOAEL = 10 mg/kg/day; Developmental NOAEL = 3 mg/kg/day, ba sed on a biologically significant increase in cardiovascular abnormalities, particularly ventricular septalPage 57 of 70

defect; at 30 mg/kg/day, statistical significance was achieved for these observations and the following additional findings were noted: increased re sorptions and decreased number of viable fetuses, decreased fetal body weight, increased abnormalities of the ribs (wavy) and scapula (curvature), and decreased numbers of ossified sacrococcygeal vertebral bodies.

The above findings were generally similar to those observed in the dermal developmental toxicity study in rats conducted with S

- 53482 (MRID No. 42684926, Teratology Study of S

53482 Administered Dermally to Rats, performed by Sumitomo Chemical Co. Ltd., for Valent U.S.A. Corporation, project No. 2018, March 14, 1991). In that study, a dose

- and treatment

related increase in the incidence of cardiovascular abnormalities, particularly ventricular septal defect, was noted for fetuses of dams treated by 6

- hour dermal exposure to the test substance on days 6

- 15 of gestation. CORE CLASSIFICATION: not acceptable/guideline; does not satisfy

the requirement (83

- 3) for an oral developmental toxicity (teratology) study in rats; this study can be upgraded to acceptable following the receipt of the following acceptable individual fetal observation data: body weight, external observations, visceral findings, and skeletal findings.

Executive Summary : In a dermal developmental toxicity study, the test substance, S

- 54382 (94.8% purity), was administered by 6

- hour daily dermal application to pregnant female Scl: SD (Sprague

- Dawley) rats on days 6

- 15 of gestation (with the day of mating defined as gestation Day 0) at dose levels of 0, 30, 100, and 300 mg/kg/day. The rats were observed for signs of toxicity; body we ight and food consumption values were recorded. On day 20 of gestation, the rats were sacrificed and necropsied; gravid uterine weights were recorded. The uteri were examined, implantation sites were counted, and the numbers of corpora lutea were determi ned. The fetuses were removed, weighed, sexed, and examined for external anomalies. They were then processed for visceral or skeletal evaluation. There were no systemic treatment

- related effects on maternal mortality, clinical observation, body weight, f ood consumption, or gross pathology data. Maternal LOAEL = not determined; Maternal NOAEL = 300 mg/kg/day.

A dose

- and treatment

- related increase in the incidence of fetuses with cardiovascular abnormalities, particularly ventricular septal defect, was obs erved. Ventricular septal defect was noted in the following numbers of fetuses (litters) for the control, 30, 100, and 300 mg/kg/day dose groups, respectively: l(l), l(l), 2(2), and 13(9); combined cardiovascular abnormalities were

noted with the followin g distribution: 5(5), 4(4), 10(7), and 19(9). These findings were both statistically significant at 300 mg/kg/day, and the increased incidence of cardiovascular abnormalities was judged to be biologically significant at 100 mg/kg/day. Appropriate histori cal control data submitted by the performing laboratory support and confirm these conclusions. At the 300 mg/kg/day dose level, an increase in fetal death (40.7% resorptions as compared to 6.0% in controls), a 40% decrease in live litter size, and a 6

- 9% d ecrease in fetal body weights were attributed to treatment. t the same dose level, significantly increased incidences of wavy ribs (18 fetuses, representing 10 of 17 litters) and a 3.4% decrease in the mean number of ossified sacrococcygeal vertebral bodi es were attributed to treatment. Developmental LOAEL = 100 mg/kg/day; Developmental NOAEL = 30 mg/kg/day, based on a biologically significant increase in cardiovascular abnormalities, particularly ventricular septal defect; at 300 mg/kg/day,

statistical s ignificance was achieved for these observations and the following additional findings were noted: increased resorptions and decreased number of viable fetuses, decreased fetal bodyPage 58 of 70

weight, increased abnormalities of the ribs (wavy), and decreased numbers o f ossified sacrococcygeal vertebral bodies. The above findings were generally similar to those observed in the oral developmental toxicity study in rats conducted with S

- 53482 (MRID No. 42684925, Teratology Study of 6 S

- 53482 Administered Orally to Rats, performed by Sumitomo Chemical Co. Ltd., for Valent U.S.A. Corporation, project No. 1759, August 28, 1990). In that study, a

dose

- and treatment

- related increase in the incidence of cardiovascular abnormalities, particularly ventricular septal defect, was noted for fetuses of dams treated on days 6

- 15 of gestation. CORE CLASSIFICATION: not acceptable/guideline; does not satisfy the requirement (83

- 3) for a dermal developmental toxicity (teratology) study in rats; this study can be upgraded to acceptable f ollowing the receipt of the following acceptable individual fetal observation data: body weight, external observations, visceral findings, and skeletal findings.

870.3700b Pre

- natal Developmental Toxicity Study

– Rabbit

Executive Summary : In a developmen tal toxicity study, New Zealand White rabbits received V

53482 (94.8% purity) daily via gavage at doses of 0, 300, 1000, or 3000 mg/kg/day on gestational days (GDs) 7

- 19, inclusively. Group mean body weight gain (kg) during dosing (gestation days 7

- 19) we re as follows (0, 300, 1000 or 3000 mg/kg/day): 0.17, 0.18, 0.14 and 0.05 (p<0.05). Group mean food consumption (g/kg/day) during dosing were as follows: 42.9, 42.1, 39.4 and 35.7 (p<0.05). No other parameters (maternal or developmental) were considered

t o have been affected by test article administration. Maternal LOAEL = 3000 mg/kg/day based on decreased body weight and food consumption mostly during the dosing period Maternal NOAEL = 1000 mg/kg/day. Developmental LOAEL = not determined Developmental N OAEL = 3000 mg/kg/day This study is considered to be acceptable/guideline and meets the requirements to fulfill 83

- 3 for a developmental toxicity study in rabbits.

A. 4 .3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat

Executive Summary : In a two

- generation reproduction study, Sprague

- Dawley rats were fed V

53482 (94.8% purity) in the diet at dosage levels of 0, 50, 100, 200 or 300 ppm (during premating, at least 0, 3.2, 6.3, 12.7, and 18.9 mg/kg/day in males and 0, 3.8, 7.6, 15. 1, and 22.7 mg/kg/day in females, respectively). There were no definitive clinical signs attributed to test article administration in males of either generation. In F0 females only, there was an increase (p<0.01) in the incidence of "red substance in vagi na" only at 300 ppm (9/25 versus 0

- 1/27

- 30 for the other 4 groups). The mortality in the F1 females was as follows for 0, 50, 100, 200 or 300 ppm: 0, 1, 0, 0 and 5 (p<0.01). Group mean body weight gains were less than control (p<0.05 or 0.01) in F1 males and females during the first week of premating. During gestation, F0 and F1 females had lower body weight gain (p<0.01) during the last 5 days and for the entire period of gestation(28

- 31% decrease in gain). There was a decrease in food consumption in 3 00 ppm females of both generations: F0, 65

- 84% of control during lactation (p<0.05 or 0.01); F1,

92

- 95% of controls during gestation (p<0.05 or 0.01); and F1, 78

- 89% of control during lactation (p<0.05 or 0.01). The incidence of grossly observable yellow livers was increased in 300 ppmPage 59 of 70

F1 females that died (p<0.01, 3/30 versus 0/30 for controls). There was a decrease (p<0.01) in absolute only testis and epididymides weights in 300 ppm F1 males (not F0). [Study authors excluded all rats with small organs fr om the analysis.] No definitive histopathological changes were attributed to test article administration. There was the suggestion of atrophied/hypoplastic/hypospermia of the testes and/or epididymides in both generations of 300 ppm males (of 30 males exa mined in 0 and 300 ppm groups, the treated group had no more than one finding more than the control group). Tissues from the 100 and 200 ppm (and most of the 50 ppm) groups were not evaluated. In F1 300 ppm females that died, liver lobular necrosis and

b ile stasis was observed (2

- 3/4 examined). Systemic LOAEL = 300 ppm (mg/kg/day: males = 18.9, females = 22.7) based on increased clinical signs (F0 females); increased mortality (Fl females), gross and histopathology findings in the liver (Fl females); dec reased body weight/weight gain (F0 and Fl females during gestation, Fl males during the early portion of premating); and decreased food consumption (F0 and Fl females during lactation). Systemic NOAEL = 200 ppm (mg/kg/day: males = 12.7, females = 15.1) I n both generations, the following reproductive parameters were affected primarily at 300 ppm and to a lesser extent at 200 ppm: females with liveborn (300 ppm, 16/21 for Fl pups and 16/18 for F2 pups; control, 23/23 and 23/23); mean number of live pups/lit ter on day one of lactation (300 ppm 7/9; control, 14/16); mean pup weight on lactation day one (300 ppm, 5.7/5.6 g; 200 ppm, 6.1/6.1; control, 6.9/6.4). Reproduction/Offspring LOAEL = 200 ppm (mg/kg/day: males = 12.7, females = 15.1) based on decreased n umber of females with liveborn and mean number of pups/litter on lactation day 1, decreased pup body weight, testicular atrophy in F1 males and decreased mating index. Reproduction/Offspring NOAEL = 100 ppm (mg/kg/day: males = 6.3, females = 7.6). This s tudy is classified acceptable/guideline and meets the requirements of

83

- 4 for a two generation reproductive toxicity study in rats.

A. 4 .4 Chronic Toxicity /Carcinogenicity

870.4200a Chronic Toxicity/ Carcinogenicity Study

– R at

In a combined chronic/onc ogenicity study (MRID 44295028), flumioxazin (technical, 94.8% a.i.,

S

- 53482) was administered in the diet for up to 24 months to 74 Crj CD (SD) rats/sex/dose at levels of 0, 50, 500, and 1000 ppm (equivalent to 0, 1.8, 18.0, and 36.5 mg/kg/day in male rat s and 0, 2.2, 21.8, and 43.6 mg/kg/day in female rats). At approximately 52 and 78 weeks 10

- 14 rats per group were terminated and all remaining animals were terminated at approximately 104 weeks. Survival rates, clinical observations, clinical chemistry, ophthalmoscopic, urinalysis, and gross pathologic parameters were unaffected by treatment with S

- 53482. Minor changes (2

- 15%) in hematological parameters (hemoglobin, MCV, MCH, MCHC) in the mid and high

- dose

females were consistent with a chronic mild an emia. The presence of circulating erythroblasts in peripheral blood, reticulocytosis, decreased bone marrow Myeloid/Erythroid ratio (949%, p<0.05) and splenic extramedullary hematopoiesis (8/10 treated; 6/10 controls, p<0.05) are

consistent with a severe stress on erythropoiesis similar to what might be observed in chronic iron deficiency. However, the relatively moderate decreases in hemoglobin and lack of progression to a more severe type of anemia such as aplastic anemia or pancytopenia indicate

succes sful compensatory erythropoiesis. Histopathological changes of the kidney indicative ofPage 60 of 70

slight to mild chronic nephropathy was found at the final necropsy in the 500 (18.0 mg/kg/day) and 1000 (36.5 mg/kg/dah) ppm male groups (26

- 27/33 treated vs 13/31 con trols, p<0.01). The chronic LOAEL is 500 ppm (equivalent to 18.0 and 21.8 mg/kg/day in males and females, respectively) based upon decreased hemoglobin, MCV, MCH and MCHC in females and increased incidence of chronic nephropathy in males. The chronic NOA EL is 50 ppm (equivalent to 1.8 and 2.2 g/kg/day in males and females, respectively). Under the conditions of this study, there was no evidence of carcinogenic potential. Dosing was considered adequate due to hematological and histopathological changes o bserved in the mid

- and high

- dose animals. This study is classified as acceptable (§83

- 5; 870.4300) and satisfies the guideline requirements for a combined chronic toxicity study and a carcinogenicity study in rats.

870.4200b Carcinogenicity (feeding)

– Mouse

In a mouse oncogenicity study (MRID 44295018), flumioxazin technical, 94.8% a.i. (S

- 53482)

was administered in the diet for 78 weeks to 51 CD

- 1 mice/sex/dose at levels of 0, 300, 3000 or 7000 ppm which is equivalent to dietary levels of 0, 31.1, 314 .9 or 754.1 mg/kg/day in males and 0, 36.6, 346.4,or 859.1 mg/kg/day in females, respectively. An additional 15 mice/sex/dose were used to provide samples for hematological examination, pathology and histopathology. These

animals were terminated at 53 we eks. All remaining animals were sacrificed at 79 weeks of the study. Survival rates, clinical observations, body weights, feed consumption, organ weights, gross pathology and hematological parameters were unaffected by treatment with S

- 53482. No

clinica l chemistry was performed. There were statistically significant increases in malignant lymphoma/leukemia in mid

- dose males (6/15 treated; 1/14 controls, p<0.05) and increases in pulmonary adenoma in mid

- dose females (5/51 treated; 0/50 control, p<0.05), t hese tumor incidences were comparable to historical controls and did not exhibit dose

- dependency. The LOAEL was not observed. The chronic NOAEL is > 7000 ppm which is equivalent to 754.1 and 859.1 mg/kg/day in male and female mice, respectively. Under t he conditions of this study, there was no evidence of carcinogenic potential. Dosing was considered adequate because the highest dose of 7000 ppm represented a "limit dose". This study is classified as acceptable (§83

- 2b; 870.4200) and satisfies the guid eline requirements for a carcinogenicity study in mice.

A. 4

. 5 Neurotoxicity

Acute Neurotoxicity Study

In an acute neurotoxicity study (MRID 48402405 )

, groups of 6 week old Crl:CD(SD) rats ( 12 /sex/dose) were given a single oral dose of Flumioxazin TG (9 9.6 % a.i.

, Lot no. 080839G) in 0.5% methylcellulose at doses of 0, 200, 700 or 2000 mg/kg bw and observed for 14 days. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 12 animals/sex/group 8 hours following dose administration and on study days 7

and 14. At study termination, 6 a nimals/sex in the control and 2000 mg/kg bw /group s were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 6

animals/sex in the co ntrol and 2000 mg/kg bw/groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues.Page 61 of 70

Significant (p<0.05 or p<0.0l) increases in mean brain width were observed in a somewhat dose

dependent manner for males in all test substance

- treated groups, however, these mean values were generally within the mean brain width in the historical control database. The brain width in males in the 2000 mg/kg group was above the range of male brain widths in the historical control

dat a base. Although, it appears that there was a dose

- related effect on mean brain width in males in this study, the re was close similarity in widths between the 2 00, 700 and 2000 mg/kg groups.

The brain widths relative to brain weights were unaffected and no histologic correlates were

evident. The me an brain weight for the 2000 mg/ kg group females was statistically lower than

for the control group; however, all individual animal data were within the historical control

range, no effects on brain length or wid th were evident, and no histologic correlates were noted.

These brain measurements differences were not considered evidence of a test substance related

effect.

Based on the effects seen in this study, the LOAEL for is > 2000 mg/kg bw. The NOAEL is 2000 mg /kg bw.

This neurotoxicity study is classified as acceptable / guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats (870.6200; OECD 424). The sensitivity of the test system was confirmed by the incorporation of positiv e control data

.

Subchronic Neurotoxicity Study

In a subchronic (90

- day) neurotoxicity study (MRID 48651401 ) Flumioxazin ( 99.6 % a.i.,

batch/lot # 080839G ) was administered to 12 Crl:CD(SD rats /sex /group at dose levels of 0, 500

, 1500 , or 4500 ppm (equival ent to 0, 37/41

, 110/124

, 323/358 mg/kg bw/day for males/females )

for 13 weeks

. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 12 animals/sex/group during pretest and at study Weeks 3, 7, 12 . At

s tudy termination, all surviving animals were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 6 animals/sex in the control and 4500

ppm groups were subjected to histopathological evaluation of brain and periphera l nervous system tissues.

All animals survived to the scheduled necropsy, except one female in the 4500 ppm group which

was euthanized in extremis on Day 70 due to moribund conditions not related to test substance treatment. In surviving animals, there w ere no test substance

- related clinical signs observed at any dietary dose level in either males or females.

No adverse, treatment

- related effects were observed on survival, clinical signs, mean body weights, body weight gains, and food consumption at any dietary concentration level in males and females. In addition, no compound

- related alterations were observed in gross histopathology observations, brain weights and measurements or microscopic neurohistopathology findings at 4500 ppm males and females.Page 62 of 70

In males, there were treatment

- related effects on hemoglobin, hematocrit, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Hemoglobin and hematocrit were significantly decreased by 6% (p≤0.01) in the 1500 ppm male group and by 13% and 10% (p≤0.01), respectively, at 4500 ppm males at Week 13. Significant (p≤0.05 or p≤0.01) decreases in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were noted in the 500 ppm, 1500 ppm, and 4500 ppm groups. However, the lower MCV (49.2 fL ) and MCH (17.1 pg) values were within the range of the WIL historical control data of 48.3

- 70.9 fL for MCV and

16.9

- 21.5 pg for MCH. Therefore, these significant decreases in the 500 ppm male group were considered not adverse effects. Increased reticulocy te values (94

- 97%, p≤0.01) were noted in the 4500 ppm males when compared to the controls at Week 13. The alterations in the hematology parameters were consistent with a regenerative microcytic, hypochromic anemia.

Similarly, i n the females, treatment

- rel ated effects were noted in the following hematologic parameters: hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and MCHC at dietary concentration levels of 1500 ppm and 4500 ppm at Week 13. At 1500 ppm, hemoglobin and hematocrit were decreased by 8% and 5%, respectively, when compared to the controls. Also, significant decreases in hemoglobin (23 %, p≤0.01) and hematocrit (16 %, p≤0.01) values were observed in the 4500 ppm females group. There were significant higher reticulocyte counts (171%

- 186%, p≤0.01) and platelet counts (24%, p≤ 0.01) and lower absolute cell count in the 4500 ppm female group when compared to controls. Significantly (p≤0.05 or p≤0.01) lower absolute lymphocyte count and white blood cell were noted in the 500 and 1500 ppm female group, and a higher red blood cell c ount in the 1500 ppm group. These results indicated that females and males exhibited a similar characteristic anemia due to exposure to the test substance. This hematotoxicity effect of Flumioxazin has been

observed in earlier studies.

The neurological test measures (FOB and motor activity) and neurohistopathology examinations in this study showed no Flumioxazin

- related neurotoxic effects in rats exposed to dietary concentration ranging up to 4500 ppm.

Based on the results of this study, the N OAEL for subchronic neurotoxicity was 4500 ppm

for males (equivalent to 323 mg/kg/day) and females (equivalent to 358 mg/kg/day)

. The systemic toxicity LOAEL for Flumioxazin is 1500 ppm (equivalent to 110/124 mg/kg bw/day for males/females, respectively), based on signs of anemia [decreased hemoglobin and hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH)]

. The NOAEL for systemic toxicity is 500 ppm (equivalent to 37/41 mg/kg bw/day for males/females, respectively ).

The study is class ified as acceptable/guideline and satisfies the guideline requirement ( OPPTS

870.6200b ; OECD 424 ) for a subchronic neurotoxicity study in rats.Page 63 of 70

A. 4

. 6 Metabolism

870.7485 Metabolism

– Rat

Executive Summary : In a metabolism study, [phenyl

- U

- ’4C)S

- 53482 was administered to Sprague

- Dawley rats (5/sex/dose) as a single oral dose of 1 mg/kg or 100 mg/kg or as a single oral dose of 1 mg/kg following a 14

- day pretreatment with unlabeled 5

- 53482 at 1 mg/kg/day. C.I. tract absorption of S

- 53482 may amount to ov er 90% of the dose at 1 mg/kg and to about 50% at 100 mg/kg. Total recovery of radioactivity in feces and urine, 7 days after dosing,

accounted for 96.5

- 100.7% of the dose in all test groups. Radioactivity excretion in urine was statistically significan tly elevated in females (38.8

- 42.8%, low dose; 22.9

- 23.4%, high dose) vs. males (28.1

- 30.8%, low dose; 12.8

- 13.0%, high dose). Highest levels of residues were found in blood cells (35.9

- 48.8 ppb, low dose and 2823

- 3040 ppb, high dose), which were much hi gher than the plasma levels (0.5

- 0.7 ppb, low dose and 53

- 37 ppb, high dose). TLC analysis of feces and urine revealed up to 35 putative metabolites. In addition to untransformed parent compound,

7 metab o lites were identified in urine and feces. Identifi ed compounds amounted to 37.5

- 46.1%

of the dose at the low dose treatments and to 70.7

- 71.5% of the dose at the high dose. The study

is classified as C o re Sup plementary Data. This study does not satisfy at present the requirement, § 85

- 1 for metabolism s tudy in rats. However, this study an be ungraded to Minimum if information (as detailed in p. 13 of the DER) clarifying discrepancies between listed Rfs and apparent TLC mobilities of standards, in addition to information on the type of TLC used, is provi ded by the Registrant and is judged to be acceptable by the Agency.

870.7600 Dermal Absorption

– Rat

Executive Summary : In a dermal absorption study. 24 male Sprague

- Dawley (CD)/dose group received (PhenylUHC)S53482 by the dermal route at levels of 0.02, 0.20, or 1.0 mg/rat (0.002, 0.020 and 0.100 mg/cm 2 ) as a suspension of 50 WDC formulation in water. Four rats/per dose level were sacrificed for assessment of dermal absorption after 0.5, 1, 2, 4, 10, and 24 hours of exposure. At 0.02 mg/rat absorption ranged from 0.48% of the dose at 0.5 hours to 5.46% by 26 hours. In addition, at 24 hours the sum of material remaining in skin plus material absorbed amounted to 8.4% of the dose at 10 hours and to 18.5% of the dose at 24 hours. At 0.2 mg/rat (0.02 mg/c m), absorption ranged from 0.007% of the dose at 0.5 hours to 0.74% at 24 hours. In addition, the sum of material remaining in skin plus material absorbed amounted to .2% of the dose at 10 hours and to 2.3% of the dose at 24 hours. At 1.0 mg/rat (0.02 mg /cm 2 ), absorption ranged from 0.006% of the dose at 0.5 hours to 0.47% at 24 hours. In addition, the sum of material remaining in skin plus material absorbed amounted to 1.4% of the dose at 10 hours and to 2.4% of the dose at 24 hours. The study is class ified as Core Minimum Data (Acceptable) and satisfies the requirement (85

- 2) for a dermal absorption study in rats.

A.4.7. Immunotoxicity Study

— Subchronic Rat

In an immunotoxicity study (MRID 48402408) Flumioxazin (99.6%, Lot No. 080839G ) was

administe red in the diet to two groups ( T

- cell dependent antibody response (TDAR) andPage 64 of 70

hematology) of female Crl:CD(SD) rats at concentrations of 0 (control), 500, 1500, or 4500 ppm for 28 consecutive days (Day 0

– 28). Test substance doses were equivalent to 0, 44, 127, and 375 mg/kg bw/day, respectively, for the TDAR groups (10 females/dose) and 0, 42, 126, and 371 mg/kg bw/day, respectively, for the hematology groups (5 females/dose). On Day 24, animals in the TDAR groups were immunized with a suspension of sheep red blood cells (SRBC) by intravenous injection (2x10 8 SRBC/animal, 0.5 mL/animal dose volume). Animals in the positive control group received an intraperitoneal injection of cyclophosphamide on Days 24

- 27 at a dose of 50 mg/kg bw (10 mL/kg bw dose volum e). All animals were evaluated for mortality, clinical signs, body weight changes, food consumption, water consumption, and gross pathology. Animals in the TDAR groups were evaluated for immunotoxicity by a splenic IgM antibody plaque

- forming cell (PFC) assay; spleen and thymus weights were determined at necropsy. Animals in the hematology groups were evaluated for hematological parameters.

There were no effects of test substance treatment on mortality, clinical signs, body weight, food consumption, wat er consumption, or gross pathology. Mean corpuscular volume and mean corpuscular hemoglobin values were significantly decreased in the 1500 and 4500 ppm groups. In the 4500 ppm group, mean hemoglobin, mean corpuscular hemoglobin concentration, and

mean he matocrit values also were significantly decreased; and mean white blood cell, absolute and percent reticulocyte, absolute neutrophil, and absolute lymphocyte counts were significantly

increased.

The systemic toxicity LOAEL for Flumioxazin in female rats is 1500 ppm (equivalent to 126 mg/kg bw/day), based on signs of anemia (decreased hemoglobin and hematocrit). The NOAEL for systemic toxicity is 500 ppm (equivalent to 42 mg/kg bw/day).

There were no effects of test substance treatment on absolute or re lative thymus weights. Significantly increased mean absolute and relative spleen weights were observed in the 4500 ppm group; however, there were no effects of test substance treatment on mean spleen cell numbers, or on the IgM antibody

- forming cell (AFC) response as evaluated by AFC/10 6 spleen cells (specific activity), or AFC/spleen (total activity ) in the PFC assay.

The Natural Killer (NK) cells activity assay was not performed in this study. The toxicology

database for flumioxazin demonstrated that toxic effects were associated with anemia as well as effects on the liver and cardiovascular system. There was no evidence that suggested this chemical directly targets the immune system. Under HED guidance, NK cells activity assay is not required at th is time.

Under conditions of this study, the immunotoxicity NOAEL for anti

- SRBC PFC response is 4500 ppm (375 mg/kg/day), the highest dose tested; a LOAEL was not established. This immunotoxicity study is classified acceptable/guideline and satisfies th e guideline requirement for an immunotoxicity study (OPPTS 870.7800) in rats

.Page 65 of 70

In an immunotoxicity study (MRID 48402408) Flumioxazin (99.6%, Lot No. 080839G ) was administered in the diet to two groups ( T

- cell dependent antibody response (TDAR) and

h ematology) of female Crl:CD(SD) rats at concentrations of 0 (control), 500, 1500, or 4500 ppm for 28 consecutive days (Day 0

– 28). Test substance doses were equivalent to 0, 44, 127, and 375 mg/kg bw/day, respectively, for the TDAR groups (10 females/dose ) and 0, 42, 126, and 371 mg/kg bw/day, respectively, for the hematology groups (5 females/dose). On Day 24, animals in the TDAR groups were immunized with a suspension of sheep red blood cells (SRBC) by intravenous injection (2x10 8 SRBC/animal, 0.5 mL/an imal dose volume). Animals in the positive control group received an intraperitoneal injection of cyclophosphamide on Days 24

- 27 at a dose of 50 mg/kg bw (10 mL/kg bw dose volume). All animals were evaluated for mortality, clinical signs, body weight cha nges, food consumption, water consumption, and gross pathology. Animals in the TDAR groups were evaluated for immunotoxicity by a splenic IgM antibody plaque

- forming cell (PFC) assay; spleen and thymus weights were determined at necropsy.

Animals in the hematology groups were evaluated for hematological parameters.

There were no effects of test substance treatment on mortality, clinical signs, body weight, food consumption, water consumption, or gross pathology. Mean corpuscular volume and mean

corpuscu lar hemoglobin values were significantly decreased in the 1500 and 4500 ppm groups. In the 4500 ppm group, mean hemoglobin, mean corpuscular hemoglobin concentration, and mean hematocrit values also were significantly decreased; and mean white blood cell, absolute and percent reticulocyte, absolute neutrophil, and absolute lymphocyte counts were significantly

increased.

The systemic toxicity LOAEL for Flumioxazin in female rats is 1500 ppm (equivalent to 126 mg/kg bw/day), based on signs of anemia (decre ased hemoglobin and hematocrit). The NOAEL for systemic toxicity is 500 ppm (equivalent to 42 mg/kg bw/day).

There were no effects of test substance treatment on absolute or relative thymus weights. Significantly increased mean absolute and relative spl een weights were observed in the 4500 ppm group; however, there were no effects of test substance treatment on mean spleen cell numbers, or on the IgM antibody

- forming cell (AFC) response as evaluated by AFC/10 6 spleen cells (specific activity), or AFC/spl een (total activity ) in the PFC assay.

The Natural Killer (NK) cells activity assay was not performed in this study. The toxicology

database for flumioxazin demonstrated that toxic effects were associated with anemia as well as

effects on the liver and cardiovascular system. There was no evidence that suggested this chemical directly targets the immune system. Under HED guidance, NK cells activity assay is not required at this time.

Under conditions of this study, the immunotoxicity NOAEL for anti

- SR BC PFC response is 4500 ppm (375 mg/kg/day), the highest dose tested; a LOAEL was not established. This immunotoxicity study is classified acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in rats

.Page 66 of 70

Appendix B. Physical/Chemical Properties

Table B.1

. Physicochemical Properties of Flumioxazin.

Parameter Value Reference Melting p oint/

r ange 202

- 204°C EPA Fact Sheet for Flumioxazin issued April 12, 2001 pH 7.29 at 25°C Density 1.51 g/m L at 20°C Water solubility 1

. 079 g/L at 25°C Solvent solubility Not available Vapor pressure 2.41x10 - 6 mm Hg Dissociation constant, pK

a None Octanol/water partition coefficient, Log(K OW ) 2.55 at 20°C

UV/visible absorption spectrum λ 218 , ε = 14700 (pH 1.9)
λ 216 , ε = 43600 (pH 6.8)
λ 216 ε = 51200 (pH 10.0) MRID No. 44295004Page 67 of 70

Table 4.1.1 , lists the updated assessment of currently registered residential handler exposur es and

risk estimates. The updated exposure and risk es timates for all residential handler use pattern scenarios result in dermal risk estimates that are greater than or equal to 100 and therefore do not exceed HED’s LOC and inhalation risk estimates that are greater than or equal to 1000 and

therefore do not exceed HED’s LOC.

Appendix C . Residential Exposure/Risk Summary Table

A summary of flumioxazin residential handler exposure/risk is presented in Table C .1 below.

Table C .1. Residential Flumioxazin Handler Short

- and Intermediate

- Term Exposure and

Ris k

Use Site Equip.

Types App

.

Rate (a) Area

Treated or

Amount

Handled Daily (b) Route of

Exposure Dose

(mg/kg/day) (c,d) MOE (e) ARI (f)

Outdoor

Ornamentals ( Gardens and Trees)

WDG

Formulations Hose

- End

Sprayer

0.0000073 1200 ft 2 Dermal 0.0074 4,100 41 Inhalation 0.00000018 17,000,000

Backpack Sprayer Dermal 0.0088 3,400 13 Inhalation 0.00014 21,000

Manually

Pressurized Handwand, Dermal 0.0088 3,400
13
Inhalation 0.00014 21,000

Sprinkler

Can Dermal 0.0074 4,100 41
Inha lation 0.00000018 17,000,000

Ornamentals (Gardens and Trees)

Granular

Formulations Push Type

Spreader

0.0000087 1200 ft 2 Dermal 0.00012 240,000 1,900

Inhalation 0.00000039 7,600,000

Belly

Grinder Dermal 0.054 550 5.5

Inhalation 0.0000058 510,000

spoon Dermal 0.00094 32,000 13 0

Inhalation 0.000013 230,000

cup Dermal 0.000017 1,800,000 1,400

Inhalation 0.000002 1,500,000

Hand Dermal 10Page 68 of 70

Table C .1. Residential Flumioxazin Handler Short

- and Intermediate

- Term Exposure and

Ris k

Use Site Equip.

Types App

.

Rate (a) Area

Treated or

Amount

Handled Daily (b) Route of

Exposure Dose

(mg/kg/day) (c,d) MOE (e) ARI (f)

Dispersal 0.024 1,200

Inhalation 0.000057 52,000

Sh aker Can Dermal 0.000017 1,800,000 1,400

Inhalation 0.000002 1,500,000

Turf (Lawns, Ornamentals,

Outdoor Premises,

Recreational Areas) Manually

Pressurized

Handwand

0.38

(lb ai/A) 0.023 A Dermal

0.0087 3,400 13

Inhala tion

0.00014 22,000

Hose

- End Sprayer Dermal

0.0017 18,000 150

Inhalation 0.0000028 1,100,000

Backpack Sprayer Dermal 0.0087 3,400 13

Inhalation 0.00014 22,000

Sprinkling

Can 1,000 ft 2 Dermal

0.0017 18,000 150

Inhalation 0.0000028 1,100,000

a) Based on registered gardens and trees labels (lb ai/A converted to lb ai/sq. ft); turf labels (lb ai/A) b) Exposure Science Advisory Council Policy #9.1 and 2011 Residential SOPs c) Dermal Dose (mg/kg/day) = daily unit expo sure (mg/ lb ai) * application rate (lb ai/gallon) * amount

handled (gallons) * dermal absorption factor (100 %) / body weight (80 kg). d) Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) * application rate (lb ai/gallon) * amount

handled (gallo ns) * inhalation absorption (100%) / body weight (80 kg). e) Dermal MOE = PoD (BMDL10 of 96.3 (mg/kg/day) / Daily dermal dose (mg/kg/day); Inhalation MOE =

PoD (BMDL1SD of 3.1 mg/kg/day) / Daily inhalation dose (mg/kg/day). Dermal Level of concern = 100

, Inhalation Level of Concern = 1,000 (Adult) f) Aggregate Risk Index (ARI) = 1 / ((1/estimated MOE for adult dermal exposure/ LOC for adult dermal

exposure ) + (1/estimated MOE for adult inhalation exposure/ LOC for adult inhalation oral exposure))Page 69 of 70 Tab le C.2 : Short

- Term Residential Handler Exposure a nd Risk Estimates for Flumioxazin.

Exposure Scenario Target MOE Maximum Application Rate a Area Treated

or Amount

Handled Daily b Dermal Inhalation

Dose (mg/kg/day) c MOE d Dose (mg/kg/day) e MOE f ARI g

Gardens and Trees

– WDG Formulations

Mixer/Loader/Applicator

Mixing/Loading/Applying WDG with Manually Pressurized

Handwand 100 0.0000073 1200 ft 2 0.0088 3,400 0.00014 21,000 13

Mixing/Loading/Applying WDG

with Hose

- end Sprayer 100 0.0000073 1200 ft 2 0.0074 4,100 0.00000018 17,000,000 41

Mixing/Loading/Applying WDG with Backpack Sprayer 100 0.0000073 1200 ft 2 0.0088 3,400 0.00014 21,000 13

Mixing/Loading/Applying WDG with Sprinkler Can 100 0.0000073 1200 ft 2 0.0074 4,100 0.00000018 17,000,000 41

Gardens and Trees

– Granular Formulations

Mixer/Loader/Applicator

Applying Granule with Push Type Spreader 100 0.0000087 1200 ft 2 0.00012 240,000 0.00000039 7,600,000 1,900

Applying Granule with Belly Grinder 100 0.0000087 1200 ft 2 0.0 54 550 0.0000058 510,000 5.5

Applying Granule with Spoon 100 0.0000087 1200 ft 2 0.00094 32,000 0.000013 230,000 130

Applying Granule with Cup 100 0.0000087 1200 ft 2 0.000017 1,800,000 0.000002 1,500,000 1,400

Applying Granule w ith Hand Dispersal 100 0.0000087 1200 ft 2 0.024 1,200 0.000057 52,000 10

Applying Granule with Shaker Can 100 0.0000087 1200ft 2 0.000017 1,800,000 0.000002 1,500,000 1,400

Turf

Mixer/Loader/Applicator

Mixing/Loading/Applying WDG with Manually Pressurized

Handwand 100 0.38 0.023 acres 0.0087 3,400 0.00014 22,000 13

Mixing/Loading/Applying WDG

with Hose

- end Sprayer

100 0.38 0.023 acres 0.0017 18,000 0.0000028 1,100,000 150

Mixing/Loading/Applying WDG

with B ackpack Sprayer 100 0.38 0.023 acres 0.0087 3,400 0.00014 22,000 13Page 70 of 70 Tab le C.2 : Short

- Term Residential Handler Exposure a nd Risk Estimates for Flumioxazin.

Exposure Scenario Target MOE Maximum Application Rate a Area Treated

or Amount

Handled Daily b Dermal Inhalation

Dose (mg/kg/day) c MOE d Dose (mg/kg/day) e MOE f ARI g

Mixing/Loading/Applying WDG with Sprinkler Can 100 0.38 1,000 ft 2 0.0017 18,000 0.0000028 1,100,000 150

a. Based on registered gardens and trees labels (lb ai/A converted to lb ai/sq. ft); turf labels (lb ai/A)

b. Exposure Science Advisory Council Policy #9.1.

c. Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) x DAF (%) / BW (kg).

d. Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).

e. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallo ns/day) / BW (kg).

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

g. ARI = 1/(1/RI dermal )+ (1/RI inhalation )

Note: 1000 sq ft per day is calculated t o be equivalent to 0.023 acres (1000 sq ft /day ) x ( 43,560 sq ft /1 acre) = 0.02 3 acres/day