![](media/image1.wmf){width="1.125in"
height="1.0534722222222221in"}UNITED STATES ENVIRONMENTAL PROTECTION
AGENCY

**WASHINGTON, DC 20460**

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

#### 

#### 

#### 

#### MEMORANDUM

**D[ate]{.smallcaps}:** 28 November 2007

S[ubject]{.smallcaps}: Flumioxazin. Human Health Risk Assessment for the
Proposed Food Use of the Herbicide Flumioxazin on Alfalfa, Asparagus,
Dry Beans, Fruiting Vegetables (Group 8, Including Okra), Melons
(Subgroup 9A), Bushberries (Subgroup 13B), and Tree Nuts (Group 14), and
a Request for an Amended Use on Garlic.

[]{.mark}

**Number range CHAPTER Petition Numbers: 6F7092, 6E7151**

**PC Code: 129034**

**DP Number: 336194**

**Regulatory Citation: 40CFR §180.568**

**Chemical Class: N-phenylphthalimide Herbicide**

**Trade Names: Valor™, Chateau™**

**F[rom]{.smallcaps}:** Number range CHAPTERDebra Rate, Ph.D., Biologist

Mark Dow, Ph.D., Occupational Exposure Assessor

> Alternative Risk Integration and Assessment (ARIA) Team
>
> Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)

Registration Division (RD) (7505P)

**T[hrough]{.smallcaps}:** Number range CHAPTER William Cutchin, Acting
Senior Branch Scientist

ARIA

RIMUERB/RD (7505P)

> William T. Drew, Chemist

Registration Action Branch 2 (RAB2)

Health Effects Division (HED) (7509P)

**T[o]{.smallcaps}:** James Stone/Joanne Miller, RM Team 23

Herbicide Branch (HB)/RD (7505P)

> Number range CHAPTERDaniel Rosenblatt, Branch Chief

RIMUERB/RD (7505P)

ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged
with estimating the risk to human health from exposure to pesticides. RD
of OPP has requested that ARIA evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from proposed and currently registered uses of the active
ingredient flumioxazin.

Valent U.S.A Corporation (Valent) and Interregional Research Project No.
4 (IR-4) have submitted petitions to establish tolerances for
flumioxazin, formulated as two 51% water-dispersible granular (WDG)
formulations in/on alfalfa, asparagus, dry beans, assorted bushberries,
fruiting vegetables (including okra), melons, and tree nuts.
Additionally, IR-4 requested that the current use directions for garlic
be amended to increase the maximum use rate to 0.38 lb ai/A for the
pre-emergence application. In this document, ARIA has conducted an
assessment of the human exposure and health risks resulting from these
proposed uses and all currently registered uses. The overall risk
assessment, residue chemistry and dietary risk assessment were provided
by Debra Rate, the water exposure assessment by Larry Lui (Environmental
Fate and Effects Division (EFED)) and the occupational exposure
assessment by Mark Dow.

**TABLE OF CONTENTS**

**1.0** **Executive Summary** 5

**2.0 Ingredient Profile** 11

2.1 Summary of Proposed
Uses........................................................................11

2.2 Structure and
Nomenclature.......................................................................13

2.3 Physical and Chemical
Properties................................................................13

**3.0 Hazard Characterization** 13

3.1 Hazard and Dose-Response
Characterization...................................................14

3.1.1.1 Studies Available and Considered (Animal, Human, general
literature)\............14

3.1.1.2 Mode of Action, Metabolism, Toxicokinetic
Data....................................14

3.1.1.3 Sufficiency of
Studies/Data\...............................................................14

3.1.2 Toxicological Effects
.....................................................................14

3.1.3
Dose-Response.............................................................................16

3.1.4
FQPA........................................................................................17

3.2 Absorption, Distribution, Metabolism, Excretion
(ADME)...................................17

3.3 FQPA
Considerations..............................................................................17

3.3.1 Adequacy of te Toxicity
Database.......................................................17

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

3.3.3 Developmental Toxicity
Studies.........................................................18

3.3.4 Reproductive Toxicity
Study.............................................................18

3.3.5 Additional Information from Literature
Sources\.......................................18

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

> 3.3.6.1 Determination of
> Susceptibility.................................................19
>
> 3.3.6.2 Degree of Concern Analysis and Residual
> Uncertainties....................19

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

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

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

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

3.5.2 Acute Reference Dose (aRfD) - General
Population\...................................21

3.5.3 Chronic Reference Dose
(cRfD)........................\..................................21

3.5.4 Incidental Oral Exposure (Short- and
Intermediate-Term)...........................21

3.5.5 Dermal
Absorption....................................\......................................22

3.5.6 Dermal Exposure (Short-, Intermediate- and
Long-Term)...........................22

3.5.7 Inhalation Exposure (Short, Intermediate- and
Long-Term)........................22

3.5.8 Inhalation Exposure (Intermediate- and
Long-Term)\.................................22

3.5.9 Level of Concern for Margin of
Exposure..............................................22

3.5.10 Recommendation for Aggregate Exposure Risk
Assessments......................23

3.5.11 Classification of Carcinogenic
Potential................................................23

> 3.5.12 Summary of Toxicological Doses and Endpoints for Flumioxazin
> for Use in Human Risk
> Assessments.................................................................23

3.6 Endocrine
Disruption..........................................\......................................25

**4.0** **Public Health and Pesticide Epidemiology Data** 25

**5.0** **Dietary Exposure/Risk Characterization** 26

5.1 Pesticide Metabolism and Environmental
Degradation.........................................26

5.1.1 Metabolism in Primary Crops and Livestock Commodities 26

5.1.2 Metabolism in Rotational Crops 26

5.1.3 Analytical Methodology 27

5.1.4 Multiresidue Methods 27

5.1.5 Storage Stability 27

5.1.6 Magnitude in Plants 28

5.1.7 Magnitude in Meat, Milk, Poultry, and Eggs 28

5.1.8 Confined and Field Rotational Crops 29

5.1.9 Pesticide Metabolites and Degradates of Concern 29

5.1.10 Drinking Water Residue Profile 30

5.2 Dietary Exposure and
Risk.........................................................................30

5.2.1 Acute Dietary
Exposure/Risk..............................................................30

5.2.2 Chronic Dietary
Exposure/Risk.........................................................\...31

5.2.3 Cancer Dietary
Risk.....................................................................\.....31

**6.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** 31

6.1 Other (Spray Drift,
etc.)...............\..............................................................31

**7.0** **Aggregate Risk Assessments and Risk Characterization** 32

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

7.2 Short-Term Aggregate
Risk.....................................................................\...32

7.3 Intermediate-Term Aggregate
Risk............................................................\...32

7.4 Long-Term Aggregate
Risk.....................................................................\...32

7.5 Cancer
Risk..........................................................................................33

**8.0** **Cumulative Risk Characterization/Assessment** 33

**9.0** **Occupational Exposure/Risk Pathway** 33

9.1 Short-/Intermediate-/Long Term Handler
Risk.................................................33

9.2 Short-/Intermediate-/Long Term Handler Post-application
Risk.............................35

9.3 Restricted Entry Interval
(REI)....................................................................36

**10.0** **Tolerance Summary** 36

**11.0** **Data Needs and Label Recommendations** 38

11.1 Toxicology
..........................................\.................................................38

11.2 Residue
Chemistry..................................................................................39

11.3 Occupational and Residential
Exposure..........................................................39

**12.0** **References** 39

**Appendix** 41

Appendix A: Toxicology Assessment 41

Appendix B: Metabolism Assessment 56

Appendix C: Tolerance Reassessment Summary and Table 56

Appendix D: Review of Human Research 57

**1.0 EXECUTIVE SUMMARY**

***Background***

This document is a human health risk assessment to support Section 3
requests (PP#: 6F7092 and 6E7151) for the establishment of permanent
flumioxazin tolerances in/on alfalfa, asparagus, dry beans, assorted
bushberries, fruiting vegetables (including okra), melons, and tree nuts
(in 40 CFR§180.568). HED previously assessed the human exposure and
health risks resulting from the use of flumioxazin on pome fruit, stone
fruit, and strawberries (DP Num: 325360 and 307333, W. Drew,
15/MAR/2006). Also, a Section 18 petition assessed by ARIA (DP Num:
331793, D. Rate, 15/NOV/2006) has resulted in the establishment of a
temporary tolerance on pumpkins. The formulated end use products (EPs)
are labeled under the registered trade names Valor™, Chateau™ (EPA Reg.
No. 59639-99 and EPA Reg. No. 59639-119). No new hazard data have been
submitted since the issuance of the last ARIA risk assessment. For full
details on the hazard assessment and residential exposure assessment,
see the following previous risk assessments: 1) PP#'s 4F6829, 4E6845,
and 04AZ02; HED Risk Assessment: *Flumioxazin. Human Health Risk
Assessment for the Proposed Food Use of the Herbicide Flumioxazin on
Pome Fruit, Stone Fruit, and Strawberries (and for a Proposed Section 18
Exemption for Use on Alfalfa in Arizona*, DP Num: 325360, 307333, W.
Drew, 15/MAR/2-006; and 2) ARIA Risk Assessment: *Human Health Risk
Assessment for the Proposed Section 18 Use on Pumpkin in Illinois*, DP
Num: 331793, D. Rate, 15/NOV/2006.

This document includes revised dietary (food and drinking water),
occupational (handler and post-application), and aggregate assessments.

***Proposed Uses***

Flumioxazin is an herbicide of the N-phenylphthalimide class (Group 14)
that is currently used for pre- and post-emergence control of
susceptible weeds in a variety of fruit, vegetable and other field
crops. Its mode of action is as an inhibitor of protoporphyrinogen
oxidase (PPO); it is active against certain grasses, broadleaf weeds,
and sedges.

The flumioxazin products to be applied are formulated as two 51%
water-dispersible granular (WDG) formulations. Flumioxazin is to be
applied as a broadcast soil or foliar spray by ground or aerial
equipment. The proposed use patterns allow up to 2 applications to be
made at an application rate of 0.375 lb ai/A/season with re-treatment
intervals (RTIs) ranging from 30 to 60 days. The proposed use on alfalfa
is for a broadcast application within 7 days after cutting, at a use
rate of 0.125 lb ai/A. A maximum of two applications are proposed per
season, and a 25-day pre-harvest interval (PHI) is specified. For
asparagus, the proposed use is for a single broadcast application prior
to spear emergence, at up to 0.375 lb ai/A, with a 14-day PHI. For
fruiting vegetables and okra, the proposed use is for up to two soil
applications, directed to row middles, at up to 0.125 lb ai/A, following
transplanting or seedling emergence and again \~21 days prior to
harvest, for a maximum use rate of 0.25 lb ai/A/season. A 21-day PHI is
specified for fruiting vegetables, and applications may include use of a
crop oil concentrate (COC) at 1% v/v. For melons, the proposed use is
for up to two soil applications, directed to row middles, at up to 0.125
lb ai/A; the applications are to be made either pre-plant or
pre-emergence and again 21-28 days later, for a maximum use rate of 0.25
lb ai/A/season. No PHI is specified for melons. For dry beans, the
proposed use is for a single broadcast application at up to 0.093 lb
ai/A, as either a pre-emergence application (weed control), or as a
late-season broadcast foliar application (harvest aid). A 5-day PHI is
specified for dry beans, and the late-season use may include a COC at 1%
v/v. For tree nuts, the proposed use is for up to two soil-directed
applications at 0.375 lb ai/A at RTIs of 60 days, for a maximum use rate
of 0.75 lb ai/A/season, with a PHI of 60 days. For bushberries, the
proposed use is for up to two soil-directed applications at 0.375 lb
ai/A, during early spring and again during the later stages of berry
development, for a maximum use rate of 0.75 lb ai/A/season. A 7-day PHI
is specified, and only the single early season application is allowed on
lowbush blueberries. The petitioner has also requested an increased
maximum use rate of 0.38 lb ai/A/season on garlic.

***Toxicology and Dose-Response***

On November 28, 2000, HED reviewed the toxicology database for
flumioxazin with regard to the acute and chronic population adjusted
doses (PAD) and the toxicological endpoint selection for use (as
appropriate) in occupational/residential exposure risk assessments. The
endpoint selected for acute dietary risk assessment was based on
cardiovascular effects (especially ventricular septal defects in
fetuses) observed in oral developmental and supplemental pre-natal
studies in rats. The acute population-adjusted dose (aPAD) is only to be
used for females of childbearing age. No acute dietary endpoint was
identified for the general population or other population subgroups. The
endpoint for chronic dietary risk assessment was based on increased
chronic nephropathy in males and decreased hematological parameters in
females (Hgb, MCV, MCH, and MCHC) observed in a 2-year
chronic/carcinogenicity study in rats. The chronic population-adjusted
dose (cPAD) is applicable to all population subgroups.

A no observable adverse effects level (NOAEL) of 30.0 mg/kg/day was
selected by HED from a rat dermal developmental toxicity study for
short- and intermediate-term dermal assessments. The NOAEL was based on
a biologically significant increase in cardiovascular abnormalities,
particularly ventricular septal defects. Since the dermal endpoints were
based on dermal studies, an absorption factor was not required for
dermal assessments

For short-term inhalation exposure, a NOAEL of 3.0 mg/kg/day was
selected by HED from an oral developmental study in rats, based on a
biologically significant increase in cardiovascular abnormalities,
particularly ventricular septal defects, at 10 mg/kg/day. For
intermediate-term inhalation exposure, a NOAEL of 2.0 mg/kg/day was
selected from a 2-year chronic rat study, based on increased chronic
nephropathy in males, and decreased hematological parameters in females.

Flumioxazin has mild or no acute toxicity (categories III or IV) when
administered orally, dermally, or by inhalation. It has little or no
toxicity (categories III or IV) with regard to eye irritation or skin
irritation. The chemical, flumioxazin, was not a dermal sensitizer.
Subchronic and chronic toxicity studies demonstrated that the target
organs of flumioxazin are the liver, spleen and cardiovascular system.
Developmental effects were observed in developmental rat studies. These
effects were fetal cardiovascular anomalies (especially ventricular
septal defects).

Number range CHAPTER

The cancer classification of flumioxazin was made by HED. HED determined
that flumioxazin should be classified as a "Not Likely Human
Carcinogen," based on the lack of carcinogenicity in a 2-year rat study,
an 18-month mouse study, and a battery of mutagenic studies.

The toxicology database is adequate to choose endpoints for the purposes
of risk assessment. The scientific quality is relatively high and the
toxicity profile can be characterized for all effects, including
developmental and reproductive.

The flumioxazin toxicology database has been re-evaluated according to
2002 Food Quality Protection Act (FQPA) policies. The FQPA safety factor
(SF) was reduced to 1x based on toxicological considerations by the FQPA
Safety Factor Committee (DP Num: 298652, A. Levy, 25/MAR/2004), the
conservative residue assumptions used in the dietary exposure risk
assessments (DP Num: 342753, D. Rate, 30/OCT/2007), and the completeness
of the residue chemistry (DP Num: 342963, D. Rate, 20/NOV/2007) and
environmental fate databases (DP Num: 336195, 342249 and 331732; L. Liu;
25/SEP/2007).

***Residue Chemistry***

The nature of the residue in plants and livestock is adequately
understood, based on adequate corn, sugarcane, grape, hen, and goat
metabolism data. For the purposes of tolerance establishment and dietary
risk assessment (in food), in primary and rotated crops, the residue of
concern is the parent compound only. For ruminants, the residues of
concern are parent, 3-OH-flumioxazin, 4-OH-flumioxazin, plus Metabolites
B, C, and F. For poultry, the residues of concern are parent,
3-OH-flumioxazin, 4-OH-flumioxazin, and 4-OH-S-53482-SA. The proposed
use on alfalfa results in livestock feed items of regulatory concern.
The petitioner submitted an adequate cattle feeding study. As residues
of flumioxazin and its two hydroxy metabolites were less than the limit
of detection (LOD) in all samples of milk and tissues from cattle dosed
for 28 days at levels equivalent to 20 ppm in their diet, or 16x the
theoretical dietary burden (TDB), quantifiable residues are unlikely to
occur in cattle, goats, horse, or sheep. Therefore, tolerances for
flumioxazin residues are not required in commodities from cattle, goats,
hogs, horses or sheep (40 CFR §180.6\[a\]\[3\]). In addition, results
from the available poultry metabolism study, in which hens were dosed
for 14 days at 9.0 ppm (1,800x TDB), indicate that quantifiable residues
are unlikely to occur in eggs or poultry tissues. Therefore, tolerances
for flumioxazin residues are also not required in eggs or poultry
tissues (40 CFR §180.6\[a\]\[3\]). An adequate confined rotational crop
study is available to support the uses on the proposed crops that can be
rotated (alfalfa, dry beans, fruiting vegetables, melon, and garlic).
Based on the results of the confined accumulation study, ARIA concludes
that the current rotational crop plant-back intervals (PBIs) are
acceptable and that field trials and tolerances in rotated crops are not
necessary.

An adequate gas chromatography/nitrogen-phosphorus detection (GC/NPD)
method is available for enforcing tolerances of flumioxazin in/on plant
commodities (Valent Method RM-30-A-1). The reported method limits of
quantitation and detection (LOQ and LOD) for flumioxazin in plant
commodities are 0.02 and 0.01 ppm, respectively. Residues of flumioxazin
in samples of raw agricultural commodities (RACs) from the current field
trials were determined using an adequate GC/NPD method (Method
RM-30A-3), which is a more recent version of the enforcement method. The
validated method LOQ for flumioxazin in/on all plant commodities is 0.02
ppm, and the LODs ranged from 0.005 to 0.01 ppm. Valent Method RM-30-A-1
has undergone a successful independent laboratory validation (ILV) trial
and a successful petition method validation (PMV) trial by the Agency.

Although the submitted field trial and processing data are adequate, and
support the proposed use patterns for flumioxazin on alfalfa, asparagus,
dry beans, assorted bushberries, fruiting vegetables (including okra),
melons, and tree nuts, the petitioner should submit a revised Section F
so the commodity definitions and proposed tolerances match those listed
in Table 10.0 and a revised label to match the proposed uses to those
submitted in the field trial data. Specifically, the following revisions
should be made to the label:

> • For dry beans, the labels may specify a maximum single and seasonal
> use rate of up to 0.093 lb ai/A, including both the preemergence and
> pre-harvest uses.
>
> • For fruiting vegetables (including okra) and melons, labels may
> allow for up to two directed applications per season at up to 0.125 lb
> ai/A/application.
>
> • For melons, applications after blooming should be prohibited.
>
> • For tree nuts, the labels should specify a minimum RTI of 60 days
> rather than 30 days.
>
> • For asparagus, a maximum single application rate of up to 0.375 lb
> ai/A may be specified.

***Dietary Risk (Food and Drinking Water)***

The estimated drinking water concentration (EDWC) for flumioxazin
residues (flumioxazin, 482-HA, and APF) used in this dietary risk
assessment was obtained from Environmental Fate and Effects Division's
(EFED's) environmental risk assessment for flumioxazin, Drinking Water
Assessment for: (1) IR-4 Registration for Flumioxazin to be used on
Asparagus, Dry Bean, Bushberry Subgroup 13B, Fruiting Vegetable Subgroup
8, Melon Subgroup 9A, Okra and Tree Nut Subgroup 14; and (2) Section 3
Registration for Use on Field Corn and Alfalfa; DP Num: 336195, 342249,
and 331732; L. Liu; 25/SEP/2007. The EDWC for flumioxazin residues (used
in both the acute and chronic dietary analyses) was 0.048 ppm, the
concentration in groundwater as estimated by the SCI-GROW (Screening
Concentration In GROundWater) model. SCI-GROW is an empirical model for
predicting pesticide levels in groundwater; the value from SCI-GROW is
considered an upper bound concentration estimate, and thus conservative.
These estimates of residues in drinking water were incorporated directly
into the DEEM-FCID model of the dietary risk assessment; i.e., into the
food categories "water, direct, all sources" and "water, indirect, all
sources."

The acute dietary exposure analysis for flumioxazin is an unrefined
assessment, assuming 100% crop treated and tolerance level residues,
modified by DEEM processing factors, Version 7.81, for processed
commodities (with the exception of tomato, which used the empirical
processing factor of one). The acute dietary endpoint is applicable only
to the population subgroup females 13- 49 years old. An acute dietary
endpoint for the general population, including infants and children was
not identified. The estimated acute dietary exposure (food and drinking
water) for females 13-49 years old occupies 8% of the aPAD and does not
exceed ARIA's level of concern.

Similarly, the chronic dietary exposure analysis for flumioxazin is an
unrefined assessment, with the same residue assumptions as the acute
analysis. The chronic dietary endpoint applies to all population
subgroups, including infants and children. The estimated chronic dietary
exposure (food and water) from flumioxazin does not exceed ARIA's level
of concern for any population subgroup. Food and water exposure occupies
6% of the cPAD for the US population and 18% of the cPAD for all infants
(\<1 year old), the subgroup with the highest exposure.

***Residential Risk***

Flumioxazin is not intended for use in public or residential settings.
Therefore, residential exposure is not expected, and no residential risk
assessment was performed.

***Aggregate Risk***

The contribution to dietary exposure arising from residues of
flumioxazin and its degradates in surface and ground water sources of
drinking water were included in the acute and chronic dietary exposure
analyses. Because there are no residential uses, the aggregate exposure
and risk are equivalent to those from dietary exposure (food and water)
and do not exceed the Agency's level of concern.

***Occupational Exposure and Risk***

Workers may be exposed to flumioxazin during mixing, loading, and
application activities associated with agricultural crops. No
chemical-specific data were available with which to assess potential
exposure to pesticide handlers, so estimates of exposure to pesticide
handlers are based upon surrogate study data available in the *Pesticide
Handler's Exposure Database* (PHED), Version 1.1 of August 1998.
Defaults established by HED's Science Advisory Council for Exposure
(ExpoSAC) were used for acres treated per day and body weight.

A margin of exposure (MOE) of 100 or more is sufficient to protect
occupational pesticide handlers. Occupational handler assessments
indicate that all MOEs are above the levels of concern at the baseline
level (total MOEs = 330 to 1,100). Post-application MOEs for melons
(irrigation) and dry beans (hand harvest) are also above the levels of
concern (430 to 540) on the day of application. The post-application
MOEs for the other commodities were not determined because the exposures
to flumioxazin for workers performing post-application activities on
these commodities are expected to be negligible. The 12-hour restricted
entry interval (REI) appearing on the label is appropriate for this
chemical.

***Environment Justice***

Potential areas of environmental justice concern, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, \"Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,\"
(<http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf>).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup's
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting. Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide. These data
are analyzed and categorized by subgroups based on age, season of the
year, ethnic group, and region of the country. Additionally, OPP is able
to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant. Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
post-application are evaluated. Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

***Review of Human Research***

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical. These studies (listed in Appendix D) have been determined to
require a review of their ethical conduct, and have received that
review.

***Additional Data Needs and Recommendations:***

No major deficiencies were noted in the subject petitions that would
preclude establishing permanent tolerances for flumioxazin in/on the
proposed commodities; however the petitioner should address the
deficiencies noted below. The available rNumber range CHAPTEResidue data
support the Number range CHAPTERestablishment of permanent tolerances
for flumioxazin residues at 0.02 ppm in/on asparagus, fruiting
vegetables, melons, okra, tree nuts and assorted bushberries, at 0.05
ppm in/on dry beans, and at 3.0 and 8.0 ppm respectively in/on alfalfa
forage and hay. Provided the following deficiencies are addressed,
Number range CHAPTERARIA recommends in favor of establishing the
tolerances as listed in Table 10.0.

> • Use directions for the proposed crops should be revised as indicated
> under the conclusions for the Use Directions Section (Section 2.1).
>
> • Section F of both petitions should be revised to reflect the
> recommended tolerance levels and correct commodity definitions listed
> in Table 10.0 (Section 10.0).

2.  **Ingredient Profile:**

Flumioxazin is an herbicide of the N-phenylphthalimide class (Group 14)
that is currently used for pre- and post-emergence control of
susceptible weeds in a variety of fruit, vegetable and other field
crops. Its mode of action is as an inhibitor of protoporphyrinogen
oxidase (PPO); it is active against certain grasses, broadleaf weeds,
and sedges. Tolerances are currently established for residues of the
flumioxazin in/on various plant commodities, at levels ranging from 0.02
to 0.70 ppm (40 CFR §180.568\[a\]). Temporary tolerances associated with
a Section 18 emergency exemption have also been established on alfalfa
forage and hay at 0.13 and 0.45 ppm, respectively (40 CFR 180.568\[b\]).

Valent has submitted a petition (PP# 6F7092) proposing the use of
flumioxazin, formulated as a 51% WDG, on alfalfa, and IR-4 has submitted
a separate petition (PP# 6E7151) proposing new uses of flumioxazin on
tree nuts, melons, dry beans, bushberries, fruiting vegetables
(including okra), and asparagus. The nomenclature and physicochemical
properties of flumioxazin are presented below in Tables 2.2 and 2.3.

**2.1 Summary of Proposed Uses:**

+-----------------+-------+----+------+-------+---+-----------------+
| **Table 2.1.    |       |    |      |       |   |                 |
| Summary of      |       |    |      |       |   |                 |
| Directions for  |       |    |      |       |   |                 |
| Use of          |       |    |      |       |   |                 |
| Flumioxazin.    |       |    |      |       |   |                 |
| ^1^**           |       |    |      |       |   |                 |
+=================+=======+====+======+=======+===+=================+
| Applic. Timing, | F     | A  | Max. | Max.  | P | Use Directions  |
| Type, and       | ormul | pp | No.  | Sea   | H | and Limitations |
| Equip.          | ation | li | App  | sonal | I | ^2^             |
|                 |       | c. | lic. | Ap    |   |                 |
|                 | \[EPA | Ra | per  | plic. | ( |                 |
|                 | Reg.  | te | Se   | Rate  | d |                 |
|                 | No.\] |    | ason |       | a |                 |
|                 |       | (  |      | (lb   | y |                 |
|                 |       | lb |      | ai/A) | s |                 |
|                 |       | a  |      |       | ) |                 |
|                 |       | i/ |      |       |   |                 |
|                 |       | A) |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| **Alfalfa       |       |    |      |       |   |                 |
| (established    |       |    |      |       |   |                 |
| plantings)**    |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| Broadcast       | 51%   | 0  | 2    | 0.25  | 2 | A minimum RTI   |
| foliar          | WDG   | .1 |      |       | 5 | of 60 days is   |
| application     | \[    | 25 |      |       |   | specified.      |
| within 7 days   | 59639 |    |      |       |   |                 |
| after cutting;  | -99\] |    |      |       |   | Do not apply    |
| ground or       |       |    |      |       |   | with any        |
| aerial          | \[5   |    |      |       |   | adjuvants or    |
| equipment       | 9639- |    |      |       |   | tank mix with   |
|                 | 119\] |    |      |       |   | EC              |
|                 |       |    |      |       |   | formulations.   |
|                 |       |    |      |       |   |                 |
|                 |       |    |      |       |   | Do not use on   |
|                 |       |    |      |       |   | mixed stands of |
|                 |       |    |      |       |   | alfalfa and     |
|                 |       |    |      |       |   | grass.          |
+-----------------+-------+----+------+-------+---+-----------------+
| **Dry Beans**   |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| **Weed          | 51%   | 0  | 1    | 0.093 | N | Apply in a      |
| control**:      | WDG   | .0 |      |       | A | minimum of 10   |
| Pre-emergence   | \[    | 93 |      | (     |   | gal/A.          |
| broadcast       | 59639 |    |      | 0.05) |   |                 |
| application;    | -99\] | (0 |      |       |   | Use is          |
| ground          |       | .0 |      |       |   | restricted to   |
| equipment       | \[5   | 5) |      |       |   | areas west of   |
|                 | 9639- |    |      |       |   | US Hwy 83 in CO |
|                 | 119\] |    |      |       |   | and NE          |
+-----------------+-------+----+------+-------+---+-----------------+
| **Harvest       |       | 0  | 1    | 0.093 | 5 | Application may |
| aid:**          |       | .0 |      |       |   | include a COC   |
| Broadcast       |       | 93 |      | (     |   | at 1% v/v.      |
| foliar          |       |    |      | 0.05) |   |                 |
| application to  |       | (0 |      |       |   | Apply in a      |
| mature beans;   |       | .0 |      |       |   | minimum of 10   |
| ground          |       | 5) |      |       |   | gal/A (15       |
| equipment       |       |    |      |       |   | gal/A).         |
+-----------------+-------+----+------+-------+---+-----------------+
| **Fruiting      |       |    |      |       |   |                 |
| Vegetables      |       |    |      |       |   |                 |
| (including      |       |    |      |       |   |                 |
| Okra)**         |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| Directed soil   | 51%   | 0  | 2    | 0.25  | 2 | Applications    |
| applications to | WDG   | .1 |      |       | 1 | may include a   |
| row middles     | \[    | 25 | \    | (0    |   | COC at 1% v/v.  |
| after           | 59639 |    | (1\) | .096) | ( |                 |
| transplanting   | -99\] | (  |      |       | N | Apply in a      |
| or emergence    |       | 0. |      |       | S | minimum of 10   |
| and             | \[5   | 09 |      |       | ) | gal/A (15       |
| approximately   | 9639- | 6) |      |       |   | gal/A).         |
| 21 days prior   | 119\] |    |      |       |   |                 |
| to harvest;     |       |    |      |       |   | Use directed    |
| ground          |       |    |      |       |   | for shielded    |
| equipment       |       |    |      |       |   | sprayers for    |
|                 |       |    |      |       |   | all             |
|                 |       |    |      |       |   | applications.   |
+-----------------+-------+----+------+-------+---+-----------------+
| **Melons**      |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| Directed soil   | 51%   | 0  | 2    | 0.25  | N | Minimum RTIs of |
| applications to | WDG   | .1 |      |       | S | 21-28 days.     |
| row middles,    | \[    | 25 | \    | (0    |   |                 |
| pre-plant or    | 59639 |    | (1\) | .096) |   | Use directed    |
| pre-emergence,  | -99\] | (  |      |       |   | for shielded    |
| and             |       | 0. |      |       |   | sprayers for    |
| post-emergence  | \[5   | 09 |      |       |   | all             |
| 21-28 days      | 9639- | 6) |      |       |   | applications.   |
| later; ground   | 119\] |    |      |       |   |                 |
| equipment       |       |    |      |       |   | Apply in a      |
|                 |       |    |      |       |   | minimum of 10   |
|                 |       |    |      |       |   | gal/A (15       |
|                 |       |    |      |       |   | gal/A).         |
+-----------------+-------+----+------+-------+---+-----------------+
| **Bushberries** |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| **Lowbush       | 51%   | 0  | 1    | 0.375 | N | Apply in a      |
| blueberry:**    | WDG   | .3 |      |       | S | minimum of 20   |
| Directed soil   | \[    | 75 |      |       |   | gal/A (15       |
| application in  | 59639 |    |      |       |   | gal/A).         |
| early spring;   | -99\] |    |      |       |   |                 |
| ground          |       |    |      |       |   | The minimum RTI |
| equipment       | \[5   |    |      |       |   | is 30 days.     |
|                 | 9639- |    |      |       |   |                 |
|                 | 119\] |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| **Other         |       | 0  | 2    | 0.75  | 7 |                 |
| bushberries:**  |       | .3 |      |       |   |                 |
| Directed soil   |       | 75 |      |       |   |                 |
| application in  |       |    |      |       |   |                 |
| early spring    |       |    |      |       |   |                 |
| and during the  |       |    |      |       |   |                 |
| later stages of |       |    |      |       |   |                 |
| berry           |       |    |      |       |   |                 |
| development.    |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| **Tree Nuts     |       |    |      |       |   |                 |
| (including      |       |    |      |       |   |                 |
| Pistachios)**   |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| Soil directed   | 51%   | 0  | 2    | 0.75  | 6 | The minimum RTI |
| applications;   | WDG   | .3 |      |       | 0 | is 60 days (30  |
| ground          | \[    | 75 |      |       |   | days). Apply in |
| equipment       | 59639 |    |      |       |   | a minimum of 20 |
|                 | -99\] |    |      |       |   | gal/A (15       |
|                 |       |    |      |       |   | gal/A).         |
|                 | \[5   |    |      |       |   |                 |
|                 | 9639- |    |      |       |   |                 |
|                 | 119\] |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| **Asparagus**   |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| Broadcast soil  | 51%   | 0  | 1    | 0.375 | 1 | Apply in a      |
| application     | WDG   | .3 |      |       | 4 | minimum of 20   |
| prior to spear  | \[    | 75 |      | (0    |   | gal/A (or 15    |
| emergence       | 59639 |    |      | .255) |   | gal/A).         |
|                 | -99\] | (  |      |       |   |                 |
|                 |       | 0. |      |       |   |                 |
|                 | \[5   | 25 |      |       |   |                 |
|                 | 9639- | 5) |      |       |   |                 |
|                 | 119\] |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| **Garlic**      |       |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+
| Pre-emergence   | 51%   | 0. | 1    | 0.38  | N | Apply in a      |
| broadcast       | WDG   | 38 |      |       | S | minimum of 10   |
| application     | \[    |    |      |       |   | gal/A.          |
| within 3 days   | 59639 |    |      |       |   |                 |
| of planting;    | -99\] |    |      |       |   |                 |
| ground          |       |    |      |       |   |                 |
| equipment       | \[5   |    |      |       |   |                 |
|                 | 9639- |    |      |       |   |                 |
|                 | 119\] |    |      |       |   |                 |
+-----------------+-------+----+------+-------+---+-----------------+

***Conclusions*** The available labels and summaries of the proposed use
directions are adequate for evaluation of the field trial data. However,
discrepancies were noted in the maximum use rates and the minimum
application volumes listed on example labels and in the use summaries
provided by IR-4. For purposes of this review, the use summaries
provided by IR-4 were considered to represent the intended 1x use rate.
For each crop, the use directions on the proposed labels must be
reconciled with the directions listed in the use summaries, and new
labels should be submitted. Based on the available field trial data, the
following revisions should also be made to the proposed labels for the
51% WDG formulations.

> • For dry beans, the labels may specify a maximum single and seasonal
> use rate of up to 0.093 lb ai/A, including both the pre-emergence and
> pre-harvest uses.
>
> • For fruiting vegetables (including okra) and melons, labels may
> allow for up to two directed applications per season at up to 0.125 lb
> ai/A/application.
>
> • For melons, applications after blooming should be prohibited.
>
> • For tree nuts, the labels should specify a minimum RTI of 60 days
> rather than 30 days.
>
> • For asparagus, a maximum single application rate of up to 0.375 lb
> ai/A may be specified.

**2.2 Structure and Nomenclature**:

  ------------------------------------------------------------------------------------------------------------------------------------------------
  **Table 2.2.        
  Flumioxazin         
  Nomenclature.**     
  ------------------- ----------------------------------------------------------------------------------------------------------------------------
  Compound            ![](media/image2.wmf){width="2.209722222222222in" height="1.4979166666666666in"}

  Common name         Flumioxazin

  Company             VC-1152
  experimental name   

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

  CAS name            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 registry number 103361-09-7

  End-use product     51% WDG, Valor Herbicide and Chateau ™ WDG Herbicide
  (EP)                
  ------------------------------------------------------------------------------------------------------------------------------------------------

**2.3 Physical and Chemical Properties**:

+--------------------------+-------------------------+-----------------+
| **Table 2.3.             |                         |                 |
| Physicochemical          |                         |                 |
| Properties of            |                         |                 |
| Flumioxazin.**           |                         |                 |
+==========================+=========================+=================+
| Parameter                | Value                   | Reference       |
+--------------------------+-------------------------+-----------------+
| Melting point/range      | 202-204 °C              | EPA Fact Sheet  |
+--------------------------+-------------------------+-----------------+
| pH                       | 7.29 at 25 °C           |                 |
+--------------------------+-------------------------+-----------------+
| Density                  | 1.51 g/ml at 20 °C      |                 |
+--------------------------+-------------------------+-----------------+
| Water solubility (25°C)  | 1079 mg/L               |                 |
+--------------------------+-------------------------+-----------------+
| Solvent solubility       | Not available           |                 |
+--------------------------+-------------------------+-----------------+
| Vapor pressure           | 2.41 x10^-6^ mm Hg      |                 |
+--------------------------+-------------------------+-----------------+
| Dissociation constant,   | None                    |                 |
| pK~a~                    |                         |                 |
+--------------------------+-------------------------+-----------------+
| Octanol/water partition  | 2.55 at 20 °C           |                 |
| coefficient, Log(K~OW~)  |                         |                 |
+--------------------------+-------------------------+-----------------+
| UV/visible absorption    | ~218~,  = 14700 (pH   |                 |
| spectrum                 | 1.9)                    |                 |
|                          |                         |                 |
|                          | ~216~,  = 43600 (pH   |                 |
|                          | 6.8)                    |                 |
|                          |                         |                 |
|                          | ~216~,  = 51200 (pH   |                 |
|                          | 10.0)                   |                 |
+--------------------------+-------------------------+-----------------+

**3.0 HAZARD CHARACTERIZATION**

The toxicology database is adequate to choose endpoints. There are no
neurotoxicity nor inhalation studies (other than acute LC50 inhalation).
The scientific quality is relatively high and the toxicity profile can
be characterized for all effects, including developmental and
reproductive. There is increased susceptibility of rats (not rabbits) to
*in-utero* and post-natal exposure to flumioxazin.

**3.1 Hazard and Dose-Response Characterization**

**3.1.1.1 Studies available and considered (animal, human, general
literature)**

[Acute]{.underline}- oral, dermal, inhalation, eye irritation, dermal
irritation, skin sensitization;

[Subchronic]{.underline}- Dermal 21-day rat; Oral 28-day mouse, oral
90-day rat, oral 90-day dog;

[Chronic]{.underline}- Oral dog and rat;

[Carcinogenicity]{.underline}- Rat and mouse;

[Reproductive/developmental]{.underline}- Oral Pre-natal developmental
rat, oral pre-natal developmental rabbit, dermal pre-natal developmental
rat, 2-generation rat;

[Other]{.underline}- Mutagenicity screens, metabolism and
pharmacokinetic studies, dermal penetration rat, and a Special Study:
Rat Developmental: Critical Time for Defects.

2.  **Mode of action, metabolism, toxicokinetic data**

Flumioxazin is an herbicide of the N-phenylphthalimide class (Group 14)
that is currently used for pre- and post-emergence control of
susceptible weeds in a variety of fruit, vegetable and other field
crops. Its mode of action is as an inhibitor of protoporphyrinogen
oxidase (PPO); it is active against certain grasses, broadleaf weeds,
and sedges.

Metabolism studies in rats indicated that there was extensive biliary
excretion following oral administration of flumioxazin. It is noted that
4-5 times more radioactivity is excreted in feces than in urine.
Radioactivity excretion in urine was statistically significantly
elevated in females (38.8-42.8%, low dose; 22.9-23.4%, high dose) vs.
males (28.1-30.8%, low dose; 12.8-13.0%, high dose). Highest levels of
residues were found in blood cells (35.9-48.8 ppb, low dose and
2823-3040 ppb, high dose), which were much higher than the plasma levels
(0.5-0.7 ppb, low dose and 53-37 ppb, high dose).

3.  **Sufficiency of studies/data**

The available studies provide sufficient information to determine
whether and to what extent flumioxazin poses a human health hazard (see
Appendix A for acute and repeated dose studies/findings). Acute and
chronic reference doses for dietary risks as well as doses for
non-dietary risks are based on guideline acceptable studies with
well-characterized endpoints and NOAEL/LOAEL values. The available
studies have been thoroughly evaluated for guideline acceptability by
individual reviewers and peer-review committees and the database is
considered sufficient to characterize and quantify risk.

**3.1.2 Toxicological Effects**

The toxicity profile of flumioxazin, including acute toxicities, may be
found in Appendix A.

[Acute Toxicity:]{.underline} The toxicology data base for flumioxazin
is considered adequate for risk assessment purposes. The overall
toxicity profile for flumioxazin is summarized in Appendix A, Table
A.2.1. Flumioxazin has mild or no acute toxicity (categories III or IV)
when administered orally, dermally, or by inhalation. It is also
classified as Toxicity Category III or IV for primary eye and skin
irritation. Flumioxazin is not a dermal sensitizer.

[Reproductive and Developmental Toxicity:]{.underline} The pre- and
post-natal toxicity database for flumioxazin include the rat and rabbit
developmental toxicity studies and the two-generation reproduction
toxicity study in rats. There is quantitative evidence of increased
susceptibility of the rat fetuses to *in-utero* exposure to flumioxazin
in the oral and dermal developmental studies. In both studies, there was
an increased incidence in fetal cardiovascular anomalies (especially
ventricular septal defects). In the oral study, no maternal effects were
seen at the highest dose tested (30 mg/kg/day); whereas, the effects in
the fetuses were observed at 10 mg/kg/day. In the dermal study, no
maternal effects were noted at the highest dose tested (300 mg/kg/day);
whereas, the effects in the fetuses were observed at 100 mg/kg/day.
Regarding the 2-generation rat reproduction study, parental effects (red
substance in vagina and increased mortality in females as well as
decreases in male and female body weights, body weight gains and food
consumption) were noted at 18.9 mg/kg/day in males at the highest dose
tested (HDT) and 22.7 mg/kg/day in females (HDT). The effects observed
regarding reproduction/offspring were a decrease in both the number of
liveborn and pup body weights at 12.7 mg/kg/day for males and 15.1
mg/kg/day for females. Therefore, it was considered that there was a
quantitative increase in susceptibility.

In a 2-generation feeding reproduction study in rats, systemic/parental
findings included increased clinical signs (red substance in vagina) and
female mortality as well as decreases in body weight, body weight gain
and food consumption (both sexes) at 19-23 mg/kg/day (HDT). There were
no apparent effects on reproductive parameters at the HDT. Regarding
offspring, at a parental dose of 12.7 mg/kg/day for males and 15.1
mg/kg/day for females, there were decreases in the number of liveborn as
well as in pup body weights.

Fetal effects seen in the two rat developmental studies and effects on
the pups noted in the reproduction study were observed at doses lower
than the effects noted in the mothers (developmental) or parents
(mothers or fathers). It was therefore considered that there was an
increase in quantitative susceptibility regarding fetus/pups in the rat
developmental and reproduction studies.

A number of mechanistic studies were submitted by the Registrant
regarding the hematopoietic and fetal effects in order to explain the
relationship of these. The Registrant submitted a document which
included the following paragraph: "An hypothesis was developed, outlined
in Figure 1, which postulates the mechanism by which developmental
toxicity is produced by flumioxazin. In this scheme, initial research
findings indicated that flumioxazin inhibits a key enzyme,
protoporphyrinogen oxidase (PPO), in rats, thereby interfering with
normal heme synthesis, and resulting in anemia. We postulate that the
fetal anemia leads to hypoxia in fetal tissues followed by suppressed
liver function and a decrease in protein synthesis. We suggest that the
decreased protein synthesis would result in wavy ribs and changes in
osmotic forces leads to the 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. Thus, we believe
the VSD \[Ventricular Septal Defect\] observed in the teratology study
is produced by mechanical distortion of the heart. The two other signs
of developmental toxicity reported, growth retardation and fetal death,
we believe, are also related to the hypoxia produced by the anemic
condition in the fetus." Based upon the results of the rat developmental
studies, and in particular the "single dose" study, there may be a
question regarding the explanation presented by the Registrant
pertaining to the hematopoietic cause for the ventricular septal defect.

HED referred the flumioxazin mechanism data to the Mechanism of Toxicity
Assessment Review Committee to determine whether or not the heart
defects are the result of anemia. At this time HED is deferring
resolution of this issue. It will be addressed with a future flumioxazin
action in light of the very low risk associated with the present
conservative assessment.

There was evidence of quantitative susceptibility following oral and
dermal exposures to rats. Following *in-utero* exposures, developmental
effects (cardiovascular anomalies) were seen at lower doses in the
absence of maternal toxicity. There was no evidence (quantitative or
qualitative) of susceptibility following *in-utero* oral exposure in
rabbits. No developmental toxicity was seen at the HDT (3x the
Limit-Dose). There was quantitative evidence of susceptibility in the
multigeneration reproduction study where effects in offspring were seen
at doses lower than those which induced effects in parental animals.

[Neurotoxicity:]{.underline} HED concluded that there is no concern for
neurotoxicity resulting from exposure to flumioxazin. None of the acute,
subchronic, chronic, developmental or reproduction studies indicated an
effect on the nervous systems.

[Carcinogenicity:]{.underline} In accordance with the 1999 *Proposed
Guidelines for Carcinogen Risk Assessment*, HED determined that the
chemical was "not likely to be a human carcinogen." Flumioxazin did not
induce significant increases in any tumor type in either rats or mice
under the conditions of the studies and it does not induce any mutagenic
activity.

**3.1.3 Dose-response**

The results of subchronic toxicity study in dogs suggest the liver as a
possible target organ; however, the hepatic effects were minimal even
following administration of a limit dose. Histopathological lesions
noted in high-dose males and females consisted of proliferation and
dilatation of bile ducts. Increased fibrous tissue around centrolobular
veins was noted in high-dose males. Gross hepatic lesions seen in
high-dose males and females consisted of rounded margin and hepatic
enlargement. Significant increases in total cholesterol levels,
phospholipid levels, and alkaline phosphatase activities were also
observed in the high-dose males and females. In addition, liver weights
were significantly increased at 1000 mg/kg in both sexes. The increase
in liver weights was associated with proliferation and dilatation of the
smooth endoplasinic reticulum in the hepatocytes, possibly indicating an
adaptive response. There were no changes in aminotransferase activities
or BSP retention test. Although not statistically significant, increases
in total cholesterol and phospholipid levels and alkaline phosphatase
activities at weeks 4, 8, and 12 were seen in males and females
administered 100 mg/kg/day (the mid-dose).

Other effects noted at 1000 mg/kg/day, included a slightly higher
frequency of loose feces, and slight increases in activated partial
thromboplastin time (females only); the toxicological significance of
the increase in APTT is not clear. Based on dose-dependent increases in
total cholesterol and phospholipid levels and alkaline phosphatase
activity, the LOAEL for systemic toxicity is 100 mg/kg/day; the NOAEL is
10 mg/kg/day.

**3.1.4 FQPA**

HED evaluated the toxicology data base of flumioxazin and determined
that it was adequate to characterize the potential for pre-natal or
post-natal risks to infants and children. On December 9, 2003, HED
reevaluated only the FQPA aspects, as required by the Food Quality
Protection Act of 1996, according to the 2002 Office of Pesticide
Programs (OPP) 10X guidance document. HED established a chronic
Reference Dose (RfD), and evaluated the need for toxicological endpoints
for acute and chronic dietary as well as occupational exposure risk
assessments. The scientific quality is relatively high and the toxicity
profile of flumioxazin can be characterized for most effects, including
potential carcinogenic, mutagenic and developmental.

**3.2 Absorption, Distribution, Metabolism, Excretion (ADME)**

The absorption, distribution, metabolism and excretion (ADME) of
flumioxazin was investigated in rats following single oral doses of
radiolabeled flumioxazin. Metabolism studies in rats indicated that
there was extensive biliary excretion following oral administration of
the flumioxazin. G.I. tract absorption of flumioxazin may amount to over
90% of the dose. Total recovery of radioactivity in feces and urine, 7
days after dosing, accounted for 96.5-100.7% of the dose in all test
groups. It was noted that 4-5 times more radioactivity is excreted in
feces than in urine. Radioactivity excretion in urine was statistically
significantly elevated in females (38.8-42.8%, low dose; 22.9-23.4%,
high dose) vs. males (28.1-30.8%, low dose; 12.8-13.0%, high dose).
Highest levels of residues were found in blood cells (35.9-48.8 ppb, low
dose and 2823-3040 ppb, high dose), which were much higher than the
plasma levels (0.5-0.7 ppb, low dose and 53-37 ppb, high dose). Thin
layer chromatography (TLC) analysis of feces and urine revealed up to 35
putative metabolites. In addition to untransformed parent compound, 7
metabolites were identified in urine and feces. Identified compounds
amounted to 37.5-46.1% of the dose at the low dose treatments and to
70.7-71.5% of the dose at the high dose.

**3.3 FQPA Considerations**

**3.3.1 Adequacy of the Toxicity Database**

The FQPA database for flumioxazin includes the following acceptable
studies:

Oral (gavage) developmental toxicity study in the rat

Dermal developmental toxicity study in the rat

Oral (gavage) developmental toxicity study in the rabbit

Oral (dietary admix) two-generation reproduction toxicity study in the
rat

Oral (gavage) "critical period" developmental toxicity study in the rat

The following neurotoxicity studies were not submitted:

Oral (gavage) acute neurotoxicity study in the rat

Oral (dietary admix) 90-day neurotoxicity study in the rat

Oral developmental neurotoxicity study in the rat

2.  **Evidence of Neurotoxicity**

There was no neurotoxicity study submitted to the Agency. However, none
of the acute, subchronic, chronic, developmental or reproduction studies
indicated an effect on the nervous systems. HED concluded that there is
no concern for neurotoxicity resulting from exposure to flumioxazin.

3.  **Developmental Toxicity Studies**

**[Oral (gavage) Developmental Toxicity Study in Rats]{.underline}**

[MRID No.: 42684930 (pilot); 42684925 (main study)]{.underline}

[CORE CLASSIFICATION]{.underline}**:** CORE-Supplementary; does not
satisfy the requirement (83-3) for an oral developmental toxicity
(teratology) study in rats; this study can be upgraded to CORE-Minimum
following the receipt of the following acceptable individual fetal
observation data: body weight, external observations, visceral findings,
and skeletal findings.

**[Dermal Developmental Toxicity Study in Rats]{.underline}**

[MRID No. 42684929 (pilot); 42684926 (main study)]{.underline}

[CORE CLASSIFICATION]{.underline}**:** CORE-Supplementary; does not
satisfy the requirement (83-3) for a dermal developmental toxicity
(teratology) study in rats; this study can be upgraded to CORE-minimum
following the receipt of the following acceptable individual fetal
observation data: body weight, external observations, visceral findings,
and skeletal findings.

**[SPECIAL STUDY]{.underline}**

[Critical Period for Developmental Toxicity Induced by S-53482 in
Rats]{.underline}

[MRID No. 42884006]{.underline}

This study was determined to be Supplementary/Acceptable. Although this
study does not satisfy the requirement (83-3) for an oral developmental
toxicity (teratology) study in rats, it provides acceptable
supplementary information related to that guideline; this study cannot
be upgraded.

4.  **Reproductive Toxicity Study**

[A Two-Generation Reproduction Study in Rats]{.underline}

[MRID No. 42684934 and 42684936 (pilot studies); 42684935 (main
study)]{.underline}

This study is classified Core Guideline and meets the requirements of
83-4 for a two generation reproductive toxicity study in rats.

**3.3.5 Additional Information from Literature Sources**

The following literature sources were searched (October 12, 2000):

• DialogClassic Web

> • Developmental and Reproductive Toxicology Databank (DART) from the
> National Library of Medicine TOX-NET system
>
> • Toxicology Literature Online Databank (TOXLINE) from the National
> Library of Medicine TOX-NET system

The following published articles were found (these appeared to be
presented in submitted studies and DERs have been generated):

> Species difference in protoporphyrin IX accumulation produced by an
> N-phenylimide herbicide in embryos between rats and rabbits, Kawamura,
> S. et at. Toxicology and Applied Pharmacology, 1996, Dec.;
> 141(2):520-5.
>
> Histological changes in rat embryonic blood cells as possible
> mechanism for ventricular septal defects produced by an N-phenylimide
> herbicide. Kawamura,S. et at Teratology, 1996, Nov.; 54(5): 237-44.
>
> Species difference in developmental toxicity of an N-phenylimide
> herbicide between rats and rabbits and sensitive period of the
> toxicity to rat embryos. Kawamura, S et ol. Congenital Anomalies,
> 1995, Mar.; 35(1): 123-32.

**3.3.6 Pre-and/or Post-natal Toxicity**

**3.3.6.1 Determination of Susceptibility**

Based upon the oral as well as the dermal developmental rat studies, due
to cardiovascular anomalies (ventricular septal defect), there appeared
to be an increase in the susceptibility of fetuses. For both the rat
developmental studies and the rat reproduction study, there were pre-
and post-natal increases in quantitative and qualitative susceptibility.

**3.3.6.2 Degree of Concern Analysis and Residual Uncertainties**

Since there is evidence of increased qualitative and quantitative
susceptibility of the young following exposure to flumioxazin in the
oral and dermal developmental toxicity studies, a Degree of Concern
Analysis was performed to: 1) determine the level of concern for the
effects observed when considered in the context of all available
toxicity data; and 2) identify any residual concerns after establishing
toxicity endpoints and traditional uncertainty factors to be used in the
risk assessment of this chemical. If residual concerns are identified,
HED examines whether these residual concerns can be addressed by a
special FQPA safety factor and, if so, the size of the factor needed.

HED did not consider that there were any data gaps in the toxicology
database even though there were no acute, subchronic or developmental
neurotoxicity studies. There was no evidence in any of the studies
reviewed that the nervous systems were affected by flumioxazin.
Therefore, the uncertainty factors (s) were considered to be 100 (based
upon 10x for intraspecies variability and 10x for interspecies
extrapolation).

A database uncertainty factor of lx is recommended because of the
adequate toxicology database. Since there will be no residual concerns,
a hazard-based FQPA safety factor is not needed.

**3.3.7 Recommendation for a Developmental Neurotoxicity Study**

Evidence that suggests requiring a Developmental Neurotoxicity study:

• Increased susceptibility to fetuses and offspring.

Evidence that does not support a need for a Developmental Neurotoxicity
study:

> • No evidence of neurotoxicity in any of the studies performed:
> chronic (rat, mouse or dog), 90 day (rat, moUse or dog), 4 week
> (mouse), 21-day rat dermal, 2-generation rat reproduction and
> developmental (oral rat, dermal rat or oral rabbit).
>
> • The developmental effects observed are not related to developmental
> effects of the central or peripheral nervous systems.

HED concluded that a developmental neurotoxicity (DNT) study was not
required because the cardiovascular defects seen in the rat fetuses were
not related to the developmental fetal nervous systems as measured in
the DNT.

3.  **FQPA Safety Factor for Infants and Children**

HED met on December 9, 2003 to evaluate the FQPA hazard and exposure
data for flumioxazin. HED recommended that the FQPA Safety Factor (as
required by the Food Quality Protection Act of August 3, 1996) be
reduced from 10X to 1X for all population subgroups for all exposure
durations (acute and chronic) in assessing the risk posed by this
chemical. Although increased pre-natal and post-natal quantitative
susceptibility was seen in rats, it was concluded that there is low
concern and no residual uncertainties for pre- and/or post-natal
toxicity because:

\(a\) HED concluded that the toxicology data base for flumioxazin is
adequate for an FQPA evaluation. The following studies are available:

Oral (gavage) developmental toxicity study in the rat

Dermal developmental toxicity study in the rat

Oral (gavage) developmental toxicity study in the rabbit

Oral (dietary admix) two-generation reproduction toxicity study in the
rat

Oral (gavage) "critical period" developmental toxicity study in the rat,

\(b\) HED concluded that there is no concern for neurotoxicity resulting
from exposure to flumioxazin. None of the acute, subchronic, chronic,
developmental or reproduction studies indicated an effect on the nervous
systems.

\(c\) Although increased prenatal and postnatal quantitative
susceptibility was seen in rats, HED concluded that there is a low
concern and no residual uncertainties for pre and/or postnatal toxicity
because: (1) developmental toxicity NOAELs/LOAELs are well characterized
after oral and dermal exposure; (2) off-spring toxicity NOAEL/LOAEL are
well characterized; (3) there is a well defined dose-response curve for
the cardiovascular effects seen following oral exposure (i.e., critical
period); and (4) the end points of concern are used for overall risk
assessments for the appropriate route and population subgroups.

The FQPA Safety Factor recommended by HED **assumes** that the exposure
databases (dietary food, drinking water, and residential) are complete
and that the risk assessment for each potential exposure scenario
includes all metabolites and/or degradates of concern and does not
underestimate the potential risk for infants and children.

4.  **Hazard Identification and Toxicity Endpoint Selection**

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

**[Study Selected:]{.underline}** Pre-natal Developmental Toxicity
Study - Rat

**[MRID No.:]{.underline}** 42684930 (pilot study); 42684925 (main
study); 42884006

**[Executive Summary]{.underline}:** See Appendix A, Guideline \[§ 870.
3700a\]

**[Dose and Endpoint for Risk Assessment:]{.underline}** NOAEL = 3
mg/kg/day

**[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}**
Based on cardiovascular effects (especially ventricular septal defects
in fetuses) seen at LOAEL =10 mg/kg/day. The uncertainty factors (UFs)
used were UF~A~ = 10, UF~H~ = 10, and FQPA SF = 1x.

**3.5.2 Acute Reference Dose (aRfD) - General Population**

No appropriate end-points were selected.

**3.5.3 Chronic Reference Dose (cRfD)**

**[Study Selected:]{.underline}** Combined chronic carcinogenicity - rat

**[MRID No.:]{.underline}** 44295028

**[Executive Summary]{.underline}:** See Appendix A, Guideline \[§
870.4300\]

**[Dose and Endpoint for Risk Assessment:]{.underline}** NOAEL = 2.0
mg/kg/day

**[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}**
Based on based on increased chronic nephropathy in males and decreased
hematological parameters in females (Hgb, MCV, MCH, and MCHC) seen at
LOAEL = 18 mg/kg/day. The uncertainty factors (UFs) used were UF~A~ =
10, UF~H~ = 10, and FQPA SF = 1x.

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

**[Study Selected:]{.underline}** Reproduction and fertility effects -
rat

**[MRID No.:]{.underline}** 42684934 and 42684936 (pilot studies);
42684935 (main study)

**[Executive Summary]{.underline}:** See Appendix A, Guideline \[§
870.3800\]

**[Dose and Endpoint for Risk Assessment:]{.underline}** NOAEL = 6.3
mg/kg/day

**[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}**
Based on decreased pup body weight and testicular atrophy in F1 males
seen at LOAEL = 12.7mg/kg/day.

**3.5.5 Dermal Absorption**

**[Study Selected:]{.underline}** Dermal penetration - rat

**[MRID No.:]{.underline}** 42684944

**[Executive Summary]{.underline}:** See Appendix A, Guideline \[§ 870.
7600\]

**[Dose and Endpoint for Risk Assessment:]{.underline}** Dermal
absorption for 200 and 800 mg/kg was 3.9 and 8.0% by 48 hours after
initiation of treatment for 6 hours.

**[Comments about Study/Endpoint/Uncertainty Factors]{.underline}:**
Blood levels at 6-24 hours after dermal dosing with 200 mg/kg were
similar to those obtained at 2-6 hours after oral dosing with 1 mg/kg.
Blood levels at 6-24 hours after dermal dosing with 800 mg/kg were
similar to those obtained at 2-6 hours after oral dosing with 30 mg/kg.

**3.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term)**

**[Study Selected:]{.underline}** Dermal Developmental Study (Rat)

**[MRID No.:]{.underline}** 42684929 (pilot); 42684926 (main study)

**[Executive Summary]{.underline}:** See Appendix A, Guideline \[§
870.3700a\]

**[Dose and Endpoint for Risk Assessment:]{.underline}** NOAEL = 30
mg/kg/day

**[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}**
Based on cardiovascular effects (especially ventricular septal defects
in fetuses) seen at LOAEL = 100 mg/kg/day.

**3.5.7 Inhalation Exposure (Short-Term), (Intermediate- and
Long-Term)**

**[Study Selected:]{.underline}** Oral Developmental Study (Rat)

**[MRID No.:]{.underline}** 42684930 (pilot study); 42684925 (main
study); 42884006

**[Executive Summary]{.underline}:** See Appendix A, Guideline \[§
870.3700a\]

**[Dose and Endpoint for Risk Assessment:]{.underline}** NOAEL = 3
mg/kg/day

**[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}**
Based on cardiovascular effects (especially ventricular septal defects
in fetuses) seen at LOAEL = 10 mg/kg/day.

8.  **Inhalation Exposure (Intermediate- and Long-Term)**

**[Study Selected:]{.underline}** 2-Year Chronic/Carcinogenicity Study
(Rat)

**[MRID No.:]{.underline}** 44295028

**[Executive Summary]{.underline}:** See Appendix A, Guideline \[§
870.4200a\]

**[Dose and Endpoint for Risk Assessment:]{.underline}** NOAEL = 2
mg/kg/day

**[Comments about Study/Endpoint/Uncertainty Factors:]{.underline}**
Inhalation absorption rate = 100%; endpoint based on increased chronic
nephropathy in males and decreased hematological parameters in females
(Hgb, MCV, MCH, and MCHC) seen at LOAEL = 18 mg/kg/day.

**3.5.9 Level of Concern for Margin of Exposure**

+-----------------+-----------------+-----------------+-----------------+
| **Table 3.5.9   |                 |                 |                 |
| Summary of      |                 |                 |                 |
| Levels of       |                 |                 |                 |
| Concern for     |                 |                 |                 |
| Risk            |                 |                 |                 |
| Assessment.**   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Duration**    | **Short-Term**  | **(1-30 Days)** | **Inte          |
|                 |                 |                 | rmediate-Term** |
| **Route**       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Occupational  |                 |                 |                 |
| (Worker)        |                 |                 |                 |
| Exposure**      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Dermal**      | 100             | 100             | 100             |
+-----------------+-----------------+-----------------+-----------------+
| **Inhalation**  | 100             | 100             | 100             |
+-----------------+-----------------+-----------------+-----------------+
| **Residential   |                 |                 |                 |
| (Non-Dietary)   |                 |                 |                 |
| Exposure**      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Oral**        | 100             | 100             | N/A             |
+-----------------+-----------------+-----------------+-----------------+
| **Dermal**      | 100             | 100             | 100             |
+-----------------+-----------------+-----------------+-----------------+
| **Inhalation**  | 100             | 100             | 100             |
+-----------------+-----------------+-----------------+-----------------+

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

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

interspecies variation)**.**

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

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

variation).

**3.5.10 Recommendation for Aggregate Exposure Risk Assessments**

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures. Since there are no
residential uses for flumioxazin, the acute and chronic aggregate
exposure is equivalent to the exposure from food and water (Sections
5.2.1 and 5.2.2).

**3.5.11 Classification of Carcinogenic Potential**

HED classified flumioxaxin as a "not likely carcinogen;" therefore,
quantification of human cancer risk was not necessary.

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

+----------+-------+----------+----------------+--------------------+
| **Table  |       |          |                |                    |
| 3.5.12a  |       |          |                |                    |
| Summary  |       |          |                |                    |
| of       |       |          |                |                    |
| Toxic    |       |          |                |                    |
| ological |       |          |                |                    |
| Doses    |       |          |                |                    |
| and      |       |          |                |                    |
| E        |       |          |                |                    |
| ndpoints |       |          |                |                    |
| for      |       |          |                |                    |
| Flu      |       |          |                |                    |
| mioxazin |       |          |                |                    |
| for Use  |       |          |                |                    |
| in       |       |          |                |                    |
| Dietary  |       |          |                |                    |
| and      |       |          |                |                    |
| Non-Occu |       |          |                |                    |
| pational |       |          |                |                    |
| Human    |       |          |                |                    |
| Health   |       |          |                |                    |
| Risk     |       |          |                |                    |
| Asses    |       |          |                |                    |
| sments** |       |          |                |                    |
+==========+=======+==========+================+====================+
| **Exp    | **    | **       | **RfD, PAD,    | **Study and        |
| osure/** | Point | Uncertai | Level of       | Toxicological      |
|          | of    | nty/FQPA | Concern for    | Effects**          |
| **Sc     | Depa  | Safety   | Risk           |                    |
| enario** | rture | F        | Assessment**   |                    |
|          | (P    | actors** |                |                    |
|          | OD)** |          |                |                    |
+----------+-------+----------+----------------+--------------------+
| Acute    | NOAEL | U        | Acute RfD =    | Oral Developmental |
| Dietary  | = 3   | F~A~=10x | [acute         | and Supplemental   |
|          |       |          | NOAE           | Pre-natal Studies  |
| Females  | mg/k  | U        | L]{.underline} | (Rat)              |
| 13-49    | g/day | F~H~=10x |                |                    |
| only     |       |          | Safety Factors | LOAEL = 10         |
|          |       | FQPA     |                | mg/kg/day, based   |
|          |       | SF=1x    | = 0.03         | on cardiovascular  |
|          |       |          | mg/kg/day      | effects            |
|          |       |          |                | (especially        |
|          |       |          | aPAD = [acute  | ventricular septal |
|          |       |          | NOAE           | defects in         |
|          |       |          | L]{.underline} | fetuses).          |
|          |       |          |                |                    |
|          |       |          | Safety Factors |                    |
|          |       |          |                |                    |
|          |       |          | = 0.03         |                    |
|          |       |          | mg/kg/day      |                    |
+----------+-------+----------+----------------+--------------------+
| Acute    | There |          |                |                    |
| Dietary  | were  |          |                |                    |
|          | no    |          |                |                    |
| [General | a     |          |                |                    |
| Po       | pprop |          |                |                    |
| pulation | riate |          |                |                    |
| i        | tox   |          |                |                    |
| ncluding | icolo |          |                |                    |
| infants  | gical |          |                |                    |
| and      | ef    |          |                |                    |
| child    | fects |          |                |                    |
| ren]{.un | at    |          |                |                    |
| derline} | tribu |          |                |                    |
|          | table |          |                |                    |
|          | to a  |          |                |                    |
|          | s     |          |                |                    |
|          | ingle |          |                |                    |
|          | exp   |          |                |                    |
|          | osure |          |                |                    |
|          | (     |          |                |                    |
|          | dose) |          |                |                    |
|          | obs   |          |                |                    |
|          | erved |          |                |                    |
|          | in    |          |                |                    |
|          | oral  |          |                |                    |
|          | tox   |          |                |                    |
|          | icity |          |                |                    |
|          | st    |          |                |                    |
|          | udies |          |                |                    |
|          | incl  |          |                |                    |
|          | uding |          |                |                    |
|          | mat   |          |                |                    |
|          | ernal |          |                |                    |
|          | ef    |          |                |                    |
|          | fects |          |                |                    |
|          | in    |          |                |                    |
|          | dev   |          |                |                    |
|          | elopm |          |                |                    |
|          | ental |          |                |                    |
|          | st    |          |                |                    |
|          | udies |          |                |                    |
|          | in    |          |                |                    |
|          | rats  |          |                |                    |
|          | and   |          |                |                    |
|          | rab   |          |                |                    |
|          | bits. |          |                |                    |
|          | There |          |                |                    |
|          | fore, |          |                |                    |
|          | a     |          |                |                    |
|          | dose  |          |                |                    |
|          | and   |          |                |                    |
|          | end   |          |                |                    |
|          | point |          |                |                    |
|          | were  |          |                |                    |
|          | not   |          |                |                    |
|          | ident |          |                |                    |
|          | ified |          |                |                    |
|          | for   |          |                |                    |
|          | this  |          |                |                    |
|          | risk  |          |                |                    |
|          | a     |          |                |                    |
|          | ssess |          |                |                    |
|          | ment. |          |                |                    |
+----------+-------+----------+----------------+--------------------+
| Chronic  | N     | U        | Chronic RfD =  | 2-Year             |
| Dietary  | OAEL= | F~A~=10x | [chronic       | Chron              |
|          | 2.0   |          | NOAE           | ic/Carcinogenicity |
| [all     | mg/k  | UFH=10x  | L]{.underline} | Study (Rat)        |
| populati | g/day |          |                |                    |
| ons]{.un |       | FQPA     | Safety Factors | LOAEL = 18         |
| derline} |       | SF=1x    |                | mg/kg/day, based   |
|          |       |          | = 0.02         | on increased       |
|          |       |          | mg/kg/day      | chronic            |
|          |       |          |                | nephropathy in     |
|          |       |          | cPAD =         | males and          |
|          |       |          | [chronic       | decreased          |
|          |       |          | NOAE           | hematological      |
|          |       |          | L]{.underline} | parameters in      |
|          |       |          |                | females (Hgb, MCV, |
|          |       |          | Safety Factors | MCH, and MCHC).    |
|          |       |          |                |                    |
|          |       |          | = 0.02         |                    |
|          |       |          | mg/kg/day      |                    |
+----------+-------+----------+----------------+--------------------+
| Short-   | N     | NA       | **LOC for      | 2-Generation       |
| (1-30    | OAEL= |          | MOE** = 100    | Reproduction Study |
| days)    | 6.3   |          |                | (Rat)              |
| and      | mg/k  |          |                |                    |
| Inter    | g/day |          |                | LOAEL = 12.7       |
| med-Term |       |          |                | mg/kg/day, based   |
| (1- 6    |       |          |                | on decreased pup   |
| months)  |       |          |                | body weight and    |
| Oral     |       |          |                | testicular atrophy |
|          |       |          |                | in F1 males.       |
+----------+-------+----------+----------------+--------------------+
| Dermal   | N     | NA       | **LOC for      | Dermal             |
| (All     | OAEL= |          | MOE** = 100    | Developmental      |
| du       | 30    |          |                | Study (Rat)        |
| rations) | mg/k  |          |                |                    |
|          | g/day |          |                | LOAEL = 100        |
|          |       |          |                | mg/kg/day, based   |
|          |       |          |                | on cardiovascular  |
|          |       |          |                | effects            |
|          |       |          |                | (especially        |
|          |       |          |                | ventricular septal |
|          |       |          |                | defects in         |
|          |       |          |                | fetuses).          |
+----------+-------+----------+----------------+--------------------+
| Short-   | NOAEL | NA       | **LOC for      | Oral Developmental |
| Term     | = 3   |          | MOE** = 100    | Study (Rat)        |
| (1-30    | mg/k  |          |                |                    |
| days)    | g/day |          |                | LOAEL = 10         |
| In       |       |          |                | mg/kg/day, based   |
| halation |       |          |                | on cardiovascular  |
|          |       |          |                | effects            |
|          |       |          |                | (especially        |
|          |       |          |                | ventricular septal |
|          |       |          |                | defects in         |
|          |       |          |                | fetuses).          |
+----------+-------+----------+----------------+--------------------+
| Inte     | N     | NA       | **LOC for      | 2-Year             |
| rmed-(1- | OAEL= |          | MOE** = 100    | Chron              |
| 6        | 2     |          |                | ic/Carcinogenicity |
| months)  | mg/k  |          |                | Study (Rat)        |
| and      | g/day |          |                |                    |
| L        |       |          |                | LOAEL = 18         |
| ong-Term | (     |          |                | mg/kg/day, based   |
| (\> 6    | inhal |          |                | on increased       |
| months)  | ation |          |                | chronic            |
| In       | absor |          |                | nephropathy in     |
| halation | ption |          |                | males and          |
|          | rate  |          |                | decreased          |
|          | =     |          |                | hematological      |
|          | 100%) |          |                | parameters in      |
|          |       |          |                | females (Hgb, MCV, |
|          |       |          |                | MCH, and MCHC).    |
+----------+-------+----------+----------------+--------------------+
| Cancer   | "Not  |          |                |                    |
|          | l     |          |                |                    |
| (oral,   | ikely |          |                |                    |
| dermal,  | to be |          |                |                    |
| inh      | a     |          |                |                    |
| alation) | carci |          |                |                    |
|          | nogen |          |                |                    |
|          | for   |          |                |                    |
|          | hum   |          |                |                    |
|          | ans," |          |                |                    |
|          | based |          |                |                    |
|          | on    |          |                |                    |
|          | the   |          |                |                    |
|          | lack  |          |                |                    |
|          | of    |          |                |                    |
|          | carci |          |                |                    |
|          | nogen |          |                |                    |
|          | icity |          |                |                    |
|          | in a  |          |                |                    |
|          | 2     |          |                |                    |
|          | -year |          |                |                    |
|          | rat   |          |                |                    |
|          | s     |          |                |                    |
|          | tudy, |          |                |                    |
|          | an    |          |                |                    |
|          | 18-   |          |                |                    |
|          | month |          |                |                    |
|          | mouse |          |                |                    |
|          | s     |          |                |                    |
|          | tudy, |          |                |                    |
|          | and a |          |                |                    |
|          | ba    |          |                |                    |
|          | ttery |          |                |                    |
|          | of    |          |                |                    |
|          | muta  |          |                |                    |
|          | genic |          |                |                    |
|          | stu   |          |                |                    |
|          | dies. |          |                |                    |
+----------+-------+----------+----------------+--------------------+

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 animal to human (intraspecies). UF~H~ =
potential variation in sensitivity among members of the human population
(interspecies). UF~L~ = use of a LOAEL to extrapolate a NOAEL. UF~S\ =~
use of a short-term study for long-term risk assessment. UF~DB~ = to
account for the absence of key data (i.e., lack of a critical study).
FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute,
c = chronic). RfD = reference dose. MOE = margin of exposure. LOC =
level of concern. NA = not applicable.

+------------+-------+----------+-----------------+--------------------+
| **Table    |       |          |                 |                    |
| 3.5.12b    |       |          |                 |                    |
| Summary of |       |          |                 |                    |
| Tox        |       |          |                 |                    |
| icological |       |          |                 |                    |
| Doses and  |       |          |                 |                    |
| Endpoints  |       |          |                 |                    |
| for        |       |          |                 |                    |
| F          |       |          |                 |                    |
| lumioxazin |       |          |                 |                    |
| for Use in |       |          |                 |                    |
| Oc         |       |          |                 |                    |
| cupational |       |          |                 |                    |
| Human      |       |          |                 |                    |
| Health     |       |          |                 |                    |
| Risk       |       |          |                 |                    |
| Ass        |       |          |                 |                    |
| essments** |       |          |                 |                    |
+============+=======+==========+=================+====================+
| Exposure/  | Point | Unc      | Level of        | Study and          |
|            | of    | ertainty | Concern for     | Toxicological      |
| Scenario   | Depa  | Factors  | Risk Assessment | Effects            |
|            | rture |          |                 |                    |
+------------+-------+----------+-----------------+--------------------+
| Dermal     | N     | UF = 100 | LOC for MOE =   | Dermal             |
| Short-     | OAEL= |          | 100             | Developmental      |
| (1-30      |       |          |                 | Study in Rats      |
| days)      | 30    |          |                 |                    |
|            | mg/k  |          |                 | LOAEL = 100        |
| Int        | g/day |          |                 | mg/kg/day based on |
| ermediate- |       |          |                 | cardiac effects    |
| (1-6       |       |          |                 | (intraventricular  |
| months)    |       |          |                 | septal defects)    |
| Long Term  |       |          |                 |                    |
| (\>6       |       |          |                 |                    |
| months) a  |       |          |                 |                    |
+------------+-------+----------+-----------------+--------------------+
| Inhalation | N     | UF = 100 | LOC for MOE =   | Oral Developmental |
| Short-Term | OAEL= |          | 100             | Study in Rats      |
| (1-30      | 3.0   |          |                 |                    |
| days)      | mg/k  |          |                 | LOAEL = 10         |
|            | g/day |          |                 | mg/kg/day based on |
|            |       |          |                 | cardiac effects    |
|            | (     |          |                 | (interventricular  |
|            | inhal |          |                 | septal defects)    |
|            | ation |          |                 |                    |
|            | absor |          |                 |                    |
|            | ption |          |                 |                    |
|            | rate  |          |                 |                    |
|            | =     |          |                 |                    |
|            | 100%) |          |                 |                    |
+------------+-------+----------+-----------------+--------------------+
| Inhalation | NOAEL | UF = 100 | LOC for MOE =   | Two-year Toxicity  |
| Int        | = 2.0 |          | 100             | Study in Rats      |
| ermediate- | mg/k  |          |                 |                    |
| (1-6       | g/day |          |                 | LOAEL = 18.0       |
| months)    |       |          |                 | mg/kg/day based on |
| Long-Term  | (     |          |                 | decreased          |
| Inhalation | inhal |          |                 | hemoglobin, MCV,   |
| (\>6       | ation |          |                 | MCH and MCHC in    |
| months)    | absor |          |                 | females and        |
|            | ption |          |                 | increased          |
|            | rate  |          |                 | incidence of       |
|            | =     |          |                 | chronic            |
|            | 100%) |          |                 | nephropathy in     |
|            |       |          |                 | males              |
+------------+-------+----------+-----------------+--------------------+
| Cancer     | 2.0   | UF = 100 | SF = 1          | Chronic            |
| (oral,     | mg/k  |          |                 | Toxici             |
| dermal,    | g/day |          | 0.02 mg/kg/day  | ty/Carcinogenicity |
| i          |       |          |                 | Study in Rats      |
| nhalation) | UF =  |          |                 |                    |
|            | 100   |          |                 | LOAEL = 18.0       |
|            |       |          |                 | mg/kg/day based on |
|            |       |          |                 | decreased          |
|            |       |          |                 | hemoglobin, MCV,   |
|            |       |          |                 | MCH and MCHC in    |
|            |       |          |                 | females and        |
|            |       |          |                 | increased          |
|            |       |          |                 | incidence of       |
|            |       |          |                 | chronic            |
|            |       |          |                 | nephropathy in     |
|            |       |          |                 | males              |
+------------+-------+----------+-----------------+--------------------+

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

**3.6 Endocrine Disruption**

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) \"may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.\"
Following the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there were
scientific bases for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. EPA
also adopted EDSTAC's recommendation that the Program include
evaluations of potential effects in wildlife. For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations. As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being
considered under the Agency's EDSP have been developed, flumioxazin may
be subjected to further screening and/or testing to better characterize
effects related to endocrine disruption.

**4.0 Public Health and Pesticide Epidemiology Data**

Number range CHAPTERThe OPP Incident Data System (23/JUL/2003) indicates
that in 2002 there were 14 reported incidents, involving 1 minor human
incident, 1 domestic animal incident, 6 for minor plant damage, and 6
for minor property damage. However, there are no new public health data
or pesticide epidemiology data to report at this time.

**5.0 Dietary Exposure/Risk Characterization**

**5.1 Pesticide Metabolism and Environmental Degradation**

1.  **Metabolism in Primary Crops and Livestock Commodities.**

Number range CHAPTERThe nature of the residue has been adequately
delineated for both plant and animal commodities. In plants, the major
metabolic pathway is hydrolysis of the imide moiety to produce the
metabolites THPA and APF. The THPA is then hydrated to produce 1-OH-HPA.
The residue of concern in plants, for both tolerance expression and risk
assessment purposes, is the parent compound only.

The results of the ruminant and poultry metabolism studies with both
phenyl- and THP-labeled flumioxazin show that the major metabolic
pathways are hydrolysis of the imide moiety, hydroxylation of the
cyclohexene ring, and the equivalent of addition of sulfonic acid to the
alkene function. The residues of concern in ruminants are the parent,
3-OH-flumioxazin, 4-OH-flumioxazin, and metabolites B, C, and F. In
poultry, the residues of concern are parent, 3-OH-flumioxazin,
4-OH-flumioxazin, and 4-OH-S-53482-SA.

(For more detailed information, refer to *Petition Number 1F06296: Human
Health Risk Assessment for the Use of the Herbicide Flumioxazin on
Cotton*; DP Num: 284045; William T. Drew et al; 24/MAY/2004.)

2.  **Metabolism in Rotational Crops**

An adequate confined rotational crop study is available reflecting
application of \[THP-^14^C\] flumioxazin at rates of 0.096 and 0.19 lb
ai/A (DP Num: 259593, D. Dotson, 12/MAR/2001). Following an application
of \[^14^C\]flumioxazin at 0.96 lb ai/A, total radioactive residues
(TRR) were 0.004-0.057 ppm in RACs from representative rotational crops
planted 30 days post-treatment (60 days for lettuce, because of
phytotoxicity). Extraction and analysis of plant samples with TRRs
\>0.01 ppm indicated that the majority of extractable ^14^C-residues
were comprised of unknown polar components each present at ≤0.015 ppm.
Low levels of flumioxazin (≤0.003 ppm) were detected in carrot tops and
wheat chaff and straw, along with trace amounts (\<0.001 ppm) of the
metabolites 482-HA, IMOXA, and 482-CA.

Following an application at 0.19 lb ai/A, TRRs were 0.003-0.072 ppm in
RACs from representative rotational crops planted 30 days post-treatment
(90 days for lettuce and 60 days for carrots, due to phytotoxicity).
Although the highest TRR values were obtained at the 120-day PBI (0.131
ppm in wheat straw), ^14^C-residues generally declined at longer PBIs.
As with the 1x-treated plant samples, the majority of extractable
^14^C-residues were comprised of unknown polar components. Flumioxazin
was detected at ≤0.009 in sample extracts from carrot tops and roots,
and wheat chaff and straw, with the exception of wheat straw (0.033 ppm)
from the 120-day PBI. Other metabolites tentatively identified included:
482-HA (≤0.002 ppm), IMOXA (\<0.001 ppm), 482-CA (\<0.001) in carrot and
wheat samples and SAT-1-OH-482 (0.008 ppm), 1-OH-HPA (0.004 ppm), THPA
(0.004 ppm), and TPA (0.0004 ppm) in wheat straw from later PBIs. Based
on the results from the confined study, the MARC has determined that the
residue of concern in rotational crops is parent compound.

In the current petitions, the maximum seasonal use rates on melons and
fruiting vegetables (0.25 lb ai/A) and on garlic and asparagus (0.38 lb
ai/A) are higher than utilized in the confined study. However, HED has
previously addressed the adequacy of the current rotational crop
restrictions at these higher use rates under a petition for use on
sugarcane (DP Num: 301247, D. Drew, 23/JUL/2004), which has a maximum
seasonal use rate of 0.38 lb ai/A. The Agency concluded that the higher
use rates (0.25 and 0.38 lb ai/A) are supported by the results from the
confined study conducted at 0.19 lb ai/A, and that field trials and
tolerances for rotational crops are not required.

3.  **Analytical Methodology**

An adequate GC/NPD method is available for enforcing tolerances of
flumioxazin in plant commodities (MRID No. 43935509, Valent Residue
Method #RM-30A-1, Determination of Flumioxazin Residues in Crops, J.
Garbus, 08/JAN/1996). This method has undergone a successful ILV trial
and a successful PMV trial by the Agency. The reported method LOQ and
LOD for flumioxazin are 0.020 and 0.010 ppm, respectively. However, the
validated LOQ was 0.010 ppm for residues in soybean seed, forage, and
hay in the PMV trial, and the LOD was 0.005 ppm.

Residues of flumioxazin and its two hydroxy metabolites
(3-OH-flumioxazin and 4-OH-flumioxazin) were determined in milk and
tissues using two related LC/MS/MS methods, Valent Methods RM-30MK for
milk and RM-30T for tissues. Recoveries from milk, cream and skim milk
averaged 84-92% (± 1-9%) for flumioxazin, 89-95% (± 8-11%) for
3-OH-flumioxazin, and 84-93% (± 6-10%) for 4-OH-flumioxazin. Recoveries
from tissues averaged 77-88% (± 3-12%) for flumioxazin, 85-102% (±
12-25%) for 3-OH-flumioxazin, and 96-102% (± 17-20%) for
4-OH-flumioxazin. For both methods, the validated LOQ is 0.02 ppm for
each analyte, and the reported LOD is 0.01 ppm.

**5.1.4 Multiresidue Methods**

Number range CHAPTERData depicting the analysis of flumioxazin through
FDA Multiresidue Protocols were submitted and will be forwarded to FDA
for review. The multiresidue method testing data indicate that
flumioxazin is not recovered through Sections 304 and 402 of PAM, Vol. I
(DP Num: 259493, D. Dotson, 12/MAR/2001).

**5.1.5 Storage Stability**

The available storage stability data are adequate and support the sample
storage durations incurred in the alfalfa, pecan, cantaloupe, dry bean,
blueberry, asparagus, tomato and pepper field trials. As frozen samples
of whole milk, cream, skim milk and tissues from the cattle feeding
study were analyzed within 30 days of collection, no storage stability
data are required to support the feeding study.

6.  **Magnitude in Plants**

The available almond, pecan, cantaloupe, dry bean, blueberry, asparagus,
tomato, and pepper field trials are adequate and support the proposed
use patterns. An adequate number of tests were conducted on each crop in
the appropriate geographical regions. Samples were analyzed for the
residue of concern using an adequate method, and sample storage
conditions and durations were supported by the available/submitted
storage stability data. As residues were \<LOQ (0.02 ppm) in/on all
commodities, except dry beans and almond hulls, the data support the
proposed 0.02 ppm tolerances in the following commodities: Tree nuts
(group 14), melons (subgroup 9A), asparagus, fruiting vegetables (group
8), okra, and assorted types of bushberries. For dry beans, residues
were \<0.02-0.05 ppm and will support a tolerance of 0.05 ppm.

The alfalfa field trial data are also adequate, and support the proposed
use of two applications per season. Utilizing the tolerance
harmonization spreadsheet, the available residue data on alfalfa
supports tolerances of 3.0 ppm for forage and 8.0 ppm for hay.

In addition, the available bulb onion field trial data will support the
requested increase in the use rate for garlic up to 0.38 lb ai/A, and
the existing 0.02 ppm tolerance for garlic is adequate.

Also, tomato is the only crop associated with the current petitions for
which a processing study is required. No tomato processing study was
submitted with these petitions. However, in one of the tomato field
trials, flumioxazin (WDG) was applied as two soil-directed applications
at 0.621-0.689 lb ai/A, for a total of 1.25 lb ai/A (5x rate). Both
applications included the use of a COC at 1% v/v. Residues were \<0.02
ppm in/on duplicate samples of tomatoes harvested at 21 DAT. As residues
were \<LOQ following applications at a 5x rate, a tomato processing
study is not required, and no tolerances are necessary in processed
tomato commodities.

7.  **Magnitude in Meat, Milk, Poultry, and Eggs**

The submitted cattle feeding study is adequate. As residues of
flumioxazin and its two hydroxy metabolites were \<LOD in all samples of
milk and tissues from cattle dosed for 28 days at levels equivalent to
20 ppm in their diet (16x TDB), quantifiable residues are unlikely to
occur in cattle, goats, horse, or sheep. Therefore, tolerances for
flumioxazin residues are not required in commodities from cattle, goats,
hogs, horses or sheep (40 CFR §180.6\[a\]\[3\]).

In addition, results from the available poultry metabolism study, in
which hens were dosed for 14 days at 9.0 ppm (1,800x TDB), indicate that
quantifiable residues are unlikely to occur in eggs or poultry tissues.
Therefore, tolerances for flumioxazin residues are also not required in
eggs or poultry tissues (40 CFR §180.6\[a\]\[3\]).

8.  **Confined and Field Rotational Crops**

An adequate confined rotational crop study is available reflecting
application of \[THP-14C\] flumioxazin at rates of 0.096 and 0.19 lb
ai/A (DP Num: 259593, D. Dotson, 12/MAR/2001).

Following an application of \[14C\]flumioxazin at 0.96 lb ai/A, total
radioactive residues (TRR) were 0.004-0.057 ppm in RACs from
representative rotational crops planted 30 days post-treatment (60 days
for lettuce, because of phytotoxicity). Extraction and analysis of plant
samples with TRRs \>0.01 ppm indicated that the majority of extractable
14C-residues were comprised of unknown polar components each present at
≤0.015 ppm. Low levels of flumioxazin (≤0.003 ppm) were detected in
carrot tops and wheat chaff and straw, along with trace amounts (\<0.001
ppm) of the metabolites 482-HA, IMOXA, and 482-CA.

In the current petitions, the maximum seasonal use rates (for rotated
crops) on melons and fruiting vegetables (0.25 lb ai/A), and on garlic
and asparagus (0.38 lb ai/A) are higher than utilized in the confined
study. However, HED has previously addressed the adequacy of the current
rotational crop restrictions at these higher use rates under a petition
for use on sugarcane (DP Num: 301247, D. Drew, 23/JUL/2004), which has a
maximum seasonal use rate of 0.38 lb ai/A. The Agency concluded that the
higher use rates (0.25 and 0.38 lb ai/A) are supported by the results
from the confined study conducted at 0.19 lb ai/A, and that field trials
and tolerances in rotational crops are not required.

9.  **Pesticide Metabolites and Degradates of Concern**

  ------------------------------------------------------------------------
  **Table 5.1.9.                                      
  Summary of                                          
  Metabolites                                         
  and Degradates                                      
  to be included                                      
  in the Risk                                         
  Assessment and                                      
  Tolerance                                           
  Expression**                                        
  -------------- --------------- -------------------- --------------------
  Matrix                         Residues included in Residues included in
                                 Risk Assessment      Tolerance Expression

  Plants         Primary Crop    Flumioxazin          Flumioxazin

                 Rotational Crop Flumioxazin          Flumioxazin

  Livestock      Ruminant        Flumioxazin;         Flumioxazin;
                                 3-OH-flumioxazin,    3-OH-flumioxazin,
                                 4-OH-flumioxazin,    4-OH-flumioxazin,
                                 and metabolites B,   and metabolites B,
                                 C, and F.            C, and F.

                 Swine           Flumioxazin;         Flumioxazin;
                                 3-OH-flumioxazin,    3-OH-flumioxazin,
                                 4-OH-flumioxazin,    4-OH-flumioxazin,
                                 and metabolites B,   and metabolites B,
                                 C, and F.            C, and F.

                 Poultry         Flumioxazin and      Flumioxazin and
                                 3-OH-flumioxazin,    3-OH-flumioxazin,
                                 4-OH-flumioxazin,    4-OH-flumioxazin,
                                 and 4-OH-S-53482-SA. and 4-OH-S-53482-SA.

  Drinking Water                 Flumioxazin, 482-HA  Not Applicable
                                 and APF              
  ------------------------------------------------------------------------

10. **Drinking Water Residue Profile**

The EDWC for flumioxazin residues (flumioxazin, 482-HA, and APF) used in
this dietary risk assessment was obtained from EFED's environmental risk
assessment for flumioxazin, *Drinking Water Assessment for: (1) IR-4
Registration for Flumioxazin to be used on Asparagus, Dry Bean,
Bushberry Subgroup 13B, Fruiting Vegetable Subgroup 8, Melon Subgroup
9A, Okra and Tree Nut Subgroup 14; and (2) Section 3 Registration for
Use on Field Corn and Alfalfa*; DP Num: 336195, 342249, and 331732; L.
Liu; 25/SEP/2007. The hydrolysis study for flumioxazin indicates that
flumioxazin forms the metabolite 482-HA, which can further hydrolyze to
the metabolites APF and THPA. The rates of the two hydrolytic reactions
are very pH dependent, but flumioxaxin (parent compound) is not very
stable at any likely environmental pH. Data also indicates that THPA and
APF are likely to be very mobile. Although THPA can comprise a major
portion of the total residue in water, it does not possess the phenyl
ring and is thus considered significantly less toxic than parent, APF,
and 482-HA. Thus, THPA has not been included in the residue of concern
for drinking water. Therefore, parent flumioxazin and the metabolites
482-HA and APF are the residues of concern in drinking water. The EDWC
for flumioxazin residues (used in both the acute and chronic dietary
analyses) was 0.048 ppm, the concentration in groundwater as estimated
by the SCI-GROW model. SCI-GROW is an empirical model for predicting
pesticide levels in groundwater; the value from SCI-GROW is considered
an upper bound concentration estimate, and thus conservative. In order
to be conservative with the estimates, the groundwater EDWC (0.048 ppm),
which is greater than the surface water EDWC (0.034 ppm), was used in
both dietary analyses. Table 5.1.10 summarizes the drinking water
concentrations provided by EFED. The model and its description are
available at the EPA internet site:
[<http://www.epa.gov/oppefed1/models/water/>.]{.underline}

  ------------------------------------------------------------------------
  **Table 5.1.10.                                       
  EDWCs for                                             
  flumioxazin and                                       
  its degradates in                                     
  surface water and                                     
  groundwater at pH                                     
  7.**                                                  
  ----------------- ----------------- ----------------- ------------------
  **Compound**      **Average 56-Day  **Peak Conc. in   **Conc. in
                    Conc. in Surface  Surface Water**   Groundwater**
                    Water**                             

  Flumioxazin       negligible        1.03 ppb          negligible

  482-HA            4.84 ppb          6.87 ppb          45.27 ppb

  APF               12.85 ppb         26.46 ppb         2.66 ppb

  THPA              19.50 ppb         27.67 ppb         182.28 ppb
  ------------------------------------------------------------------------

**5.2 Dietary Exposure and Risk**

**5.2.1 Acute Dietary Exposure/Risk**

The analysis summarized in Table 5.2.2 (below) is based on
tolerance-level residues in all RACs (modified by DEEM processing
factors, Version 7.81, for processed commodities), and 100% CT
assumptions. Dietary exposure via drinking water was also included in
this assessment. Even with the conservative assumptions utilized, the
risk estimate is well below ARIA's level of concern. The only population
subgroup analyzed is females 13-49 (only subgroup with an identified
acute dietary endpoint), which has an exposure estimate of 0.002524
mg/kg/day at the 95th percentile, and utilizes 8% of the aPAD.

1.  **Chronic Dietary Exposure/Risk**

The analyses summarized in Table 5.2.2 (below) are based on
tolerance-level residues in all RACs (modified by DEEM processing
factors, Version 7.81, for processed commodities), and 100% CT
assumptions. Dietary exposure via drinking water was also included in
these assessments. Even with the conservative assumptions utilized, the
risk estimates are well below ARIA's level of concern. The most highly
exposed population subgroup is all infants \<1, which has an exposure
estimate of 0.003689 mg/kg/day, and utilizes 18% of the cPAD.

+---------------+------+---------+-------+---------+---------+-------+
| **TABLE 5.2.2 |      |         |       |         |         |       |
| Summary of    |      |         |       |         |         |       |
| Dietary       |      |         |       |         |         |       |
| Exposure and  |      |         |       |         |         |       |
| Risk for      |      |         |       |         |         |       |
| F             |      |         |       |         |         |       |
| lumioxazin.** |      |         |       |         |         |       |
+===============+======+=========+=======+=========+=========+=======+
| **Population  | **   |         |       | **DEEM  |         |       |
| Subgroup      | DEEM |         |       | Chronic |         |       |
| ^1^**         | A    |         |       | Dietary |         |       |
|               | cute |         |       | Ana     |         |       |
| **\[Years of  | Die  |         |       | lysis** |         |       |
| Age\]**       | tary |         |       |         |         |       |
|               | Ana  |         |       |         |         |       |
|               | lysi |         |       |         |         |       |
|               | s,** |         |       |         |         |       |
|               |      |         |       |         |         |       |
|               | **95 |         |       |         |         |       |
|               | ^th^ |         |       |         |         |       |
|               | Perc |         |       |         |         |       |
|               | enti |         |       |         |         |       |
|               | le** |         |       |         |         |       |
+---------------+------+---------+-------+---------+---------+-------+
|               | **   | **E     | **%   | **cPAD  | **E     | **%   |
|               | aPAD | xposure | a     | (mg/kg  | xposure | c     |
|               | (    | (mg/kg  | PAD** | /day)** | (mg/kg  | PAD** |
|               | mg/k | /day)** |       |         | /day)** |       |
|               | g)** |         |       |         |         |       |
+---------------+------+---------+-------+---------+---------+-------+
| General US    | NA   |         |       | 0.02    | 0       | 6     |
| Population    | **^  |         |       |         | .001207 |       |
|               | 2^** |         |       |         |         |       |
+---------------+------+---------+-------+---------+---------+-------+
| **All Infants |      |         |       | *       | **0.0   | *     |
| \[\<1\]**     |      |         |       | *0.02** | 03689** | *18** |
+---------------+------+---------+-------+---------+---------+-------+
| Children      |      |         |       | 0.02    | 0       | 11    |
| \[1-2\]       |      |         |       |         | .002168 |       |
+---------------+------+---------+-------+---------+---------+-------+
| Children      |      |         |       | 0.02    | 0       | 10    |
| \[3-5\]       |      |         |       |         | .001958 |       |
+---------------+------+---------+-------+---------+---------+-------+
| Children      |      |         |       | 0.02    | 0       | 7     |
| \[6-12\]      |      |         |       |         | .001299 |       |
+---------------+------+---------+-------+---------+---------+-------+
| Youths        |      |         |       | 0.02    | 0       | 5     |
| \[13-19\]     |      |         |       |         | .000900 |       |
+---------------+------+---------+-------+---------+---------+-------+
| Adults        |      |         |       | 0.02    | 0       | 5     |
| \[20-49\]     |      |         |       |         | .001076 |       |
+---------------+------+---------+-------+---------+---------+-------+
| Adults        |      |         |       | 0.02    | 0       | 6     |
| \[50+\]       |      |         |       |         | .001121 |       |
+---------------+------+---------+-------+---------+---------+-------+
| **Females     | **0. | **0.0   | **8** | 0.02    | 0       | 5     |
| \[13-49\]**   | 03** | 02524** |       |         | .001076 |       |
+---------------+------+---------+-------+---------+---------+-------+

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

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

2.  **Cancer Dietary Risk**

HED classified flumioxazin as a "not likely carcinogen." Therefore,
quantification of human cancer risk was not necessary.

6.  **Residential (Non-Occupational) Exposure/Risk Characterization**

Flumioxazin is not intended for use in public or residential settings.
Therefore, residential exposure is not expected, and no residential risk
assessment was performed.

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

Spray drift is always a potential source of exposure to residents nearby
to spraying operations. This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for flumioxazin.
The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices. On a
chemical by chemical basis, the Agency is now requiring interim
mitigation measures for aerial applications that must be placed on
product labels/labeling. The Agency has completed its evaluation of the
new database submitted by the Spray Drift Task Force, a membership of
U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods. After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

7.  **Aggregate Risk Assessments and Risk Characterization**

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

**7.1 Acute Aggregate Risk**

There were no appropriate toxicological effects attributable to a single
exposure (dose) for the general population; therefore, a dose and
endpoint were not identified for this risk assessment. The aPAD for
females 13-49 years was 0.03 mg/kg/day. To assess the aggregate acute
risk, EDWCs were incorporated directly into the dietary exposure
analysis. Refer to section 5.2.1 for this risk estimate. The aggregated
risk does not exceed ARIA's level of concern.

2.  **Short-Term Aggregate Risk**

Because there are no short-term exposures due to residential use, no
short-term aggregate risk assessment is required.

3.  **Intermediate-Term Aggregate Risk**

Because there are no intermediate-term exposures due to residential use,
no intermediate-term aggregate risk assessment is required.

4.  **Long-Term Aggregate Risk**

Because there are no long-term (chronic) exposures due to residential
use, long-term aggregate risk is solely due to chronic dietary risk and
risk contributed from drinking water. Refer to section 5.2.2 for the
long-term aggregate risk (chronic dietary and drinking water) estimates.
The aggregated risk does not exceed ARIA's level of concern.

5.  **Cancer Risk**

In accordance with the EPA Draft Guidelines for Carcinogen Risk
Assessment (July, 1999), HED classified flumioxazin as a \"not likely"
human carcinogen. Therefore, flumioxazin is not expected to pose a
cancer risk.

8.  **Cumulative Risk Characterization/Assessment**

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to flumioxazin and any other
substances and flumioxazin does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that flumioxazin has a common mechanism
of toxicity with other substances. For information regarding EPA's
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA's Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA's website at
[[http://www.epa.gov/pesticides/cumulative/.]{.underline}](http://www.epa.gov/pesticides/cumulative/.)

**9.0 Occupational Exposure/Risk Pathway**

**9.1 Short-/Intermediate-/Long-Term Handler Risk**

Based upon the proposed use pattern, ARIA believes the most highly
exposed occupational pesticide handlers are mixer/loaders using
open-pour loading of granules and applicators using open-cab ground-boom
spray machinery. ARIA believes pesticide handlers will be exposed to
short-term duration (1-30 days) exposures but not for intermediate-term
duration (1-6 months) exposures. For the proposed uses, ARIA believes it
is unlikely that pesticide handlers would be exposed continuously for
more than 30 days. Therefore, only short-term duration risks were
assessed.

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material. The HED ExpoSAC SOP Number 12 (29
March 2000) directs that although the same individual may perform all
those tasks, they shall be assessed separately. The available exposure
data for combined mixer/loader/applicator scenarios are limited in
comparison to the monitoring of these two activities separately. These
exposure scenarios are outlined in the PHED Surrogate Exposure Guide
(August 1998). HED has adopted a methodology to present the exposure and
risk estimates separately for the job functions in some scenarios and to
present them as combined in other cases. Most exposure scenarios for
hand-held equipment (such as hand wands, backpack sprayers, and
push-type granular spreaders) are assessed as a combined job function.
With these types of hand held operations, all handling activities are
assumed to be conducted by the same individual. The available monitoring
data support this and HED presents them in this way. Conversely, for
equipment types such as fixed-wing aircraft, groundboom tractors, or
air-blast sprayers, the applicator exposures are assessed and presented
separately from those of the mixers and loaders. By separating the two
job functions, HED determines the most appropriate levels of personal
protective equipment (PPE) for each aspect of the job without requiring
an applicator to wear unnecessary PPE that might be required for a
mixer/loader (e.g., chemical resistant gloves may only be necessary
during the pouring of a liquid formulation).

No chemical specific data were available with which to assess potential
exposure to pesticide handlers. The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998). It should be noted that the PHED does not contain handler
specific data for use of a water dispersible granule. Therefore, as a
surrogate for use in risk assessment, ARIA has used PHED data for
handling a dry flowable formulation.

HED also identified a short-term inhalation toxicological endpoint. The
NOAEL for inhalation exposure is 3.0 mg ai/kg bw/day and was identified
from an oral developmental study in the rat. The effects seen were
similar to those noted in the dermal study i.e., cardiovascular effects
especially ventricular septal defects in fetuses. Since the toxic
effects were identified from a developmental study with fetal effects, a
60 kg bw is used to calculate exposure. ARIA assumes 100% absorption via
the inhalation route of exposure.

The current risk assessment uses toxicological endpoints cited in the
December 9, 2003 HED report. Relative to the assessment herein, HED
identified a short-term duration (1-30 days) dermal toxicological
endpoint from a 28-day dermal toxicity study in the rat. The toxic
effects seen were increases in mean absolute and relative liver and
kidney weights. The NOAEL is 30.0 mg ai/kg bw/day and the effects seen
were cardiovascular effects, especially ventricular septal defects
infetuses. The level of concern for occupational exposures is for MOEs
\< 100. Since the toxicological endpoint was identified from a dermal
study, dermal exposure is not corrected for dermal absorption. Also,
since the effects were identified from a developmental study with fetal
toxicological effects, a 60 kg body weight is used to calculate average
daily exposure.

HED also identified a short-term inhalation toxicological endpoint. The
NOAEL for inhalation exposure is 3.0 mg ai/kg bw/day and was identified
from an oral developmental study in the rat. The effects seen were
similar to those noted in the dermal study i.e., cardiovascular effects
especially ventricular septal defects in fetuses. Since the toxic
effects were identified from a developmental study with fetal effects, a
60 kg bw is used to calculate exposure. ARIA assumes 100% absorption via
the inhalation route of exposure.

Flumioxazin is classified as \"not likely\" to be a human carcinogen.
Therefore a cancer risk assessment is not necessary.

See Table 9.1 for a summary of exposures and risks to occupational
pesticide handlers and see Table 3.5.11b for a summary of toxicological
endpoints used for risk assessment purposes.

+-----------------+------+------+---------+--------+--------+--------+
| **Table 9.1     |      |      |         |        |        |        |
| Summary of      |      |      |         |        |        |        |
| Exposure & Risk |      |      |         |        |        |        |
| for             |      |      |         |        |        |        |
| Occupational    |      |      |         |        |        |        |
| Handlers        |      |      |         |        |        |        |
| Applying        |      |      |         |        |        |        |
| Flumioxazin**   |      |      |         |        |        |        |
+=================+======+======+=========+========+========+========+
| **Unit          | *    | **U  | **Avg.  | **NOAE | **MO   | **Comb |
| Exposure^1^**   | *App | nits | Daily   | L^5^** | E^6^** | ined** |
|                 | lic. | Trea | Do      |        |        |        |
| mg ai/lb        | R    | ted^ | se^4^** | mg/kg  |        | **MO   |
| handled         | ate^ | 3^** |         | bw/day |        | E^7^** |
|                 | 2^** |      | mg      |        |        |        |
|                 |      | Per  | ai/kg   |        |        |        |
|                 | lb   | Day  | bw/day  |        |        |        |
|                 | ai/  |      |         |        |        |        |
|                 | unit |      |         |        |        |        |
+-----------------+------+------+---------+--------+--------+--------+
| **              |      |      |         |        |        |        |
| *Mixer/Loader - |      |      |         |        |        |        |
| Dry Flowable -  |      |      |         |        |        |        |
| Open Pour       |      |      |         |        |        |        |
| Loading***      |      |      |         |        |        |        |
+-----------------+------+------+---------+--------+--------+--------+
| Dermal:         | 0    | 200  | Dermal: | Dermal | Dermal | 325    |
|                 | .375 | A    |         |        |        |        |
| SLNoGlove 0.066 |      |      | No      | 30     | 363    | 325    |
| LC              | lb   |      | Glove   |        |        |        |
|                 | ai/A |      | 0.0825  | Inha   | 363    |        |
| SLWithGlove     |      |      |         | lation |        |        |
| 0.066 HC        |      |      | W Glove |        | Inhal. |        |
|                 |      |      | 0.0825  | 3      | 3115   |        |
| Inhal. 0.00077  |      |      |         |        |        |        |
| HC              |      |      | Inhal.  |        |        |        |
|                 |      |      | 0       |        |        |        |
|                 |      |      | .000963 |        |        |        |
+-----------------+------+------+---------+--------+--------+--------+
| ***Applicator - |      |      |         |        |        |        |
| Open-cab -      |      |      |         |        |        |        |
| Ground-boom***  |      |      |         |        |        |        |
+-----------------+------+------+---------+--------+--------+--------+
| Dermal:         | 0    | 200  | Dermal: | Dermal | Dermal | 1126   |
|                 | .375 | A    |         |        |        |        |
| SLNoGlove 0.014 |      |      | No      | 30     | 1714   | 1126   |
| HC              | lb   |      | Glove   |        |        |        |
|                 | ai/A |      | 0.0175  | Inha   | 1714   |        |
| SLWithGlove     |      |      |         | lation |        |        |
| 0.014 MC        |      |      | W Glove |        | Inhal. |        |
|                 |      |      | 0.0175  | 3      | 3243   |        |
| Inhal. 0.00074  |      |      |         |        |        |        |
| HC              |      |      | Inhal.  |        |        |        |
|                 |      |      | 0       |        |        |        |
|                 |      |      | .000925 |        |        |        |
+-----------------+------+------+---------+--------+--------+--------+

^1^ Unit Exposures are taken from "PHED SURROGATE EXPOSURE GUIDE",
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998. Dermal: = Dermal exposure; SLNo glove
= single layer work clothing and no gloves; SLW gloves = single layer
work clothing WITH the use of protective gloves. Inhal. = Inhalation.
Units = mg a.i./pound of active ingredient handled. Data Confidence: LC
= Low Confidence, MC = Medium Confidence, HC = High Confidence.

^2^ Applic. Rate. = Taken from the IR4 request, Sections B.

^3^ Units Treated are taken from "Standard Values for Daily Acres
Treated in Agriculture"; SOP No. 9.1. Science Advisory Council for
Exposure; Revised 5 July 2000;

^4^ Average Daily Dose = Unit Exposure \* Applic. Rate \* Units Treated
÷ Body Weight (60 kg since NOAELs are identified from developmental
studies with fetal effects).

^5^ NOAEL = No Observable Adverse Effect Level (30 mg a.i./kg bw/day for
short-term dermal and 3.0 mg ai/kg bw/day for short-term inhalation)

^6^ MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL) ÷ ADD.

^7^ Since the toxicological effects are similar yet are identified from
different studies and have different NOAELs, the MOEs are combined using
the following:

1/1/MOE~Dermal~ +1/MOE~Inhalation~

A MOE of 100 is adequate to protect occupational pesticide handlers from
short-term exposures to flumioxazin. Since the combined MOEs are \> 100
the proposed use does not exceed ARIA's level of concern.

2.  **Short-/Intermediate-/Long-Term Post-application Risk**

It is possible for agricultural workers to have post-application
exposures to pesticide residues during the course of standard
agricultural activities. HED in conjunction with the Agricultural
Re-entry Task Force (ARTF) has identified a number of post-application
agricultural activities that may occur and which may result in
post-application exposures to pesticide residues. HED has also
identified Transfer Coefficients (TC) (cm²/hr) relative to the various
activities which express the amount of foliar contact over time, during
each of the activities identified.

The TCs used in this assessment are from an interim TC Standard
Operating Procedure (SOP) developed by HED's ExpoSAC using proprietary
data from the ARTF database (SOP \# 3.1). It is the intention of HED's
ExpoSAC that this SOP will be periodically updated to incorporate
additional information about agricultural practices in crops and new
data on transfer coefficients. Much of this information will originate
from exposure studies currently being conducted by the ARTF, from
further analysis of studies already submitted to the Agency, and from
studies in the published scientific literature.

There are few \"early season\" activities (*i.e*., around bloom time)
that require re-entry shortly after application. Irrigation activities
are identified as the most likely activities. The TC for irrigation is
1,500 cm^2^/hr.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20% of the application rate is available as DFR on day zero
after application. This is adapted from the ExpoSAC SOP No. 003 (7 May
1998 - Revised 7 August 2000).

Therefore, as a screening level assessment, ARIA herein uses the TC of
1,500 cm^2^/hr for a conservative estimate of agricultural worker
exposure to post-application residues of flumioxazin.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures. Since the estimated MOEs are \> 100 base
upon conservative assumptions, the proposed uses do not exceed ARIA's
levels of concern.

3.  **Restricted Entry Interval (REI)**

The Chateau^TM^ label lists a restricted entry interval of 12 hours.
Flumioxazin is classified in acute Toxicity Category III for acute
dermal toxicity and primary eye irritation. It is classified in Toxicity
Category IV for acute inhalation and primary skin irritation. It is not
a dermal sensitizer. Therefore, the interim Worker Protection Standard
(WPS) REI of 12 hours is adequate to protect agricultural workers from
post-application dislodgeable residues of flumioxazin. The proposed
label REI is adequate to protect agricultural workers.

**10.0 Tolerance Summary**

HED has previously determined that the tolerance expression for primary
and rotational crops should include only parent flumioxazin. Tolerances
for flumioxazin residues are currently established on plant commodities
at levels ranging from 0.02 ppm on various commodities to 0.70 ppm on
almond hulls (40 CFR §180.568\[a\]). Number range CHAPTER The tolerances
currently being proposed by Valent and IR-4 are listed below in Table
10.0, along with the Agency's recommended tolerance levels.

In the almond, pecan, cantaloupe, blueberry, asparagus, tomato, and
pepper field trials conducted at 1x the proposed rate, flumioxazin
residues were \<LOQ in/on all RACs (except hulls) harvested at the
proposed PHIs. Therefore, the Agency recommends in favor of establishing
tolerances in/on tree nuts (group 14), melons (subgroup 9A), fruiting
vegetables (group 8), asparagus, and assorted bushberries at the method
LOQ of 0.02 ppm. The existing tolerance in almond hulls is adequate, and
the residue data on tomatoes and peppers will also support a separate
tolerance in okra at 0.02 ppm. Once the tolerance in the tree nuts crop
group has been established, the separate tolerances on almond and
pistachio should be deleted.

In accordance with the Agency's proposed revisions to the Berry Crop
Group (Memo, B. Schneider, 28/MAR/2006), separate tolerances should be
established in any new members of the bushberry subgroup 13B, until the
revisions to the crop group have been approved. However, as a tolerance
is being established in the bushberry subgroup (13-B), the current crops
listed under this subgroup will not require separate tolerances. These
crops include blueberry (lowbush and highbush), currants (red and
black), elderberry, gooseberry, and huckleberry.

For dry beans treated at a 1x rate, residues were \<0.02-0.05 ppm in/on
samples harvested at the proposed PHI. As 22 of the 26 dry bean samples
had residues that were \<LOQ, the recommended tolerance in dry beans was
determined using the CA Method (μ + 3σ), which gave a recommended
tolerance of 0.05 ppm.

The recommended tolerance levels in alfalfa forage and hay were
determined using Agency Guidance (Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP), as all the field trials were
conducted at a \~1x rate and quantifiable residues were detected in
\>90% of the samples. The appropriate tolerances for alfalfa forage and
hay were calculated to be 3.0 and 8.0 ppm, respectively.

Separate tolerances are not required in processed tomato commodities as
flumioxazin residues were \<LOQ in/on tomatoes treated at a 5x rate and
harvested at the proposed PHI.

Data from the available cattle feeding study, conducted at 20 ppm (16x
MDB), indicate that quantifiable residues are unlikely to occur in
cattle, goats, hogs, horses, or sheep. Likewise, the data from the
available poultry metabolism studies, conducted at \>1,800x MDB,
indicate that quantifiable residues are also unlikely to occur in eggs
and poultry tissues. Therefore, tolerances for flumioxazin residues in
livestock commodities are not required for these petitions
(40CFR§180.6\[a\]\[3\]).

Number range CHAPTERNo international harmonization issues are associated
with these petitions, as there are no established or proposed Canadian,
Mexican or Codex MRLs for residues of flumioxazin in plant commodities.

+-----------------+--------------+------------+-----------------------+
| **Table 10.0.   |              |            |                       |
| Tolerance       |              |            |                       |
| Summary for     |              |            |                       |
| Flumioxazin.**  |              |            |                       |
+=================+==============+============+=======================+
| Commodity       | Proposed     | R          | Comments;             |
|                 | Tolerance    | ecommended |                       |
|                 | (ppm)        | Tolerance  | *Correct Commodity    |
|                 |              | (ppm)      | Definition*           |
+-----------------+--------------+------------+-----------------------+
| Alfalfa, forage | 1.0          | 3.0        | Adequate residue data |
|                 |              |            | are available, and    |
|                 |              |            | the tolerances were   |
|                 |              |            | calculated using the  |
|                 |              |            | tolerance             |
|                 |              |            | harmonization         |
|                 |              |            | spreadsheet.          |
+-----------------+--------------+------------+-----------------------+
| Alfalfa, hay    | 2.0          | 8.0        |                       |
+-----------------+--------------+------------+-----------------------+
| Tree Nut Crop   | 0.02         | 0.02       | Adequate almond and   |
| Group 14        |              |            | pecan field trial     |
|                 |              |            | data are available.   |
|                 |              |            |                       |
|                 |              |            | *Nut, tree, group 14* |
+-----------------+--------------+------------+-----------------------+
| Melon subgroup  | 0.02         | 0.02       | Adequate cantaloupe   |
| 9-A             |              |            | field trial data are  |
|                 |              |            | available.            |
|                 |              |            |                       |
|                 |              |            | *Melon, subgroup 9A*  |
+-----------------+--------------+------------+-----------------------+
| Asparagus       | 0.02         | 0.02       | Adequate asparagus    |
|                 |              |            | field trial data are  |
|                 |              |            | available.            |
+-----------------+--------------+------------+-----------------------+
| Bean, dry, seed | 0.06         | 0.05       | Adequate dry bean     |
|                 |              |            | field trial data are  |
|                 |              |            | available. As         |
|                 |              |            | residues were \<LOQ   |
|                 |              |            | in/on 22 out of 26    |
|                 |              |            | samples, the          |
|                 |              |            | recommended tolerance |
|                 |              |            | was determined using  |
|                 |              |            | the CA method (μ +    |
|                 |              |            | 3σ).                  |
+-----------------+--------------+------------+-----------------------+
| Fruiting        | 0.02         | 0.02       | Adequate tomato and   |
| Vegetable Crop  |              |            | pepper field trial    |
| Group 8         |              |            | data are available.   |
|                 |              |            |                       |
|                 |              |            | *Vegetable, fruiting, |
|                 |              |            | except cucurbits,     |
|                 |              |            | group 8*              |
+-----------------+--------------+------------+-----------------------+
| Okra            | 0.02         | 0.02       | The tolerance for     |
|                 |              |            | okra is supported by  |
|                 |              |            | the available tomato  |
|                 |              |            | and pepper field      |
|                 |              |            | trial data.           |
+-----------------+--------------+------------+-----------------------+
| Bushberry       | 0.02         | 0.05       | Adequate lowbush and  |
| subgroup 13-B   |              |            | highbush blueberry    |
|                 |              |            | field trial data are  |
|                 |              |            | available and support |
|                 |              |            | establishing a        |
|                 |              |            | tolerance for the     |
|                 |              |            | *Bushberry, subgroup  |
|                 |              |            | 13B.*                 |
|                 |              |            |                       |
|                 |              |            | In accordance with    |
|                 |              |            | the Agency's proposed |
|                 |              |            | revisions to the      |
|                 |              |            | Berry Crop Group,     |
|                 |              |            | separate tolerances   |
|                 |              |            | should be established |
|                 |              |            | for new members of    |
|                 |              |            | the bushberry         |
|                 |              |            | subgroup 13-B, until  |
|                 |              |            | the revised crop      |
|                 |              |            | group is approved.    |
|                 |              |            | However, separate     |
|                 |              |            | tolerances are not    |
|                 |              |            | required for the      |
|                 |              |            | existing members of   |
|                 |              |            | the bushberry         |
|                 |              |            | subgroup.             |
+-----------------+--------------+------------+-----------------------+
| Aronia berry    | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Blueberry,      | 0.02         | None ^1^   |                       |
| lowbush         |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Blueberry,      | 0.02         | None ^1^   |                       |
| highbush        |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Buffalo currant | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Chilean guava   | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Currant, black  | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| Currant, red    | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| Elderberry      | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| European        | 0.02         | 0.02       |                       |
| barberry        |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Gooseberry      | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| Highbush        | 0.02         | 0.02       |                       |
| cranberry       |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Honeysuckle     | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Jostaberry      | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Juneberry,      | 0.02         | 0.02       |                       |
| including       |              |            |                       |
| Saskatoon berry |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Lingonberry     | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Native currant  | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Salal           | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Sea buckthorn   | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+

^1^ As a tolerance is being established for bushberry, subgroup 13-B,
separate tolerances are not required for the existing members of this
subgroup, including: lowbush and highbush blueberries, currants,
elderberry, gooseberry, and huckleberry.

**11.0 Data Needs and Label Recommendations**

**11.1 Toxicology**

HED has previously recommended a 28-day inhalation study due to exposure
concern via this route. The Registrant should follow the 90-day study
protocol (870.3465), except treatment can be terminated after 28 days.

**11.2 Residue Chemistry**

1\) The following revisions should be made to the proposed labels:

> • For dry beans, the labels may specify a maximum single and seasonal
> use rate of up to 0.093 lb ai/A, including both the pre-emergence and
> pre-harvest uses.
>
> • For fruiting vegetables (including okra) and melons, labels may
> allow for up to two directed applications per season at up to 0.125 lb
> ai/A/application.
>
> • For melons, applications after blooming should be prohibited.
>
> • For tree nuts, the labels should specify a minimum RTI of 60 days
> rather than 30 days.
>
> • For asparagus, a maximum single application rate of up to 0.375 lb
> ai/A may be specified.

2\) The following revisions should be made to the Section F:

-   Section F of both petitions should be revised to reflect the
    recommended tolerance levels and correct commodity definitions as
    listed in Table 10.0.

**11.3 Occupational and Residential Exposure**

No additional data is required.

**12.0 References:**

**Endpoint Selection Document**

HIARC briefing package Flumioxazin 129034, File R086827, A. Levy,
09/DEC/2003.

Flumioxazin. Second Report of the Hazard Identification Assessment
Review Committee, A. Levy, DP Num: 298652, TXR Number 0052446,
25/MAR/2004.

**Dietary Exposure Memorandum**

*Flumioxazin. Acute and Chronic Dietary (Food and Water) Exposure
Assessments for Section 3 Registration for Tolerances in/on Alfalfa,
Asparagus, Dry Beans, Fruiting Vegetables (Group 8, including Okra),
Melon (Subgroup 9A), Bushberries (Subgroup 13B), and Tree Nuts (Group
14)*, DP Num: 342753, D. Rate, 30/OCT/2007.

**Drinking Water Memorandum**

*Section 3 Registration for Use on Field Corn and Alfalfa*; DP Num:
336195, 342249, 331732; L. Liu; 25/SEP/2007.

**Product Chemistry Memorandum**

EPA Fact Sheet for Flumioxazin.

**Residue Chemistry Data Reviews**

*Flumioxazin. Petitions for Tolerances on Alfalfa, Asparagus, Dry Beans,
Fruiting Vegetables (Group 8, including Okra), Melons (Subgroup 9A),
Bushberries (Subgroup 13B), and Tree Nuts (Group 14, and a Request for a
Amended Use on Garlic. Summary of Analytical chemistry and Residue Data.
PP#s: 6F7092 and 6E7151*, DP Num: 342963, D. Rate, 20/NOV/2007.

**Occupational and Residential Exposure Memorandum**

*FLUMIOXAZIN - Human, Non-Dietary Exposure/Risk Assessment for the
Proposed Use of Flumioxazin on Tree Nuts, Melons, Beans, Bushberry,
Asparagus, Fruiting Vegetables and Okra*, DP Num: 340409, M. Dow,
25/JUN/2007.

**Appendix A: Toxicology Assessment**

**A.1 Toxicology Data Requirements**

The requirements (40 CFR 158.340) for food use for flumioxazin are in
Table A.1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

+-----------------------------------------+-------------+-------------+
| **Test**                                | **          |             |
|                                         | Technical** |             |
+=========================================+=============+=============+
|                                         | *           | **          |
|                                         | *Required** | Satisfied** |
+-----------------------------------------+-------------+-------------+
| 870.1100 Acute Oral Toxicity            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | yes         | yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | yes         | NO          |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | NO          |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | yes         |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | yes         | NO          |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | NO          |
| 870.5300 Mutagenicity---Gene Mutation - |             |             |
| mammalian                               | yes         | yes         |
|                                         |             |             |
| 870.5375 Mutagenicity---Gene Mutation   | yes         | yes         |
| -- CHO cells                            |             |             |
|                                         | yes         | yes         |
| 870.5395 Mutagenicity--- *In vivo* rat  |             |             |
| bone marrow                             |             |             |
|                                         |             |             |
| 870.5550 Mutagenicity---Other Genotoxic |             |             |
| Effects- UDS assay                      |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | no          | \-          |
| Battery (rat)                           |             |             |
|                                         | no          | \-          |
| 870.6200b 90-Day Neuro. Screening       |             |             |
| Battery (rat)                           | no          | \-          |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular Effects      | no          | \-          |
|                                         |             |             |
| > Acute Oral (rat)                      |             |             |
| >                                       |             |             |
| > Subchronic Oral (rat)                 |             |             |
| >                                       |             |             |
| > Six-month Oral (dog)                  |             |             |
+-----------------------------------------+-------------+-------------+

**A.2 Toxicity Profiles**

  --------------- ----------------------- ---------- ---------------- -------------
  **Table A.2.1                                                       
  Acute Toxicity                                                      
  Profile for                                                         
  Flumioxazin**                                                       

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

  870.1100        Acute oral \[rat\]      42684911   LD~50~\>5000     IV
                                                     mg/kg M & F      

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

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

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

  870.2500        Acute dermal irritation 42684917   Non-irritating   IV
                  \[rabbit\]                                          

  870.2600        Skin sensitization      42684921   Non-sensitizer   N/A
                  \[guinea pig\]                                      
  --------------- ----------------------- ---------- ---------------- -------------

+--------+------------+-----------------+------------------------------+
| *      |            |                 |                              |
| *Table |            |                 |                              |
| A.2.2  |            |                 |                              |
| Subch  |            |                 |                              |
| ronic, |            |                 |                              |
| C      |            |                 |                              |
| hronic |            |                 |                              |
| and    |            |                 |                              |
| Other  |            |                 |                              |
| To     |            |                 |                              |
| xicity |            |                 |                              |
| Pro    |            |                 |                              |
| file** |            |                 |                              |
+========+============+=================+==============================+
| **Gui  | **Study    | **MRID No.      | **Results**                  |
| deline | Type**     | (year)/         |                              |
| No.**  |            | Classification  |                              |
|        |            | /Doses**        |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 42684923        | NOAEL = 69.7 (M), 71.5 (F)   |
| 0.3100 | oral       |                 | mg/kg/day                    |
|        | toxicity - | dose levels: 0, |                              |
|        | rat        | 2.3, 20.7,      | LOAEL = 243.5 (M), 229.6 (F) |
|        |            | 69.7, and 243.5 | mg/kg/day based on a         |
|        |            | mg/kg/day (M)   | decrease in MCV both sexes;  |
|        |            |                 | increase in platelets F      |
|        |            | and 0, 2.2,     | only.                        |
|        |            | 21.7, 71.5, and |                              |
|        |            | 229.6 mg/kg/day |                              |
|        |            | (F)             |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 42683922        | NOAEL = 65.0 (M), 72.9 (F)   |
| 0.3100 | oral       |                 | mg/kg/day LOAEL = 196.7 (M), |
|        | toxicity - | dose levels: 0, | 218.4 (F) mg/kg/day based on |
|        | rat        | 1.9, 19.3,      | hematology changes.          |
|        |            | 65.0, and 196.7 |                              |
|        |            | mg/kg/day (M)   |                              |
|        |            | and 0, 2.2,     |                              |
|        |            | 22.4, 72.9, and |                              |
|        |            |                 |                              |
|        |            | 218.4 mg/kg/day |                              |
|        |            | (F)             |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | MRID unknown    | NOAEL = 429 mg/kg/day        |
| 0.3100 | oral       | (referred to in |                              |
|        | toxicity - | 79-week study,  | LOAEL = 1429 mg/kg/day based |
|        | mouse      | MRID 44295018)  | on increased liver weight in |
|        |            |                 | males.                       |
|        |            | dose levels: 0, |                              |
|        |            | 143, 429, or    |                              |
|        |            | 1429 (M & F)    |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 4-Week     | 44307301 (see   | NOAEL = 151.5 (M), 164.5 (F) |
| 0.3100 | oral       | MRID 44295018   | mg/kg/day                    |
|        | toxicity - | DER#2)          |                              |
|        | mouse      |                 | LOAEL = 419.9 (M), 481.6 (F) |
|        |            | dose levels: 0, | mg/kg/day based on increased |
|        |            | 151.5, 419.9 or | absolute &/or relative liver |
|        |            | 1366.5 (M) and  | weights in M & F.            |
|        |            | 0, 164.5, 481.6 |                              |
|        |            | or 1698.3 (F)   |                              |
|        |            | mg/kg/day       |                              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | 42684924        | NOAEL = 10 mg/kg/day         |
| 0.3150 | capsule -  |                 |                              |
|        | dog        | dose levels of  | LOAEL = 100 mg/kg/day based  |
|        |            | 0, 10, 100, or  | on dose dependent increase   |
|        |            | 1000 mg/kg/day  | in total cholesterol,        |
|        |            |                 | phospholipid & alkaline      |
|        |            |                 | phosphatase activity.        |
+--------+------------+-----------------+------------------------------+
| 87     | 21-Day     | 44295016        | NOAEL = mg/kg/day: 1000      |
| 0.3200 | dermal     |                 | (LIMIT DOSE)                 |
|        | toxicity - | dose levels: 1, |                              |
|        | rat        | 100, 300, or    | LOAEL = mg/kg/day: \>1000    |
|        |            | 1000 mg/kg/day  | based on no effects.         |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | \[ \]           | NOAEL = \[ \] mg/kg/day      |
| 0.3250 | dermal     |                 |                              |
|        | toxicity   |                 | LOAEL = \[ \] mg/kg/day      |
|        | (species)  |                 | based on \[ \].              |
+--------+------------+-----------------+------------------------------+
| 87     | 90-Day     | \[ \]           | NOAEL = \[ \] mg/kg/day      |
| 0.3465 | inhalation |                 |                              |
|        | toxicity   |                 | LOAEL = \[ \] mg/kg/day      |
|        | (species)  |                 | based on \[ \].              |
+--------+------------+-----------------+------------------------------+
| 870    | Pre-natal  | (1)42684930     | Maternal NOAEL = 30          |
| .3700a | devel      | (pilot study);  | mg/kg/day (HDT)              |
|        | opmental - | 42684925 (main  |                              |
|        | rat (oral) | study); (2)     | LOAEL = \>30 mg/kg/day (HDT) |
|        |            | 42884006        |                              |
|        |            |                 | Developmental NOAEL = 3      |
|        |            | dose levels: 0, | mg/kg/day                    |
|        |            | 1, 3, 10 and 30 |                              |
|        |            | mg/kg/day       | LOAEL = 10 mg/kg/day based   |
|        |            |                 | on cardiovascular effects    |
|        |            |                 | (especially ventricular      |
|        |            |                 | septal defects ).            |
+--------+------------+-----------------+------------------------------+
| 870    | Pre-natal  | 42684929        | **Maternal** NOAEL = 300     |
| .3700a | devel      | (pilot);        | mg/kg/day (HDT)              |
|        | opmental - | 42684926 (main  |                              |
|        | rat        | study)          | LOAEL = \>300 mg/kg/day      |
|        |            |                 | (HDT)                        |
|        | **         | dose levels: 0, |                              |
|        | (dermal)** | 30, 100, and    | **Developmental** NOAEL = 30 |
|        |            | 300 mg/kg/day   | mg/kg/day                    |
|        |            |                 |                              |
|        |            |                 | LOAEL = 100 mg/kg/day based  |
|        |            |                 | on cardiovascular effects    |
|        |            |                 | (especially ventricular      |
|        |            |                 | septal defects).             |
+--------+------------+-----------------+------------------------------+
| 870    | Pre-natal  | 42684927        | **Maternal** NOAEL = 1000    |
| .3700b | devel      | (               | mg/kg/day                    |
|        | opmental - | range-finding); |                              |
|        | rabbit     | 42684928 (main  | LOAEL = 3000 mg/kg/day (HDT) |
|        | **(oral)** | study)          | based on decrease in body    |
|        |            |                 | weight and food consumption  |
|        |            | dose levels: 0, | during dosing                |
|        |            | 300, 1000, or   |                              |
|        |            | 3000 mg/kg/day  | **Developmental** NOAEL =    |
|        |            |                 | 3000 mg/kg/day (HDT) LOAEL = |
|        |            |                 | \>3000 mg/kg/day             |
+--------+------------+-----------------+------------------------------+
| 87     | Re         | 42684934 and    | **Parental/Systemic** NOAEL  |
| 0.3800 | production | 42684936 (pilot | = 12.7 (M), 15.1 (F)         |
|        | and        | studies);       | mg/kg/day; LOAEL = 18.9 (M), |
|        | fertility  | 42684935 (main  | 22.7 (F) mg/kg/day based on  |
|        | effects -  | study)          | increase in clinical signs   |
|        | rat)       |                 | (red substance in vagina)    |
|        |            | dose levels: 0, | and increased female         |
|        |            | 3.2, 6.3, 12.7, | mortality as well as         |
|        |            | and 18.9        | decreased body weight, body  |
|        |            | mg/kg/day (M)   | weight gain and food         |
|        |            | and 0, 3.8,     | consumption.                 |
|        |            | 7.6, 15. 1, and |                              |
|        |            | 22.7 mg/kg/day  | **Reproductive** NOAEL =     |
|        |            | (F)             | 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 and a decrease in   |
|        |            |                 | pup body weight.             |
+--------+------------+-----------------+------------------------------+
| 870    | 12-Month   | 44295017        | NOAEL = 100 mg/kg/day (M &   |
| .4100b | capsule -  |                 | F)                           |
|        | dog        | dose levels: 0, |                              |
|        |            | 10, 100 or 1000 | LOAEL = 1000 mg/kg/day (M    |
|        |            | mg/kg/day       | &F), (LIMIT DOSE) based on   |
|        |            |                 | the following for males and  |
|        |            |                 | females: increased absolute  |
|        |            |                 | and relative liver weights;  |
|        |            |                 | 300% increase in alkaline    |
|        |            |                 | phosphatase values           |
+--------+------------+-----------------+------------------------------+
| 870    | Chronic    | \[ \]           | NOAEL = \[ \] mg/kg/day      |
| .4100a | toxicity   |                 |                              |
|        | (species)  |                 | LOAEL = \[ \] mg/kg/day      |
|        |            |                 | based on \[ \].              |
+--------+------------+-----------------+------------------------------+
| 870    | Carcino    | 44295018        | NOAEL = 754.1 (M), 859.1 (F) |
| .4200b | genicity - |                 | mg/kg/day (LIMIT DOSE);      |
|        | mouse      | dose levels: 0, | LOAEL = no systemic effects  |
|        |            | 31.1, 314.9 or  | at LIMIT DOSE in males or    |
|        |            | 754.1 mg/kg/day | females                      |
|        |            | in males and 0, |                              |
|        |            | 36.6, 346.4, or | **No evidence of             |
|        |            | 859.1 mg/kg/day | carcinogenicity**            |
|        |            | in females      |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Combined   | 44295028        | NOAEL = 1.8 (M), 2.2 (F)     |
| .4200a | chronic    |                 | mg/kg/day                    |
|        | carcino    | dose levels: 0, |                              |
|        | genicity - | 1.8, 18.0, and  | LOAEL = 18.0 (M), 21.8 (F)   |
|        | rat        | 36.5 mg/kg/day  | mg/kg/day based on increased |
|        |            | in male rats    | chronic nephropathy in males |
|        |            | and 0, 2.2,     | and decreased hematological  |
|        |            | 21.8, and 43.6  | parameters in females (Hgb,  |
|        |            | mg/kg/day in    | MCV, MCH and MCHC).          |
|        |            | female rats     |                              |
|        |            |                 | **No evidence of             |
|        |            |                 | carcinogenicity**            |
+--------+------------+-----------------+------------------------------+
| Gene   | Gene       | 42684938        | Neither cytotoxic nor        |
| Mu     | mutation   |                 | mutagenic up to 2000         |
| tation | in *S.     | dose levels:    | µg/plate. There were         |
|        | ty         | with or without | reproducible increases in    |
| 87     | phimurium* | metabolic       | revertant colonies of *S.    |
| 0.5100 | and *E.    | activation to   | typhimurium* strains TA1538  |
|        | coli*      | 0, 50, 100,     | and TA98 in S9 activated     |
|        |            | 200, 500, 1000, | phases of the preliminary    |
|        |            | or 2000         | cytotoxicity and both        |
|        |            | μg/plate        | mutation assays. \[Results   |
|        |            |                 | are considered to be         |
|        |            |                 | equivocal.\]                 |
+--------+------------+-----------------+------------------------------+
| Gene   | Gene       | 42684939        | Precipitation at ≥200 µM.    |
| Mu     | mutation   |                 | Cytotoxicity at 500 µM.      |
| tation | in chinese | nonactivated    | Positive +S9 ≥100 µM and     |
|        | hamster    | levels, 30,     | negative at 30-500 µM -S9.   |
| 87     | ovary      | 100, 200, and   | Aberrations were chromatid   |
| 0.5375 | cells      | 500 μM (11, 35, | breaks and exchanges.        |
|        |            | 70, and 177     |                              |
|        |            | μg/mL,          |                              |
|        |            | respectively)   |                              |
+--------+------------+-----------------+------------------------------+
| 87     | *In vivo*  | 42684940        | Negative in male (up to 5000 |
| 0.5395 | rat bone   |                 | mg/kg) and female rats (up   |
|        | marrow     | dose levels:    | to 4400 mg/kg) when tested   |
|        |            | 1250, 2500, or  | orally.                      |
|        |            | 5000 mg/kg      |                              |
+--------+------------+-----------------+------------------------------+
| 87     | UDS assay  | 42684941        | Negative up to 5000 mg/kg.   |
| 0.5550 |            |                 |                              |
|        |            | dose levels: by |                              |
|        |            | oral gavage to  |                              |
|        |            | 5000 mg/kg or   |                              |
|        |            | 12 hours post   |                              |
|        |            | exposure to     |                              |
|        |            | 1250 or 2500    |                              |
|        |            | mg/kg           |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Acute      |                 | Not required.                |
| .6200a | neu        |                 |                              |
|        | rotoxicity |                 |                              |
|        | screening  |                 |                              |
|        | battery    |                 |                              |
+--------+------------+-----------------+------------------------------+
| 870    | Subchronic |                 | Not required.                |
| .6200b | neu        |                 |                              |
|        | rotoxicity |                 |                              |
|        | screening  |                 |                              |
|        | battery    |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Dev        |                 | Not required.                |
| 0.6300 | elopmental |                 |                              |
|        | neu        |                 |                              |
|        | rotoxicity |                 |                              |
+--------+------------+-----------------+------------------------------+
| 87     | Metabolism | 42684943        | Gastrointestinal tract       |
| 0.7485 | and        |                 | absorption \>90% at 1 mg/kg  |
|        | pharmaco   | single oral     | and up to 50% at 100 mg/kg.  |
|        | kinetics - | dose of 1 mg/kg | At least 97% recovery in     |
|        | rat (oral) | or 100 mg/kg,   | feces and urine 7 days after |
|        |            |                 | dosing. Highest levels of    |
|        |            |                 | residues (36-49 ppb) in      |
|        |            |                 | blood cells at low dose and  |
|        |            |                 | 2800-3000 ppm at high dose   |
|        |            |                 | (RBC levels \> plasma). In   |
|        |            |                 | addition to untransformed    |
|        |            |                 | parent, 7 metabolites        |
|        |            |                 | identified in urine and      |
|        |            |                 | feces (38-46% for low dose   |
|        |            |                 | and about 71% at high dose). |
+--------+------------+-----------------+------------------------------+
| 87     | Dermal     | 42684944        | Females dosed with 200 or    |
| 0.7600 | pen        |                 | 800 mg/kg b.w. Dermal        |
|        | etration - | dose levels:    | absorption for 200 and 800   |
|        | rat        | 200 or 800      | mg/kg was 3.9 and 8.0% by 48 |
|        |            | mg/kg bw        | hours after initiation of    |
|        |            |                 | treatment for 6 hours. Blood |
|        |            |                 | levels at 6-24 hours after   |
|        |            |                 | dermal dosing with 200 mg/kg |
|        |            |                 | were similar to those        |
|        |            |                 | obtained at 2-6 hours after  |
|        |            |                 | oral dosing with 1 mg/kg.    |
|        |            |                 | Blood levels at 6-24 hours   |
|        |            |                 | after dermal dosing with 800 |
|        |            |                 | mg/kg were similar to those  |
|        |            |                 | obtained at 2-6 hours after  |
|        |            |                 | oral dosing with 30 mg/kg.   |
+--------+------------+-----------------+------------------------------+
| 8      | Special    | 42694931,       | Pregnant females were        |
| 70.XXX | Study -    | 42684932        | administered 400 mg/kg by    |
|        |            |                 | gavage on gestation day 11   |
|        | Rat        | single dose:400 | or 12 or 13 or 14 or 15. Day |
|        | Deve       | mg/kg bw        | 12 administration showed:    |
|        | lopmental: |                 | largest incidence of         |
|        | Critical   |                 | embryonic death, lowest      |
|        | Time for   |                 | fetal body weights and       |
|        | Defects    |                 | greatest incidence of        |
|        |            |                 | ventricular septal defects.  |
+--------+------------+-----------------+------------------------------+

**A.3 Executive Summaries**

**A.3.1 Subchronic Toxicity**

**870.3100 90-Day Oral Toxicity - Rat**

In a 13-week subchronic feeding study S-53482 Technical (98.4% purity)
was administered to Crj:CD(SD) rats from Charles River Japan
(12/sex/dose level) for a period of 13 weeks in the diet at dose levels
of 0, 30, 300, 1000 or 3000 ppm (approximately 0, 2.3, 20.7, 69.7, and
243.5 mg/kg b.w./day, respectively in males and 0, 2.2, 21.7, 71.5, and
229.6 mg/kg b.w./day, respectively in females). Mean body weight gains
by week 13 were statistically significantly smaller than in controls at
3000 ppm (amounting to 83-89% of controls) in both sexes. Hematology
parameters and bone marrow examination were consistent with anemia and
bone marrow response in both sexes. In males there were statistically
significant decreases in hemoglobin (by 8.2%), hematocrit (by 8.4%), MCH
(by 9.4%) at 3000 ppm and of MCV at 1000 ppm (by 3.8%) and at 3000 ppm
(by 9.9%). In addition, reticulocytes were statistically significantly
increased from 0.9% to 1.7% at the 3000 ppm level. There were also
statistically significant changes in bone marrow parameters:
erythroblasts were increased from 0.4 to 7.8 per 100 WBC and the
granulocyte/erythroblast ratio was decreased from 1.7 to 1.0 in 3000 ppm
rats. In females there were statistically significant decreases at 3000
ppm in erythrocyte count (by 11.2%), hemoglobin (by 25.5%), hematocrit
(by 25.1%), MCH (by 15.9%), and MCV (by 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 ppm
\[mg/kg/day: males = 243.5, females = 229.6\] and statistically
significant increases in platelets at 3000 ppm \[mg/kg/day: 229.6\] in
females). The NOAEL = 1000 ppm (mg/kg/day: males = 69.7, females =
71.5)**

This study is classified as **Core Supplementary**. This study does not
satisfy the requirement (82-1) for a subchronic oral toxicity study in
rodents. This study may be upgraded to **Core Minimum** if the following
additional information is provided and is judged to be acceptable: (1)
Data to support the stability of the test material in the prepared diets
under the condition of storage between the time of preparation and use;
(2) Clinical chemistry data for individual males (only summary tables
were available); (3) Individual gross pathology data for all animals
except the 1000 and 3000 ppm males (summary tables and individual data
for 1000 and 3000 ppm males were available).

In a subchronic feeding study, S-53482 Technical (94.8%) was
administered to male and female Crj:CD Sprague-Dawley rats
(16/sex/group) at dietary levels of 0, 30, 300, 1000, and 3000 ppm
(approximate doses of 0, 1.9, 19.3, 65.0, and 196.7 mg/kg/day for males,
and 0, 2.2, 22.4, 72.9, and 218.4 mg/kg/day for females) for 90 days.
Dose-related changes in hematology parameters and histopathology,
associated with anemia, were seen in females at 300 ppm and above and in
males at 1000 ppm and above. In females, decreases (p\<0.05) in MCV (3%)
and MCH (3%) and increased extramedullary hematopoiesis in spleen (1/10
vs 0/10 in controls) were observed at 300 ppm. At 3000 ppm, decreases
(p\<0.05) in MCV (18%), MCH (25%), MCHC (9%) and other hematology
parameters were coupled to increased reticulocyte count (up to 3.9%) and
extramedullary hematopoiesis in spleen (10/10) and liver (5/10). In
males, decreases (p\<0.05) in MCV (6%) and MCH (7%) and increased
extramedullary hematopoiesis in spleen (1/10 vs 0/10 in controls) were
observed at 1000 ppm. At 3000 ppm, decreases (p\<0.05) in MCV (11%), MCH
(14%), MCHC (9%) were coupled to increased reticulocyte count (up to
1.4) and extramedullary hematopoiesis in the spleen (6/10). **LOAEL =
3000 ppm (196.7 mg/kg/day for males and 218.4 mg/kg/day for females) are
based on dose-related alterations in hematology parameters and
histologic alterations associated with anemia. NOAEL = 1000 ppm (65.0
mg/kg/day for males and 72.9 mg/kg/day for females).** This study is
**Core Minimum** and satisfies the requirement (82-1) for a subchronic
oral toxicity study in rats.

**870.3100 90-Day Oral Toxicity - Mouse**

**870.3150 90-Day Oral Toxicity - Dog**

S-53482 Technical was administered to beagle dogs of both sexes for a
period of 13 weeks via gelatin capsules at dose levels of 0, 10, 100, or
1000 mg/kg/day. Clinical chemistry parameters showed dose-related
increases in total cholesterol, phospholipid and alkaline phosphatase,
which became statistically significant in 1000 mg/kg/day males
(cholesterol, phospholipid) cr females (alkaline phophatase). In
addition, at 1000 mg/kg/day, treatment-related effects in male and fmalc
dogs included increased liver weights, gross hepatic lesions (rounded
margin and enlargement) and microscopic hepatic lesions (proliferation
and dilatation of bile duct and smooth endoplasmic reticulum in
hepatocytes and increased fibrous tissue around the centrilobular
veins). LOEL: 100 mg/kg/day (based on dose dependent increases in
dose-dependent increases in total cholesterol, and phospholipid levels
and alkaline ph,sphatase activity). NOEL: 10 mg/kg/day. CORE
Classification: Supplementary. The study is upgradeable pending
submission of stability data in the used diet.

**870.3200 21/28-Day Dermal Toxicity -- Rat**

**870.3465 90-Day Inhalation -- Rat**

**A.3.2 Pre-natal Developmental Toxicity**

**870.3700a Pre-natal Developmental Toxicity Study - Rat**

[Executive Summary:]{.underline} 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 consumption values were
recorded. On day 20 of gestation, the rats were sacrificed and
necropsied; gravid uterine weights were recorded. The uteri were
examined, implantation sites were counted, and the numbers of corpora
lutea were determined. The fetuses were removed, weighed, sexed, and
examined for external anomalies. They were then processed for visceral
or skeletal evaluation.

There were no treatment-related effects on maternal mortality, clinical
observations, body weight, food consumption or gross pathology data.
**Maternal LOAEL = Not** **determined; Maternal NOAEL** = **30
mg/kg/day.** At the 30 mg/kg/day dose level, a treatment-related
increase in fetal death (5.6% resorptions in control versus 20.4% at the
high-dose), a 21% decrease in mean live litter size, and a decrease in
male (14.3%) and female (15.2%) fetal body weights were noted as
compared to control. A dose and treatment-related increase in the
incidence of fetuses with cardiovascular abnormalities, particularly
ventricular septal defect, was observed. Ventricular septal defect was
noted in the following numbers of fetuses (litters) for the control, 1,
3, 10 and 30 mg/kg/day dose groups, respectively: 2(2), l(l), 2(2),
6(6), and 26(12); combined cardiovascular abnormalities were noted with
the following distribution: 8(6), 7(6), 10(8), 13(9), and 36(14). These
findings were both statistically significant at 30 mg/kg/day, and the
increased incidence of cardiovascular abnormalities was judged to be
biologically significant at 10 mg/kg/day. Appropriate historical control
data submitted by the performing laboratory support and confirm these
conclusions. Also at the 30 mg/kg/day dose level, significantly
increased incidences of wavy ribs (27 fetuses, representing 12 of 18
litters) and curvature of the scapula (10 fetuses in 4 litters) and a
significant 4-7% decrease in the number of ossified sacrococcygeal
vertebral bodies as compared to control were attributed to treatment.
**Developmental LOAEL = 10 mg/kg/day; Developmental NOAEL = 3
mg/kg/day,** based on a biologically significant increase in
cardiovascular abnormalities, particularly ventricular septal defect; at
30 mg/kg/day, statistical significance was achieved for these
observations and the following additional findings were noted: increased
resorptions and decreased number of viable fetuses, decreased fetal body
weight, increased abnormalities of the ribs (wavy) and scapula
(curvature), and decreased numbers of ossified sacrococcygeal vertebral
bodies.

The above findings were generally similar to those observed in the
dermal developmental toxicity study in rats conducted with S-53482 (MRID
No. 42684926, Teratology Study of 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]{.underline}: In a dermal developmental toxicity
study, the test substance, S-54382 (94.8% purity), was administered by
6-hour daily dermal application to pregnant female Scl: SD
(Sprague-Dawley) rats on days 6-15 of gestation (with the day of mating
defined as gestation Day 0) at dose levels of 0, 30, 100, and 300
mg/kg/day. The rats were observed for signs of toxicity; body weight and
food consumption values were recorded. On day 20 of gestation, the rats
were sacrificed and necropsied; gravid uterine weights were recorded.
The uteri were examined, implantation sites were counted, and the
numbers of corpora lutea were determined. The fetuses were removed,
weighed, sexed, and examined for external anomalies. They were then
processed for visceral or skeletal evaluation. There were no systemic
treatment-related effects on maternal mortality, clinical observation,
body weight, food consumption, or gross pathology data. **Maternal**
**LOAEL = not determined; Maternal NOAEL**= **300 mg/kg/day.**

A dose- and treatment-related increase in the incidence of fetuses with
cardiovascular abnormalities, particularly ventricular septal defect,
was observed. Ventricular septal defect was noted in the following
numbers of fetuses (litters) for the control, 30, 100, and 300 mg/kg/day
dose groups, respectively: l(l), l(l), 2(2), and 13(9); combined
cardiovascular abnormalities were noted with the following distribution:
5(5), 4(4), 10(7), and 19(9). These findings were both statistically
significant at 300 mg/kg/day, and the increased incidence of
cardiovascular abnormalities was judged to be biologically significant
at 100 mg/kg/day. Appropriate historical control data submitted by the
performing laboratory support and confirm these conclusions. At the 300
mg/kg/day dose level, an increase in fetal death (40.7% resorptions as
compared to 6.0% in controls), a 40% decrease in live litter size, and a
6-9% decrease in fetal body weights were attributed to treatment. t the
same dose level, significantly increased incidences of wavy ribs (18
fetuses, representing 10 of 17 litters) and a 3.4% decrease in the mean
number of ossified sacrococcygeal vertebral bodies were attributed to
treatment. **Developmental LOAEL = 100 mg/kg/day; Developmental NOAEL =
30 mg/kg/day,** based on a biologically significant increase in
cardiovascular abnormalities, particularly ventricular septal defect; at
300 mg/kg/day, statistical significance was achieved for these
observations and the following additional findings were noted: increased
resorptions and decreased number of viable fetuses, decreased fetal body
weight, increased abnormalities of the ribs (wavy), and decreased
numbers of ossified sacrococcygeal vertebral bodies. The above findings
were generally similar to those observed in the oral developmental
toxicity study in rats conducted with S-53482 (MRID No. 42684925,
Teratology Study of 6 S-53482 Administered Orally to Rats, performed by
Sumitomo Chemical Co. Ltd., for Valent U.S.A. Corporation, project No.
1759, August 28, 1990). In that study, a dose- and treatment-related
increase in the incidence of cardiovascular abnormalities, particularly
ventricular septal defect, was noted for fetuses of dams treated on days
6-15 of gestation. CORE CLASSIFICATION: **not acceptable/guideline; does
not satisfy the requirement (83-3) for a dermal developmental toxicity
(teratology) study in rats;** this study can be upgraded to acceptable
following the receipt of the following acceptable individual fetal
observation data: body weight, external observations, visceral findings,
and skeletal findings.

**870.3700b Pre-natal Developmental Toxicity Study - Rabbit**

[Executive Summary]{.underline}: In a developmental 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) were as follows (0, 300, 1000 or 3000 mg/kg/day):
0.17, 0.18, 0.14 and 0.05 (p\<0.05). Group mean food consumption
(g/kg/day) during dosing were as follows: 42.9, 42.1, 39.4 and 35.7
(p\<0.05). No other parameters (maternal or developmental) were
considered to have been affected by test article administration.
**Maternal LOAEL = 3000 mg/kg/day based on decreased body weight and
food consumption mostly during the dosing period Maternal NOAEL = 1000
mg/kg/day. Developmental LOAEL = not determined Developmental NOAEL =
3000 mg/kg/day** This study is considered to be **acceptable/guideline**
and meets the requirements to fulfill 83-3 for a developmental toxicity
study in rabbits.

**A.3.3 Reproductive Toxicity**

**870.3800 Reproduction and Fertility Effects - Rat**

[Executive Summary]{.underline}: 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 vagina\" only at 300 ppm (9/25
versus 0-1/27-30 for the other 4 groups). The mortality in the F1
females was as follows for 0, 50, 100, 200 or 300 ppm: 0, 1, 0, 0 and 5
(p\<0.01). Group mean body weight gains were less than control (p\<0.05
or 0.01) in F1 males and females during the first week of premating.
During gestation, F0 and F1 females had lower body weight gain (p\<0.01)
during the last 5 days and for the entire period of gestation(28-31%
decrease in gain). There was a decrease in food consumption in 300 ppm
females of both generations: F0, 65-84% of control during lactation
(p\<0.05 or 0.01); F1, 92-95% of controls during gestation (p\<0.05 or
0.01); and F1, 78-89% of control during lactation (p\<0.05 or 0.01). The
incidence of grossly observable yellow livers was increased in 300 ppm
F1 females that died (p\<0.01, 3/30 versus 0/30 for controls). There was
a decrease (p\<0.01) in absolute only testis and epididymides weights in
300 ppm F1 males (not F0). \[Study authors excluded all rats with small
organs from the analysis.\] No definitive histopathological changes were
attributed to test article administration. There was the suggestion of
atrophied/hypoplastic/hypospermia of the testes and/or epididymides in
both generations of 300 ppm males (of 30 males examined in 0 and 300 ppm
groups, the treated group had no more than one finding more than the
control group). Tissues from the 100 and 200 ppm (and most of the 50
ppm) groups were not evaluated. In F1 300 ppm females that died, liver
lobular necrosis and bile stasis was observed (2-3/4 examined).
**Systemic LOAEL = 300 ppm (mg/kg/day: males = 18.9, females = 22.7)
based on increased clinical signs (F0 females); increased mortality (Fl
females), gross and histopathology findings in the liver (Fl females);
decreased body weight/weight gain (F0 and Fl females during gestation,
Fl males during the early portion of premating); and decreased food
consumption (F0 and Fl females during lactation). Systemic NOAEL = 200
ppm (mg/kg/day: males = 12.7, females = 15.1)** In both generations, the
following reproductive parameters were affected primarily at 300 ppm and
to a lesser extent at 200 ppm: females with liveborn (300 ppm, 16/21 for
Fl pups and 16/18 for F2 pups; control, 23/23 and 23/23); mean number of
live pups/litter on day one of lactation (300 ppm 7/9; control, 14/16);
mean pup weight on lactation day one (300 ppm, 5.7/5.6 g; 200 ppm,
6.1/6.1; control, 6.9/6.4). **Reproduction/Offspring LOAEL = 200 ppm
(mg/kg/day: males = 12.7, females = 15.1) based on decreased number of
females with liveborn and mean number of pups/litter on lactation day 1,
decreased pup body weight, testicular atrophy in F1 males and decreased
mating index. Reproduction/Offspring NOAEL = 100 ppm (mg/kg/day: males =
6.3, females = 7.6).** This study is classified **acceptable/guideline**
and meets the requirements of 83-4 for a two generation reproductive
toxicity study in rats.

**A.3.4 Chronic Toxicity**

**870.4100a (870.4300) Chronic Toxicity -- Rat**

**870.4100b Chronic Toxicity - Dog**

**A.3.5 Carcinogenicity**

**870.4200a Carcinogenicity Study - rat**

In a combined chronic/oncogenicity study (MRID 44295028), flumioxazin
(technical, 94.8% a.i., S-53482) was administered in the diet for up to
24 months to 74 Crj CD (SD) rats/sex/dose at levels of 0, 50, 500, and
1000 ppm (equivalent to 0, 1.8, 18.0, and 36.5 mg/kg/day in male rats
and 0, 2.2, 21.8, and 43.6 mg/kg/day in female rats). At approximately
52 and 78 weeks 10-14 rats per group were terminated and all remaining
animals were terminated at approximately 104 weeks. Survival rates,
clinical observations, clinical chemistry, ophthalmoscopic, urinalysis,
and gross pathologic parameters were unaffected by treatment with
S-53482. Minor changes (2-15%) in hematological parameters (hemoglobin,
MCV, MCH, MCHC) in the midand high-dose females were consistent with a
chronic mild anemia. The presence of circulating erythroblasts in
peripheral blood, reticulocytosis, decreased bone marrow
Myeloid/Erythroid ratio (949%, p\<0.05) and splenic extramedullary
hematopoiesis (8/10 treated; 6/10 controls, p\<0.05) are consistent with
a severe stress on erythropoiesis similar to what might be observed in
chronic iron deficiency. However, the relatively moderate decreases in
hemoglobin and lack of progression to a more severe type of anemia such
as aplastic anemia or pancytopenia indicate successful compensatory
erythropoiesis. Histopathological changes of the kidney indicative of
slight to mild chronic nephropathy was found at the final necropsy in
the 500 (18.0 mg/kg/day) and 1000 (36.5 mg/kg/dah) ppm male groups
(26-27/33 treated vs 13/31 controls, p\<0.01). **The chronic LOAEL is
500 ppm (equivalent to 18.0 and 21.8 mg/kg/day in males and females,
respectively) based upon decreased hemoglobin, MCV, MCH and MCHC in
females and increased incidence of chronic nephropathy in males. The
chronic NOAEL is 50 ppm (equivalent to 1.8 and 2.2 g/kg/day in males and
females, respectively).** Under the conditions of this study, there was
no evidence of carcinogenic potential. Dosing was considered adequate
due to hematological and histopathological changes observed in the mid-
and high-dose animals. This study is classified as acceptable (§83-5;
870.4300) and satisfies the guideline requirements for a combined
chronic toxicity study and a carcinogenicity study in rats.

**870.4200b Carcinogenicity (feeding) - Mouse**

In a mouse oncogenicity study (MRID 44295018), flumioxazin technical,
94.8% a.i. (S-53482) was administered in the diet for 78 weeks to 51
CD-1 mice/sex/dose at levels of 0, 300, 3000 or 7000 ppm which is
equivalent to dietary levels of 0, 31.1, 314.9 or 754.1 mg/kg/day in
males and 0, 36.6, 346.4,or 859.1 mg/kg/day in females, respectively. An
additional 15 mice/sex/dose were used to provide samples for
hematological examination, pathology and histopathology. These animals
were terminated at 53 weeks. All remaining animals were sacrificed at 79
weeks of the study. Survival rates, clinical observations, body weights,
feed consumption, organ weights, gross pathology and hematological
parameters were unaffected by treatment with S-53482. No clinical
chemistry was performed. There were statistically significant increases
in malignant lymphoma/leukemia in mid-dose males (6/15 treated; 1/14
controls, p\<0.05) and increases in pulmonary adenoma in mid-dose
females (5/51 treated; 0/50 control, p\<0.05), these tumor incidences
were comparable to historical controls and did not exhibit
dose-dependency. The LOAEL was not observed. The chronic NOAEL is \>
7000 ppm which is equivalent to 754.1 and 859.1 mg/kg/day in male and
female mice, respectively. Under the conditions of this study, there was
no evidence of carcinogenic potential. Dosing was considered adequate
because the highest dose of 7000 ppm represented a \"limit dose\". This
study is classified as acceptable (§83-2b; 870.4200) and satisfies the
guideline requirements for a carcinogenicity study in mice.

**A.3.6 Mutagenicity**

Gene Mutation

+-----------------------+----------------------------------------------+
| Guideline 870.5100,   | Neither cytotoxic nor mutagenic up to 2000   |
| Gene mutation in *S.  | µg/plate. There were reproducible increases  |
| typhimurium* and *E.  | in revertant colonies of *S. typhimurium*    |
| coli*                 | strains TA1538 and TA98 in S9 activated      |
|                       | phases of the preliminary cytotoxicity and   |
| MRID 42684938         | both mutation assays.                        |
|                       |                                              |
| Acceptable            |                                              |
+-----------------------+----------------------------------------------+

**Cytogenetics**

+-----------------------+----------------------------------------------+
| Guideline 870.5375,   | Precipitation at ≥200 µM. Cytotoxicity at    |
| CHO cells             | 500 µM. Positive +S9 ≥100 µM and negative at |
|                       | 30-500 µM -S9. Aberrations were chromatid    |
| MRID 42684939         | breaks and exchanges.                        |
|                       |                                              |
| Acceptable            |                                              |
+-----------------------+----------------------------------------------+

+-----------------------+----------------------------------------------+
| Guideline 870. 5395,  | Negative in male (up to 5000 mg/kg) and      |
| *In Vivo* Chromosome  | female rats (up to 4400 mg/kg) when tested   |
| Aberration            | orally.                                      |
|                       |                                              |
| MRID 42684940         |                                              |
|                       |                                              |
| Acceptable            |                                              |
+-----------------------+----------------------------------------------+

**Other Genotoxicity**

+-----------------------+----------------------------------------------+
| Guideline 870.5550,   | Negative up to 5000 mg/kg.                   |
| UDS assay             |                                              |
|                       |                                              |
| MRID 42684941         |                                              |
|                       |                                              |
| Acceptable            |                                              |
+-----------------------+----------------------------------------------+

**A.3.7 Neurotoxicity**

**870.6100 Delayed Neurotoxicity Study -- Hen : Not Required**

**870.6200 Acute Neurotoxicity Screening Battery: Not Required**

**870.6200 Subchronic Neurotoxicity Screening Battery: Not Required**

**870.6300 Developmental Neurotoxicity Study: Not Required**

**A.3.8 Metabolism**

**870.7485 Metabolism - Rat**

[EXECUTIVE SUMMARY]{.underline}: In a metabolism study,
\[phenyl-U-'4C)S-53482 was administered to Sprague-Dawley rats
(5/sex/dose) as a single oral dose of 1 mg/kg or 100 mg/kg or as a
single oral dose of 1 mg/kg following a 14-day pretreatment with
unlabeled 5-53482 at 1 mg/kg/day. C.I. tract absorption of S-53482 may
amount to over 90% of the dose at 1 mg/kg and to about 50% at 100 mg/kg.
Total recovery of radioactivity in feces and urine, 7 days after dosing,
accounted for 96.5- 100.7% of the dose in all test groups. Radioactivity
excretion in urine was statistically significantly elevated in females
(38.8-42.8%, low dose; 22.9- 23.4%, high dose) vs. males (28.1-30.8%,
low dose; 12.8-13.0%, high dose). Highest levels of residues were found
in blood cells (35.9-48.8 ppb, low dose and 2823-3040 ppb, high dose),
which were much higher than the plasma levels (0.5-0.7 ppb, low dose and
53-37 ppb, high dose). TLC analysis of feces and urine revealed up to 35
putative metabolites. In addition to untransformed parent compound, 7
metab, lites were identified in urine and feces. Identified compounds
amounted to 37.5-46.1% of the dose at the low dose treatments and to
70.7-71.5% of the dose at the high dose. The study is classified as CQre
Suptlem.ntar-y Data. This study does not satisfy at present the
requirement, § 85-1 for metabolism study in rats. However, this study an
be ungraded to Minimum if information (as detailed in p. 13 of the DER)
clarifying discrepancies between listed Rfs and apparent TLC mobilities
of standards, in addition to information on the type of TLC used, is
provided by the Registrant and is judged to be acceptable by the Agency.

**870.7600 Dermal Absorption - Rat**

[Executive Summary]{.underline}: 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/cm), absorption ranged
from 0.007% of the dose at 0.5 hours to 0.74% at 24 hours. In addition,
the sum of material remaining in skin plus material absorbed amounted to
.2% of the dose at 10 hours and to 2.3% of the dose at 24 hours. At 1.0
mg/rat (0.02 mg/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 classified as Core
Minimum Data (Acceptable) and satisfies the requirement (85-2) for a
dermal absorption study in rats.

**Appendix B: Metabolism Assessment**

Not included.

**Appendix C: Tolerance Reassessment Summary and Table**

+-----------------+--------------+------------+-----------------------+
| **Table C.1.    |              |            |                       |
| Tolerance       |              |            |                       |
| Summary for     |              |            |                       |
| Flumioxazin.**  |              |            |                       |
+=================+==============+============+=======================+
| Commodity       | Proposed     | R          | Comments;             |
|                 | Tolerance    | ecommended |                       |
|                 | (ppm)        | Tolerance  | *Correct Commodity    |
|                 |              | (ppm)      | Definition*           |
+-----------------+--------------+------------+-----------------------+
| Alfalfa, forage | 1.0          | 3.0        | Adequate residue data |
|                 |              |            | are available, and    |
|                 |              |            | the tolerances were   |
|                 |              |            | calculated using the  |
|                 |              |            | tolerance             |
|                 |              |            | harmonization         |
|                 |              |            | spreadsheet.          |
+-----------------+--------------+------------+-----------------------+
| Alfalfa, hay    | 2.0          | 8.0        |                       |
+-----------------+--------------+------------+-----------------------+
| Tree Nut Crop   | 0.02         | 0.02       | Adequate almond and   |
| Group 14        |              |            | pecan field trial     |
|                 |              |            | data are available.   |
|                 |              |            |                       |
|                 |              |            | *Nut, tree, group 14* |
+-----------------+--------------+------------+-----------------------+
| Melon subgroup  | 0.02         | 0.02       | Adequate cantaloupe   |
| 9-A             |              |            | field trial data are  |
|                 |              |            | available.            |
|                 |              |            |                       |
|                 |              |            | *Melon, subgroup 9A*  |
+-----------------+--------------+------------+-----------------------+
| Asparagus       | 0.02         | 0.02       | Adequate asparagus    |
|                 |              |            | field trial data are  |
|                 |              |            | available.            |
+-----------------+--------------+------------+-----------------------+
| Bean, dry, seed | 0.06         | 0.05       | Adequate dry bean     |
|                 |              |            | field trial data are  |
|                 |              |            | available. As         |
|                 |              |            | residues were \<LOQ   |
|                 |              |            | in/on 22 out of 26    |
|                 |              |            | samples, the          |
|                 |              |            | recommended tolerance |
|                 |              |            | was determined using  |
|                 |              |            | the CA method (μ +    |
|                 |              |            | 3σ).                  |
+-----------------+--------------+------------+-----------------------+
| Fruiting        | 0.02         | 0.02       | Adequate tomato and   |
| Vegetable Crop  |              |            | pepper field trial    |
| Group 8         |              |            | data are available.   |
|                 |              |            |                       |
|                 |              |            | *Vegetable, fruiting, |
|                 |              |            | except cucurbits,     |
|                 |              |            | group 8*              |
+-----------------+--------------+------------+-----------------------+
| Okra            | 0.02         | 0.02       | The tolerance for     |
|                 |              |            | okra is supported by  |
|                 |              |            | the available tomato  |
|                 |              |            | and pepper field      |
|                 |              |            | trial data.           |
+-----------------+--------------+------------+-----------------------+
| Bushberry       | 0.02         | 0.05       | Adequate lowbush and  |
| subgroup 13-B   |              |            | highbush blueberry    |
|                 |              |            | field trial data are  |
|                 |              |            | available and support |
|                 |              |            | establishing a        |
|                 |              |            | tolerance for the     |
|                 |              |            | *Bushberry, subgroup  |
|                 |              |            | 13-B.*                |
|                 |              |            |                       |
|                 |              |            | In accordance with    |
|                 |              |            | the Agency's proposed |
|                 |              |            | revisions to the      |
|                 |              |            | Berry Crop Group,     |
|                 |              |            | separate tolerances   |
|                 |              |            | should be established |
|                 |              |            | for new members of    |
|                 |              |            | the bushberry         |
|                 |              |            | subgroup 13-B, until  |
|                 |              |            | the revised crop      |
|                 |              |            | group is approved.    |
|                 |              |            | However, separate     |
|                 |              |            | tolerances are not    |
|                 |              |            | required for the      |
|                 |              |            | existing members of   |
|                 |              |            | the bushberry         |
|                 |              |            | subgroup.             |
+-----------------+--------------+------------+-----------------------+
| Aronia berry    | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Blueberry,      | 0.02         | None ^1^   |                       |
| lowbush         |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Blueberry,      | 0.02         | None ^1^   |                       |
| highbush        |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Buffalo currant | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Chilean guava   | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Currant, black  | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| Currant, red    | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| Elderberry      | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| European        | 0.02         | 0.02       |                       |
| barberry        |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Gooseberry      | 0.02         | None ^1^   |                       |
+-----------------+--------------+------------+-----------------------+
| Highbush        | 0.02         | 0.02       |                       |
| cranberry       |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Honeysuckle     | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Jostaberry      | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Juneberry,      | 0.02         | 0.02       |                       |
| including       |              |            |                       |
| Saskatoon berry |              |            |                       |
+-----------------+--------------+------------+-----------------------+
| Lingonberry     | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Native currant  | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Salal           | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+
| Sea buckthorn   | 0.02         | 0.02       |                       |
+-----------------+--------------+------------+-----------------------+

^1^ As a tolerance is being established for bushberry, subgroup 13-B,
separate tolerances are not required for the existing members of this
subgroup, including: lowbush and highbush blueberries, currants,
elderberry, gooseberry, and huckleberry.

**Appendix D: Review of Human Research**

No MRID - PHED Surrogate Exposure Guide