UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		28 November 2007

Subject:	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.

	  SEQ CHAPTER \h \r 1 	Petition Numbers:		6F7092, 6E7151

		PC Code:			129034

		DP Number:			336194

		Regulatory Citation:		40CFR §180.568

		Chemical Class:		N-phenylphthalimide Herbicide

		Trade Names:		Valor™, Chateau™

From:		  SEQ CHAPTER \h \r 1 Debra 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)

Through:	  SEQ CHAPTER \h \r 1  	William Cutchin, Acting Senior Branch
Scientist

			ARIA

			RIMUERB/RD (7505P)

	William T. Drew, Chemist

		Registration Action Branch 2 (RAB2)

		Health Effects Division (HED) (7509P)

To:		James Stone/Joanne Miller, RM Team 23

		Herbicide Branch (HB)/RD (7505P)

	  SEQ CHAPTER \h \r 1 Daniel 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

  TOC \f  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

<IP_ADDRESS>	Studies Available and Considered (Animal, Human, general
literature)...………14

<IP_ADDRESS>	Mode of Action, Metabolism, Toxicokinetic
Data………………………………14

<IP_ADDRESS>	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

<IP_ADDRESS>	Determination of
Susceptibility.…………………………………………19

<IP_ADDRESS>	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  TC \l1 "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).

  SEQ CHAPTER \h \r 1

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," (  HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"
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 r  SEQ CHAPTER \h \r 1 esidue
data support the   SEQ CHAPTER \h \r 1 establishment 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,   SEQ CHAPTER \h \r 1 ARIA 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).

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, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations 2

Alfalfa (established plantings)

Broadcast foliar application within 7 days after cutting; ground or
aerial equipment	51% WDG [59639-99]

[59639-119]	0.125	2	0.25	25	A minimum RTI of 60 days is specified.

Do not apply with any adjuvants or tank mix with EC formulations.

Do not use on mixed stands of alfalfa and grass.

Dry Beans

Weed control: Pre-emergence broadcast application; ground equipment	51%
WDG [59639-99]

[59639-119]	0.093

(0.05)	1	0.093

(0.05)	NA	Apply in a minimum of 10 gal/A.

Use is restricted to areas west of US Hwy 83 in CO and NE

Harvest aid:  Broadcast foliar application to mature beans; ground
equipment

0.093

(0.05)	1	0.093

(0.05)	5	Application may include a COC at 1% v/v.

Apply in a minimum of 10 gal/A (15 gal/A).

Fruiting Vegetables (including Okra)

Directed soil applications to row middles after transplanting or
emergence and approximately 21 days prior to harvest; ground equipment
51% WDG [59639-99]

[59639-119]	0.125

(0.096)	2

(1)	0.25

(0.096)	21

(NS)	Applications may include a COC at 1% v/v.

Apply in a minimum of 10 gal/A (15 gal/A).

Use directed for shielded sprayers for all applications.

Melons

Directed soil applications to row middles, pre-plant or pre-emergence,
and post-emergence 21-28 days later; ground equipment	51% WDG [59639-99]

[59639-119]	0.125

(0.096)	2

(1)	0.25

(0.096)	NS	Minimum RTIs of 21-28 days.

Use directed for shielded sprayers for all applications.

Apply in a minimum of 10 gal/A (15 gal/A).

Bushberries

Lowbush blueberry:  Directed soil application in early spring; ground
equipment	51% WDG [59639-99]

[59639-119]	0.375	1	0.375	NS	Apply in a minimum of 20 gal/A (15 gal/A).

The minimum RTI is 30 days.

Other bushberries:  Directed soil application in early spring and during
the later stages of berry development.

0.375	2	0.75	7

	Tree Nuts (including Pistachios)

Soil directed applications; ground equipment	51% WDG [59639-99]

[59639-119]	0.375	2	0.75	60	The minimum RTI is 60 days (30 days).  Apply
in a minimum of 20 gal/A (15 gal/A).

Asparagus

Broadcast soil application prior to spear emergence	51% WDG [59639-99]

[59639-119]	0.375

(0.255)	1	0.375

(0.255)	14	Apply in a minimum of 20 gal/A (or 15 gal/A).

Garlic

Pre-emergence broadcast application within 3 days of planting; ground
equipment	51% WDG [59639-99]

[59639-119]	0.38	1	0.38	NS	Apply in a minimum of 10 gal/A.

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

Common name	Flumioxazin

Company experimental name	VC-1152

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

CAS name
2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5
,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione

CAS registry number	103361-09-7

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

2.3	Physical and Chemical Properties:

218,  = 14700 (pH  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

<IP_ADDRESS>	Studies available and considered (animal, human, general
literature)

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

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

Chronic- Oral dog and rat;

Carcinogenicity- Rat and mouse;

Reproductive/developmental- Oral Pre-natal developmental rat, oral
pre-natal developmental rabbit, dermal pre-natal developmental rat,
2-generation rat;

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

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).

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:  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:  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:  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:  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

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.

Developmental Toxicity Studies

Oral (gavage) Developmental Toxicity Study in Rats

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

CORE CLASSIFICATION: 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

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

CORE CLASSIFICATION: 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

Critical Period for Developmental Toxicity Induced by S-53482 in Rats

MRID No. 42884006

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.

Reproductive Toxicity Study

A Two-Generation Reproduction Study in Rats

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

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

<IP_ADDRESS>	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.

<IP_ADDRESS>	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.

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.

Hazard Identification and Toxicity Endpoint Selection

3.5.1    Acute Reference Dose (aRfD) - Females age 13-49  TC \l3 "3.5.1
  Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Pre-natal Developmental Toxicity Study - Rat

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

Executive Summary:  See Appendix A, Guideline [§ 870. 3700a]

Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:   Based on
cardiovascular effects (especially ventricular septal defects in
fetuses) seen at LOAEL =10 mg/kg/day.    The uncertainty factors (UFs)
used were UFA = 10, UFH = 10, and FQPA SF = 1x.

3.5.2	Acute Reference Dose (aRfD) - General Population  TC \l3 "3.5.2
Acute Reference Dose (aRfD) - General Population

No appropriate end-points were selected.

3.5.3	Chronic Reference Dose (cRfD)   TC \l3 "3.5.3	Chronic Reference
Dose (cRfD)

Study Selected: Combined chronic carcinogenicity - rat

MRID No.: 44295028

Executive Summary:  See Appendix A, Guideline [§ 870.4300]

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:   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 UFA = 10, UFH = 10,
and FQPA SF = 1x.

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: Reproduction and fertility effects - rat

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

Executive Summary:  See Appendix A, Guideline [§ 870.3800]

Dose and Endpoint for Risk Assessment: NOAEL = 6.3 mg/kg/day

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

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption

Study Selected: Dermal penetration - rat

MRID No.: 42684944

Executive Summary:  See Appendix A, Guideline [§ 870. 7600]

Dose and Endpoint for Risk Assessment: 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:  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)   TC \l3
"3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected: Dermal Developmental Study (Rat)

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

Executive Summary:  See Appendix A, Guideline [§ 870.3700a]

Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:   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)
TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)

Study Selected: Oral Developmental Study (Rat)

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

Executive Summary:  See Appendix A, Guideline [§ 870.3700a]

Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day

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

Inhalation Exposure (Intermediate- and Long-Term)

Study Selected: 2-Year Chronic/Carcinogenicity Study (Rat)

MRID No.:  44295028

Executive Summary:  See Appendix A, Guideline [§ 870.4200a]

Dose and Endpoint for Risk Assessment: NOAEL = 2 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:   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  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure

Table 3.5.9 Summary of Levels of Concern for Risk Assessment.

                 Duration

Route	Short-Term	(1-30 Days)	Intermediate-Term

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  TC \l3
"3.5.9	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  TC \l3 "3.5.11	Summary of Toxicological
Doses and Endpoints for [Chemical] for Use in Human Risk Assessments

Table 3.5.12a  Summary of Toxicological Doses and Endpoints for
Flumioxazin for Use in Dietary and Non-Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure (POD) 	Uncertainty/FQPA Safety Factors	RfD,
PAD, Level of Concern for Risk Assessment	Study and Toxicological
Effects

Acute Dietary

Females 13-49 only	NOAEL = 3

mg/kg/day

 	UFA=10x

UFH=10x

FQPA SF=1x 	Acute RfD = acute NOAEL

                      Safety Factors

= 0.03 mg/kg/day

aPAD = acute NOAEL

              Safety Factors

= 0.03 mg/kg/day	Oral Developmental and Supplemental Pre-natal Studies
(Rat)

LOAEL = 10 mg/kg/day, based on cardiovascular effects (especially
ventricular septal defects in fetuses).

Acute Dietary

General Population including infants and children	There were no
appropriate toxicological effects attributable to a single exposure
(dose) observed in oral toxicity studies including maternal effects in
developmental studies in rats and rabbits.  Therefore, a dose and
endpoint were not identified for this risk assessment.

Chronic Dietary

all populations	NOAEL= 2.0 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF=1x	Chronic RfD = chronic NOAEL

                           Safety Factors

= 0.02 mg/kg/day

cPAD = chronic NOAEL

               Safety Factors

= 0.02 mg/kg/day	2-Year Chronic/Carcinogenicity Study (Rat)

LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males
and decreased hematological parameters in females (Hgb, MCV, MCH, and
MCHC).

Short- (1-30 days) and Intermed-Term (1- 6 months) Oral	NOAEL= 6.3
mg/kg/day	NA	LOC for MOE = 100 	2-Generation Reproduction Study (Rat)

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

Dermal (All durations)	NOAEL= 30 mg/kg/day

	NA	LOC for MOE = 100 	Dermal Developmental Study (Rat)

LOAEL = 100 mg/kg/day, based on cardiovascular effects (especially
ventricular septal defects in fetuses).

Short- Term (1-30 days) Inhalation	NOAEL = 3 mg/kg/day	NA	LOC for MOE =
100

	Oral Developmental Study (Rat)

LOAEL = 10 mg/kg/day, based on cardiovascular effects (especially
ventricular septal defects in fetuses).

Intermed-(1- 6 months) and Long-Term (> 6 months) Inhalation	NOAEL= 2
mg/kg/day

(inhalation absorption rate = 100%)	NA	LOC for MOE = 100

	2-Year Chronic/Carcinogenicity Study (Rat)

LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males
and decreased hematological parameters in females (Hgb, MCV, MCH, and
MCHC).

Cancer

(oral, dermal, inhalation)	“Not likely to be a carcinogen for
humans,” based on the lack of carcinogenicity in a 2-year rat study,
an 18-month mouse study, and a battery of mutagenic studies.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level.
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  NA = not applicable.

Table 3.5.12b  Summary of Toxicological Doses and Endpoints for
Flumioxazin for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short- (1-30 days)

Intermediate- (1-6 months) Long Term (>6 months) a	NOAEL=

30 mg/kg/day

	UF = 100	LOC for MOE = 100	Dermal Developmental Study in Rats

LOAEL = 100 mg/kg/day based on cardiac effects (intraventricular septal
defects)

Inhalation Short-Term (1-30 days) 	NOAEL= 3.0 mg/kg/day

(inhalation absorption rate = 100%)	UF = 100	LOC for MOE = 100	Oral
Developmental Study in Rats

LOAEL = 10 mg/kg/day based on cardiac effects (interventricular septal
defects)

Inhalation Intermediate- (1-6 months) Long-Term Inhalation (>6 months)
NOAEL = 2.0 mg/kg/day

(inhalation absorption rate = 100%)	UF = 100	LOC for MOE = 100	Two-year
Toxicity Study in Rats

LOAEL = 18.0 mg/kg/day based on decreased hemoglobin, MCV, MCH and MCHC
in females and increased incidence of chronic nephropathy in males

Cancer (oral, dermal, inhalation)	2.0 mg/kg/day

UF = 100	UF = 100	SF = 1

0.02 mg/kg/day	Chronic Toxicity/Carcinogenicity Study in Rats

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

  SEQ CHAPTER \h \r 1 The 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

Metabolism in Primary Crops and Livestock Commodities.

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

The results of the ruminant and poultry metabolism studies with both
phenyl- and THP-labeled flumioxazin show that the major metabolic
pathways are hydrolysis of the imide moiety, hydroxylation of the
cyclohexene ring, and the equivalent of addition of sulfonic acid to the
alkene function.  The residues of concern in ruminants 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.)

Metabolism in Rotational Crops

 ≤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.

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.

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

  SEQ CHAPTER \h \r 1 Data depicting the analysis of flumioxazin through
FDA Multiresidue Protocols were submitted and will be forwarded to FDA
for review.  The multiresidue method testing data indicate that
flumioxazin is not recovered through Sections 304 and 402 of PAM, Vol. I
(DP Num: 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.

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.

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]).

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.

Pesticide Metabolites and Degradates of Concern

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

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Flumioxazin	Flumioxazin

	Rotational Crop	Flumioxazin	Flumioxazin

Livestock

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

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

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

Drinking Water

	Flumioxazin, 482-HA and APF	Not Applicable

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:
HYPERLINK "http://www.epa.gov/oppefed1/models/water/"
http://www.epa.gov/oppefed1/models/water/ .

Table 5.1.10.  EDWCs for flumioxazin and its degradates in surface water
and groundwater at pH 7.

Compound	Average 56-Day Conc. in  Surface Water	Peak Conc. in Surface
Water	Conc. in Groundwater

Flumioxazin	negligible	1.03 ppb	negligible

482-HA	4.84 ppb	6.87 ppb	45.27 ppb

APF	12.85 ppb	26.46 ppb	2.66 ppb

THPA	19.50 ppb	27.67 ppb	182.28 ppb

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.

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 Flumioxazin.

Population Subgroup 1

[Years of Age]

DEEM Acute Dietary Analysis,

95th Percentile

DEEM Chronic Dietary Analysis

aPAD (mg/kg)

Exposure (mg/kg/day)

% aPAD

cPAD (mg/kg/day)

Exposure (mg/kg/day)

% cPAD

General US Population

NA 2

0.02

0.001207

6

All Infants [<1]

0.02

0.003689

18

Children [1-2]

0.02

0.002168

11

Children [3-5]

0.02

0.001958

10

Children [6-12]

0.02

0.001299

7

Youths [13-19]

0.02

0.000900

5

Adults [20-49]

0.02

0.001076

5

Adults [50+]

0.02

0.001121

6

Females [13-49]

0.03

0.002524

8

0.02

0.001076

5

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.

Cancer Dietary Risk

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

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.

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.

Short-Term Aggregate Risk

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

Intermediate-Term Aggregate Risk

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

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.

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.

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
HYPERLINK http://www.epa.gov/pesticides/cumulative/.
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 Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3

Per Day	Avg. Daily Dose4

mg ai/kg bw/day	NOAEL5

mg/kg bw/day	MOE6	Combined

MOE7

Mixer/Loader - Dry Flowable - Open Pour Loading

Dermal:

SLNoGlove      0.066 LC

SLWithGlove   0.066 HC

Inhal.            0.00077 HC	0.375

 lb ai/A	200 A	Dermal:

No Glove 0.0825

W Glove  0.0825

Inhal.   0.000963	Dermal

30

Inhalation

3	Dermal

363

363

Inhal.  3115

325

325

Applicator - Open-cab - Ground-boom

Dermal:

SLNoGlove     0.014 HC

SLWithGlove  0.014 MC

Inhal.           0.00074 HC	0.375

 lb ai/A	200 A	Dermal:

No Glove 0.0175

W Glove  0.0175

Inhal.   0.000925	Dermal

30

Inhalation

3	Dermal

1714

1714

Inhal.  3243

1126

1126

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/MOEDermal +1/MOEInhalation

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.

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 cm2/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 cm2/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.

Restricted Entry Interval (REI)

The ChateauTM 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]).   SEQ CHAPTER \h \r 1  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]).

  SEQ CHAPTER \h \r 1 No 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 Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity 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 Group 14	0.02	0.02	Adequate almond and pecan field trial
data are available.

Nut, tree, group 14

Melon subgroup 9-A	0.02	0.02	Adequate cantaloupe 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 Vegetable Crop Group 8	0.02	0.02	Adequate tomato and pepper
field trial 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 subgroup 13-B	0.02	0.05	Adequate lowbush and 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, lowbush	0.02	None 1

	Blueberry, highbush	0.02	None 1

	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 barberry	0.02	0.02

	Gooseberry	0.02	None 1

	Highbush cranberry	0.02	0.02

	Honeysuckle	0.02	0.02

	Jostaberry	0.02	0.02

	Juneberry, including Saskatoon berry	0.02	0.02

	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  TC \l1 "Appendix A:  Toxicology
Assessment

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements

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

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    21-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation		yes

yes

yes

yes

yes	yes

yes

yes

NO

yes

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	NO

yes

yes

yes

NO

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5375    Mutagenicity—Gene Mutation – CHO cells

870.5395    Mutagenicity— In vivo rat bone marrow

870.5550    Mutagenicity—Other Genotoxic Effects- UDS assay		yes

yes

yes

yes

yes	yes

NO

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotox. Screening Battery (rat)

870.6200b  90-Day Neuro. Screening Battery (rat)

870.6300    Develop. Neuro		no

no

no

no

no	-

-

-

-

-

870.7485    General Metabolism

870.7600    Dermal Penetration		yes

yes	yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)		no	-

A.2  Toxicity Profiles TC \l2 "A.2  Toxicity Profiles

Table A.2.1	Acute Toxicity Profile for Flumioxazin

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

870.1100	Acute oral [rat]

42684911

LD50>5000 mg/kg M & F

IV

870.1200	Acute dermal [rat]

42684913

LD50>2000 mg/kg

III

870.1300	Acute inhalation [rat]

42684915

LC50 =3.93 mg/L

IV

870.2400	Acute eye irritation [rabbit]

42684917

Not an ocular irritant

III

870.2500	Acute dermal irritation [rabbit]

42684917

Non-irritating

IV

870.2600	Skin sensitization [guinea pig]

42684921

Non-sensitizer

N/A

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

Guideline No. 	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3100

	90-Day oral toxicity - rat	 42684923

dose levels: 0, 2.3, 20.7, 69.7, and 243.5 mg/kg/day (M)

and 0, 2.2, 21.7, 71.5, and 229.6 mg/kg/day (F)	NOAEL = 69.7 (M), 71.5
(F)  mg/kg/day

LOAEL = 243.5 (M), 229.6 (F) mg/kg/day based on a decrease in MCV both
sexes; increase in platelets F only.

870.3100

	90-Day oral toxicity - rat	42683922

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

218.4 mg/kg/day (F)	NOAEL = 65.0 (M), 72.9 (F)  mg/kg/day    LOAEL =
196.7 (M), 218.4 (F) mg/kg/day based on hematology changes.

870.3100

	90-Day oral toxicity - mouse	MRID unknown (referred to in 79-week
study, MRID 44295018)

dose levels:  0, 143, 429, or 1429 (M & F) mg/kg/day	NOAEL = 429
mg/kg/day

LOAEL = 1429 mg/kg/day based on increased liver weight in males.

870.3100

	4-Week oral toxicity - mouse	44307301 (see MRID 44295018 DER#2)

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

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

870.3150

	90-Day capsule - dog	42684924

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

LOAEL = 100  mg/kg/day based on dose dependent increase in total
cholesterol, phospholipid & alkaline phosphatase activity.

870.3200

	21-Day dermal toxicity - rat	44295016

dose levels:  1, 100, 300,  or 1000 mg/kg/day	NOAEL = mg/kg/day: 1000
(LIMIT DOSE)

LOAEL = mg/kg/day: >1000 based on no effects.

870.3250

	90-Day dermal toxicity (species)	[ ]	NOAEL = [ ] mg/kg/day

LOAEL = [ ] mg/kg/day based on [ ].

870.3465

	90-Day inhalation toxicity (species)	[ ]	NOAEL = [ ] mg/kg/day

LOAEL = [ ] mg/kg/day based on [ ].

870.3700a

	Pre-natal developmental - rat (oral)

	(1)42684930 (pilot study); 42684925 (main study); (2) 42884006

dose levels: 0, 1, 3, 10 and 30 mg/kg/day	Maternal NOAEL = 30 mg/kg/day
(HDT)

LOAEL = >30 mg/kg/day (HDT)

Developmental NOAEL = 3 mg/kg/day

LOAEL = 10 mg/kg/day based on cardiovascular effects (especially
ventricular septal defects ).

870.3700a	Pre-natal developmental - rat

(dermal)	42684929 (pilot); 42684926 (main study)

dose levels: 0, 30, 100, and 300 mg/kg/day

Maternal NOAEL = 300 mg/kg/day (HDT)

LOAEL = >300 mg/kg/day (HDT)

Developmental NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on cardiovascular effects (especially
ventricular septal defects).

870.3700b

	Pre-natal developmental - rabbit (oral)	42684927 (range-finding);
42684928 (main study)

dose levels:  0, 300, 1000, or 3000 mg/kg/day	Maternal NOAEL = 1000
mg/kg/day

LOAEL = 3000 mg/kg/day (HDT) based on decrease in body weight and food
consumption during dosing

Developmental NOAEL = 3000 mg/kg/day (HDT) LOAEL = >3000 mg/kg/day

870.3800

	Reproduction and fertility effects - rat)	42684934 and 42684936 (pilot
studies); 42684935 (main study)

dose levels:  0, 3.2, 6.3, 12.7, and 18.9 mg/kg/day (M) and 0, 3.8, 7.6,
15. 1, and 22.7 mg/kg/day (F)	Parental/Systemic NOAEL = 12.7 (M), 15.1
(F) mg/kg/day;  LOAEL = 18.9 (M), 22.7 (F) mg/kg/day based on increase
in clinical signs (red substance in vagina) and increased female
mortality as well as decreased body weight, body weight gain and food
consumption.

Reproductive NOAEL = 18.9 (HDT) (M), 22.7 (HDT) (F) mg/kg/day;  LOAEL =
>18.9 (HDT) (M), >22.7 (HDT) (F) mg/kg/day

Offspring NOAEL = 6.3 (M), 7.6 (F) mg/kg/day;  LOAEL = 12.7 (M), 15.1
(F) mg/kg/day based on a decrease in the number of liveborn and a
decrease in pup body weight.

870.4100b

	12-Month capsule - dog	44295017

dose levels:  0, 10, 100 or 1000 mg/kg/day	NOAEL = 100 mg/kg/day (M & F)

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

870.4100a

	Chronic toxicity (species)	[ ]	NOAEL = [ ] mg/kg/day

LOAEL = [ ] mg/kg/day based on [ ].

870.4200b

	Carcinogenicity - mouse	44295018

dose levels: 0, 31.1, 314.9 or 754.1 mg/kg/day in males and 0, 36.6,
346.4, or 859.1 mg/kg/day in females 	NOAEL = 754.1 (M), 859.1 (F)
mg/kg/day (LIMIT DOSE); LOAEL = no systemic effects at LIMIT DOSE in
males or females

No evidence of carcinogenicity

870.4200a

	Combined chronic carcinogenicity - rat	44295028

dose levels: 0, 1.8, 18.0, and 36.5 mg/kg/day in male rats and 0, 2.2,
21.8, and 43.6 mg/kg/day in female rats	NOAEL = 1.8 (M), 2.2 (F)
mg/kg/day

LOAEL = 18.0 (M), 21.8 (F) mg/kg/day based on increased chronic
nephropathy in males and decreased hematological parameters in females
(Hgb, MCV, MCH and MCHC).

No evidence of carcinogenicity

Gene Mutation

870.5100	Gene mutation in S. typhimurium and E. coli	42684938

dose levels:  with or without metabolic activation to 0, 50, 100, 200,
500, 1000, or 2000 μg/plate	Neither cytotoxic nor mutagenic up to 2000
µg/plate.  There were reproducible increases in revertant colonies of
S. typhimurium strains TA1538 and TA98 in S9 activated phases of the
preliminary cytotoxicity and both mutation assays. [Results are
considered to be equivocal.]

Gene Mutation

870.5375	Gene mutation in chinese hamster ovary cells	42684939

μM (11, 35, 70, and 177 μg/mL, respectively)	Precipitation at (200
µM.  Cytotoxicity at 500 µM.  Positive +S9 (100 µM and negative at
30-500 µM -S9.  Aberrations were chromatid breaks and exchanges.

870.5395

In vivo rat bone marrow	42684940

dose levels: 1250, 2500, or 5000 mg/kg

Negative in male (up to 5000 mg/kg) and female rats (up to 4400 mg/kg)
when tested orally.

870.5550	UDS assay	42684941

dose levels: by oral gavage to 5000 mg/kg or 12 hours post exposure to
1250 or 2500 mg/kg

Negative up to 5000 mg/kg.

870.6200a

	Acute neurotoxicity screening battery

Not required.

870.6200b

	Subchronic neurotoxicity screening battery

Not required.

870.6300

	Developmental neurotoxicity

Not required.

870.7485

	Metabolism and pharmacokinetics - rat (oral)	42684943

single oral dose of 1 mg/kg or 100 mg/kg,	Gastrointestinal tract
absorption >90% at 1 mg/kg and up to 50% at 100 mg/kg.  At least 97%
recovery in feces and urine 7 days after dosing.  Highest levels of
residues (36-49 ppb) in blood cells at low dose and 2800-3000 ppm at
high dose (RBC levels > plasma).  In addition to untransformed parent, 7
metabolites identified in urine and feces (38-46% for low dose and about
71% at high dose).

870.7600	Dermal penetration - rat	42684944

dose levels:  200 or 800 mg/kg bw

	Females dosed with 200 or 800 mg/kg b.w.  Dermal absorption for 200 and
800 mg/kg was 3.9 and 8.0% by 48 hours after initiation of treatment for
6 hours.  Blood levels at 6-24 hours after dermal dosing with 200 mg/kg
were similar to those obtained at 2-6 hours after oral dosing with 1
mg/kg.  Blood levels at 6-24 hours after dermal dosing with 800 mg/kg
were similar to those obtained at 2-6 hours after oral dosing with 30
mg/kg.

870.XXX 	Special Study -

Rat Developmental: Critical Time for Defects	42694931, 42684932

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

A.3  Executive Summaries TC \l2 "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:  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: 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