UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

MEMORANDUM

	  PC Code: 125851

  DP Barcode:  D341496

					     June 7, 2010

SUBJECT:	Environmental Fate and Ecological Risk Assessment for the
Section 3 New Uses of Isoxaben on Bearing Nut Trees and Vineyards

TO:		Bethany Benbow, Product Review Manager

Kathryn Montague, Product Manager

Registration Division (7505P)

FROM:	Brian Kiernan, Biologist

Charles Peck, Environmental Engineer

		Environmental Risk Branch IV

		Environmental Fate and Effects Division (7507P)

REVIEWED

BY:		Thomas Steeger, Ph.D., Senior Biologist

		R. David Jones, Ph.D., Senior Agronomist

		Environmental Risk Branch IV

		Environmental Fate and Effects Division (7507P)

APPROVED

BY:		Mark Corbin, Acting Branch Chief

		Environmental Risk Branch IV

		Environmental Fate and Effects Division (7507P)

I.  Executive Summary

	Dow AgroSciences is seeking registration for a new use of the active
ingredient isoxaben (PC Code 125851) as the sole active ingredient in
the herbicidal end use product FN-3133 (Reg. No. 62719-LIN).
Registration is being requested nationally for pre-emergent control of
broadleaf weeds in bearing nut trees (e.g., almonds, beech nut, Brazil
nut, butternut, cashew, chinquan, filbert, hickory nut, macadamia nut,
pecan, pistachio, and walnuts) and grapes.  There are currently twelve
Section 3 registrations based on isoxaben as the active ingredient (ai).
 There are no current food-use registrations.  The proposed method of
application evaluated for this assessment is ground spray but the label
is not explicit.  The proposed maximum single application rate is 1.0 lb
ai/A.  FN-3133 may not be applied more than twice per crop year up to a
maximum total of 1.0 lb ai/A per crop year.  No reapplication interval
is specified on the label.

Conclusions – Exposure Characterization

Isoxaben is moderately persistent and mobile (Kd = 0.81 to 6.63 mL/g).
The mobility of isoxaben may decrease with increasing soil clay content
and cation exchange capacity (CEC), although not significantly enough to
consider isoxaben bound to soil or sediments.  The compound may
represent a ground water concern when applied to certain soils and/or
where high water tables (shallow ground waters) are present (i.e. less
than one foot below grade) and high rainfall/ irrigation occurs.

	Isoxaben does not hydrolyze and does not appear to readily degrade in
terrestrial environments.  Primary routes of degradation appear to be
biodegradation in aerobic and anaerobic water bodies and photolysis in
shallow, clear water bodies.

	Four major degradates detected in laboratory biometabolism studies
include: hydroxyisoxaben; dimethoxybenzamide; methoxyphenylpyrimidinol
and AEM hexenoylisoxaben.  Four minor degradates identified include:
hydroxymethoxybenzamide; oxypropyl isoxaben; desmethyl isoxaben and
methoxyphenyl pyrimidinol.  One available mobility study and an EPISuite
analysis indicate that several of these isoxaben degradates are more
mobile than the parent.  The four major degradates identified above are
included in aquatic estimated environmental concentrations using a total
toxic residues approach.

Conclusions – Effects Characterization

Consistent with isoxaben’s intended use as a herbicide, the compound
is toxic to aquatic and terrestrial plants.  Isoxaben is practically
nontoxic to aquatic and terrestrial animal species on an acute exposure
basis.  Sublethal effects (abnormal larvae) were noted in an acute
estuarine/marine invertebrate study with clams, but no data are
available on the chronic effect of isoxaben on estuarine/marine species.
 No effects from chronic exposure were observed in studies with
freshwater species.  Chronic effects on the growth and reproduction of
birds and mammals were reported in the available toxicity studies.

The four major degradates identified in the exposure characterization
are considered to be as toxic as the parent compound based on their
structural similarity and are included in estimates of total toxic
residues.

	Potential Risks to Non-target Organisms

Isoxaben is moderately persistent and combined with its potential
chronic effects, the proposed use of the compound the proposed use of
isoxaben on grapes and bearing nut trees has the potential to adversely
affect the growth of birds, terrestrial-phase amphibians, reptiles and
mammals from chronic exposure.  Depending on soil conditions and
weather, isoxaben can move to surface water via spray drift, direct
runoff or through runoff of sediment-bound residues.  Estimated
concentrations in water are considered likely to adversely affect
aquatic plant growth and this could significantly impair primary
productivity.  Impaired primary productivey could in turn lead to
decreased water quality and reduced forage for aquatic biota and result
in secondary effects across a broad range of aquatic animals.  Acute and
chronic risk estimates for direct effects on aquatic animals are below
levels of concern; however, there is uncertainty regarding the extent to
which secondary effects from decreased primary productivity will impact
the aquatic community.

Additonally, growth of nontarget aquatic and terrestrial plants is
expected to be adversely affected.  Because there is differential
toxicity across the species of plants in the available studies, it is
possible that this could lead to shifts in nontarget plant communities
exposed to isoxaben.  Changes in plant communities, which provide
habitat, food and are primary producers in ecosystems, can lead to
indirect effects to terrestrial organisms.

Potential effects to federally-listed endangered and threatened species
(listed species) based on exceedances of Agency Levels of Concern (LOCs)
require an in-depth listed species evaluation to determine the extent of
potential co-occurrence of listed species and the areas in which use is
proposed on grapes and bearing nut trees .  Identified potential risks
to listed species are summarized in Table 1.  Listed terrestrial plants
may be directly affected by isoxaben use, and indirect effects on other
listed species are possible.

Table 1.  Potential Listed Species Risks Associated with Direct or
Indirect Effects Due to the Proposed Application of Isoxaben on Bearing
Nut trees and Grapes.

Listed Taxon	Direct Effects	Indirect Effects

Terrestrial and semi-aquatic plants - monocots	Yes	Yes1

Terrestrial and semi-aquatic plants - dicots	Yes	Yes1

Birds	Yes	Yes1

Terrestrial-phase amphibians	Yes	Yes1

Terrestrial invertebrates	Yes	Yes1

Reptiles	Yes	Yes1

Mammals	Yes	Yes1

Aquatic vascular plants	Yes	Yes1

Aquatic nonvascular plants	Yes	Yes1

Freshwater fish	No	Yes1

Aquatic-phase amphibians	No	Yes1

Freshwater invertebrates	No	Yes1

Mollusks	No	Yes1

Marine/estuarine fish	No	Yes1

Marine/estuarine crustaceans	Yes	Yes1

1Nonlisted LOC exceeded for terrestrial plants, therefore there is
potential for adverse effects to those species that rely either on a
specific plant species or multiple plant species.  Plant indirect
effects may include general habitat modification, host plant loss, and
food supply disruption.

II.  Problem Formulation

A.  Nature of the Regulatory Action

	Dow AgroSciences is seeking registration for a new use of the active
ingredient isoxaben (PC Code 125851) as the sole active ingredient in
the herbicidal end use product FN-3133 (Reg. No. 62719-LIN).
Registration is being requested nationally for pre-emergent control of
broadleaf weeds in bearing nut trees and grapes.  There are currently
twelve Section 3 registrations based on isoxaben as the active
ingredient (ai).  There are no current food-use registrations.  The
proposed method of application evaluated for this assessment is ground
spray but the label is not explicit.  The proposed maximum single
application rate is 1.0 lb ai/A.  FN-3133 may not be applied more than
twice per crop year up to a maximum total of 1.0 lb ai/A per crop year.
No reapplication interval is specified on the label.

B.  Previous Assessments

Isoxaben was registered for use as a pre-emergent herbicide in 1989.
There are currently twelve Section 3 registrations based on isoxaben as
the active ingredient (ai), including use on rights-of-ways, turf,
landscaping, nurseries, other industrial (noncrop) areas and non-bearing
fruit and nut crops.  There are no current food-use registrations.  The
reregistration review docket for isoxaben was opened in 2008.  No
ecological risk assessments have been conducted previously for isoxaben.

C.  Stressor Source and Distribution

	1.  Nature of the Chemical Stressor

	Isoxaben is a pre-emergent benzamide herbicide used for the control of
broadleaf (dicotyledonous) weeds.  The specific mode of action for
isoxaben is not well understood, but isoxaben has been shown to inhibit
the conversion of glucose to cellulose in cell wall synthesis in
sensitive species, with grasses (Family: Poaceae) tending to be more
tolerant than other plant groups (Salihue et al. 1998).  Isoxaben is not
thought to be highly mobile in adult plant tissues, apparently limiting
its toxicity to older plants, but allowing increased efficacy in
emerging seedlings.  Nonetheless, the vegetative vigor of early growth
plants, particularly ryegrass, is affected by isoxaben, as discussed in
the Ecological Effects Characterization.  Chemical properties of
isoxaben are presented inTable 2, while the structure of isoxaben is
depicted inFigure 1.

Table 2.  Nature of the Chemical Stressor

Common name	Isoxaben (EL-107)

Chemical Name	N-
[3-(methylpent-3-yl)isoxazol-5-yl]-2,6-dimethoxy-benzamide

Pesticide type, such as herbicide or insecticide,	Herbicide

Chemical class	benzamide

CAS number	82558-50-7

Empirical formula	C18H24N2O4

Molecular Mass (g/mol)	332.39 g · mol-1

Vapor pressure (torr)	<3.9 X 10 -7

Henry’s Law Constant at 20oC

(atm-m3/mole)	8.5x10-10

Solubility in water (ppm)	1

Log Kow 	2.64

pKa at 25oC	9.78

Figure 1. Chemical structure of isoxaben.

	Isoxaben is moderately persistent and (Kd = 0.81 to 6.63 mL/g) mobile
(MRID 41106303).  There is some indication that the mobility of isoxaben
decreases with increasing soil clay content and cation exchange capacity
(CEC) (MRID 41106303), although not significantly enough to consider
isoxaben bound to soil or sediments.  The compound may represent a
ground water concern when applied to certain soils and/or where high
water tables (shallow groundwater) are present (i.e. less than one foot
below grade) and high rainfall/ irrigation occurs (MRID 40059508).

	Isoxaben does not hydrolyze and does not appear to readily degrade in
terrestrial environments (MRIDs 41106302, 143786, and 164646).  Primary
routes of degradation appear to be biodegradation in aerobic and
anaerobic water bodies and photolysis in shallow, clear water bodies
(MRIDs 40059507, 46393201 and 46393202).

Major degradates detected during aerobic and anaerobic soil metabolism
studies and aerobic and anaerobic aqueous metabolism studies include:
hydroxyisoxaben; dimethoxybenzamide; methoxyphenylpyrimidinol and amino
ethyl methyl (AEM) hexenoylisoxaben.  A mobility study (MRID 41106303)
and EPISuite analysis indicate that several of these isoxaben degradates
are more mobile than the parent.  Additionally, four major photolytic
degradates (Unk 3, Unk 3i, Unk 5a, and Unk 5b) were detected but not
conclusively identified (MRID 47140003).  The Health Effects Division
(HED) evaluated the isoxaben residues of concern for human health.
Because the formation of the photodegradates was considered minimal
(e.g., formed only during aqueous photolysis) and a structural activity
relationship (SAR) analysis performed by HED concluded that none of
these degradates were expected to be more toxic than the parent
compound, these photodegradates were not of exposure concern and were
excluded as residues of concern.  HED concluded that the major
degradates detected during the aerobic and anaerobic soil and aqueous
metabolism studies were not expected to be more toxic to humans than the
parent compound, but data were not available to exclude them as residues
of concern.  As such, the degradates hydroxyisoxaben,
dimethoxybenzamide, methoxyphenylpyrimidinol, and AEM hexenoylisoxaben
were included as residues of concern for human health (USEPA, 2010).
For this assessment, in the absence of ecotoxicity data, these
degradates were also included as residues of concern for aquatic
organisms using a total toxic residue (TTR) analysis.

	2.  Overview of Pesticide Usage

Isoxaben was registered in 1989 for various uses, including:
rights-of-ways, turf, landscaping, nurseries, other industrial (noncrop)
areas and non-bearing fruit and nut crops.  The majority of uses have an
application rate of 1.0 lb ai/A/application, three applications per year
with a 60-day reapplication interval, applied either as a dry flowable
product in a broadcast spray or as a granular product in a spreader.
Some uses are only 0.5 lbs ai/A/application and there are hand-applied
soil treatments at rates up to 2.0 lbs ai/A/application.

	Based on label instructions for the 12 registered isoxaben product
labels, most prohibit aerial application; however, it is not clear
whether all of the current uses prohibit aerial application (e.g. usage
on conifer seed orchards).  There are label prohibitions on chemigation
and direct applications to water.  Warnings regarding the potential
toxicity to aquatic organisms and avoidance of spray drift are on the
labels as well.  Isoxaben is not for sale, distribution or use in New
York State.

In a memo from the OPP Biological and Economic Analysis Division (BEAD)
dated 08/01/2007, national non-crop usage accounted for nearly 19,000
(94%) of the 20,372 lbs applied annually (on average) for the years
2003-2005, with rights-of-way alone accounting for an annual average of
11,619 lbs (57% of total applied).

	Isoxaben is currently limited to non-bearing food crops (i.e. food
crops not yet producing a marketable harvest); therefore, historically,
only a small percentage of total target crop area planted is expected to
be treated.  For instance, according the Screening Level Usage Analysis
(SLUA, 2007) for isoxaben, the maximum area treated for almonds, apples
grapes and walnuts is less than 2.5% of total area planted for each
crop.  Registered non-bearing crop uses include almond, apple, apricot,
avocado, banana, blackberry (and other raspberry crops), blueberry,
cherry, citrus fruits, elderberry, fig, grapes, nut trees, olive and
pomegranate.  Approval of the new food use on bearing tree nuts and
grapes would likely increase the amount of isoxaben used on these crops
and as such increase the percent crop treated.

D.  Receptors

	1.  Aquatic Effects and Terrestrial Effects

The receptor is the biological entity that is exposed to the stressor
(USEPA, 1998).  Aquatic and terrestrial receptors that may be exposed to
isoxaben include any organism within the action area.

Consistent with the process described in the Overview Document (USEPA,
2004), this risk assessment uses a surrogate species approach in its
evaluation of isoxaben toxicity.  T  SEQ CHAPTER \h \r 1 oxicological
data generated from surrogate test species, which are intended to be
representative of broad taxonomic groups, are used to extrapolate to
potential effects on a variety of species (receptors) included under
these taxonomic groupings.

Acute and chronic toxicity data from studies submitted by pesticide
registrants along with the available open literature are used to
evaluate the potential direct effects of isoxaben to the aquatic and
terrestrial receptors identified in this section.  This includes
toxicity data on the technical grade active ingredient, formulated
products and, when available, degradates.  Open literature studies are
identified through EPA’s publically available ECOTOX database (
HYPERLINK "http://cfpub.epa.gov/ecotox/"  http://cfpub.epa.gov/ecotox/
), which employs a literature search engine for locating chemical
toxicity data for aquatic and terrestrial wildlife and plants.  The
evaluation of both sources of data may also provide insight into the
direct and indirect effects of isoxaben on biotic communities from loss
of species that are sensitive to the chemical and from changes in
structure and functional characteristics of the affected communities.

	Isoxaben’s effect on aquatic organisms is estimated from acute and
chronic laboratory studies submitted to the Agency by the technical
registrant.  The registrant has submitted acute and chronic studies on
aquatic vertebrates and invertebrates and studies on the effects of
exposure on aquatic plants.  Freshwater fish, e.g., bluegill sunfish
(Lepomis macrochirus) and rainbow trout (Oncorhynchus mykiss), are used
as surrogates for all freshwater fish species.  Freshwater fish are
usually used as surrogates for aquatic-phase amphibians unless
amphibian-specific data are available; amphibian data are unavailable
for isoxaben.  Freshwater invertebrate effects are estimated from
studies using the waterflea (Daphnia magna).  Effects of isoxaben on all
estuarine/marine fish are estimated from effects on sheepshead minnow
(Cyprinodon variegatus), while estuarine/marine invertebrate effects are
estimated from studies on Quahog clam (Mercenaria mercenaria) and grass
shrimp (Palaemonetes pugio).  Effects on aquatic vascular plants are
estimated from studies on duckweed (Lemna gibba), while effects on
aquatic non-vascular plants are similarly estimated from studies on
surrogate species of microalgae.

The effect of isoxaben on all bird species is estimated from acute oral,
subacute dietary and chronic dietary studies on two species, bobwhite
quail (Colinus virginianus) and mallard duck (Anas platyrhynchos).
Recent changes in the study guidelines require an acute passerine study,
which is not available for this assessment.  Birds serve as surrogates
for reptiles and terrestrial-phase amphibians.  Effects on mammals are
estimated from acute and chronic rat studies submitted to and reviewed
by the Health Effects Division (HED). Potential effects on beneficial
insects are estimated using the honey bee (Apis mellifera) as a
surrogate.

Ten species of terrestrial crop plants are studied to estimate the
effect of isoxaben on all terrestrial plant species.

Table 3 provides a summary of the taxonomic groups and the surrogate
species tested to evaluate potential ecological effects of isoxaben to
these non-target taxonomic groups.

Table 3.  Test Species Evaluated for Assessing Potential Ecological
Effects of Isoxaben

		Taxonomic Group	Surrogate Species	Acute Toxicity Classification

Birds1	  SEQ CHAPTER \h \r 1 Mallard (Anas platyrhynchos)

Bobwhite (Colinus virginianus)	Practically non-toxic

  SEQ CHAPTER \h \r 1 Mammals	  SEQ CHAPTER \h \r 1 Laboratory rat
(Rattus rattus)	Practically non-toxic

  SEQ CHAPTER \h \r 1 Insects	  SEQ CHAPTER \h \r 1 Honey bee (Apis
mellifera L.)	Practically non-toxic

  SEQ CHAPTER \h \r 1 Freshwater fish	  SEQ CHAPTER \h \r 1 Bluegill
sunfish (Lepomis macrochirus)

Rainbow trout (Oncorhynchus mykiss)	Moderately toxic

Moderately toxic

  SEQ CHAPTER \h \r 1 Freshwater invertebrates	  SEQ CHAPTER \h \r 1
Water flea (Daphnia magna)	Moderately toxic

  SEQ CHAPTER \h \r 1 Estuarine/marine fish	  SEQ CHAPTER \h \r 1
Sheepshead minnow (Cyprinodon variegatus)	Moderately toxic

Estuarine/marine invertebrates	Grass shrimp (Palaemonetes pugio)

Quahog clam (Mercenaria mercenaria)	Moderately toxic

  SEQ CHAPTER \h \r 1 Terrestrial plants	  SEQ CHAPTER \h \r 1 Monocots
– onion (Allium cepa)

Dicots – soybean (Glycine max)	Not classified

  SEQ CHAPTER \h \r 1 Aquatic plants and algae	  SEQ CHAPTER \h \r 1
Duckweed (Lemna gibba)

Green algae (Pseudokirchneriella subcapitata)	Not classified

	2.  Ecosystems at Risk

The ecosystems at risk are often extensive in scope, and as a result it
may not be possible to identify specific ecosystems during the
development of a baseline risk assessment.  However, in general terms,
terrestrial ecosystems potentially at risk could include the treated
vineyard or orchard and areas immediately adjacent to the treated field
that may receive drift or runoff.  Areas adjacent to the treated field
could include cultivated fields, fencerows and hedgerows, meadows,
fallow fields or grasslands, woodlands, wetlands, riparian habitats, and
other uncultivated areas.

	Aquatic ecosystems potentially at risk include water bodies adjacent
to, or down stream from, the treated vineyard or orchard and might
include impounded bodies such as ponds, lakes and reservoirs, or flowing
waterways such as streams or rivers.  For uses in coastal areas, aquatic
habitat also includes marine ecosystems, including estuaries.

E.  Assessment Endpoints

	Assessment endpoints are intended to be representative estimates of
biological entities to be protected, and their attributes that might be
affected by exposure to the pesticide stressor.  The valued entities are
terrestrial and aquatic vertebrates and invertebrates, aquatic vascular
and nonvascular plants, and terrestrial plants.  The attributes used to
gauge the effects of isoxaben on the valued entities are mortality (or
phytotoxicity) from acute exposure and reproductive, growth (length and
weight) and survival effects from chronic exposure.

	Guideline toxicity tests are intended to determine pesticidal effects
on ecological entities that include birds, mammals, fish, terrestrial
and aquatic invertebrates and plants.  The most sensitive toxicity
endpoints are used from surrogate test species (receptors) to estimate
treatment-related direct effects on acute and chronic reproductive,
growth and survival assessment endpoints.  The studies are used to
evaluate the potential of a pesticide to cause adverse effects, to
determine whether further testing is required, and to determine the need
for precautionary label statements to minimize the potential adverse
effects to non-target animals and plants.

F.  Conceptual Model

For a pesticide to pose an ecological risk, it must reach ecological
receptors in biologically significant concentrations.  An exposure
pathway is the means by which a pesticide moves in the environment from
a source to an ecological receptor.  For an ecological pathway to be
complete, it must have a source, a release mechanism, an environmental
transport medium, a point of exposure for ecological receptors and a
feasible route of exposure.

A conceptual model provides a written description and visual
representation of the predicted relationships between isoxaben,
potential routes of exposure, and the predicted effects for the
assessment endpoint.  The conceptual model consists of two major
components: risk hypothesis and a conceptual diagram (USEPA, 1998).

This risk assessment does not take into account atmospheric transport in
estimating environmental concentrations (note, very low vapor pressure
indicates that vapor-phase transport will be negligible), nor does it
account for ingestion of isoxaben residues by animals in drinking water
or contaminated grit, ingestion through preening activities, or uptake
through inhalation or dermal absorption by terrestrial animals.
Exposure to terrestrial animals is based primarily on dietary
consumption of residues while aquatic assessments assume that all
potential routes of direct exposure are accounted for.  Plant exposure
is based on spray drift and runoff.

	1.  Risk Hypothesis

Isoxaben is proposed for use as an herbicide on bearing nut trees and
grapes, which involves situations in the environment where potential
routes of exposure can result in direct contact to forage items (e.g.,
grass), as well as indirect contamination of adjacent bodies of water.
Since no previous ecological risk assessment has been conducted, the
following generic ecological risk hypothesis is being employed for this
risk assessment:

Given the uses of isoxaben and its environmental fate properties, there
is a likelihood of exposure to non-target terrestrial and aquatic
organisms.  When used in accordance with the label, isoxaben can result
in reduced survival, growth and/or reproductive success in both
terrestrial and aquatic organisms, either directly or indirectly.  As an
herbicide, direct effects to plants are expected and subsequently
indirect to effects to other organisms dependent on both terrestrial and
aquatic plants may occur as a result of the proposed used of isoxaben on
orchards and/or vineyards.

	2.  Diagrams

Figure 2.  Conceptual model for isoxaben exposure to terrestrial
organisms.  BOLD lines indicate route of exposure considered of higher
importance for isoxaben.  Dotted lines represent low likelihood routes
of exposure.

Figure 3.  Conceptual model for isoxaben effects to aquatic organisms.
BOLD lines indicate route of exposure considered of higher importance
for isoxaben. Dotted lines represent low likelihood routes of exposure.

G.  Analysis Plan

	This document characterizes the environmental fate of isoxaben to
assess the extent to which non-target organisms might be exposed through
the proposed uses of this herbicide on bearing tree nut orchards and
vineyards.  The toxicity of isoxaben is also characterized, based
primarily on registrant-submitted toxicity tests.  Estimated exposure
(based on total toxic residues) and effects are integrated to calculate
risk quotients (RQs) for non-target endangered/threatened and
non-endangered animals and plants.  These RQs are compared to
predetermined levels-of-concern (LOCs) to determine which taxa may be
potentially affected.

	Although risk, in the context intended here, is often defined as the
likelihood and magnitude of adverse ecological effects, the risk
quotient-based approach does not provide a quantitative estimate of
likelihood and/or magnitude of an adverse effect.  Such estimates may be
possible through a more refined, probabilistic assessment.  However,
this is beyond the scope of this screening-level assessment.

	1.  Measures to Evaluate Risk Hypotheses and Conceptual Model

		a.  Measures of Exposure

	Measures of exposure to aquatic animals and plants are concentrations
in surface water based on aquatic and terrestrial models that predict
estimated environmental concentrations (EEC) of isoxaben using maximum
labeled application rates and application methods that have the greatest
potential for off-site transport of the chemical.  The models used to
predict aquatic EECs are the Pesticide Root Zone Model coupled with the
EXposure Analysis Model System (PRZM/EXAMS).  The model used to predict
terrestrial EECs on food items is T-REX.  The model used to derive EECs
relevant to terrestrial and wetland plants is TerrPlant.

PRZM and EXAMS are simulation models coupled with a graphical user
interface to generate daily exposures and 1-in-10-year estimated EECs of
isoxaben that may occur in surface water bodies adjacent to application
sites receiving isoxaben through runoff and spray drift.  PRZM simulates
pesticide application, movement and transformation on an agricultural
field and the resultant pesticide loadings to a receiving water body via
runoff, erosion, and spray drift.  EXAMS simulates the fate of the
pesticide and resulting concentrations in the water body.  The standard
watershed geometry used for ecological pesticide assessments assumes
application to a 10-hectare agricultural field that drains into an
adjacent 1-hectare water body that is 2 meters deep (20,000 m3 volume)
with no outlet.  The linked PRZM/EXAMS models are used to estimate
screening-level exposure of aquatic organisms to isoxaben.  The measure
of exposure for aquatic species is the 1-in-10-year return peak or
rolling mean concentration.  The 1-in-10-year peak is used for
estimating acute exposures of direct effects to aquatic organisms.  The
1-in-10-year 60-day mean is used for assessing chronic exposure to fish
and aquatic-phase amphibians.  The 1-in-10-year 21-day mean is used for
assessing aquatic invertebrate chronic exposure.

Measures of exposure to terrestrial plants irrigated with ground water
were simulated using EECs from the Screening Concentration In GROund
Water model (SCI-GROW, v2.3, Jul. 29, 2003) that were postprocessed
(procedure outlined in Appendix A).  SCI-GROW was a regression model
used as a screening tool to estimate pesticide concentrations found in
ground water.  SCI-GROW was developed by fitting a linear model to
ground water concentrations with the Relative Index of Leaching
Potential (RILP) as the independent variable.  Ground water
concentrations were taken from 90-day average high concentrations from
Prospective Ground Water studies.  The RILP is a function of aerobic
soil metabolism and the soil-water partition coefficient.  The output of
SCI-GROW represents the concentrations of isoxaben residue that might be
expected in shallow unconfined aquifers under sandy soils, which is
representative of the ground water most vulnerable to pesticide
contamination.  Postprocessing assumes that ground water concentrations
estimated by SCI-GROW are applied to a field via one inch of irrigation.

Exposure to terrestrial animals through consumption of treated feed
items was calculated from the maximum proposed label rate using a
nomogram derived from the work of Hoerger and Kenaga (1972) and Fletcher
et al. (1994) using the spreadsheet model T-REX (version 1.4.1).

	Measures of exposure to terrestrial plants were expressed as a fraction
of the mass of isoxaben applied to a treated field.  The screening model
TerrPlant (version 1.2.2) assumes that default fractions of the intended
application will be transported to an adjacent field through runoff and
spray drift.  To evaluate the spatial extent of risk to nontarget
terrestrial plants, AgDRIFT® v2.01 was used to determine at what
distance from the application area LOCs are no longer exceeded.

		b.  Measures of Effect

	Measures of effect are obtained from a suite of OCSPP guideline studies
conducted with a limited number of surrogate species.  The test species
are intended to be representative of the most sensitive species, but are
typically selected based on their ability to thrive under laboratory
conditions.  Consistent with EPA test guidelines, the registrant has
provided a suite of ecological effects data to the Agency.  Acute
measures of effect are typically the median lethal concentrations that
produce 50% mortality in the test organisms (e.g. LC50).  Measures of
chronic exposure typically result from reproduction studies for which a
no-observed-adverse-effect-concentration (NOAEC) is determined.  The
measure of effect for terrestrial plants is the EC25.  Endangered plant
effects endpoints are the lowest test rate where there is no observed
effect on survival or growth.

III.  Analysis

A.  Exposure Characterization

	1.	Environmental Fate and Transport Characterization

	The physical and chemical properties and the environmental fate source
data from submitted studies for isoxaben and its major degradates are
summarized in   REF _Ref239065349 \h  \* MERGEFORMAT  Table 4 .
Environmental fate and transport properties of isoxaben are
characterized in further detail in the following sections.

Table 4. Physical/chemical properties and environmental fate source data
for isoxaben and its degradates.

Property	Value	Source 	Comments

Chemical Name	N-
[3-(methylpent-3-yl)isoxazol-5-yl]-2,6-dimethoxy-benzamide	-

	Molecular Weight (g/mol)	332.39	-

	Solubility in Water

(mg/L @ 20°C)	1	MRID 40059506

	Vapor Pressure

(torr @ 26°C)	<3.9x10-7	MRID 40059506

	Octanol-water partition coefficient (Kow) 	434	MRID 40059506

	Hydrolysis Half-life

(pH 5, 7, and 9; 25°C)	Stable	MRID 00250449

	Aqueous Photolysis Half-life (days)	6 	MRID 47140003

	Soil Photolysis Half-life (days)	49	MRID 47428403

	Aerobic Soil Metabolism Half-life (days)	161 (sandy loam)

210 (silt loam)

277 (silt loam)

866 (sand)	MRID 47140004

	Anaerobic Soil Metabolism Half-life (days)	224	MRID 41106302

	Aerobic Aquatic Metabolism Half-life (days)	21 (sand and sandy loam)
MRID 46393202

	Anaerobic Aquatic Metabolism Half-life (days)	18	MRID 46393201

	Soil-Water Partition Coefficients (mL/g) (Kd)	0.81 (sand)

2.48 (sandy loam)

4.41 (loam)

6.63 (clay loam)

2.18 (loamy sand)	MRID 41106303

	Henry’s Law Constant (atm-m3/mol)	8.5x10-10	–	Calculated from vapor
pressure, molecular weight, and solubility.

Bioaccumulation	At 0.25 ppm:

14x for edible, 134x for non-edible, 70x for whole fish tissues

92-99% of 14C residues eliminated by 14 days	MRID 40059509

	Terrestrial field dissipation half-life (soil texture) in top 6 inches
of soil	34-55 days in spring treated sand soil (Florida) and loam soil
(Indiana)

78-174 days in autumn treated sand soil (Florida) and sandy loam soil
(Texas)

72 days in clay loam soil (Illinois)

122-134 days in silt loam soil (Indiana)	MRID  40059508

MRID 40059508

MRIDs 40532102 & 40532103

MRID 00250449 & 00153107

Isoxaben is moderately persistent and mobile (Kd = 0.81 to 6.63 mL/g)
(MRID 41106303).  There is some indication that the mobility of isoxaben
decreases with increasing soil clay content and cation exchange capacity
(CEC) (MRID 41106303), although not significantly enough to consider
isoxaben bound to soil or sediments.  Isoxaben does not hydrolyze and
does not appear to readily degrade in terrestrial environments (MRIDs
41106302, 143786, and 164646).  Primary routes of degradation appear to
be biodegradation in aerobic and anaerobic water bodies and photolysis
in shallow, clear water bodies (MRIDs 40059507, 46393201 and 46393202).

a. Transport and Mobility

	Isoxaben is not volatile, with a vapor pressure of less than 3.9 x 10-7
torr at 26ºC (MRID 40059506).  The compound exhibits weak acid behavior
(pKa = 9.8), is neutral environmental pHs, and is moderately soluble in
water at environmental pH=7 (1 mg/L; MRID 40059506).  The reported Kow
for isoxaben was 434 (MRID 40059506).

	Isoxaben is considered mobile, with reported soil-water partition
coefficients (Kd) from five soils ranging from 0.81 to 6.63 (MRID
41106303).  A regression analysis of the adsorption coefficients versus
the organic carbon content yielded a p-value>0.1; as such, the Koc model
was deemed inappropriate and Kd values were used in the modeling.

	A leaching and adsorption/desorption study was conducted on one of the
identified major degradates: hydroxyisoxaben.  With reported Kd from
five soils ranging from 0.06 to 0.84, this compound was more mobile than
the parent (MRID 41106303).

	Compounds with Kd values less than five present a potential concern for
ground water (USEPA, 2008a).  Therefore, isoxaben and its major
degradate hydroxyisoxaben, based on study data, present a potential
ground water concern in some soils, especially those that are sandy and
have low organic carbon content (all Kd values for both compounds,
except for clay loam soil, were less than 5; MRID 41106303).

b. Degradation

Isoxaben is stable to hydrolysis at pH 5, 7 and 9 (MRID 00250449).  It
is rapidly photolyzed in shallow, clear water, with a corrected
environmental half-life of 6 days at pH 7 (MRID 47140003).  Major
degradates include dimethoxybenzamide and four degradates that were
detected but not conclusively identified; a uracil (Unk 3), an oxime
(Unk 3i), a pyrazolone (Unk 5a), and an isoquinolone (Unk 5b).  Study
authors indicated that extensive efforts were made to identify the
compounds, but in the end the best that could be done was to identify
structural and functional group changes that occurred during
photodegradation.  The names and structures of these unknowns that were
proposed by the study authors based on this analysis are provided in
Appendix B.  Isoxaben photodegrades comparatively slowly in soil, with a
corrected environmental photodegredation half-life in soil of 49 days in
sandy loam soil at pH 7.0 and 0.99% organic carbon (MRID 47428403).

Isoxaben does not readily biodegrade in soil under aerobic or anaerobic
conditions, with half lives of greater than 150 days.  In four foreign
soils held under aerobic conditions, isoxaben degraded with half-lives
of 161 days (sandy loam), 210 days (silt loam), 277 days (silt loam),
and 866 days (sand) (MRID 47140004).  Overall recoveries were greater
than 90%.  The only major degradate identified in the study was
hydroxisoxaben. The study was classified as supplemental, as all of the
soils were foreign and it was unclear if they were comparable to soils
in the United States.  Loam soil was incubated anaerobically for 60 days
after 60 days of aerobic incubation (MRID 41106302).  Isoxaben degraded
with a half-life of 224 days.  Overall recoveries were greater than 90%.
 The only major degradate identified in the study was hydroxisoxaben.
The study was classified as acceptable.

Primary routes of biodegradation are in aerobic and anaerobic water
bodies.  In two aerobic aquatic systems (brook water-sand sediment and
brook water-sandy loam sediment), isoxaben degraded with a half-life of
21 days (MRID 46393202).  Major degradates include dimethoxybenzamide
and AEM hexenoyl-isoxaben.  The study was classified as acceptable.  In
an anaerobic aquatic system (water and sandy clay loam soil), isoxaben
degraded with a half-life of 18 days (MRID 46393201).  Overall
recoveries were above 90%.  Major degradates include dimethoxybenzamide,
methoxyphenylpyrimidinol, and AEM hexenoyl-isoxaben.  The study was
classified as acceptable.

c. Field Studies

yisoxaben was ≤1% of the applied in all soil samples collected below 6
inches.  However, in a Florida study (MRID 40532101), was detected in
four soil samples at depths of 15-30 cm at levels ≤2% of the applied.
The limit of detection (LOD) in the studies was 0.01 lbs ai/A (MRID
40059508) and 0.02 lbs ai/A (MRID 40532102).  Half-lives for isoxaben
ranged from 34 to 147 days.

A third field dissipation study (MRID 00250449/00153107) was conducted
using two outdoor lysimeter-enclosed bareground plots (0.656 m2) of silt
loam soil in Indiana.  In the first test, isoxaben (14C isoxaben labeled
on the carbonyl carbon) was applied at a target rate of 250 g ai/ha
(0.22 lbs ai/A) to two plots seeded with winter barley in October, 1980.
 In a second test, isoxaben was applied at a target rate of 150 g ai/ha
(0.13 lbs ai/A) to two plots (one plot received 14C isoxaben labeled on
the carbonyl carbon while the second plot received 14C isoxaben labeled
in the 5-position on the isoxazole ring) which were maintained free of
vegetation in November, 1981.  Soil samples were collected to a depth of
15 cm in the first test and 37.5 cm in the second test.  In the second
test radiolabeled isoxaben was not detected below 15 cm until week 50
and was always below 4%.  The half-life for isoxaben ranged from 122 to
134 days.  In the second test, two degradates were identified in samples
collected to a depth of 15 cm: hydroxisoxaben and hydroxyethylisoxaben.
The maximum amount of hydroxyisoxaben occurred on Day 32 at 8.6% of the
applied amount and declined to 4.6% at Day 100.  The maximum amount of
hydroxyisoxaben occurred on Day 86 at 3.9% of the applied amount and
declined to 3.8% at Day 100.  This study was classified as supplemental,
as the use of lysimeter plots were not truly representative of field
plots due to their limited size.

d. Bioconcentration

Isoxaben residues accumulated in bluegill sunfish with maximum
bioconcentration factors of 14x in edible tissue, 134x in non-edible
tissue, and 70x in whole fish tissue during 28 days of exposure (MRID
40059509).  Residues accumulated by exposure day 28 were depurated
quickly; at day 14 of depuration, isoxaben residues had been reduced by
92-99% in the edible, non-edible, and whole fish tissues.  The study was
classified as supplemental because isoxaben residues were incompletely
characterized and residues in the whole fish tissue were not determined
experimentally.  Due to the relatively low KOW and bioconcentration
factors in fish, isoxaben is not expected to accumulate in aquatic or
terrestrial food chains.

		e.  Degradates

Major biodegradates of isoxaben include hydroxyisoxaben,
dimethoxybenzamide, methoxyphenylpyrimidinol, and AEM hexenoyl-isoxaben.
 Additionally, four major photolytic degradates (Unk 3, Unk 3i, Unk 5a,
and Unk 5b) were detected but not conclusively identified (MRID
47140003). Chemical names, structures, and fate data for these
degradates are provided in Appendix B.  Based on structural analysis of
the biodegradates in EPISuite, three of the biodegradates (hydroxy
isoxaben, dimethoxy benzamide, and AEM hexenoyl isoxaben) have the
potential to be more mobile than isoxaben, with methoxyphenyl
pyrimidinol appearing to be very immobile.  As mentioned above,
hydroxyisoxaben was detected in all of the terrestrial field studies.
In two of the studies (MRIDs 40059508 and 40532102), hydroxyisoxaben was
≤1% of the applied in all soil samples collected below 6 inches.
However, in the Florida study (MRID 40532101), was detected in four soil
samples at depths of 15-30 cm at levels ≤2% of the applied.  In a
third study (MRID 00250449/00153107), the degradate hydroxisoxaben was
detected in samples collected to a depth of 15 cm.  Hydroxyisoxaben was
≤9% of the applied in all soil samples collected below 15 cm.

f.  Residues of Concern

Major degradates detected during aerobic and anaerobic soil metabolism
studies and aerobic and anaerobic aqueous metabolism studies include:
hydroxyisoxaben; dimethoxybenzamide; methoxyphenylpyrimidinol and amino
ethyl methyl (AEM) hexenoylisoxaben.  Additionally, four major
photolytic degradates (Unk 3, Unk 3i, Unk 5a, and Unk 5b) were detected
but not conclusively identified (MRID 47140003).  The Health Effects
Division (HED) evaluated the isoxaben residues of concern for human
health.  Because the formation of the photodegradates was considered
minimal (e.g., formed only during aqueous photolysis) and a structural
activity relationship (SAR) analysis performed by HED concluded that
none of these degradates were expected to be more toxic than the parent
compound, these photodegradates were not of exposure concern and were
excluded as residues of concern.  HED concluded that the major
degradates detected during the aerobic and anaerobic soil and aqueous
metabolism studies were not expected to be more toxic to humans than the
parent compound, but data were not available to exclude them as residues
of concern.  As such, the degradates hydroxyisoxaben,
dimethoxybenzamide, methoxyphenylpyrimidinol, and AEM hexenoylisoxaben
were included with isoxaben as residues of concern for human health
(USEPA, 2010).

For this assessment, in the absence of ecotoxicity data, these
degradates were included as residues of concern for aquatic organisms
using a total toxic residue (TTR) analysis.  Using fate data for
isoxaben and the degradates of concern, half-lives were recalculated for
the TTR, as provided in Table 5.

Table 5. Physical/chemical properties and environmental fate source data
for residues of concern

Property	Value	Source

Aqueous Photolysis Half-life (@ pH 7; in days)	6 - 15	MRID 47140003

Soil Photolysis Half-life (days)	63	MRID 47428403

Aerobic Soil Metabolism Half-life (days)	206 (sandy loam)

342 (silt loam)

358 (silt loam)

1,116 (sand)	MRID 47140004

Anaerobic Soil Metabolism Half-life (days)	446 	MRID 41106302

Aerobic Aquatic Metabolism Half-life (days)	62 (sand)

166 (sandy loam)	MRID 46393202

Anaerobic Aquatic Metabolism Half-life (days)	265	MRID 46393201

Freundlich Adsorption Coefficient (mL/g) (Kd)	0.81 (isoxaben, sand)

2.48 (isoxaben, sandy loam)

4.41 (isoxaben, loam)

6.63 (isoxaben, clay loam)

2.18 (isoxaben, loamy sand)

0.06 (hydroxyisoxaben, sand)

0.22 (hydroxyisoxaben, sandy loam)

0.37 (hydroxyisoxaben, loam)

0.84 (hydroxyisoxaben, clay loam)

0.3 (hydroxyisoxaben, loamy sand)	MRID 41106303

		g.  Transport and Dissipation Pathways

	In addition to its degradation via aquatic metabolism and aqueous
photolysis (in clear, shallow water), isoxaben and its degradates are
likely to dissipate off site mainly via leaching through soil and runoff
of dissolved residues from treated fields.  Deposition off-field or into
surface water via spray drift may also occur.  Isoxaben and its
degradates are not expected to be subject to soil, water, or air
transport via soil-bound residues (very low adsorption) or atmospheric
transport via partitioning to air through spray drift or volatization
(low vapor pressure).

	2.  Measures of Aquatic Exposure

		a.  Surface Water Aquatic Exposure Modeling

	In order to model aquatic EECs of isoxaben originating from ground
applications to control broadleaf weeds around bearing nut trees and
grape vineyards, PRZM scenarios were modeled. Sensitivity analysis of
PRZM indicates that precipitation and curve number (CN) contribute
significantly to variability in EECs (FEMVTF 2001).  For grapes,
scenarios representing wine grape vineyards in San Francisco, CA and
grapes grown in New York were modeled.  While isoxaben use is prohibited
in New York by the proposed label, the New York grape scenario was used
as a surrogate for grapes grown on the east coast of the United States.
Modeling was conducted for bearing nut trees using the Georgia pecan,
the Oregon filbert, and the California almond scenarios.  These
scenarios are used as surrogates for the bearing nut tree orchards on
the proposed label (e.g., almonds, beech nut, Brazil nut, butternut,
cashew, chinquan, filbert, hickory nut, macadamia nut, pecan, pistachio,
and walnuts). For this assessment, only the highest exposure values
(e.g., those from the New York grape and Georgia pecan scenario) have
been reported.  In less vulnerable areas, EECs may be substantially
reduced (i.e. > 25%).

Input Parameters

Input parameters for the PRZM/EXAMS model for applications to bearing
nut tree orchards and grape vineyards appear in Table 6, respectively;
data source and comments accompany values for each parameter.  SCI-GROW
input parameters are presented in Table 7.  Methods used to derive input
values are consistent the EFED Input Parameter Guidance.

Table 6. PRZM/EXAMS input parameters for isoxaben applied to bearing nut
tree orchards and grape vineyards

Input Parameter	Value	Source	Comment

Application Rate in

lbs ai/A (kg ai/ha)	1.0 (1.21)	Proposed label.	The maximum proposed
application rate considered for this assessment is 1.0 lbs
ai/acre/application, with a total annual application rate of 1.0 lbs
ai/acre.

Applications per Year	1	Proposed label.

	Application Intervals (days)	NA	Proposed label.

	Modeled Scenario	Grapes: NY Grapes

Nut Trees: GA Pecan

Date of Initial Application	Grapes: September 14

Nut trees: September 21	---	Selected day with largest precipitation
event between emergence and harvest dates.

CAM	1	Proposed label	---

IPSCND	1	Proposed label

	Molecular Weight (g/mol)	332.39	Product chemistry data.	---

Henry's Law Constant (atm-m3/mol)	8.5x10-10	---	Calculated using vapor
pressure, molecular weight, and solubility.

Solubility in Water at 25oC (mg/L)	1.0	MRID 40059506

	Freundlich Adsorption Coefficient (mL/g) (Kd)	3.3 (isoxaben)

0.36 (hydroxyisoxaben)	MRID 41106303	Mean Kd value.1

Application Efficiency	0.99

Input parameter guidance.1

Spray Drift Fraction	0.01

Input parameter guidance.1

Aerobic Soil Metabolism Half-life (days)	710 (TTR)	MRID 47140004
Represents the 90th percentile of the upper confidence bound on the mean
(450) of 5 TTR half-life values.1

Aerobic Aquatic Metabolism Half-life (days)	274 (TTR)	MRID 46393202
Represents the 90th percentile of the upper confidence bound on the mean
(114) of 2 TTR half-life values.1

Anaerobic Aquatic Metabolism Half-life (days)	795 (TTR)	---	3 x single
half-life. 1

Hydrolysis Half-lives (days)	Stable	MRID 00250449	No significant
degradation in study.

Aqueous Photolysis

Half-life (days)	15 (TTR)	MRID 47140003	Maximum dark control corrected
half-life.1

1  EFED input parameter guidance is located at:
http://www.epa.gov/oppefed1/models/water/input_parameter_guidance.htm.

Table 7. SCI-GROW input parameter values for isoxaben and its degradates

Input Parameter	Value	Source	Comment

Aerobic Soil Metabolism Half-life (days)	342 (TTR) 	MRID 47140004	Median
value 1

Organic Carbon Normalized Partition Coefficient  Koc	434 (isoxaben)

57 (hydroxyisoxaben)	MRID 41106303	Values derived from regression
analysis. See discussion below.

Application Rate (lb ai/A)	1	Proposed label	–

Maximum No. of Applications/Year	1	Proposed label	–

1  EFED input parameter guidance is located at:
http://www.epa.gov/oppefed1/models/water/input_parameter_guidance.htm.

Because isoxaben has a number of major degradates with similar toxicity
as isoxaben, a total toxic residue (TTR) approach was used in the
modeling.  Half-lives for all of the studies were estimated for the TTR
by summing the amounts of isoxaben, hydroxyisoxaben, dimethoxybenzamide,
methoxyphenylpyrimidinol, and AEM hexenoylisoxaben for each sampling
period and performing a regression on the log-transformed data.  For
adsorption to soil, a regression analysis of the adsorption coefficients
versus the organic carbon content yielded a p-value>0.1; as such, the
Koc model was deemed inappropriate and soil-water partition coefficient
(Kd) values were used in the modeling.  Per EFED’s Input Parameter
Guidance, the arithmetic mean of the Kd values was used.  However, a
mobility study (MRID 41106303) and EPISuite analysis indicated that
several of the isoxaben degradates were more mobile than the parent.  As
such, two sets of PRZM/EXAMS and SCI-GROW modeling runs were completed:
one set using the mobility estimates of the parent (Kd = 3.3 mL/g) and
one set using mobility estimates derived from the degradate study (Kd =
0.36 mL/g).

While aerial application of isoxaben on bearing nut tree orchards and
grape bearing vineyards was not specifically prohibited on the label,
EFED modeled ground application of isoxaben because: (1) isoxaben is a
preemergence herbicide proposed for control of broadleaf weeds; and, (2)
aerial application of isoxaben on bearing nut tree orchards and grape
vineyards would likely destroy the crops it is meant to protect.  It
should be noted that aerial application of pesticides normally results
in higher EECs.  As such, higher concentrations would be expected if
isoxaben had been modeled using the aerially application method.  For
the PRZM input “chemical application method” (CAM), a value of 1 was
selected to represent foliar applications for grape vineyards and
bearing nut tree orchards.  For the PRZM input “condition for
disposition of foliar pesticide after harvest” (IPSCND), a value of 1
was selected for both applications as the pesticide is surface applied
to control broadleaf weeds.  Ground applications were modelled, using a
spray drift fraction of 0.01 and an application efficiency of 0.99, per
the Input Guidance.  Application dates were selected by examining the
precipitation events in the corresponding meteorological files and
selecting the date with the highest precipitation that fell between the
emergence date and the harvest date for the respective crop.

c. Modeling Results

PRZM/EXAMS EECs representing 1-in-10-year peak, 21-day, and 60-day
average concentrations are located in   REF _Ref238379248 \h  \*
MERGEFORMAT  Table  8.  SCI-GROW EECs are presented in   REF
_Ref261415707 \h  \* MERGEFORMAT  Table  9.

Table 8. PRZM/EXAMS-simulated EECs for isoxaben applied at maximum
application rates to grape vineyards and bearing nut tree orchards

Scenario	1-in-10 yr Peak

(µg ai/L)	21-d Avg Conc

(µg ai/L)	60-d Avg Conc

(µg ai/L)

Parent Kd Data (Kd = 3.3 mL/g)

Grapes	14.2	13.9	13.2

Bearing Nut Trees	22.2	19.4	18.1

Degradate Kd Data (Kd = 0.36 mL/g)

Grapes	12.0	12.0	11.5

Bearing Nut Trees	18.0	17.1	16.0

Table 9. SCI-GROW EECs for isoxaben applied at maximum application rates
to grape vineyards and bearing nut tree orchards (µg ai/L).

Scenario	Acute

(µg ai/L)	Chronic

		(µg ai/L)

Parent Kd Data (Kd = 3.3 mL/g)

Grapes / Bearing nut trees	0.71	0.71

Degradate Kd Data (Kd = 0.36 mL/g)

Grapes / Bearing nut trees	14.5	14.5

FN-3133 may not be applied more than twice per crop year up to a maximum
total of 1.0 lb ai/A per crop year.  As such, EFED performed PRZM/EXAMS
and SCIGROW runs for two applications of isoxaben at 0.5 lbs
ai/acre/application, using the scenario with the highest EECs, bearing
nut trees.  As the label does not specify a retreatment interval (RTI),
EFED conducted PRZM/EXAMS runs at RTIs of 3, 7, 15, 30, 60, 90, 120, and
180 days, using the same fate parameters outlined in Table 8 and a Kd of
3.3 mL/g.  SCIGROW runs were conducted using the same fate parameters as
presented in   REF _Ref261415556 \h  \* MERGEFORMAT  Table  9.  Results
for all model runs indicate EECs were at or below the values derived for
a single application of isoxaben to bearing nut tree orchards.

e. Monitoring Data

Isoxaben is not included as one of the analytes monitored in U.S.
surface and groundwater under the USGS’s National Water Quality
Assessment (NAWQA) program (  HYPERLINK "http://water.usgs.gov/nawqa"
http://water.usgs.gov/nawqa ).  Surface water and sediment monitoring
data from the California Department of Pesticide Regulation (CDPR)
indicate that six surface water samples were collected and analyzed for
isoxaben in 2006 in Stanislaus County, but all of the reported
concentrations were 0 µg/L.  The database did not provide the limit of
detection for these samples, so it is unclear what the concentration
truly was.  Monitoring data for isoxaben degradates were not available.

	3.  Measures of Terrestrial Exposure

	The proposed application method for isoxaben being evaluated is ground
broadcast spray.  This application method can result in various routes
of exposure to non-target terrestrial organisms, including ingestion of
treated foods, spray drift and runoff.  The label specifies no more than
two applications per year but does not specify limitations on
application intervals.  The seasonal maximum application (1.0 lbs ai/A)
can be applied at one time.

		a.  Terrestrial Animals

	Exposure estimates for terrestrial animals assumed to be in the target
area or in an area exposed to spray drift are derived using the T-REX
model (version 1.4.1, 10.09.2008).    SEQ CHAPTER \h \r 1 This model
incorporates the Kenaga nomograph, as modified by Fletcher et al.
(1994), which is based on a large set of actual field residue data.  The
upper limit dietary-based values (Table 10) from the nomograph represent
the 95th percentile of residue values from actual field measurements
(Hoerger and Kenega, 1972) and are based on the proposed maximum single
application rate of 1.0 lb a.i./Acre..  The Fletcher et al. (1994)
modifications to the Kenega nomograph are based on measured field
residues from 249 published research papers, including information on
118 species of plants, 121 pesticides, and 17 chemical classes.

Table 10.  Unadjusted* Dietary EECs from TREX v1.4.1 based on a single
application of 1 lb ai/acre.

Terrestrail Animal Forage Item	Dietary-based

EECs

(mg ai/kg diet)

Short Grass 	240.00

Tall Grass 	110.00

Broadleaf plants/sm Insects	135.00

Fruits/pods/seeds/lg insects	15.00

*not adjusted for size class or nutritive value of food item

		b.  Terrestrial Plants

	Exposure to upland and wetland plants is estimated using the TerrPlant
(v1.2.2) screening model and AgDRIFT (v2.01).  TerrPlant estimates
potential exposure from a single application using default assumptions
for runoff and spray drift (Table 11).  For runoff plus drift, TerrPlant
incorporates two similar conceptual models for depicting dry and
semi-aquatic (wetland) areas of terrestrial habitats.  For both
scenarios, a non-target area is adjacent to the treated field.
Herbicide exposures to plants adjacent to the treated field are
estimated to receive runoff and drift from the treated field.  For a dry
area adjacent to the treated orchard or vineyard, runoff exposure is
estimated as sheet runoff.  In the model, sheet runoff is defined as the
amount of herbicide in water that runs off of the soil surface of a
treated field which is equal in size to the non-target area (1:1 ratio
of areas).  For wetland areas, runoff exposure is estimated as
channelized runoff.  In the model, channelized runoff is the amount of
herbicide that runs off of a treated orchard or vineyard 10 times the
size of the area adjacent to the treated orchard or vineyard (10:1 ratio
of areas).  Estimated exposures through runoff plus drift and drift
alone are then compared to measures of plant survival and growth (e.g.
effects to seedling emergence and vegetative vigor) to develop RQ
values.  AgDRIFT provides point estimates of mass deposition at
distances from the application site.

Table 11. EECs for isoxaben (lbs ai/A) based on the proposed maximum
single application rate of 1.0 lb ai./Acre.

Description	Equation	EEC

Runoff to dry areas	(A/I)*R	0.001

Runoff to semi-aquatic areas	(A/I)*R*10	0.01

Spray drift	A*D	0.001

Total for dry areas	((A/I)*R)+(A*D)	0.002

Total for semi-aquatic areas	((A/I)*R*10)+(A*D)	0.011

B.  Ecological Effects Characterization

	All toxicity studies were conducted with isoxaben, with the exception
of terrestrial plant studies, which were conducted with a formulated
product, i.e., FN-3133.  A search of the publically available ECOTOX
database (05/04/2010) resulted in no relevant open literature toxicity
data.

1.  Aquatic Effects Characterization

The registrant has submitted a suite of studies, as required by CFR 40
Part 158, which examine the toxicity of isoxaben to representative
aquatic organisms that serve as surrogates for organisms that may be
exposed.  Both acute and chronic effects were determined for freshwater
fish and invertebrates.  Acute effects on marine/estuarine fish and
invertebrates and aquatic vascular and nonvascular plants were also
examined.  However, some data gaps remain and will be discussed later in
the document.

		a.  Aquatic Animals

		i.  Effects from Acute Exposure

	Most of the available aquatic effects studies were conducted at nominal
concentrations of 0 (control) and 100 mg ai/L.  Very few were conducted
with a co-solvent, and the water solubility of isoxaben is 1 mg/L.
There was no reported effort to centrifuge or filter the solute.  If the
solutions were actually prepared with a nominal concentration of 100 mg
ai/L and the measured concentration is roughly 1 mg ai/L in the acute
studies, a precipitate should have been reported.  However, no
precipitate is reported for any of the available studies.

Freshwater Fish

		In 96-h acute toxicity studies, rainbow trout (Oncorhynchus mykiss;
MRID 00132146), bluegill sunfish (Lepomis macrochirus; MRID 00132145)
and common carp (Cyprinus carpio; MRID 00137844) were exposed to
isoxaben at mean-measured concentrations of 0 (negative control) and 1.0
mg ai/L.  No sub-lethal effects were observed in any study.  The LC50
and NOAEC values (Table 12), based on a lack of mortality and sub-lethal
effects, were >1.0 and 1.0 mg ai/L.  Based on the results of these
studies, isoxaben is classified as moderately toxic to freshwater fish
on an acute exposure basis.

Table 12.  Freshwater fish and amphibian acute toxicity for technical
grade isoxaben.

Species	96-hour

LC50 mg ai/L 	Toxicity Category	MRID No.	Study Classification

Rainbow trout

(Oncorhynchus mykiss)	>1.0 	Moderately toxic	00132146	Supplementa

Bluegill sunfish

(Lepomis macrochirus)	>1.0	Moderately toxic	00132145	Supplemental

Common carp

(Cyprinus carpio)	>1.0	Moderately toxic	00137844	Supplemental

Estuarine/marine Fish

In a 96-h acute toxicity study, sheepshead minnows (Cyprinodon
variegatus; MRID 40531304) were exposed to isoxaben at time-weighted
average (TWA) concentrations were <0.02 (<LOQ; controls) and 0.86 mg
ai/L.  The 96-h LC50 was >0.86 mg ai/L. The LC50 and NOAEC values (Table
13), based on a lack of mortality and sub-lethal effects, were 0.86 and
>0.86 mg ai/L, respectively.  Isoxaben is classified as moderately toxic
to estuarine/marine fish at the limit of its water solubility.

Table 13.  Estuarine/marine fish acute toxicity to technical grade
isoxaben.

Species	96-hour

LC50 mg ai/L 	Toxicity Category	MRID No.	Study Classification

Sheepshead minnow

(Cyprinodon variegatus)	>0.86	Moderately toxic	40531304	Supplemental

Freshwater Invertebrates

Water fleas, Daphnia maga (MRID 00132444), were exposed to isoxaben at
mean-meausured concentrations of 0 (control) and 1.3 mg ai/L.  No
effects were seen in either the control or treatment groups.  Therefore
the 48-h EC50 and NOAEC were >1.3 mg ai/L and 1.3 mg ai/L, respectively
(Table 14).  Isoxaben is classified as moderately toxic -toxic to
estuarine/marine fish at the limit of its water solubility.

Table 14.  Freshwater invertebrate acute toxicity for technical grade
isoxaben.

Species	96-hour

LC50 mg ai/L 	Toxicity Category	MRID No.	Study Classification

Waterflea

(Daphnia magna) 	>1.3	Moderately toxic	00132444	Supplemental

*at the limit of solubility

Estuarine/marine

	Quahog clam larvae (Mercenaria mercenaria; MRID 40531302) were exposed
to isoxaben at for 48-h under static conditions.  Larvae were exposed to
mean-measured concentrations of <0.02 (<LOQ; negative control) and 0.96
mg ai/L.  The 48-hr EC50 was >0.96 mg ai/L (Table 15).  The NOAEC was
<0.96 mg ai/L, based on a 40% reduction in normally developed larvae.
The only observed toxic effect was an inhibition of normal larval
development.  It is not clear from the study how ‘normal larvae’ is
differentiated from ‘abnormal larvae’.  Isoxaben is classified as
moderately toxic to this species; however, the 40% effect on larval
developmental is discussed further in the Risk Description..

	Grass shrimp (Palaemonetes pugio; MRID 40531303) demonstrated no effect
from exposure to a measured concentration of 1 mg ai/L of isoxoaben.
Isoxaben is classified as moderately toxic to this species at the limit
of its water solubility

Table 15. Estuarine/marine invertebrate acute toxicity for technical
grade isoxaben.

Species	96-hour LC50

mg ai/L 	Toxicity Category	MRID No.	Study Classification

Quahog clam

(Mercenaria mercenaria)	>0.96	Moderately toxic	40531302	Supplemental

Grass shrimp

(Palaemonetes pugio)	>1.0	Moderately toxic	40531303	Supplemental

	ii.  Effects from Chronic Exposure

	Aquatic vertebrates

	A 66-day early-life stage study of the effect of chronic exposure of
isoxaben to rainbow trout (MRID 00137847) was conducted under
flow-through conditions.  Fertilized eggs/embryos (100/level, early-eyed
stage) of rainbow trout were exposed to mean-measured concentrations of
<0.002 (<LOD, controls), 0.024, 0.048, 0.093, 0.19, and 0.42 mg ai/L,
respectively.  No treatment-related effects were observed on any
measured parameter during the study.  The 66-day NOAEC and LOAEC were
0.42 and >0.42 mg ai./L, respectively (Table 16).

	A 33-day early-life stage study of isoxaben with fathead minnows
(Pimephales promelas; MRID 00137848) was conducted under flow-through
conditions.  Fertilized eggs/embryos (100/level, <48 hours old) of
fathead minnow were exposed to mean-measured concentrations of <0.002
(<LOD, controls), 0.025, 0.048, 0.095, 0.18, and 0.40 mg ai/L,
respectively.  No treatment-related effects were observed on any
measured parameter during the study.  The 33-day NOAEC and LOAEC values
were 0.40 and >0.40 mg ai/L, respectively.

Table 16.  Early life-stage toxicity of technical grade isoxaben to
freshwater fish.

Species	NOAEC

mg ai/L	LOAEC

mg ai/L	Endpoints Affected	MRID No.	Study Classification

Rainbow trout (Oncorhynchus mykiss)	0.42	>0.42	None	00137847
Supplemental

Fathead minnow (Pimphales promelas)	0.40	>0.40	None	00137848
Supplemental

	No chronic toxicity data were submitted for estuarine/marine fish.
However, given the reported effect on estuarine/marine invertebrates in
the acute exposure study, these data are needed for risk assessment
purposes.

	Aquatic Invertebrates

	In a 21-day static renewal life-cycle study, first instar daphnids
(MRID 00137845) were exposed to isoxaben at mean-measured concentrations
of 0 (control), 0.13, 0.69 and 1.01 mg ai/L.  No effects were observed
in the control, 0.13 or 0.69 mg ai/L treatment groups (Table 17), but
13% of the daphnids were immobilized in the highest treatment group.
Additionally, statistically significant effects were reported for growth
and reproduction (brood size) at the highest treatment concentration.
The NOAEC and LOAEC for the study are 0.69 mg ai/L and 1.01 mg ai/L,
respectively, based on impaired growth and reproduction.

Table 17.  Freshwater invertebrate full life-cycle toxicity for
technical grade isoxaben.

Species	NOAEC

mg ai/L	LOAEC

mg ai/L	Endpoints Affected	MRID No.	Study Classification

Waterflea

(Daphnia magna)	0.69	1.01	None	00137845	Supplemental

	No chronic toxicity data were submitted for estuarine/marine
invertebrates.  However, given the effects observed on larval
development in the acute Quahog clam study suggest these data are
necessary for risk assessment.

	b.  Aquatic Plants

		Three studies assessing the effect of isoxaben on the aquatic vascular
plant duckweed, Lemna gibba, are available (Table 18).  In a 14-day
toxicity study, the freshwater floating aquatic vascular plant duckweed
(MRID 47428401) was exposed to isoxaben (technical grade active
ingredient;TGAI) at mean-measured concentrations of<0. 5 (<LOQ,
control), 5.8, 13, 24, 46, and 93 µg ai/L.  A NOAEC was not defined in
the study. The EC05 and EC50 values for decreased biomass, the most
sensitive endpoint, were 2.9 and 13 (g ai/L, respectively.  Inhibition
in biomass in the treatment groups ranged from 13 to 96%.

		In a 7-day acute toxicity study, duckweed (MRID 47428402) was exposed
to isoxaben TGAI at mean-measured concentrations of <0.50 (<LOQ,
control), 3.1, 6.0, 12.3, 23.6, and 45.9 (g ai/L.  The 7-day NOAEC and
EC50 values for biomass inhibition, the most sensitive endpoint, were
6.0 and 10 (g ai/L, respectively.  The inhibition in biomass in the
treatment groups ranged from -1 to 95%.

		In a 14-day acute toxicity study (MRID 47428406), duckweed was exposed
to Isoxaben® 500 SC (formulation) at mean-measured concentrations of
<0.5 (<LOD, control), 5.1, 10.1, 20.3, 38.5, 84.2 and 172.1 (g ai/L.
The 14-day NOAEC and EC50 values for biomass inhibition, the most
sensitive endpoint, were 10.1 and 15 (g ai/L, respectively.  A hormetic
(low-dose stimulatory) effect of 18% increased biomass was seen at the
lowest test concentration.  In the remaining treatment groups, percent
inhibition in biomass ranged from 6 to 95%.

		Studies of nonvascular plants are also required and typically involve
microalgae.  A supplemental 14-day static study reports a NOAEC of 1.4
mg ai/L for the green algae Pseudokirchneriella subcapitata (formerly
Selenastrum capricornutum).  The study is from 1984, before microalgae
studies were routinely submitted to the Agency; raw data were not
included and the study is not consistent with Agency guidelines.  A
complete suite of the four aquatic nonvascular plant studies has been
requested in the Registration Review process.

Table 18.  Toxicity of technical grade isoxaben to aquatic plant
species.

Species/

 (duration)	% ai	EC50

(g ai/L	NOAEC

(g ai/L 	MRID	Study Classification

Duckweed (Lemna gibba)

 (14 days)	Technical	13	2.9	47428401	Supplemental

Duckweed (Lemna gibba)

(7 days)	Technical	10	6	47428402	Supplemental

Duckweed (Lemna gibba)

 (14 days)	Formulationl	15	10.1	47428406	Supplemental

Green algae (Pseudokirchneriella subcapitata)	Technical	>1400*	1400*
00153111	Supplemental

*Supplemental data not used in Risk Estimation

	2.	Terrestrial Effects Characterization

The registrant has submitted a battery of studies that examine the
toxicity of isoxaben to representative terrestrial organisms that stand
as surrogates for animals and plants at risk of exposure.  Effects of
acute and chronic exposure were evaluated for mammals; data are also
available for birds which serve as a surrogate for terrestrial-phase
amphibians and reptiles.  Data on the effects of isoxaben on terrestrial
invertebrates are available with studies of the honeybee (Apis
mellifera).  The toxicity of isoxaben to terrestrial plants was
evaluated using representative monocotyledonous (monocots) and
dicotyledonous (docots) plants.

a.  Terrestrial Animals

		i.  Effects from Acute Exposure

	Birds

	The acute oral toxicity of isoxaben to 20-wk-old bobwhite quail
(Colinus virginianus; MRID 00132146) was assessed over 14 days.
Isoxaben was administered by oral gavage at nominal doses of 0 (vehicle
control), 125, 250, 500, 1000 and 2000 mg/kg.  The 14-day acute oral
LD50 was >2000 mg/kg-bw (Table 19).  Since no effects were observed in
any of the treatment levels, the 14-day NOAEL, based on a lack of
treatment-related effects, was 2000 mg/kg-bw. Isoxaben is classified as
practically non-toxic to bobwhite quail (Colinus virginianus) on an
acute oral exposure basis.

Table 19.  Avian acute oral toxicity for technical grade isoxaben.

Species	LD50

(mg ai/kg bw)	Toxicity Category	MRID	Study

Classification

Northern bobwhite quail (Colinus virginianus)	>2000	Practically

 non-toxic  	00132146	Acceptable

	The subacute dietary toxicity of isoxaben to 12-d old bobwhite quails
(Colinus virginianus; MRID 00132142) was assessed over 8 days (5 days
with treated feed and 3 days with basal diet).  Isoxaben was
administered to the birds in their diet at measured concentrations of 0
(negative control), 56, 180, 480, 1500, and 4500 mg ai/kg diet.  The
8-day subcute dietary LC50 was >4500 mg ai/kg diet (Table 20).  The
NOAEC, based on a lack of treatment-related effects, was 4500 mg
ai/kg-diet.  Isoxaben is considered to be practically nontoxic to
bobwhite quail on an subacute dietary exposure basis.

The subacute dietary toxicity of isoxaben to 10-d-old mallard ducks
(Anas platyrhynchos; MRID 00132143) was assessed over 8 days.  Measured
concentrations were 0 (negative control), 63, 190, 540, 1600, and 4800
mg ai/kg diet.  The 8-day subacute dietary LC50 was >4800 mg ai/kg diet.
 The NOAEC, based on a lack of treatment-related effects, was 4800 mg
ai/kg diet.  Isoxaben is considered to be practically nontoxic to
mallard ducks on an subacute dietary exposure basis

Table 20.  Avian subacute dietary toxicity for technical grade isoxaben.

Species	LC50

(mg ai/kg diet) 	Toxicity Category	MRID	Study Classification

Northern bobwhite quail

(Colinus virginianus)	>4500

	Practically

 non-toxic	00132142	Acceptable

Mallard duck

(Anas platyrhynchos)	>4800

	Practically

non-toxic	00132143	Acceptable

	Mammals

		Rats (Rattus norvegicus) are typically used as surrogates for all
mammals, and the data are typically reviewed by the Health Effects
Division (HED).  The following paragraph is taken directly from the HED
‘Toxicology Chapter of the New Chemical Registration of Isoxaben’
(125851_121587_TX006559_R023250.tif).

		‘Sufficient data are available to show that Technical Isoxaben is
not lethal to laboratory animals when taken by the oral touts (MRID
MJ031, MJ032).  All test rats (10/sex) survived a 14 day study in which
Technical Isoxaben was administered orally by gavage at a dose of 10,000
mg/kg in approximately 34 mi/kg dosage volume (category IV). In a study
with mice (10/sex), all animals survived to 14 days after a dose of
10,000 mg/kg (category XV).’

		Therefore the LD50 used in this assessment is >10,000 mg ai/kg-bw
(Table 21) and is classified as practically nontoxic to mammals on an
acute oral exposure basis.

Table 21.  Acute oral mammalian toxicity for isoxaben.

Species

	LD50 	Toxicity Category	Affected

Endpoints	MRID No.	Classification

Wistar rat

Rattus rattus	>10000 mg ai/kg-bw	practically non-toxic

	none	MJ031, MJ032	Acceptable

	Terrestrial Invertebrates

		Honeybees (Apis mellifera) were exposed via contact to doses of
isoxaben technical at 0 (control), 33.9, 67.4 and 101.7 µg ai/bee (MRID
0015311).  No mortality or other subeffects were reported at any of the
doses tested.  The LD50 for isoxaben is >101.7 μg ai/bee and isoxaben
is classified as practically nontoxic to honeybees on an acute contact
exposure basis.

		ii.  Chronic Effects

	Birds

		The one-generation reproductive toxicity study of isoxaben to 20 pairs
per level of 17-week old northern bobwhite quail (Colinus virginianus;
MRID 00153110) -was assessed over 24 weeks.  Isoxaben was administered
to the birds in the diet at mean-measured concentrations of <LOD
(control), 105, 313, and 1073 mg ai/kg-diet, respectively.  No
treatment-related effects were observed on any adult or offspring
parameter at any treatment level.  Therefore the NOAEC and LOAEC for the
study are 1073 and >1073 mg ai/kg-diet, respectively (Table 22).

		The one-generation chronic toxicity of isoxaben to 12 pairs per level
of 20-week old mallard duck (Anas platyrhynchos; MRID 00153109) was
assessed over 23 weeks.  Isoxaben was administered to the birds in their
diet at mean-measured concentrations of <LOD (control), 100, 298, and
946 mg ai/kg-diet, respectively.  The study is classified as
‘Supplemental’, because it provides insight into the potential for
effects of chronic exposure of isoxaben to avian species, but the study
is insufficient to provide a definitive endpoint.  There was a
significant reduction in the proportion of eggs hatched to live 3-wk old
embryos, indicating reproductive effects at least as low as 298 mg ai/kg
diet.  There was a high percentage of cracked eggs in the control (11%),
nearly double the high-end normal value (6%) as stated in the OPPTS
850.2300 harmonized guideline; the elevated number of cracked eggs in
the control raises uncertainty regarding the conditions under which the
study was conducted.  Furthermore, the number of eggs laid per hen was
higher than expected (59 vs 38), and the mean percentage of viable
embryos per eggs set was very low in the control (71% vs 85-98%).  There
was also an apparent effect on hatchling survival per egg set and the
number of hatchlings per pen, but high control variability did not allow
for statistical detection.  Additionally, data for two important growth
endpoints, hatchling weight and 14-d survivor weight were not provided.
While these problems are not enough to invalidate the study, a
definitive endpoint could not be determined.

Table 22.  Avian reproduction chronic toxicity for technical grade
isoxaben.

Species

	% a.e.	NOAEC

(mg ai/kg diet)	LOAEC

(mg ai/kg-diet)	MRID	Study Classification

Northern bobwhite quail

(Colinus virginianus)	94.5

Technical	1073	>1073	00153110	Supplemental

Mallard duck

(Anas platyrhynchos)	94.5

Technical	Not established	100	00153109	Supplemental

	Mammals

	Rats (Rattus norvegicus) are typically used as surrogates for all
mammals, and the data are typically reviewed by HED.  The following
paragraph is taken directly from the HED ‘Toxicology Chapter of the
New Chemical Registration of Isoxaben’
(125851_121587_TX006559_R023250.tif).  It is worth noting that HED
considered isoxaben to be a Class ‘C’ carcinogen.

		‘Rats (25/sex/dose) were administered 0, 500, 2500, or 12500 ppm (0,
25, 125, or 625 mg/kg/day) Technical Isoxaben in the diet in a three
generation reproduction study (MRID MJ019, core grade minimum).
Parental female toxicity was demonstrated in lowered mean bodyweight,
lowered mean bodyweight gain, and lowered food efficiency during growth,
gestation and lactation at 2500 ppm and 12500 ppm.  Parental male
toxicity was found in lowered mean bodyweight during the growth phases.
Both parental males and females showed increased mean relative liver
weight at 12500 ppm and females only at 4500 ppm. (NOEL= 500 ppm).
Reproductive toxicity was demonstrated at 12500 ppm in significantly
(p<0.05) decreased numbers of viable pups born and depression in mean
body weight of progeny on postpartum day 21 (NOEL = 2500 ppm).’

Therefore the NOAEL used in this assessment is 25 mg ai/kg-bw/day (Table
23)

Table 23.  Chronic toxicity of isoxaben to mammals.

Species

	% a.e.	NOAEL

(mg ai/kg-bw) 	LOAEL

(mg ai/kg-bw)	MRID	Study Classification

Wistar rat

(Rattus norvegicus)	94.5

Technical	25	125	MJ019	Supplemental

		b.  Terrestrial Plants

	Seedling emergence testing (MRID 47428404) indicate moncot grass
species (Family: Poaceae) tested were unaffected at treatment rates
equivalent to an application rate of 0.888 lbs ai/A, the highest rate
tested.  However, only three monocot species were tested.  Corn (Zea
mays), a required test species, was not included in the study.  Onion
(Allium cepa), which typically represents non-graminoid monocot species
such as lilies and orchids, was also not included.  Among broadleaf
plants (dicots), cucumber (Cucumis sativus) was unaffected at the
highest rate tested, while fresh weight was affected in pea (Pisum
sativum) and sugarbeet (Beta vulgaris).  Emergence was the most
sensitive endpoint for carrot (Daucus carota), lettuce (Lactuca sativa),
oil seed rape (Brassica napus), and tomato (Solanum lycopersicum).
Lettuce was the most sensitive dicot (EC25 = 0.0095 lbs ai/A); a NOAEC
was not established in the study, but the lettuce EC05 (0.0014 lbs ai/A)
is used in lieu of a NOAEC.

Vegetative vigor testing (MRID 4748405) indicated that all species
tested except wheat (Triticum aestivum) and tomato were at least
somewhat sensitive to isoxaben.  Among monocots, ryegrass (Lolium
perenne) was particularly sensitive to isoxaben and was the most
sensitive species tested (EC25 = 0.014 lbs ai/A; NOAEC 0.0034 lbs ai/A.
As with the seedling emergence study, only three monocot species were
tested.  Corn, a required test species, was not included in the study.
Onion, which typically represents non-graminoid monocot species such as
lilies and orchids, was also not included. Among broadleaf plants,
cucumber was the most sensitive species, with an EC25 of 0.089 lbs ai/A,
and the NOAEC was 0.028 lbs ai/A.  Table 24 provides the most sensitive
endpoints from all plant species tested.

Table 24. The most sensitive terrestrial plant endpoints (lbs ai/A) in
the studies submitted for isoxaben.

Species	Seedling emergernce	Vegetative vigor

	Endpoint	NOAEC	EC25	Endpoint	NOEC	EC25

Oat	None	0.888	>0.888	Fresh weight	0.0069	>0.888

Ryegrass	None	0.888	>0.888	Fresh weight	0.0034	0.014

Wheat	None	0.888	>0.888	None	0.888	>0.888

Oilseed rape	Emergence	0.020*	0.028	Survival	0.444	<0.888

Pea	Fresh weight	0.056	0.29	Fresh weight	0.056	>0.056

Cucumber	None	0.888	>0.888	Fresh weight	0.028	0.089

Carrot	Emergence	0.0138	0.043	Fresh weight	0.0034	0.888

Lettuce	Emergence	0.0014*	0.0095	Fresh weight	0.056	>0.888

Tomato	Emergence	0.0067	0.016	Fresh weight	0.888	>0.888

Sugarbeet	Fresh weight	0.056	0.073	None	0.444	0.73

*-EC05 is used when calculated EC25 is less than derived NOAEC.

	3. Ecological Incidents

Both the Agency’s Ecological Incident Information System (EIIS) and
the Avian Incident Monitoring System (AIMS;) were checked for incidents
involving isoxaben.  No incidents involving animals were reported in
either database as of 5/11/2010.

	Five incidents involving plants are reported for isoxaben in EIIS
(Table 25).  Four of the incidents have a certainty index of
‘Possible’ and one as ‘Unlikely’ to involve the use of isoxaben.
 The ‘Possible’ incidents span 1994 to 2003 and involved ornamental
and tree farm applications.  The reported numbers of affected plants
range from 298,346 to 676,000, and included woody plants.  All incidents
report the application rate as 1.0 lbs ai/A.

Table 25.  Summary of incident information reported to the Agency as of
05/10/2010.

Incident ID	Use Site	Legality	Certainty	State	County	Year	Total No.
Total Area

I014702-017	Ornamental, woody	Registered use	Possible	CA	Santa Cruz	2003
35000	NR*

I013636-027	Ornamental	Registered use	Possible	OR	Washington	2002	NR	6
acres

I001485-001	Tree farm/plantation	Undetermined	Possible	NR	NR	1994	676000
NR

I010414-002	Ornamental	Registered Use	Possible	CA	Santa Cruz	2000	627405
6.5 acres

I006865-001	Nursery	Registered Use	Unlikely	OR	Multnomah	NR	298346	NR

*Not reported

IV.  Risk Characterization

A.  Risk Estimation

	The risk quotient (RQ) approach, comparing the ratio of estimated
exposure concentrations (EECs) to toxicity endpoints with predetermined
levels of concern (LOC), is used in this assessment to estimate
potential risk.  If the RQs exceed the LOCs, the Agency presumes
potential for risk to the taxa.  These LOCs (Table 26) are the
Agency’s interpretive policy and are used to determine the need to
consider regulatory action by indicating whether a pesticide, used as
directed on the label, has the potential to cause adverse effects on
non-target organisms.  Although risk is often defined as the likelihood
and magnitude of adverse ecological effect, the risk quotient-based
approach does not provide a quantitative estimate of likelihood and/or
magnitude of an adverse effect.

Table 26.  Levels of concern (LOCs) for various taxa.

Risk Presumption	RQ	LOC

Birds

	Acute Risk to Non-listed Species	EEC/LC50 or LD50/sqft or LD50/day	0.5

	Acute Restricted Use	EEC/LC50 or LD50/sqft or LD50/day (or LD50 < 50
mg/kg)	0.2

	Acute Risk to Endangered Species	EEC/LC50 or LD50/sqft or LD50/day	0.1

	Chronic Risk	EEC/NOAEC	1

Wild Mammals

	Acute Risk to Non-listed Species	EEC/LC50 or LD50/sqft or LD50/day	0.5

	Acute Restricted Use	EEC/LC50 or LD50/sqft or LD50/day (or LD50 < 50
mg/kg)	0.2

	Acute Risk to Endangered Species	EEC/LC50 or LD50/sqft or LD50/day	0.1

	Chronic Risk 	EEC/NOAEC	1

Aquatic Animals

	Acute Risk to Non-listed Species	EEC/LC50 or EC50	0.5

	Acute Restricted Use	EEC/LC50 or EC50	0.1

	Acute Risk to Endangered Species	EEC/LC50 or EC50	0.05

	Chronic Risk	EEC/NOAEC	1

Terrestrial and Semi-Aquatic Plants

	Acute Risk to Non-listed Species	EEC/EC25	1

	Acute Risk to Endangered Species	EEC/NOAEC or EC05	1

Aquatic Plants

	Acute Risk to Non-listed Species	EEC/EC50	1

	Acute Risk to Endangered Species	EEC/NOAEC or EC05	1

Aquatic

	Isoxaben is soluble in water to 1.0 mg ai/L, and the measured
soncentrations in the aquatic studies were at this reported limit of
solubility.  The studies were conducted in the 1980s and did not attempt
to increase the solubility by use of a cosolvent, as recommend in
current protocols.  As previously mentioned, the reported nominal
concentrations for most of the studies was 100 mg ai/L, however no
precipitate was reported.  All aquatic studies are considered
supplemental.

Acute Fish

	Because the LC50 for fish is non-definitive (i.e.LC50 >0.86 mg ai/L),
RQs are not presented.  The EEC/LC50 ratio calculated with the highest
concentration tested for reference purposes (0.03) would not exceed the
LOC for risk of acute mortality to listed species.  Freshwater fish
serve as surrogates for aquatic-phase amphibians.  Since no mortality or
sublethal effects were reported in the any of the freshwater or
estuarine/marine fish studies, risk is considered low for these taxa.

Chronic Fish

	No effects to freshwater fish from chronic exposure to isoxaben were
reported up to the maximum concentration tested for fathead minnows,
i.e. NOAEC=400 µg ai/L.   The maximum 60-day TTR EEC is 21.1 µg ai/L
and the resulting RQ is 0.05.  The chronic RQ for freshwater fish of
0.05 is two orders of magnitude below the chronic risk LOC of 1.0.
There are no chronic toxicity data available for estuarine/marine fish,
so RQs cannot be calculated.  However, based on the available freshwater
fish data, no chronic effects to estuarine/marine fish are expected.

Acute Invertebrates

	Because the most sensitive acute LC50 or EC50 for across the aquatic
invertebrates (freshwater and estuarine/marine) is non-definitive (i.e.
Quahog clamEC50 >960 µg ai/L), individual RQs are not presented.  The
RQ calculated with the highest peak TTR EEC of 24.5 µg ai/L and the
non-definitive toxicity estimate for the clam is < 0.03 and would not
exceed the LOC (0.05) for acute riskto listed species.  While no
sublethal effects were seen daphnids or grass shrimp, 40% abnormal
larvae were reported in the clam study.

Chronic Invertebrates

Based on the maximum 21-day TTR EEC of 22.7 µg ai/L and a 21-day life
cycle test with the cladoceran Daphnia magna NOAEC of 690 µg ai/L, the
highest chronic RQ value is 0.03.  The highest chronic RQ (0.03) for
freshwater invertebrates from the proposed uses does not exceed the
chronic risk LOC (1.0).  No effects were reported in the daphnid
life-cycle study.  No data for chronic exposure to estuarine/marine
species are available.  Given the developmental effects observed in the
acute Quahog clam study, there is uncertainty regarding the potential
chronic effects of isoxaben on estuarine/marine invertebrates.  As such,
risk to estuarine/marine invertebrates cannot be precluded.

Plants

	Frank effects on duckweed biomass were reported in all three studies
available.  Effects were roughly equivalent at both 7- and 14-days and
for both formulated product and TGAI.  The RQs (Table 27) based on the
most sensitive of the available endpoints exceeds both the listed and
nonlisted LOCs for the proposed uses.

Table 27.  RQs for aquatic vascular plants from the proposed uses of
isoxaben.

Proposed Use	Maximum TTR EEC

µg ai/L	Nonlisted

Species RQ

EC50 = 10 µg ai/L	Listed Species RQ

EC05=6 µg ai/L

Grapes	14.2	1.4	2.4

Bearing nut trees	22.2	2.2	3.7

	Appropriate endpoints for aquatic nonvascular plants are not available
for this assessment; therefore risk cannot be quantitatively assessed
and is presumed for these taxa.

Terrestrial Animals

Birds

Potential risks to birds are evaluated below.  Risk estimates for birds
are also used as surrogates for reptiles and terrestrial-phase
amphibians.

Acute

	No acute toxic effects were observed in either acute oral or subacute
dietary studies with either mallard ducks or bobwhite quail.  The acute
and subacute endpoints for avian species are non-definitive (i.e. >
highest limit dose and dietary concentration tested), therefore RQs are
not presented.  Although ‘RQs’ calculated with the highest dose
tested in the acute oral study (2000 mg ai/kg-diet) would exceed the
acute risk LOC (0.1) for listed species foraging on short grass and
broadleaf plants/small insects the absence of any sign of toxicity among
the birds tested makes the likelihood of actual risk low.

Chronic

Because a NOAEC is not available for birds, potential risk cannot be
precluded.  For the proposed new uses, a reference RQ calculated with
the mallard chronic LOAEC (100 mg ai/kg-diet; Table 28) exceeds the
chronic risk LOC (1.0) for birds by more than two-fold for species
foraging on short grass.  Avian RQs are surrogates for terrestrial-phase
amphibians and reptiles.

Table 28.  Upper Bound Chronic Avian Dietary Based Risk Quotients

NOAEC (ppm)	EECs and RQs

	Short Grass	Tall Grass	Broadleaf Plants/

Small Insects	Fruits/Pods/

Seeds/

Large Insects

	EEC (ppm)	RQ	EEC (ppm)	RQ	EEC (ppm)	RQ	EEC (ppm)	RQ

100	240	>2.40*	110	>1.10*	135	>1.35*	15	>0.15

* bold indicates RQ exceeds chronic risk LOC (RQ≥1.0)

Mammals

Acute

	Although the acute oral LD50 for rats is nondefinitive and exceeds
10,000 mg ai/kg-bw, no mortality was observed in any of the treated
animals; therefore RQs are not presented.  Since isoxaben is considered
practically nontoxic to mammals on an acute oral exposure basis and no
sublethal effects were reported, risk is considered low.

Chronic

	For the proposed new uses of isoxaben, dose-based chronic RQs exceed
the chronic risk LOC of 1.0 (Table 29) for all size classes of mammals
foraging on short grass, tall grass and broadleaf plant/small insects
except large (1000 g) mammals foraging on tall grass.  The RQ for small
mammals (15 g) foraging on short grass exceeds the LOC by more than
four-fold.  All chronic dietary–based RQs are below the chronic risk
LOC (Table 30).

Table 29.  Upper Bound Kenaga, Chronic Mammalian Dose-Based Risk
Quotients.  EEC in ppm.

Size Class

(grams)	Adjusted NOAEL	EECs and RQs

Short Grass	Tall Grass	Broadleaf Plants/

Small Insects	Fruits/Pods/

Seeds/

Large Insects	Granivore

EEC	RQ	EEC	RQ	EEC	RQ	EEC	RQ	EEC	RQ

15	54.95	228.82	4.16a	104.88	1.91	128.71	2.34	14.30	0.26	3.18	0.06

35	44.46	158.15	3.56	72.48	1.63	88.96	2.00	9.88	0.22	2.20	0.05

1000	19.23	36.67	1.91	16.81	0.87	20.63	1.07	2.29	0.12	0.51	0.03

abold indicates RQ exceeds chronic risk LOC (RQ≥1.0)

Table 30.  Upper Bound Kenaga, Chronic Mammalian Dietary Based Risk
Quotients.  EEC in ppm.

NOAEC (ppm)	EECs and RQs

	Short Grass	Tall Grass	Broadleaf Plants/

Small Insects	Fruits/Pods/

Seeds/

Large Insects

	EEC	RQ	EEC	RQ	EEC	RQ	EEC	RQ

500	240.00	0.48	110.00	0.22	135.00	0.27	15.00	0.03

Size class not used for dietary risk quotients

Terrestrial Plants

The most sensitive monocot and dicot in the vegetative vigor and
seedling emergence studies are used to derive the RQs in TerrPlant.  In
the seedling emergence study, no monocots were affected; however, only
three species were included in the study, and they were all grasses.
The most sensitive dicot was lettuce (EC25 = 0.0095 lbs ai/A).  Rye
grass is the most sensitive monocot in the vegetative vigor study (EC25
= 0.014 lbs ai/A) and pea is the most sensitive dicot, with an EC25
>0.056 lbs ai/A (NOAEC = 0.056 lbs ai/A).

At the maximum seasonal application rate, RQs for both listed and
non-listed dicots exceed the risk to terrestrial plant LOC for species
exposed to runoff plus drift in adjacent upland and wetlands as well as
drift alone (Table 31).  The LOC for nonlisted plants is exceeded by
more than 11-fold and exceeded for listed species by over 78-fold.  The
RQ for listed monocots exceeds the risk to terrestrial plant LOC by
nearly 3-fold.

Table 31.  Risk quotients for plants and endangered terrestrial plants
for ground application of isoxaben at the maximum seasonal application
rate (1.0 lbs ai/A).1

Terrestrial Plant Group	Ground Spray

	Adjacent uplands	Adjacent wetlands	Drift Only

Monocots	<0.1	0.12	0.71

Dicots	2.11	12	2.9

Listed Monocots	<0.1	0.12	1.0

Listed Dicots	14	79	7.1

1Bold values denote an exceedance of the LOC (RQ≥1.0).

B.  Risk Description

	Isoxaben is characterized as a moderately persistent and mobile
compound.  Although primary routes of degradation include aqueous
photolysis, aerobic aqueous metabolism and anaerobic aqueous metabolism,
uncertainty regarding the potential toxicity of its residues increases
estimated environmental concentrations. Consistent with the risk
hypothesis, potential direct risk to both plant and animal species is
possible from the proposed uses of isoxaben.  Since risk to both aquatic
and terrestrial plants is indicated, indirect effects to other taxa may
occur.  Since the screening-level assessment uses few surrogate species
to estimate risk to all aquatic and terrestrial organisms, it is
possible that some species will be more sensitive than those tested.

	Although the label is not explicit, the proposed uses are thought to be
ground spray, to avoid injury to the proposed uses on bearing nut
orchards and vineyards.  This assessment however, does not evaluate
aerial applications.  If the proposed uses are intended to be applied
aerially, the potential risk in this assessment will be under estimated.
 Risk in this document is calculated based on a single application of
1.0 lb ai/A, the total annual rate.  The label allows for two
applications at a lower rate, but additional modeling indicates that
this scenario has no appreciable effect on the risk estimates.

Since the acute aquatic studies reported endpoints greater than the
highest dose tested, RQs were not presented in the Risk Estimation
section.  However, there is uncertainty in the assessment.  The studies
did not attempt to increase the solubility of isoxaben in water beyond
the reported limit of solubility of 1.0 mg ai/L.  However, EECs were
modeled using a total toxic residue approach (TTR) because degradate
toxicity is unknown.  Therefore, EECs are thought to be conservative and
as such are likely to be protective for aquatic species.

No adverse effects were reported in the either the acute or chronic
toxicity studies of fish, therefore risk to fish is thought to be low.
Although chronic exposure data are not available for estuarine/marine
fish, the absence of effects in the available acute and chronic studies
suggests effects are likely to be minimal.  Also, since isoxaben has
limited solubility in freshwater, its solubility in salt water is likely
to be lower than that in freshwater and as a result make it less likely
of causing adverse effects.

The sublethal effects reported in the acute exposure estuarine/marine
clam study, i.e., 40% abnormal larvae at the highest dose tested,
suggest that isoxaben may have an effect on sensitive aquatic
invertebrates.  Abnormal larvae were defined in the study as number of
normal larvae minus total number of larvae.  Although the clam is an
estuarine/marine species, it may represent freshwater mollusc species
more sensitive to isoxaben than daphnids.  ‘RQs’ calculated with
highest test concentration are <0.02 and are below the acute risk LOC
for listed aquatic invertebrates.  Because of these sublethal effects in
the acute clam study and in the absence of estuarine/marine chronic
toxicity data, the potential for chronic effects cannot be precluded for
estuarine/marine invertebrates.

There is potential for the proposed uses of isoxaben to adversely affect
aquatic vascular plant based on frank effects seen in the submitted
studies.  The RQ for listed aquatic vascular species exceeds the LOC
nearly four-fold for the bearing nut tree use, based on a relatively
conservative scenario.  In less vulnerable areas, the LOC exceedance
will be less, proportional to the lower EEC.

	Isoxaben is classified as practically nontoxic to birds on an acute
oral exposure basis and no effects were reported at the highest dose
tested.  Given the absence of effects in the acute oral and subacute
dietary studies, acute and subacute risks to birds are considered to be
low.

	The lack of a chronic NOAEC for avian species (mallards) means that
potential risk from chronic exposure to birds is assumed.  The RQ
calculated with the LOAEC (100 mg ai/kg-diet) from the mallard duck
study exceeds the chronic risk LOC of 1.0 by more than two-fold.  No
effects were reported in the bobwhite quail reproduction study.  There
was a great deal of variability in the mallard duck study’s controls
and the study was marginally considered supplemental.  Additionally,
both studies lacked important growth endpoints.

While risk of mortality from acute exposure to isoxaben is expected to
be low for mammals from the proposed uses of isoxaben, chronic risk is
indicated.  Although dietary-based RQs do not exceed the chronic risk
LOC of 1.0, dose-based RQs exceed the LOC by over four-fold for small
mammals foraging on short grass.  The dose-based calculation takes into
account that different-sized animals have to consume different amounts
of food and that the food itself has differing nutritional value.
Overall, small- and medium-sized mammals foraging on short grass, tall
grass and broadleaf plants/small insects exceed the chronic risk LOC, as
do large mammals foraging on short grass and broadleaf plants/small
insects.

Given that risk from chronic exposure from the proposed uses of isoxaben
is indicated for birds (and surrogates) and mammals, this route of
exposure is a primary concern for these taxa.  This assessment is based
on a single application at the seasonal maximum application rate, but
the label allows for up to two applications per season.  Two
applications of isoxaben at 0.5 lbs ai/A seven days apart does not
appreciably change the risk estimates using the default foliar
dissipation half-life.  However, if the foliar dissipation half-life
was, hypothetically, found to be 3 days, two applications of 0.5 lbs
ai/A would roughly halve the chronic RQs.  Reducing the application rate
by one half also reduces the RQs by one half, but there are still
exceedances.

There is uncertainty with respect to the species chosen for testing and
their relative sensitivity compared to the range in potential
sensitivities found in the ecosystem.  Animal species selected for
toxicity testing have generally been selected for their ease of
husbandry in laboratory environments.  It is possible that exposed
species will be more or less sensitive to isoxaben than wild type
species.  The predominant direction of this uncertainty is unknown.

Although considered a preemergent herbicide, isoxaben may injure plants
in later stages of development as well.  Although the seedling emergence
RQs, derived from runoff plus drift, are much higher than those for
drift alone, derived using the vegetative vigor endpoint, RQs for dicots
and listed monocots exceed the risk to terrestrial plant LOC.  While
grasses do not appear to be affected by isoxaben based on seedling
emergence, some grasses appear to be susceptible to injury by isoxaben
at later growth stages.

Although sublethal effects on growth are used to calculate RQs for
nontarget plants, only ten crop species are used to estimate
phytotoxicity to the entire terrestrial plant population, including
trees, mosses, ferns, etc.  It is uncertain how well the tested species
represent the sensitivity distribution of the terrestrial plants as a
whole that may come in contact with isoxaben.  Additionally, since
chronic and reproductive effects in particular are not evaluated at this
time, the sublethal endpoints should be considered the best available
indication of potentially critical effects to individual plant species
and plant communities.

	Runoff is a major factor in nontarget terrestrial plant exceedances
based on TerrPlant.  It is difficult to estimate how far from the
application site adverse effects may occur.  While RQs cannot be
directly used to estimate the magnitude or likelihood of effects, it is
true that lower application rates result in lower EECs.  However, given
the LOC for listed dicots would be exceeded more than 79-fold at a
single application of 1.0 lbs ai/A, even with a reduction in application
rate the potential for nontarget plant effects would remain.

It is also important to consider that modeled runoff is only compared to
endpoints from the seedling emergence study.  The method of pesticide
application in the guideline studies allows for analysis of effects to
seedlings from both spray drift and runoff, but the vegetative vigor
studies can only be analyzed for effects from spray drift.  The
potential for effects on older plants, such as those in the vegetative
vigor study, from runoff through stem contact or root uptake remains an
uncertainty and plant risk may be underestimated in this assessment.

There is uncertainty with respect to the species chosen for testing and
their relative sensitivity compared to the range in potential plant
sensitivities found in the ecosystem.  Plants tested are crop plants,
typically subjected to hundreds of years of human selection.  It is
possible that crop species will be more or less sensitive to isoxaben
than native wild type species.  The predominant direction of this
uncertainty is unknown.  The only monocots tested were grass species
(Family: Poaceae), which are generally not sensitive to isoxaben at the
application rates tested.  Typically, onion (Family: Liliaceae) is the
tested species representing the other monocot families (e.g.
Orchidaceae, Smilacaceae).  The lack of a second monocot family tested
results in considerable uncertainty about the potential risk to
non-grass species.

Effects to sensitive trees and other perennial species may occur that
cannot be accounted for by current modeling and phytotoxicity studies.
Changes in plant community composition may occur due to differences in
species sensitivity.  Such changes could lead to local reductions in
biodiversity and influence animal species through changes in available
habitat and preferred food sources.

The drift RQs in TerrPlant are based on estimated exposure roughly 200
feet from the application site, and exceed the LOC by over 7-fold for
listed nontarget plants.  The AgDRIFT model was used to refine the
potential effect of isoxaben drift to nontarget plants.  Ground
applications at the total annual application rate, 1.0 lbs ai/A, were
modeled for all of the species in the seedling emergence and vegetative
vigor studies (Table 32).  This table indicates the distance from the
edge of the application area where the RQ for that endpoint falls below
the risk to terrestrial plant LOCs.  For the most sensitive species,
lettuce, effects on seedling emergence may be seen at out to 249 ft from
the application area, and beyond 997 ft for listed species.  For
vegetative vigor, effects may be seen out to 174 ft from the application
area, and out to 554 ft for listed species.

Table 32 Distance (feet) from the edge of field where the RQ falls below
the risk to terrestrial plant LOC for seedling emergence endpoints for
ground application, based on AgDRIFT EECs.

Plant Species	Seedling Emergence	Vegetative vigor

	Listed	Nonlisted	Listed	Nonlisted

Oat	3.3	<3.3	325	<3.3

Ryegrass	3.3	<3.3	554	174

Wheat	3.3	<3.3	3.3	<3.3

Oilseed rape	125	92	6.6	>3.3

Pea	46	10	46	<46

Cucumber	3.3	<3.3	92	30

Carrot	177	49	554	<3.3

Lettuce	>997	249	46	<3.3

Tomato	331	154	3.3	<3.3

Sugarbeet	46	36	6.6	3.3

	The distance estimates are derived using EFED’s AgDRIFT default
values, which include the use of a high-boom (50 in height) ground
application and ASABE droplet size spectrum ‘very fine to fine’.
However, herbicides are often applied with larger droplets sizes and the
proposed use sites, bearing nut orchards and vineyards, together with
the use of isoxaben as a preemergent herbicide, suggest these may be
highly conservative assumptions.  AgDRIFT modeling was also conducted
using low boom (20 in height) and ASAE droplet size spectrum ‘fine to
medium/coarse’.  Using these parameters, the longest distance to an
exposure value equal to the vegetative vigor NOAEC is 144 ft and to the
seedling emergence NOAEC is 430 ft.  While this is still a considerable
distance from the edge of the application area, it is appreciably less
than the undefined >997 ft distance predicted using the default
parameters.

	Adding addition uncertainty to the drift estimates is the assumption of
the model of a bare ground fetch for the wind to traverse before
carrying the droplets out to the predicted distance.  While this is an
uncertainty regardless of the application of the model, the assumption
is less likely to be true for many of the bearing nut orchards.  Most of
these orchards feature a fairly dense stand of trees with a relatively
closed canopy, which would presumably alter the flow of air across the
application site.  Therefore, even the estimate of 430 ft may be very
conservative for many (but not all) of the proposed application sites.
Large tree orchards (e.g. pecans) and vineyards are less likely to have
the degree of air flow interruption as the smaller tree orchards (e.g.
apples).

Because isoxaben is moderately persistant and moderately mobile,
contamination of ground water used as irrigation was considered as a
possible route of exposure to terrestrial plants.  The highest estimated
groundwater concentration value from SciGrow (14.5 ppb) applied in one
inch of water on an acre of land corresponds to an application rate of
0.0032 lbs ai/A, roughly one third of the most sensitive terrestrial
plant endpoint, lettuce seedling emergence (Appendix A).  Therefore,
this route of exposure is not expected to pose a significant risk to
nontarget terrestrial plants.  However, should this estimated ground
water concentration result in exposure to aquatic plants via ground
water recharge, the aquatic plants may be affected.

No incidents involving animals have been reported to the Agency's EIIS
database, and no incidents involving birds are reported in the AIMS
database.  However, the absence of reported incidents should not be
construed as the absence of incidents.  Incident reports for non-target
organisms typically provide information only on mortality events and
plant damage.  Sublethal effects in organisms such as abnormal behavior,
reduced growth and/or impaired reproduction are rarely reported, except
for phytotoxic effects in terrestrial plants.  EPA’s changes in the
registrant reporting requirements for incidents in 1998 may account for
lack of reported incidents.  Registrants are now only required to submit
detailed information on ‘major’ fish, wildlife, and plant incidents.
 Minor fish, wildlife, and plant incidents, as well as all other
non-target incidents, are generally reported aggregately and are not
included in EIIS.  In addition, there have been changes in State
monitoring efforts due to a lack of resources.  However, the incident
data discussed earlier suggest that, at least for plants, exposure
pathways for isoxaben are complete and that exposure levels are
sufficient to result in field-observable effects.

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations. Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data. Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Isoxaben is not among the group of 58 pesticide active ingredients on
the initial list to be screened under the EDSP.  Under FFDCA sec. 408(p)
the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients.

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:    HYPERLINK
"http://www.epa.gov/endo/"  http://www.epa.gov/endo/ .

C. Uncertainties and Data Gaps

	The aerobic soil metabolism study upon which this assessment is based
was conducted on four foreign soils.  The study was classified as
supplemental, as all of the soils were foreign and it was unclear if
they were comparable to soils in the United States, adding to the
uncertainty of how quickly isoxaben degrades in an aerobic soil
environment.  A study conducted on soils from the United States would
provide better clarity on the degradation of isoxaben and confirm the
results obtain herein.  However, using a TTR modeling approach and
employing the 90th percentile of the upper confidence bound on the mean
of the five TTR half-life values reduces the level of uncertainty in the
conservative nature of the EEC estimates.

Several studies were submitted to fulfill the adsorption/desorption data
requirement.  MRID 00164645 was classified as not acceptable for a
number of reasons, primarily because the leaching was not continuous and
done in a timely manner, a complete material balance was not provided,
and the soil samples were not analyzed for residues.  MRID 00132124 was
classified as unacceptable for a number for reasons, primarily because
isoxaben and its transformation products were not identified after
aging, prior to leaching, or after leaching.  MRID 41106303 was reviewed
in 1990 and classified as acceptable, provided the “toxicology branch
determines that degradates other than 201469 (hydoxyisoxaben) are not of
toxicological concern.”  For the drinking water and ecological risk
assessments, the degradates hydroxyisoxaben, dimethoxybenzamide,
methoxyphenylpyrimidinol, and amino ethyl methyl (AEM) hexenoylisoxaben
were not expected to be more toxic to humans than the parent compound,
but data were not available to exclude them as residues of concern.  As
such, mobility data on isoxaben and its degradates of concern would
provide better clarity on the mobility of isoxaben and its degradates
and confirm the results obtain herein. Alternatively, toxicity data
which precludes the degradates hydroxyisoxaben, dimethoxybenzamide,
methoxyphenylpyrimidinol, and AEM hexenoylisoxaben as residues of
concern would eliminate the need for mobility data for the isoxaben
degradates and a new mobility study.

The bioconcentration study for isoxaben residues accumulated in bluegill
was classified as supplemental because isoxaben residues were
incompletely characterized and residues in the whole fish tissue were
not determined experimentally.  While the relatively low Kow and these
bioconcentration factors in fish suggest that isoxaben is not expected
to accumulate in aquatic or terrestrial food chains, an acceptable study
would reduce uncertainty with regards to aquatic exposure effects.

	There is also uncertainty associated with the ability of the aquatic
exposure modeling to simulate aquatic exposures as well as in the
selection of input parameters.  In this regard, one of the potentially
important parameters that can impact concentration estimates is the
selection of appropriate application dates.  Although the pesticide
application dates were selected to be most appropriate with
considerations for application recommendations, model simulated cropping
dates, and label restrictions, variability nevertheless results because
the the time span that a pesticide may likely be applied may be large
and the actual application dates are unknown.  Such variability is
caused by the temporal proximity of a pesticide application to rain
events.  As with all model estimates, the values presented here should
not be viewed as precise estimates.

V.  Federally Threatened and Endangered (Listed) Species

Chronic risk to estuarine/marine invertebrates is presumed due to lack
of data and sublethal effects in an acute study.  Risk to aquatic
vascular and terrestrial plants is indicated.  In addition to listed
plant species risk, the Agency considers the LOC exceedances as
indicative of a potential for secondary (indirect) adverse effects to
those listed species that rely either on a specific plant species (plant
species obligate) or multiple plant species (plant dependant) for some
important aspect of their life cycle (indirect effects).  Indirect
effects may include general habitat modification, host plant loss, and
food supply disruption.  Further analysis regarding the overlap of
individual species with each use site is required prior to determining
the likelihood of potential impact to listed species.  Such a refinement
is outlined in the following sections.

	a.	Action Area

For listed species assessment purposes, the action area is considered to
be the area affected directly or indirectly by the Federal action and
not merely the immediate area involved in the action.  At the initial
screening level, the risk assessment considers broadly described
taxonomic groups and so conservatively assumes that listed species
within those broad groups are co-located with the pesticide treatment
area.  This means that terrestrial plants and wildlife are assumed to be
located on or adjacent to the treated site and aquatic organisms are
assumed to be located in a surface water body adjacent to the treated
site.  The assessment also assumes that the listed species are located
within an assumed area, which has the relatively highest potential
exposure to the pesticide, and that exposures are likely to decrease
with distance from the treatment area.

If the assumptions associated with the screening-level action area
result in RQs that are below the listed species LOCs, a "no effect"
determination conclusion could be made with respect to listed species in
that taxa, and no further refinement of the action area is necessary.
Furthermore, RQs below the listed species LOCs for a given taxonomic
group indicate no concern for indirect effects upon listed species that
depend upon the taxonomic group covered by the RQ as a resource.
However, in situations where the screening assumptions lead to RQs in
excess of the listed species LOCs for a given taxonomic group, a "may
affect" designation cannot be precluded and may be associated with
direct effects on listed species belonging to that taxonomic group or
may extend to indirect effects upon listed species that depend upon that
taxonomic group as a resource.  In such cases, additional information on
the biology of listed species, the locations of these species, and the
locations of use sites need to be considered along with available
information on the fate and transport properties of the pesticide to
determine the extent to which screening assumptions regarding an action
area apply to a particular listed organism.  These subsequent refinement
steps could delineate how this information would impact the action area
for a particular listed organism and may potentially include areas of
exposure that are downwind and downstream of the pesticide use site.

	b.	Taxonomic Groups Potentially at Risk

The RQs calculated based on the ratio of EECs to toxicity endpoints
exceed the LOC in this case the chronic exposure endpoints for bird and
mammals and the NOAEC values from aquatic and terrestrial plant toxicity
studies. Should estimated exposure levels occur in proximity to listed
resources, direct risk to listed birds, terrestrial-phase amphibians,
reptiles, mammals and plant species and indirect effects on animal
species (aquatic and terrestrial; Table 34) are possible.  Appendix C
provides a count-by-state listing of species for each taxon that may be
affected by this action.  This screening-level assessment is based on
the initial assumption that listed species within the taxonomic groups
of concern are actually present in areas for which the estimated
exposure levels used for RQ calculation can be expected to occur.  A
specific determination for any RQ in excess of listed species LOCs
cannot be made until a determination of the co-occurrence of the listed
species with the action area has been determined.  This was not done for
this assessment.

Table 33.  Potential Listed Species Risks Associated with Direct or
Indirect Effects Due to the Proposed Application of Isoxaben on Grapes
and Bearing Nut Trees.

Listed Taxon	Direct Effects	Indirect Effects

Terrestrial and semi-aquatic plants - monocots	Yes	Yes1

Terrestrial and semi-aquatic plants - dicots	Yes	Yes1

Birds	Yes	Yes1

Terrestrial-phase amphibians	Yes	Yes1

Terrestrial invertebrates	Yes	Yes1

Reptiles	Yes	Yes1

Mammals	Yes	Yes1

Aquatic vascular plants	Yes	Yes1

Aquatic nonvascular plants	No	Yes1

Freshwater fish	No	Yes1

Aquatic-phase amphibians	No	Yes1

Freshwater invertebrates	No	Yes1

Mollusks	No	Yes1

Marine/estuarine fish	No	Yes1

Marine/estuarine crustaceans	Yes	Yes1

1Nonlisted LOC exceeded for terrestrial plants, therefore there is
potential for adverse effects to those species that rely either on a
specific plant species or multiple plant species.  Plant indirect
effects may include general habitat modification, host plant loss, and
food supply disruption.

		c.	Indirect Effects Analysis

Because terrestrial plant RQs are above risk to non-endangered species
LOCs, there is a potential for adverse effects to those listed species
that are plant species obligates or plant dependant for some important
aspect of their life cycle.  The extent to that the new uses of isoxaben
will indirectly affect listed animal species will require identification
of listed species that co-occur in areas of isoxaben use and an
evaluation of critical habit as described below.  Because of the
potential extent of the use of isoxaben, EFED cannot preclude the
possibility of a ‘likely to adversely affect’ designation for listed
species based on this assessment.

	d.	Critical Habitat

The screening-level risk assessment has identified potential concerns
for direct and indirect effects on listed species associated with action
areas where isoxaben is used.  In light of the potential for effects on
listed species, the next step for EPA and the Services is to identify
which listed species and critical habitat are potentially implicated.
Analytically, the identification of such species and critical habitat
can occur in either of two ways.  First, the agencies could determine
whether the action area overlaps critical habitat or the occupied range
of each listed species.  If so, EPA would examine the potential impact
of the use of isoxaben on listed species and whether impacts on
non-endangered species would affect the listed species indirectly or
directly affect a constituent element of the critical habitat.  Then EPA
would determine whether use of the pesticide overlaps the critical
habitat or the occupied range of those listed species.  At present, the
information reviewed by EPA does not permit use of either analytical
approach to make a definitive identification of species that are
potentially impacted indirectly or critical habitats that are
potentially impacted directly by the use of the pesticide.  EPA and the
Services will work together to conduct the necessary analysis.

	e.	Co-occurrence Analysis

The goal of the analysis for co-location is to determine whether sites
of pesticide use are geographically associated with known locations of
listed species.  At the screening level, this analysis is accomplished
using the Agency’s LOCATES (v. 2.10.3) database.  The database uses
location information for listed species at the county level and compares
it to agricultural census data for crop production at the same county
level of resolution.  The database contains Federally-listed species
that are located within states known to produce the crop upon which the
pesticide will be used.  Because the screening-level assessment
considers both direct and indirect effects across generic taxonomic
groupings, it is not possible to exclude any taxonomic group from a
LOCATES database query for a screening-level risk assessment.
Therefore, a ‘may affect’ designation cannot be precluded for listed
animals based on this assessment.

VI.  Literature Cited

FEMVTA. 2001. FIFRA Environmental Model Validation Task Force, Final
Report. Editors: Jones, R.L. and M.H. Russell. Available online at:
HYPERLINK "http://femvtf.com/femvtf/index.htm"
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Fletcher, J.S., J.E. Nellessen, T.G. Pfleeger.  1994.  Literature review
and evaluation of the EPA food-chain (Kenaga) nomogram, an instrument
for estimating pesticide residues on plants.  Environ. Tox. Chem.
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Hoerger, F. and E.E. Kenaga.  1972.  Pesticide residues on plants:
Correlation of representative data as a basis for estimation of their
magnitude in the environment.  In F. Coulston and F. Korte, eds.,
Environmental Quality and Safety: Chemistry, Toxicology, and Technology,
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Salihue, S., Hatzios, K.K., Derr, J.F. 1998. Comparative Uptake,
Translocation, and Metabolism of Root-Applied Isoxaben in Ajuga (Ajuga
reptans) and Two Ornamental Euonymus Species. Pesticide Biochemistry and
Physiology, 60:2 pp. 119-131

USEPA.  1998.  Guidelines for Ecological Risk Assessment.  Risk
Assessment Forum, Office of Research and Development,  Washington, D.C.
EPA/630/R-95/002F.  April 1998.

USEPA. 2004b. Overview of the Ecological Risk Assessment Process in the
Office of Pesticide Programs. U.S. Environmental Protection Agency,
Office of Prevention, Pesticide and Toxic Substances, Office of
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US EPA. 2006. Standard Soil Mobility Classification Guidance. U.S.
Environmental Protection Agency, Office of Pesticide Programs,
Environmental Fate and Effects Division. April 21, 2006.

USEPA. 2009. Guidance for Selecting Input Parameters in Modeling the
Environmental Fate and Transport of Pesticides, Version 2.1, October 22,
2009. Office of Pesticide Programs, Environmental Fate and Effects
Division.

USEPA. 2010. Memorandum from George Kramer to Isoxaben Risk Assessment
Team. Isoxaben.  Report of the Residues of Concern Knowledgebase
Subcommittee (ROCKS). March 31, 2010.

Willis, G. H. and L..L. McDowell, 1987.  Pesticide Persistence on
Foliage. in Reviews of Environmental Contamination and Toxicology.
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