Isoxaben Summary Document

Registration Review Docket

December 2007REGISTRATION REVIEW

Preliminary Work Plan

for

Isoxaben

CASE 7219

December 2007

Approved by:	______________________________

Steven Bradbury, PhD.

Director

Special Review and Reregistration Division

Date:	______________________________

 TABLE OF CONTENTS

											  Page #

Preliminary Work Plan (PWP)						 1

Fact Sheet                                       					 6

Ecological Risk Assessment Problem Formulation  	12

Human Health Effects Scoping Document                               	38

Glossary of Terms and Abbreviations					45

I. Preliminary Work Plan

Introduction:

The Food Quality Protection Act of 1996 mandated a new program:
registration review. All pesticides distributed or sold in the United
States generally must be registered by EPA, based on scientific data
showing that they will not cause unreasonable risks to human health,
workers, or the environment when used as directed on product labeling.
The new registration review program is intended to make sure that, as
the ability to assess risk evolves and as policies and practices change,
all registered pesticides continue to meet the statutory standard of no
unreasonable adverse effects.  Changes in science, public policy, and
pesticide use practices will occur over time.  Through the new
registration review program, the Agency periodically reevaluates
pesticides to make sure that as change occurs, products in the
marketplace can be used safely.  Information on this program is provided
at the following website:    HYPERLINK
"http://www.epa.gov/oppsrrd1/registration_review/"
http://www.epa.gov/oppsrrd1/registration_review/ .

The Agency has begun to implement the new registration review program
pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA), and will review each registered pesticide every
15 years to determine whether it continues to meet the FIFRA standard
for registration.  The public phase of registration review begins when
the initial docket is opened for each case.  This docket is the
Agency’s opportunity to state what it knows about the pesticide and
what additional risk analyses and data or information it believes are
needed to make a registration review decision.  After reviewing and
responding to comments and data received in the docket during this
initial comment period, the Agency will develop and commit to a final
work plan and schedule for the registration review of isoxaben.

  SEQ CHAPTER \h \r 1 Isoxaben is a broad-spectrum benzamizole herbicide
with pre-emergent activity for broadleaf weeds, grasses, and vines.  EPA
first registered isoxaben use in 1989.  It works by disrupting an enzyme
(found only in plants) necessary for protein synthesis.  Isoxaben is
used around non-bearing food crops, ornamental trees, and shrubs.  It is
used in agriculture, nurseries, rights-of way, and urban settings.

Anticipated Risk Assessment and Data Needs:

The Agency anticipates conducting a comprehensive human health and
ecological risk assessments for isoxaben.  These risk assessments will
include an endangered species assessment, and a complete dietary
assessment to cover proposed new food uses.  In addition, at this time,
environmental fate and plant toxicity studies are required to complete
the ecological risk assessment.  Additional environmental fate and
effects studies may be needed, pending EPA’s review of submitted
studies.

Ecological Risk and Data Needs:

Although most environmental fate and ecological effects studies have
been submitted, their review by EPA is not yet completed.  If any of
these studies are determined to be not scientifically valid, then
replacement studies will be included in a data call-in (DCI).  No matter
the outcome of the preceding studies, EPA will issue a DCI for soil
photolysis and terrestrial plant toxicity data that has not been
submitted for this herbicide.

Isoxaben has chemical characteristics similar to pesticides that have
been shown to leach through soil to groundwater.  The drinking water
assessment for the registration of proposed new food uses of isoxaben
under Pesticides Registration Improvement Act (PRIA) will include an
estimate of potential groundwater concentrations.  If the risk
assessment indicates that concentrations of isoxaben in drinking water
might pose a risk to human health, a prospective groundwater monitoring
study may be required as a condition of registration for these new uses.

No ecological risk assessment is available to draw from; however, in the
Registration Review – Problem Formulation for the Ecological Risk
Assessment of Isoxaben, estimates of risk, based on provisional data,
are provided to help guide the reader in understanding the potential for
environmental risks of concern.  A full ecological risk assessment, and
an estimate of potential drinking water exposure, will be completed for
registration review.

The planned ecological risk assessment will allow the Agency to
determine whether isoxaben use has "no effect" or "may affect" federally
listed threatened or endangered species (listed species) or their
designated critical habitat.  If the assessment indicates that isoxaben
“may affect" a listed species or its designated critical habitat, the
assessment will be refined.  The refined assessment will allow the
Agency to determine whether use of isoxaben is “likely to adversely
affect” the species or critical habitat or "not likely to adversely
affect" the species or critical habitat.  When an assessment concludes
that a pesticide's use "may affect" a listed species or its designated
critical habitat, the Agency will consult with the U.S. Fish and
Wildlife Service and National Marine Fisheries Service (Services), as
appropriate.

Human Health Risk and Data Needs:

At this time, there are no established tolerances on food or animal
commodities.  Therefore, EPA does not consider isoxaben to have a food
use, and a dietary assessment is not required.  However, with the
proposed food uses in the upcoming PRIA action, dietary assessments
(acute, chronic, and cancer) will be required and isoxaben will be
subject to the Food Quality Protection Act (FQPA).

The toxicological and exposure database for isoxaben are adequate for
the purpose of registration review and most likely for the proposed food
uses in the upcoming PRIA action.  EPA will need to select additional
endpoints for dietary, incidental oral, dermal, and inhalation exposures
for the new uses.  These endpoints will be used in registration review
as well.  Additionally, EPA will need to revisit the cancer potency
estimate based on the lack of a dose-response relationship.

Drinking water risks have not been assessed for isoxaben.  The current
turf use requires screening-level groundwater and surface water exposure
assessments.  The proposed food uses in the upcoming PRIA action will
also require screening-level groundwater and surface water exposure
assessments.

Occupational and residential handler and post-application assessments,
with the exception of cancer risks for children on treated turf, have
not been conducted for isoxaben and will be required during the
registration review process.  Moreover, the children turf scenario
cancer assessment will be updated depending on the outcome of the cancer
re-evaluation to reflect current Agency policies.

Timeline:

EPA has created the following estimated timeline for the completion of
the isoxaben registration review.

Activities	Estimated Year / Month

Phase 1: Opening the docket

Open Isoxaben Public Docket  	2007 – Dec

Close Public Comment Period  	2008 -  Mar

Phase 2:  Case Development

Develop Final Work Plan (FWP)	2008 -  May

Issue DCI 	2009 -  Jan - Mar

Data Submission	2011  - Jan - Mar

Preliminary Risk Assessments	2012 – July - Sept

Open Public Comment Period for Preliminary Risk Assessments 	2012 –
Oct – Dec

Phase 3: Registration Review Decision

Proposed Registration Review Decision 	2013 – Jan - Mar

Public Comment Period 	2013 – Apr - Jun

Final Reg Review Decision & Begin Post-Decision Follow-up	2013

Total (years)	6 years

Guidance for Commenters:

The public is invited to comment on EPA’s preliminary registration
review work plan and rationale.  The Agency will carefully consider all
comments as well as any additional information or data provided prior to
issuing a final work plan for the isoxaben case.

Through the registration review process, the Agency intends to solicit
information on trade irritants and, to the extent feasible, take steps
toward facilitating irritant resolution.  Growers and other stakeholders
are asked to comment on any trade irritant issues resulting from lack of
Maximum Residue Limits (MRLs) or disparities between proposed U.S.
tolerances and MRLs in key export markets, providing as much specificity
as possible regarding the nature of the concern.

Isoxaben is not identified as a cause of impairment for any water bodies
listed as impaired under section 303(d) of the Clean Water Act, based on
information provided at   HYPERLINK
"http://oaspub.epa.gov/tmdl/waters_list.impairments?p_impid=3"
http://oaspub.epa.gov/tmdl/waters_list.impairments?p_impid=3 .  The
Agency invites submission of water quality data for this pesticide.  To
the extent possible, data should conform to the quality standards in
Appendix A of the “OPP Standard Operating Procedure: Inclusion of
Impaired Water Body and Other Water Quality Data in OPP’s Registration
Review Risk Assessment and Management Process” (see:   HYPERLINK
"http://www.epa.gov/oppfead1/cb/ppdc/2006/november06/session1-sop.pdf"
http://www.epa.gov/oppfead1/cb/ppdc/2006/november06/session1-sop.pdf ),
in order to ensure they can be used quantitatively or qualitatively in
pesticide risk assessments.

EPA seeks to achieve environmental justice, the fair treatment and
meaningful involvement of all people, regardless of race, color,
national origin, or income, in the development, implementation, and
enforcement of environmental laws, regulations, and policies.  To help
address potential environmental justice issues, the Agency seeks
information on any groups or segments of the population who, as a result
of their location, cultural practices, or other factors, may have
atypical, unusually high exposure to isoxaben, compared to the general
population.  Please comment if you are aware of any sub-populations that
may have atypical or unusually high exposure compared to the general
population.

Stakeholders are also specifically asked to provide information and data
that will assist the Agency in refining the human health and ecological
risk assessments, including any species-specific effects determinations.
 The Agency is interested in the following information:

confirmation on the following label information

a. sites of application

b. formulations

c. application methods and equipment

d. maximum application rates

e. frequency of application, application intervals, and maximum number
of 	                                              	    applications per
season

f. geographic limitations on use

use or potential use distribution (e.g., acreage and geographical
distribution of relevant crops)

use history

median and 90th percentile reported use rates (lbs ai/acre) from usage
data – national, state, and county

application timing (date of first application and application intervals)
by use site – national, state, and county

usage/use information for non-agricultural uses (e.g., forestry,
residential)

directly acquired county-level usage data (not derived from state level
data)

	a. maximum reported use rate (lbs ai/acre) from usage data – county

	b. median and 90th percentile number of applications – county

	c. total pounds per year – county

	d. the year the pesticide was last used in the county/sub-county area

	e. the years in which the pesticide was applied in the
county/sub-county area

typical interval (days)

state or local use restrictions

ecological incidents (non-target plant damage and avian, fish,
reptilian, amphibian and mammalian mortalities) not already reported to
the Agency

monitoring data

Next Steps:

After the 90-day comment period closes in March of 2008, the Agency will
review any comments received, and then issue a Final Work Plan for this
pesticide.

II. FACT SHEET

Background Information:

Isoxaben Registration Review case number: 7219

Isoxaben PC Code: 125851  /  CAS#:  82558-50-7

Technical registrant:  Dow Agrosciences

First approved for use in a registered product in 1989.

There are 15 FIFRA Section 3 active registrations for isoxaben.

Not subject to reregistration because it was first registered after
1984; therefore, no Reregistration Eligibility Decision (RED) was
prepared.

Chemical Review Managers:	Mark Howard (  HYPERLINK
<EMAIL_ADDRESS><EMAIL_ADDRESS>)

	Jacqueline Guerry (  HYPERLINK<EMAIL_ADDRESS><EMAIL_ADDRESS>)

Product Managers:	Joanne Miller (  HYPERLINK
<EMAIL_ADDRESS><EMAIL_ADDRESS>)   Team Leader

                           	Eugene Wilson (  HYPERLINK
<EMAIL_ADDRESS><EMAIL_ADDRESS>)

Use and Related Information:

Isoxaben is a preemergent herbicide mainly used to control broadleaf
weed species by inhibiting cell wall growth in weed seedlings.

Uses include: Christmas trees, conifer trees, ornamentals (container
grown, field grown, and landscape), ornamental bulbs, non-bearing fruit
and nut trees, non-bearing vineyards, and non-commercially grown turf.

Up to 150,000 lbs active ingredient (ai)/year is used (EPA estimates).

Isoxaben is formulated as a granular, a water dispersible granule (also
referred to as a dry flowable), and an impregnated material.

Use information, such as application rates and number of applications,
can be found in Appendix A in the docket.

Recent Regulatory Actions:

Dow AgroSciences has proposed to establish tolerances in or on the
following food commodities:  grapes, grape juice; nut trees, pistachio
and almond hulls, and has requested a waiver for the requirement of
tolerances in or on the raw agricultural commodities:  cattle, meat
byproducts; meat and milk.   (See 72 FR 42073 and Regulations.gov Docket
no. EPA-HQ-OPP-2007-0504.)

Two environmental fate studies (aerobic and anaerobic aqueous metabolism
studies) were submitted in 2006, under section 6(a)(2) of FIFRA (adverse
effects reporting requirement) for concerns about the potential for
isoxaben residues in rotational crops.  EPA has reviewed those studies
and concluded, "given the limited persistence of isoxaben in aerobic and
anaerobic aquatic systems, exposure to subsequent rotational crops is
unlikely."

Environmental Risk Assessment Status:

To meet current standards, a complete ecological risk assessment
(including a risk assessment for threatened and endangered plants and
animals) is needed.  However, EPA has conducted a preliminary review of
the available environmental fate and ecotoxicity data to determine the
scope of work necessary to support the registration review process for
isoxaben.  Subject to the Agency’s decision on the proposed addition
of isoxaben use on food crops, an FQPA aggregate assessment is required,
necessitating the preparation of estimated drinking water
concentrations.  Please refer to Section III of this document,
Registration Review – Preliminary Problem Formulation for the
Ecological Risk Assessment of Isoxaben, for a detailed discussion of the
anticipated environmental risk assessment needs.  A summary follows:

Environmental Fate

Based on a preliminary assessment of the fate data, isoxaben is expected
to be moderately persistent and may be mobile.  There is some indication
that the mobility of isoxaben decreases with increasing soil clay
content and soil cation exchange capacity.  It may represent a ground
water concern when applied to certain soils and/or where high water
tables are present (i.e., less than one foot below grade) and high
rainfall/irrigation occurs.

Isoxaben does not appear to readily undergo aerobic and anaerobic
degradation in soil.  Primary routes of degradation appear to be aqueous
photolysis, aerobic aqueous metabolism and anaerobic aqueous metabolism.

A fish bioconcentration study submitted to the Agency indicated that
there was some concentration of isoxaben in fish tissues during the
exposure period, but that isoxaben rapidly depurated when exposure
ceased.  EPA considered this information along with the low
octanol-water partition coefficient (Kow) of isoxaben to conclude that
bioaccumulation of isoxaben is not likely in aquatic ecosystems.  A
different mode of exposure was considered in nine single dose rat
metabolism studies.  Radiolabeled isoxaben was also accounted for as
metabolites in the urine in most of these studies.  However, only 85% of
the radioactivity was accounted for in male rats in one metabolism
study, compared to 92.6% in female rats.  The Agency’s review of this
study interpreted this as a sign of "possible bioaccumulation" which
should be reevaluated at a future date.  The potential for accumulation
in meat and milk will be assessed as part of the risk assessments for
the food uses proposed for registration under PRIA.

Two recent environmental fate studies were submitted to EPA in 2006,
under section 6(a)(2) of FIFRA (adverse effects reporting requirement)
for potential concerns about rotational crops.  EPA has concluded,
"given the limited persistence of isoxaben in aerobic and anaerobic
aquatic systems, exposure to subsequent rotational crops is unlikely."

Several studies (leaching/adsorption/desorption, hydrolysis, aqueous
photolysis, and aerobic soil metabolism) are currently under review.

Ecotoxicity

All ecological effects studies are currently under review.

EPA has provisional environmental effects endpoints in its Pesticide
Ecotoxicity Database; however, no formal, signed, data evaluation
records (DERs) are available to verify that these studies have been
reviewed.

Based on a preliminary review of the ecological effects database,
isoxaben is expected to be practically non-toxic to birds, mammals, and
insects; and moderately toxic to aquatic animals and plants.  There is
insufficient information to predict a level of toxicity to terrestrial
plants.

Risk to the Environment

EPA has not conducted a formal ecological risk assessment on isoxaben.
However, in the Registration Review – Preliminary Problem Formulation
for the Ecological Risk Assessment of Isoxaben estimates of risk, based
on provisional data, are provided to help guide the reader in
understanding the potential for environmental risks of concern.

Initial reviews suggest potential concern for acute effects to
endangered aquatic animals and small birds, and for chronic effects to
mammals.  The Agency cannot assess plant risks since no plant studies
have been submitted.

The addition of food uses for isoxaben will expand the scope of the
environmental risk assessment due to increase acreage and need for a
drinking water assessment.

Human Health Risk Assessment Status:

Please refer to Section IV of this document, Human Health Effects
Scoping Document, for a detailed discussion of the anticipated risk
assessment needs for human health.  A summary follows:

Toxicology & Exposure Database

The toxicological database for isoxaben is adequate for the purpose of
registration review and is expected to be adequate for the proposed food
uses in the upcoming PRIA action.

EPA does not anticipate requesting any new toxicological or exposure
data.

The toxicological and exposure database for isoxaben are adequate for
the purpose of registration review and most likely for the proposed food
uses in the upcoming (Pesticides Registration Improvement Act) PRIA
action.  EPA will need to select additional endpoints for dietary,
incidental oral, dermal, and inhalation exposures for the new uses.
These endpoints will be used in registration review as well.
Additionally, EPA will need to revisit the cancer potency estimate based
on the lack of a dose-response relationship.

A turf transferable residue study and a dislodgeable foliar residue
study were submitted in 2000.  These studies will be used in the
occupational and residential exposure assessments.

Dietary Risk

No dietary risk assessments have been conducted for isoxaben, as there
are currently no registered food uses.  However, the new proposed food
uses will require an acute, chronic, and cancer dietary risk
assessments.

There are no drinking water risk assessments for isoxaben.  The current
turf use requires a screening level groundwater and surface water
analysis.  The proposed food uses in the upcoming PRIA action will also
require screening-level groundwater and surface water analysis.

Occupational & Residential Risk

Occupational and residential handler and post application assessments,
with the exception of cancer risks for children on treated turf, have
not been conducted for isoxaben.  These assessments will be required
during the registration review process.  Also the cancer assessment
needs to be reevaluated.

Aggregate Risk

An aggregate assessment was not required previously, as there are
(currently) no food uses for isoxaben.  However, aggregate assessments
(acute, chronic, and cancer) will be necessary in the isoxaben
registration review based on the anticipated registration of food uses.

Cumulative

  SEQ CHAPTER \h \r 1 EPA does not anticipate performing a cumulative
risk assessment for isoxaben as part of its registration review, because
the Agency has not yet determined if there are any other chemical
substances that have a mechanism of toxicity common with that of
isoxaben.  For purposes of the Preliminary Work Plan, EPA has assumed
that isoxaben does not have a common mechanism of toxicity with other
substances.

Incident Reports:

The Agency has received reports on five incidents (of phytotoxocity) in
which use of isoxaben allegedly caused damage to tree seedlings and
ornamental plants.  These plants were treated directly with isoxaben.
No reports have been received of damage to plants from movement of
isoxaben off the site of treatment.  Also, the agency has received no
report of adverse field effects to animals attributed to use of
isoxaben, and no report from pesticide registrants of isoxaben
contamination of ground or surface water.

Seventeen human incidents have been reported on isoxaben.  Four were in
an occupational setting with 3 symptomatic cases, two of which visited a
health care facility.  The non-occupational group had 8 exposures with
two symptomatic cases.  Four exposures were found in a group of children
5 and under with two symptomatic cases.  One involved a 67 year old
woman who reported respiratory problems after an application near her
home.  There were no hospitalizations or ICU (Intensive Care Unit)
treatments reported for these incidences. (For more details, see Review
of Isoxaben Incident Reports; M. Hawkins; Aug 30, 2007.)

Tolerances:

There are no tolerances for food crops, nor for meat, milk, fat, and
meat by-products, nor any (Section 18 Emergency Exemptions) time limited
US tolerances.

Maximum Residue Levels (MRLs) for isoxaben have not been established by
the Codex Commission or by Canada’s Pest Management Regulatory Agency.

The registrant has submitted an application for food uses on fruit, tree
nuts, and vineyards.  This review is anticipated to be completed by
March 2009.

Data Call-In Status:

 No Data Call-Ins (DCIs) have been issued for isoxaben.

At present, EPA anticipates that the following studies, at a minimum,
will be included in a DCI, pending review of submitted environmental
fate and ecological effects studies:  Seedling emergence 850.4100
(123-1a) and Vegetative vigor 850.4150 (123-1b), Lemna study 850.4400
(123-2), and soil photolysis (835.3410).

Labels:

Currently registered isoxaben products are listed below.  Their labels
can be obtained from the Pesticide Product Label System (PPLS) website:
  HYPERLINK "http://oaspub.epa.gov/pestlabl/ ppls.home"
http://oaspub.epa.gov/pestlabl/ ppls.home .

Registration #	Registration Name	Company Name	% Active Ingredient

961-370	Lebanon Preen Pro 1.875g	Lebanon Seaboard Corp	.375

961-408	Preen Landscape Mulch	Lebanon Seaboard Corp	.0008

34704-917	Isoxaben 75DF Specialty Herbicide	Loveland Products, Inc.	75

52287-13	Weed-Free One Eleven	Harrell's Inc	.05

62719-144	Gallery Technical	Dow Agrosciences LLC	93.5

62719-145	Gallery 75 Dry Flowable	Dow Agrosciences LLC	75

62719-175	Snapshot 2.5 Tg	Dow Agrosciences LLC	.5

62719-178	Gallery Turf Fertilizer	Dow Agrosciences LLC	.38

62719-192	Turf Fertilizer Contains Gallery Plus Team	Dow Agrosciences
LLC	.29

62719-219	Gallery Milled Concentrate	Dow Agrosciences LLC	50

62719-280	T&O Fertilizer-Contains Gallery Plus Team	Dow Agrosciences LLC
.38

62719-516	Showcase	Dow Agrosciences LLC	.25

62719-565	Turf Fertilizer - Contains Gallery Plus Team Pro	Dow
Agrosciences LLC	.38

70506-53	Up-Shot DF Herbicide	United Phosphorus, Inc	20

70506-55	Turf Fertilizer Contains Galley Plus Surflan	United Phosphorus,
Inc	.29

III. ECOLOGICAL RISK ASSESSMENT PROBLEM FORMULATION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

August 30, 2007

	PC Code:  125851

	DP Barcode:  D341566

MEMORANDUM

Subject:	Registration Review – Preliminary Problem Formulation for the
Ecological Risk Assessment of Isoxaben

To:		Kevin Costello, Team Leader

		Jacqueline Guerry, Chemical Review Manager

		Special Review Branch

		Special Review and Reregistration Division

From:		Brian D. Kiernan, Biologist

		Amy A. McKinnon, Environmental Scientist

		Environmental Risk Branch IV

		Environmental Fate and Effects Division

Through:	Elizabeth Behl, Chief

		Environmental Risk Branch IV

		Environmental Fate and Effects Division

Attached is the preliminary problem formulation for the environmental
fate and ecological risk assessment to be conducted as part of the
Registration Review of the herbicide isoxaben.

REGISTRATION REVIEW

ECOLOGICAL RISK ASSESSMENT PROBLEM FORMULATION FOR:

ISOXABEN

N-[3-(1-ethyl-1-methylpropyl)-1,2-oxazol-5-yl]-2,6-dimethoxybenzamide

CAS Registry Number: 82558-50-7

PC Code: 125851

	Prepared by:

	Brian D. Kiernan, Biologist

Amy A. McKinnon, Environmental Scientist	U. S. Environmental Protection
Agency

Office of Pesticide Programs

Environmental Fate and Effects Division

Environmental Risk Branch IV

1200 Pennsylvania Ave., NW

Mail Code 7507P

Washington, DC 20460

Reviewed by:

Elizabeth Behl, Branch Chief

	Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc175025718"  I.	Background
PAGEREF _Toc175025718 \h  15

  HYPERLINK \l "_Toc175025719"  II.	Problem Formulation	  PAGEREF
_Toc175025719 \h  15

  HYPERLINK \l "_Toc175025720"  A.	Nature of Regulatory Action	  PAGEREF
_Toc175025720 \h  15

  HYPERLINK \l "_Toc175025721"  B.	Stressor Source and Distribution
PAGEREF _Toc175025721 \h  16

  HYPERLINK \l "_Toc175025722"  1.	Nature of the Chemical Stressor
PAGEREF _Toc175025722 \h  16

  HYPERLINK \l "_Toc175025723"  2.	Overview of Pesticide Usage	7

  HYPERLINK \l "_Toc175025724"  C.	Receptors	  PAGEREF _Toc175025724 \h
18

  HYPERLINK \l "_Toc175025725"  1.	Aquatic and Terrestrial Effects
PAGEREF _Toc175025725 \h  18

  HYPERLINK \l "_Toc175025726"  2.	Ecosystems Potentially at Risk
PAGEREF _Toc175025726 \h  19

  HYPERLINK \l "_Toc175025727"  D.	Assessment Endpoints	  PAGEREF
_Toc175025727 \h  19

  HYPERLINK \l "_Toc175025728"  E.	Conceptual Model	  PAGEREF
_Toc175025728 \h  19

  HYPERLINK \l "_Toc175025729"  1.	Risk Hypothesis	  PAGEREF
_Toc175025729 \h  20

  HYPERLINK \l "_Toc175025730"  2.	Conceptual Diagram	  PAGEREF
_Toc175025730 \h  20

  HYPERLINK \l "_Toc175025731"  F.	Analysis Plan	  PAGEREF _Toc175025731
\h  21

  HYPERLINK \l "_Toc175025732"  1.	Preliminary Identification of Data
Gaps	  PAGEREF _Toc175025732 \h  21

  HYPERLINK \l "_Toc175025733"  2.	Measures of Effect	  PAGEREF
_Toc175025733 \h  22

  HYPERLINK \l "_Toc175025734"  3.	Incident Reports	  PAGEREF
_Toc175025734 \h  23

  HYPERLINK \l "_Toc175025735"  4.	Measures of Exposure	  PAGEREF
_Toc175025735 \h  23

  HYPERLINK \l "_Toc175025736"  III.	Risk Estimation	  PAGEREF
_Toc175025736 \h  28

  HYPERLINK \l "_Toc175025737"  A.	Preliminary Aquatic Risk	  PAGEREF
_Toc175025737 \h  30

  HYPERLINK \l "_Toc175025738"  B.	Terrestrial Risk	  PAGEREF
_Toc175025738 \h  31

  HYPERLINK \l "_Toc175025739"  IV.	References	  PAGEREF _Toc175025739
\h  37

Background

The Environmental Fate and Effects Division (EFED) has conducted a
preliminary review of the available environmental fate and ecotoxicity
data to determine the scope of work necessary to support the
registration review process for isoxaben.  Isoxaben is a pre-emergent
herbicide for various non-bearing food crops (e.g. apples, tree nuts),
commercial turf, nursery/ornamentals, rights-of-way and other industrial
uses.  No ecological risk assessment is available to draw from, although
the environmental fate for isoxaben is summarized in the registration
standard (Fate Data Summary, 2/22/90).

The purpose of this scoping effort is to determine the extent of data
available to support an environmental fate and ecological risk
assessment for the reregistration review of isoxaben.  This document is
not an environmental fate and ecological risk assessment, although
preliminary estimates of risk, based on provisional data, are provided
to help guide the problem formulation.

Problem Formulation

The purpose of problem formulation is to provide the foundation for the
environmental fate and ecological risk assessment that will be conducted
for the pre-emergent herbicide isoxaben.

Nature of Regulatory Action

	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).  There are no current food-use
registrations.  Beginning in 2008, isoxaben is scheduled to undergo
reregistration review.  This document provides the initial problem
formulation for the ecological risk assessment in support of the
reregistration review of isoxaben.

	A Section 3 new use (first food use) has been received by the Agency.
The new use application is for the use of isoxaben on tree nuts and
grapes grown for harvest.  Approval of this use would likely expand the
total acreage of isoxaben usage for the affected crops.  The PRIA
decision date on the new use is March 2009 and therefore will be
included in the reregistration review risk assessment.

	No ecological risk assessments have been conducted previously for
isoxaben.  Most environmental fate data are summarized below from the
registration standard.  Recently submitted aerobic and anaerobic aqueous
metabolism studies were reviewed by EFED in 2006 (MRIDs 46393201 and
46393202).  The studies were submitted as 6 a)(2) data, and were
reviewed because the Agency was concerned that there may be a rotational
crop problem with soil residues.  EFED concluded that "given the limited
persistence of isoxaben in aerobic and anaerobic aquatic systems,
exposure to subsequent rotational crops is unlikely".  In addition,
several hydrolysis, aqueous photolysis, aerobic soil metabolism and
leaching/adsorption/desorption studies are currently under review
(MRIDs132123 & 132124 under accession number 250449; 143786, 153107,
164645, 40532101).

Provisional environmental effects endpoints are reported in the EFED
Pesticide Ecotoxicity Database; however, no data evaluation records
(DERs) are available to verify that these studies have been reviewed.
All ecological effects studies are currently under review.

Stressor Source and Distribution

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. 1994).  Isoxaben is not
thought to be highly mobile in adult plants, apparently limiting its
toxicity to older plants, but allowing efficacy in emerging seedlings.

Table 1.  Nature of the Chemical Stressor

39 g · mol-1

Vapor pressure	<3.9 X 10 -7

Henrys Law Constant at 20oC (dimensionless)	7.10E-06

Solubility in water 	1 to 2 ppm

Log Kow 	2.64

PKa at 25oC	9.78

Figure 1. Chemical structure of isoxaben.

	Isoxaben is moderately persistent and may be mobile (MRIDs164646 and
41106303).  There is some indication that the mobility of isoxaben
decreases with increasing soil clay content and cation exchange capacity
(CEC) (MRID 41106303).  The compound may represent a ground water
concern when applied to certain soils and/or where high water tables are
present (i.e. less than one foot below grade) and high rainfall/
irrigation occurs (MRID 40059508).

	Isoxaben does not appear to readily undergo aerobic and anaerobic
degradation in soil (MRIDs 41106302, 143786, and 164646).  Primary
routes of degradation appear to be aqueous photolysis, aerobic aqueous
metabolism and anaerobic aqueous metabolism (MRIDs 40059507, 46393201
and 46393202).

Major degradates detected during aerobic and anaerobic soil metabolism
studies and aerobic and anaerobic aqueous metabolism studies include:
N-[3-(2-hydroxybut-2-yl)-isoxazol-5-yl]-2,6-dimethoxybenzamide (201469);
N-[3-(1-hydroxyl-1-methylpropyl)-5-isoxazoyl]-2,6-dimethoxy-benzamide;
dimethoxy benzamide; methoxyphenyl pyrimidinol and AEM hexenoyl
isoxaben.  Minor degradates identified include:
N-[3-(1-acetyl-1-methylpropyl)-5-isoxazoyl]-2,6-dimethoxybenzamide;
N-[3-(1-hydroxyl-1-ethyl)-5-isoxazoyl]-2,6-dimethoxy-benzamide;
N-[3-(1-ethyl-1-methylpropyl)-5-isoxazoyl]-2-hydroxy-6-methoxyl-benzamid
e; hydroxyl methoxybenzamide; oxypropyl isoxaben, hydroxy isoxaben;
desmethyl isoxaben and methoxyphenyl pyrimidinol (MRIDs 40059507,
46393201, 46393202, 41106302, 143786, and 164646).  The major degradate
(201469) may be more mobile than the parent compound (MRID 164646).  To
date, no degradates of concern have been identified by the Health
Effects Division (HED because no food uses have been previously proposed
for registration.  For that same reason, a drinking water assessment has
not been conducted.  A drinking water assessment will be conducted in
support of the Section 3 new use on tree nuts and grapes.

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 13 registered isoxaben product
labels, most prohibit aerial application; it is not clear whether all of
the current uses prohibit aerial application (e.g. usage on conifer seed
orchards).  There appears to be consistent 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.

In a memo from BEAD dated 08/01/2007, 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 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 tree nuts and grapes would
likely increase the amount of isoxaben used on these crops.

Receptors

Aquatic and Terrestrial Effects

The receptor is the biological entity that is exposed to the stressor
(US EPA, 1998).  For isoxaben, biological entities potentially exposed
include birds, mammals, terrestrial-phase amphibians, reptiles,
freshwater fish and invertebrates, estuarine/marine fish and
invertebrates, aquatic-phase amphibians and terrestrial and aquatic
plants.

Consistent with the process described in the Overview Document (US EPA,
2004), this risk assessment relies on surrogate species toxicity data to
evaluate the potential ecological effects of isoxaben.  T  SEQ CHAPTER
\h \r 1 oxicity data generated from surrogate test species are intended
to be representative of broad taxonomic groups and 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 pertinent open literature are used to evaluate
potential direct effects of isoxaben to the aquatic and terrestrial
biological receptors.  This includes toxicity data on the technical
grade active ingredient, degradates, and when available, formulated
products.  Open literature studies available through EPA’s ECOTOX
database (  HYPERLINK "http://cfpub.epa.gov/ecotox/"
http://cfpub.epa.gov/ecotox/ ), provide EFED scientists the source for
locating single chemical toxicity data for aquatic life, terrestrial
plants, and wildlife.  The evaluation of both sources of data can also
provide insight into the indirect effects of isoxaben on biotic
communities due to loss of species that are sensitive to the chemical
and changes in structure and functional characteristics of the affected
communities.

Table 2 provides a summary of the taxonomic groups and the surrogate
species tested to help understand potential acute ecological effects of
pesticides to these non-target taxonomic groups.  In addition, the table
provides a preliminary overview of the potential acute toxicity of
isoxaben by providing the acute toxicity classifications. Based on this
preliminary overview, isoxaben is characterized as practically nontoxic
to terrestrial animals and is moderately toxic to aquatic animals on an
acute exposure basis.  No data are available to assess the toxicity of
isoxaben to terrestrial plants or aquatic vascular plants; however, the
compound is moderately toxic to the one aquatic nonvascular for which
data are reported.

Table 2.  Test Species Evaluated for Assessing Potential Ecological
Effects of Isoxaben.

Taxonomic Group	Example(s) of Surrogate Species	Acute Toxicity
Classification

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

Bobwhite quail (Colinus virginianus)	Practically non-toxic

  SEQ CHAPTER \h \r 1 Mammals	  SEQ CHAPTER \h \r 1 Laboratory rat
(Rattus norvegicus)	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 fish2		  SEQ CHAPTER \h \r 1 Bluegill
sunfish (Lepomis macrochirus)

Japanese carp (Cyprinus carpio)	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)
Moderately toxic

  SEQ CHAPTER \h \r 1 Terrestrial plants3	  SEQ CHAPTER \h \r 1 Monocots
–

Dicots –	No data

  SEQ CHAPTER \h \r 1 Aquatic plants 	Green algae 	Moderately toxic

  SEQ CHAPTER \h \r 1 1 Birds are surrogates for terrestrial-phase
amphibians and reptiles.

2 Freshwater fish are surrogates for aquatic-phase amphibians.

3 Four species of two families of monocots, of which one is corn; six
species of at least four dicot families, of which one is soybeans.

Ecosystems Potentially at Risk

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

	Aquatic ecosystems potentially at risk include water bodies adjacent
to, or down stream from, the treated field 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.

	As an herbicide, isoxaben can potentially affect plant growth, survival
and reproduction and thereby affect primary productivity in both aquatic
and terrestrial environments thereby impacting both aquatic and
terrestrial ecosystems.  The extent that aquatic and terrestrial
communities are dependent of specific sources of primary productivity
that may be impacted by isoxaben will dictate the extent to entire
ecosystems may be at risk.

Assessment Endpoints

Assessment endpoints represent the actual environmental value that is to
be protected, defined by an ecological entity (species, community, or
other entity) and its attribute or characteristics (US EPA, 1998).  For
isoxaben, the ecological entities may include the following:  birds,
mammals, freshwater fish and invertebrates, estuarine/marine fish and
invertebrates, terrestrial plants, insects, and aquatic plants and
algae.  The attributes for each of these entities may include growth,
reproduction, and survival.

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 use
patterns, potential routes of exposure, and the predicted effects on the
assessment endpoint.  The conceptual model consists of two major
components: risk hypotheses and a conceptual diagram (US EPA, 1998).

Risk Hypothesis

	Risk hypotheses are specific statements about potential adverse effects
(i.e., changes in assessment endpoints) and are tested using theory and
logic, empirical data, mathematical models, or probability models (USEPA
2004).  For this assessment, the risk is stressor-initiated, where the
stressor is the release of isoxaben to the environment.  The following
risk hypothesis is presumed for this screening level assessment:

Based on the application methods, mode of action, persistence and
mobility of isoxaben, direct deleterious effects to non-target
terrestrial and aquatic plant communities and indirect effects to both
aquatic and terrestrial species through habitat modification are likely.
 Direct acute toxic effects to animals are expected to be limited,
although chronic effects may occur.

Conceptual Diagram

	Ecological receptors that may be exposed to isoxaben include
terrestrial wildlife (i.e., mammals, birds, terrestrial-phase
amphibians, terrestrial invertebrates, reptiles, and plants) through
ingestion or, in the case of plants, direct contact.  Pathways not
considered include inhalation and root uptake.  Aquatic receptors
(freshwater and estuarine/marine fish and invertebrates, aquatic-phase
amphibians, and aquatic plants) may also be exposed as a result of
potential migration of isoxaben via spray drift and/or runoff from the
site of application to various aquatic environments.  These potential
exposure pathways form the basis for identifying potential receptors and
ecological effects associated with isoxaben use (see Figure 2).

	The assessment will not quantitatively account for potential
atmospheric transport in estimating environmental concentrations, or
potential exposure via groundwater, nor will it account for ingestion of
isoxaben residues by animals in 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 foliar (and insect) residues.
Aquatic assessments assume that all potential routes of direct exposure
are accounted for.

Figure 2.  Conceptual model of the transport and effects of isoxaben in
the environment from ground spray application.

*Dotted lines indicate that although this exposure route or pathway was
considered, it was not thought to contribute significantly to the fate
and transport of isoxaben.

Analysis Plan

Preliminary Identification of Data Gaps

	A total of thirty-six registrant-submitted studies are available for
assessing the environmental fate of isoxaben.  At this time no
hydrolysis DERs were available for review and isoxaben was presumed to
be stable to hydrolysis.  In addition, aqueous photolysis appears to be
a route of dissipation for isoxaben in the aquatic environment.
However, degradates were not completely characterized in the available
study.  Several hydrolysis and aqueous photolysis studies are currently
under review (MRIDs 132123 & 132124 under accession number 250449 and
47140003).  These studies may provide additional data that is needed to
determine the degradation pathways for isoxaben and degradates.
However, if any of the studies under review are found to be
unacceptable, data gaps could be discovered.  The only available soil
photolysis half-life study indicated that isoxaben had a half life of
198 days on clay loam soil, however the study was deemed unacceptable
because only the parent compound was analyzed for; the test substance
was not technical grade or purer; and the artificial light source was
not comparable to natural sunlight.  Therefore, this degradation pathway
cannot be properly assessed.

Isoxaben has demonstrated the ability to leach and may present a
groundwater concern.  Groundwater monitoring studies may need to be
provided in the future for EFED to determine under what conditions
isoxaben could pose a threat to groundwater.  To date, no food uses have
been assessed and a drinking water assessment has not been conducted,
therefore degradates of concern have not been identified.  Once the
first food uses are assessed the Health Effects Division (HED) may be
able to characterize degradates of concern if appropriate data is
available.  If degradates of concern are identified, a prospective
groundwater study may be required to determine if they pose a threat to
human health and the environment.

	Provisional environmental effects endpoints are available in the EFED
Pesticide Ecotoxicity Database; however, no DERs are available to verify
that these studies have been reviewed.  All ecological effects studies
are currently under review (expected completion early 2008).  If the
submitted studies are found to be acceptable, many of the ecological
effects guideline data requirements could be considered to be met.
However, if any of the studies under review are found to be
unacceptable, data gaps could be discovered.  Submitted terrestrial
plant toxicity studies have been previously classified
‘unacceptable’ in draft DERs; should final review of these studies
uphold the initial classification, no data on terrestrial plant toxicity
would be available for the risk assessment.  Additionally, no aquatic
vascular plant toxicity data are reported in the OPPIN bibliography;
only one non-guideline aquatic nonvascular plant (green algae, species
uncertain) is reported.  Therefore, effects to aquatic plant
communities, and indirect effects to higher trophic populations, would
not be able to be assessed and direct risk to plants and indirect
effects to both aquatic and terrestrial wildlife would be presumed in
the absence of data.

Measures of Effect

Each assessment endpoint requires one or more measures of ecological
effect, which are measurable changes in the attribute of an assessment
endpoint in response to a stressor (e.g. avian acute oral LD50).  Table
3 summarizes the ecotoxicity data for isoxaben available in OPP’s
Pesticide Ecotoxicity Database.  However, all of the endpoints are
provisional pending scientific review of the studies.  Although two
terrestrial plant studies have been submitted, the draft review
categorized both as ‘unacceptable’.  There are no other data
available through the Agency’s database of open literature, ECOTOX
(www.epa.gov/ecotox).

Table 3.  Summary of Unreviewed Ecotoxicological Endpoints Available for
Isoxaben.

	AI	Species	Duration	Dose	Toxicity	Level	Year	Epaident

Aquatic

Freshwater	92.4	Japanese carp	96 hr	LC50	>1.1	mg ai/L	1982	00137844

	92.4	Bluegill sunfish	96 hr	LC50	>1.1	mg ai/L	1982	00132145

	92.4	Water flea	48 hr	EC50	>1.3	mg ai/L	1982	00132144

	95.5	Water flea	21 D	NOAEC	0.69	mg ai/L	1984	00137845

	95.5	Fathead minnow	33 D	NOAEC	0.4	mg ai/L	1983	00137848

	95	Rainbow trout	28 D	NOAEC	0.42	mg ai/L	1983	00137847

Estuarine/

marine	95.5	Grass shrimp	96 hr	LC50	>1.0	mg ai/L	1987	40531303

	95.5	Sheepshead minnow	96 hr	LC50	>0.87	mg ai/L	1987	40531304

	95.5	Quahog clam	48 hr	EC50	>0.96	mg ai/L	1987	40531302

Plants	92.4	Green algae	14 D	EC50	>1.4	mg ai/L	1982	00132147

Terrestrial

	92.4	Bobwhite quail	8 D	LC50	>5000	mg ai/kg-diet	1982	00132142

	92.4	Mallard duck	8 D	LC50	>5000	mg ai/kg-diet	1982	00132143

	92.4	Bobwhite quail	14 D	LD50	>2000	mg ai/kg-bw	1982	00132141

	95.5	Mallard duck	24WKS	NOAEL	300	mg ai/kg-diet	1984	00153109

	95.5	Bobwhite quail	24WKS	NOAEL	1000	mg ai/kg-diet	1984	00153110

	Tech	Laboratory rat	14 D	LD50	>10000	mg ai/kg-bw

MJ031

	Tech	Laboratory rat

NOAEL	500	mg ai/kg-diet

MJ019

	Tech	Earthworm	14 D	LC50	>100	mg ai/kg-soil	1982	ACC250793

	95.5	Honey bee	96 hr	LD50	>101.7	µg ai/bee	1984	0015311

Incident Reports

	The Agency has received reports on five incidents in which use of
isoxaben allegedly caused damaged to tree seedlings and ornamental
plants treated directly with isoxaben.  No reports have been received of
damage to plants from movement of isoxaben off the site of treatment.
Also, the agency has received no report of adverse field effects to
animals attributed to use of isoxaben, and no report from pesticide
registrants of isoxaben contamination of ground or surface water.

	A lack of reported incidents does not necessarily mean that such
incidents have not occurred.  In addition, incident reports for
non-target plants and animals typically provide information on mortality
events only.  Reports for other adverse effects, such as reduced growth
or impaired reproduction, are rarely received.

	EPA has looked at three databases to review any unintentional exposure
to isoxaben.  A total of 16 people have reported exposures to isoxaben.
 Four involved workers, two of which required treatment at a health care
facility.  Four occurred with children aged 5 and under.  The other
eight incidents involved non-occupational adults.

The Agency is not expecting to recommend any mitigation actions based on
these incidents.

Measures of Exposure

Fate Characteristics

	Isoxaben is moderately persistent and may be mobile (MRIDs 164646 and
41106303).  There is some indication that the mobility of isoxaben
decreases with increasing soil clay content and cation exchange capacity
(CEC) (MRID 41106303).  The compound may present a ground water concern,
especially when high water tables are present (i.e. less than one foot
below grade) and high rainfall/ irrigation occurs (MRID 40059508).

	Isoxaben does not appear to readily undergo aerobic and anaerobic
degradation in soil (MRIDs 41106302, 143786, and 164646 and Microfiche
265370).  Primary routes of degradation appear to be aqueous photolysis,
aerobic aqueous metabolism and anaerobic aqueous metabolism (MRIDs
40059507, 46393201 and 46393202).  Major degradates (>10% of total
residues) detected during aerobic and anaerobic soil metabolism studies
and aerobic and anaerobic aqueous metabolism studies include:
N-[3-(2-hydroxybut-2-yl)-isoxazol-5-yl]-2,6-dimethoxybenzamide (201469);
 N-[3-(1-hydroxyl-1-methylpropyl)-5-isoxazoyl]-2,6-dimethoxy-benzamide;
dimethoxy benzamide; methoxyphenyl pyrimidinol and AEM hexenoyl
isoxaben.  Minor degradates identified include:
N-[3-(1-acetyl-1-methylpropyl)-5-isoxazoyl]-2,6-dimethoxybenzamide;
N-[3-(1-hydroxyl-1-ethyl)-5-isoxazoyl]-2,6-dimethoxy-benzamide;
N-[3-(1-ethyl-1-methylpropyl)-5-isoxazoyl]-2-hydroxy-6-methoxyl-benzamid
e; hydroxyl methoxybenzamide; oxypropyl isoxaben, hydroxy isoxaben;
desmethyl isoxaben and methoxyphenyl pyrimidinol (MRIDs 40059507,
46393201, 46393202, 41106302, 143786, and 164646).  Benzamide,
pyrazolone, an isoquinolone and benzopyrrolidone were identified as
degradates during the aqueous photolysis study.  However, these
degradates have not been fully characterized as to percentage of parent
(MRID 40059507).  The major degradate (201469) may be more mobile than
the parent compound (MRID 164646).

	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 during 28 days of exposure.  Residues
accumulated by exposure day 28 were depurated quickly; at day 14 of
depuration, isoxaben residues were approximately 1.28 ppm in edible,
nonedible, and whole fish tissues.  This study is considered
supplemental because isoxaben residues were incompletely characterized
and residues in whole fish were not determined experimentally (MRID
40059509).

Table 4.  General Chemical Properties and Environmental Fate Parameters
of Isoxaben

332.39 g · mol-1	Fate Data Summary, 2/22/90

Vapor Pressure (25°C)	<3.9 X 10 -7	Fate Data Summary, 2/22/90

Solubility (20°C)	1 to 2 ppm	Fate Data Summary, 2/22/90

Octanol-water partition coefficient (K ow)	434	Fate Data Summary,
2/22/90

Mean adsorption coefficient (K d); organic carbon partioning coefficient
(K oc)	Kd = 0.81-6.6

Koc = 162-330

	Fate Data Summary, 2/22/90

Hydrolysis half-life (pH 5, 25 °C)	Presumed stable	Data under review

Hydrolysis half-life (pH 7, 25 °C)	Presumed stable	Data under review

Hydrolysis half-life (pH 9, 25 °C)	Presumed stable	Data under review

Aqueous photolysis half-life; Total residues of concern half-life
(original data of study) % of parent curve of decline for parent – add
in % of degradate	7-15 days; degradates not completely characterized
MRID 40059507

Additional data under review

Soil photolysis half-life; Total residues of concern half-life	Not
available	Data gap

Aerobic soil metabolism half-life; Total residues of concern half-life
(soil texture)	4.3 months;n/a (clay loam soil)

5.6 months; n/a (loam soil)

10.6 months; n/a (sandy loam soil)	MRID 164646

Additional data under review

Anaerobic soil metabolism half-life; Total residues of concern half-life
(soil texture)	>120 days; n/a (loam soil)	MRIDs 41106302, 00143786 &
00164646

Aerobic aqueous metabolism half-life; Total residues of concern
half-life	13 days (linear)/13 days (non-linear)	MRID 46393202

Anaerobic aqueous metabolism half-life; Total residues of concern
half-life (soil texture)	18 days (linear)/3 days (non-linear)	MRID
46393201

Terrestrial field dissipation half-life (soil texture)	30-40 days
(spring treated sand soil – Florida and loam soil Indiana); 60-182
days (autumn treated sandy loam soil – Texas); 66-106 days (clay loam
soil, Illinois)	MRIDs  40059508, 40532102 & 40532103

Aquatic Exposure

	To assess the risk to aquatic life posed by a chemical, OPP estimates
pesticide concentrations which would be expected in the environment from
labeled uses (exposure) and compares them to concentrations known to be
toxic from laboratory tests (hazard).  To initially screen exposure of
isoxaben to aquatic life, the Tier I screening model GENEEC (GENeric
Estimated Exposure Concentration; Parker, et. al., 1995) was used.
Initial aquatic exposure estimates are presented in Table 5.

Table 5.  Preliminary Aquatic EECs (GENEEC) for Isoxaben Applied as a
Ground Spray at 1.0 lbs ai/A, three Applications 60 Days Apart (mg
ai/L).

PEAK	4 DAY	21 DAY	60 DAY	90 DAY

0.141	0.141	0.140	0.138	0.137

Input parameter values are selected from the environmental fate data
submitted by the registrant and in accordance with US EPA-OPP EFED water
model parameter selection guidelines, Guidance for Selecting Input
Parameters in Modeling the Environmental Fate and Transport of
Pesticides, Version II, February 28, 2002.  In the absence of valid
input data, conservative assumptions were made when running the GENEEC
model.  Isoxaben use was modeled at an application rate of 1.0 lb. ai/A,
three applications per year at 60 day intervals.  Conservative
assumptions likely to increase estimated environmental concentrations
(EEC) include the following:

the lowest Koc value was used and aerobic soil metabolism was assumed
stable (i.e. half life of zero).

Ground spray was assumed since aerial applications are prohibited on all
labels (except the conifer seed label).

The EFED defaults of high boom sprayer, fine spray quality, a no spray
zone of zero feet and a zero depth of incorporation were also used.

The upper limit of solubility (2 ppm) was chosen.

Aerobic aquatic metabolism, hydrolysis, and photolysis were all assumed
to be stable.

GENEEC is presumed to result in conservative EECs.  Since the resulting
RQs exceed some LOCs, a second tier of aquatic exposure modeling could
be performed to refine the aquatic EECs.  The PRZM/EXAMS (Pesticide Root
Zone Model (PRZM) (Carsel et al., 1984), and the EXposure Analysis
Modeling System (EXAMS) (Burns et al., 1991) models would be used for
scenario-specific refinement.  PRZM simulates pesticide fate and
transport as a result of leaching, direct spray drift, runoff and
erosion from an agricultural field, and EXAMS estimates environmental
fate and transport of pesticides in a surface water body for a 30-year
period.  The combined model is designed to estimate pesticide
concentrations found in water at the edge of the treated field. As such,
it provides high-end values of the pesticide concentrations that might
be found in ecologically sensitive environments following pesticide
application.  Standard scenarios simulate a 10-hectare field draining
into a 1-hectare static pond that is 2-meters deep and does not have an
outlet.  The pond serves as a surrogate for a variety of small water
bodies that can be found at the top of a watershed.  It is assumed that
runoff is equally likely to flow into the pond from all areas of the
treated field, and that the entire field is cropped and treated.  The
location of the field is specific to the crop being simulated using
site-specific information on the soils, weather, cropping, and
management factors associated with the scenario. The crop/location
scenario is intended to represent a high-end exposure site on which the
crop is normally grown.  Based on historical rainfall patterns, the
receiving water body receives multiple runoff events during the years
simulated.  Weather and agricultural practices are simulated for 30
years so that the 10-year exceedance probability at the site can be
estimated.  The simulation was generated using 30 years of
meteorological data, encompassing the years from 1961 to 1990.
Additional information on these models can be found at:     HYPERLINK
"http://www.epa.gov/oppefed1/models/water/index.htm"
http://www.epa.gov/oppefed1/models/water/index.htm .

Aquatic Exposure Monitoring

	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.  OPP is not aware of other water monitoring
data for isoxaben.

Terrestrial Exposure

Animals

EECs are typically calculated for birds and mammals emphasizing a
dietary uptake of pesticide through residues on vegetative and insect
forage items.  Avian terrestrial EECs are considered representative of
potential exposure for terrestrial-phase amphibians and reptiles as
well.  For exposure to terrestrial organisms, pesticide residues on food
items are estimated, based on the assumption that organisms are exposed
to a single pesticide residue in a given exposure scenario and obtain
100% of their diet from treated areas.  EECs are currently generated
from a spreadsheet-based screening model (TREX v.1.3.1) that calculates
the exposure via food ingestion rates of various size/forage item
categories for birds and mammals.  The terrestrial food item residue
estimates are based on the methods of Hoerger and Kenaga (1972) as
modified by Fletcher et al. (1994) and food ingestion rates are
estimated using allometric equations (USEPA, 1993).  When data on the
foliar dissipation of a chemical are absent, as in this case, EFED
assumes a 35-day foliar dissipation half-life.  Initial unadjusted
exposure estimates are presented in Table 6.

Table 6.  Unadjusted dietary-based estimated environmental
concentrations (EECs) on terrestrial animal forage items following three
applications of isoxaben with a 60-day reapplication interval, based on
TREX (version 1.3.2).

Application Rate

Food Items

Upper-bound EEC (ppm)a

Mean EEC

(ppm)a

1.0 lbs ai/A

Three applications/60 day interval

Short grass	335	119

Tall grass	154	50

Broadleaf plants/small insects	189	63

Fruits, pods, seeds, and large insects	21	10

a Predicted residues based on Hoerger and Kenaga (1972) as modified by
Fletcher et al. (1994).

Plants

Currently, terrestrial plant exposure is estimated using the TerrPlant
(v1.2.2) screening model.  TerrPlant estimates potential exposure from a
single application using default assumptions for runoff and spray drift.
 For runoff plus drift, TerrPlant incorporates two similar conceptual
models for depicting dry and semi-aquatic areas of terrestrial habitats.
 For both conceptual models, a non-target area is adjacent to the target
area.  Pesticide exposures to plants in the non-target area are
estimated to receive runoff and drift from the target area.  For a dry
area adjacent to the treatment area, runoff exposure is estimated as
sheet runoff.  In the model, sheet runoff is defined as the amount of
pesticide in water that runs off of the soil surface of a target area of
land which is equal in size to the non-target area (1:1 ratio of areas).
 For semi-aquatic areas, runoff exposure is estimated as channelized
runoff.  In the model, channelized runoff is the amount of pesticide
that runs off of a target area 10 times the size of the non-target area
(10:1 ratio of areas).  The drift component is calculated as 1% of
applied mass for ground spray and 5% for aerial application.  There is
no drift assumed for granular applications.  Estimated exposures through
runoff plus drift and drift alone are then compared to measures of
survival and growth (e.g. effects to seedling emergence and vegetative
vigor) to develop RQ values.  Initial exposure estimates are presented
in Table 7.

Table 7.  Preliminary estimated environmental concentrations (EECs) for
plant exposure following label-specified applications of isoxaben
determined using the TerrPlant model (lbs ai/A)

Rate	Application Method	Adjacent Upland Loadinga	Adjacent Wetland
Loading	Drift Only

1.0 lbs ai/A	Ground	0.02	0.11	0.01

aLoading is runoff plus drift (lbs ai/A)

	Risk Estimation

	The risk quotient (RQ) approach will be used in the isoxaben
environmental risk assessment, comparing the ratio of exposure
concentrations to effects endpoints with predetermined levels of concern
(LOCs).  Laboratory environmental fate, laboratory ecological effects,
and use data that will provide the basis for these risk quotients have
been discussed previously in the assessment.  Estimated environmental
concentrations (EECs) are divided by acute and chronic toxicity values
to calculate RQs.  Table 8 summarizes the measure of exposure and
measure of effect the will be used to calculate RQs.  If the RQs exceed
the LOCs, the Agency presumes potential for risk to the taxa.  These
LOCs (Table 9) 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 8.  Measures of Effect and Exposure for Isoxaben.

Assessment Endpoint

	Surrogate Species and Measures of Ecological Effect1	Measures of
Exposure

Birds2

Survival

	Bobwhite acute oral LD50

Bobwhite and mallard subacute dietary LC50

Maximum residues on food items

Reproduction and growth	Bobwhite and mallard chronic reproduction NOAEC
and LOAEC

	Mammals

Survival

Laboratory rat acute oral LD50

Reproduction and growth	Laboratory rat oral reproduction chronic NOAEC
and LOAEC

	Freshwater fish3

Survival	Japanese carp and bluegill sunfish acute LC50

Peak EEC4

Reproduction and growth	Fathead minnow chronic (early life-stage) NOAEC
and LOAEC

60-day average EEC4

Freshwater invertebrates

Survival

Water flea acute EC50

Peak EEC4

Reproduction and growth

Water flea chronic (life cycle) NOAEC and LOAEC

21-day average EEC4

Estuarine/marine fish

Survival

Sheepshead minnow acute LC50

Peak EEC4

Reproduction and growth

No data

60-day average EEC4

Estuarine/marine invertebrates

Survival

Quahog clam acute EC50 and Grass shrimp acute LC50

Peak EEC4

Reproduction and growth

No data

21-day average EEC4

Terrestrial plants5

Survival and growth

Monocot and dicot seedling emergence and vegetative vigor EC25, and
NOAEC values (no data)

Estimates of runoff and spray drift to non-target areas

Insects

Survival (not quantitatively assessed)

Honeybee acute contact LD50

Maximum application rate

Aquatic plants and algae

Survival and growth	Algal and vascular plant (i.e., duckweed) EC50 and
NOAEC values for growth rate and biomass measurements (limited data)

Peak EEC

1 If species listed in this table represent most commonly encountered
species from registrant-submitted studies, risk assessment guidance
indicates most sensitive species tested within taxonomic group are to be
used for baseline risk assessments.  LD50 = Lethal dose to 50% of the
test population; NOAEC = No observed adverse effect concentration; LOAEC
= Lowest observed adverse effect concentration; LC50 = Lethal
concentration to 50% of the test population; EC50/EC25 = Effect
concentration to 50%/25% of the test population.

2 Birds represent surrogates for amphibians (terrestrial phase) and
reptiles.

3 Freshwater fish may be surrogates for amphibians (aquatic phase).

4 One in 10-year return frequency.

5 Four species of two families of monocots (including corn), six species
of at least four dicot families (including soybeans.)

Table 9.  Levels of concern (LOCs) for various taxa.

Risk Presumption	RQ	LOC

Birds

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

	Chronic Risk	EEC/NOAEC	1

Wild Mammals

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

	Chronic Risk 	EEC/NOAEC	1

Aquatic Animals

	Acute Risk	EEC/LC50 or EC50	0.5

	Acute Restricted Use	EEC/LC50 or EC50	0.1

	Acute Endangered Species	EEC/LC50 or EC50	0.05

	Chronic Risk	EEC/NOAEC	1

Terrestrial and Semi-Aquatic Plants

	Acute Risk	EEC/EC25	1

	Acute Endangered Species	EEC/NOAEC or EC05	1

Aquatic Plants

	Acute Risk	EEC/EC50	1

	Acute Endangered Species	EEC/NOAEC or EC05 	1

Preliminary Aquatic Risk

	Based on preliminary results from GENEEC and the provisional
ecotoxicological endpoints, RQs do not exceed the acute risk LOCs, but
do exceed the endangered species LOCs for fish, aquatic invertebrates
and aquatic-phase amphibians (Table 10).  Chronic RQs are below the LOC,
as is the RQ for aquatic nonvascular plants.  Due to lack of data, risk
to aquatic vascular plants is presumed.

Table 10.  RQs for Aquatic Species Based on Preliminary EECs and
Provisional Ecotoxicological Endpoints.

Species

Endpoint

	EEC	RQ

Freshwater	Acute	Carp

LC50	>1.1	PPM	0.141	<0.13

Bluegill sunfish

LC50	>1.1	PPM	0.141	<0.13

Water flea

EC50	>1.3	PPM	0.141	<0.11

	Chronic	Fathead minnow

NOEC	0.4	PPM	0.138	0.35

Rainbow trout

NOEC	0.42	PPM	0.138	0.33

Water flea

NOEC	0.69	PPM	0.140	0.20

Estuarine/marine	Acute	Grass shrimp

LC50	>1	PPM	0.141	<0.14

Sheepshead minnow	LC50	>0.87	PPM	0.141	<0.14

Quahog clam

EC50	>0.96	PPM	0.141	<0.15

Plants	Acute	Aquatic vascular

EC50	No data

0.141	--

Green algae

EC50	>1.4	PPM	0.141	<0.10

*Bold indicates exceedance of LOC

Because the many of the studies do not result in definitive endpoints,
the exceedances noted above are uncertain.  Typically acute aquatic
limit tests are conducted to at least 100 ppm, but the solubility of
isoxaben may have been a limitation in the submitted studies.  While the
actual acute RQs are less than the calculated RQ presented, it is not
known how much lower the actual RQ would be.  Review of the studies may
provide insight into the degree of actual exceedance, if any, but that
is uncertain at this time.  As noted in guideline 850.1000, in cases
where solubility of a chemical limits the ability to determine toxicity
(i.e. testing limited to below 100 ppm), the use of formulated product
in toxicity tests could provide a reasonable upper-bound estimate of
possible exposure.  However, given that isoxaben is a dry flowable
formulation, the use of appropriate levels of solvent in the submitted
studies must be confirmed to assure toxic effects are above reasonable
solubility limits.

	While GENEEC is generally considered a Tier 1 model, there are
PRZM/EXAMS scenarios (such as turf) that, in some instances, could
result in higher EECs.  Given that the vast majority of isoxaben is used
in rights-of-way, turf, landscaping and other non-crop sites, specific
scenarios may need to be developed to characterize the extent to which
isoxaben may be present in aquatic ecosystems, given the potential risk
to listed aquatic resources.

Terrestrial Risk

Avian

Dietary-based and dose-based avian RQ values are calculated using the
sub-acute dietary LC50 and the acute oral LD50, respectively.  The
dose-based calculation takes into account that different-sized animals
have to consume different amounts of food and the differing nutritional
value of feed items.  The LD50 may give a better indication of inherent
toxicity than the LC50 in cases where food avoidance may be an issue in
the test animals.  The greater energy demands in wild birds could make
similar avoidance in natural settings unlikely.  The subacute dietary
LC50 for isoxaben exceeded the highest dietary test concentration (2000
ppm; practically non-toxic); therefore, a definitive dietary-based RQs
cannot be calculated.  Using the highest dose tested to calculate RQs
(Table 11), the acute risk listed species LOC would be exceeded for
birds foraging on short grass.  However, it is not known how much higher
than the highest dose tested the actually LC50 would be, and based on
the scientific review of the study, acute avian dietary risk might not
be of concern.

Table 11.  Upper-bound Kenega Subacute Avian Dietary-based Risk
Quotients

LC50	EECs and RQs

	Short Grass	Tall Grass	Broadleaf Plants/

Small Insects	Fruits/Pods/

Seeds/

Large Insects

	EEC	RQ	EEC	RQ	EEC	RQ	EEC	RQ

>2000	335	<0.18	154	<0.08	189	<0.09	21.0	<0.01

Size class not used for dietary risk quotients

A definitive dose-based LD50 for isoxaben was not defined, and the LD50
exceeded the highest test dose (5000 ppm; practically non-toxic),
definitive dose-based RQs cannot be calculated.  Using the highest dose
tested to calculate RQs (Table 12), the acute risk listed species LOC
would be exceeded for the short grass forage category.  However, it is
not known how much higher than the highest dose tested the actually LD50
would be, and based on the review of the study, acute avian dietary risk
might not be of concern.

Table 12.  Upper-bound Kenega Acute Avian Dose-based Risk Quotients

Size Class

(grams)	Adjusted

LD50	EECs and RQs

Short Grass	Tall Grass	Broadleaf Plants/

Small Insects	Fruits/Pods/

Seeds/

Large Insects

EEC	RQ	EEC	RQ	EEC	RQ	EEC	RQ

20	>3602	382	<0.11	175	<0.05	215	<0.06	24	<0.01

100	>4586	218	<0.05	100	<0.02	122	<0.03	14	<0.01

1000	>6477	98	<0.02	45	<0.01	55	<0.01	6.1	<0.01

	Based on provisional data regarding avian reproduction, the chronic LOC
is exceeded for birds foraging on short grass at the upper-bound of the
Kenega nomogram (Table 13).  There are no chronic avian exceedances at
the mean Kenega EEC, but the mean is expected to be exceeded about half
the time.  Terrestrial animal RQs are calculated using a default foliar
dissipation half life of 35 days.  If data were generated that
demonstrated, hypothetically, three-day half life was appropriate, the
maximum RQ would be 0.8.

Table 13.  Upper-bound Kenega 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	RQ	EEC	RQ	EEC	RQ	EEC	RQ

300	335	1.1	154	0.51	189	0.63	21	0.07

Size class not used for dietary risk quotients

Mammalian

With an LD50 >10,000 mg/kg-bw is classified as practically non-toxic to
mammals on an acute exposure basis.  RQs calculated for illustrative
purposes fall well below the acute risk LOC (Table 14).

Table 14.  Upper-bound Kenaga Acute Mammalian Dose-Based Risk Quotients

Size Class

(grams)	Adjusted

LD50	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	21978	320	<0.01	147	<0.01	180	<0.01	20	<0.01	4.0	<0.01

35	17783	221	<0.01	101	<0.01	124	<0.01	14	<0.01	3.0	<0.01

1000	7692	51	<0.01	23	<0.01	29	<0.01	3.2	<0.01	0.71	<0.01

Two methods (dietary-based and dose-based) are used to estimate chronic
risk to mammals and can result in considerably different RQ estimates.
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.  The dose-based RQ may give a
better indication of inherent toxicity than the dietary-based RQ in
cases where food avoidance may be an issue in the test animals.  If the
dietary-based RQ values are adjusted to account for these factors, it is
possible that these RQs would be roughly similar to the dose-based RQ
values.  Dose-based chronic RQs using the upper-bound residues exceed
the chronic risk LOC for all size classes foraging on short grass, tall
grass and broadleaf plant/small insect by factors of up to 6-fold (Table
15).  Dietary-based chronic risk quotients do not exceed the LOC using
upper-bound residue estimates for mammals (Table 16).  Using the mean
residues, dose-based RQs exceed the LOC only for small and medium size
classes foraging on short grass and small mammals foraging on broadleaf
plants/small insects.  However, the mean residues are expected to be
exceeded about half of the time.

Table 15.  Upper-bound Chronic Mammalian Dose-Based Risk Quotients

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	320	5.8	147	2.7	180	3.3	20	0.36	4.4	0.08

35	44.46	221	5.0	101	2.3	124	2.8	14	0.31	3.1	0.07

1000	19.23	51	2.7	23.5	1.2	29	1.5	3.2	0.17	0.71	0.04

Table 16.  Upper-bound Chronic Mammalian Dietary-Based Risk Quotients

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	335	0.67	154	0.31	189	0.38	21	0.04

Size class not used for dietary risk quotients

There are both broadcast spray and granular applications for isoxaben.
While not presented here, the acute RQs from granular uses (EEC/LD50 per
ft2) are similar to the broadcast acute RQs presented for both birds and
mammals.  Currently, chronic exposure from granular uses is not
typically assessed, but because of the chronic LOC exceedances,
potential chronic exposure from granular uses will need to be evaluated
in the risk assessment.

Plants

Given that isoxaben is used as an herbicide, effects on plants are to be
expected.  However, there are no data with which to evaluate the extent
of effect isoxaben might have on non-target terrestrial plants.  Given
the role of plants in any given ecosystem (e.g. primary productivity,
habitat), negative effects on plant species, populations, and community
composition could have appreciable indirect effects on higher
trophic-level organisms, including endangered species.

Preliminary Identification of Data Gaps

Until the submitted studies are fully reviewed, the extent of
environmental fate data needed to conduct an ecological risk assessment
is uncertain.  If the provisional data can be used, need for new data
may be limited.

Table 17. Evaluation of the need for additional fate data on isoxaben

Assessment endpoint with data gap	Projected status of

data gap	Basis for decision

Photodegradation in soil (161-3)	Required	A soil photolysis study is
required under 40 CFR Part 158, Data Requirements for Registration.  In
addition, no route of dissipation for isoxaben in the terrestrial
environment has been established.  Therefore, the soil photolysis study
is required to determine if this is a route of dissipation for isoxaben
in the terrestrial environment.

Prospective groundwater study (166-1)	Proposed to hold study

‘In Reserve’	Isoxaben has demonstrated the ability to leach and may
present a groundwater concern.  However, no food uses have been assessed
to date, therefore degradates of concern and potential negative effects
to human health have not been evaluated.  Therefore, a prospective
groundwater study should be held ‘In Reserve’ at this time.

Hydrolysis (161-1)	Required

(pending review of submitted studies MRIDs 132123 & 132124)	At this time
no hydrolysis DERs were available for review and isoxaben was presumed
to be stable to hydrolysis.  If the hydrolysis studies submitted for
review are found to be acceptable, the data gap may be filled.  However,
if these studies are not acceptable, the data gap may remain and present
additional uncertainty when assessing the fate of isoxaben.

Aqueous photolysis (161-2)

	Required

(pending review of submitted study MRID 47140003)	Aqueous photolysis
appears to be a route of dissipation for isoxaben in the aquatic
environment.  However, degradates were not completely characterized in
the available study.  An additional aqueous photolysis was submitted for
review and if this study is found to be acceptable, the data gap may be
filled.  However, if this study is not acceptable, the data gap may
remain and present additional uncertainty when assessing the fate of
isoxaben.

Based on the information presented in this problem formulation, a soil
photolysis study will be needed to conduct an environmental risk
assessment.  A soil photolysis study is required under 40 CFR Part 158,
Data Requirements for Registration.  In addition, no route of
dissipation for isoxaben in the terrestrial environment has been
established.  Therefore, the soil photolysis study is required to
determine if this is a route of dissipation for isoxaben in the
terrestrial environment.  At this time no hydrolysis DERs were available
for review and isoxaben was presumed to be stable to hydrolysis.  In
addition, aqueous photolysis appears to be a route of dissipation for
isoxaben in the aquatic environment.  However, degradates were not
completely characterized in the available study.  Additional hydrolysis
and aqueous photolysis studies were submitted for review and if these
studies are found to be acceptable, the data gaps may be filled.
However, if these studies are not acceptable, the data gaps may remain
and present additional uncertainty when assessing the fate of isoxaben.
Finally, isoxaben has demonstrated the ability to leach and may present
a groundwater concern.  However, no food uses have been assessed to
date, therefore degradates of concern and potential negative effects to
human health have not been evaluated.  Therefore, a prospective
groundwater study should be held ‘In Reserve’ at this time.

Table 18. Evaluation of the need for additional effects data on isoxaben

Assessment endpoint with data gap	Projected status of data gap	Basis for
decision

Toxicity to non-target terrestrial plants, crops and non-crop species
(850.4100, 850.4150, seedling emergence and vegetative vigor)	Required
Scientifically justifiable alternative conservative assumptions will be
made concerning potential risk to terrestrial plants in the absence of
terrestrial plant toxicity data for an herbicide.  These data are
considered critical for herbicides.

An action area for endangered species is dependent on toxicity to
terrestrial plants.  Also, potential mitigation measures cannot be
evaluated without valid terrestrial plant studies.

Toxicity to non-target aquatic vascular plants (850.4500)	Required
Scientifically justifiable alternative conservative assumptions will be
made concerning potential risk to aquatic vascular plants in the absence
of toxicity data for an herbicide.  Indirect effects to endangered
species through forage reduction and habitat alteration cannot be
evaluated in the absence of toxicity data

Toxicity to Aquatic Non-vascular plants

(850.4400)	Required

(pending review of submitted study MRID 00132147)	This study is
non-guideline, but may be sufficient for an ecological risk assessment
pending review.  However, four aquatic non-vascular plants should be
tested.

Avian Single Dose Oral Toxicity

(71-1)	Required

(pending review of submitted study MRID 00132141)	These data are
required to assess the potential risk the use of isoxaben may pose to
birds, reptiles and terrestrial-phase amphibians.

Avian Dietary Toxicity

(71-4)	Required

(pending review of submitted studies MRIDs 00132142 & 00132143)	These
data are required to assess the potential risk the use of isoxaben may
pose to birds, reptiles and terrestrial-phase amphibians.

Avian Reproduction

(71-4)	Required

(pending review of submitted studies MRIDs 00153109; & 00153110)	These
data are required to assess the potential risk the use of isoxaben may
pose to birds, reptiles and terrestrial-phase amphibians.

Acute Toxicity to Freshwater Fish

(72-1)	Required

(pending review of submitted studies MRIDs 00132145, 00132146 &
00137844)	These data are required to assess the potential risk the use
of isoxaben may pose to fish and aquatic-phase amphibians.

Acute Toxicity to Freshwater Invertebrates

(72-2)	Required

(pending review of submitted study MRID 00132144)	These data are
required to assess the potential risk the use of isoxaben may pose to
freshwater invertebrates.

Acute Toxicity to Estuarine/Marine Organisms

(72-3)	Required

(pending review of submitted studies MRIDs 40531302, 40531303 &
40531304)	These data are required to assess the potential risk the use
of isoxaben may pose to estuarine/marine organisms.

Fish Early Life-stage/Aquatic Invertebrate Life Cycle

(72-4 )	Required

(pending review of submitted studies MRIDs 00137845, 00137847, &
00137848)	These data are required to assess the potential risk the use
of isoxaben may pose to fish and aquatic-phase amphibians.

The full extent of ecotoxicological data needed to conduct an ecological
risk assessment will not be known until the submitted data is fully
reviewed.  If the provisional data can be used, the need for new data
may be limited.  Based on the information presented in this problem
formulation, terrestrial plant vegetative vigor and seedling emergence
studies will be needed to conduct an environmental risk assessment.
Without these studies, risk to all plants will need to be presumed, and
it will not be possible to evaluate potential risk mitigation measures
nor will it be possible to define the action area for direct and
indirect effects to Federally-listed threatened and endangered species.
Similarly, there are no data assessing the potential effect of isoxaben
to aquatic vascular plants, and therefore risk will need to be presumed,
and the same limitations on the risk assessment listed above for
terrestrial plants will apply.

References

Fletcher, J.S., J.E. Nellessen, and T.G. Pfleeger. 1994. Literature
review and evaluation of the EPA food-chain (Kenaga) nomogram, an
instrument for estimating pesticide residues on plants. Environ.
Toxicol. Chem.  13: 1383-1391.

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. Environmental Quality and Safety. 1: 9-28.

Salihu S., K. K. Hatzios and J. F. Derr. 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

Urban D.J. and N.J. Cook. 1986. Hazard Evaluation Division Standard
Evaluation Procedure Ecological Risk Assessment. EPA 540/9-85-001. U.S.
Environmental Protection Agency, Office of Pesticide Programs,
Washington, DC.

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.  2000.  Risk Characterization Handbook.  Science Policy Council,
U.S. Environmental Protection Agency, Washington, D.C.  20460.  EPA
100-B-00-002.  December 2000.

USEPA. 2002. Guidance for Selecting Input Parameters in Modeling the
Environmental Fate and Transport of Pesticides. U.S. Environmental
Protection Agency, Office of Prevention, Pesticides and Toxic
Substances, Office of Pesticide Programs, Environmental Fate and Effects
Division. Feb. 28, 2002. Online at:
http://www.epa.gov/oppefed1/models/water/input_guidance2_28_02.htm/.

USEPA.  2004.  Overview of the Ecological Risk Assessment Process in the
Office of Pesticide Programs, U.S. Environmental Protection Agency.
Endangered and Threatened Species Effects Determinations.  Office of
Prevention, Pesticides and Toxic Substances, Office of Pesticide
Programs, Washington, D.C.  January 23, 2004.

USEPA.  2005.  Generic Format and Guidance for the Level I Screening
Ecological Risk Assessments Conducted in the Environmental Fate and
Effects Division.  Office of Pesticide Programs, Washington, D.C.
January 24, 2005.

USEPA. 2006. Water Models. U.S. Environmental Protection Agency,
Pesticides: Science and Policy. Last updated May 2, 2006. Online at:
ttp://www.epa.gov/oppefed1/models/water/.

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:  	August 16, 2007

SUBJECT:	Isoxaben:  Registration Review Scoping Document for Human
Health Assessments; PC Code: 125851; DP Number: D341567; Registration
Review Case Number: 7219.

REVIEWER:	Charles Smith, Risk Assessor/Environmental Scientist

		Deborah C. Smegal, M.P.H, Toxicologist

		Donald Wilbur, Chemist

		Reregistration Branch 2

Health Effects Division (7509P)

THROUGH:	Jack Housenger, Associate Division Director

		Health Effects Division (7509P)

TO:		Jaqueline Guerry, Chemical Review Manager

		Reregistration Branch III

		Special Review and Reregistration Division (7508C)

Attached is the human health scoping document to support the
registration review of the herbicide isoxaben.

HED Preliminary Work Plan for the Registration Review of Isoxaben

(PC Code 125851)

Introduction

The Health Effects Division (HED) Isoxaben Registration Review Team has
evaluated the status of the human health assessments for the herbicide
isoxaben to determine the scope of work necessary to support
registration review.  The team looked at the hazard and exposure
databases for isoxaben to determine whether changes in science policy,
newly available data or deficiencies in the databases materially
affected the overall risk picture.  The primary sources for the status
update were HED and OPPIN databases and a search of the open literature
using Google Scholar.  The HED Risk Assessment team includes Charles
Smith, Deborah Smegal, and Donald Wilbur.

Isoxaben is a preemergent herbicide mainly used to control broadleaf
weed species.  The primary effect of isoxaben is on seedling growth;
germination is not prevented, but once germination occurs, growth is
inhibited.  It was first registered by the Environmental Protection
Agency on December 4, 1989.  Both residential and occupational exposures
can be expected to occur from the registered uses of isoxaben which
includes uses on Christmas trees, conifer trees, ornamentals (container
grown, field grown, and landscape), ornamental bulbs, non-bearing fruit
and nut trees, non-bearing vineyards, and turf (not for use on
commercially grown turf).  The Agency has also recently received a
request to register isoxaben for food uses under the Pesticide
Registration Improvement Act (PRIA).

HED does not believe that any new toxicological or exposure data are
needed for isoxaben.  The toxicological database for isoxaben is
adequate for the purpose of registration review and most likely also for
the proposed food uses in the upcoming PRIA action.  HED will need to
revisit the cancer potency estimate based on the lack of a dose-response
relationship as well as select additional endpoints for acute dietary,
incidental oral, dermal and inhalation exposures during the registration
review process.

Isoxaben currently has no established tolerances on food or animal
commodities.  Therefore isoxaben is currently considered to be a
non-food use and a dietary assessment is not required.  The proposed
food uses in the upcoming PRIA action will require dietary assessments
(acute, chronic, and cancer) and will be subject to FQPA.

Drinking water risks have not been assessed for isoxaben.  The current
turf use requires screening level groundwater and surface water
analyses.  The HED isoxaben team believes that drinking water risks
should be evaluated to ensure the turf use is acceptable at current use
rates.  The proposed food uses in the upcoming PRIA action will also
require screening level groundwater and surface water analyses.

Occupational and residential handler and postapplication assessments,
with the exception of cancer risks for children on treated turf (USEPA
1989); have not been conducted for isoxaben.  These assessments will be
required during the registration review process.

Section 1.  Chemical Identity

Section 2.  Toxicology

Isoxaben is a pre-emergent herbicide for control of broadleaf weeds.
The technical chemical consists of three isomers, which differ in the
isoxazolyl side chain.  Pesticidal uses of isoxaben do not currently
involve use on food and therefore, are not subject to the Food Quality
Protection Act (FQPA) (1996).  However, the Agency has recently received
a request to register isoxaben for food uses under the Pesticide
Registration Improvement Act (PRIA).  This new action would be subject
to FQPA.

Isoxaben has low acute toxicity via the oral and dermal routes (category
III and IV), and is slightly more toxic via the inhalation route
(category II and III).  It is not an acute eye or skin irritant and is
not a dermal sensitizer.  The major target organ for isoxaben is the
liver in rats, dogs and mice.  In rats, liver effects include increased
enzymes, and organ weight with concurrent liver hypertrophy.  In dogs,
increased liver weight and enzyme induction were noted.   In the chronic
mouse study, liver adenomas, hyperplasia, increased liver weight,
hepatocytomegaly and hepatocelluar vacuolation were observed at high
doses following chronic exposure.

The evidence from the considerable body of metabolism data indicates a
possible concern for bioaccumulation.  However, there are currently
adequate metabolism data to support evaluation of the existing uses.

In the rat developmental study, fetal toxicity manifested as increased
preimplantation loss, increased resorptions, smaller litter size and
increased numbers of runt fetuses and occurred in the presence of
maternal toxicity (decreased body weight) at the limit dose of 1000
mg/kg.  There was no significant maternal or fetal toxicity in rabbits
at the limit dose of 1000 mg/kg.  In a three generation rat reproductive
study, developmental toxicity (decreases in viable fetuses/litter,
increased hydroureter, and microphthalmia) occurred only in the presence
of maternal toxicity (decreased body weight/body weight gain, increased
liver/body weight ratios).

The toxicological database for isoxaben is adequate for the purpose of
registration review and most likely also for the proposed food uses in
the upcoming PRIA action.  A short-term inhalation study is not
available to assess occupational and residential risk.  As such an oral
guideline toxicity study and endpoint will likely be used to estimate
risk from inhalation exposure.  The toxicity endpoints shown in Table
2.1, below were selected by HED in 1987 and 1989.

In 1987, HED evaluated the existing toxicology data and selected an RfD
(Acceptable daily intake) that was verified by the Agency-wide RfD
Committee and is currently available on the Integrated Risk Information
System (IRIS).  In addition, HED classified isoxaben as a group C
(possible human carcinogen), without a quantitative risk assessment
based on a statistically significant increase in benign tumors in one
species only (mouse).  The tumors in the mouse (liver adenomas) were
present in both sexes however, tumor incidence was statistically
increased at the high dose only, the tumors were of a common type, were
predominantly benign, and there was no decrease in latency.  The
incidence was above historical controls, but a dose-response
relationship was not found.  The weight-of-evidence suggests there is
not an overt mutagenicity concern for isoxaben.   Subsequently, HED
estimated an oral cancer potency value (Q1*) and dermal absorption
factor to assess the hypothetical cancer risks for a child playing on
treated turf.

The risk assessment team has reevaluated the existing RfD and found this
value to be consistent with current science policy.  Since Agency cancer
policies have changed since the 1987 isoxaben cancer review, HED
recommends that the cancer potency estimate be re-evaluated based on the
lack of a dose-response relationship.  This re-evaluation will be
performed by the HED Cancer Assessment Review Committee (CARC) and based
on the recent EPA Guidelines for Carcinogen Risk Assessment (March
2005).  HED will also need to select additional endpoints for incidental
oral, dermal and inhalation exposures to assess the residential and
occupational uses of isoxaben.  The HED team believes that there are
reliable data to select these endpoints and determine the appropriate
uncertainty factors for the process of registration review.  In
addition, the HED team believes there are reliable toxicological data to
select an acute dietary endpoint to assess potential drinking water and
future food exposures.

Table 2.1  Summary of Toxicological Doses and Endpoints for Isoxaben
for Use in Human Risk Assessments

Exposure

Scenario	Point of Departure	Uncertainty

Factor	RfD, Level of Concern for Risk Assessment	Study and Toxicological
Effects

Acute Dietary

(females 13-49) and General population	Value not previously selected,
but database is sufficient to identify an endpoint.

Chronic Dietary

(all populations)	NOAEL = 5 mg/kg/day	UFA  = 10x

UFH = 10x	RfD  = 0.05

mg/kg/day	Combined chronic toxicity/ carcinogenicity study in rats.

LOAEL=50.7 mg/kg/day based on increased blood urea nitrogen (BUN),
decreased alkaline phosphatase and aspartate aminotransferase (AST),
decreased food efficiency and increased heart/body weight in males.

Incidental Oral

(all durations) 	Value not previously selected, but database is
sufficient to identify an endpoint.

Dermal

(all durations)	Value not previously selected.  No systemic toxicity was
found in the dermal 21-day study at the limit dose of 1055 mg/kg/day.

Inhalation

(All durations)	Value not previously selected, but database is
sufficient to identify an endpoint.

Cancer Classification	Group “C”, without quantitative risk
assessment.

Previous Screening Level Q1*= 2.3x10-3 (mg/kg/day)-1 and dermal
absorption factor of 11%.

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies). UFH = potential variation in
sensitivity among members of human population (intraspecies).  RfD =
reference dose.  MOE = margin of exposure.  LOC = level of concern.  RA
= risk assessment.

HED does not anticipate that any new toxicology data would be required
for the registration review process.

Section 3. Current Dietary Assessments

Isoxaben currently has no established tolerances on food or animal
commodities.  Therefore isoxaben is currently considered to be a
non-food use pesticide and a dietary assessment is not required.
However, the Agency has recently received a request to register isoxaben
for food uses under the PRIA.  These new food uses will require dietary
assessments (acute, chronic, and cancer) and will be subject to FQPA.

Drinking water risks have not been assessed for isoxaben.  The current
turf use requires a screening level groundwater and surface water
analysis.  The HED isoxaben team believes that drinking water risks
should be evaluated to ensure the turf use is acceptable at current use
rates.  The proposed food uses in the upcoming PRIA action will also
require screening level groundwater and surface water analysis.

Section 4.  Aggregate and Cumulative Exposure

An aggregate assessment is not required since there are currently no
food uses for isoxaben.  However, aggregate assessments (acute, chronic,
and cancer) will be necessary in the future based on the recent request
to register food uses for isoxaben.

Section 5.  Occupational and Residential Exposure

Occupational handler and postapplication assessments have not been
conducted for isoxaben.  Occupational handler assessments will be
required in registration review for ornamentals, conifers, bulbs, and
turf.  Occupational postapplication assessments will be required in
registration review for ornamentals and conifers.

Residential handler and postapplication assessments have not been
conducted for isoxaben with the exception of a 1989 cancer risk
assessment for children on treated turf (USEPA 1989).  The children turf
scenario cancer assessment will need to be updated depending on the
outcome of the cancer re-evaluation (discussed in Section 2) and to
reflect current Agency policies.   Residential handler and
postapplication assessments will be required in registration review for
ornamentals and turf.

The isoxaben registrants have previously submitted a Turf Transferable
Residue (TTR) study (MRID 45040701) and a Dislodgeable Foliar Residue
(DFR) study (MRID 45249801) in 2000.  Both of these studies will be used
by HED in the occupational and residential exposure assessments produced
for isoxaben during the registration review process.

Section 6.  Anticipated Data Needs

HED does not believe additional data are needed for registration review.

Section 7.  Tolerances

Isoxaben currently has no tolerances established under 40 CFR.

Section 8.  Overall Conclusions

HED does not believe that any new toxicological or exposure data are
needed for isoxaben.  The toxicological database for isoxaben is
adequate for the purpose of registration review and most likely also for
the proposed food uses in the upcoming PRIA action.  During the
registration review process, HED will need to revisit the cancer potency
estimate based on the lack of a dose-response relationship as well as
select additional endpoints for acute dietary, incidental oral, dermal
and inhalation exposures.

Isoxaben currently has no established tolerances on food or animal
commodities.  Therefore isoxaben is currently considered to be a
non-food use and a dietary assessment is not required.  The proposed
food uses in the upcoming PRIA action will require dietary assessments
(acute, chronic, and cancer) and will be subject to FQPA.

Drinking water risks have not been assessed for isoxaben.  The current
turf use requires a screening level groundwater and surface water
analysis.  The HED isoxaben team believes that drinking water risks
should be evaluated to ensure the turf use is acceptable at current use
rates.  The proposed food uses in the upcoming PRIA action will also
require screening level groundwater and surface water analysis.

Occupational and residential handler and postapplication assessments
have not been conducted for isoxaben.  These assessments will be
required during the registration review process.

Section 9.  Reference Memoranda

The memoranda and studies listed in Table 9.1 were considered in the
development of this document.

Table 9.1. HED Memoranda Relevant to Registration Review

Author	Barcode	Date	Title

Becky Daiss	D263674, D235658, D235659	2/05/03	Review of  “Dissipation
of Transferable Residues of Isoxaben and Oryzalin on Turf Treated with
Formulations of the Pesticides”

Michael Firestone	N/A	3/14/89	Isoxaben Exposure Estimate for Children
Playing on Treated Lawns

Margaret L. Jones	TXR 006559	12/15/87	EL-107 (Isoxaben) Toxicology
Chapter of the New Chemical Registration Standard

C.J. Nelson	R055411	5/1/87	Isoxaben, Rat and Mouse study—Qualitative
Risk Assessment of Combined Toxicity and Oncogenicity Study

Esther Rinde	TXR 0052703	10/3/87	Peer Review of Isoxaben

K. Clark Swentzel	TXR 004012	5/4/89	Isoxaben 9Gallery):  Risk Assessment
for Children Playing on Treated Lawns

K. Deerfield	037073.pdf	6/17/88	Overview of Submitted Mutagenicity
Studies on Isoxaben

V. Glossary of Terms and Abbreviations

ai		Active Ingredient

AR		Anticipated Residue

CFR		Code of Federal Regulations

cPAD		Chronic Population Adjusted Dose

CSF		Confidential Statement of Formula

CSFII		USDA Continuing Surveys for Food Intake by Individuals

DCI		Data Call-In

DEEM		Dietary Exposure Evaluation Model

DFR		Dislodgeable Foliar Residue

DNT		Developmental Neurotoxicity

DWLOC		Drinking Water Level of Comparison

EC		Emulsifiable Concentrate Formulation

EDWC		Estimated Drinking Water Concentration

EEC		Estimated Environmental Concentration

EPA			Environmental Protection Agency

EUP		End-Use Product

FDA		Food and Drug Administration

FIFRA		Federal Insecticide, Fungicide, and Rodenticide Act

FFDCA		Federal Food, Drug, and Cosmetic Act

FQPA		Food Quality Protection Act

FOB		Functional Observation Battery

GENEEC		Tier I Surface Water Computer Model

IR		Index Reservoir

LC50	Median Lethal Concentration.  A statistically derived concentration
of a substance that can be expected to cause death in 50% of test
animals.  It is usually expressed as the weight of substance per weight
or volume of water, air or feed, e.g., mg/l, mg/kg or ppm.

LD50	Median Lethal Dose.  A statistically derived single dose that can
be expected to cause death in 50% of the test animals when administered
by the route indicated (oral, dermal, inhalation).  It is expressed as a
weight of substance per unit weight of animal, e.g., mg/kg.

LOC		Level of Concern

LOAEL		Lowest Observed Adverse Effect Level

µg/g		Micrograms Per Gram

µg/L		Micrograms Per Liter

mg/kg/day		Milligram Per Kilogram Per Day

mg/L		Milligrams Per Liter

MOE		Margin of Exposure

MRID	Master Record Identification (number).  EPA's system of recording
and tracking submitted studies.

MUP		Manufacturing-Use Product

NA		Not Applicable

NAWQA		USGS National Ambient Water Quality Assessment

NPDES		National Pollutant Discharge Elimination System

NR		Not Required

NOAEL		No Observed Adverse Effect Level

OPP		EPA Office of Pesticide Programs

OPPTS		EPA Office of Prevention, Pesticides and Toxic Substances

PAD		Population Adjusted Dose

PCA		Percent Crop Area

PDP		USDA Pesticide Data Program

PHED		Pesticide Handler's Exposure Data

PHI		Preharvest Interval

ppb		Parts Per Billion

PPE		Personal Protective Equipment

ppm		Parts Per Million

PRZM/EXAMS		Tier II Surface Water Computer Model

Q1*	The Carcinogenic Potential of a Compound, Quantified by the EPA's
Cancer Risk Model

RAC		Raw Agriculture Commodity

RED		Reregistration Eligibility Decision

REI		Restricted Entry Interval

RfD		Reference Dose

RQ		Risk Quotient

SCI-GROW		Tier I Ground Water Computer Model

SAP		Science Advisory Panel

SF		Safety Factor

SLN		Special Local Need  (Registrations Under Section 24©) of FIFRA)

SOP		Standard Operating Procedure

TGAI		Technical Grade Active Ingredient

USDA		United States Department of Agriculture

UF		Uncertainty Factor

WPS		Worker Protection Standard

WQ		Water Quality

 PAGE

Docket Number: EPA-HQ-OPP-2007-1038

www.regulations.gov

	  PAGE  ii 	Isoxaben Summary Document

Table of Contents	  PAGE  iii 	Isoxaben Summary Document

Preliminary Work Plan	  PAGE  3 	Isoxaben Summary Document

Preliminary Work Plan	  PAGE  1 	Isoxaben Summary Document

Fact Sheet	  PAGE  11 	Isoxaben Summary Document

Fact Sheet	  PAGE  6 	Isoxaben Summary Document

Problem Formulation	  PAGE  32 	Isoxaben Summary Document

Problem Formulation	  PAGE  12 	Isoxaben Summary Document

Scoping Document	  PAGE  44 	Isoxaben Summary Document

Scoping Document	  PAGE  38 	Isoxaben Summary Document

Glossary	  PAGE  46 	Isoxaben Summary Document

Glossary	  PAGE  45 	Isoxaben Summary Document

Uptake/ Adsorption

Aquatic Plants

Plant Population

Reduced population growth

Individual Vertebrates and Invertebrates Reduced survival or
reproduction

Individual Plants

Reduced survival, growth, or
rep潲畤瑣潩൮圍瑥慬摮 楒慰楲湡倍慬瑮൳䄍畱瑡捩䤠
癮牥整牢瑡獥ബ敖瑲扥慲整൳䤍摮癩摩慵湁浩污൳敒
畤散畳癲癩污漠⁲敲牰摯捵楴湯഍敔牲獥牴慩൬灕慬
摮倍慬瑮൳名牥敲瑳楲污嘠牥整牢瑡獥ഺ楂摲ⱳ䴠浡慭
獬ബ敒瑰汩獥敔牲獥牴慩桐獡流桰扩慩獮഍瑁牴
扩瑵൥桃湡敧൳

hd#

hd#

摧⍤

`

a

j–

䡅

h!K

hX

h!K

hX

h!K

h!K

j

 h

✆

耀✆

耀✆

摧瘒h

耀✆

耀✆

耀✆

耀✆

耀✆

耀✆

耀✆

$

kd

µ

kd

µ

摧瘒h

摧瘒h

Ã

É

Ê

c

c



ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

㓿ۖĀ̊>㸃昀Ĵ

㓿ۖĀ̊>㸃昀Ĵ

㓿ۖĀ̊>㸃昀Ĵ

㓿ۖĀ̊>㸃昀Ĵ

㓿ۖĀ̊>㸃昀Ĵ

kds

Ff

 h7

␃؁Ĥ옍)

昀Ĵ,̀Ĥ␅؁Ĥ옍)

@

@

6

”ÿ-	~

 h>

옍)

옍)

옍)

옍)

옍)

 h_

옍)

옍)

hÝ

Receptors

Gill/Integument Uptake; Ingestion

Direct Contact/

Root Uptake

Direct Contact/

Root Uptake

Ingestion

Exposure

Route

Ground Water

Receiving Water Body/ Sediment

Riparian/

Wetland Foliage/Soil

Upland

Foliage/Soil

Terrestrial Food Items (foliage, fruit, insects, seeds)

Source/

Exposure

Media

Leaching

(Infiltration/

Percolation

Direct Application

Source/

Transport

Pathways

Isoxaben Application

Stressor

Spray

Drift