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

www.regulations.gov

 

Isoxaben Summary Document 

Registration Review Docket 

December 2007
 ii Isoxaben Summary Document 

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 iii Isoxaben Summary Document 

TABLE OF CONTENTS

 Page # 

I. Preliminary Work Plan (PWP) 1 

II. Fact Sheet 6 

III. Ecological Risk Assessment Problem Formulation 12 

IV. Human Health Effects Scoping Document 38 

V. Glossary of Terms and Abbreviations 45 
Preliminary Work Plan 1 Isoxaben Summary Document 

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: 

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. 

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 
Preliminary Work Plan 2 Isoxaben Summary Document 

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. 
Preliminary Work Plan 3 Isoxaben Summary Document 

• 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 
Preliminary Work Plan 4 Isoxaben Summary Document 

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: 

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: 

1. 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 

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

3. use history 

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

and county 

5. application timing (date of first application and application intervals) by use site – national, 

state, and county 

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

7. 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 

9. typical interval (days) 

10. state or local use restrictions 
Preliminary Work Plan 5 Isoxaben Summary Document 

11. ecological incidents (non-target plant damage and avian, fish, reptilian, amphibian and 

mammalian mortalities) not already reported to the Agency 

12. 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. 
Fact Sheet 6 Isoxaben Summary Document 

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 (howard.markt@epa.gov) 

 Jacqueline Guerry (guerry.jacqueline@epa.gov) 

• Product Managers: Joanne Miller (miller.joanne@epa.gov) Team Leader 

 Eugene Wilson (wilson.eugene@epa.gov) 

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-OPP2007-0504.) 

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." 
Fact Sheet 7 Isoxaben Summary Document 

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. 
Fact Sheet 8 Isoxaben Summary Document 

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. 
Fact Sheet 9 Isoxaben Summary Document 

• 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 

• 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. 
Fact Sheet 10 Isoxaben Summary Document 

• 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 nonoccupational 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: 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 
Fact Sheet 11 Isoxaben Summary Document 

Registration # Registration Name Company Name % Active 

Ingredient

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 
Problem Formulation 12 Isoxaben Summary Document 

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. 
Problem Formulation 13 Isoxaben Summary Document 

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

Reviewed by: 

Elizabeth Behl, Branch Chief

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
Problem Formulation 14 Isoxaben Summary Document 

Table of Contents 

I. Background............................................................................................................... 15 

II. Problem Formulation ................................................................................................ 15 

A. Nature of Regulatory Action..................................................................... 15 

B. Stressor Source and Distribution .............................................................. 16 

1. Nature of the Chemical Stressor ....................................................................... 16 

2. Overview of Pesticide Usage.............................................................................. 7 

C. Receptors................................................................................................... 18 

1. Aquatic and Terrestrial Effects ......................................................................... 18 

2. Ecosystems Potentially at Risk ......................................................................... 19 

D. Assessment Endpoints .............................................................................. 19 

E. Conceptual Model..................................................................................... 19 

1. Risk Hypothesis ................................................................................................ 20 

2. Conceptual Diagram ......................................................................................... 20 

F. Analysis Plan ............................................................................................ 21 

1. Preliminary Identification of Data Gaps........................................................... 21 

2. Measures of Effect ............................................................................................ 22 

3. Incident Reports................................................................................................ 23 

4. Measures of Exposure....................................................................................... 23 

III. Risk Estimation..................................................................................................... 28 

A. Preliminary Aquatic Risk.......................................................................... 30 

B. Terrestrial Risk.......................................................................................... 31 

IV. References............................................................................................................. 37 
Problem Formulation 15 Isoxaben Summary Document 

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). 
Problem Formulation 16 Isoxaben Summary Document 

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

Common name Isoxaben (EL-107) 

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

dimethoxy-benzamide 

Pesticide type, such as herbicide or 

insecticide, 

Herbicide 

Chemical class benzamide 

CAS number 82558-50-7 

Empirical formula C18H24N2O4

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

Vapor pressure <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. 
Problem Formulation 17 Isoxaben Summary Document 

 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)-isoxazol5-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-benzamide; 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-ofway 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 
Problem Formulation 18 Isoxaben Summary Document 

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. Toxicity 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 (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 Mallard duck (Anas platyrhynchos) 

Bobwhite quail (Colinus virginianus) Practically non-toxic 

Mammals Laboratory rat (Rattus norvegicus) Practically non-toxic 

Insects Honey bee (Apis mellifera L.) Practically non-toxic 

Freshwater fish2 Bluegill sunfish (Lepomis macrochirus) Moderately toxic 
Problem Formulation 19 Isoxaben Summary Document 

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

Japanese carp (Cyprinus carpio) Moderately toxic 

Freshwater invertebrates Water flea (Daphnia magna) Moderately toxic 

Estuarine/marine fish Sheepshead minnow (Cyprinodon 

variegatus) Moderately toxic 

Estuarine/marine 

invertebrates Grass shrimp (Palaemonetes pugio) Moderately toxic 

Terrestrial plants3 Monocots – 

Dicots – No data 

Aquatic plants Green algae Moderately toxic 

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 
Problem Formulation 20 Isoxaben Summary Document 

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. 
Problem Formulation 21 Isoxaben Summary Document 

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 

Stressor Isoxaben Application

Source/ 

Transport 

Pathways 

Direct 

Application 

Leaching 

(Infiltration/ 

Percolation

Source/ 

Exposure 

Media 

Terrestrial Food 

Items (foliage, 

fruit, insects, 

seeds) 

Upland 

Foliage/Soil 

Riparian/ 

Wetland 

Foliage/Soil 

Receiving 

Water Body/ 

Sediment 

Ground Water 

Exposure 

Route Ingestion 

Direct Contact/ 

Root Uptake 

Direct Contact/ 

Root Uptake Gill/Integument 

Uptake; 

Ingestion 

Receptors 

Attribute 

Changes 

Terrestrial Vertebrates: 

Birds, Mammals, 

Reptiles, Terrestrial 

Phase Amphibians 

Terrestrial 

Upland 

Plants 

Individual Animals

Reduced survival or 

reproduction 

Aquatic 

Invertebrates, 

Vertebrates 

Wetland/ 

Riparian 

Plants 

Individual Plants

Reduced survival, 

growth, or reproduction 

Individual 

Vertebrates and 

Invertebrates

Reduced survival 

or reproduction 

Plant Population

Reduced 

population 

growth 

Aquatic 

Plants 

Uptake/ 

Adsorption 

Spray 

Drift 
Problem Formulation 22 Isoxaben Summary Document 

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

marine 95.5 Sheepshead 96 hr LC50 >0.87 mg ai/L 1987 40531304 
Problem Formulation 23 Isoxaben Summary Document 

AI Species Duration Dose Toxicity Level Year Epaident 

minnow 

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 
Problem Formulation 24 Isoxaben Summary Document 

(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-benzamide; 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 

Chemical Fate / Parameter Value Source 

Chemical Name N- [3-(methylpent-3-

yl)isoxazol -5-yl]-2,6-

dimethoxy-benzamide 

Fate Data Summary, 2/22/90 

Molecular Mass 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; 4.3 months;n/a (clay loam soil) MRID 164646 
Problem Formulation 25 Isoxaben Summary Document 

Chemical Fate / Parameter Value Source 

Total residues of concern half-life 

(soil texture) 

5.6 months; n/a (loam soil) 

10.6 months; n/a (sandy loam 

soil) 

Additional data under review 

Anaerobic soil metabolism halflife; 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 (nonlinear) MRID 46393202 

Anaerobic aqueous metabolism 

half-life; Total residues of 

concern half-life (soil texture) 

18 days (linear)/3 days (nonlinear) MRID 46393201 

Terrestrial field dissipation halflife (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). 
Problem Formulation 26 Isoxaben Summary Document 

• 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: 

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 
Problem Formulation 27 Isoxaben Summary Document 

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

Short grass 335 119 

Tall grass 154 50 

Broadleaf plants/small insects 189 63 

1.0 lbs ai/A 

Three applications/60 day 

interval 

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 semiaquatic 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 

a

Loading is runoff plus drift (lbs ai/A) 
Problem Formulation 28 Isoxaben Summary Document 

 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 

Survival 

Bobwhite acute oral LD50

Bobwhite and mallard subacute 

dietary LC50

Birds2

Reproduction and growth 

Bobwhite and mallard chronic 

reproduction NOAEC and LOAEC 

Survival Laboratory rat acute oral LD50

Mammals 

Reproduction and growth 

Laboratory rat oral reproduction 

chronic NOAEC and LOAEC 

Maximum residues on 

food items 

Survival 

Japanese carp and bluegill sunfish 

acute LC50 Peak EEC4

Freshwater fish3

Reproduction and growth 

Fathead minnow chronic (early 

life-stage) NOAEC and LOAEC 60-day average EEC4

Survival Water flea acute EC50 Peak EEC4

Freshwater 

invertebrates 

Reproduction and growth Water flea chronic (life cycle) 

NOAEC and LOAEC 

21-day average EEC4

Survival Sheepshead minnow acute LC50 Peak EEC4

Estuarine/marine 

fish 

Reproduction and growth No data 60-day average EEC4

Survival Quahog clam acute EC50 and Grass 

shrimp acute LC50

Peak EEC4

Estuarine/marine 

invertebrates 

Reproduction and growth No data 21-day average EEC4
Problem Formulation 29 Isoxaben Summary Document 

Assessment Endpoint Surrogate Species and Measures 

of Ecological Effect1

Measures of Exposure 

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 
Problem Formulation 30 Isoxaben Summary Document 

Risk Presumption RQ LOC

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 
Problem Formulation 31 Isoxaben Summary Document 

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

EECs and RQs 

Short Grass Tall Grass 

Broadleaf 

Plants/ 

Small Insects 

Fruits/Pods/ 

Seeds/ 

Large Insects 

LC50 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. 
Problem Formulation 32 Isoxaben Summary Document 

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

EECs and RQs 

Short Grass Tall Grass 

Broadleaf 

Plants/ 

Small Insects 

Fruits/Pods/ 

Seeds/ 

Large Insects 

Size 

Class 

(grams) 

Adjusted 

LD50 

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

EECs and RQs 

Short Grass Tall Grass 

Broadleaf 

Plants/ 

Small Insects 

Fruits/Pods/ 

Seeds/ 

Large 

Insects NOAEC 

(ppm) 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

EECs and RQs 

Short Grass Tall Grass 

Broadleaf 

Plants/ 

Small Insects 

Fruits/Pods/ 

Seeds/ 

Large Insects 

Granivore 

Size Class 

(grams) 

Adjusted 

LD50 

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 
Problem Formulation 33 Isoxaben Summary Document 

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

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

EECs and RQs 

Short Grass Tall Grass 

Broadleaf 

Plants/ 

Small Insects 

Fruits/Pods/ 

Seeds/ 

Large 

Insects 

NOAEC 

(ppm) 

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 

EECs and RQs 

Short Grass Tall Grass 

Broadleaf 

Plants/ 

Small Insects 

Fruits/Pods/ 

Seeds/ 

Large 

Insects 

Granivore Size Class 

(grams) 

Adjusted 

NOAEL 

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 
Problem Formulation 34 Isoxaben Summary Document 

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 
Problem Formulation 35 Isoxaben Summary Document 

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 Nonvascular 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. 
Problem Formulation 36 Isoxaben Summary Document 

Assessment endpoint with 

data gap

Projected status of 

data gap 

Basis for decision

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. 
Problem Formulation 37 Isoxaben Summary Document 

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/. 

Willis, Guye H., and Leslie.L. McDowell. 1987. Pesticide Persistence on Foliage. in Reviews of 

Environmental Contamination and Toxicology. 100:23-73.
Scoping Document 38 Isoxaben Summary Document 

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.
Scoping Document 39 Isoxaben Summary Document 

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. 
Scoping Document 40 Isoxaben Summary Document 

Section 1. Chemical Identity 

Table 1.1 Chemical Identity 

Common Name Isoxaben 

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

CAS name N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2,6-dimethoxybenzamide 

PC Code 125851 

CAS registry number 82558-50-7 

Registration Review 

Case No. 

7219 

Chemical Structure 

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 
Scoping Document 41 Isoxaben Summary Document 

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. 
Scoping Document 42 Isoxaben Summary Document 

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 
Scoping Document 43 Isoxaben Summary Document 

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 doseresponse 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. 
Scoping Document 44 Isoxaben Summary Document 

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 
Glossary 45 Isoxaben Summary Document 

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 
Glossary 46 Isoxaben Summary Document 

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