2

Table of Contents

Contents

I. INTRODUCTION .................................................................................................................. 3

A. Summary of Isoxaben Registration Review......................................................................3

B. Public Comments ..............................................................................................................4

II. USE AND USAGE.............................................................................................................. 6

III. SCIENTIFIC ASSESSMENTS ........................................................................................... 6

A. Human Health Risk Assessment.............................................................................................6

1. Risk Conclusions.......................................................................................................... 6

2. Human Incidents........................................................................................................... 7

3. Tolerances..................................................................................................................... 7

B. Ecological Risk Assessment..................................................................................................7

1. Risk Conclusions.......................................................................................................... 8

2. Ecological Incidents ..................................................................................................... 9

3. Characterization of Ecological Risk........................................................................... 10

C. Benefits.................................................................................................................................11

D. Endangered Species Assessment ..........................................................................................12

E. Endocrine Disruptor Screening Program...............................................................................13

IV. PROPOSED INTERIM REGISTRATION REVIEW DECISION ................................... 14

A. Risk Mitigation and Regulatory Rationale......................................................................14

1. Environmental Effects................................................................................................ 14

2. Herbicide Resistance .................................................................................................. 14

B. Tolerance Amendments...................................................................................................15

C. Proposed Interim Registration Review Decision ............................................................16

V. NEXT STEPS AND TIMELINE.......................................................................................... 16

A. Interim Registration Review Decision ............................................................................16

B. Implementation of Mitigation Measures.........................................................................16

Appendix A: Isoxaben Label Table ............................................................................................. 17
3

I. INTRODUCTION

This document is the Environmental Protection Agency’s (EPA or the Agency) Proposed Interim 

Registration Review Decision for Isoxaben (case 7219, PC code 125851) and is being issued 

pursuant to 40 CFR sections 155.56 and 155.58. A registration review decision is the Agency's 

determination whether a pesticide meets, or does not meet, the standard for registration in the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The Agency may issue, when it 

determines it to be appropriate, an Interim Registration Review Decision before completing a 

registration review. Among other things, the Interim Registration Review Decision may: 1)

require new risk mitigation measures; 2) impose interim risk mitigation measures; 3) identify 

additional data or other information required to complete the review; and 4) include schedules 

for submitting the required data, conducting the new risk assessment, and completing the 

registration review. For further information on isoxaben, additional documents can be found in 

EPA’s public docket (EPA-HQ-OPP-2007-1038) at www.regulations.gov. 

FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandated the 

continuous review of existing pesticides. All pesticides distributed or sold in the United States 

generally must be registered by the EPA based on scientific data showing that they will not cause 

unreasonable risks to human health or to the environment when used as directed on product 

labeling. The registration review program is intended to make sure that, as the ability to assess 

and reduce 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 registration review 

program, the Agency periodically re-evaluates pesticides to make sure that as these changes 

occur, products in the marketplace can continue to be used safely. Information on this program is 

provided as www.epa.gov/oppsrrd1/registration_review/.

In 2006, the Agency implemented the registration review program pursuant to FIFRA section 

3(g) and will review each registered pesticide every 15 years to determine whether it continues to 

meet the FIFRA standard for registration.

Isoxaben is a broad spectrum pre-emergent herbicide used to control broadleaf weeds, grasses, 

and vines. The first product containing isoxaben was registered by EPA in 1989; therefore,

isoxaben was not subject to EPA’s reregistration of older pesticides. Isoxaben is used around 

non-bearing food crops, ornamental trees, and shrubs in agriculture nurseries, rights-of-way, and 

urban areas. The first food uses of isoxaben on bearing nut trees and grape vineyards were 

registered in November 2010, and four pesticide tolerances were established for residues of 

isoxaben in or on almond hulls; grape; nut, tree, group 14; and pistachio.

A. Summary of Isoxaben Registration Review 

Pursuant to 40 CFR section 155.50, EPA formally initiated registration review for isoxaben (case 

7219) in 2009. The following list highlights significant events that have occurred during the 

registration review of isoxaben. Documentation of these events for isoxaben can be found in 

EPA’s public docket, EPA-HQ-OPP-2007-1038, accessed at www.regulations.gov:
4

 December 19, 2007 – Publication of Isoxaben Preliminary Work Plan (PWP) for a 60-

day public comment period. The Preliminary Work Plan (PWP) was accompanied by the 

scoping document and problem formulation.

 June 13, 2008 – Final Work Plan (FWP) for Isoxaben was issued. Public comments were 

received from two sources during the 60-day comment period for the isoxaben PWP;

however, these comments did not change the risk assessment or data needs identified in 

the PWP. Therefore, the FWP did not modify the PWP.

 February 18, 2010 – Generic Data Call-In (GDCI) for isoxaben was issued. 

 April 7, 2011 – Second GDCI issued for environmental fate and effects data needs 

identified during EPA’s review of a petition for the first isoxaben food use. 

 June 17, 2011 – Amended Final Work Plan for Isoxaben was issued to include additional 

environmental fate and effects data requirements and a revised registration review 

schedule for isoxaben. The registration review timeline for isoxaben was extended two

years to allow for generation of additional data.

 September 24, 2014 – EPA published the preliminary risk assessments for isoxaben for a 

60-day public comment period: Preliminary Ecological Risk Assessment for the 

Registration Review of Isoxaben and Isoxaben – Preliminary Human Health Risk 

Assessment for Registration Review. EPA received comments from the Center for 

Biological Diversity (CBD) and Dow AgroSciences (Dow), one of two isoxaben 

technical registrants. 

 June 2015 – The Agency is now publishing the Isoxaben Proposed Interim Registration 

Review Decision in the registration review docket (EPA-HQ-OPP-2007-1038) for a 60-

day public comment period. In addition to this document, the Agency is also publishing 

the following supporting documents:

o Response to Comments on the Isoxaben Registration Review Preliminary Risk 

Assessment, February 3, 2015;

o Non-Agricultural Use and Usage Report for the Herbicide Isoxaben in Support of 

Risk Mitigation & Preliminary Interim Decision, May 21, 2015; and

o Isoxaben Qualitative Benefits Assessment. June 18, 2015.

B. Public Comments

EPA received two public comments during the 60-day comment period on the Isoxaben

Preliminary Risk Assessments, which opened on September 24, 2014 and closed on November 

24, 2014. Comments were submitted by Dow, one of the isoxaben technical registrants, and by 

CBD, an environmental and public interest group. Comments from Dow focused on various 

technical aspects of the preliminary environmental and human health risk assessments, but did 
5

not change the risk assessment conclusions. EPA’s response to Dow’s comments may be found 

in the February 3, 2015, Response to Comments on the Isoxaben Registration Review 

Preliminary Risk Assessment. This section does not capture every comment made about the 

preliminary risk assessments nor all of the Agency’s responses. Summarized below are public 

comments that are of a broader regulatory nature. Public comments and EPA responses in their 

entirety are located in the docket, EPA-HQ-OPP-2007-1038. 

COMMENTS RECEIVED FROM CBD (EPA-HQ-2007-1038-0028)

Comment: The CBD comments focus on the EPA’s duty to consult with the U.S. Fish and 

Wildlife Service and the National Marine Fisheries Service (the Services) on the registration 

review of isoxaben in accordance with the Endangered Species Act (ESA). The CBD comments 

mention various aspects of the risk assessment process, including use of the best available data 

to develop threatened and endangered (listed) species risk assessments, and evaluation of effects 

on listed species and their designated critical habitat. CBD also expresses concern regarding 

the rigor of the Agency’s preliminary determinations regarding the effects of isoxaben on listed 

species and their designated critical habitat for the isoxaben registration review. 

Response: EPA has reviewed the comments from CBD and plans to address many of the 

concerns raised by CBD as part of the implementation plan for assessing the risks of pesticides to 

listed species based on the recommendations of the April 2013 National Academy of Sciences 

(NAS) report. EPA will address concerns specific to isoxaben in connection with the 

development of its final registration review decision for this pesticide. See Section IIID of this 

document for more information.

COMMENTS RECEIVED FROM DOW (EPA-HQ-2007-1038-0029)

Comments: Dow’s comments focus on the inclusion of metabolites/environmental degradates in 

the aquatic risk assessment and the use of data on isoxaben and its degradates in the 

environmental risk assessment. Dow requested that EPA consider data for two isoxaben 

metabolites/degradates in the risk assessment because these data show the degradates to be less 

toxic than the parent compound. Dow also offered to submit additional data on the isoxaben 

degradates in Lemna (duckweed). Last, Dow provided technical corrections to a few study 

citations in the risk assessment. 

Response: EPA considered isoxaben metabolites/degradates in the risk assessment through the 

use of a total toxic residues approach. Although the additional Lemna data would help refine the 

estimated environmental concentrations (EECs) for isoxaben, risk quotients (RQs) calculated 

using the EECs for isoxaben parent alone exceeded the level of concern (LOC). Therefore, EPA 

does not believe that inclusion of additional data for degradates in Lemna will change the overall 

isoxaben risk conclusions for plants. The Agency is not requesting submission of the Lemna data 

at this time. Last, EPA acknowledged errors in a few study citations. See the February 3, 2015 

memo, Response to Comments on the Isoxaben Registration Review Preliminary Risk 

Assessment, for details.
6

II. USE AND USAGE

Isoxaben is a pre-emergent benzamide herbicide registered for use to control broadleaf weeds. It 

is classified by the Weed Science Society of America (WSSA) as a Group 21 herbicide that 

inhibits cell wall biosynthesis. Isoxaben is registered for the following non-agricultural uses: 

turfgrass, ornamentals (landscape, container and field), groundcovers/perennials, conifer 

plantations/hardwood nurseries, non-bearing fruit and nut trees, non-bearing vineyards, and other 

non-cropland. It is also registered for agricultural use on bearing fruit and nut trees and 

vineyards. Much of the orchard and vineyard use is in California. The majority of uses have a 

maximum application rate of 1.0 lb ai/A/application, three applications per year, with a 60-day 

re-application interval. Isoxaben products are generally registered for both non-residential and 

residential uses. In terms of percent crop treated, greatest use was on grapes (2.5-5% crop 

treated), followed by pistachios (≤2.5%)1. Aerial applications of isoxaben are not permitted. 

For additional details on isoxaben use and usage see the January 28, 2014 Isoxaben Screening 

Level Usage Analysis, and the May 21, 2015 Non-Agricultural Use and Usage Report for the 

Herbicide Isoxaben (PC Code #125851) in Support of Risk Mitigation & Preliminary Interim

Decision.

 

III. SCIENTIFIC ASSESSMENTS

A. Human Health Risk Assessment

A summary of the Agency’s human health risk assessment is presented below. The Agency used 

the most updated Agency science policies and risk assessment methodologies to prepare a 

quantitative risk assessment in support of the isoxaben registration review. For a detailed 

discussion of the human health assessment for isoxaben, see Isoxaben – Preliminary Human 

Health Risk Assessment for Registration Review, dated September 11, 2014, available in the 

public docket EPA-HQ-OPP-2007-1038, at: http://www.regulations.gov/.

1. Risk Conclusions

EPA has no human health risks exceeding the Agency’s level of concern for isoxaben. There are 

no dietary (food and drinking water), residential handler, residential post-application, aggregate

(combined food, drinking water, residential/bystander), or occupational risks exceeding the 

Agency’s level of concern for all registered uses of isoxaben. No dermal endpoint was identified, 

therefore exposure assessments were not required for this exposure scenario. 

In addition, isoxaben does not appear to share a common mechanism of toxicity with other 

substances and does not appear to produce any toxic metabolite or degradates also produced by 

other substances. Therefore, EPA has not made a common mechanism of toxicity finding for 

isoxaben and any other substance. For more information on EPA’s efforts to determine which 

 

1 2011-2013 usage data. 
7

pesticides share a common mechanism of toxicity and to evaluate cumulative effects, see 

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

2. Human Incidents

EPA consulted the Office of Pesticide Programs Incident Data System (IDS), the National

Institute of Occupational Safety and Health Sentinel Event Notification System for Occupational 

Risks (SENSOR/NIOSH) database, and the National Poison Center System (NPCS) database for 

potential human poisonings related to isoxaben. IDS reported one case related to exposure to 

isoxaben. From 1998 to 2003, there were no cases of human poisoning reported for isoxaben in 

the SENSOR/NIOSH database. From 1993 through 2005 there were sixteen exposures to 

isoxaben in the NPCS. At this time, there is no evidence suggesting a plausible association 

between exposure to isoxaben and a moderate or severe health outcome. Therefore, the Agency 

believes that no further investigation of human incidents is warranted at this time. However, if 

additional information comes in, the Agency will further examine. 

3. Tolerances

Although EPA has determined that there are no adverse human health effects from use of 

isoxaben, the Agency will pursue changes to the tolerance for isoxaben to update the crop group 

tolerances for tree nuts. Specific changes are described in the September 11, 2014 document,

Isoxaben: Preliminary Human Health Risk Assessment for Registration Review, and in Section 

IV, B. of this document. The Agency is not aware of any international harmonization issue 

related to the existing isoxaben tolerances.

B. Ecological Risk Assessment 

A summary of the Agency’s ecological risk assessment is presented below. The Agency used 

the most up-to-date Agency science policies and risk assessment methodologies to prepare a 

quantitative ecological risk assessment in support of the registration review of isoxaben. For a 

detailed discussion of the ecological assessment for isoxaben, see the following documents, 

available in the public docket EPA-HQ-OPP-2007-1038, at: http://www.regulations.gov/

 Preliminary Ecological Fate and Ecological Risk Assessment in Support of the 

Registration Review of Isoxaben, September 3, 2014, and

 Response to Comments on the Isoxaben Registration Review Preliminary Risk 

Assessment, February 3, 2015.

EPA is currently working with its federal partners and other stakeholders to implement an 

interim approach for assessing potential risk to listed species and their designated critical 

habitats. Once the scientific methods necessary to complete risk assessments for listed species 

and their designated critical habitats are finalized, the Agency will complete its endangered 

species assessment for isoxaben. As such, potential risks to listed species will not be discussed 

further in this document. EPA’s risk concerns for nonlisted, nontarget species only are described 

further below. 
8

1. Risk Conclusions

The Agency completed its preliminary ecological risk assessment for isoxaben in September 

2014. This assessment showed that isoxaben is not expected to cause adverse effects to 

freshwater or estuarine/marine organisms. Acute and chronic risk quotients (RQs) for fish, 

aquatic invertebrates, and aquatic nonvascular plants (algae) are below EPA’s level of concern.2

In addition, acute and chronic risk estimates for birds, reptiles, and amphibians are below EPA’s 

level of concern. Therefore, EPA does not have acute or chronic risk concerns for these taxa. 

The Agency does not anticipate acute risks to mammals, but some chronic RQs for mammals 

exceed the level of concern. These RQs are ≤3.84. 

The preliminary ecological risk assessment showed potential risks of concern to terrestrial and 

aquatic vascular plants. RQs for terrestrial plants range from 1-12; RQs for aquatic plants range 

from 1-9. EPA also has potential chronic risk concerns to non-listed mammals (RQs range from 

1-4). The risk concerns for nontarget species will be described further below. 

When initially scoping the registration review for isoxaben, EPA did not identify the need for 

any additional studies to evaluate potential effects on pollinators. However, since the issuance of 

the June 2014 Guidance for Assessing Pesticide Risks to Bees3, EPA has begun to require these 

data where applicable. EPA is currently determining whether additional pollinator data are 

needed for active ingredients in registration review whose dockets opened prior to June 2014. 

For those active ingredients where EPA determines that additional pollinator exposure and 

effects data are necessary to help make a final registration review decision, EPA intends to issue 

a DCI to obtain these data. In the near future, EPA will provide further information and 

guidance on this effort. For isoxaben, the pollinator studies that could be required are included in 

Table 1 below. The Agency will require data it believes are needed to help inform the pollinator 

risk assessment.

Table 1. Potential Pollinator Data Requirements

Guideline # Study

850.3020*† Acute contact toxicity study with adult honey bees

850.3030*† Honey bee toxicity of residues on foliage

850.3040** Field testing for pollinators

Non-Guideline*†(OECD 213) Honey bee adult acute oral toxicity

Non-Guideline* (OECD 237) Honey bee larvae acute oral toxicity

Non-Guideline* Honey bee adult chronic oral toxicity

Non-Guideline* Honey bee larvae chronic oral toxicity

Non-Guideline** Residues in pollen and nectar/field residue analysis

Non-Guideline** (OECD 75) Semi-field testing for pollinators (tunnel or colony feeding studies)

*Tier 1 Laboratory-based studies. **Tier 2 and 3 (Semi-field and full field colony-level studies) The need for a 

higher tier test for pollinators will be determined based upon lower-tiered tests and/or other lines of data and the 

need for a refined pollinator risk assessment. † Acceptable data have already been submitted for isoxaben or the 

study is waived based on available data. 

 

2 For non-listed species, the Level of Concern (LOC) is 1; RQs > 1 exceed the LOC. 

3 http://www2.epa.gov/sites/production/files/2014-6/documents/pollinator_risk_assessment_guidance_06_19_14.pdf
9

Terrestrial and Aquatic Vascular Plants. In the preliminary risk assessment for isoxaben, the 

Agency used the TerrPlant model to calculate RQs for nontarget terrestrial and semiaquatic

plants exposed to isoxaben from spray drift alone and for spray drift and runoff combined, in 

both dry upland and semi-aquatic wetland habitats. The preliminary risk assessment showed 

potential risk concerns for nontarget terrestrial plants (RQs ≤12) and for nontarget aquatic 

vascular plants (RQs ≤8.2). The RQs for terrestrial plants were based on isoxaben parent only;

however, the RQs for aquatic plants were based on estimated environmental concentrations 

(EECs) for isoxaben and its degradates4(total toxic residues, TTR) using the conservative 

assumption that the degradates are as toxic as isoxaben, the parent compound. RQs calculated 

using the EEC for isoxaben alone also exceeded the LOC (RQs ≤3.2). 

EPA examined the effect of spray drift to nontarget plants using the AgDrift model. Ground 

application at the maximum single application rate, 1.0 lbs ai/A, was modeled for all of the 

species tested in the seedling emergence and vegetative vigor studies. Lettuce was the most 

sensitive species tested. An effects distance is the estimated distance (feet) from the edge of the 

treated field where an herbicide has the potential to adversely effect nontarget plants due to spray 

drift. The effects distance for seedling emergence for lettuce, the most sensitive species, was 249 

feet from the edge of the field. The effects distance for vegetative vigor for ryegrass, the most 

sensitive plant species, was 174 feet from the edge of field. 

Mammals. In the preliminary risk assessment for isoxaben, the Agency estimated potential 

chronic risks to mammals. Because the available acute toxicity data for isoxaben showed no 

mortality, and no sublethal effects were observed in any of the mammalian studies at the highest 

levels tested, acute RQs were not calculated. Only nondefinitive acute and subacute toxicity 

endpoints were available for mammals; therefore, acute RQs were not calculated. EPA does not 

anticipate acute risks of concern for mammals. 

EPA estimated chronic RQs for isoxaben using both a dietary and dose basis. Chronic RQs did 

not exceed the LOC for mammals when exposure was calculated on a dietary basis for mammals. 

However, there were limited RQ exceedances on a dose basis for all registered uses; dose-based 

RQs ranged from <1 to 3.84. The Agency used an endpoint of reduced parental body weight 

from a rat reproductive toxicity study to evaluate chronic risk to mammals. The study No 

Observed Adverse Effect Level (NOAEL) was 40 mg/kg body weight; the Lowest Observed 

Adverse Effect Level (LOAEL) was 200 mg/kg body weight. Chronic mammalian RQs were 

calculated using the NOAEL of 40 mg/kg, high end residue values from the Kenega nomogram, 

and the maximum label application rate and number of applications per year for isoxaben. 

2. Ecological Incidents

Between 1994 and 2010, EPA received reports of six incidents involving plants associated with 

herbicide products containing isoxaben. No incident reports have been received since 2010. 

Most of these incidents were the result of legal registered use of herbicides containing isoxaben, 

but there was one incident of misuse. When the number of affected plants was reported, between 

35,000 and 676,000 individual nursery or ornamental plants were affected, including woody 

 

4 The isoxaben degradates identified in an aqueous photolysis study were considered in the preliminary risk 

assessment. 
10

plants. EPA has not received any incident reports for isoxaben since 2010, but this lack of 

reporting does not necessarily indicate a lack of incidents. For a detailed discussion of the 

ecological incidents for isoxaben, see Preliminary Ecological Fate and Ecological Risk 

Assessment in Support of the Registration Review of Isoxaben, dated September 3, 2014.

3. Characterization of Ecological Risk

The preliminary risk assessment for isoxaben identified some RQs that exceeded EPA’s level of 

concern (LOC) for nontarget species. Although the Agency uses the LOC as an indicator of 

potential adverse effects to nontarget organisms, LOC exceedances are only one line of evidence 

used by EPA to describe the risks posed by a pesticide to nontarget organisms. This risk 

characterization section describes other lines of evidence for isoxaben, puts the LOC 

exceedances into a broader context, and provides additional perspective on the exceedences. 

Aquatic Vascular Plants. The preliminary risk assessment for isoxaben identified potential risk 

concerns for aquatic vascular plants from potential runoff; RQs were ≤8.2 for TTR (isoxaben 

parent and degradates) and ≤3.2 for isoxaben parent only. The isoxaben degradates considered 

in the risk assessment were based on aquatic photolysis data. Thus, the TTR RQs might be more 

relevant for shallow or clear water bodies where photolysis of isoxaben is more likely to occur. 

Furthermore, by using the TTR approach, EPA assumed that the isoxaben degradates had 

equivalent toxicity to the parent. Therefore, the TTR RQs might overestimate the risk to aquatic 

vascular plants. 

Terrestrial Plants. The preliminary risk assessment for isoxaben indicated potential risk to 

nontarget terrestrial plants; RQs for plants were ≤11.8 (ground spray application, 1 lb ai/A, 

single application). Although runoff is a major factor in nontarget terrestrial plant exceedances, 

it is difficult to estimate how far from the application site adverse effects may occur as a result of 

runoff. However, the Agency was able to estimate spray drift effects distances for isoxaben to be 

249 feet from the edge of the field for seedling emergence (lettuce) and 174 feet from the edge of 

field for vegetative vigor (ryegrass). The effects distance is the off-field area of potential adverse 

effects to nontarget plants. Beyond this distance, there would be low potential for adverse effects 

to nontarget plants. These effects distance estimates were derived using from AgDrift model 

default values, including a 50 inch release height (high boom for ground application) and an 

ASABE5 droplet size spectrum of “very fine to fine.” These model defaults were used because 

not all of the current sulfentrazone product labels specify droplet size distributions, boom 

heights, or other drift reduction measures that would reduce the effects distance for isoxaben. For 

example, using a low boom (20 inch release height) and spray nozzles producing an ASABE 

droplet size spectrum of “fine to medium/ coarse” spray droplets would reduce the effects 

distance for lettuce from 249 to 36 feet from edge of field. To address concerns for spray drift, 

EPA is proposing label amendments to reduce drift. By reducing spray drift, these label 

amendments will reduce the likelihood of exposure and risk to nontarget plants and animals. The 

technical registrants for isoxaben (Dow and Celsius) have agreed to these drift reduction 

measures.

 

5 ASABE is the American Society of Agricultural and Biological Engineers. 
11

Terrestrial Mammals. The preliminary risk assessment for isoxaben showed chronic dose-based 

RQs ≤3.84, exceeding the target LOC of 1 for mammals; however, dietary-based RQs did not 

exceed the LOC. Nonetheless, EPA does not expect chronic risk to mammals because the 

assessment is based on a number of conservative assumptions. The only endpoint available to 

evaluate chronic risk to mammals was for reduced parental weight gain from a rat reproductive 

toxicity study. No other adverse effects were seen in the study. Furthermore, no effects on 

developmental or maternal toxicity were observed at doses up to 1000 mg/kg/day in prenatal 

developmental studies on isoxaben in the rat and rabbit. In addition, the RQ values also assume 

that the mammalian diet consists of a single food item, all of which is treated with isoxaben at 

the maximum label application rate and number of applications; these are conservative 

assumptions. 

C. Benefits

In support of registration review, a qualitative assessment of the benefits of isoxaben was 

conducted. The largest use of isoxaben is to manage pre-emergent broadleaf weeds in ornamental 

nurseries and on golf course turf. There is also some use for managing pre-emergent broadleaf 

weeds in bearing and non-bearing fruit and nut orchards and vineyards. Isoxaben is an effective 

broad spectrum herbicide for target weeds. For additional details on the benefits of isoxaben see 

the June 18, 2015 memo, Isoxaben Qualitative Benefits Assessment and the May 21, 2015 memo, 

Non-Agricultural Use & Usage Report for the Herbicide Isoxaben in Support of Risk Mitigation 

& Preliminary Interim Decision.

Isoxaben is the only benzamide chemical (WSSA Group 21)6that inhibits cell wall biosynthesis. 

While there are some other cell wall biosynthesis inhibitor herbicides (WSAA Groups 20, 28, 

29), isoxaben is the only biosynthesis inhibitor herbicide of the benzamide chemistry. Therefore, 

isoxaben provides a unique chemistry as a pre-emergence herbicide where there are limited 

modes of action available for controlling more problematic weeds. Cooperative extension 

specialists report that isoxaben is among the most effective herbicides for difficult to control 

weeds in nurseries, turf, and orchards/vineyards.

Boom height and droplet size are key factors to reduce the potential for drift to non-target plants. 

Although the Agency does not have information specific to isoxaben applications regarding 

droplet size or boom height, it appears to be a chemical that is amenable to application with 

course droplet and low boom height. This is supported by its low volatility and presumed 

efficacy when applied at low boom height and coarse droplet size.

Turf. On turf, isoxaben is registered for use for pre-emergence control of a number of difficult to 

control annuals and perennial weeds. The unique mode of action and effectiveness of isoxaben 

may provide a particular benefit for the user in a weed control program.

Nurseries. Benefits of isoxaben nursery use are its effectiveness against difficult-to-control 

weeds and long-term weed control. For production of container-grown ornamentals, isoxaben 

 

6 Weed Science Society of America. 2014. Herbicide Handbook, 10th Edition. Dale L. Shaner Ed. Herbicide 

Handbook Committee. 
12

has been recommended for control of bittercress, common groundsel, creeping woodsorrel, 

pearlwort, and spurge. It is considered an excellent herbicide for broadleaf weed control; some 

weeds may be controlled for up to 18 months. 

Orchards and Vineyards. For orchards and vineyards, isoxaben is particularly effective for

managing weeds such as fleabane that have been difficult to control with other herbicide 

chemistries. When applied in the fall or winter, isoxaben can provide 4-5 months of weed 

control. Because isoxaben has a unique mode of action, it is a good rotational herbicide with 

other herbicide modes of action to manage weed resistance, and it targets a wide range of weed 

pests. Limited pre-emergence chemistries are available for orchards and vineyards. Weeds such 

as hairy fleabane, common mallow and marestail are important orchard weeds effectively 

managed by isoxaben. Integrated weed management programs that include pre-emergence 

herbicides can be effective for orchard and vineyard cropping systems. 

 D. Endangered Species Assessment

In November 2013, the EPA, along with the Services and the USDA, released a summary of 

their joint Interim Approaches for assessing risks to endangered and threatened (listed) species 

from pesticides. The Interim Approaches were developed jointly by the agencies in response to 

the National Academy of Sciences’ (NAS) recommendations and reflect a common approach to 

risk assessment shared by the agencies as a way of addressing scientific differences between the 

EPA and the Services. The NAS report7 outlines recommendations on specific scientific and 

technical issues related to the development of pesticide risk assessments that EPA and the 

Services must conduct in connection with their obligations under the ESA and FIFRA. 

The joint Interim Approaches were released prior to a stakeholder workshop held on November 

15, 2013. In addition, the EPA presented the joint Interim Approaches at the December 2013 

Pesticide Program Dialogue Committee (PPDC) and State-FIFRA Issues Research and 

Evaluation Group (SFIREG) meetings. The agencies also held stakeholder workshops —in April 

and October 2014, and in April 2015 — allowing additional opportunities for stakeholders to 

comment on the Interim Approaches. Additional workshops are planned to enhance stakeholder 

involvement. As part of a phased, iterative process for developing the Interim Approaches, the 

agencies will also consider public comments on the Interim Approaches in connection with the 

development of upcoming Registration Review decisions. The details of the joint Interim 

Approaches are contained in the white paper Interim Approaches for National-Level Pesticide 

Endangered Species Act (ESA) Assessments Based on the Recommendations of the National 

Academy of Sciences April 2013 Report8, dated November 1, 2013.

Given that the agencies are continuing to develop and work toward implementation of the 

Interim Approaches to assess the potential risks of pesticides to listed species and their 

designated critical habitat, the ecological risk assessment supporting this Proposed Interim 

 

7 Assessing Risks to Endangered and Threatened Species from Pesticides. Available at 

http://www.nap.edu/catalog.php?record_id=18344

8 Available at http://www.epa.gov/espp/2013/nas.html
13

Decision for Isoxaben does not contain a complete ESA analysis that includes effects 

determinations for specific listed species or designated critical habitat. Although EPA has not 

yet completed effects determinations for specific species or habitats, for this preliminary 

assessment EPA’s evaluation assumed, for all taxa of non-target wildlife and plants, that listed 

species and designated critical habitats may be present in the vicinity of the application of 

isoxaben. This assessment will allow EPA to focus its future evaluations on the types of species 

where the potential for effects exists once the scientific methods being developed by the agencies 

have been fully vetted. While the agencies continue to develop a common method for ESA 

analysis, the regulatory section of the Proposed Interim Registration Review Decision document 

will describe the level of ESA analysis completed for this particular registration review case. 

Once the agencies have fully developed and implemented the scientific methodology for 

evaluating risks for listed species and their designated critical habitats, these methods will be 

applied to subsequent analyses for isoxaben as part of completing this registration review.

E. Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for isoxaben, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), isoxaben is

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 
14

chemicals identified for EDSP screening was published on June 14, 20139and includes some 

pesticides scheduled for Registration Review and chemicals found in water. Neither of these 

lists should be construed as a list of known or likely endocrine disruptors. For further 

information on the status of the EDSP, the policies and procedures, the lists of chemicals, future 

lists, the test guidelines and the Tier 1 screening battery, please visit EPA’s EDSP website.10 

In this proposed interim decision, EPA is making no human health or environmental safety 

findings associated with the EDSP screening of isoxaben. Before completing this Registration 

Review, the Agency will make an EDSP FFDCA section 408(p) determination.

IV. PROPOSED INTERIM REGISTRATION REVIEW DECISION

A. Risk Mitigation and Regulatory Rationale

1. Environmental Effects

As discussed in the Ecological Risk Assessment section of this document, isoxaben has been 

determined to pose a potential risk concern for nontarget terrestrial plants and aquatic vascular 

plants. In addition, there is a lack of consistency across isoxaben product labels regarding label 

language to reduce potential off-target spray drift. To address these concerns, the Agency is 

proposing label changes for isoxaben products to reduce spray drift. EPA’s intention is to 

establish a baseline level of protection against spray drift that is consistent across all isoxaben 

products registered for use in agricultural settings. By reducing spray drift, these label 

amendments will reduce the likelihood of exposure and risk to nontarget plants and animals. The 

Agency is proposing the following label restrictions for isoxaben. Both isoxaben technical 

registrants (Dow Chemical and Celsius) have agreed to these proposed label amendments: 

 Use of spray nozzles limiting product droplet size during applications to medium or coarse in 

accordance with the American Society of Agricultural and Biological Engineering (ASABE) 

standard S-572;

 Spray boom applications at the lowest height that safely permits uniform coverage of the soil 

and minimizes droplet evaporation;

 Boom or nozzle shielding to reduce the effects of wind or air current on drift; and

 Spray application is allowed only when wind speed is between 2 and 10 mph.

2. Herbicide Resistance 

To prevent the development of resistance to isoxaben among common weeds, the Agency is 

proposing that all herbicide products containing isoxaben (except for those registered solely for 

homeowner use) contain resistance-management labeling. These specifications follow the 

 

9 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.

10 http://www.epa.gov/endo/
15

recommendations of the Weed Science Society of America publication, Reducing the Risks of 

Herbicide Resistance, Best Management Practices and Recommendations11. The Agency first 

provided guidance on resistance management labeling in Pesticide Registration (PR) Notice 

2001-5, Guidance for Pesticide Registrants on Resistance Management Labeling. EPA is 

proposing the following herbicide-resistance labeling for isoxaben: 

 Mandatory listing of herbicide mechanism of action, and/or Weed Science Society of 

America herbicide group number, at the top of the first page of each product label; 

 Instructions to alternate use of products containing isoxaben with other herbicides with 

different mechanisms of action;

 Instructions to use the highest practical finished spray volume; 

 Recommendations to scout for weeds before and after isoxaben application, to ensure 

proper identification of weeds and growth stage and to confirm product performance; 

 Instructions to report herbicide failure to local extensions specialists, certified crop 

advisors, and/or isoxaben registrants; and

 Instructions to clean application equipment between sites, and to avoid moving plant 

material between sites. 

EPA believes that the inclusion of herbicide-resistance management language on isoxaben labels 

is important to slow the development of resistance to this herbicide while maintaining flexibility 

for growers. Weed resistance is a complex issue and registrants play an important role in 

ensuring effective resistance management. Educating all stakeholders on best practices for 

managing herbicide resistance is important, and the product label is a critical part of this effort.

3. Tolerance Amendments

Although EPA has determined that there are no adverse human health effects from use of 

isoxaben, the Agency will pursue changes to the tolerances for isoxaben to correct commodity 

definitions, update crop tolerances, and correct tolerances values for indirect or inadvertent

residues. 

EPA will pursue the following changes to the isoxaben tolerances listed in 40 CFR § 180.650:

 The tolerance for “Nut, tree, group 14” will be updated to “Nut, tree, group 14-12.” The 

tolerance level remains unchanged at 0.02 ppm. 

 The tolerance for “Pistachio” will be revoked concomitant with the revision of the 

tolerance for tree nuts to include pistachio. 

 

11 Norsworthy et al. 2012. Weed Science 2012. Special Issue: 31-62. 
16

 The tolerances for indirect or inadvertent residues of isoxaben established in 40 CFR § 

180.650(d) will be corrected to three significant figures, in accordance with current

policy. 

EPA will conduct rulemaking to implement these tolerance changes, in accordance with FFDCA. 

B. Proposed Interim Registration Review Decision

In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this Proposed 

Interim Registration Review Decision. Except for the EDSP and ESA components of this case, 

the Agency has made the following Proposed Interim Registration Review Decision: (1) no 

additional data are required at this time; and (2) changes to the affected registrations and their 

labeling are needed at this time.

In this proposed interim registration review decision, EPA is making no human health or 

environmental safety findings associated with the EDSP screening of isoxaben, nor is it making a 

complete endangered species finding. The Agency’s final registration review decision for 

isoxaben will depend upon both the result of an ESA Section 7 consultation with the Services, an 

EDSP FFDCA section 408(p) determination, and an assessment of non-target exposure to bees.

V. NEXT STEPS AND TIMELINE

A. Interim Registration Review Decision

In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this Proposed 

Interim Registration Review Decision, and placing it in the isoxaben registration review docket 

(EPA-HQ-OPP-2007-1038) for public comment for 60 days. A Federal Register Notice will 

announce the availability of this Proposed Interim Registration Review Decision for isoxaben 

and initiate a 60-day comment period. If there are no significant comments or additional 

information submitted to the docket during the comment period that leads the Agency to change 

its proposed decision, EPA may issue an Interim Registration Review Decision for isoxaben 

(case 7219). The Agency’s final decision on the isoxaben registration review case will depend 

upon the results of the EDSP determination, an ESA consultation with the Services, and an 

assessment of non-target exposure to bees. 

B. Implementation of Mitigation Measures

Registrants must submit amended labels, which implement the label changes summarized in 

Appendix A, to EPA within 60 days of issuance of the Final Interim Registration Review 

Decision for isoxaben. 
17

Appendix A: Isoxaben Label Table

Summary of Proposed Labeling Changes for Isoxaben

Description Amended Labeling Language for Isoxaben Products Placement on Label

Products Labeled for Agricultural Use

HERBICIDE RESISTANCE MANAGEMENT

Herbicide Mode of 

Action 

“Group 21 HERBICIDE” Front Panel, upper right 

quadrant, surrounded by a 

black (or suitable color) 

rectangle

Weed Resistance 

Management

“Weed Resistance Management:”

 Instructions to alternate use of products containing 

isoxaben with other herbicides with different 

mechanisms of action;

 Recommendations to scout for weeds before 

isoxaben application for identification and growth 

stage and after isoxaben application to look for poor 

performance or likely resistance; 

 Instructions to clean application equipment between 

sites and to avoid moving plant material between 

sites; and 

 Instructions to report herbicide failure to local 

extension specialists, certified crop advisors, and/or 

isoxaben registrants. 

Directions for Use, prior to 

directions for specific crops 

under the heading” WEED 

RESISTANCE 

MANAGEMENT” 

Best Management 

Practices

Best Management Practices:

Proactively implementing diversified weed control strategies 

to minimize selection for weed populations resistant to one or 

more herbicides is recommended. A diversified weed 

management program may include the use of multiple 

herbicides with different modes of action and overlapping 

weed spectrum with or without tillage operations and/or other 

cultural practices. Research has demonstrated that using the 

labeled rate and directions for use is important to delay the 

selection for resistant weeds. Scouting after herbicide 

application is important because it can facilitate the early 

identification of weed shifts and/or weed resistance and thus 

provide direction on future weed management practices. One 

of the best ways to contain resistant weed populations is to 

implement measures to avoid allowing weeds to reproduce by 

seed or to proliferate vegetatively. Cleaning equipment 

between sites and avoiding movement of plant material 

between sites will greatly aid in reducing the spread of 

resistant weed seed.

Directions for Use, prior to 

directions for specific crops 

under the heading “BEST 

MANAGEMENT 

PRACTICES” 

ENVIRONMENTAL HAZARDS

General Labelling 

Statement is Consistent 

Across All Residential 

Use Products

Liquid Concentrate - Do not allow pesticide to enter or run 

off into storm drains, drainage ditches, gutters or surface 

waters. Applying this product in calm weather when rain is 

not predicted for the next 24 hours will help to ensure that 

wind or rain does not blow or wash pesticide off the 

treatment area. Rinsing application equipment over the 

treated area will help avoid run off to water bodies or 

drainage systems.

Environmental Hazards section
18

Summary of Proposed Labeling Changes for Isoxaben

Description Amended Labeling Language for Isoxaben Products Placement on Label

Broadcast Granular - Do not allow pesticide to enter or run 

off into storm drains, drainage ditches, gutters or surface 

waters. Applying this product in calm weather when rain is 

not predicted for the next 24 hours will help to ensure that 

wind or rain does not blow or wash pesticide off the 

treatment area. Sweeping any product that lands on a 

driveway, sidewalk, or street, back onto the treated area of 

the lawn or garden will help to prevent run off to water 

bodies or drainage systems. 

Dust - Do not allow pesticide to enter or run off into storm 

drains, drainage ditches, gutters or surface waters. Applying 

this product in calm weather when rain is not predicted for 

the next 24 hours will help to ensure that wind or rain does 

not blow or wash pesticide off the treatment area. 

Liquid Ready-to-Use (RTU) - Do not allow pesticide to enter 

or run off into storm drains, drainage ditches, gutters or 

surface waters. Applying this product in calm weather when 

rain is not predicted for the next 24 hours will help to ensure 

that wind or rain does not blow or wash pesticide off the 

treatment area. 

Ground Water 

Advisory

Ground Water Advisory: This pesticide has properties and 

characteristics associated with chemicals detected in ground 

water. This chemical may leach into ground water if used in 

areas where soils are permeable, particularly where the water 

table is shallow.

Environmental Hazards section

Surface Water 

Advisory

This pesticide may impact surface water quality due to runoff 

of rain water. This is especially true for poorly draining soil 

and soils with shallow ground water. This product is 

classified as having a high potential for reaching surface 

water via runoff for several months or more after 

application. A level, well-maintained vegetative buffer strip 

between areas to which this product is applied and surface 

water features such as ponds, streams, and springs will reduce 

the potential loading of isoxaben from runoff water and 

sediment.

Environmental Hazards section

USE RESTRICTIONS

Consistent Application 

of NY State 

Restrictions

Not for sale, distribution or use in New York State. Use Restrictions section

Consistently Prohibit 

Aerial Uses

Do not apply by air. Use Restrictions section

USE PRECAUTIONS

For Labels with Turf 

Use Patterns, 

consistently establish 

Restrictions on Use in 

Turfgrass Grown for 

Seed

Do not apply <PRODUCT NAME> to turfgrass grown for 

seed.

Use Precautions section

SPRAY DRIFT MANAGEMENT

Spray drift language Spray equipment and weather affect spray drift. Consider all 

factors when making application decisions. Where states 

have more stringent regulations, they must be 

Directions for Use, prior to 

directions for specific crops 
19

Summary of Proposed Labeling Changes for Isoxaben

Description Amended Labeling Language for Isoxaben Products Placement on Label

observed. Avoiding spray drift is the responsibility of the 

applicator or grower. To reduce the potential for drift, the 

application equipment must be set to apply medium to coarse 

droplets (i.e., ASAE Standard 572) with corresponding spray 

pressure. Use high flow rate nozzles to apply the highest 

practical spray volume. With most nozzle types, narrower 

spray angles produce larger droplets. Follow the nozzle 

manufacturer's directions on pressure, orientation, spray 

volume, etc. in order to minimize drift and optimize coverage 

and control.

Wind: Avoid making applications when spray particles may 

be carried by air currents to areas where sensitive crops and 

non-target plants are growing. Do not spray near sensitive 

plants if wind is gusty, below 2 mph, or in excess of 10 mph 

and moving in the direction of adjacent areas of sensitive 

areas. Local terrain may influence wind patterns; the 

applicator must be familiar with local conditions and 

understand how they may impact spray drift.

Sensitive Areas: Sensitive areas to this product are defined 

as bodies of water (ponds, lakes, rivers, streams, and ditches), 

wetlands, habitats of endangered species, and non-labeled 

agricultural crop areas. Applicators must take all precautions 

necessary to keep spray drift from reaching those areas.

Temperature Inversion: A surface temperature inversion 

(i.e., increasing temperature with increasing altitude) greatly

increases the potential for drift. Presence of ground fog is a 

good indicator of a surface temperature inversion. Do not 

apply during temperature inversions. Always make 

applications when there is some air movement to determine 

the direction and distance of possible spray drift.

Boom Height: Set the boom and make applications at the 

lowest height that safely permits uniform coverage of the soil 

and minimizes droplet evaporation. Boom or nozzle 

shielding can reduce the effects of wind or air currents on 

drift. Verify that the shields do not interfere with uniform 

deposition of product prior to application.

under the heading “SPRAY 

DRIFT MANAGEMENT”