2 

### Table of Contents

Contents

I. INTRODUCTION ................................

................................................................ .................. 3

A. Summary of Isoxaben Registration Review

................................ ................................ ...... 4

B. Public Comments

................................ ................................................................ .............. 5

II. USE AND USAGE

................................ ................................................................ .............. 7

III. SCIENTIFIC ASSESSMENTS

................................................................ ........................... 7

A. Human Health Risk Assessment

................................................................ ............................. 7

1. Risk Conclusions

................................ ................................................................ .......... 8

2. Human Incidents

................................ ................................................................ ........... 8

3. Tolerances

................................ ................................................................ ..................... 8
B. Ecological Risk Assessment

................................................................ ................................ .. 8

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

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

................................ ... 11
3. Characterization of Ecological Risk

................................................................ ........... 11

C. Benefits................................

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

.......................... 13

E. Endocrine Disruptor Screening Program

................................ ................................ ............... 14

IV. INTERIM REGISTRATION REVIEW DECISION................................

......................... 15

A. Risk Mitigation and Regulatory Rationale

................................ ................................ ...... 15

1. Environmental Effects

................................ ................................ ................................ 15

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

................................ .. 16

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

................................ ... 16

C. Interim Registration Review Decision

................................ ................................ ............ 17

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

.......................... 17

A. Interim Registration Review Decision

................................ ................................ ............ 17

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

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

............................. 193



### I. INTRODUCTION

This document is the Environmental Protection Agency’s (EPA or the Agency) Interim Registration Review Decision for Isoxaben (case 72 19 , PC code 12 5851 ) 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
det ermines it to be appropriate, a n I nterim R egistration R eview D ecision before completing a registration review. Among other things, the I nterim R egistration R eview D ecision 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 i soxaben , additional documents can be found in EPA’s public docket (EPA

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.

FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandated the
continuous revie w 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 direct ed 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 unreasonab le 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 mark etplace can continue to be used safely. Information on this program is provided as http://www2.epa.gov/pesticide

- reevaluation

. In 2006, the Agency implemented the registration review program pursua nt 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.

EPA is issuing an interim registration review decis ion for i soxaben so that it can (1) move forward with aspects of t he registration review that are complete and (2) implement interim risk mitigation. The Agency is currently working with the U.S. Fish and Wildlife Service and the
National Marine Fisheries Service to deve lop methodologies for conducting national endangered species assessments for pesticides. Therefore, although EPA has not yet fully evaluated risks to threatened and endangered species, the Agency will complete its endangered species assessment and any nec essary consultation with the S ervices for i soxaben prior to completing the isoxaben registration review. Likewise, the Agency will complete endoc rine screening for isoxaben

, pursuant to the Federal Food

, Drug

, and Cosmetic Act (FFDCA) section 408(p), befo re completing this registration review. Last, EPA will determine whether additional pollinator exposure and effects data are necessary to make a final re gistration review decision for i soxaben
and issue a data call

- in (DCI) to obtain any suc h data prior t o completing the i soxaben registration review.

Isoxaben is a broad spec trum pre

- emergent herbicide registered for use 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 used4

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.

This document is organized in five sections: the Introduction, whic h includes this summary and a summary of public comments and EPA’s response; Use and Usage, which describes how and why i soxaben is used and summarizes data on its use; Scientific Assessments, which summarizes EPA’s risk assessment, any revisions, and ris k conclusions; Interim Registration Review Decision, which describes the mitigation measures to address risks of concern and the regulatory rationale for EPA’s registration review decision; and, last, the Next Steps and Timeline for completion of this regi stration review.

A. Summary of Isoxaben Registration Review

Pursuant to 40 CFR section 155.50, EPA formally initiated registration review for isoxaben (case
72 19 ) 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

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- 1038 , accessed at www.r egulations.gov :

 December 19 , 200 7

– Publication of Isoxaben Preliminary Work Plan (PWP) for a 60

- day public comment period. The P reliminary W ork P lan (PWP) was accompanied by the scoping document and problem formulation.

 June 13, 2008

– Final Work Plan (FWP) for Isoxaben was issued

. P ublic 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 no t modify the PWP.

 February 18, 2010

– Generic Data Call

- In Notice (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 reflect the additional environmental fate and effects data requirements and a revised registration
review schedule for isoxaben. The registration review timeline for isoxabe n 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 D ow AgroSciences (Dow)

, one of two isoxaben
technical registrant s

. These comments did not change the risk assessment conclusions.5

For further information see the Isoxaben Proposed Interim Registration Review Decision

, June 23, 2015

.

 June 2015

– The Agency published the Iso x aben Proposed Interim Registration Review
Decision

, June 23, 2015 ,Response to Comments on the Isoxaben Registration Review Preliminary Risk Assessment, February 3, 2015, Non

- Agricultural Use and Usage Re port for the Herbicide Isoxaben in Support of Risk Mitiga tion & Preliminary Interim
Decision , May 21, 2015, and the Iso xaben Qualitative Benefits Assessment

, June 18,
2015

, in the registration review docket (EPA

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- day public comment period. One comment was received from the Center for Bi ological Diversity (CBD), which is addressed below.

 December 2015

– The Agenc y is now publishing the Isoxaben Interim Registration
Review Decision

.

B. Public Comments

During the 60

- day public comment period on the Isoxaben Proposed Interim Decision, which opened on August 11, 2015 and closed on October 9, 2015 , the Agency received one comment, from the Center for Biological Diversity, an environmental and public interest group. The public comments, and EPA’s response, are summarized below. Public comments in their entirety are located in the docket, EPA

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COMMENTS RECEIVED FROM CBD (EPA

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Comment : CBD opposes the proposed reregistration of isoxaben at this time as premature
because the y assert that the Agency has determined that isoxaben has the potential to cause adverse effects to species. In CBD’s comments on the Proposed Interim Registration Review Decision for Isoxaben, they focus on EPA’s duty to initiate consultation with the U. S. Fish and Wildlife Service and the National Marine Fisheries Service (the Services) prior to completion of the registration review process for i soxaben

. CBD stat es that the reregistration of i soxaben cannot be completed in compliance with EPA’s obligations under both FIFRA and the ESA until
the EPA concl udes that the continued use of i soxaben will have “no effect” on listed species or critical habitat or completes consultation. CBD also contends tha t there are readily available data and information sources that would allow EPA to complete Step 1 of the Interim Approaches for National Level Endangered Species Assessments Based on the Recommendations of the National Academy of Science. CBD refer s to their previous comments 1 on EPA’s draft ecological risk assessment , which provided specific label language to implement the Bulletins
Live! System, stating that this label language would enable EPA to comply with current and continuing ESA duties. ( CBD inc orporated these and all other previous comments on the draft ecological risk assessment by reference. ) Last, they state that EPA must take a precautionary approach and enter into consultations with the Services on isoxaben as outlined in the Interim Appro aches document

.

1 EPA

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Response : As an initial matter, CBD’s comments suggest that it may not fully appreciate the distinction between EPA’s interim and final registration review decision. Additionally, CBD seems to use “reregistration” interchangeably with “ registration review.” Both are separa te programs mandated by FIFRA; i soxaben is currently undergoing Registration Review. As provided in EPA’s registration review regulations at 40 CFR section 155.56, EPA may, in its discretion, issue an interim decision before the completion of registration review when, among other things, it determines that it cannot complete registration review because additional information is necessary to complete the Agency’s assessment. In addition, section 155.56 also provides th at EPA may require risk mitigation measures in an interim decision. Consistent with this provision, EPA is issuing this interim re gistration review decision for i soxaben in part so that it can move forward with aspects of the registration review decision that are complete while EPA continues to work with the Services on developing the interim approaches that will be used to complete its registration review end angered species assessment for i soxaben. Under section 3(g) of FIFRA, EPA must complete the reg ist ration review of isoxaben by October 1, 2022. While EPA could, therefore, choose not to complete any aspect of the i soxaben registration review for several more years until it completes its endangered species assessment and any necessary consultation, EPA believes the public and the environment benefit from EPA’s early
action on the matters cov ered by this interim decision including risk mitigation, such as use of

spra y nozzles limiting isoxaben droplet size, a spray minimum release height, boom or nozz le shielding, and restricting application to only when wind speed is between 2 and 10 mph

-- as described in Section IV of this document. EPA does not believe the Endangered Species Act compels a contrary result. Taking early action to address some risks now serves to benefit the environment and does not preclude EPA from taking any additional necessary actions to address effects to listed species that EPA concludes are necessary as it works to complete registration
review.

Accordingly, EPA’s previous res ponse to CBD’s comments on the draft ecological risk assessment (in the Proposed Interim Decision) stated that EPA plans to address CBD’s concerns with the development of its Final Registration Review Decision. This is still EPA’s plan. EPA anticipates i nitiating consultation with the Services after issuing the Interim Registration Review Decision, but prior to issuing the Final Registration Review Decision. The Agency’s Interim Registration Review Decision, like the Proposed Interim Decision, state s tha t EPA is not making a complete endangered species finding, and that EPA’s Final Registration Review Decision for isoxaben will depend upon the result of an ESA Section 7 consultation with the Services , an assessment of non

- target exposure to bees, as well as the FFDCA section 408(p) endocrine screening requirements

.

EPA is still in the process of developing the interim approaches based on the 2013 NAS Report recommendations, including Steps 1 and 2 of the Biological Evaluation for listed species. CBD’s previous comments provide reference to the available critical hab itat; however, as CBD noted, not all species have critical habitat. Furthermore, critical habitat is just one piece of the species’ range. EPA is working with the Services to obtain the best available species range information for all listed species. We are also working together to determine the appropriate pesticide use footprint. EPA will be taking public comment on our interim approaches as developed and implemented for the three pilot chemicals: chlorpyrifos, diazinon and malathion. As a result, EP A may develop a revised approach for Steps 1 and 2 through work on the three pilot chemical s before completing Step 1 for i soxaben.7

CBD’s previous comments also provided label language referring pesticide applicators to EPA’s
Bulletins Live! System, and a stateme nt that all product labels for i soxaben must contain this language. However, si nce there are no Bulletins for i soxaben in Bulletins Live! Two , it is unnecessary, at this point in time, to include this language on the label for i soxaben. Inclusi on of a reference to Bulletins on the product label when no Bulletins exist is likely to result in confusion for pesticide applicators and growers. However, EPA is in agreement with CBD that Bulletins are the appropriate mechanism to implement any necessa ry geographically

- specific pesticide use limitations intended to protect listed species. EPA plans to use Bulletins Live! Two to implement any Bulletins that would be generated as we complete the ev aluation of potential
risks of i soxaben to listed species and designated critical habitat.



### II. USE AND USAGE

Isoxaben is a pre

- emergent benzamide herbicide registered for use to control broadleaf weeds

, grasses and vines

. It is classified by the Weed Science Society of America (WSSA) as a Group
21 herbicide that inhibits cell wall biosynthesis. Isox a b e n 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 registe re d for agricultural use on bearing fruit and nut trees and vineyards

. Much of the orchard and vineyard use is in California. The majority of use s have a maximum application ra te of 1.0 lb ai/ A/application, three applications per year, with a 6 0

- 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%) 2

. Aerial applications of isoxaben are not permitted

.

For additional details on isoxaben use and usage s ee 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

qua nti tative risk assessment in support of the isoxaben registration review

. For a detailed
discussion of the human hea lth assessment for isoxaben , see Isoxaben

– Preliminary Human
Health Risk Assessment for R e gistrat i on Review

, dated September 11 , 2014, available in the public docket EPA

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.

2 2011

- 2013 usage data.8

1. Risk Conclusions

EPA has no human health risks exceeding th e 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, r esidential/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 toxici ty finding for
isoxaben and any other substance. For more information on EPA’s efforts to determine which pesticides share a common mechanism of toxicity and to evaluate cumulative effects, see http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/cumulative

- assessment

risk

- pesticides

.

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) datab ase for potential human poisonings related to isoxaben

. ID S reported one case r elated to exposure to
isoxaben. From 1998 to 2003, there were no case s of human poisoning reported for isoxaben in
the SENSOR/NIOSH database. F rom 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
addition al information comes in, the Agenc y 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 i soxa ben to update the crop group

to lerances for tree nuts. S pecific changes are described in the September 11 , 2014 document,
Isoxaben: Preliminary Human Health Risk Assessment for Registration Review

, and in Section
IV , A . 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 present ed below. The Agency used
the most up

- to

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

qua nt itative 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

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, a t : http://www.regulations.gov/9

 Preliminary Ecological Fate and Ecological Risk Assess ment in Support of the Registration Review of Isoxaben

, September 3, 2014

, and

 R esponse to Comments on the Isoxaben Registration Review Preliminary Risk
Assessment

, February 3, 201 5

.

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 crit ical 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.

1. Risk Conclusions

T he Agency co mplete d its preliminary ecological risk assessment for isoxaben in September
2014 . This assessment show ed 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. 3 In addition, a cute an d 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 mam mals exceed the level of concern. These RQs are ≤3.8 4.

T he 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 poten tial chronic risk concerns to non

- listed mammals ( RQs range from
1

- 4 )

. The r isk concerns for non target species will be described further below.

When initially scoping the registration review for isoxaben, EPA did not ident ify 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 Bees 4 , EPA has begun to require these data where applicable. EPA is currently dete rmining 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 necessar y 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 inc luded in
Table 1 below. The Agency will require data it believes are needed to help inform the pollinator
risk assessment.

3 For non

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

4 http://www2.epa.gov/sites/production/files/2014

- 6/documents/pollinator_risk_assessment_guidance_06_19_14.pdf10

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 ri sk assessment. † Acceptable data hav e already been submitted for isoxaben or the study is waived based on available data.

Terrestrial and Aquatic Vascular Plants. In the preliminary risk assessment for isoxaben, t he Agency used the TerrPlant model to calculate RQs for n ontarget terrestrial and semiaquatic plant s 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 sh owed poten tial risk concerns for nontarget terrestrial plants ( RQs ≤ 12 ) and for non target 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 degradates 5 (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 e mergence 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

. T he effects distance for seedling emergence for lettuce, the most sensitive species

, was 249
f ee t f rom t he edge of the field. The effects distance f or vegetative vigor for ryegrass, the most
sensitive plant species

, was 174 f ee t from the edge of field.

Mammals. I n the preliminary risk assessment for isoxaben, the Agency estimated potential
chronic risks to mammals. Because t he available acute toxicity data for isoxaben showed no mortality

, a nd 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.

5 The isoxaben degradate s identified in an aqueous photolysis study were considered in the preliminary risk

assessment.11

EPA estimated c hronic 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 endp oint 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 bod y 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 cont aining 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

, includ ing woody plants. EPA has not received any i ncident reports fo r isoxaben since 2010 , bu t 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 Regis tration 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 non target species. Although t he 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 n ontarget organisms. This risk
characterization section des cribe s other lines of evidence for isoxaben , put s 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. Th us, the TTR RQs m ight 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 (grou n d spray application, 1 lb ai/A, sing le application)

. Although r unoff is a major factor i n nontarget terrestrial plant excee dances

, 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 s pray drift e ffects distance s 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 adverse12

effect s to nontarget plants. Beyond this distance, there would be low potential for adverse effects to nontarget plants. The se effects distance estimates were derived using from AgD rift model default values, includ ing a 50 in ch release height (high boom for gr ound application ) and an
ASABE 6 droplet size spectrum of “very fine to fine

. ” These model defaults were used because

not all of the current isoxaben product labels spec if y droplet size distributions

, boom h ei ghts , or other drift reduction measures t hat would reduce the effects distance for isoxaben

. For example, using a low boom (20 inch release height ) and spray nozzles producing an ASA B E 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 f or spray drift, EPA is requiring0 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. T he technical registrants for isoxaben (Dow and Celsius ) have agreed to these drift reduction measures.

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 mammal s wa s for reduced parental weight gain from a rat reproductive toxicity study . No other adverse effects were seen in the study. Furthermore, n o effects on developmental or maternal toxicity were observed at doses up to 1000 mg/kg/day in prenatal developmental studi es 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 conserva tive assumptions

.

C. Benefits

In support of registration review, a qualitative assessment of the ben efits 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

- e mergent broadleaf weeds in bearing and non

- bearing fruit and nut orchards an d vineyards

. Isoxaben is an effective broad spectrum herbicide for target weeds

. For additional details on the benefits of isoxaben s ee 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) 7 that inhibits cell wall biosynthesis.
While there are some other cell wall biosynthesis inhibitor herb i cides (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

6 ASABE is the American Society of Agricultural and Biological Engineers.

7 Weed Science Society of America. 2014. Herbicide Handbook, 10 th Edition. Dale L. S haner Ed. Herbicide
Handbook Committee.13

specialists report that isoxaben is among the most effective herbicides f or d ifficult 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 coa rse droplet size

.

Turf. On turf, isoxaben is register e d 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, isox aben 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 Viney ards

. For orchards a nd vineyards , isoxaben is particularly effective for managing weeds such as fleabane that have been difficult to control with other herbicide
chemistries. When a pplied 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 chem istries are available for orchards and vineyards. W eeds 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 effe ctive 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 a s a way of addressing scientific differences between the
EPA and the Services. The NAS report 8 outlines recommendations on specific scientific and technical issues related to the development of pesticide risk assessments that EPA and the
Services must con duct 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
Pes ticide Program Dialogue Committee (PPDC) and State

- FIFRA Issues Research and

8 As s essing Risks to Endangered and Threatened Species from Pesticides. Available at http://www.nap.edu/catalog.php?record_id=1834414

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 Appro aches 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 Report 9 , 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 Interim Decision for
i soxaben does not contain a complete ESA analysis that includes effects determinations for specific listed species or designated cr itical 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 critic al 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 age ncies have been fully vetted. Once the agencies have fully developed and implemented the scientific method ology for evaluating risks for listed species and their designated critical habitats, these methods will be applied to subsequent analyses for isoxabe n 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, neurotoxici ty, 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 maturati on, 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

9 Available at http://www2.epa.gov/endangered

- species/assessing

- pesticides

- under

- endangered

- species

- act#report15

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a
chemical substance to interact with the estr ogen, 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 ef fect.

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 iner t ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 10 and includes some pesticides scheduled for Registration Review and chemicals found in water. Neither of these
lists should be construed as a list of kn own 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. 11

In this in terim 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.



### I V

. INTERIM REGISTRATION REVIEW DECISION

A. Risk Mitigation and Regulatory Rationale

1. Environmen tal 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 p lants 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 i soxaben product labels must be amended (see Appendix A) 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
amend ments will reduce the likelihood of exposure and risk to nontarget plants and animals.
Both isoxaben technic al registrants (Dow Chemical and Celsius ) have agreed to the following
label amendments :

 Use of spray nozzles limiting product droplet size durin g applications to medium or coarse in accordance with the American Society of Agricultural and Biological Engineering (ASABE)
standard S

- 572;

10 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of
chemicals.

11 http://www2.epa.gov/endocrine

- disruption16

 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, product labels
must be amended for all isoxaben herbicide products (except for those registered solely for homeowner use) to contain resistance

- management labeling. These label requirements follow the
recommendations of the Weed Science Society of America publication, Reducing the Risks of Herbicide Resistance, Best Management Practices and Recommendations 12

. The Agency first provided guidance on resistance management labeling in Pesticide Registration (PR) Notice
2001

- 5, Guid

ance for Pesticide Registrants on Re sistance Management Labeling. EPA is requiring the following herbicide

- resistance labeling for isoxaben:

 Mandatory listing of herbicide mechanism of action, and/or Weed Science Society of America herbicide group numbe r, 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;

 Recommend ations 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
adviso rs, 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 s t akeholders about 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

12 Norsworthy et al. 2012. Weed Science 2012. Special Issue: 31

- 62.17

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

EPA will pursue the following c hanges to the isoxaben tolerance listed in 40 CFR § 180. 650 :

 T he t olerance for “ Nut, tree, group 14 ” will be updated to “ Nut, tree, group 14

- 12 .” The
tolerance level remains unchanged at 0.02 ppm.

 T he t olerance for “ Pistachio ” will be revoked concomitant with the revision of the tolerance for tree nuts to include pistachio.

 T he t olerances for indirect or inadvertent residues of isoxaben established in 40 CFR § 180. 650 (d) will be corrected to three significant figures, i n accordance with current policy.

EPA will conduct rulemaking to implement these t olerance change s, in accordance with FFDCA

.

B. Interim Registration Review Decision

In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this In terim Registration Review Decision. Except for the EDSP , pollinator, and ESA components of this case, the Agency has made the following Interim Registration Review Decision: (1) with the possible exception of pollinator studies listed in Section IIIB 1 of t his document, no additional data are required at this time; and (2) changes to the affected registratio ns and their labeling are

necessary at this time.

In this 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 dec ision fo r isoxaben will depend upon 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 Interim Registration Review Decision, and placing it in the isoxaben registration review docket (EPA

HQ

- OPP

- 2007

- 1038). 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 Measures18

Registrants must submit amended labels, which implement the label changes summarized in Appendix A, to EPA within 60 days of issuance of the Interim Registration Review Decision for
isoxaben.19 Appendix A: I soxaben Label Table

Summary of 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 suitab le 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

 Instruction s 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
he rbicides 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 res istant 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 sect ion20 Summary of 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 drain s, 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 whe re 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 fro m 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 crops21 Summary of Labeling Changes for Isoxaben
Description Amended Labeling Language for Isoxaben Products Placement on Label

observed. Avoiding spray drift is the responsibility of t he 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 sp ray 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 adja cent 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 wate r (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. A lways 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 dr oplet 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”