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 Regist ration Review Decision

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

B. Implementation of Mitigation Measures

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

Appendix A: Isoxaben Label Table

................................ ................................ ............................. 173



### I. INTRODUCTION

This document is the Environmental Protection Agency’s (EPA or the Agency) Proposed 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 1 55.58. 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 t o 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) ide ntify
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 , additio nal documents can be found in EPA’s public docket (EPA

- HQ

- OPP

- 200 7

- 1038 ) at www.regulations.gov

.

FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandated the continuous review of existing pe sticides. 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
la beling. 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 effec ts. 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 cont inue 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 FIF RA 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, gro up 14; and pistachio.

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

r egistration review of isoxaben . Documentation of these events for isoxaben can be found in EPA’s public docket, EPA

- HQ

- OPP

- 200 7

- 1038 , accessed at www.regulations.gov :4

 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 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 iss ued 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.

 Septem ber 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 Regis tration Review. EPA received comments from the Center for Biological Diversity (CBD) and D ow AgroSciences (Dow)

, one of two isoxaben
technical registrant s

.

 June 2015

– The Agency is now publishing the Iso x aben Proposed Interim Registration

Review Decisio n in the registration review docket (EPA

- HQ

- OPP

- 200 7

- 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 Pre lim inary Risk

Assessment

, February 3 , 2015 ;

o Non

- Agricultural Use and Usage Re port 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 Com ments

EPA received two public comments d uring the 60

- day comment period on the Isoxaben Preliminary Risk A ssessments, which opened on September 24, 2014 and closed on November 24, 2014

. Comments were submitted by Dow, one of the isoxaben technical regist rant s , and by CBD, an environmental and public interest group. C omments from Dow focused on various technical aspects of the preliminary environmental and human health risk assessments , but did5

not change the risk assessment conclusions

. EPA’s respon se t o D ow’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 re sponses. 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

- 20 0 7

- 1038

.

C OMMENTS R ECEIVED FROM CBD ( EPA

- HQ

- 2007

- 1038

- 0028 )

Comment : Th e 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 revie wed the commen ts from CBD a nd 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 wi ll add ress 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.

C OMMENTS R ECEIVED FROM D OW (EPA

- HQ

- 2007

- 1038

- 0029)

Comment s : 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

me tabolites/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 correction s 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 e nvironmental 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 c hange 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 Reg istration 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 her bicide 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 nu t 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 rate 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%) 1

. 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 m ost 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 health assessment for isoxaben , see Isoxaben

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

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

- HQ

- OPP

- 200 7

- 1038 , at : http://www.regulations.gov/

.

1. Risk Conclusions

EPA has no human health r isks 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 toxici ty 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) datab ase for potential human poisonings related to isoxaben

. IDS 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 sixtee n 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 inciden ts is warranted at this time. However, if additional 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
tolerances 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 , B. of this documen t. 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 pre sented 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 ecologica l assessment for isoxaben , see the following documents, available in the public docket EPA

- HQ

- OPP

- 200 7

- 1038

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

 Preliminary Ecological Fate and Ecological Risk Assessment in Suppor t 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 implemen t 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 Ag ency 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 Co nclusions

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. 2
In addition, a cute 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 ≤3.8 4.

T he preliminary ecological risk assessment showed pot ential 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 conc erns for non target 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 Bees 3 , 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 ass essment.

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 * † (OE CD 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 t est 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 hav e 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.pdf9

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 drif t and runoff combined, in both dry upland and semi

- aquatic wetland habitats. The preliminary risk assessment sh owed potential risk concerns for nontarget terrestrial plants ( RQs ≤ 12 ) and for non target aquatic vascular plants (RQs ≤ 8.2 ). The RQs for terre strial 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 4 (total toxic residues, TTR) using the conservative assumption that the degrad ates 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

, w as modeled for all of the species tested in the seedling emergence and vegetative vigo r 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 d istance 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.

EPA estimat ed 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

. H owever, there were limited RQ exceedances on a dose basis for all registered use s ; 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 mammal s. 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 applicatio ns 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 inci dents 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

, inclu d ing woody

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

as sessment.10

plants. EPA has not received any i ncident reports for 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 Ecolog ical 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 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 describe 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 isox aben 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 p lants.

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, single 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 f ee t f rom t he edge of the field for seedling emergence (lettuce) and 174 f ee t from the edge of
field f or 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. 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 ground application ) and an

ASABE 5 droplet size spectrum of “very fine to fine

. ” These model defaults were used because

not all of the current sulfentrazone 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 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

. T he 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 avail able 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 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 ma ximum label applica tion rate and number of applications ; these are conservative 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 wee ds in ornamental
nurseries and o n 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 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) 6 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. Th erefore,
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 herbici des f or 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 appli cations 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 dr oplet 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, isoxaben

6 Weed Science Society of America. 2014. Herbicide Handbook, 10 th Edition. Dale L. Shaner Ed. Herbicide
Handbook Committee.12

has been recommended for control of bittercre ss, 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 a nd vineyards , isoxaben is part icularly 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 chemistries are available for orchards and vineyards. W eeds such

as hairy fleabane, commo n 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 Asse ssment

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 report 7 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 Approache s 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 ( S FIREG) 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 Report 8 , 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 supporti ng this Proposed Interim

7 As s essing Risks to Endangered and Threate ned Species from Pesticides. Available at http://www.nap.edu/catalog.php?record_id=18344

8 Available at http://www.epa.gov/espp/2013/nas .html13

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 assess ment 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 fo r 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 method ology 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 Progr am

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, neuroto xicity, 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 matu ration, 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), isoxa ben 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 wild life 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 batt ery 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 caus ed 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 c all

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of14

chemicals identified for EDSP screening was published on June 14, 2013 9 and includes some pesticides scheduled for Registr ation 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.



### I V

. PROPOSED 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 plants and aquatic vascular plants. In addition, there is a lack of consistency across isoxaben product labels regarding label language to re duce 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 acr oss 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 restrictio ns for isoxaben . Both isoxaben technic al 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 Soc iety 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 c ontaining 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 Recommendations 11

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

2001

- 5, Guidance for Pesticide Registrants on Re sistance 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 m echanisms of action;

 Instructions to use the highest practical finished spray volume;

 Recommendations to scout for weeds before and after isoxaben application, to ensure proper ident ification 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 betw een 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 cr itical 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 cro p tolerances, and correct tolerances values for indirect or inadvertent
residues.

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

 T he t olerance for “ Nut, tree, group 14 ” will be updated to “ Nut, tree, group 1 4

- 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.

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

- 62.16

 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, in accordance with current policy.

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

.

B. Proposed Interim Registration Review D ecision

In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this Proposed
Interim Registration Review D ecision. Except for the EDSP and ESA components of this case, the Agency has made the following Proposed Interim Registration Re view 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
environmenta l 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 t he 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 Pr oposed 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 N otice will announce the availability of this Proposed Interim R egistration R e view D ecision 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 Inter im R egistration R eview D ecision for isoxaben (case 7219). The Agency’s final decision on the isoxaben registration review case will depend

up o n the results of the EDSP determination, an ESA consultation with the Services, and an
assessment of non

- target e xposure 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: I soxaben 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 o f
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 herb icides 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 applicat ion equipment between sites and to avoid moving plant material between sites; and

 Instructions to report herbicide failure to local extension specialists, certified crop advisor s , and/or
isoxaben registrants. Directions for Use, prior to
directions for s pecific 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 herbicide s 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 av oiding 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 Lab elling
Statement is Consistent
Across All Residential
Use Products Liquid Concentrate

- D o 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 predic ted 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 section18 Summary of Proposed Labeling Changes for Isoxaben
Description Amended Labeling Language for Isoxaben Products Placement on Label

Broadcast Granular

- D o 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 pest icide 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

- D o 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.

Li quid Ready

- to

- Use (RTU)

- D o 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 rai n 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 bu ffer 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

Consis tent 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 c rops19 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 mus t 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. Follo w 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. 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”