Docket Number EPA

- HQ

- OPP

- 2010

- 0979

www.regulations.gov



## Isoxaflutole Final Work Plan

Registration Review

November 201 13

Introduction

This is the Environmental Protection Agency‟s (EPA or the Agency) Final Work Plan (FWP) for the registration review of isoxaflutole . The FWP includes the expected registration review

timeline. The FWP also addresses any public comments received on the Pre liminary Work Plan (PWP) in the Summary Document, which was posted in the isoxaflutole registr ation review docket (EPA

- HQ

- OPP

- 2010

- 0979 ). The Summary Document, dated June 22 , 2011, provided

information on what EPA knows about the pesticide and what additio nal risk analyses and data

or information the Agency believes are needed to make a registration review decision.

The Agency‟s implementation of the registration review program requires review of each registered pesticide every 15 years to determine whethe r i t continues to meet the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) standa rd for registration. Changes in science, public policy, and pesticide use practices occur ove r time. The registration review program is intended to make sure that, as the ability to assess r isk evolves and as policies and practices change, all registered pesticides continue to meet that statutor y standard. The public phase of registration review begins when the initial docket is op ened for each case. Information

on this program is provided at http://www.epa.gov/oppsrrd1/registration_review/

.

Isoxaflutole is an herbicide activ e ingredient registered for use on corn for control of broadleaf and grass weeds

. Isoxaflutole products are manufactured as suspension concentrates or dry flowables and are applied through various ground methods , such as ground booms and soil incorporation equipment

. Isoxaflutole is a Restricted U se Pesticide (i.e., applications of RUPs can be made by certified applicators only) due to concerns over phytotoxicity to non

- target plants

. There are no registered residential uses. Isoxaflutole was first registered in the U.S. in

1998 and

, therefore

, it was not subject to the FIFRA r eregistration program.

Comments Received on the Summary Document

There was a 60 day public comment period following the opening of the isoxaflutole registration review docket on June 29, 2011. The i soxaflutole technical registrant

, Bayer CropScience (BC S)

, submitted a document containing a number of comme nts on the PWP and Fact Sheet sections of the Summary Document. This document is available in the isoxaflutole registration review

docket.

The comments specific to the anticipated data requirements for the registration review of isoxaflutole, as well as the Agency‟s responses, are summarized in this FWP. As a result of these comments, the Agency anticipates requiring fewer studies than were identified in the PWP.

The registrant also provided a correcti on to the description of the formulations of isoxaflutole end use products, as described in the PWP. The PWP included emulsifiable concentrates and dry flowables as available formulations. However, the registrant clarified that the only formulations

of iso xaflutole end use products are suspension concentrates and dry flowables.

Additionally, the registrant provided an updated list of states where the federal isoxaflutole label permits use on corn : Alabama, Arkansas, Colorado, Georgia, Illinois, Indiana, Iowa, Kansas,4

Kentucky, Louisiana, Mississippi, Missouri, Montana, Nebraska, New Mexico, North Dakota, Ohio, Oklahoma, Pennsylvania, South Carolina, South Dakota, Tennessee, Texas and Wyoming.

EPA also solicited comments, through the PWP, on three specifi c topics: environmental justice, water body impairment, and trade irritants. No comments or information were received during the comment period concerning these issues.

Summary of Comments and Agency Responses

A summary of the comments and responses is provided below , based on the November 17, 2011

“ Isoxaflutole: Response to Amended Comments by Bayer CropScience to the Isoxaflutole Summary Document ,” available in the isoxaflutole registration review docket.

Comment 1 : BCS would like to remind the Agency of the extensive additional ecotoxicology studies, environmental fate studies, and environmental monitoring studies that were conducted after the 1997 assessment as summarized by Allen et al. (2004, MRID 46330201). Examples would

include a comment made o n page 9 of the Isoxaflutole Ecological Problem Formulation

Document (June 2, 2011) wherein EPA states: Isoxaflutole‟s terminal metabolite, RPA 203328 is expected to persist and accumulate. The results of the field dissipation, ground water, tile drain,

an d surface water studies as summarized by Allen et al. (2004, MRID 46330201) do not support the statement that RPA 203328 persists and accumulates in the environment.

EPA Response 1 : The Agency will re

- examine existing data and information on the physica l

- chemical and fate properties of the RPA 203328 degradate. Any changes in EPA‟s characterization of that degradate will then be reflected in the forthcoming drinking water and ecological risk assessments in support of registration review.

Comment 2 : As described in Allen et al. (2004, MRID 46330201), three aerobic soil metabolism studies have been conducted on a total of six different soils (Ferreira et al., 1994, MRID 43588006; Ferreira et al., 1996, MRID 45658805; Burr, 1996a; MRID 45658804). Kinetic s evaluations conducted by Hardy et al. (2002, MRID 45658807) for all six soils are also summarized in Allen et al. (2004, MRID 46330201). This information should be sufficient to meet the aerobic soil metabolism study requirements. EPA may not have consid ered Ferreira et al., 1996, MRID 45658805, such that only the data from three soils were considered for aerobic soil metabolism results. Also, in these studies the degradation rate for RPA 202248 has been determined, so these studies should be sufficient to meet the aerobic soil metabolism study requirements for the RPA 202248 degradate.

EPA Response 2: GLN 835.4100, a erobic soil metabolism data on parent isoxaflutole and RPA 202248 will not be required for registration review.5

As noted in the environmental fate data table 9 of the Isoxaflutole Ecological Problem

Formulation Document (June 2, 2011), MRID‟s 43588006 and 45658804 are categorized a s „supplemental‟. As such they may contain useful information that may be used in the Agency‟s assessment of parent isoxaflutole but do not fully meet the requirements of Guideline No. 835.4100. More specifically, the individual study results are not bas ed on the analyses of four soil samples. Collectively, however, since the total number of studies account for four or more soils, no additional data are needed.

Comment 3: As summarized by Allen et al. (2004, MRID 46330201), an aerobic aquatic metabolism study on two water sediment systems was conducted by Ayliffe and Newby (1995, MRID 44291502). Isoxaflutole was rapidly degraded in both systems and no longer detected after 7 days. This study should satisfy the requirements for an aerobic aquatic metabo lism study for parent isoxaflutole and degradate RPA 202248

. Note that in response to the slow degradation rate encountered in the laboratory study, an outdoor mesocosm study was also performed (Lui et al., 2003, MRID 46081105; also Rupprecht et al., 2004) . This study should also be considered as fulfilling this requirement.

EPA Response 3: GLN 835.4300, aerobic aquatic metabolism data on parent isoxaflutole and degradate RPA

202248 will not be required for registration review.

The Agency completed a review of an aerobic aquatic metabolism s tudy by Ayliffe and Newby (MRID 44291502) in February 1998 and found it to be acceptable with one notable exception. The analysis only satisfied the data requirements for the parent and the metabolite RPA 202248;

i t did not include the metabolite RPA 203328. As a result, the analysis was considered incomplete. Subsequent to that review the Agency has determined that the RPA 203328 metabolite is not a chemical of toxicological concern. Therefore, no additional dat a are needed.

Comment 4:

In the Isoxaflutole Ecological Problem Formulation Document (June 2, 2011) , EPA stated that “There have been no registrant submitted environmental fate studies for the compound‟s primary degradate.” Numerous studies for RPA 20224 8 have been submitted for review by the Agency. For example, three of the adsorpt ion/desorption studies cited in table 9 of the formulation document used RPA 202248 degradate as the test material. In many of the degradation studies,

the behavior of the R PA 202248 degradate can be determined from the studies starting with parent isoxaflutole.

EPA Response 4:

EPA note s the correction and agrees data on isoxaflutole degradate RPA 202248 are available

.

Comment 5:

Three available isoxaflutole adsorption/de sorption studies (MRID s 43940301

, 44065801 , and 48108103) were conducted with RPA 202248. These studies were included in the environmental

fate data table 9 of the Isoxaflutole Ecological Problem Formulation Document (June 2, 2011)

.6

EPA classified these st udies as acceptable

. Therefore, BCS does not see the need for additional adsorption/desorption data on RPA 202248.

EPA Response 5:

Guideline No. 835.1230

, adsorption /desorption (batch equilibrium) data on isoxaflutole degradate RPA 202248 will not be required for registration review. The Agency agrees with the

comment.

Comment 6:

The leaching study cited for parent isoxaflutole (MRID 43588008) should satisfy the leaching

data requirement for RPA 2 02248 since the parent isoxaflutole had degraded to RPA 202248 before the start of the leaching phase of the study.

EPA Response 6: Guideline No. 835.1240, leaching studies data on isoxaflutole degradate RPA 202248 will not be required for registration r eview. The Agency agrees with the comment.

Comment 7 : The anaerobic soil metabolism study with parent isoxaflutole is not being required since

environmental fate data table 9 of the Isoxaflutole Ecological Problem Formulation Document (June 2, 2011) states “additional data are not expe cted to change risk conclusions.” Given the relatively rapid degradation of RPA 202248, the same reasoning applies to RPA 202248 and

therefore an anaero bic soil metabolism with RPA 202248 should not be required.

EPA Response 7 : Guideline No. 835.4200, anaerobic soil metabolism data on isoxaflutole degradate RPA 202248 will not be required for registration review. The Agency agrees with the comment.

Comment 8 : As summarized by Allen et al. (MRID 46330201), an anaerobic aquatic metabolism study on one water sediment system was conducted by Burr et al. (MRID 43588007). This study was found to be acceptable to satisfy the requirement for parent and so s hould also satisfy the requirement for RPA 202248 since isoxaflutole was rapidly degraded to RPA 202248, which remained stable throughout the remainder of the study.

EPA Response 8 : Guideline No. 835.4400

- anaerobic aquatic metabolism data on isoxaflutol e degradate RPA 202248 will not be required for registration review. The Agency agrees with the comment.

Comment 9 : The methods and associated independent laboratory validations (ILV) that apparently were acceptable for parent isoxaflutole (since there wa s no data requirement in this area) also include RPA 202248. Therefore, no additional work is needed to meet this guideline for RPA 202248.

EPA Response 9 :7

Guideline No. 835.6200, environmental chemistry analytical methods and ILV (water) data on

isoxaf lutole degradate RPA 202248 will not be required for registration review. The Agency agrees with the comment.

Comment 1 0 : All available data indicate that RPA 203328 is not of toxicological significance as indicated in the recent assessment for soybean uses (USEPA, 2010). No or limited toxicity has been observed with all species (plants, fish, Daphnia , algae, Lemna , birds, s oil microorganisms

, earthworms and rats) tested to date with RPA 203328. In the few cases where a toxicological response has been observed, it has been at high dose levels. Requiring extensive chronic ecotoxicity testing of a metabolite solely based on t he potential for trace levels in the environment, when data exists to demonstrate the lack of toxicity, appears to a major policy shift by the Agency. Based on how the Agency has historically handled metabolites, in general and specifically in this case, and the available Agency guidance on this topic, BCS believes that additional testing is not warranted with RPA 203328.

As summarized in Allen et al., 2004 and Allen et al., 2010, an extensive set of monitoring data are available for RPA 203328, RPA 2022 48 and parent isoxaflutole. In the vast majority of samples, RPA 203328 concentrations were below 0.3 ppb. A comparative example from these data indicate that the lowest EC50 value (for algae) was estimated by EPA to be 5900 ppm. Even

the estimated envir onmental concentrations ( EECs ) estimated by the Agency using PRZM

EXAMS in 1997 (EPA, 1997) are 1000x lower than the lowest toxicity value. Based on the depth and breadth of available information, BCS requests that the Agency reconsider their request for additional ecoto xicity testing with RPA 203328.

EPA Response 1 0 : In order to evaluate the utility of degradate toxicity data, the Agency uses both exposure potential and available toxicity data to determine if additional data would be useful to the risk assessment process. In the case of isoxaflutole, the two major degradates are converted at fairly high rates, and they are expected to be persistent and mobile. Therefore, evaluating potential risks from these degradates is considered an important aspect of the risk assessment. In light of comments received from the registrant, the Agency has re

- evaluated the utility of obtaining

addition al data on the two degradates as explained in the following comments below

. The Agency notes that monitoring data rarely captures high

- end exposure values from vulnerable

areas.

Comment 1 1 : The A gency has requested tier II seeding emergence and vegetativ e vigor studies with RPA 202248. With respect to the vegetative vigor study request, it is difficult for BCS to come up with a scenario where plants would be directly oversprayed with RPA 202248, which makes such a study irrelevant to the risk assessment. If additional data are necessary, then it would seem that exposure via the soil (seedling emergence study design) would be the more relevant route of exposure for any additional non

- target terrestrial plant ( NTTP ) testing with RPA

202248.8

As stated by E PA, a NTTP screening study with RPA 202248 exists, and BCS has acknowledged that RPA 202248 is herbicidally active at a level similar to parent. BCS believe the toxicity of RPA 202248 is covered in studies with parent, since it is so rapidly formed in plants and soils after application of the parent isoxaflutole. A large number of NTTP studies, lab and field, are available with isoxaflutole, its form ulations and to a lesser extent metabolites. Additional standard NTTP studies are unlikely to change the characterization of isoxaflutole‟s risk to terrestrial plants. With the exception of more recent studies, this work has been summarized in Cappy, et a l., 2002 and Dobbs et al. , 2002.

EPA Response 1 1 : The Agency agrees with the comment that vegetative vigor studies conducted with parent isoxaflutole would also include exposures of plants to degradate RPA 202248. Since toxicity endpoints from vegetative vigor studies are expressed in terms of the amount of parent applied to the plant and they are intended to be compared to exposures of non

- target plants to pesticide exposures through spray drift, existing studies with parent isoxaflutole are sufficient t o characterize the effects of spray drift transport of isoxaflutole and its herbicidally active degradate, RPA 202248.

The Agency will require guideline no. 850.4100, terrestrial plant toxicity (s eedling e m ergence ) data for RPA 202248 because 1) RPA 2022 48 may form on the treated field for days before runoff events occur, leading to an exposure of non

- target plants to RPA 202248 through runoff transport and 2) the available seedling emergence studies with isoxaflutole may have a smaller proportion of RPA 202248 than could be found on non

- target areas exposed to this degradate through runoff. Therefore, it is important to have an understanding of the effects of RPA 202248 to the seedling emergence of non

- target plants.

Guideline No. 850.4150, terrestrial plant toxicity (vegetative vigor) data on isoxaflutole degradate RPA 202248 will not be required for registration review.

Comment 1 2 : The A gency has requested three avian reproduction studies that include a mallard duck and bobwhite quail study with RPA 2 03328, and a mallard study with RPA 202248 (a quail study already exists). While BCS believes that the available information is adequate to assess the risk to birds, BCS agrees to perform a mallard reproduction study with RPA 202248 as requested.

However , as previously mentioned, BCS strongly disagrees that additional test ing of RPA 203328 is necessary.

EPA Response 1 2 : Guideline No. 850.2300, avian reproduction data on isoxaflutole degradates RPA 202248 and RPA 203328 will not be required for registration review.

A vailable reproduction test with the bobwhite quail exposed to degradate RPA 202248 did not show reproductive effects at 500 mg/kg

- food, which is an order of magnitude below the expected environmental concentration (EEC) of isoxafluto le on potential food items of birds (if 100% conversion of isoxaflutole to degradate RPA 202248 is assumed, the most con servative EEC is 34 mg/kg

- food)

.9

The Agency no longer considers degradate RPA 203328 to be of toxicological concern for avian reproduc tive effects. This conclusion is based on three lines of evidence. First, this degradate would need to be at least an order of magnitude more toxic that degradate 202248 to pose a concern for birds on a chronic exposure basis. Second, a developmental toxic ity study in rats conducted with RPA 203328 has been submitted to the Agency (MRID 45655906). The results of the study show that in the presence of material toxicity at the highe st doses tested (750 mg/kg/day) there was no teratogenicity or developmental toxicity. Third, the Agency has determined that degradate RPA 203328 is not of toxicological concern for humans.

Although the registrant has indicated willingness to conduct a mallard reproduction study with RPA 202248, the Agency is not requiring this study.

Comment 1 3 : The Agency expressed concern about the lack of chronic invertebrate studies with isoxaflutole or

its metabolites. Three studies are available to address this concern and will be submitted for review by the Agency. These studies include two Daphnia magna studies that examined the impact of isoxaflutole around the practical limit of solubility and a limit test with Chironomous riparius at much lower concentration.

The first Daphnia magna study was a flow

- through study (McElligott, 1995; M

- 213123

- 01

- 1)

wher e undissolved test material, that likely confounded the study results, was present at the two high test concentrations (0.75 and 1.5 mg/L nominal). The rapid addition of a concentrated stock to water with insufficient mixing time likely led to precipitate formation and continual delivery to the test chambers. Survival was impacted (65 and 73%) at the two high treatment levels where undissolved test substance was observed, but not at any of the treatment levels (0.09, 0.9, and 0.38 mg/L) where the test com pound appeared to be fully in solution. No treatment related effects on reproduction were observed.

A second Daphnia chronic study (Putt, 1998; M

- 210464

- 01

- 1) was conducted with isoxaflutole, using a static renewal study design. Nominal test levels is t his study were 10, 3.1, 0.98, 0.31, 0.095, and 0.030 mg/L. Undissolved test material was observed at the highest treatment of 10 mg/L after mixing of new test solution, but prior to distribution to individual replicates, consistent with the reported solub ility limit for isoxaflutole of 6.2 mg/L. No treatment related effects were observed at any test level, resulting in a NOEC of 5.7 mg/L based on measured

concentrations.

A water

- sediment study (Odin

- Feurtet, M., 1997; (M

- 211474

- 01

- 1) with Chironomous ri parius is available. There was a single treatment level of 100 ug/L of isoxaflutole spiked to the water. The isoxaflutole did degrade to predominately RPA 202248 during the 28 study. No negative effects were observed during the study.

The 1997 studies showed no negative effect to aquatic invertebrates due to chronic exposure of solubilized isoxaflutole. Acute exposure testing of parent isoxaflutole, and the two primary metabolites, indicated no toxicity to Daphnia . While BCS believes there is sufficien t information available to conclude that RPA 202248 and RPA 202328 pose minimal risk to aquatic10

invertebrates, BCS is willing to conduct a Daphnia magna chronic study with RPA 202248 to increase the Agency confidence in the risk assessment.

EPA Response 1 3 : When the chronic invertebrate studies conducted with isoxaflutole that were referenced by BCS are submitted, the Agency will review them and determine whether or not they are sufficient for risk assessment under the guideline requirement. The Agency agrees that submission of chronic toxicity data for RPA 202248 would increase the Agency‟s confidence in the risk assessment for

isoxaflutole. If these studies are acceptable, the Agency will consider using the submitted chronic toxicity studies involvin g exposures of D. magna to isoxaflutole to derive acute

- to

chronic ratios ( ACRs ). These ACRs may be applied to the acute toxicity data for RPA 202248 and RPA 203328 to estimate the chronic toxicities of these degradates to freshwater

invertebrates.

Co mment 1 4 : The Agency anticipates requiring chronic mysid studies with RPA 202248 and RPA 203328. A mysid chronic study is available for isoxaflutole, along with acute mysid studies with parent and both metabolites. As noted by the Agency in the Isoxaflut ole Ecological Problem Formulation Document (June 2, 2011) document, the metabolites are over two and close to four orders of magnitude less toxic to shrimp than parent. The 96

- hr mysid LC 50 values are 0.0178, 3.6. and 145 mg/L for isoxaflutole. The acut e values for the two metabolites are above the 1 mg/L criteria as listed in the 40 CFR Part 158 guidance and the expected EECs for the metabolites are well below the LC50 values. The statement by the Agency that the chronic mysid study with

parent suggest s the potential for reproductive effects is difficult to understand. Survival was the most sensitive endpoint in mysid chronic with parent and there were not significant effects on reproduction. Even at the two highest test levels, where survival was 13 and 48 percent, respectively , reproduction on an offspring/female/reproductive day was comparable to the

control.

BCS requests the Agency to reconsider their request for mysid chronic studies with two metabolites, or possibly provide a more detail explana tion as to why these studies are trigge red based on existing guidance.

EPA Response 1 4 : Guideline No. 850.1350, saltwater invertebrate life cycle data on isoxaflutole degradate s RPA 202248 and RPA 203328 will not be required for registration review.

Avai lable acute toxicity data for isoxaflutole and RPA 202248 indicate that this degradates is less toxic (on an acute exposure basis) than isoxaflutole by two orders of magnitude. If the available ACR for available toxicity data for the mysid shrimp exposed t o isoxaflutole (17.8) is applied to the acute toxicity endpoint for RPA 202248 (3600 ppb), the estimated chronic toxicity endpoint for mysid shrimp exposed to this degradate would be 200 ppb. In the most recent ecological risk assessment of isoxaflutole (2 010)

, the Agency derived a 21

- d ay EEC of 7.6 ppb for RPA 202248. If this EEC and the estimated chronic toxicity endpoint were used to determine risk to estuarine/marine invertebrates, this degradate would not be of concern. In order to pose a11

risk to estuarine/marine invertebrates, RPA 202248 would have to be 2 orders of magnitude more toxic on a chronic exposure basis to be of concern.

Available acute toxicity data for isoxaflutole and RPA 203328 indicate that this degradates is

less toxic t han isoxaflutole by four orders of magnitude. Using the ACR for isoxaflutole (17.8) and the acute toxicity endpoint for RPA 203328, the estimated chronic toxicity endpoint for this degradate is 8300 ppb. Given that the EEC for isoxaflutole‟s other degradat e, i.e., RPA 202248 is orders of magnitude below this level, it is not expected that degradate RPA 203328 will be present at levels sufficient to pose a risk.

The Agency believes that available acute and chronic toxicity data for isoxaflutole are suffici ent to derive ACRs that may be used to estimate the chronic toxicities of degradates RPA 202248

and RPA 203328 to estuarine/marine invertebrates.

Comment 1 5 : BCS will conduct a freshwater fish early life stage ( ELS ) study with RPA 202248

as is anticipat ed to be requ ired by the Agency, but requests that an estuarine fish ELS study be held in reserve contingent on the outcome of the freshwater ELS. As discussed, based on the structure and activity information available for RPA 203328, BCS does not believe additional testing of RPA 20 3328 is necessary or warranted.

EPA Response 1 5 : If the registrant conducts an acceptable ELS study with a freshwater fish (of most interest would be a test species for which acute toxicity data are ava ilable) exposed to RPA 202248, the Agency would be willing to consider applying an ACR based on RPA 202248 to estimate the chronic toxicity of RPA 203328 to freshwater fish. This same ACR could also be applied to

estuarine/marine fish.

Comment 1 6 : The Ag ency appears to have requested a total of six (6) additional algal studies with RPA

202248 and RPA 203328 that include Navicula pelliculosa

, Anabaena flos

- aquae , and

Skeletonema costatum for each metabolite. BCS targets metabolite testing to determine the relative toxicity of the metabolite to parent. In the case of isoxaflutole, RPA 202248 and RPA 203328, and this specific data request, both metabolites are orders magnitude less toxic to Selenastrum capricornutum . In fact, for all aquatic taxa tested is oxaflutole metabolites are at least an order less toxic than parent. BCS believes that the additional algal testing with the metabolites is excessive and requests that the Agency reconsider the nee d for these additional

studies.

EPA Response 1 6 : Guidelin e No. 850.5400, aquatic non

- vascular plant growth data on isoxaflutole degradates RPA 202248 and RPA 203328 will not be required for registration review.

The Agency agrees that the available green algae ( S. capricornutum ) toxicity data are sufficient to allow for characterization of the relative toxicities of isoxaflutole, RPA 202248 and 203328 to algae.12

Risk Assessment and Data Needs

The Agency will require data for use in conduct ing an ecological risk assessment

, in cluding an

end angered species risk assessment . The Agency will also update the human health risk

assessment for isoxaflutole

. Below is a summary of the issues relevant to the registration review

of isoxaflutole and the data the Agency will require

.

Ec ological Risk:

The most r ecent isoxaflutole ecological risk assessment was conducted in April 2010 for an Experimental Use Permit (EUP) for use on soybeans.

The Agency has not conducted an ecological risk assessment that supports a complete endangered species determination for isoxaflutole

. The ecological risk assessment planned during registration review will allow the Agency to determine whether

isoxaflutole ‟s use has “no effect” or “may affect” federally listed threatened or endangered species (list ed species) or their designated critical habitats. When an assessment concludes that a pesticide‟s use “may affect” a listed species or its designated
critical habitat, th e Agency will consult with the U.S. Fish and Wildlife Service ( FWS )

and/or National Marine Fisheries Service (NMFS) (the Services), as appropriate.

On January 19, 2011, the Center for Biological Diversity and the Pesticide Action

Network North America filed a lawsuit in the United States District Court for the

Northern District of California, against the EPA for allegedly failing to undergo

consultation with the U.S. FWS and NMFS regarding the effects of over 350 pesticides, including isoxaflutole, on over 200 endangered and threatened species throughout the United States (Center fo r Biological Diversity, et al. v. EPA, et al., No. C 11

- 00293 (N.D.Cal.).

The Agency will require the following data for use in conducting a complete ecological

risk assessment , including an endangered species assessment

, for isoxaflutole :

For degradate RPA 202248

o Guideline No. 850.4100

- Terrestrial plant toxicity, Tier II (seeding emergence)

For degradates RPA 202248 and 203328

o Guideline No. 850.1300

- Freshwater invertebrate life cycle 1

o Guideline No. 850.1400

- Freshwater and saltwater fish early life stage 2

Please refer to the June 2, 2011 “ EFED Registration Review Problem Formulation for Isoxaflutole

, ” and the November 17, 2011 “ Isoxaflutole: Response to Amended Comments by Bayer CropScience to the Isoxaflutole Summary Document ,” available in

1 The Agency notes that f reshwater invertebrate life cycle data on RPA 202248 may satisfy the need for f reshwater invertebrate life cycle data on

RPA 203328.

2 The Agency notes that freshwater fish early life stage data on RPA 202248 may satisfy the need for saltwater fish early life stage data on RPA 202248, as well as both freshwater and saltwater fish early life st age data on RPA 203328.13

the is oxaflutole registration review docket, for a more detailed discussion of the anticipated ecological risk assessment and data needs.

Human Health Risk:

The most recent isoxaflutole human health risk assessment was conducted in March 2010

for an Experimental Use Permit (EUP) for use on soybeans.

The isoxaflutole toxicity endpoint/dose selection and FQPA Safety Factor may be re

evaluated during registration review consistent with current policy.

The Agency anticipates updating the drinking water exposure assessment.

During registration review, the Agency may revise the dietary risk assessment if drinking

water concentrations , food residues, points of departure, or uncertainty factors are

revised.

Because there are no registered residential uses of isoxaflutole, the Agency does not anticipate conducting a residential exposure assessment.

The isoxaflutole tolerance expression will be reviewed during registration review to ensure that it appropriately covers the metabolites and de gradates of isoxaflutole and that it specifies the residues to be measured for each commodity.

An analytical method for isoxaflutole residues on plants is currently under review by the Agency‟s Analytical Chemistry Laboratory.

The Agency expects to updat e the occupational exposure assessment for isoxaflutole with an assessment of the cancer risk to occupational handlers from use of the dry flowable

isoxaflutole formulation s

. The assumptions used in the exposure and risk calculations are currently differe nt than those used in the previous occupational handler cancer risk assessment for dry flowable isoxaflutole formulations

The Agency may conduct a quantitative occupational and residential bystander post

application inhalation exposure assessment based on the result of the Agency‟s

evaluation of a March 2010 Sc ientific Advisory Panel (SAP) report on issues related to volatilization of pesticides.

The Agency has sufficient data to conduct a human health risk assessment for the registration review of isoxaflutole. Therefore, t he Agency does not anticipate requiring human health data for registration review.

Please refer to the June 17, 2011 “ Isoxaflutole Human Health Assessment Scoping Document in Support of Registration Review

, ” available in the iso xaflutole registration

review docket, for a detailed discussion of the available isoxaflutole human health data

and anticipated human health risk assessments.14

Agricultural Health Study

Isoxaflutole is among several agricultural chemicals included in the Agricultural Health Study (AHS). The AHS began in 1993 and is a collaboration of the National Institute of Environmental Health Sciences (NIEHS), the National Cancer Institute (NCI), the EPA, and the National Institute for Occupational Safety and Health (NIOSH). Designed as a large long

- term epidemiological study, the AHS collects and analyzes data on the health and work practices of nearly 90,000 farmers and their families in Iowa and N orth Carolina who enrolled in the study before any disease developed. The study focuses particularly on farmers' exposure to 50 chemicals including many of the most widely used pesticides. As data are collected over a period of years, scientists can comp are overall health outcomes for people who differ in whether they have had exposure to various chemicals. While these comparisons cannot conclusively demonstrate how exposure affects health, they can show some statistical associations. More

information o n the AHS can be found at: http://aghealth.nci.nih.gov . EPA is monitoring the results of the AHS and will consider this study in the registration review of isoxaflutole as appropriate.

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 carcinoge nicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclic ity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different

ta xonomic groups. As part of its most recent registration decision , 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), is oxaflutole is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

determinations. Tier 1 consists o f a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to

inter act 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 eff ects caused by the substance, and

establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between15

October 2009 and February 2010, EPA issued test orde rs/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 in ert ingredients. Isoxaflutole is not among the group of 58 pesticide active ingredients on the initial list to be screened under the

EDSP. Accord ingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays for isoxaflutole

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chem icals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Timeline

The Agency has created the following estimated timeline for the completion of the isoxaflutole registration review.

Registration Review for Isoxaflutole

– Projected Registration Review Timeline

Activities Estimated Date Opening the D ocket Open Docket and Public Comment Period 2011

– June

Close Public Comment 2011

– August Case Development

Final Work Plan 2011

– November

Issue DCI 2012

– July

– Sept.

Data Submission 2014

– July

– Sept. Open Public Comment Period for Draft Risk Assessments 2016

– Jan.

– March

Close Public Comment Period 2016

– April

– June Registration Review Decision Open Public Comment Period for Proposed Registration Review

D ecision 2016

– July

– Sept.

Close Public C omment P eriod 2016

– Oct.

– Dec. Registration Review D ecision and Begin P ost

- D ecision F ollow

- up 2017 Total ( years ) 6

Next Steps

The Agency plans to develop a Data Call

- In (DCI) Notice for this pesticide and plans to issue it

in 2012. This new information will be used to conduct complete risk assessments for all registered uses of isoxaflutole. T h e i s o x a f l u t o l e r e g i s t r a t i o n r e v i e w t i m e l i n e m a y b e a d j u s t e d

d e p e n d i n g o n t h e o u t c o m e o f s t u d i e s s u b m i t t e d i n r e s p o n s e t o t h e D C I

. I f s u b m i t t e d i s o x a f l u t o l e d e g r a d a t e R P A 2 0 2 2 4 8 d a t a a r e f o u n d t o s a t i s f

y t h e n e e d f

o r d a t a o n t h e d e g r a d a t e R P A 2 0 3 3 2 8

, t h e n t h e r e g i s t r a t i o n r e v i e w t i m e l i n e f o r i s o x a f l u t o l e w i l l b e shortened b y o n e y e a r

.16

Summary of Isoxaflutole Data to be Required for Registration Review

Guideline

Number Study Title Test Material Estimated

Timeframe (Measured in Months)

850.1300 Freshwater invertebrate life cycle Degradate RPA 202248 12

850.1300 Freshwater invertebrate life cycle Degradate RPA 203328 3 24

850.1400 Freshwater fish early life stage Degradate RPA 202248 12

850.1400 Saltwater fish early life stage Degradate RPA 202248 4 24

850.1400 Freshwater and saltwater fish early life stage Degradate RPA 203328 5 24

850.4100 Nontarget area phytotoxicity , seedling

emergence , T ier II Degradate RPA 202248 12

3 The Agency notes that freshwater invertebrate life cycle data on RPA 202248 may satisfy the need for freshwater invertebrate life cycle data on RPA 203328. The additional time is provided in case the RPA data does not satisfy

the RPA 203328 data need. The isoxaflutole r egistration review timeline may be adjusted depending on the outcome

of the submitted data.

4 The Agency notes that freshwater fish early life stage data on RPA 202248 may satisfy the need for saltwater fish early l ife stage data on RPA 202248 . The additional time is provided in case the freshwater data does not satisfy the

saltwater data need. The isoxaflutole r egistration review timeline may be adjusted depending on the outcome of the

submitted data.

5 The Agency notes that freshwater fish early life stage data on RPA 202248 may satisfy the need for both freshwater and saltwater fish early life stage data on RPA 203328. The additional time is provided in case the RPA data does not satisfy the RPA 203328 data need. The isoxaflutole r egistration review timeline may be adjusted depending on the outcome of the submitted data.17

References

46330201 Allen, R.; Cain, P.; Freesman, P.; et. al. (2004) The Environmental Fate of

Isoxaflutole Following Use on Corn in the U.S. Project Number: B004653. Unpublished study prepared by Bayer Cropscience LP, Bayer Corp. and Battelle Agrifood, Ltd. 374 p.

44291502 Ayliffe, J.; Newby, S. (1995) RPA 201772: Degradation and Retention in Two

Water/Sediment Systems: Lab Project Number: P94/095: 200934: 94/095. Unpublished study prepared by Rhone

- Poulenc Agriculture Ltd. 83 p.

43940301 Burr, C. (1995) RPA 202248: Adsor ption/Desorption to and from Four Soils: Lab

Project Number: 200995: P 95/062. Unpublished study prepared by Rhone

- Poulenc Agriculture Ltd. 69 p.

44065801 Burr, C. (1996) (Carbon 14)

- RPA 202248: Adsorption/Desorption to and from Four

Soils and an Aquatic Sediment: Lab Project Number: 11486: 201213. Unpublished study prepared by Rhone

- Poulenc Agriculture Ltd. 124 p.

45658804 Burr, C. (1996) Herbicides: Isoxaflutole Route of Degradation (Aerobic Metabolism)

in One Soil: Final Report: Lab Project Number: P 94/094: B003826: 2001142. Unpublished study prepared by Rhone

- Poulenc Agriculture Limited. 87 p.

43588007 Burr, C.; Jones, M.; Newby, S. (1995) RPA 201772: Anaerobic Aquatic Metabolism:

Lab Project Number: P 93

- 045: 200730. Unpublished study prepared by Rhone

Poulenc Agriculture Ltd. 145 p.

45658805 Ferreira, E.; Bullus , C.; Jones, M.; et al. (1996) RPA 201772: Rate of Degradation

Under Aerobic Conditions in Three Soil Types: Lab Project Number: P 94/093: B003827: 201036. Unpublished study prepared by Rhone

- Poulenc Agriculture Limited. 138 p.

43588006 Ferreira, E.; Jon es, M.; Newby, S. (1994) RPA 201772: Aerobic Soil Metabolism:

Lab Project Number: P 92

- 332. Unpublished study prepared by Rhone

- Poulenc Agriculture Ltd. 79 p.

45658807 Hardy, I. (2002) Isoxaflutole: Kinetic Modelling Analysis of Data from Laboratory

Aero bic Soil Degradation Studies: Lab Project Number: 29056: CX/01/037: C015654. Unpublished study prepared by Battelle AgriFood, Ltd. 53 p.

48108103 Lowden, P. ; Cooper, I.; Simmonds, M. (2004) (Carbon 14)

- RPA202248:

Adsorption/Desorption to and from Four S oils and an Aquatic Sediment

- Addendum Report. Project Number: C040671, CX/03/071A, GOOD/11486. Unpublished study prepared by Battelle Agrifood, Ltd. 29 p.

43588008 Newby, S.; Godward , P.; Jones, M. (1995) RPA 201772: Aged Leaching Study in

Four Soils and a Sediment: Lab Project Number: P93/124: 200778. Unpublished study prepared by Rhone

- Poulenc Agriculture Ltd. 88 p.

45655906 Repetto

- Larsay, M. (1999) RPA 203328 Developmental Toxic ology Study in the Rat

by Gavage: Lab Project Number: SA 98427: R014875. Unpublished study prepared by Rhone

- Poulenc Agro. 190 p.