Docket Number EPA-HQ-OPP-2010-0979

www.regulations.gov

Isoxaflutole Final Work Plan

Registration Review

November 2011

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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 Preliminary Work Plan 

(PWP) in the Summary Document, which was posted in the isoxaflutole registration 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 additional 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 whether it continues to meet the Federal 

Insecticide, Fungicide, and Rodenticide Act (FIFRA) standard for registration. Changes in 

science, public policy, and pesticide use practices occur over time. The registration review 

program is intended to make sure that, as the ability to assess risk evolves and as policies and 

practices change, all registered pesticides continue to meet that statutory standard. The public 

phase of registration review begins when the initial docket is opened for each case. Information 

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

Isoxaflutole is an herbicide active 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 Use 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 reregistration 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 isoxaflutole technical registrant, Bayer CropScience (BCS), 

submitted a document containing a number of comments 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 correction 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 isoxaflutole 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,
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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 specific 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 on 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, 

and 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 physical-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). Kinetics 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 considered 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, aerobic soil metabolism data on parent isoxaflutole and RPA 202248 will not be 

required for registration review.
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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 as 

„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 based 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 metabolism 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 study 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; 

it 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 data 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 202248 have been submitted for review by the Agency. 

For example, three of the adsorption/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 RPA 202248 degradate can be determined from the studies starting with 

parent isoxaflutole.

EPA Response 4:

EPA notes the correction and agrees data on isoxaflutole degradate RPA 202248 are available. 

Comment 5:

Three available isoxaflutole adsorption/desorption studies (MRIDs 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).
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EPA classified these studies 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 202248 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 review. 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 expected to change risk conclusions.” Given the 

relatively rapid degradation of RPA 202248, the same reasoning applies to RPA 202248 and 

therefore an anaerobic 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 should 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 isoxaflutole 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 was 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:
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Guideline No. 835.6200, environmental chemistry analytical methods and ILV (water) data on 

isoxaflutole degradate RPA 202248 will not be required for registration review. The Agency 

agrees with the comment.

Comment 10:

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, soil 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 the 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 202248 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 environmental concentrations (EECs) estimated by the Agency using PRZMEXAMS 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 ecotoxicity testing with RPA 203328.

EPA Response 10:

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 

additional 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 11:

The Agency has requested tier II seeding emergence and vegetative 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.
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As stated by EPA, 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 formulations 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 al., 2002 and Dobbs et al., 2002.

EPA Response 11:

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 to 

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 (seedling emergence)

data for RPA 202248 because 1) RPA 202248 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 12:

The Agency has requested three avian reproduction studies that include a mallard duck and 

bobwhite quail study with RPA 203328, 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 testing of RPA 

203328 is necessary.

EPA Response 12:

Guideline No. 850.2300, avian reproduction data on isoxaflutole degradates RPA 202248 and 

RPA 203328 will not be required for registration review.

Available 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 isoxaflutole on potential food items of birds (if 100% 

conversion of isoxaflutole to degradate RPA 202248 is assumed, the most conservative EEC is 

34 mg/kg-food). 
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The Agency no longer considers degradate RPA 203328 to be of toxicological concern for avian 

reproductive 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 toxicity 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 highest 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 13:

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) 

where 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 compound 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 this 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 solubility 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 riparius 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 sufficient information 

available to conclude that RPA 202248 and RPA 202328 pose minimal risk to aquatic 
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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 13:

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 involving exposures of D. magna to isoxaflutole to derive acute-tochronic 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. 

Comment 14:

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 Isoxaflutole 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 LC50 values are 0.0178, 3.6. and 

145 mg/L for isoxaflutole. The acute 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 suggests 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 explanation as to why these studies are triggered 

based on existing guidance.

EPA Response 14:

Guideline No. 850.1350, saltwater invertebrate life cycle data on isoxaflutole degradates RPA 

202248 and RPA 203328 will not be required for registration review.

Available 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 to 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 (2010), the Agency derived a 21-day 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 a 
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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 than 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 degradate, 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 sufficient 

to derive ACRs that may be used to estimate the chronic toxicities of degradates RPA 202248 

and RPA 203328 to estuarine/marine invertebrates. 

Comment 15: BCS will conduct a freshwater fish early life stage (ELS) study with RPA 202248 

as is anticipated to be required 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 203328 is necessary or warranted.

EPA Response 15:

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 available) 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 16:

The Agency 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 isoxaflutole 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 need for these additional 

studies.

EPA Response 16:

Guideline 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. 
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Risk Assessment and Data Needs

The Agency will require data for use in conducting an ecological risk assessment, including an 

endangered 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. 

Ecological Risk:

The most recent 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 (listed 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, the 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 for 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 cycle1

o Guideline No. 850.1400 - Freshwater and saltwater fish early life stage2

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 freshwater invertebrate life cycle data on RPA 202248 may satisfy the need for freshwater 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 stage data on RPA 203328.
13

the isoxaflutole 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 reevaluated 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 degradates 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 update the occupational exposure assessment for isoxaflutole with 

an assessment of the cancer risk to occupational handlers from use of the dry flowable

isoxaflutole formulations. The assumptions used in the exposure and risk calculations are 

currently different 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 postapplication inhalation exposure assessment based on the result of the Agency‟s 

evaluation of a March 2010 Scientific 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, the 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 isoxaflutole registration 

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

and anticipated human health risk assessments.
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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 North 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 compare 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 on 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 carcinogenicity, neurotoxicity, developmental, 

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

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

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

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

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

taxonomic groups. As part of its most recent registration decision, 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), isoxaflutole is subject to the 

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

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

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

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

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

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

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

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

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

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

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

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 
15

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

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Isoxaflutole is 

not among the group of 58 pesticide active ingredients on the initial list to be screened under the 

EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data callins, 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 chemicals, 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 Docket

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 

Decision

2016 – July – Sept.

Close Public Comment Period 2016 – Oct. – Dec.

Registration Review Decision and Begin Post-Decision Follow-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. The isoxaflutole registration review timeline may be adjusted

depending on the outcome of studies submitted in response to the DCI. If submitted isoxaflutole

degradate RPA 202248 data are found to satisfy the need for data on the degradate RPA 203328,

then the registration review timeline for isoxaflutole will be shortened by one year.
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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 324

850.1400 Freshwater fish early life stage Degradate RPA 202248 12

850.1400 Saltwater fish early life stage Degradate RPA 202248424

850.1400 Freshwater and saltwater fish early life stage Degradate RPA 203328524

850.4100 Nontarget area phytotoxicity, seedling 

emergence, Tier 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 registration 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 life stage data on RPA 202248. The additional time is provided in case the freshwater data does not satisfy the 

saltwater data need. The isoxaflutole registration 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 registration review timeline may be adjusted 

depending on the outcome of the submitted data.
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References

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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. 

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

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Unpublished study prepared by Rhone-Poulenc Agriculture Limited. 87 p. 

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

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

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C015654. Unpublished study prepared by Battelle AgriFood, Ltd. 53 p. 

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Adsorption/Desorption to and from Four Soils and an Aquatic Sediment - Addendum 

Report. Project Number: C040671, CX/03/071A, GOOD/11486. Unpublished study 

prepared by Battelle Agrifood, Ltd. 29 p.

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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 Toxicology Study in the Rat 

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

by Rhone-Poulenc Agro. 190 p.