Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 2 of 20 The critical effects resulting from oral administration with is oxaflutole were reported as ocular toxicity in rats, hepatotoxicity (including tumor formation)

, thyroid tumors in rats and mice, and hematotoxicity in dogs and mice. The liver and ocular toxicities are consistent with the proposed mode of action of isoxa flutole involving inhibition of the hepatic enzyme 4

- hydroxyphenylpyruvate dioxygenase (HPPD) that leads to the build

- up of tyrosine in the blood and eyes, respectively.

Developmental toxicity was observed in rats and rabbits as growth retardations includ ing delays in skeletal ossification, effects that have been observed with other HPPD inhibitors (e.g., pyrasulfotole ). T here was evidence of increased susceptibility in the rabbit study in the form of increased incidence of fetuses with 27 th pre

- sacral ve rtebrae at a dose much lower than those causing maternal deficits in body weight and food consumption. Neither the rat developmental study nor the rat 2

- generation reproductive toxicity studies revealed any evidence of increased susceptibility. H owever, both adults and offspring in the 2

- generation reproductive toxicity study exhibited ocular and liver toxicities seen in long

- term studies.

Isoxaflutole was negative in a variety of genotoxicity screening assays. However, in carcinogenicity studies, isoxa flutole induced liver and thyroid tumors in rats and liver tumors in mice. Based on the tumor findings, the HED Carcinogenicity Peer Review Committee (CPRC; 1997) classified isoxaflutole as “likely to be a human carcinogen.”

A cute and chronic aggregate (food + dietary water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID , ver. 2.03). The acute and chronic analyse s incorporated the drinking water estimates provided by the Environmental Fate and Effects Division (EFED)

. The estimated drinking water concentrations (EDWCs) were Tier 1 estimates for surface water using the FIRST model [ Food Quality Protection Act (FQPA) Index Reservoir Screening Tool ] for isoxa flutole and its degradate of concern, RPA 202248. EDWCs of 0.00739 ppm and 0.00186 ppm were used in the acute and chronic analysis, respectively.

The acute analysis assumed DEEM TM (ver. 7.81) default processing factors, 100% crop treated (CT), and toler ance

- level residues for all commodities. The resulting acute food plus water
exposure estimates are not of concern to HED ( ≤ 100% acute population

- adjusted dose (aPAD)) at the 95 th percentile of the exposure distribution for all population subgroup s of int erest ; the

res ulting acute exposure estimate for females 13 to 49 years old (the subgroup with the greatest risk) was 2.3 % of the aPAD at the 95 th percentile of the exposure.

The chronic and cancer analyse s assumed DEEM TM (ver. 7.81 ) default processing factors, 100% CT , and tolerance

- lev el residues for all commodities . The chronic and cancer analyse s also incorporated the drinking water estimates provided by EFED (see above). The resulting chronic and cancer risk estimates are not of concern to HED. The most highly exposed population was all infants (<1 year old ) utilizing 9.1 % of the chronic PAD (cPAD). The cancer risk for the general U.S. population was 9 x 10 - 7

. The residue chemistry database is sufficient t o support the current registrations. The following data requirement remain s outstanding: successful petition method validation (PMV) of the proposed plant enforcement method.

T here are no established Mexican or Codex maximum residue limits (MRLs) for residues of isoxaflutole

. Therefore, issues of compatibility with respect to U.S. tolerances and Codex MRLsIsoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 3 of 20 do not exist. However, as the Canadian tolerance for corn grain contains an additional metabolite ( 2

- metylsulfonyl

- 4

- trifluorometyl benzoic acid ), harmonization is not possible at this time. In addition, Canadian MRLs are established for livestock commodities.

There is sufficient information available to assess occupational exposure to isoxaflutole. All of the occupational exposure scenarios for the registered uses of isoxaflutole have been assessed adequately, except for the occupational handler cancer risks from the dry

- flowable (DF) formulation registered on corn. This assessment has been conducted in the past, but needs to be updated using cu rrent HED assumptions. In addition, based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment has not been performed for isoxaflutole; however, if new policies or procedures are put into place, th e Agency may revisit the need for a quantitative occupational post

- application inhalation exposure
assessment.

Introduction

Isoxaflutole, an isoxazole herbicide (Group 27) for control of broadleaf and grass weeds, is registered by Bayer CropScience for a Section 3 use as a pre

- emergent or early post

- emergence broadcast treatment to field corn (the only registered food use) ; and a crop

- destruct Section 5 EUP use as a pre

- plant, pre

- emergent, or early post

- emergent broadcast treatment to i soxaflutole

t olerant soybeans. The registered products include the SC formulations Balance ® PRO (EPA Reg. No. 264

- 600), Balance ® FLEXX (EPA Reg. No. 264

- 1067), and Corvus ® (EPA Reg. No. 264

- 1066); containing isoxaflutole at concentrations of 4.0 lb ai/gal, 2.0 lb ai/g al, and 1.88 lb ai/gal, respectively. Use on corn is limited to a single pre

- emergent or early post

- emergence application at a maximum rate of 0.094 lb ai/ A . There are no registered or proposed residential

uses.
HED recently evaluated a crop

- destruct EU P for use on soybeans (D 370958 , G. Kramer, et al

. ; 09

- MAR

- 2010). A Section 3 request for use on soybeans is currently under evaluation.

The nature of the residue in corn is understood, based on metabolism studies with corn treated with isoxaflutole . The residues of concern for both the tolerance expression and risk assessment

are isoxaflutole and RPA 202248 . The nature of the residue in livestock is understood based on metabolism studies with goats and hens. The residues of concern in livestock f or tolerance enforcement are isoxaflutole and RPA 202248; for risk assessment, the residues of concern are isoxaflutole, RPA 202248, RPA 205834, and RPA 207048. The residue chemistry database is sufficient to support the current registrations.

Data nee ds and risk assessment updates required under registration review for isoxaflutole are as follows:

Toxicology: T he toxicity endpoint/dose selection along with the FQPA Safety Factor (SF) will need to be re

- evaluated according to current policy.

Residue Chemistry: Successful PMV of the proposed plant enforcement method. The tolerance expression for isoxaflutole residues needs to be updated to reflect current Agency policy: “Tolerances are established for residues of the herbicide isoxaflutole

,Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 4 of 20 including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of isoxaflutole ( (5

- cyclopropyl

- 4

- isoxazolyl)[2

- (methylsulfonyl)

- 4

- (trifluorome thyl)phenyl]methanone ) and its metabolite 1

- (2

- methylsulfonyl

- 4

- trifluoromethylphenyl)

- 2

- cyano

- 3

- cyclopropylpropan

- 1,3

- dione , calculated as the stoichiometric equivalent of isoxaflutole , in or on the following commodities:”

Dietary Exposure: A new dietary risk assessment incorporating updated EDWCs may be required

. Occupational Exposure: A revised occupational exposure assessment.

Hazard Identification/Toxicology

Isoxaflutole is an isoxazole herbicide registered for control of broadleaf and grass weeds in corn. In acute toxicity studies, isoxaflutole was minimally toxic by the oral (Category IV), dermal (Category III) and inhalation ( Category IV) routes of exposure. It was n ot a der mal irri tant, an eye irritant, or a dermal sensitizer.

Following oral administration in the rat, radiolabeled isoxaflutole was rapidly and extensively absorbed and metabolized. No sex

- related differences in metabolism were observed. Eliminati on was dose

- depend ent, with the majority of the radiolabel being eliminated in the first 24 and 48 hrs for the low (1 mg/kg) and high (100 mg/kg) dose, respectively. Very low levels of radioactivity were observed in tissues at 168 hours post

- dosing. Elimination half

- lives were similar between the low

- and high

- dose groups, with an estimated mean blood half

- life of 60 hrs.

The critical effects resulting from oral administration with isoxaflutole were reported as ocular toxicity in rats, hepatotoxicity (including tumor for mation)

, thyroid tumors in rats and mice, and hematotoxicity in dogs and mice. The liver and ocular toxicities are consistent with the proposed mode of action of isoxaflutole involving inhibition of the hepatic enzyme HPPD that leads to the build

- up of ty rosine in the blood and eyes, respectively.

Developmental toxicity was observed in rats and rabbits as growth retardations including delays in skeletal ossification, effects that have been observed with other HPPD inhibitors (e.g., pyrasulfotole ). T here was evidence of increased susceptibility in the rabbit study in the form of increased incidence of fetuses with 27 th pre

- sacral vertebrae at a dose much lower than those causing maternal deficits in body weight and food consumption. Neither the rat developmental study nor the rat 2

- generation reproductive toxicity studies revealed any evidence of increased susceptibility. H owever, both adults and offspring in the 2

- generation reproductive toxicity study exhibited ocular and liver toxicities seen in long

- term studies.

In acute and subchronic neurotoxicity studies in adult rats, mild changes in functional observation battery (FOB) parameters (grip strength and/or landing foot splay) were observed. However, such effects were not observed in either pre gnant animals or offspring in a developmental

- neurotoxicity study (DNT) study in rats. In both maternal animals and offspring, body

- weight changes and/or food consumption were the primary effects noted and at the same dose tested. Decreased brain weights were observed in offspring on PND 11 at the high doseIsoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 5 of 20 only, but not at a later time point, which is an indicator of a developmental delay and/or a secondary effect of the decreased body weight also observed in the offspring. Although morphometric analyse s were not performed in the DNT study, there were no effects on pup swimming ability, learning, memory, motor activity, or auditory startle response at any dose, nor was there any evidence of neuropatho logy at any dose

. As a result, the missing morphometr ic measurements, while required, are unlikely to affect the tentative LOAEL of the study (highest dose tested).

A 21

- day dermal toxicity study with isoxaflutole showed that a dose as high as 1000 mg/kg failed to induce any type of dermal or systemic toxi city.

Isoxaflutole was negative in a variety of genotoxicity screening assays. However, in carcinogenicity studies, isoxaflutole induced liver and thyroid tumors in rats and liver tumors in mice. Based on the tumor findings, the HED CPRC (1997) classifi ed isoxaflutole as “likely to be a human carcinogen.”

In the last risk assessment ( D 370958 , G. Kramer, et al

. ; 09

- MAR

- 2010 ), the only database deficiency noted was a guideline immunotoxicity study as part of new toxicity data requirements in the 40 CFR Part 158 for conventional pesticide registration . Since then, an immunotoxicity study has been submitted and reviewed by the Agency. The results of this study indicate that there were n o immunosu ppressive effects following repeated daily dosing with isoxaflutole up to the highest dose tested of 279 mg/kg/day. Thus, the immune system does not appear to be a target for isoxaflutole.

Endocrine Disruption As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturat ion, 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 r egistration 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 subje ct 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 s creening 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.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 6 of 20 Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins fo r 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 r egistration 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 chemicals, future lists , the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

. Inhalation Toxicity Study Based on the available toxicity database and the Agency's current practices, t he inhalation risk for isoxaflutole was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route

- to

- route extrapolation approach (i.e.

, the use of oral toxicity studies for inhalation risk assessment) f rom its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agenc y is in the process of evaluating the SAP report and may, as appropriate, re

- examine and develop new policies and procedures for conducting inhalation risk assessments, including route

- to

- route extrapolation of toxicity data. If any new policies or proced ures are developed, the Agency may revisit the need for an inhala tion toxicity study for isoxaflutole and/or a re

- examination of the inhalation toxicity risk assessment.

Conclusion s The toxicity database for isoxaflutole is adequate to support existing registrations and registration review . T he toxicity endpoint/dose selection along with the FQPA SF will need to be re

- evaluated according to current policy.

Residue Chemistry

The nature of the residues in corn is understood, based on metabolism studies with corn treated with isoxaflutole. The HED Residues of Concern Knowledgebase Subcommittee (ROCKS) determined that the residues of concern for both the tolerance expression and risk assessment are isoxaflutole and RPA 202248 ( DP# 3 5 4 076

, 7 / 10 /08, R. Dai ss). The nature of the residue in livestock is understood based on metabolism studies with goats and hens. The residues of concern in livestock for tolerance enforcement are isoxaflutole and RPA 202248; for risk assessment, the residues of concern are is oxaflutole, RPA 202248, RPA 205834, and RPA 207048 ( DP# 3 5 4 076

, 7 / 10 /08, R. Daiss).

A liquid chromatography with tandem mass spectrometry ( LC / MS/MS) method is available for the enforcement of the proposed tolerances for corn commodities. The method was forwarded to Agency chemists at Analytical Chemistry Laboratory/Biological and Economics Analysis Division (ACL/BEAD) for a petition method validation (PMV)

. Adequate crop field trial data are available to support the proposed tolerances. Quantifiable

r esidues of isoxaflutole and RPA 202248 analytes were found only in forage samples from a single trial (out of 20 trials) . Based on the results of these trials, the established tolerances for field corn grain

, forage, and stover are appropriate.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 7 of 20 Adequate livestock feeding studies have been submitted. The livestock feeding study data with the estimated maximum dietary burden s indicate that tolerances are not needed for the combined residues of parent and RPA 202248 in meat, milk, poultry, and eggs

. Adeq uate confined and field rotational crop studies have been submitted; the residues of concern in rotational crops are isoxaflutole and its metabolite RPA 202248. These data indicated that plantback intervals (PBIs) of 4 months for wheat and 6 months for al l other crops are appropriate for isoxaflutole; no rotational crop tolerances are required.

Conclusions The qualitative nature of isoxaflutole residues in corn, rotational crops, and livestock is adequately understood. The residues of concern for both the tolerance expression and risk
assessment are isoxaflutole and RPA 202248 . The nature of the residue in livestock is understood based on metabolism studies with goats and hens. The residues of concern in livestock for tolerance enforcement are isoxaflutole and RPA 202248; for risk assessment, the residues of concern are isoxaflutole, RPA 202248, RPA 205834, and RPA 207048. The residue chemistry database is sufficient to support the current registrations. The following data requirement remain s outstanding: successful PMV of the proposed plant enforcement method.

Dietary Exposure

The most recent chronic dietary

- exposure assessment was performed in conjunction with the March 20 1 0 human

- health risk assessment conducted by HED ( D 370958 , G. Kramer, et al

. ; 09

- MAR

- 2010 )

. D ietary risk assessments were conducted using DEEM

- FCID , ver. 2.03 , which incorporates consumption data from the United States Department of Agriculture (USDA) Continuing Surveys of Food Intake s by Individuals (CSFII; 1994

- 1996 and 1998). The acute analysis assumed DEEM TM (ver. 7.81) default processing factors, 100% CT

, and tolerance

- level residues for all commodities. The resulting acute food plus water exposure estimates are not of
concern to HED ( ≤ 100% aPAD) at the 95 th percentile of the exposure distribution for all population subgroup s of interest , the res ulting acute exposure estimate for females 13 to 49 years old (the subgroup with the greatest risk) was 2.3 % of the aPAD at the 95 th percentile of the
exposure. The chronic analysi s assumed DEEM TM (ver. 7.81) default processing factors, 100% CT , and tolerance

- lev el residues for all commodities . The resulting chronic and cancer risk estimates are not of concern to HED. The most highly exposed population was all infants (<1
year old ) utilizing 9.1 % of the cPAD. The cancer analysi s assumed DEEM TM (ver. 7.81) default processing factors, 100% CT , and tolerance

- lev el residues for all commodities . The resulting

canc er risk estimate, 9 x 10 - 7 for the general U.S. population

, is not of concern to HED.

The HED Residues of Concern Knowledgebase Subcommittee (ROCKS) determined that the residues of concern for drinking water are isoxaflutole and RPA 202248 (DP# 354076, 7/10/08, R. Daiss). Drinking water residues were incorporated directly into the acute and chronic dietary analyses ( “ water, direct, all sources” and “water, indirect, all sources”) and were provided by EFED ( D P# 370959 ; 1/29/2010, W. Shaughnessy). The EDWCs were Tier 1 estimates for ground water using the SCI

- GROW model and surface water using the FIRST model for isoxaflutole and RPA 202248 . The models utilized an application rate of 0. 141 lbs. ai/A with a single appli cation to corn per season (highest previously registered/proposed use rate)

. HED notes that the maximum use rate has been subsequently lowered to 0. 094 lbs. ai/A

.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 8 of 20 Conclusions The dietary

- exposure database is adequate to support the existing registrations . However, a new dietary assessment may be required during Registration Review to incorporate potential changes to the isoxaflutole estimated drinking water concentrations.

Residential Exposure

There are currently no registered residential uses of isoxaflutole . Therefore, residential handler and post

- application exposures have not been assessed.

Residential Bystander Post

- application Inhalation Exposure Based on the Agency's current practices, a quantitative residential bystander post

- application inhalation exposure assessment was not performed for isoxaflutole at this time . However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought ex pert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in t he process of evaluating the SAP report and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies o r procedures are put into place, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for isoxaflutole

. Spray Drift Spray drift is always a potential source of exposure to residents nearby to spraying operati ons. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for isoxaflutole

. The Agency has been working with the Spray Drift Task Force, E PA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm) . On a chemical

- by

- chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Ta sk Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. A fter the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks associated with drift.

Conclusions Residential handler and post

- application exposures are not permitted by the label and have not been previously assessed, nor are they expected. Because there are currently no registered residential uses, an assessment is not required at this time.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 9 of 20 Agg regate Risk Assessment

In the most recent risk assessment of isoxaflutole ( D 370958 , G. Kramer, et al

. ; 09

- MAR

- 2010 ), the dietary exposure analysis represented the aggregate chronic risk assessment because it included drinking water estimates. Since there are no registered or proposed uses that result in residential exposures, only chronic aggregate exposure assessments considering exposure from food and water are required.

Conclusions A new aggregate risk assessment may be required during Registration R eview to incorporate potential changes to the isoxaflutole EDWC s.

Occupational Exposure

Isoxaflutole is registered for a Section 3 use as a pre

- plant or pre

- emergent broadcast treatment to field corn; and a crop

- destruct Section 5 EUP use as a pre

- plan t, pre

- emergent, or early post

emergent broadcast treatment to isoxaflutole

- tolerant soybeans. Previous occupational exposure assessments addressing both cancer and non

- cancer risks have been conducted for field corn (Memos, T. Keigwin, 10/21/97, D238846; 11/26/97, D241075) and isoxaflutole

- tolerant soybeans (Memo, A. Nowotarski , 3/9/10 ; D 373091 ).

Occupational Handlers : HED has determined that there is potential handler exposure to isoxaflutole from the following scenarios: 1) mixing and loading DF formulations in support of groundboom applications; 2) mixing and loading liquid formulations in support of groundboom operations; and 3) applying liquids using open

- cab groundboom equipment

. HED h as completed cancer and non

- cancer handler assessments for the scenarios above ( see Tables A4.2 and A4.3 in the attachments). It should be noted that both DF and liquid formulations are registered for the corn use; however, only the DF formulation was assessed in previous risk assessments. The registered soybea n use is for a liquid formulation and has been assessed at the same rate as that registered for the corn use. Therefore, the assessment for the soybean use covers the corn use.

Non

- c ancer : As no chemical

- specific data were available with which to asse ss potential exposure to pesticide handlers, the occupational handler non

- cancer assessments were based primarily on surrogate unit exposures from the Pesticide Handlers Exposure Database (PHED), the maximum application rates allowed on registered labels a nd assuming default maximum area treated per day for specific crops

. Handler's exposure and risk were calculated at the following levels of mitigation: baseline (long pants, a long

- sleeved shirt, no chemical

- resistant gloves, and no respirator) and with p ersonal

- protective equipment (PPE; baseline clothing with chemical

resistant gloves

, when necessary). Provided that commercial pesticide handlers use label prescribed PPE ( i.e. , long pants, long sleeved shirt, shoes + socks and the respective protective
g loves), all assessed MOEs were not of concern to HED (MOE ≥3 00).

C ancer : The occupational handler cancer risk estimates resulting from exposures to isoxaflutole were calculated using a linear low

- dose extrapolation approach (Q 1 *). For the field corn use, occupational handler scenarios were assessed for Pesticide Control Officers (PCOs) and individual farmers, assuming different acres treated/day for each. The assumptions used in the exposure and risk calculations for the corn use a re different from current HED assumptions and; therefore, the cancer assessment for the DF formulation would need to be re

- assessed. As withIsoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 10 of 20 the non

- cancer assessment, the liquid formulation corn use is covered by the assessment that was conducted for the soybean use.

For the soybean use, occupational handler exposure scenarios were assessed for individuals employed by multiple establishments ( i.e. , commercial or migratory farmworkers) and were assumed to be exposed for 30 days per year. Provided that commercial pesticide handlers and farmers use label prescribed PPE ( i.e., long pants, long

- sleeved shirt, shoes + socks and the respective protective gloves), estimated cancer risks are below 10 - 6

. Occupational Post

- Applicatio n : For the corn use, an occ upational postapplication dermal assessment was not performed. The past risk assessments state that considering the labeled use pattern (pre

- plant or pre

- emergent)

, post

- application exposure is not expected because no corn foliage is present

. For the soy bean use, the current label also limits the timing of applications to
pre

- plant, pre

- emergence or pre

- bloom (up to, but not including first bloom); therefore, post

application cancer and non

- cancer dermal assessments were conducted for those activities ass umed most likely to occur when minimal foliage is present.

Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment has not been performed for isoxaflutole . However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pe sticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109mee ting.html ). The Agency is in the process of evaluating the SAP report as well as available postapplication inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for isoxaflutole.

Non

- c ancer : For the non

- cancer dermal risk from use on soybeans, no chemical

- specific data were available with which to estimate dermal post

- application exposure of agricultural workers to dis lodgeable residues of isoxaflutole. Therefore, post

- application worker exposure was estimated using a default HED procedure that assumes 20% of the application rate is available as dislodgeable foliar residue (DFR) on the day of treatment and that there i s 10% dissipation each day following application. The calculated residues were then used with default transfer coefficients taken from the HED Science Advisory Council for Exposure (ExpoSAC) Policy 003.1, which lists a number of possible post

- application agricultural activities relative to some of the subject crops, to estimate potential pesticide exposure to agricultural workers. HED has determined that short

- and intermediate

- term risk estimates are not of concern (i.e., MOEs ≥3 00) on the day of treatme nt (i.e., Day 0) for all post

- application exposure activities associated with the soybean use ( see Table A4.4 in the attachments )

.

C ancer : Occupational post

- application dermal exposure scenarios for the soybean use were assessed for individuals employed by multiple establishments (i.e., commercial or migratory farmworkers) and were assumed to be exposed 30 days per year. D FRs were estimated using the method described above (assuming 20% of the active ingredient is available initially andIsoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 11 of 20 dissipation of 1 0% per day thereafter). HED used the average residue over 30 days to estimate cancer risk. Estimated cancer risks are below 10 - 6 ( see Table A4.5 in the attachments ).

Conclusions There is sufficient information available to assess occupational exposure to isoxaflutole. All of the occupational exposure scenarios for the registered uses of isoxaflutole have been assessed adequately, except for the occupational handler cancer risks f rom the DF formulation registered

on corn. This assessment has been conducted in the past, but needs to be updated using current HED assumptions. In addition, b ased on the Agency's current practices, a quantitative occupational post

- application inhalatio n exposure assessment has not been performed for isoxaflutole; however, i f new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment.

Public Health and Pesticide Epidemiology Data

For this evaluation, the OPP Incident Data System (IDS) w as utilized for pesticide incident data on the active ingredient isoxaflutole . The purpose of the database search is to identify potential patterns on the frequency and severity of the health effects attributed to isoxaflutole exposure. The IDS includes reports of alleged human health incidents from various sources, including mandatory FIFRA Section 6 (a) (2) report s from registrants, other federal and state health and environmental agencies

, and individual consumers. Since 1992, OPP has compile d these reports in IDS. IDS contain reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report. The Agricultural Health Study (AHS) is a high

quality

, prospective epidemiology study evaluating the link between pesticide use and various health outcomes including cancer. The AHS includes private and commercial pesticide applicators and their spouses

. If there are AHS findings relevant to a particular pesticide going through registration review, then the Agency will ensure th ey are considered in the problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk assessment phase of the process

. The AHS includes information on use of 50 different pesticide active ingredients commonly used in ag riculture

.

IDS records incidents resulting in high er severity outcomes in more detail, in a module called the Main IDS module . This system stores incident data for death, major and moderate incidents, and it includes more details about the location, date

, and nature of the incident. Main IDS incidents involving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesticide , and therefore , if present, these incidents are listed in a t able at the end of this report. Additionally, since higher

- severity incidents are generally of greater concern, incidents involving death and major outcomes would also include a narrative summary. The less severe human incidents (minor, unknown , or no eff ects outcomes) are reported by registrants as counts called aggregate summaries and are recorded in separate module called Aggregate IDS

. In Aggregate IDS , from January 1, 200 2 to May 27 , 2010

, there are three case s reported for isoxaflutole . Because it falls within the categories reported as counts (which includes minor, unknown

, or no effects)

, there is no unique report that provides details about the incident and single chemical incidents are not distinguished from multiple chemical incidents ; however, a high frequency of incidents indicates there is a high potential for exposure and vice versa

. For isoxaflutole, there appears to be a low potential for exposure. For the Main IDS, from January 1, 2002 to November 30, 2010, there are no cases reported t hat involve the active ingredient isoxaflutole.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 12 of 20 Isoxaflutole is in cluded in AHS, but it is part of phase III and those data have not been published yet.

Based on the lack of incident cases reported to IDS , there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk
assessment.

Toler ance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR 180. 537 ) and MRLs are summarized in Attachment 6

. T here are no established Mexican or Codex MRLs for residues of isoxaflutole

. Therefore, issues of compatibility with respect to U.S. tolerances and Codex MRLs do not exist. However, as the Canadian tolerance for corn grain contains an additional metabolite ( 2

- metylsulfonyl

- 4

- trifluorometyl benzoic acid ), harmonization is not possible at this time. In addition, Ca nadian MRLs are established for livestock commodities.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the human

- health risk assessment, in accordance with U.S. Executive Order 12898, " Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf ). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variabi lity of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best availa ble information.

Human Studies

Past isoxaflutole risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED, the Outdoor Residential Exposure Task Force (ORETF) Database , and the Agricultural Reentry Task Force (ARTF) Database . EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 13 of 20 Data Requirements

Toxicology: T he toxicity endpoint/dose selection along with the FQPA SF will need to be re

evaluated according to current policy.

Residue Chemistry: Successful PMV of the proposed plant enforcement method. The tolerance expression for isoxaflutole residues needs to be updated to reflect current Agency policy: “T olerances are established for residues of the herbicide isoxaflutole

, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of isoxaflutole ( (5

- cyclopropyl

- 4

- isoxazolyl)[2

- (methylsulfonyl)

- 4

- (trifluoromethyl)phenyl]methanone ) and its metabolite 1

- (2

- methylsulfonyl

- 4

- trifluoromethylphenyl)

- 2

- cyano

- 3

- cyclopropylpropan

- 1,3

- dione , calculated as the stoichiometric equivalent of isoxaflutole , in or on the following commodities:”

Dietary Exposure: A new dietary risk assessment incorporating updated EDWCs may be required

. Occupational Exposure: A revised occupational exposure assessment.

References

Table 1. Memoranda Relevant to Registration Review. Author Barcode Date Title

G. Kramer, et al

. 370958 09

- MAR

- 2010 Isoxaflutole

. Crop

- Destruct Experimental Use Permit (EUP) for Use on Soybeans. Human

- Health Risk Assessment.

G. Kramer 373360 26

- FEB

- 2010 Isoxaflutole

. Crop

- Destruct Experimental Use Permit (EUP) for Use on Soybeans. Acute and Chronic Dietary Exposure and Risk Assessments. W. Shaughnessy 370959 29

- JAN

- 2010 Experimental Use Permit Drinking Water Assessment of Isoxaflutole for Use on Soybeans

. G. Kramer 354799 01

- AUG

- 2008 Isoxaflutole in/on Corn. Request for Petition Method Validation (PMV).

G. Kramer 349689 22

- JUL

- 2008 Isoxaflutole . Petition to Remove the Benzoic Acid Metabolite (RPA 203328) From the Tolerance Expression. Summary of Analytical Chemistry and Residue Data

. R. Daiss 354076 10

- JUL

- 2008 Isoxaflutole

. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS).

G. Kramer 340598 11

- APR

- 2008 Isoxaflutole

. Application for Registration of Two New Products for Use on Corn: SC 465 Herbicide and SC 480 Herbicide. Summary of Analytical Chemistry and Residue Data

. A

. Nowotarski 373091 0 9

- MAR

- 2010 Isoxaflutole: Occupational and Residential Exposure/Risk Assessment for Proposed Experimental Use on Soybeans. T. Keigwin 238845 21

- OCT

- 97 Occupational Exposure Assessment for the Use of Isoxaflutole (Balance) on Corn. T. Keigwin 241075 26

- NOV

- 97 Correction to Occupational Exposure Assessment for the Use of Isoxaflutole (Balance) on Corn.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 14 of 20 Table 1. Memoranda Relevant to Registration Review. Author Barcode Date Title B. Madden 243997 27

- JUL

- 98 Isoxaflutole

– 123000: Revised Health Effects Division Risk Characterization Document for the First Food Use of Isoxaflutole in/on Corn (6F4664).

Attachments :
Attachment 1: Chemical Identity Table

. Attachment 2: Isoxaflutole Endpoint Selection Table s . Attachment 3 : Exposure Potential for Adult and Child Aggregate Risk Estimates

. Attachment 4 : Occupational Use Patterns/Exposure Scenarios for Isoxaflutole

. Attachment 5 : Isoxaflutole International Residue Limit Statu s Sheet

.

cc: J

. Tyler (RAB1), G. Kramer (RAB1), C. Rodriguez (RAB1) RDI: RAB1 ( 3 / 9 /1 1 ) , J. Fowle ( 3 / 16 /11) G.F. Kramer: S10957 :PY

- S:(703)305

- 5079:7509P:RAB1Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 15 of 20 Attachment 1: Chemical Identity Table

.

Isoxaflutole Nomenclature

. Chemical structure of parent

Common name Isoxaflutole Company experimental name RPA 201772; AE B197278
IUPAC name 5

- cyclopropyl

- 4

- (2

- mesyl

- 4

- trifluoromethylbenzoyl)isoxazole
CAS name (5

- cyclopropyl

- 4

- isoxazolyl)[2

- (methylsulfonyl)

- 4

- (trifluoromethyl)phenyl]methanone CAS registry number 141112

- 29

- 0
End

- use product (EP) BALANCE ® PRO, EPA Reg. No. 264

- 600
Chemical structure of regulated metabolite

Common name Isoxaflutole diketonitrile ; RPA 202248
Chemical name 1

- (2

- methylsulfonyl

- 4

- trifluoromethylphenyl)

- 2

- cyano

- 3

- cyclopropyl propane

1,3

- dione
Chemical structure of metabolite included in risk assessment for livestock commodities

Common name RPA 205834
Chemical structure of metabolite included in risk assessment for livestock commodities

Common name RPA 207048Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 16 of 20 Attachment 2: Isoxaflutole Endpoint Selection Table s .

Table A 2.1. Summary of Toxicological Doses and Endpoints for Isoxaflutole in the 2010 Dieta ry Human

Health Risk Assessment

.
Exposure Scenario Point of Departure Uncertainty

Factors LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary

- females 13

- 49 years old LOAEL = 5 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 3X (includes UF L ) aRfD = aPAD =

0.02 mg/kg Prenatal developmental toxicity

(rabbit)

. Offspring LOAEL = 5 mg/kg/day based on increased incidence of fetuses with 27 th pre

- sacral vertebrae.
Acute Dietary

- general population, including infants and children NOAEL = 12 5 mg/kg UF A = 10X

UF H = 10X UF FQPA = 1X aRfD = aPAD =

1.25 mg/kg Acute neurotoxicity (rat)

.

LOAEL = 500 mg/kg based on significant decreases in hind limb grip strength and landing foot splay on day 15.

Chronic Dietary NOAEL = 2 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 1X cRfD = cPAD =

0.02 mg/kg/day Combined chronic

toxicity/carcinogenicity (rat)

. LOAEL = 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity (M) and liver toxicity (F).

Cancer Q 1 * (mg/kg/day) - 1 of 1.14 x 10 - 2 from the male CD

- 1 mouse liver for the linear low

- dose extrapolation based on statistically significant increases in liver tumors in both sexes of mice and rats. Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF L = extrapolation due to the use of a LOAEL in the absence of a NOAEL, UF FQPA = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

- observed adverse

- effect level, RfD = reference dose (a = acute, c = chronic).

Table A 2.2. Summary of Toxicological Doses and Endpoints for Isoxaflutole in the 2010 Occupation al Human

- Health Risk Assessm ent

.
Exposure Scenario Point of Departure Uncertainty

Factors RfD, LOC for

Risk Assessment Study and Toxicological Effects Dermal Short

- and Intermediate

- Term (1

- 30 days and 1

- 6 months) LOAEL = 5 mg/kg/day

Dermal

absorption factor = 3.5% UF A = 10X

UF H = 10X UF L = 3X Occupational

LOC for MOE <300 Prenatal developmental toxicity

(rabbit)

. Offspring LOAEL = 5 mg/kg/day based on increased incidence of fetuses with 27 th pre

- sacral vertebrae. Inhalation Short

- and Intermediate

- Term (1

- 30 days and 1

- 6 months) LOAEL = 5 mg/kg/day

100% inhalation assumed UF A = 10X

UF H = 10X UF L = 3X Occupational

LOC for MOE <300 Prenatal developmental toxicity

(rabbit)

. Offspring LOAEL = 5 mg/kg/day based on increased incidence of fetuses with 27 th pre

- sacral vertebrae. Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF L = extrapolation due to the use of a LOAEL in the absence of a NOAEL, UF FQPA = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

- observed adverse

- effect level, LOC = level of concern, MOE = margin of exposure.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 17 of 20 Attachment 3 : Exposure Potential for Adult and Child Aggregate Risk Estimates

.

(From D 370958 , G. Kramer, et. al ; 09

- MAR

- 2010 )

Summary of Dietary (Food and Drinking Water) Exposure and Risk for Isoxaflutole.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Cancer
Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.000442 <1 0.000077 3.8 0.000077 9 x 10 - 7 All Infants (<1 year old) 0.001555 1.2 0.000181 9.1

N/A N/A Children 1

- 2 years old 0.000736 <1 0.000132 6.6 Children 3

- 5 years old 0.000680 <1 0.000142 7.1 Children 6

- 12 years old 0.000475 <1 0.000105 5.3 Youth 13

- 19 years old 0.000375 <1 0.000082 4.1 Adults 20

- 49 years old 0.000391 <1 0.000067 3.4 Adults 50+ years old 0.000342 <1 0.000055 2.7 Females 13

- 49 years old 0.000392 2.3 0.000067 3.4 *The values for the highest risk population for each type of risk assessment are bolded.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 18 of 20 Attachment 4: Occupational Use Patterns/Exposure Scenarios for Isoxaflutole

.

Table A4.1. Summary of Occupational Uses for Isoxaflutole.

Use Sites Product

Type (s) 1 Application

Equipment Application Type Timing Maximum Single Application Rate (lb ai/A) REI

Section 3 Registrations

Field Corn EC ground burndown, soil band, soil broadcast, soil
treatment pre

- plant, pre

emergence 0.094 12 hours

DF/WDG ground burndown, soil band, soil broadcast, soil incorporated, soil
treatment pre

- plant, pre

emergence 0.14 12 hours

Section 5 Registration

Isoxaflutole

- tolerant Soybeans SC ground Groundboom pre

- plant, pre

emergence, early post

emergent 0.094 12 hours

1. DF = dry flowable, WDG = water dispersible granules, EC = emulsifiable concentrate, SC = soluble concentrate.
Table A4.2. Summary of Representative Occupational Handler Non

- Cancer Exposure Scenarios and Risks for Isoxaflutole 1

.
Exposure Scenario Assessed DP# App. Rate (lb ai/A) Daily

Amount Treated Unit Exposure

(mg/lb ai) Short

- and Intermediate

Term MOE Inhalation Dermal Inhalation Dermal Field Corn

Mixer/Loader Open pour

– water

dispersible granule

D238846 0.2 farmer 105 PCO 2 200 0.00077 SLNG 0.0633 farmer 4500

PCO 2500 Applicator Applicator

–

groundboom

– open cab 0.00074 SLNG 0.014 farmer 12000 PCO 6100 Mixer/Loader /Applicator Open pour

– DF/WDG

-

groundboom

– open cab 0.015 0.077 farmer 3300

Isoxaflutole

- Tolerant Soybeans

Mixer/Loader Open pour

– liquid

–

groundboom D373091 0.094 200 0.0012 SLNG 2.9 SLWG 0.023 13,000 SLNG 130 SLWG 20,000 Applicator Applicator

–

groundboom

– open cab 0.00074 SLNG 0.014 22,000 33,000
1. SLNG = Dermal Single Layer Work Clothing No Gloves ; SLWG = Dermal Single Layer Work Clothing With Gloves

. 2. PCO = Pesticide Control Officer.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 19 of 20 Table A4.3. Summary of Representative Occupational Handler Cancer Exposure Scenarios and Risks for Isoxaflutole.

Exposure Scenario Assessed DP# App. Rate (lb ai/A) Daily

Amount Treated Dose 1

(mg/kg/day) Combined ADD 2 (mg/kg/day) LADD 3

(mg/kg/day) Cancer

Risk 4 Inhalation Dermal Field Corn

Mixer/Loader Open pour

– water

dispersible granule

D238846 0.2 farmer 105 PCO 2 200 - - farmer 1.1E

03 PCO 2.0E

- 03 farmer

3.1E

- 06 PCO 1.8E

- 05 farmer

3.5E

- 08 PCO 2.0E

- 07

Applicator Applicator

–

groundboom

– open cab - - farmer 4.3E

04 PCO 8.2E

- 04 farmer

1.3E

- 06 PCO 7.2E

- 06 farmer

1.5E

- 08 PCO 8.2E

- 08

Mixer/Loader/ Applicator Open pour

–

DF/WDG

- groundboom

– open cab - - farmer 1.5E

03 farmer

4.4E

- 06 farmer

5.0E

- 08

Isoxaflutole

- Tolerant Soybeans

Mixer/Loader Open pour

– liquid

– groundboom D373091 0.094 200 0.0003223 SLNG 0.02726 SLWG 0.0002162 SLNG 0.028

SLWG 0.00054 SLNG

1.1E

- 03 SLWG 2.2E

- 05 SLNG

1.3E

- 05 SLWG 2.5E

- 07

Applicator Applicator

–

groundboom

– open cab 0.0001987 SLNG 0.0001316 0.00033 1.4E

- 05 1.5E

- 07

1. Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x %Absorption ( 3.5% dermal and 100% inhalation) / Body weight ( 60 kg in corn assessment and 70 kg in soybean assessment ). 2. Combined ADD (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day). 3. Corn assessment: [PHED Unit Exposure (μg/lb ai handled) x % absorption x application rate (lb ai/acre) x acres treated/day x 1 mg/1000 μg 7 0

- kg body weight *] x # of days to treat average field x number applications/year x # of farms treated by commercial handler 365 days/year x 35/70**. Soybean assessment: Commercial Applicator LADD (mg/kg/day) = ADD x [(30 days/yr)/ (365 days/yr)] x (35 yrs/70yrs). 4 Commercial Applicator Cancer Risk = Commercial LADD x Q 1 * [1.14 x 10
- 2 (mg/kg/day)
- 1 ].

Table A4.4. Summary of Occupational Post

- application Non

- Cancer Exposure Scenarios and Risk for Isoxaflutole.

Soybeans Exposure

Scenario Assessed DP # Application Rate (lb ai/A) DFR 1 Transfer Coefficient (cm 2 /hr) Daily Dose 2

(mg/kg/day) MOE 3

ST IT Field/row crop, low/medium Scouting D373091 0.094 0.21 100 0.0001 51,000 The information in the table is based on proprietary and non

- proprietary data. 1. DFR (μg/cm 2 ) = Application rate (lb ai/A) x (1

- daily dissipation rate) t x CF (4.54E+8 μg/lb) x CF (2.47E

- 8 A/cm 2 ) x 20% DFR after initial treatment. 2. Daily Dose = [DFR (ug/cm 2 ) x TC (cm 2 /hr) x 0.001 mg/μg x Dermal Absorption (3.5%) x 8 hrs/day] ÷ Body Wei ght (60 kg). 3. LOAEL/Daily Dose (LOAEL = 5.0 mg/kg/day) ; ST = Short

- Term , IT = Intermediate

- Term

. Table A4.5. Summary of Occupational Post

- application Cancer Exposure Scenarios and Risk for Isoxaflutole.

Soybeans Exposure

Scenario Assessed DP # DAT 1 DFR 2 (ug/cm 2 ) Transfer

Coefficient 3 (cm 2 /hr) Daily Dose 4

(mg/kg/day) LADD 5 Cancer Risk 6
Field/row crop, low/medium Scouting D373091 1

- 30 0.21 100 0.000028 1.2E

- 06 1.31E

- 08

1. DAT = 30 day residue average

. 2. DFR value used is based on HED standard assumption of 20% of the active ingredient available initially and dissipation of 10% per day thereafter. 3. Transfer c oefficients selected in accordance with Expo SAC Policy 3.1 (August 2000)

. 4. Daily Dose (mg/kg/d ay) = DFR (μg/cm 2 ) x 0.001 mg/ug x TC (cm 2 /hr) x DA ( 3.5 %) x ET (8 hr/day)/70 kg

. 5. LADD (mg/kg/day) = DD x [(30 days/yr)/ (365 days/yr)] x (35 yrs/70yrs). 6. Cancer Risk = LADD x Q 1 * [ 1.14 x 10
- 2 (mg/kg/day)
- 1 ]

.Isoxaflutole Registration Review Human

- Health Assessment Scoping Document

Page 20 of 2 0 Attachment 5 : Isoxaflutole International Residue Limit Status Sheet.

Isoxaflutole 

### ( 123000 ; 1/11/2011 ) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : U

. S

. Canada Mexico 2 Codex 40 CFR 180. 537 : Plant : isoxaflutole , 5

- cyclopropyl

4

- (2

- methylsulfonyl

- 4

- trifluoromethylbenzoyl) isoxazole and its metabolite 1

- (2

- methylsulfonyl

- 4

- trifluoromethylphenyl)

- 2

- cyano

- 3

- cyclopropyl propan

- 1,3

- dione (RPA 202248), ca lculated as the parent compound.

Livestock : N one Plant : (5

- cyclopropyl

- 4

- isoxazoly)[2

- (methylsulfonyl)

- 4

- (trifluoromethyl)phenyl]methanone, including the metabolites 1

- (2

- methylsulfonyl

- 4

- trifluorometylphenyl)

- 2

- cyano

- 3

- cyclopropylpropane and 2

- mety h lsulfonyl

- 4

- trifluorometyl benzoic acid, as parent equivalent

. Livestock/Dairy Commodities : (5

- cyclopropyl

4

- isoxazoly)[2

- (methylsulfonyl)

- 4

- (trifluoromethyl)phenyl]methanone, including the metabolite 1

- (2

- methylsulfonyl

- 4

- trifluoromethylphenyl)

- 2

- cyano

- 3

- cyclopropylpropane, as parent equivalent. None

Commodity 1 Tolerance (ppm)/Maximum Residue Limit (mg/kg) U.S. Canada Mexico 2 Codex Corn, field, forage 0.04 Corn, field, grain 0.02 0.02 Field corn Corn, field, stover 0.02 MRLs with no U.S. equivalent Eggs 0.01 Liver of cattle 0.5 Liver of poultry 0.3 Meat byproducts of cattle 0.1 Meat byproducts of hogs 0.1 Meat byproducts of horses 0.1 Meat byproducts of poultry 0.1 Meat byproducts of sheep 0.1 Meat of cattle 0.2 Meat of hogs 0.2 Meat of horses 0.2 Meat of poultry 0.2 Meat of sheep 0.2 Milk 0.02 Completed: M. Negussie; 1/11/2010

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.