Is oxaben D376428

Page 1 of 90 UNITED STATES ENVIRONMENTA L PROTECTION A GENCY WA SHINGTON, D.C. 20460 Office of Chemical Safety and Pollution Prevention Date: July

2 8 , 2010 MEMORANDUM SUBJECT: Is oxaben . Human Health Risk Assessment for the First Food Uses of the Herbi cide o n Grape s , T ree Nuts and Pistachios . PC Code: 125851 DP Barcode: D376428 Decision No.: 379577 File Symbol : 62719 - LIN , 62719 - ARE Petition No.: 7F7222 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate C ase No.: NA T XR No.: NA CAS No.: 82558 - 50 - 7 MRID No.: NA 40 CFR: 180.xxx (first food use) FROM: Dennis McNeill y, Chemist/Risk Assessor

Elizabeth Holman, Chemist William T. Drew, Chemist Linnea Hansen , Ph.D., Toxicologist Suku Oonn ithan , Biologist Risk Assessment Branch II (RAB2) Health Effects Division (HED) (7509P) THROUGH: Christina Swartz, Chief

Risk Assessment Branch II (RAB2) Health Effects Division (HED) (7509P) and Michael S. Metzger , Designated Reviewe r P . V . Shah, Ph . D., Designated Reviewer Risk Assessment Review Committee Health Effects Division (7509P) TO: Kathry

n V. Montague , PM - 23 Herbicide Branch Registration Division (7505P)Is oxaben D376428

Page 2 of 90 Table of Contents 1.0 Executive Summary ................................ ................................ ................................ .......... 4 2.0 Ingredient Profile ................................ ................................ ................................ .............. 7 2.1 Summary

of Proposed Uses ................................ ................................ .................... 7 2.2 Structure and Nomenclature ................................ ................................ ................... 9 2.3 Phy sical and Chemical Properties ................................ ................................ ........... 9 3.0 Hazard Characterization/Assessment ................................ ................................ ........... 10 3.1 Hazard and Dose - Response Characterization ................................ ....................... 10 3.1.1 Database Summary ................................ ................................ ................... 10 3.1.1.1 Studies available and considered (animal, human, general literature ) ................................ ................................ ................................ ... 10 3.1.1.2 Mode of action, metabolism, toxicokinetic data ........................ 10 3.1.1.3 Sufficiency

of studies/data ................................ ......................... 10 3.1.2 Toxicological Effects ................................ ................................ ................ 11 3.1.3 Dose - response ................................ ................................ ........................... 12 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) ................................ . 12 3.3 FQPA Considerations ................................ ................................ ........................... 13 3.3.1 Adequacy

of the Toxicity

Database ................................ .......................... 13 3.3.2 Evidence of Neurotoxicity ................................ ................................ ........ 13 3.3.3 Developmental Toxicity Studies ................................ ............................... 13 3.3.4 Reproductive Toxicity Study ................................ ................................ .... 14 3.3.5 Additional Information from L iterature Sources ................................ ...... 15 3.3.6 Pre - and/or Postnatal Toxicity ................................ ................................ ... 15 3.3.6.1 Determination of Susceptibility ................................ ................. 15 3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre and/or Postnatal Susceptibility ................................ ................................ .. 16 3.3.7 Recommendation for a Developmental Neurotoxicity Study ................... 16 3.4 Safety

Fac tor for Infants and Children ................................ ................................ .. 16 3.5 Hazard Identification and Toxicity Endpoint Selection ................................ ........ 17 3.5.1 Acute Reference Dose (aRfD) ................................ ................................ .. 17 3.5.2 Chronic Reference Dose (cRfD) ................................ ............................... 17 3.5.3 In cidental Oral Exposure, Short - Term (1 to 30 days) ............................... 17 3.5.4 In cidental Oral Exposure, Intermediate - Term (1 to 6 months) ................. 17 3.5.5 Dermal Absorption ................................ ................................ .................... 18 3.5.6 Residential/Occupational Dermal Exposure, Short - Term (1 to 30 day s ) . 19 3.5.7 Residential/Occupational Dermal Exposure, Long - Term (>30 day s ) ...... 19 3.5.8 Residential/Occup ational Inhalation Exposure, Short - Term .................... 19 3.5.9 Residential and Occupational Inhalation Exposure (Intermediate - Term) 19 3.5.10 Residential and Occupational Inhalation Exposure (L ong - Term) .......... 20 3.5.11 Level of Concern for Margin of Exposure ................................ .............. 20 3.5.12 Recommendation for Aggregate Exposure Risk Assessments ............... 20 3.5.13 Classification of Carcinogenic Potential ................................ ................. 21 3.5.14 Summary

of Toxicological Doses and Endpoints for Use in Human Risk Assessments ................................ ................................ ................................ .......... 22 3.6 Endocrine disruption ................................ ................................ ............................. 25 4.0 Public Health and Pesticide Epidemiology Data and Incident Reports .................... 25 5.0 Dietary Exposure/Risk Characterization ................................ ................................ ..... 25Is oxaben D376428

Page 3 of 90 5.1 Pesticide Metabolism and Environmental Degradation ................................ ........ 26 5.1.1 Metabolism in Primary Crops ................................ ................................ ... 26 5.1.2 Metabolism in Rotational Crops ................................ ............................... 27 5.1.3 Metabolism in L ivestock ................................ ................................ ........... 27 5.1.4 Analy

tical Methodology ................................ ................................ ........... 28 5.1.5 Environmental Degradation ................................ ................................ ...... 29 5.1.6 Comparative Metabolic Profile ................................ ................................ . 30 5.1.7 Toxicity

Profile of Major Metabolites and Degradates ............................ 30 5.1.8 Pesticide Metabolites and Degradates of Concern ................................ .... 31 5.1.9 Drinking Water Residue Profile ................................ ................................ 31 5.1.10 Food Residue Profile ................................ ................................ ............... 33 5.1.11 International Residue Limits ................................ ................................ ... 34 5.2 Dietary

Exposure and Risk ................................ ................................ ................... 34 5.2.1 Acute Dietary

Exposure/Risk ................................ ................................ ... 34 5.2.2 Chronic Dietary

Exposure/Risk ................................ ................................ 35 5.2.3 Cancer Dietary

Risk ................................ ................................ .................. 35 5.3 Anticipated Residue and Perc ent Crop Treated (%CT) Information .......................... 36 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ............................ 36 6.1 Residential Postapplication Exposure . ................................ ................................ .. 38 6.2 Other (Spr ay

Drift, etc .) ................................ ................................ ........................ 40 7.0 Aggregate Risk Assessments and Risk Characterization ................................ ............ 41 7.1 Acute Aggregate Risk ................................ ................................ ........................... 41 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ..................... 41 7.3 Chronic Aggregate Risk ................................ ................................ ........................ 42 7.4 Aggregate Cancer Risk ................................ ................................ ......................... 42 8.0 Cumulative Risk Characterization/Assessment ................................ ........................... 43 9.0 Occupational Exposure/Risk Pat hway ................................ ................................ .......... 43 9.1 Short - and Intermediate - Term Handler Risk ................................ ........................ 43 9.2 Short - and Intermediate - Term Postapplication Risk ................................ ............. 45 10.0 Data Needs, Label Recommendations & Environment al Justice ............................... 45 10.1 Toxicology ................................ ................................ ................................ ............ 45 10.2 Residue Chemistry ................................ ................................ ................................ 46 10.3 Occupational and Residential Exposure ................................ ............................... 46 10.4 Label Recommendations ................................ ................................ ....................... 46 10.5 Environmental Justice ................................ ................................ ........................... 47 References: ................................ ................................ ................................ ................................ ... 47 Appendix A: Toxicology Assessment ................................ ................................ ........... 49 A.1 Toxicology

Data Requirements ................................ ................................ ................ 49 A.2 Acute Toxicity

Profile for Isoxaben ................................ ................................ .......... 50 A.3 Executive Summaries ................................ ................................ ................................ 55 A.4 Rationale for Toxicology Data Requirements ................................ .......................... 71 Appendix B: Metabolism Assessme nt ................................ ................................ .......... 74 B.1 Metabolism Guidance and Considerations ................................ ........................... 74 B.2 Tabular Summary of Metabolites and Degradates ................................ ................ 76 Appendix C: Tolerance Reassessment Summary and Table ................................ ..... 90 Appendix D: Review of Human research ................................ ................................ .... 90Is oxaben D376428

Page 4 of 90 1.0 Executive Summary Dow AgroSciences has submitted a petition, 7F7222, proposing the establishment of tolerances for residue s of the herbicide isoxaben [N - [3 - (1 - ethyl - 1 - methylprop yl ) - 5 - isoxazolyl] - 2,6 - dimethoxy

benzamide] in/on the following raw agricultural commodities: Grape ................................ ................................ ........... 0.01 ppm Grape, juice ................................ ................................ . 0.01 ppm Grape, raisin ................................ ................................ 0.01 ppm Nut, tree, group ................................ ........................... 0.03 ppm Pistachio ................................ ................................ ...... 0.03 ppm Alm ond, hulls ................................ .............................. 0.35 ppm The petitioner has also requested a waiver from the requirement for a tolerance for isoxaben in or on cattle meat b yproducts, meat, and milk . In conjunction with this petition, Dow AgroSciences has submitted a request to register an e nd use product, FN - 3133 Specialt y Herbicide , a 75% dry flowable (DF) formulation of isoxaben. The product is proposed for use on grapes and tree nuts with multiple soil applications ranging from 0.5 - 1.0 lb. ai/A/application , and a maximum of 1.0 lb. ai/A per crop year (harvest to harvest). No minimum retreatment interval (RTIs) is specified on the label. Preharvest intervals (PHI s) of 60 day s for tree nuts and 165 day s for grapes have been proposed. Is oxaben is already registered for non - food uses on turf, ornamentals, non - bearing fruit and nut trees, and non bearing vineyards. A human health risk assessment scoping document was completed for isoxaben in conjunction with Registration Review in August 2007 (D341567) . An addendum to the scoping document was completed in June, 2008 (D341543) to incorporate new toxicology data requirements under current 40 CFR Part 158 guidelines . For the purposes of this petition only , the nature of the residue in grapes and tree nuts (earl y season use onl y) is adequate ly understood based on grape and barley metabolism studies . This use is considered to fall under 40 CFR 180.6 (a)(3), i.e., no expectation of finite residue in meat, milk, poultry

and eggs ; tolerances are therefore not required. Isoxaben has low acute t oxicity via all routes. No toxicity was observed in subchronic oral or dermal studies. The liver and kidney were target organs in chronic studies. Significant liver toxicity was seen in mice but was limited to adaptive (non - adverse) changes in rats and dogs. Nephropath y was observed in the rat. Body weight and/or body weight gain were reduced in all species. Rat acute and subchronic neurotoxicity studies and an immunotoxicity study have not been submitted and are required; however, there was no eviden ce for these effects in the available data. The cancer classification is “Suggestive Evidence of Carcinogenic Potential,” based on an increased incidence of benign liver tumors in mice at the highest dose. Concern for genotoxicity

is low based on general ly negative studies. Cancer risk was not quantified because the RfD is considered protective.Is oxaben D376428

Page 5 of 90 No developmental toxicity was observed in the rat or rabbit. In the rat reproductive toxicity study , decreased corpora lutea and offspring toxicity (decreased body

weight and survival) occurred in the presence of maternal effects . M alformations (microphthalmia, coloboma) and hydroureter were observed in later offspring generations. Although offspring lineage suggested a genetic predisposition for these effects , a relationship to treatment could not be conclusivel y ruled out and the malformations were considered a possible treatment - related effect. However, they are not considered single - dose effects since they were only

increased in F2 offspring. The FQPA saf

et y factor was reduced to 1X. The d egree of concern for neurotoxicity and immunotoxicity

data gaps is low due to lack of evidence for these effects in the available studies. Concern for increased qualitative susceptibility in the rat reproductive study i s low, since a clear offspring NOAEL was identified ; m alformations were seen onl y at the limit dose and did not occur in developmental studies , and the exposure assessment does not underestimate exposure. The proposed use on grapes and tree nuts is supp orted by adequate field trial data, storage stability and processing studies. Detectable residues in grapes and tree nuts are not expected as a result of the proposed use s , except for almond hulls, a livestock feed item. N o acute d ietary

endpoint was ide ntified; therefore, no acute dietary risk assessment was conducted. HED performed a chronic dietary assessment using HED recommended tolerance level residues in grapes and tree nuts, and assum ed 100% crop treated . The dietary exposure estimates are base d on highl y conservative, health - protective assumptions regarding residue levels in food and water. For the general U.S. population and all population subgroups, th e chronic dietary

exposure estimates are below HED’s level of concern (LOC), i.e., 1 00% of the chronic population adjusted dose (cPAD) . The most highly exposed population subgroup is i nfants <1 yr, which utilizes 17% of the cPAD. The general U.S. population utilizes 5.1% of the cPAD. The proposed use of isoxaben in orchards of tree nuts and grapes is expected to result in short and intermediate - term occupational exposures to mixers, loaders, and applicators. The registrant did not submit a chemical - specific exposure study for assessing occupational exposures. Instead, surrogate unit exposures from the Pesticide Handlers Exposure Database (PHED) were used. S hort - and intermediate - term dermal risks were not calculated due to the absence of respective endpoints. Short - and intermediate - term inhalation margins of exposure ( MOEs ) are not of co ncern (MOEs ≥2,700). Only one application of isoxaben is allowed per season at the maximum rate per application (two at lower rates) on tree nuts and grapes. Risks to workers are not of concern because of the soil - directed application method proposed for appl yi ng isoxaben formulations, thereb y minimizing inhalation exposure, and due to the lack of a dermal endpoint. The labels also recommend incorporation of the spray by rainfall or irrigation for maximum efficacy as a preemergence herbicide, thereb y further minimizing postapplication exposures. With respect to existing residential uses, risks to homeowners who apply isoxaben are not of concern. Postapplication risk to adults are also not of concern. HED assumed that incidental ingestion of soil represents the worst case for oral postapplication exposure to young children , since no other oral scenarios would be expected to have an equivalent duration of exposure toIs oxaben D376428

Page 6 of 90 residues , or residues as high as those possible in soil. The MOE associated with soil ingesti on is 1 300000 with an LOC of 100, and therefore is not of concern. This scenario is expected to be protective of all other oral postapplication risks for children in residential settings. Postapplication inhalation exposures are expected to be negligible based on the low volatility of isoxaben and label instructions to incorporate after application. Dermal exposures are not of concern due to the absences of toxicity by this route. For the U.S. population and all population subgroups, short - and interm ediate - term aggregate risk estimates do not exceed HED’s level of concern for an y of the residential exposure scenarios. The short - term aggregate MOEs range from 6 2 ,000 to 66 ,000, for the U.S. population and females 13 - 49, respectively . The intermediate - term aggregate risk MOE estimate is 5 1 ,0 00 for children 1 - 2 years old. The chronic aggregate assessment is equivalent to the chronic dietary (food + water) risk assessment , which indicates chronic dietary /aggregate risks are below HED’s LOC as described a

bove. For the purposes of this tolerance action, HED has not assumed that isoxaben has a common mechanism of toxicity

with other substances. Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations, ” http://www.eh.doe. gov/oepa/guidance/justice/eo12898.pdf . CONCLUSIONS & RECOMMENDATIONS There are no data deficiencies that would preclude establishing tolerances for isoxaben as shown below in Table 1. H ED recommends the registration be made conditional, pending receipt of the required acute and subchronic neurotoxicity studies in the rat , 90 - day inhalation toxicity

in the rat and an immunotoxicity study , as required in the registration review scoping document addendum for isoxaben. In response to the scoping document, the Registrant has requested a waiver for the inhalation study , which is currentl y under review . A dditional residue chemistry data requirements and label recommendations are described in detail in Section 10 of the document . Additional tolerance recommen dations are described below: 1) HED recommends the isoxaben tolerance expression be established as follows: “Tolerances are established for residues of the herbicide isoxaben , including its metabolites and degradates, in or on the commodities in the tab le below. Compliance with the tolerance levels is to be determined b y measuring only isoxaben ( N - [3 - (1 - ethyl - 1 - methylprop yl ) - 5 - isoxazolyl] - 2,6 - dimethoxy

benzamide ) in or on the commodity .” 2 ) The tolerance for grape should be set at the LOQ, 0.01 ppm. The maximum residues observed in almond and pecan were 0.015 ppm; therefore, the proposed tolerance of 0.03 ppm for the tree nut group is too high. A tolerance of 0.02 ppm would be appropriate for the tree nut crop group.Is oxaben D376428

Page 7 of 90 3 ) HED has determined that pist achio should be added to the tree nut crop group; almond and pecan would remain the representative commodities for this group. Until the crop is officially added to the crop group listings in 40 CFR, residue data for almond and pecan may be used to establ ish a tolerance for pistachio, which is to be set at the same level as the tree nut tolerance. Therefore, the proposed tolerance of 0.03 ppm for pistachio is too high; a tolerance of 0.02 ppm would be appropriate. 4 ) The available data indicate that a 0. 40 ppm tolerance for almond hulls is appropriate. 5 ) The available processing data indicate that residues of isoxaben do not concentrate in grape juice or raisins. Therefore, separate tolerances are not needed for grape processed commodities. The proposed tolerances should be removed from Section F. 6 ) HED concludes that residues in milk, eggs and ruminant and poultry meat, fat, and meat by products remain a 40 CFR §180.6[a][3] situation (there is no expectation of finite residues in these commodi ties). Therefore, no tolerances are needed for livestock commodities. Table 1 . Tolerance Summary for Isoxaben. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Grape 0.01 0.01 Grape, juice 0.01 Remove A separate tolerance for grape juice is not needed. Grape, raisin 0.01 Remove A separate tolerance for raisin is not needed. Nut, tree, Group 14 0.03 0.02 Nut, tree, Group 14 Pistachio 0.03 0.02 Almond, hulls 0.35 0. 40 2.0 Ingredient Profi le Isoxaben is a benzamide herbicide (Group 21) used for control of broadleaf weeds. Isoxaben acts via inhibition of cell wall sy nthesis. The herbicide is currentl y registered for non - food uses on turf, ornamentals, non - bearing fruit and nut trees, and non - bearing vineyards. The chemical structure and nomenclature of isoxaben are presented in Table 2.2 , and the phy sicochemical properties of the technical grade of isoxaben are presented in Table 2 .3. 2.1 Summary of Propo sed Uses Dow AgroSciences has submitted a request to register an end - use product, FN - 3133 Specialty Herbicide , with EPA File Sy mbol No. 62719 - LIN. The product is proposed for use on grapes and tree nuts (including p istachio) with up to two soil applications at application rates ranging from 0.5

– 1.0 lb. ai/acre. The proposed label limits the seasonal application rate to no more than 1.0 lb ai/acre per crop ye ar ( i.e., harvest to harvest). No minimum retreatment inte rval (RTI) was specified on the proposed label . The proposed p re - harvest intervals ( PHIs ) are 60 day s for treeIs oxaben D376428

Page 8 of 90 nuts, and 165 day s for grapes. The product is also being proposed for use on nonbearing fruit and nut trees and nonbearing vineyards. HED also evaluated the proposed product AmoreTM DF, which contains 75% isoxaben and 3.12% penoxsulam. This product is also proposed for use on non - bearing tree nuts and non - bearing vineyards. A summary of the proposed use pattern is presented in Table 2.1. Table 2.1 Summary of Directions for Use of Isoxaben. Applic. Timing, Ty pe, and Equip. Form

ulation [EPA File Symbol No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations Grape ( American, European, Muscadine) Soil application, e quipment type not specified 75% DF

[62719 - LIN] 0.50 - 1.0 2 1.0 per crop season (harvest to harvest) 165 The label states: Not to be

used in NY. Application is to be made prior to germination of target weed s or immediately after cultivation. Application is to be made in a minimum of 10 gal/A. Almond; Beech Nut; Brazil Nut; Butternut; Cashew; Chestnut; Chinquapin; Filbert (Hazelnut); Hickory Nut;

Macadamia Nut (Bush Nut); Pecan; Pistachio; and Walnut (Black , English/Persian) Soil application, e quipment type not specified 75% DF

[62719 - LIN] 0.50 - 1.0 NS 1.0 per crop season (harvest to harvest) 60 The label states: Not to be

used in NY. Application is to be made prior to germination of target weeds or immedi ately after cultivation. Application is to be made in a minimum of 10 gal/A. Non - bearing tree nuts and nonbearing grape vines Soil application, equipment type not specified 75%DF

[62719 - ARE, 62719 - LIN] Single

appl. rate = 1.0 - 1.33 lbs product/A Max . single appl. rate =1.0 lb ai/A) 1 1.0 lb ai/A NA The label states: Not to be used in NY. Application is to be made prior to germination of target weeds or immediately after cultivation. Application is to be made in a minimum of 10 gal/A. Note: with 3.12% Penoxsulam . The product is not to be applied through an y t yp e of irrigation sy stem or to crops grown in containers. The draft label of FN - 3133 Specialt y Herbicide has CAUTION as Signal Word and the following PPE: Applicators and other handlers must wear a long sleeved shirt and long pants, chemical resistant gloves made of an y waterproof material and shoes plus socks. In addition, the label has a 12 hour restricted entry interval (REI) per the worker protection standards (WPS). Conclusions . The proposed use directions are adequate to allow evaluation of the crop field trial data submitted with this petition. The proposed use directions represent maximum seasonal ratesIs oxaben D376428

Page 9 of 90 at 1x those used in the crop field trials. The available crop field trial data support a maximum seasonal rate of 1 lb ai/A. The label should specify that non - bearing means trees or vines where nuts and/or fruit are not harvested for food within one year of treatment. 2.2 Structure and Nomenclature Table 2.2. Isoxaben Nomenclature . Com pound

O C H 3 N H O O N C H 3 C H 3 C H

3 O C H 3

Common name Isoxaben Com pany experimental name EL - 107 IUPAC name N - [3 - (1 - ethyl - 1 - methylpropyl)isoxazol - 5 - yl] - 2,6 - dimethoxybenzamide CAS name N - [3 - (1 - ethyl - 1 - methylpropyl) - 5 - isoxazolyl] - 2,6 - d imethoxybenzamide CAS registry number 82558 - 50 - 7 End - use product s (EP s ) FN - 3133 Specialty Herbicide (75% DF formulation; EPA File Symbol , 62719 - LIN) , Gallery 75 Dry Flowable (75% DF, EPA Registration Number, 62719 - 145) Amore DF (75% DF formulation; EPA File Symbol, 62719 - ARE), which also contains 3.12% penoxsulam 2.3 Physical and Chemical Properties Table 2. 3. Physicochemical Properties of Isoxaben. Parameter Value Reference Melting range 173 - 176.5oC MRID 47140001 Density (relative) 0.580 g/ml at 22oC MRID 47140001 Water solubility 1.42 mg/L at 20oC MRID 47140001 Solvent solubility, at 20oC Acetone 270 g/L Methanol 98 g/L 1 - Octanol 29 g/L Ethyl acetate 88 g/L 1,2 - Dichloroethane 51 g /L Xylene 4.0 g/L Hexane 0.028 g/L MRID 47140001

Vapor pressure 1.3 x 10 - 8 Pa at 25oC Email fr om DowAgrosciences (5/19/10) revising vapor pressure Dissociation constant, pK a 9.78 ± 0.06 at 20oC EFSA 1 (May 2006 Draft Report)Is oxaben D376428

Page 10 of 90 Table 2. 3. Physicochemical Properties of Isoxaben. Parameter Value Reference Octanol/water partition coefficient, Log(KOW ) 3.83 at 20oC MRID 47140001 UV/visible absorption spectrum  max1 = 2 02 nm / 26000 mol - 1 cm- 1  max2 = 2 52 nm

/ 16500 mol - 1 cm- 1  max3 = 2 75 nm

/ 20800 mol - 1 cm- 1 EFSA 1 (May 2006 Draft Report) 1 - European Food Safety Authority (EFSA) 3.0 Hazard Charac terization/Assessment This hazard characterization updates the previous assessment for isoxaben, prepared in December, 1987 for the New Chemical Registration Standard. However, a human health risk assessme nt scoping document was completed for isoxaben in conjunction with Registration Review in August 2007 (D341567) . An addendum to the scoping document was completed in June, 2008 (D341543) to incorporate new toxicology data requirements under 40 CFR Part 15 8. 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary 3.1.1.1 Studies available and considered (animal, human, general literature) Studies considered for this assessment included acute lethality (oral, dermal and inhalation routes); primary

eye and dermal irritation, dermal sensitization, subchronic oral toxici ty (rat, mouse and dog), rabbit 21 - day dermal toxicity , dog chronic toxicity , rat chronic toxicity and combined chronic toxicity /carcinogenicity , mouse carcinogenicity , developmental toxicity (rat and rabbit), rat multigenerational reproductive toxicity , genotoxicity , rat metabolism and a dermal absorption study in the monkey (see Appendix A ). 3.1.1.2 Mode of action, metabolism, toxicokinetic data Isoxaben is a pre - emergent benz amide herbi cide that is used for control of broadleaf weeds. In plants, it inhibits growth via inhibition of cellulose biosy nthesis in dicots, but does not affect germination. Its mode of action for mammalian toxicity has not been characterized. In metabolism studies conducted in the rat, oral absorption of isoxaben is limited . The majority of the administered radioactivity was excreted as unmetabolized parent compound. 3.1.1.3 Sufficiency of studies/data The av ailable toxicity

data are considered adequate for conducting this risk assessment for the proposed first food use of isoxaben. However, in accordance with the recently revised 40 CFR Part 158, an immunotoxicity study and rat acute and subchronic neurotoxi city studies are required. A 90 - day

inhalation toxicity

study in the rat is also required to support registration of isoxaben, based on the potential for inhalation exposure and potential portal of entry effects. TheIs oxaben D376428

Page 11 of 90 required studies were requested durin g the registration review scoping process (D3415 43 ) . Rationales for data requirements are provided in Appendix A.4. In the absence of inhalation data, an inhalation point of departure was selected for this assessment using route - to - route extrapolation of oral data , i.e., assuming toxicity via the inhalation route is similar to the oral route . In response to the scoping document, the Registrant has submitted a waiver request for the inhalation study , which is under review . 3.1.2 Toxicological Effects The primary

target organs identified for isoxaben are the liver and kidney . Although liver effects were observed in all species tested (rat, dog, mouse), adverse change s were only observed in the mouse following chronic oral exposure . These effects included histopatholog y and increased blood alkaline phosphatase and alanine aminotransferase activities at high doses. In the dog and rat, liver effects were considered adaptive and consisted of enlargement, hepatocellular hy pertrophy and induction of hepatic microsomal enzy mes. Increased incidence and severity of nephropath y was observed in the rat following chronic (two - ye ar) exposure. No adverse renal effects were reported in the dog or mouse . There was no indication o f neurotoxicity or immunotoxicity in the available studies, which generall y tested up to or above the limit dose. No maternal or developmental effects were seen in the rabbit or rat developmental studies . In the rat reproductive toxicity study , two mat ings (a and b generations) per F0 and F1 parental generations were c onducte d, plus two additional matings (F2c and F3a) to examine developmental effects on gestation day 20. Effects included a decrease in corpora lutea, resulting in a decrease in the mean number of implantations and mean live fetuses per litter. Nursing pups showed decreased body weight gain at the highest dose tested. An increase in the incidence of several malformations (exencephal y, microphthalmia/coloboma and h ydroureter) was seen in the F2b, F2c and F3a mating generations at the limit dose of 1000 mg/kg/day (HDT), but not in the F1a , F1b or F2a offspring. The relationship of these findings to treatment is unclear because an examination of the genealogy of these offspring suggests a possible heritable component. A large percentage of the affected litters were the result of either cousin matings or had in common F0 progenitors derived from several F0 litters from the supplier. However, because the relationship to treatment could not be ruled out , the malformations were considered a possible treatment - related effect. No effects of treatment were reported in a 21 - day repeated application dermal toxicity study in the rabbit. This is consistent with relatively low dermal absorption ( ≤11 % of administered dose) observed in a dermal penetration study in the monkey

and the low oral toxicity observed in subchronic oral studies in the rat, mouse and dog. Isoxaben is classified as having “suggestive evidence of carcinogenicity to humans.” An increased incidence of benign liver tumors was observed in male and female mice at the high dose only . Isoxaben was negative in most genotoxicity studies: weak positive increases in bone marrow micronucleus formation were seen in two out of three studi es but may have been due to low concurrent control values. Isoxaben is of low acute toxicity when administered orall y (Toxicity Category IV), dermall y (Category III), or via inhalation (Category III). Itis not a dermal sensitizer or irritant (CategoryIs oxaben D376428

Page 12 of 90 IV ) and causes onl y minor transient irritation to the eye (Category III). 3.1.3 Dose - response An acute reference dose (aRfD) was not selected for an y population, including females ages 13 - 49 because there were no toxic effe cts resulting from a single dose . Although malformations were observed in the rat reproductive study, they were not considered single - dose effects because no malformations were observed in the F1 of F2a offspring, or in developmental studies in rat and ra bbit. The offspring effects were, however, the basis for short - and intermediate - term inhalation exposure assessment. There were no effects seen in the developmental toxicity studies or from subchronic oral exposure . Therefore, for short - term residenti al incidental oral exposure to young children, an appropriate endpoint was not identified. For occupational and residential short - and intermediate - term dermal exposure, an appropriate endpoint was not identified , due to a lack of dermal toxicity . Alth ough toxicity

was not observed in subchronic oral studies, body weight decreases in females were observed following exposures of several months in both the rat reproductive study and at six months in the rat one year dietary study . Offspring effects were also observed in the reproductive study. Therefore, these two studies were selected as co - critical for assessment of intermediate - term residential and occupational risk, including incidental oral exposure to young children and intermediate - term inhalation exposure . In the reproductive study , decreased body weight gain in F1 females at Day 70 was seen at 1000 mg/kg/day , but not at 200 mg/kg/day . This effect level was supported by decreased body

weight gain in females at around six months at 625 mg/kg/day

i n the rat one year dietary study (NOAEL = 62.5 mg/kg/day). This endpoint provided a protective exposure level for developmental toxicity based on the offspring NOAEL of 200 mg/kg/day , which was based on decreased offspring weights, gestation survival and live litter size at 1000 mg/kg/day . This approach is considered to be conservative, given the lack of other effects and absence of findings in oral studies up to 90 day s . Toxicity was observed at lower dose levels with long - term oral administration. Fo r chronic dietary exposure, the chronic reference dose RfD was based on a NOAEL of 5.0 mg/kg/day in male rats from the two - year chronic toxicity /carcinogenicity

feeding study . This provided the lowest NOAEL and the most sensitive point of departure (POD) available for long - term dietary exposure. Males were affected with progressive glomerulonephrosis , which showed increas ed incidence and severity

with increasing dose. Female rats showed this effect, along with decreased body weight and weight gain, but o nly at the highest dose tested (647 mg/kg/day). In mice, liver effects (including hepatocellular tumors) were observed but only at the highest dose tested, which exceeded the limit dose. However, only adaptive liver changes were observed in the dog foll owing one ye ar oral administration. 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) Oral a bsorption of isoxaben was incomplete , particularly at higher doses, where it appeare d to achieve saturat ion based on increased percent dose excreted in feces and decreased urinary and biliary excretion observed at increasing dose levels. The primary route of excretion was fecalIs oxaben D376428

Page 13 of 90 (up to about 90% of administered radioactivity). Urinary ex cretion accounted for 2 - 13% of the administered radioactivity and decreased with increasing dose. Biliary excretion was observed in both sexes, at the lower dose of 10 mg/kg representing about 23% and 39% of the dose in males and females, respectively but decreasing to 17% and 15% at the higher dose of 250 mg/kg , consistent with rate - limiting absorption. The majority of radioactivit y was excreted b y 24 hr postdosing, with some additional excretion seen between 24 - 72 hr. The total radioactivit y excreted t ended to be slightly lower in males (71 to 95%) than females (88 to 106%). Exhalation of radiolabeled carbon dioxide was limited to <3% of the administered radioactivity . Repeated dosing did not significantly affect the excretion pattern of isoxaben and by 7 day s, the amount of radioactivity

left in the carcass was 0.4% or less of the administered dose with negligible radioactivity

remaining in tissues. In tissue distribution studies, most of the radioactivity remained in the intestinal tract, but the ra dioactivity that was absorbed was widely distributed, with the majority

of the examined tissues showing tissue:plasma ratios greater than one at 4 hrs. Except for the GI tract, tissue levels were greatest in the liver, pituitary , thyroid, kidney , adrenals and prostate. At 24 hrs postdosing, tissue:plasma ratios generally decreased, but radioactivity remained in most tissues ; radioactivity was not assessed at later times. The majority of radioactivity

excreted in the feces was unmetabolized isoxaben (up to 90% of fecal radioactivity); other fecal metabolites were not characterized. In the urine, 15 to 20 metabolites were observed. The major routes of metabolism were oxidation of position 2 of the alkyl side chain yi elding either an alcohol or a ketone, hydroxylation of the aromatic ring adjacent to one of the methox y groups or O - demeth yl ation of the methoxy groups. Overall metabolite profiles were similar for males and females, with minor quantitative differences observed. 3.3 FQ PA Considerations 3.3.1 Adequ acy of the Toxicity Datab ase The database is considered adequate for the purpose of assessment of susceptibility of infants and children to the effects of isoxaben. Acceptable developmental toxicity studies in two species (rat, rabbit) and a multigeneration reproductive toxicity study (rat) are available. There is no evidence of neurotoxicity or immunotoxicity . Therefore, although neurotoxicity and immunotoxicity studies have not been submitted, these studies are not considered likel y to identify more sensitive endpoints (and lower points of departure) than those already selected for isoxaben , and an additional safet y factor to account for data gaps is not required . For inhalation exposure, oral endpoints were selected and 100% inhalation absorption assumed. 3.3.2 Evidence of Neurotoxicity Isoxaben did not show evidence of neurotoxicity in the available studies. Rat ac ute and subchronic neurotoxicity

studies have not been submitted and are required. 3.3.3 Developmental Toxicity Studies Acceptable developmental toxicity studies in the rat and rabbit are available (see Appe ndix A.3 for executive summaries). Both studies tested at 0, 100, 320 and 1000 mg/kg/day . No developmental or maternal toxicity was observed in either species at doses up to the limit dose of 1000 mg/kg/day .Is oxaben D376428

Page 14 of 90 3.3.4 Reproductive Toxicity Study An acceptable multigeneration reproductive toxicity study in the rat is available (see Appendix A.3 for the executive summary) in which Wistar rats were dosed at 0, 40, 200 or 1000 mg/kg/day in the diet. Maternal toxicity was observed at 200 mg/kg/day as mildly decreased body weight gain in F2 females during the growth phase and decreased body weight in F2b females during gestation. At 1000 mg/kg/day , F1 and F2 females showed pronounced weight decrements during growth phas es, gestation and postpartum. Pup/fetal effects were observed at 1000 mg/kg/day in F2b, F2c and F3 offspring, especiall y F2b pups, and included decreased pup weight during lactation. An increase in the incidence of microphthalmia, coloboma and/or exencep hal y and hydroureter, was also reported. In the F2b litters there was a decrease in live pups/litter and gestation survival which was associated with decreased corpora lutea. In additional litters used for prenatal assessments of the malformations (F2c and F3a litters), decreases in corpora lutea, implantations and live fetuses were seen. There were no malformations observed in either developmental study at doses up to the limit dose of 1000 mg/kg/day . The malformations in the reproductive toxicity study were therefore examined more closel y. In the reproductive toxicity study , a dose - response was not observed: no increases were seen at 40 or 200 mg/kg/day . No increases were observed in the first three matings (F1a, F1b, F2a): the F2b litters were the first to show the increase. The subsequent additional F2c and F3a matings also showed increases, but the incidence did not increase relative to the F2b generation. Based on an assessment of the pup lineage and several interrelationships among affected offspring, there appeared to be a heritable component to these malformations. The study report provided genealogy charts showing the F0 lineage of the litters affected with the malformations and noting offspring that were descendents of cousin matings. Details of these lineages may

be found in the Appendix to the supplemental DER for this study (TXR# 0051626). The genealogy evaluation shows a high percentage of the litters affected with malformations were descended from a relativel y s mall number of F0 l itters. An examination of offspring lineage shows several interrelationships, including the following: (1) Of the 17 affected high dose litters/38 offspring, 8 litters/17 offspring (F1, F2 and F3 offspring generations) were derive d from a single F0 mating pa ir. Cousin matings involving this pair produced 5 of the affected high dose litters; (2) The same F0 mating pair noted in (1) were among the progenitors of 3 of the 4 affected high dose litters in the F3a generation, and of abnormal litters in four F2 matings . Another F0 female was also associated with a severely affected F2c litter and 3 of the 4 affected F3a litters (total of 11 affected offspring) ; (3) T wo high dose F0 siblings from F0 litter 9 were progenitors of four affected litters (F2b, F2c, F3a), includ ing those described in (4); (4) T wo high dose F1 siblings produced two of the most severel y affected F2b litters, with 4/4 and 7/10 abnormal progen y, respectively, most with both exencephaly and microphthalmia. (5) Sibling relationships were observed for some F 0 animals that produced affected litters but were in different dose groups. For example, littermates from F0 litter 5 produced affected litters in the control group, the 40 mg/kg/day group and the 1000 mg/kg/day

group.Is oxaben D376428

Page 15 of 90 The overall findings indicate a high percentage of affected fetuses/litters were derived from a relativel y small number of F0 progenitor animals and/or matings of cousins. Insome instances, several generations of affected litters were derived from the same progenitors. The data suggest that there may

have been a genetic predisposition to these abnormalities and that affected animals may

have been more susceptible as a result of genetic factors. E xposure to high doses of isoxaben may

have enhanced the effect in these more susceptible offs pring. The relationship of the malformations to treatment is unclear, since no abnormalities were observed in the developmental studies and the y were onl y seen at a high dose. However, the malformations are considered a potential effect of treatment in the absence of conclusive evidence to the contrary . F or example, epigenetic effects such as spindle disruption, could potentially

cause effects in later generations of offspring. HED cannot discount that the adverse effects discussed above are treatment related, but they are unlikel y to have result ed from a single dose exposure . Therefore, an acute dietary assessment is not n eeded. HED has selected a chronic dietary

point of departure with a NOAEL of 5.0 mg/kg/day which would be protective of these eff ects observed at much higher doses, i.e., 1000 mg/kg/day . The European Food Safety Commission (European Economic Community , prepared by Rapporteur Member State Sweden) also reviewed the toxicity of isoxaben in a draft document published in May , 2006. For the malformations in the reproductive toxicity study , the report concluded that the weight - of - the - evidence indicated that congenital abnormalities were associated with genetic, i.e. heritable , factors that were traced back to specific litters from whi ch the F0 generation was derived, rather than to administration of isoxaben. 3.3.5 Additional Information from Literature Sources T he European Union Food Safety Authority (EFSA) published a draft assessment report which evaluated toxicology

and metabolism in May 2006: http://www.efsa.europa.eu/ en/scdocs/scdoc/58r.htm . A screening - level literature search was conducted for information on the toxicity of isoxaben. No relevant studies providing additional information were identified. 3.3.6 Pre - and/or Postnatal Toxicity 3.3.6.1 Determination of Susceptibility There was no evidence of increased quantitative susceptibility for pre - and/or postnatal effects in developmental toxicity

studies in two species and a rat multigeneration reproductive toxicity study . In creased qualitative susceptibility was obser

ved in the rat reproductive toxicity study as decreased live pups/litter and decreased gestation survival in F2b litters (relative to body weight effects in mothers) . However, concern for qualitative susceptibility is low because these effects may have be en partl y due to decreases in corpora lutea and they were onl y observed at the limit dose (1000 mg/kg/day) in the presence of maternal effects . The NOAEL/LOAEL for these effects is well - defined , and risk assessment points of departure ( PODs ) were selected to beIs oxaben D376428

Page 16 of 90 protective for these effects . Increases in fetal malformations (microphthalmia, coloboma and/or exencephal y) were also noted in later offspring generations (see Section 3.3.4 for discussion). 3.3.6.2 Degree of Concern Analy sis and Residual Uncertainties for Pre - and/or Postnatal Susceptibility There is low concern for postnatal susceptibility for the reasons dis cussed above (Section 3.3.6.1). 3.3.7 Recommendation for a Developmental Neurotoxicity Study A developmental neurotoxicity study is not recommended for isoxaben. No developmental abn ormalities were observed in either the rat or rabbit developmental toxicity studies at doses up to the limit dose. No evidence of neurotoxicity was observed in the available toxicology database. As noted previously , malformation s in the rat reproductive toxicity study were well characterized, increased only at the limit dose (1000 mg/kg/day) in later generations and appeared due, in part, to heritable factors. 3.4 FQ PA S afety Factor for Infants and Children It is recommended that the 10x FQPA safet y factor for infants and children be reduced to 1x for isoxaben, for the following reasons:

 The toxicology

database for isoxaben is largely complete, missing only

the neurotoxicity , immunotoxicity and subchron ic inhalation stud ies ; however, there is no evidence that isoxaben targets the nervous sy stem or the immune s ys tem . . Overall the toxicity

of isoxaben is low: the available oral studies of short - term (e.g., developmental toxicity) o r subchronic exposure d uration did not show toxicity up to the limit dose. Effects observed at exposures of intermediate - term duration were minimal in adult animals (decreased body weight) and malformations seen in offspring of the rat reproduction study were of uncertain relat ionship to treatment. T he endpoints selected were therefore considered conservative but were assumed to be treatment - related to be protective of potential effects. Based on these considerations, the required studies are not expected to provide lower PODs than those currently selected.

 Based on the lack of neurotoxicity in the database, a developmental neurotoxicity study is not needed.

 There is a low degree of concern for the increased qualitative susceptibility observed in the multigenerational reprod uctive toxicity

study , due to evidence th at observed malformations were due in part to heritable factors and additionally were onl y seen at the limit dose in later generations, and not observed in the developmental studies . The relationship of these effec ts to treatment is unclear. There are low concerns for effects on offspring viability because they were only observed at the limit dose and may have been secondary

to effects on the dams. The endpoints for risk assessment are protective of these effects.Is oxaben D376428

Page 17 of 90  The exposure assessment s for food , drinking water and residential uses will not underestimate potential exposure to isoxaben, and a conservative approach was used for aggregate risk assessment. 3.5 Hazard Identification and Toxicity Endpoint Selection 3.5.1 Acute Reference Dose (aRfD) – All Populations (Including Females Age 13 to 49, Infants and Children) An acute reference dose was not d etermined . An a ppropriate endpoint w as not identified that c ould occur following a single exposure. Malformations in the reproductive study were onl y observed after several matings and were not seen in either the rat or rabbit developmental studies. The refore, HED concluded these effects , if treatment - related, were unlikel y to result from a single dose. 3.5. 2 Chronic Reference Dose (cRfD ) Study Selected: Chronic Toxicity /Carcinogenicity

in the Rat (Dietary) MRID No : 00164553 Dose and Endpoint for Risk Assessment : NOAEL= 5.0 mg/kg/day , based on renal toxicity in males observed at the LOAEL of 50.7 mg/kg/day . Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = ) ( 100 / / 0 . 5 UF day kg mg = 0.0 5 mg /kg/day Comments about Study/Endpoint/Uncertainty Factors : The study is of the appropriate duration and exposure route (i.e., long - term oral exposure) and represents the most conservative available endpoint and do se available in the database for assessment of chronic dietary exposure. 3.5.3 Incidental Oral Exposure, Short - Term (1 to 30 days ) An appropriate endpoint was not identified. No maternal to xicity was observed in the rat or rabbit, both of which tested up to the limit dose of 1000 mg/kg/day . Offspring e ffects relevant to postnatal exposure (e.g., decreased body weights, clinical effects in young pups) identified in the reproductive toxicity study were not observed within the short term exposure time frame. Subchronic toxicity studies did not report effects. There is no hazard associated with short - term incidental oral exposure, and therefore, no risk. 3.5.4 Incidental Oral Exposure, Intermediate - Term (1 to 6 months) Stud ies Selected: Reproductive toxicity in the rat and chronic toxicity (1 year dietary) in the rat, co - critical studies . MRID No : 00153529, 00164552Is oxaben D376428

Page 18 of 90 Dose and Endpoint for Risk Assessment : The NOAEL of 200 mg/kg/day is based on decreased body weight gain in F1 females at Day 70 at 1000 mg/kg/day and decreased pup weight, gestation survival and live pups/litter in the F2b generation in the rat reproductive toxicity

study . This dose selection is s upported by the co - critical rat one ye ar dietary

study , where females showed decreased body weights by

six months at 625 mg/kg/day

and a NOAEL of 62.5 mg/kg/day . Uncertainty Factor: 100x (10x interspecies extrapol ation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: The endpoint selected for this risk assessment is based on a study of the appropriate duration and route, and represents a conservative endpoint for this duration. The endpoint is protective of potential postnatal effects, based on the offspring NOAEL/LOAEL of 200/1000 mg/kg/day

in the rat reproductive toxicity study . Although the NOAELs for subchronic toxicity and maternal toxicity (in the developmental toxicity studies) were much higher (at or above the limit dose of 1000 mg/kg/day), in the rat reproductive toxicity study decreased body weight and weight gain were observed in F1 females at 1000 mg/kg/day . Body weight effects in the rat chronic toxicity /carcinogen icity

study were observed in females b y six months at 625 mg/kg/day, with a NOAEL of 62.5 mg/kg/day. The higher NOAEL of 200 mg/kg/day (reproduction study) together with the lower LOAEL of 625 mg/kg/day (chronic study) was used to establish the dose and e ndpoint. Although the low dose of 40 mg/kg/day in the reproduction study was identified as a parental NOAEL, it was not selected because body weight changes at 200 mg/kg/day w e re minimal and only seen at later times in the study (F2 animals’growth period and later). The mid dose of 200 mg/kg/day

was therefore considered a more robust endpoint. 3.5. 5 Dermal Absorption Dermal absorption of 11% wa s estimated, based on absorption values obtained from an in vivo dermal absorption study in the monkey

(MRID 00153113). This value was obtained from a comparison of the area under the curve (AUC) of intravenous vs. d ermal dosing with radiolabeled isoxaben. The low absorption value is consistent with the lac k of sy stemic effects seen in the rabbit 21 - day dermal toxicity

study . A relative dermal absorption value was estimated since oral absorption was shown to be incomplete . Relative dermal absorption was calculated to determine whether endpoints from the av ailable oral data adjusted for dermal absorption were more sensitive than the 21 - day dermal study . In the rat metabolism study at the low dose , a total oral absorption of 47% was calculated by adding urinary

+ bili ary + exhaled CO 2 excretion of radioactiv ity (using the average percent dose f or male and female excretion values) . Absorption values from the low dose were selected as more appropriate than the higher dose for human exposure and to provide a more conservative value. The average values were as follows: 13% (urinary) + 31% (biliary) + 2.6% (CO 2 ) = 47 % To estimate a relative dermal absorption factor for comparison of doses in oral studies with those in dermal studies, the average oral absorption of 47% was compared to theIs oxaben D376428

Page 19 of 90 dermal absorption of 11% , a difference of approximately four - fold . A dermal absorption factor of 2 3% is therefore used to adjust oral studies for percent dermal absorption . 3.5.6. Residential and Occupational Dermal Exposure, Short - Term (1 to 30 days) and Intermediate - Term (1 to 6 months) Quantitative s hort - and intermediate - term dermal exposure assessments were not performed for isoxaben. No effects were observed in the rabbit 21 - day dermal toxicity study at 1000 mg/kg/day . An appropriate dose and endpoint from an oral study were identified (NOAEL of 200 mg/kg/day from the r at reproductive toxicity study , based on offspring and parental effects at 1000 mg/kg/day) . However, route - to - route ex trapolation with adjustment of the oral NOAEL for relative dermal absorption (23%; see 3.5.5) resulted in a NOAEL of 870 mg/kg/day , comparable to the NOAEL of 1000 mg/kg/day in the dermal study , with a LOAEL of 2300 mg/kg/day , a value above the limit dose . Therefore, significant dermal hazard does not exist, and quantitative assessment of dermal risk is not require d. 3.5.7 Residential and Occupational Dermal Exposure, Long - Term (>6 months) A long - term residential or occupational risk assessment is not required because long - term dermal exposure is not anticipated from the proposed or existing uses. 3.5. 8 Residential and Occupational Inhalation Exposure, Short - Term (1 to 30 days) Study Selected: Rat reproducti ve toxicity MRID No : 00153529 Dose and Endpoint for Risk Assessment : 200 mg/kg/day , based on an increased incidence of malformations at 2000 mg/kg/day . Comments about Study/Endpoint/Uncertainty Factors: See Section 3.5.4. The malformations seen in the reproductive study are considered potential developmental effects in offspring that may result from short - term exposure . Inthe absence of inhalation data, inhalation absorption of 100% is assumed for route - to - route extrapolation from oral to inhalation exposure , i.e., inhalation toxicity is assumed to be equivalent to toxicity via the oral route. An additional uncertainty factor for lack of the 90 - day r at inhalation study

is not needed, based on the low vapor pressure and frequency of application, and persistence in soil (i.e., not volatilizing from the soil). When conducting the risk a ssessment, a body weight of 60 k g should be used to protect for offs pring effects. 3.5. 9 Resi dential and Occupational Inhalation Exposure, Intermediate - Term (1 to 6 months) Study Selected: Rat reproducti on toxicity and rat chronic toxic ity

(1 year dietary), co critical . MRID Nos : 00153529, 00164552 Dose and Endpoint for Risk Assessment : 200 mg/kg/day , based on decreased body weight gain in F1 females at Day 70 at 1000 mg/kg/day

in the reproductive study .Is oxaben D376428

Page 20 of 90 Decreased pup weight and decre ased corpora lutea, live pups/litter , gestation survival in F2 offspring and malformations in F2 and F3 offspring were also observed. This endpoint is s upported by

decreased body weight gain in females at 625 mg/kg/day by six months in the one year rat di etary study , with a NOAEL of 62.5 mg/kg/day . Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: See Section 3.5.4. In the absence of inhalation data, inhalation to xicity is assumed to be equivalent to toxicity via the oral route . An additional uncertainty factor for lack of the 90 - day rat inhalation study is not needed, based on the low vapor pressure and frequency of application, and persistence in soil (i.e., not volatilizing from the soil). When conducting the risk assessment, 60 kg body weight should be used to protect for offspring effects. 3.5.1 0 Residential and Occupational Inhalation Exposure, Long - Term (> 6 months) A long - term residential or occupational risk assessment is not required because long - term inhalation exposure is not anticipated from the proposed or existing uses. 3.5. 1 1 Level of Concern for Margin of Exposure (MO E) Table 3.5.1 2 Summary of Levels of Concern for Risk Assessment. Route Short - Term (1 - 30 Day s) Intermediate - Term

(1 - 6 Months) Long - Term

(> 6 Months) Occupational (Worker) Exposure Dermal N/A N/A N/A Inhalation 100 100 N/A Residential Exposure Dermal N/A N/A N/A Inhalation 100 100 N/A 3.5. 1 2 Recommendation for Aggregate Exposure Risk Assessments For the chronic diet ary

assessments, exposure from food and drinking water should be combined. For children, intermediate - term aggregate assessment should combine incidental oral exposure from soil ingestion with exposure to average food and water exposure (chronic dietary e xposure). An appropriate short - term incidental oral endpoint was not identified. For adults, short - and intermediate - term aggregate exposure assessments should combine residential inhalation exposure with exposure to average food and water exposure (chro nic dietary exposure). Although there is a potential for short - or intermediate - term residential dermal exposure based on the existing uses on turf, there is no short - term dermal hazard, and therefore dermal exposure should not be included in the aggregate assessment. For intermediate - term exposure the oral and inhalation points of departure are based on the same toxic effects. Therefore, combining such exposures and risks is appropriate.Is oxaben D376428

Page 21 of 90 3.5. 1 3 Classification of Carcinogenic Potential Isoxaben was reviewed by the Cancer Assessment Review Committee (CARC) to determine the cancer classification under the current (2005) US EPA Guidelines for Assessment of Carcinogenicit y. Isoxaben is classified a s “Suggestive Evidence of Carcinogenic Potential,” based on an increased incidence of benign hepatocellular tumors in male and female mice (Isoxaben: Second Report of the Cancer Assessment Review Committee, dated October 7, 2008). The liver tumors were obs erved onl y in one species, were not malignant and were observed in the presence of liver toxicity at dietary levels exceeding the limit dose (1000 mg/kg/day)

. The chronic RfD/PAD is based on the chronic toxicity NOAEL of 5 mg/kg/day in the rat, which is m ore than 200 - fold lower than the dose at which tumors were observed in the mouse. Therefore, the cRfD/PAD is considered to be protective of potential carcinogenicity .Is oxaben D376428

Page 22 of 90 3.5. 14 Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments Table 3.5.2a. Summary of Toxicological Doses and Endpoints for Isoxaben for Use in Dietary and Non - Occupational Human Health Risk Assessments Exposure/ Scenari o Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects Ac ute Dietary, All Population s including Females Age 13 to 49, Infants and Children Not required. An appropriate endpoi nt for this risk assessment w as not identified. Chronic Dietary (All Populations) NOAEL= 5.0

mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1x Chronic RfD =

0.05 mg/kg/day cPAD = 0.05 mg/kg/day Chronic oral toxicity/carcinogenicity in

the rat . LOAEL = 50.7 mg/kg/day, based on renal toxicity in males. Incidental Oral Short - term

(1 to 30 days) Not required. An appropriate endpoint was not identified.

Incidental Oral Intermediate term (1 to 6 mo nths) NOAEL =

200 mg/kg/day UF A=10x

UF H =10x FQPA SF= 1x LOC f or MOE = 100 Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, based on decreased body weight gain in F1 females on Day 70. One year dietary study in the rat (co critical supporting study) LOAEL = 625 mg/kg/day based on decreased body weight gain in females during the first six months with a NOAEL of 62.5 mg/kg/day. Dermal Short Term (1 to 30 days) and Intermediate Term (1 to 6 mo nths) Not required. An appropriate endpoint was not identified. Dermal Long Term (>6 mo nths) Not re quired. Long - term dermal exposure is not anticipated from current and proposed uses.

Inhalation Short - Term

(1 to 30 days) NOAEL =

200 mg/kg/day (inhalation toxicity assumed to be equivalent to oral toxicity) UF A=10x

UF H =10x FQPA SF= 1x LOC for MOE

= 100 Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, based on increase d in cidence of malformations .Is oxaben D376428

Page 23 of 90 Table 3.5.2a. Summary of Toxicological Doses and Endpoints for Isoxaben for Use in Dietary and Non - Occupational Human Health Risk Assessments Exposure/ Scenari o Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Inhalation Intermediate Term (1 to 6 mo nths) NOAEL =

200 mg/kg/day (inhalation toxicity assumed to be equivalent to oral to xicity ) UF A=10x

UF H =10x FQPA SF= 1x LOC for MOE

= 100 Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, based on decreased body weight gain in F1 females on Day 70 , decreased F2 pup weights, gestation survival and live pups/li tter, and increased incidence of malformations. One year dietary study in the rat (co critical supporting study) , LOAEL = 625 mg/kg/day based on decreased body weight gain in females during the first six months in the one year dietary study with a NOAE L of 62.5 mg/kg/day. Inhalation Long - Term

(> 6 mo nths) Not required. Long - term inhalation exposure is not anticipated from current and proposed uses. Cancer (oral, dermal, inhalation) Classification: Suggestive Evidence of Carcinogenic Potential, base d on increased incidence of

hepatocellular adenomas in male and female mice. A quantitative assessment of cancer risk using a cancer potency factor is not required. The chronic RfD is protective of potential cancer risk. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LO AE L = lowest observed adverse effect level. 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 = use of a LOAEL to extrapo late a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key dat a (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = r eference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Is oxaben D376428

Page 24 of 90 Table 3.5.2b Summary of Toxicological Doses and Endpoints for Isoxaben for Use in Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects Dermal Short Term (1 to 30 days) and Intermediate Term (1 to 6 mo nths) Not required. An appropriate endpoint was not identified. Dermal Long Term (> 6 mo nths) Not required. Long - term dermal exposure is not anticipated from current and proposed uses.

Inhalation Short - Term

(1 to 30 days) NOAEL =

200 mg/kg/day (inhalation toxicity assumed to be equivalent to oral toxicity ) UF A=10x

UF H =10x Occupational LOC

for MO E = 100 Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, based on decreased F2 p up weights, gestation survival , live pups/litter and increased malformations .

Inhalation Intermediate Term (1 to 6 mo nths) NOAEL =

200 mg/kg/day ( inhalation toxicity assumed to be equivalent to oral toxicity) UF A=10x

UF H =10x Occupational LOC

for MOE = 100 Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1000 mg/kg/day, based on decreased body weight gain in F1 females on Day 70 , decreased F2 p up weights, gestation survival , live pups/litter and incidence of malformations . One year dietary study in the rat (co critical supporting study) LOAEL = 625 mg/kg/day based on decreased body weight gain in females during the first six months with a NOAEL of 62.5 mg/kg/day. Inhalation Long - Term

(> 6 months) Not required. Long - term inhalation exposure is not anticipated from current and proposed uses. Cancer (oral, dermal, inhalation) Classification: Suggestive Evidence of Carcinogenic Potential, b ased on increased incidence of

hepatocellular adenomas in male and female mice. A quantitative assessment of cancer risk using a cancer potency factor is not required. The chronic RfD is protective of potential cancer risk.. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 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 = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key dat a (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Is oxaben D376428

Page 25 of 90 3.6 Endocrine dis ruption As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans or wildlife similar to an effect produced b y a naturall y occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations . Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have th e potential to interact with E, A, or T hormonal sy stems 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 designated 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. Between October, 2009 and earl y 2 010, EPA issu ed test orders/data call - ins for the first group of 67 chemicals, whic h contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity , and certain post - application agricultural scen arios. This list should not be construed as a list of known or likely endocrine disruptors. I soxaben is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p), the Agency must sc reen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/ . 4.0 Public Health and Pesticide Epidemiology Data and Incident Reports Seventeen human incidents were reported in the Isoxaben Scoping Document (Nov. 2007). Four were in an occupational setting with 3 sy mptomatic cases, two of which visited a health care facility . The non - occupatio nal group had 8 exposures with two sy mptomatic cases. Four exposures were found in a group of children 5 and under , with two sy mptomatic cases. One involved a 67 year old woman who reported respiratory problems after an application near her home. There were no hospitalizations or Intensive Care Unit treatments report e d for these incidences (See Review of Isoxaben Incident Reports, M. Hawkins; Aug 30, 2007). 5.0 Dietary Exposure/Risk Characterization For the purposes of this petition only , the nature of the residue in grapes and tree nuts is adequatel y understood based on grape and barley metabolism studies. With respect to future uses, HED concludes that the submitted plant metabolism studies are ade quate for uses on cereal grains, grasses, and tree nuts. For grapes and tree nuts the grape metabolism study is adequate only for earl y s eason uses (i.e., prior to or at bloom). Additional radiolabeled studies would be needed for later season uses on tre e nuts or grapes and for an y uses on other crops beyond grains and grasses .Is oxaben D376428

Page 26 of 90 The petitioner provided adequate grape and tree nut field trial data and processing studies in support of the proposed tolerances. The available processing data indicate that res idues of isoxaben do not concentrate in grape juice or raisins; therefore, no tolerances are needed for grape processed commodities . There are no processed commodities for tree nuts and pistachios. For dietary

risk assessment purposes , HED concludes that the tolerance based on the parent will be adequate. In the grape metabolism study , the TRR was <0.008 ppm in the fruit, after a single application of isoxaben ranging from 1.79 - 1.97 lbs ai/A (1.8 - 2.0x proposed seasonal rate). Grapes harvested 60 days fo llowing a single broadcast application of the 75% DF formulation of isoxaben to the soil at 5.0 lb ai/A (5x the proposed rate) had residues below the L OQ (0.01 ppm) in/on all samples of grapes and raisins. Therefore, use of the LOQ (0.01 ppm) for the pare nt in grapes represents a conservative estimate of dietary exposure. Although radiolabeled data have not been provided for tree nuts to make a similar comparison with field trial results, it is unlikely that at the requested PHIs significant uptake of res idues from a soil - directed application into the edible nutmeat would occur. 5.1 Pesticide Metabolism and Environmental Degradation 5.1.1 Metabolism in Primary Crops DER Reference: 47140006.der.doc (Barley)

47175101.der.doc (Grape) Residue Chemistry Memo PP#5G3216, 5/17/85, J. Worthington Grape . Dow AgroSciences submitted a study investigating the metabolism of [isoxazole - 5 - 14 C]isoxaben and [p henyl 14 C]isoxaben in grape. The radiolabeled test substances were applied as a single broadcast application to the soil surrounding grape vines at the dormant stage at 1.97 lb ai/A for the isoxazole label and 1.79 lb ai/A for the phen yllabel. The appli cation rates used in the study are approximately 1. 8 x - 2.0x the proposed maximum seasonal rate and maximum individual application rate of 1.0 lb ai/A . TRR were below the LOQ (<0.008 ppm) in/on grape fruit harvested 165 day s following soil treatment with i soxazole - or phen yl - labeled isoxaben at 1.79 or 1.97 lb ai/A. TRR were 0.304 and 0.288 ppm in grape foliage following soil treatment with isoxazole - or phenyl - labeled isoxaben, respectivel y. Because TRR were <LOQ in/on grape fruit, no attempts were made to characterize or identify

metabolites in the fruit. Based on the submitted grape metabolism study , the petitioner proposed that following application of isoxaben to the soil, low levels of radioactivity are taken up by

the grape vine roots, and even low er levels of radioactivity are translocated into the edible fruit. The metabolism of isoxaben in grape leaves appears to proceed through h ydroxylation of the methylprop ylgroup. Ultimately , the soil degradation/plant metabolism proceeds to low level, mul tiple, polar components, presumably through cleavage of the benzamide bridge.Is oxaben D376428

Page 27 of 90 B arley . Dow AgroSciences submitted a study investigating the metabolism of [isoxazole - 5 - 14 C]isoxaben and [phenyl 14 C]isoxaben in barley. Each radiolabeled test substance was formulated with blank suspension concentrate ( SC ) formulation, diluted with water, and applied as a single foliar application at 0.178 lb ai/A (200 g ai/ha) to barley at the BBCH 13 growth stage (3 unfolded leaves) grown outdoors. The application rate us ed in the study is 0.1x the proposed maximum seasonal rate of 1.3 lb ai/A for grapes and tree nuts . (Note: This is a new study , not the study reviewed b y HED in 1985.) TABLE 5.1.1 Total Radioactive Residues (TRR) in Barley at 0.1 78x Application Rate. M atrix Application rate (lb ai/A) PHI (days) Isoxazole label Phenyl label

p pm p pm Immature plant 0.178 0 5.731 4.718 7 3.129 1.307 14 0.376 0.341 28 0.084 0.052 Grain 87 0.019 (0.019) 0.012 (0.011) Straw 0.281 (0.298) 0.222 (0.213) Chaff 0.458 (0.475) 0.279 (0.295) Based on the submitted barley metabolism studies, the petitioner proposed that isoxaben is significantl y metabolized in summer barley . Hydroxylation of the aliphatic side chain of the intact molecule is the major route of metabolism in barley ; cleavage of the amide bond was not observed. Isoxaben and metabolites were also present as acid - hydrolyzable conjugates. Isoxaben and metabolites, as well as conjugates/polar compounds, were partly incorporated into the nonextractab le residues of barley matrices. (See Figures in Appendix B2.) The metabolism of isoxaben was similar in both plant ty pes and confirms the major metabolic pathway is hydro x yl ation of the aliphatic side chain of the parent compound , followed b y further con jugation reactions . The grape metabolism study suggested cleavage of the benzamide bridge, which was not reflected in the barley study . The difference may be due to the longer PHI reflected in the grape study , compared to the barley study (165 vs. 87 day s). Additional details for the plant and animal metabolism studies can be found in the I soxaben Chemistry

Summary

(D341694, D. McNeill y, 21 July 2010 ). 5.1.2 Metabolism in Rotational Crops Data depicting the metabolism of isoxaben in rotational crops have not been submitted. Grape vines and tree nuts are perennial and under normal practices there are no succeeding crops . Therefore, such data are not required at this time. 5.1.3 Metabolism in Livestock DER Reference: 47825501.der.docIs oxaben D376428

Page 28 of 90 D ow AgroSciences LLC has submitted a study investigating the metabolism of [isoxazole - 5 - 14 C]isoxaben and [phenyl 14 C]isoxaben in goats. Based on the results of the study , i soxaben me tabolism in the lactating goat is proposed to occur by hydrox yl ation to form the 3 - hydr oxy isoxaben metabolite and the hydrox yl ated isoxaben metabolite (with the hydrox yl ation occurring on the methyl pentanyl moiety). Oxidation of these hydroxylated metab olites is hy pothesized to result in the carbox yl ic acid metabolite of isoxaben. Two oxime metabolites (of unclear stereochemistry) are then formed by hydryol yt ic cleavage of the isoxazole ring. Finally , cleavage of the amide link in isoxaben causes the fo rmation of the 2,6 dimethoxy benzamide, 2,6 - dimethoxy

benzoic acid, and 2 - hydrox y - 6 - methoxy benzamide metabolites (minor residues identified in liver, kidney, and muscle in the phen yl - label goat matrices). The majority

of the administered isoxaben (74% in the isoxazole label, 63% in the phen yllabel) was excreted in urine and feces. Only a small portion of the administered dose was recovered in milk, with less than 0.22% of the dose recovered in the isoxazole label and 0.09% in the phenyl label. The highe st concentration was observed in liver matrices, with the maximum TRR of 2.026 ppm observed in the isoxazole label (accounting for 2% of the administered dose). The parent isoxaben was onl y identified as a major metabolite in fat matrices. An oxime isomer was found to be a major metabolite in liver and kidney matrices, whereas a second oxime isomer was identified as a major metabolite only in kidney . A carbox yl ic acid metabolite was also identified as a major metabolite, but only in kidney matrices. Min or metabolites of 2,6 - dimethoxy

benzamide (muscle, liver, kidney , milk), 2,6 - dimethoxy benzoic acid (kidney), and 2 - hydrox y - 6 - methoxy - benzamide (liver and kidney) were also identified A significant portion of the TRR (14 - 68% TRR across matrices) could not be conclusivel y identified, either because the components were <LOQ or the components were tentatively identified as being one to four possible metabolites (oxime isomer, 3 - hydrox y isoxaben, carbox yl ic acid metabolite, hydrox yl ated isoxaben). This metabol ism study is sufficient for the purposes of the new proposed use s on tree nuts and vineyards currently under review. However, future new uses involving significant livestock feed items may need additional metabolism studies given the inconclusive results of metabolite identification for a large portion of the TRR across matrices. 5.1.4 Analytical Methodology DER References: 47140007.der.doc (M ethod GRM 02.26 )

47492601.der.doc ( revised M ethod GRM 02.26.S.1 ) Enforcement method: Dow AgroSciences has proposed an LC/MS/MS method, GRM 02.26.S.1, for the enforcement of tolerances for residues of isoxaben in/on crop commodities. The method is entitled “Determination of Residues of Isoxaben in Cereals, Chicory , Endives, Almonds, Pecans and Grapes b y Li quid Chromatograph y with Tandem Mass Spectrometry .” Briefl y, residues of isoxaben are extracted from crop samples with ACN:water (70:30, v:v). An aliquot of the extract is diluted with water and subjected to liquid - liquid extraction on a diatomaceous column, using dichloromethane to elute the residues. The eluate is evaporated to dry ness, redissolved in methanol:water (50:50, v:v) containing 5 mM ammonium acetate, and anal yz ed b y liquid chromatograph y with positive - ion atmospheric pressure chemical ionization tandem mass spectrometry (LC/MS/MS). The validated LOQ is 0.01 ppm for isoxaben in each matrix.Is oxaben D376428

Page 29 of 90 An independent laboratory validation ( ILV ) study

was not submitted for the enforcement method GRM 02.26.S.1. However, an ILV was submitted for the initial method GRM 02.26 with wheat grain and endive leaves fortified with isoxaben at 0.01 ppm, 0.02 ppm, and 0.10 ppm. Adequate recoveries were obtained for both commodities using the method as written. Data collection: T he originall y proposed enforcement method, L C/MS/MS method GRM 02.26, was used for data collection in samples of grape and tree nut commodities from the crop field trial and processing studies associated with this petition. Conclusions . The plant commodi ty anal yt ical method data are adequate for both data collection and tolerance enforcement. No multiresidue method testing data were submitted with this petition. The FDA PESTDATA database (dated 06/05) indicates that isoxaben is completely recovered usin g multiresidue method Section 302. The database did not include an y information for an y of the other test methods. 5.1.5 Environmental Degradation D341497, C. Peck, 18 March 2010 There is no significant evidence that isoxaben degrades by hydrol ys is. Isoxaben does not readil y undergo aerobic or anaerobic degradation in soil , half lives are greater than 150 day s. Isoxaben degrades via soil photolysis with a half life of 49 day s. Primary routes of degradation are aqueous photoly sis, aerobic aqueous metabolism and anaerobic aqueous metabolism with half lives ranging from 6 to 18 day s. Isoxaben is not expected to volatize based on its low vapor pressure . I soxaben is classified as moderatel y mobile based on adsorpt ion Kd values in five ty pes of soils ranging from 0.81 to 6.63 ml/g. Major degradates of isoxaben include hydroxyisoxaben, dimethoxy

benzamide, methoxy

phenylpy rimidinol, and AEM hexenoylisoxaben. Based on structural anal ys is of these degradates in EPI Suit e, three of the degradates ( hydrox yi soxaben, dimethoxy

benzamide, and AEM hexenoylisoxaben) have the potential to be more mobile than isoxaben (Koc values ranging from 4.6 to 102 ml/g oc ), with methoxy phen yl py rimidinol appearing to be very immobile (Koc valu es from 4,800 to 38,000 ml/g oc ). There is a potential for isoxaben and its degradates to reach surface water through spray drift, as products may

be applied via ground spray . Because isoxaben and its degradates are persistent in surface soils, there is a lso the potential for them to reach surface water through surface runoff either in solution or adsorbed to the soil. I soxaben and its degradates have the potential to leach to ground water when applied to certain soils, where high water tables are present , and high rainfall/ irrigation occurs. Isoxaben residues accumulated in bluegill sunfish with maximum bioconcentration factors of 14x in edible tissue, 134x in non - edible tissue, and 70x in whole fish tissue during 28 day s of exposur e. The r esidues accumulated b y day 28 were depurated quickl y; at day 14 of dupuration, isoxaben residues had been reduced b y 92 - 99% in the edible, non - edible, and whole fish tissue.Is oxaben D376428

Page 30 of 90 Isoxaben is not expected to accumulate in aquatic or terrestrial food chains as used under th e currentl y registered and/or proposed uses. 5.1.6 Comparative Metabolic Profile In rats, the major routes of metabolism were oxidation of position 2 of the alkyl side chain yi elding either an alcohol or a ket one, h ydrox yl ation of the aromatic ring adjacent to one of the methoxy groups or O - demethylation of the methoxy groups. Overall metabolite profiles were similar for males and females, with minor quantitative differences observed. H ydrox yl ated metabolites ( e.g., 1 - hydrox yl , 2 - hydroxyl , 3 - hydroxyl ) were major residues in the plant metabolism stud ies . S imilar metabolic pathway s w ere also observed in the livestock metabolism and the rat metabolism study . 5.1.7 Toxicity Profile of Major Metabolites and Degra dates Plants: For dietary

risk assessment purposes , Residues of Concern Knowledgebase Subc ommittee ( ROCKS ) conclude d that the tolerance based on the parent will be adequate. In the grap e metabolism study , the TRR was <0.008 ppm in the fruit, after a single application of isoxaben ranging from 1.79 - 1.97 lbs ai/A ( roughl y 1.8 - 2.0x proposed seasonal rate). Grapes harvested 60 day s following a single broadcast application of the 75% DF formulation of isoxaben to the soil at 5.0 lb ai/A (5x the proposed rate) had residues below the L OQ (0.01 ppm) in/on all samples of grapes and raisins. Therefore, use of the LOQ (0.01 ppm) for the parent in grapes represents a conservative estimate of dietary exposure. Although radiolabeled data have not been provided for tree nuts to make a similar comparison with field trial results, it is unlikely that significant uptake of residues from a soil - directed application into the edible nutmeat would occur. F or the primary

crop s grapes and tree nuts, isoxaben parent can serve as an adequate measure of misuse based on its percentage of the total radioactive residue (TRR) in the barley metabolism study and the field trial residues observed in almond hulls and nutmeat. ROCKS recommended using the p arent onl y for compliance purposes. Three h ydrox yl ated metabolites ( 1 - hydroxyl , 2 - hy drox yl , 3 - hydroxyl ) were major residues in the barley metabolism study . Structure - activity relationship ( SAR) analy sis (DEREK) did no t reveal any alerts for the parent compound or the 1 - hydroxyl metabolite. Due to structural similarity , all of the hydroxylated metabolites are assumed to have comparable toxicity to the parent; therefore, for an y future uses on grains or grasses, the pet itioner is advised to include residue data on the three h ydrox yl ated metabolites as they are likel y t o be included ( at least for risk assessment purposes ) on those crops. Livestock : HED concludes that residues in milk, ruminant and poultry meat, fat, and meat by products and eggs remain a 40CFR §180.6[a][3] situation ( i.e., no expectation of finite residues in these commodities). Although the goat metabolism study identified low percentages of the total radioactive residues in most matrices, it is adequat e for the proposed uses, based on the very low dietary

burden for cattle. Another goat metabolism study with better identificationIs oxaben D376428

Page 31 of 90 and characterization of the residues will be needed to support any additional uses of isoxaben that result in significantly higher dietary burdens. Drinking Water: Major degradates (>10% of total residues) detected during aerobic and anaerobic soil metabolism studies and aerobic and anaerobic aqueous metabolism studies include hydrox y isoxaben, dimethox y benzamide, methoxy phe nyl py rimidinol, and AEM hexenoyl isoxaben. These degradates are more mobile than the parent , except for methoxy phen yl py rimidol . SAR anal ys is (DEREK) did not reveal any alerts for the parent compound but did produce alerts for the methoxy phen ylpy rimidi nol ( carcinogenicit y , skin sensitization ) and AEM hexenoyl isoxaben ( skin sensitization ) metabolites. ROCKS is not concerned for these alerts because substituted p yri midine/ purine carcinogenicity is only seen at very

high doses (as a result of bladder cal culi) and dermal exposure to metabolites is not expected to be significant. None of the environmental degradates are thus expected to be more toxic than the parent compound, but data are not available to exclude them as residues of concern. 5.1.8 Pestici de Metabolites and Degradates of Concern Table 5.1.8 Summary of Metabolites and Degradates to be included in th e Risk

Assessment and Tolerance Expression Matrix Residues included in Risk Asse ssment Residues included in Tolerance Expression for Compliance Monitoring Plants Primary Crop Isoxaben Isoxaben

Rotational Crop Not Applicable Not Applicable Livestock Ruminant Not Applicable Not Applicable

Poultry Not Applicable Not Applicable Dri nking Water Isoxaben + Hydroxy isoxaben + Methoxyphenyl pyrimidinol + AEM hexenoyl isoxaben + Dimethoxy

benzamide . Not Applicable Isoxaben = N

- [3 - (1 - ethyl - 1 - methylpropyl) - 5 - isoxazolyl] - 2,6 - dimethoxy benzamide. Hydroxy isoxaben = N

- [3 - (1 - hydroxyl - 1 - methylpr opyl) - 5 - isoxazoyl] - 2,6 - dimethoxy - benzamide. Methoxyphenyl pyrimidinol =6 - (1 - ethyl - 1 - methylpropyl) - 2 - (2 - hydroxy - 6 - methoxyphenyl) - 4 - py rimidinol. AEM hexenoyl isoxaben = N - [3 - amino - 4 - ethyl - 4 - methyl - 2 - hexenoyl] - 2,6 - dimethoxybenzamide. Dimethoxy benzamide = 2,6 - Dimethoxybenzamide. 5.1.9 Drinking Water Residue Profile D341497, C. Peck, 3/18/2010 The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Divis ion (EFED) in the following memorandum: “T ier I Drinking Water Assessment for the Isoxaben New Use on Bearing Nut Trees and Vineyards ” (D3 41497 , C. Peck, 3 / 18 /20 10 ) and were incorporated directl y into th e dietary assessment . Monitoring data are not availa ble to assess isoxaben residue concentrations in surface and groundwater sources of drinking water .Is oxaben D376428

Page 32 of 90 E stimated drinking water concentrations ( EDWCs ) were generated using EFED’s standard suite of models. The FQPA Index Reservoir Screening Tool (FIRST) is a surface water model that is used to estimate both acute and chronic potential pesticide concentrations in untreated drinking water. EDWCs from FIRST represent concentrations which might occur from a single 1 - in - 10 - ye ar storm event following the last appli cation of pesticide at a location more vulnerable than most locations in the United States to runoff, regardless of the crop being produced. The model considers reductions in dissolved concentration due to the percentage of the watershed which is cropped (percent cropped area - PCA), due to adsorption of pesticide to field soil and to reservoir bottom sediment, due to incorporation of the pesticide at the time of application, due to degradation in soil before washoff to the reservoir, and due to degradation of the pesticide within the water body. A more detailed description of the index reservoir watershed can be found in Jones et al. , 1998. Percent Cropped Areas (PCA) that account for the maximum area within a watershed that may

be planted with the modele d crop are applied to concentrations predicted by PRZM/EXAMS (Pesticide Root Zone Model/Exposure Anal ys is Modeling Sy stem) . Screening Concentration in Ground Water (SCI - GROW v2.3, Jul. 29, 2003) is a regression m odel used as a screening tool to estimate p esticide concentrations found in ground water used as drinking water. SCI - GROW was developed by fitting a linear model to ground water concentrations with the Relative Index of Leaching Potential (RILP) as the independent variable. The RILP is a function of aerobic soil metabolism and the soil - water partition coefficient. The output of SCI - GROW represents the concentrations of isoxaben residue that might be expected in shallow unconfined aquifers under sandy soils, which is representative of the ground w ater most vulnerable to pesticide contamination and likely to serve as a drinking water source. The SCI - GROW model and user’s manual may also be downloaded from the EPA Water Models web - page ( http://www.epa.gov/oppefed1/models /water/#scigrow ). The EDWCs are based on the maximum proposed application rates specified in the product labels. Because the maximum annual application rate for the new use s assessed here is less than the application rate for ornamentals on the label for Isoxaben 75DF (EPA Reg. No. 34704 - 917), the values for ornamentals are recommended for use in the human health risk assessment. The annual application rate for ornamentals, which is used in this current assessment, is 3 lbs ai/A/year with a 60 day

re - treatment interval. The EDWCs for the human health risk assessment are presented in Table 5.1.9 . Because isoxaben has a number of major degradates predicted to have similar toxicity

as isoxaben, a total toxic residu e (TTR) approach was used in the modeling. In the TTR approach, half - lives are calculated for the combined isoxaben and degradate residue and modeling runs are conducted using these half - lives. Additionally , a mobility study and EPI Suite anal ys is indicat ed that several of the isoxaben degradates were more mobile than the parent. As such, two sets of modeling runs were completed: one set using the mobility estimates of the parent and one set using mobility estimates derived from the degradate study . The maximum 1 - in - 10 - year peak and annual mean EDWCs in surface water were 284 and 120 μg/L, respectivel y, for ornamental use. The maximum estimated acute concentration in groundwater was 43.6 μg/L for ornamental use. The maximum 1 - in - 10 - year peak and annual mean EDWCs in surface water were 87.6 and 37 μg/L, respectively , for bearing nut trees and vineyards. The maximum estimated acute concentration in groundwater was 14.5 μg/L for bearing nut trees and vineyards.Is oxaben D376428

Page 33 of 90 Table 5.1.9. Tier I Estimated Drinking Wate r Concentrations (EDWCs) resulting from applications of isoxaben and its degradates on ornam entals and bearing nut trees. Drinking water source (m odel) Use (m odeled rate) Acute 1 ( μg/L ) C hronic

( μg/L ) Parent Kd Data Surface water (FIRST) Ornamental 54.7 Groundwater (SCIGROW) Ornamental 2.13 Surface water (FIRST) Bearing nut trees and vineyards 16.9 Groundwater (SCIGROW) Bearing nut trees and vineyards 0.71 Degradate Kd Data Surface water (FIRST) Ornamental 120 2 Groundwater (SCIGROW) Ornamental 43.6 Surface water (FIRST) Bearing nut trees and vineyards 37.0 Groundwater (SCIGROW) Bearing nut trees and vineyards 14.5 1 - An acute dietary analysis was not conducted due to the absence of an appropriate end - point. 2 - The value used in the chronic d ietary assessment. Monitoring Data Isoxaben is not included as one of the anal yt es monitored in U.S. surface and groundwater under the USGS’s National Water Quality Assessment (NAWQA) program ( http://water.usgs .gov/nawqa). There were no detections in six surface water and sediment samples collected and analyzed for isoxaben by California Department of Pesticide Regulation (CDPR) in 2006 in Stanislaus County . 5.1.10 Food Residue Profile DER Reference: 47140008.der.doc (Almond)

47140009.der.doc (Pecan) 47040010.de1.doc (Grape) To support the proposed uses on grapes and tree nuts, Dow AgroSciences has submitted crop field trial data for grapes, a grape processing study, and crop field trial data for almonds and pecans , the representative commodities of the tree nut crop group. The submitted studies are adequate to satisfy

data requirements. Both table and wine grape varieties were included in the grape field trials. A suitable method was used for determination of residues of isoxaben, and adequate storage stability data were included . The grape processing study indicates residues do not concentrate in raisins or juice. A recommended tolerance summary for isoxaben is p resented in Appendix C . Grape Residues of isoxaben were below the LOQ of 0.01 ppm in/on all grape samples. Tree nut, group 14 Almond: Residues of isoxaben were <LOQ in/on all almond nutmeat samples from Treatment Plot Nos. 2 and 3, with the exceptio n of two samples collected from Treatment Plot No. 3 in theIs oxaben D376428

Page 34 of 90 decline trial (sampling interval of 68 day s) which bore residues of 0.014 and 0.015 ppm. Residues of isoxaben were below the LOQ in/on all samples of almond hulls from Treatment Plot No. 2, inclu ding samples from the decline trials. Residues of isoxaben were <0.01 - 0.301 ppm in/on almond hull samples (including samples from decline trials) from Treatment Plot No. 3. In the decline trial for Treatment Plot No. 2, isoxaben residues were below the LO Q in/on all sample s of almond nutmeat and hulls. In the decline trial from Treatment Plot No. 3, residues of isoxaben were <LOQ in/on all samples of nutmeat except those harvested at the 68 - day sampling interval (as noted above). For almond hulls from Treatment Plot No. 3, residues of isoxaben increased from the 54 - day sampling interval (average of 0.103 ppm) to the 68 - day sampling interval (average of 0.267 ppm) and then decreased at the 75 - day sampling interval (average of 0.123 ppm). Pecan : Resid

ues of isoxaben were <LOQ in/on all pecan nutmeat samples. Grape Processing DER Reference: 47140010.de2.doc Dow AgroSciences submitted a processing study with isoxaben on grapes. Samples used for processing were generated from one trial conducted in NY during the 2006 growing season. Grapes were harvested 60 day s following a single broadcast application of the 75% DF formulation of isoxaben to the soil at 5.0 lb s ai/A (5x the field trial rate). Application was made using ground equipment in 25 gal/A s pray volumes without an adjuvant. Whole grapes were processed into raisins and juice using simulated commercial processes. All residues were below the L OQ in/on all samples of grapes, raisins, and grape juice; therefore, process ed commodit y tolerances ar e not required and the data indicate that residues in processed commodities treated at 1x would be well below the LOQ . 5.1.11 International Residue Limits No Codex, Canadian, or Mexican MRL s have been establis hed for isoxaben . 5.2 Dietary Exposure and Risk D3 75246 , E . Holman, 7 / 13 /20 10 A chronic dietary

risk assessment was conducted using the Dietary Exposure Evaluation Model (DEEM - FCID, Version 2.03), which uses food c onsumption data from the USDA’s Continuing Survey s of Food Intakes by Individuals (CSFII) from 1994 - 1996 and 1998. This analy sis is based on t olerance level residues and 100% crop treated assumptions. 5.2.1 Acute Dietary Exposure/Risk An acute reference dose has not been established for either the general population (including infants and children) or for females age s 13 - 49 years . There were no studies that demonstratedIs oxaben D376428

Page 35 of 90 evidence of toxicity

attributable to a si ngle dose . As a result, a quantitative acute dietary exposure assessment has not been performed. 5.2.2 Chronic Dietary Exposure/Risk The chronic dietary (food + water) risk estimates are below HED’s LOC fo r the general U.S. population and all population subgroups, including those comprised of infants and children. The general U.S. population and all population subgroups have risk estimates that are well below HED’s LOC (i.e., 100% of the chronic population adjusted dose (cPAD)). The most highl y exposed population subgroup is In fants <1 yr, which utilizes 1 7 % of the cPAD. The general U.S. population utilizes 5.1 % of the cPAD.

Table 5.2.2 Summary of Dietary Exposure and Risk for Isoxaben 1

Populatio n Subgroup* Ac ute Dietary 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 N/A No acute dietary endpoint wa s identified N/A 0.002536 5.1 N/A N/A All Infants (< 1 year old) 0.008303 17 Children 1 - 2 y ears old 0.003794 7.6 Children 3 - 5 y ears old 0.003540 7.1 Children 6 - 12 y ears old 0.002434 4.9 Youth 13 - 19 y ears old 0.001832 3.7 Adults 20 - 49 y ears old 0.002366 4. 7 Adults 50+ years old 0.002490 5.0 Females 13 - 49 y ears old 0.002356 4.7 1 The value for the highest exposed population in this chronic risk assessment is bolded. 5.2.3 Cancer Dietary Risk Isoxaben was re viewed by the Cancer Assessment Review Committee (CARC) to determine the cancer classification under the current (2005) US EPA Guidelines for Assessment of Carcinogenicit y. Isoxaben is classified as “Suggestive Evidence of Carcinogenic Potential,” based o n an increased incidence of benign hepatocellular tumors in male and female mice (Isoxaben: Second Report of the Cancer Assessment Review Committee, dated October 7, 2008). The liver tumors were observed onl y in one species, were not malignant and were obs erved in the presence of liver toxicity at dietary levels exceeding the limit dose (1000 mg/kg/day)

. The chronic RfD/PAD is based on the chronic toxicity NOAEL of 5 mg/kg/day in the rat, which is more than 200 - fold lower than the dose at which tumors were observed in the mouse. Therefore, the cRfD/PAD is considered to be protective of potential carcinogenicity and quantification of cancer risk using a cancer potency factor is not required .Is oxaben D376428

Page 36 of 90 5.3 Anticipated Residue and Percent Crop Treated (%CT) Informatio n No Percent Crop Treated (PCT) i nformation was incorporated into the current dietary exposure and risk assessment; that is, HED assumed 100 %CT for grapes and tree nuts . Toleran ce level residue levels were assumed ; no anticipated residues were used in this assessment. 6.0 Residential (Non - Occupational) Exposure/Risk Characterization D 3 68834 , S. Oonnith an, 7 /2 6 / 10 With the proposed first food use of isoxaben (EPA File Sy mbol 62719 - LIN), the registrant did not propose an y new residential uses. There are several registered liquid and solid end - use product formulations available for weed control on home l awns, recreational turf areas and ornamental plantings. Some products are labeled for use b y homeowners and others are for use by professional applicators. No new residential uses for isoxaben are being requested with this application. Even though iso xaben is already registered for weed control in residential areas, quantitative homeowner (handler) and postapplication exposure assessments were not previously conducted due to the lack of short - term incidental oral, dermal and inhalation endpoints needed to estimate these risks. Based on the current hazard characterization and in order to complete an aggregate risk assessment in conjunction with the proposed first food use of isoxaben, residential exposures were estimated, taking into consideration all end - use products registered for residential uses. For assessing residential handler exposure, two representative product formulations having the highest single application rates were selected. They are an EC (Lawn 3iP Herbicide Concentrate, Reg. No. 7215 5 - 87) and a granule (T&O Fertilizer - Contains Gallery plus Team, EPA Reg. No. 62719 - 280). The liquid and granule have maximum single application rates of 0.49 and 1.0 lb ai/A, respectively . The granule product is packaged and marketed individually as home owner and commercial products and both labels have almost identical use patterns (Table 6a).Is oxaben D376428

Page 37 of 90 Table 6a. Use Pattern of Isoxaben End - use Products Selected for Residential Handler and Postapplication Exposure Assessments. EPA Reg. No. 1 Applic ation Equipment Appl. rates No. appls./ season & interval 2 Comments Lawn 3iP Herbicide Conc., Reg. No. 72155 - 87 (EC, Isoxaben = 2.63%) Hom eowner/Commercial Label

After mixing with water

- pum p style hand held spraye r

- concentrate plus water hose - end sprayer Without mixing with water

- dial - style hose - end sprayer

- single - rate or dual - rate hose - end sprayer Rate/appl.= 1.6 - 3.2 fl. oz. /500 sq. ft Max/appl.= 0.49 lb ai/A Max/year = 0.98 lb ai/A 2/year

60 days NA

T&O Fertilizer, EPA Reg. No. 62719 - 280 (Granule) Isoxaben = 0.38%) Hom eowner/Commercial Label

- drop or rotary - type granule spreader Rate/appl.= 174 - 265 lbs/A Max/appl.= 1.0 lb ai/A Max/year = 2.0 lb ai/A 2 - 7/y ear

56 days Sprinkler

irrigation or rainfall within a few hours is recommended Isoxaben 75DF Specialty Herbicide EPA Reg. No. 34704 - 917, DF Isoxaben=75% Commercial Label

- herbicide sprayer

- spray volume ≥10 gal/A Rate/appl.= 0.66 - 1.33 lbs/A Max/appl.= 1.0 lb ai/A Max/year = 4 lbs/A (3.0 lb ai/A) 3 or more

60 days Sprinkler

irrigation or rainfall after application is recommended Abbreviations used: DF = dry flowable, EC = emulsifiable concentrate, NA = not applicable 1. Lawn 3iP Herbicide Concentrate/Ready - to - Spray (Reg. No. 72155 - 87) is an EC containing isoxaben (2.63%), 2,4 - D dimethylamine salt (4.73%), dicamba (0.52%) and mecoprop - p potassium salt (1.1%). T&O Fertilizer Contains Gallery plus Team (EPA Reg. No. 62719 - 280) is a granule + fertilizer containing isoxaben (0.38%) , trifluralin (0.39%) and benefin (0.76%). 2. Repeat applications may represent rates that are lower than the maximum single rate/A. Exposure and Risk to Homeowners : The use patterns used for a quantitative assessment of homeowner exposures are from EC and granule products (Table 6a). Potential Exposure Scenarios : The following scenarios were assessed: 1. mixing/loading/appl yi ng EC using a hose - end sprayer 2. mixing/loading/appl yi ng EC using a hand - held pump sprayer 3. loading/appl yi ng granules u sing a granular push - ty pe spreader Application Rate and Exposure Durations : For residential handler exposure assessment, HED uses maximum single application rates and frequency of treatments for determining short - and intermediate - term exposures. The E C product label recommends two application s per year for weed control on home lawns at a single maximum rate of 0.49 lb ai/A . The minimum interval between treatments is 60 day s. T herefore, homeowners have the potential for only short - term dermal and inha lation exposure . The granule product label recommends repeat applications at anIs oxaben D376428

Page 38 of 90 interval of 56 day s on cool season grass and 70 day s on warm season grass at a single maximum single rate of 0.99 lb ai/A, resulting in short - term exposures. There are some di stributor products sold in Florida (both homeowner and commercial labels) that recommend up to 7 applications per year on Bermuda grass with a maximum rate of 2 lb ai/A/year. These repeated applications are assumed to be made at an average rate of 0.3 lb ai/A/application taking into account an annual limit of 2.0 lb ai/A. Despite the potential for repeated applications, HED continues to consider residential handler exposures to be short - term in duration based on the 56 day retreatment interval . Exposure and Risk to Residential Handlers : No chemical specific exposure data have been submitted by

the registrant to estimate the inhalation unit exposures for residential handlers. Therefore, surrogate unit exposures from the Outdoor Residential Exposure Task Force database (ORETF) were selected. Short - term dermal risks were not estimated due to the lack of a dermal endpoint. The short - term inhalation MOEs ranged from 2.9E+06 to 2.8E+07 (LOC=100) and are not of concern (Table 6b). Table 6 b . Exposure s and Ri sks to Hom eowners R esulting from Applying Liquid and Solid Formulations of Isoxaben on Residential Lawns. 1 Exposure Scenario s Max. Single

Appl. rate, lb ai/A 2 Area

treated A/day 3 Inhal. U.E.

mg/kg/day (ORETF) Inh alation

dose mg/kg/day 4 Sh ort - term

Inh al. MOE 5 M/L/A, liquid, hose - end sprayer 0.49 0.5 0.017 6.9 4 E - 05 2.9 E+06 M/L/A, liquid, hand - held sprayer 0.49 0.5 0.0038 1.55 E - 05 1.3 E+07 L/A, granules, push ty pe spreader 0.99 0. 5 0.00088 7.2 E - 0 6 2.8 E+0 7 Abbreviations used: A= applicator, L= loader, M= mixer, ORETF = Outdoor residential exposure task force. 1. Short - term

dermal exposures were not estimated due to the absence of a dermal endpoint. 2. The maximum single application r ates are from Table 6a . 3. The area treated (acres per day) are assumed to be 0.5 A/day for hose - end and hand - held sprayers and for granules. 4. Inhalation dose (mg/kg/day) = (application rate * area treated/day * inhalation unit exposure * inhal ation absorption rate) / body wt. (60 kg). 5. Inhalation MOE = Short - term Inhalation NOAEL (200 mg/kg/day)/inhalation dose 6.1 Residential Postapplication Exposure . For evaluating the residential postapplication exposure of isoxaben, EC, granule and solid formulations were considered (Table 6a ). Since the Isoxaben 75 DF Specialty Herbicide, EPA Reg. No. 34704 - 917, had the highest application rate/year, it was assumed that the estimated risks would be protective of those associated with other formulations and application rates. This solid formulation is labeled for use b y professional applicators on established turf, landscape, container and field grown ornamentals, non - cropland, non - bearing fruit and nut trees and non bearing vineyards. It has a maximum single application rate of 1.0 lb ai/A (similar to EC and granule), with a ye arl y rate of 3.0 lb ai/A.Is oxaben D376428

Page 39 of 90 Dermal E xposures to C hildren, Y outh and A dults : D ermal endpoint s were not selected for iso xaben, for an y duration of exposure, due to the lack of toxic effects via the dermal route; therefore, the risk associated with dermal postapplication exposure is not of concern. Short - Term Incidental Oral Exposures to Children from Hand - to - Mouth and Obje ct - to - Mouth Events : Itis likel y that children playing in treated turf areas would ingest residues of isoxaben from h and - to - m outh and o bjects - to - m outh events. However, there is no endpoint applicable to short - term oral exposure, and therefore, there are no risks of concern associated with hand - to mouth and object - to - mouth exposure. Episodic Oral Exposures to Children from Ingestion of Granules : In gestion of isoxaben granules following application of T &O Fertilizer - Contains Gallery plus Team to turf is c onsidered to be an episodic event for children playing on treated lawns. The granules are not likely to be present on treated turf for up to 30 day s (i.e., short - term durations) due to the label recommendation for irrigation/watering within hours of appli cation. Further, in the absence of an acute dietary endpoint attributable to a single exposure , episodic ingestion of granules was not assessed . By stander Inhalation Exposure : Based on the Agency 's current practices, residential postapplication inhal ation risk to children is not assessed; however, b ys tander exposure could occur for children playing in areas adjacent to pesticide applications. For adult by standers, postapplication inhalation exposure is expected to be negligible because (i) technical isoxaben has low inhalation toxicity (Category

III); (ii) label recommended incorporation by rainfall or irrigation after application; (iii) isoxaben has low volatility (vapor pressure of 1.3E - 8 Pa at 25  ̊ C , McNeilly , July 2010); and (iv) products are not applied using air blast or aerial equipment that would result in significant inhalation exposure. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure t o individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 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 Agency is in the 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 postapplication 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 postapplication inhalation exp osure assessment for isoxaben. Intermediate - term Incidental Oral Exposure to Children resulting from Soil Ingestion : HED does not ty

picall y consider soil ingestion to occur over intermediate - term durations, i.e., from 1 - 6 months, largel y due to use patt ern and the fact that residues are removed by precipitation or through microbial degradation in soil. In the case of isoxaben, HED estimated incidental oral exposure from ingestion of soil because the use pattern calls for repeat applications, and because the environmental fate data indicated that isoxaben is persistent in the soil, with a half life of ≥150 day s ( C. Peck., D341497, 3/18/2010) . Because of the likel y persistence of isoxaben in soil, HED conducted a conservative assessment of potential intermediate - term oral risk from soil ingestion b y using an ye arly application rate of 3.0 lb ai/A from Isoxaben 75 DF instead of the maximum single rate of 1.0 lb ai/A.Is oxaben D376428

Page 40 of 90 To address the persistence of isoxaben in the soil , HED assumed that exposure resulting from incidental oral ingestion of soil ( intermediate - term ) at an exaggerated rate of 3.0 lb ai/A/ye ar would be a conservative estimate that would address the potential build up of isoxaben in the soil. The exposure and risk from incidental oral ingestion of soil was calculated using the following formula : ADD = (SR * IgR2 * CF4 ) / BW where, SR = AR * F3 * CF1 * CF2 * CF3 MOE = NOAEL / ADD SR = 3.0 lb ai/A * 100%/cm * 4.54E+08 μg/lb * 2.47E - 08 A/cm2 * 0.67 cm3 /g soil = 22.54 μg ai/g ADD = [22.54 μg ai/g * 100 mg/day * 0. 000001 g/ μg] / 15 kg = 1.50E - 04 mg/kg/day MOE = 200 mg/kg/day / 1.50E - 04 mg kg/day = 1.30E+06 where, ADD = Average daily dose (mg/kg/day) AR = Application rate (3.0 lb ai/A/year) BW = Body weight of child ( 15 kg) CF1 = Conversion factor for μ g/lb (4.54E+08) CF2 = Conversion factor for A/cm2 (2.47E - 08) CF3 = conversion fa ctor for volume to weight (0.67 cm3 /g soil) CF 4 = conversion factor for g/μg (0.000001) F3 = Percent of ai available in uppermost cm of soil (100% assumed) IgR2 = Ingestion rate of soil (100 mg/day) MOE = NOAEL (intermediate - term , mg/kg/day) / ADD (mg/kg/day) NOAEL (intermediate - term) = 200 mg/kg/day SR = Soil residue at intermediate - term (μg ai/g soil) t = postapplication day on which exposure is assessed (intermediate - term) It is emphasized here that the application rate of 3.0 lb ai/A/year used f or estimating the intermediate - term exposure is an exaggerated rate when compared with the single application rate of 1.0 lb ai/A of granule and DF formulations. At the intermediate - term exposure duration, the risk was found to be not of concern to childr en who may ingest soil treated with isoxaben (MOE = 1.30E+06, LOC =100). 6. 2 Other (Spray Drift, etc .) Spray drift is a potential source of exposure for residents living in close proximity to spraying operations. T his situation is particularl y the case with aerial application. However, to a lesser extent, spray

drift resulting from the ground application of isoxaben could also be a potential source of exposure. The Agency has been working with the Spray Drift Task Force (a membership of US pesticide registrants), EPA Regional Offices, State l ead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aeri al applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management pract ices to reduce off - target drift and risks associated with pesticide application .Is oxaben D376428

Page 41 of 90 7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e.g., NOAEL or PAD), or the risks themselves can b e aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. 7.1 Acute Aggregate Risk An acute reference dose has not been established for either th e general population (including infants and children) or for females ages 13 - 49 years . There were no studies that demonstrated evidence of toxicity

attributable to a si ngle dose . As a result, a quantitative acute dietary exposure assessment has not been performed , and acute aggregate risk is not of concern . 7. 2 Short - Term and Intermediate - Term Aggregate Risk Short - and intermediate - term aggregate exposure takes into account residential exposure plus average exposures levels from food and water (considered to be a background exposure level). Isoxaben residential uses constitute short - and intermediate - term exposure scenarios; endpoints have been selected for intermediate - term incidental oral (ch ildren onl y), and short - and intermediate - term inhalation exposures. The target MOEs for short - term and intermediate - term exposures are both 100. For children, an intermediate

–term aggregate assessment was conducted b y adding the incidental soil ingestio n exposure (see Section 6.1) and average food and water exposure (chronic dietary exposure). A short - term aggregate assessment for children was not conducted due to the absence of an appropriate end - point. For adults, a short - term aggregate assessment wa s conducted by adding inhalation exposure (assuming that the inhalation exposure is toxicologicall y equivalent to oral exposure), resulting from residential lawn treatment, with the average food and water exposures. Since exposures from the use of the granular formulation in a push - ty pe applicator resulted in the highest exposure, that short - term exposure scenario was evaluated. The liquid formulation applied in a hose - end sprayer also reflects short - term exposure (only two applications per ye ar) and has less exposure and risk. Children are not expected to make pesticide treatments with isoxaben. For all of the population subgroups shown in Table 7.1., short - and intermediate - term aggregate risk estimates do not exceed HED’s level of concern ( i.e., an MO E < 100) for any of the residential exposure scenarios examined. The short - term aggregate risk MOEs range from 6 2 ,000 to 66 ,000, for the U.S. population and females 13 - 49 , respectivel y . The intermediate term aggregate risk estimate is 5 1 , 0 00 for children 1 - 2 years old. The incidental oral residential exposure value selected for the aggregate anal ys is is based on children ingesting soil particles containing pesticide residues while playing in treated turf. Due to the persistence of isoxaben in the soil, HED took a conservative approach b y using the maximum seasonal application rate for estimating soil ingestion by children rather than the standard maximum single application rate. Th i s scenario resulted in the highest calculated exposure level s , and, ther efore, is protective forIs oxaben D376428

Page 42 of 90 all other postapplication risk for children in residential settings . Table 7. 1 . Aggregate Risk Calculations Population NOAEL

mg/kg/day LOC 1 Max Allowable Exposure 2 m g/kg/day Average

Food & Water Exposure mg/kg/day Residential

Exposure 3 mg/kg/day Aggregate MOE

(food and residential) 4 US Population 200 100 2.0 0.002536 6.94 E - 04 62, 000 Females 13 - 49 200 100 2.0 0.002356 6.94 E - 04 66, 000 Children 1 - 2 years old 5 200 100 2.0 0.003794 0. 000 15 51,000 1 T he LOC includes the standa rd inter- and intra species uncertainty factors for a total of 100 . 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC 3 Residential Exposure (

adults and reproductive females) = [ Inhalation Exposure ]. See Table 6b . Residential Exposure (children) = [ Incidental Soil Ingestion ] See Section 6.1 . 4 Aggregate MOE = [(NOAEL  (Avg. Food &W ater Exposure + Residential Exposure)] 5 Children 1 - 2 were selected for the aggregate risk evaluation as the sentinel population, i.e. , a subpopulation more likely to be exposed than infants <1 year old. Infants <1 year old did have a h igher background ( chronic dietary

) exposure, and the MOE for that population subgroup is 24,000 . A short - and intermediate - term dermal risk was not estimated due to the lack of an appropriate end - point. 7.3 Chronic Aggregate Risk Since there are no long - term or chronic residential scenarios associated with isoxaben uses, the chronic aggregate risk is equivalent to the chronic dietary (food and drinking water) risk . As shown in Table 5.2.2, th ese risks are not of concern. 7.4 Aggregate Cancer Risk Isoxaben was reviewed by the Cancer Assessment Review Committee (CARC) to determine the cancer classification under the current (2005) US EPA Guidelines for As sessment of Carcinogenicit y. Isoxaben is classified as “Suggestive Evidence of Carcinogenic Potential,” based on an increased incidence of benign hepatocellular tumors in male and female mice (Isoxaben: Second Report of the Cancer Assessment Review Committee, dated October 7, 2008). The liver tumors were observed onl y in one species, were not malignant and were observed in the presence of liver toxicity at dietary levels exceeding the limit dose (1000 mg/kg/day)

. The chronic RfD/PAD is based on the chroni c toxicity NOAEL of 5 mg/kg/day in the rat, which is more than 200 - fold lower than the dose at which tumors were observed in the mouse. Therefore, the cRfD/PAD is considered to be protective of potential carcinogenicity . As noted above, chronic aggregate risk estimates do not exceed HED’s level of concern.Is oxaben D376428

Page 43 of 90 8.0 Cumulative Risk Characterization/Assessment FQPA (1996) stipulates that when determining the safet y of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary , residential, or other non - occupational exposure to other substances that hav e a common mechanism of toxicity . The reason for consideration of other substances is due to the possibility that low - level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse hea lth effect as would a higher level of exposure to any of the other substances individually . A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a comm on toxic effect b y a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding as to isoxaben and any

other substances, and isoxaben does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that isoxaben has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity

and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Pathway D3 74750 , S . Oonithan , 7 / 16 /2010. No chemical - specific data for assessing handler expos ures were submitted to the Agency in support of the proposed uses associated with the subject petition. T herefore, when estimating occupational exposures, HED used : 1) surrogate data from the Pesticide Handlers Exposure Data Base (PHED v 1.1 ) ; 2) standard assessment variables established b y the Health Effects Division Science Advisory Council for Exposure (e.g. maximum application rates, standard acres treated per day , 6 0 kg body weight for workers); and, 3 ) standard protection factors assumed with specif

ied personal protective equipment. The estimated exposures are believed to be reasonable high - end estimates . The proposed use pattern for isoxaben in orchards of tree nuts and grapes is expected to result in short - and intermediate - term occupational inh alation and dermal exposures to mixers, loaders, and applicators. S hort - and intermediate - term dermal MOEs were not calculated due to the absence of respective endpoints. 9.1 Short - Term and Intermediate - Term Handler Risk The registrant has not submitted a chemical specific exposure study to determine the dermal and inhalation unit exposures (exposed ai per lbs of ai handled per day) needed to estimate the exposure to handlers. In the absence of che mical - specific data , surrogate unit exposures wereIs oxaben D376428

Page 44 of 90 selected from PHED that are specific to the formulation, application equipment and personal protective equipment ( PPE ) . ExpoSAC Policy No. 9 estimates that 40 - 200 acres can be treated/day

with a tractor m ounted ground boom sprayer depending upon the crop treated. For this assessment, 80 A/day was selected as a high end average for the orchard setting based on treatment of one row at a time, thereb y reducing the acreage treated on a given day. Areas not c overed with a ground - boom sprayer or spot treatments may be treated using a tractor mounted low - pressure hand wand sprayer. Itis assumed that a handler (M/L/A) can mix, load and apply 40 gal/day

( ExpoSAC Policy

No. 9 ) ; at the label recommended spray volume of 10 gal/A ( 4 acres/day) , HED estimates 4 acres/day could be treated for the low - pressure hand wand (tractor mounted) scenario. Baseline PPE ( long sleeved shirt, pants and shoes with socks) was used as a starting point to calculate handler exposures. For the present assessment, additional protection (e.g., respirator s , and engineering controls (enclosed cab and cockpit, closed sy stems) ) was not needed to obtain an MOE that is higher than the LOC . The label allows onl y 1 application of FN - 3133 (a 75% DF formulation) at the maximum single rate of 1.0 lb ai/A (harvest to harvest) on tree nuts, grape, and non - bearing fruit tree and grapevine orchards, resulting in short - term exposure to occupational handlers. However, it is possible that contract appli cators may use FN - 3133 Herbicide on several fields, with sequential applications lasting longer than a month during the weed growing season, resulting in intermediate - term exposure to handlers. A body weight of 60 kg was used for handlers because the toxic ity endpoints selected for assessing inhalation risks are based on offspring effects in the reproductive toxicity study . S ummaries of the short - and intermediate - term inhalation risks for handlers are included in Table 9 .1. The maximum application rate f or each exposure scenario is presented as the worst case scenario. All handler scenarios resulted in total MOEs greater than the LOC (MOEs ≥ 100) at baseline . The intermediate - term combined dermal and inhalation MOEs ranged from 2,700 to 200,000 for hand lers, which are not of concern. Table 9.1. Short - and Intermediate - term Exposure s Resulting from t h e Use of FN - 3133 Specialty Herbicide and Am oreTM DF Herbicide in Orchards of Bearing and Non - bearing Fruit and Nut Trees and Grape Vines 1 . Exposure Scenar io Appl . rate Area treated (A/day) PPE &

Eng . Control 2 Inhal. u nit

exposure (m g/lb ai) 3 Inhalation, Short - and

Interm ediate - term Exposure mg/kg/day 4 MOE 5 1. Mixing/loading DF for ground boom spray (open mixing) 1.0 lb al/A 80 Baseline 0.00077 0.00103 190,000 2. Applying spray using ground boom Baseline & open cab. 0.00074 0.00099 200,000 3. Mixing, loading, and applying using a tractor powered low pressure hand wand 4 Baseline 1.1 0.07333 2,700 1. MOE = Margin of exposure and PPE = Personal protective equipment. The inputs used for calculations are explained under Exposure Scenarios, Inputs and Assumptions.Is oxaben D376428

Page 45 of 90 2. Baseline PPE includes long sleeved shirt, long pants and shoes with socks. Engineering controls include open cab (tractor) for applicators. 3. Lacking unit exposures in PHED for a DF formulation, unit exposures for mixing, loading and applying a wettable powder formulation with a low - pressure handwand were used as s urrogate. 4. I nhalation exposure = [Inhalation unit exposure (m g/lb ai) * appl. rate (lb ai/A) * area treated/day (acres) * inhalation absorption 100 %] / body wt (60 kg). 5. MOE = Short - and intermediate - term NOAEL (200 mg/kg/day) /inhalation exposure ( mg/kg/day). 9.2 Short -/Intermediate - Term Postapplication Risk Workers entering treated areas to do crop - related cultural practices such as irrigation, scouting, pruning, etc., may

be expose d to isoxaben residues via dermal and inhalation routes for short term durations. However, postapplication dermal risk for workers is not of concern because of the absence of a short - term dermal endpoint. Based on the Agency 's current practices, a quant itative occupational postapplication inhalation exposure assessment was not performed for isoxaben at this time. However, there are multiple potential sources of postapplication inhalation exposure to individuals performing postapplication activities in p reviously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency

sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 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 Agency is in the process of evaluating the SAP report as well as available postapplication inhalation exposure data generated b y 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 postapplication 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 postapplication inhalation exposure ass essment for isoxaben. Restricted Entry Interval : A 12 - hour REI for isoxaben was set based on the acute toxicity properties of the technical material which is classified as Categories III (acute dermal, inhalation and eye irritation) and IV (acute oral an d skin irritation). Is oxaben is not a dermal sensitizer. The 12 - hour REI is appropriate for isoxaben based on the W PS for a gricultural p esticides . 10.0 Data Needs , Label Recommendations & Environmental Justice 10.1 Toxicology Additional toxicology

data are required to support registration of isoxaben. Although isoxaben did not show evidence of neurotoxicity or immunotoxicity

in the available studies, in accordance with the revised 40 CFR Part 158 Guidelines, acute and subchronic neurotoxicity studies in the rat and an immunotoxicity study are required . The registrant in a May 20, 2010 letter to the EPA stated that they

were developing these data for sub mission. A 90 - day inhalation toxicity

study in the rat is required based on the potential for inhalation exposure. These study requirements were identified during the Registration Review Scoping process for isoxaben. Inresponse to the scoping document, the Registrant has submitted a waiver request for the inhalation study , whichIs oxaben D376428

Page 46 of 90 will be reviewed b y the Agency . (Note: One of the incidents discussed in Section 4 involved potential post - application inhalation exposure.) 10.2 Residue Chemistry A revised Section F should be submitted with grape juice and raisins removed and the tolerance for almond hulls revised to 0. 40 ppm. The proposed tolerances for the tree nut group and pistachios should be revised to 0.02 ppm and the commodity definition for the tree nut group should be revised to “Nut, tree, Group 14.” NOTES: The submitted livestock metabolism study is sufficient for the proposed uses currentl y under review. However, additional ruminant metabolism data with better identification and characterization of the residue will be needed for any additional uses of isoxaben that result in significantl y higher livestock dietary burdens. HED ’s review of the livestock metabolism indicates that a cattle feeding study is no t needed for the proposed uses currently under consideration. However, a cattle feeding study may be needed for an y additional uses of isoxaben that result in significantly higher livestock dietary burdens. NOTE: The h ydrox yl ated metabolites of isoxaben are assumed to have comparable toxicity to the parent due to structural similarity ; therefore, for any future uses on grains or grasses, the petitioner is advised to include residue data on the three h ydrox yl ated metabolites as they are likely to be inclu ded (at least for risk assessment purposes) on those crops. 10.3 Occupational and Residential Exposure Based on the Agency 's current practices, a quantitative postapplication inhalation exposure assess ment was not performed for isoxaben at this time because of (i) the absence of a short - term inhalation endpoint; (ii) the low acute inhalation toxicity of isoxaben (Toxicity

Category III); and (iii) the soil - directed application method, which does not include the use of air blast or aerial equipment that could result in higher postapplication inhalation exposures. However, volatilization of pesticides may be a source of postapplication inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2 010 ( http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the 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 po stapplication inhalation exposure into the Agency 's risk assessments. If new policies or procedures are developed, the Agency

may revisit the need for a quantitative postapplication inhalation exposure assessment for isoxaben. 10.4 Label recommendation s The label should specify

that non - bearing nut tree or vines means trees or vines where nuts and/or grapes are not harvested for food /wine within one year of treatment.Is oxaben D376428

Page 47 of 90 10.5 Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Popul ations and L ow - Income Populations, ” http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variet y of consumer s ubgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the hom e that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by

Individuals (CSFII) and are used in pesticide risk assessments for all registered fo od uses of a pesticide. These data are anal yz ed and categorized by

subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure as sessments are performed when conditions or circumstances warrant. Whenever appropriate, nondietary

exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on tre ated areas postapplication are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifest yl e and traditional dietary patterns among specific subgroups. References: European Union Food Safety Authority

(EFSA) , D raft R eport for Isoxaben; May , 2006 . http://www.efsa.europa.eu/ en/scdocs/scdoc/58r.htm . Jones, R. D., S. Abel, W. R. Effland, R. Matzner, R. Parker. 1998. An Index Reservoir for Use in Assessing Drinking Water Exposure. Proposed Methods for Basin - scale Estimation of Pesticide Concentrations in Flowing Water and Reservoirs for Tolerance Reassessment. Presentation to FIFRA Science Advisory Panel, June 29 - 30, 1998. Online at : http://www.epa.gov/scipoly/sap/1998/index.htm USEPA. 2002. SCIGROW: Users Manual. Online at: http://www.epa.gov/oppefed1/models/ water/#scigrow D341567. Is oxaben: Registration Review Scoping Document for Human Health Assessments; PC Co de: 125 85 1; Reg istration Review Case Number: 7219. August 16 , 2007 . C harles Smith D341543. Is oxaben . Addendum to the Registration Review Scoping Document for Human Health Assessments. June 10, 2008. L innea Hansen, Ph.D. PP #5G3216. EL - 107® on wheat and barley . Comments on the analy tical method and residue data. RCB #591, J. Worthington, 5/17/85. MRIDs: 073291 and 072296Is oxaben D376428

Page 48 of 90 D341497, C. Peck ; March 18, 2010. Tier I Drinking Water Assessment for the I soxaben Proposed New Use on Bearing Nut Trees and Vineyards . D340895 , D. McNeill y, July 21 , 2010. Isoxaben. Petition for Establishment of Tolerances for Residues of Isoxaben in/on Grapes and Tree Nuts (including Pistachio). Summary of Anal yt ical Chemistry

and Residue Data. D 375246 , E. Holman; July 13 , 2010 . I soxaben: Chronic Aggregate Dietary Exposure (Food and Drinking Water) and Risk Assessment for the Section 3 Registration on Grapes. D3 68834 , S. Oonithan; July 2 6 , 2010 . Isoxaben: Occupational and Residential Exposure Assessment for the Registration of a New End - use Product Formulation for Use in Orchards of Nut Trees, Grapes and Non - bearing Fruit and Nut Trees. D353925, S. Oonnithan, 4/13/09. I soxaben: Occupational and Residential Exposure Assessment for the Registration of Two New Formulations for Use on Residential Lawns. Isoxaben: Second Report of the Cancer Assessment Review Committee. October 7, 2008. Review of Isoxaben Incident Reports, M. Hawkins; Aug 30, 2007Is oxaben D376428

Page 49 of 90 Appendix A: Toxicology Assessment A. 1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for are shown below in Table 1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. T est Isoxaben Technical Required Satisfied 870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitiz ation ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... yes yes yes no yes yes

yes yes

- n o 1 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 87 0.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

— Gene Mutation - mammalian ................ 870.5375 Mutagenicity

— Structural Chromosoma l Aberrations ... 870.5550 Mutagenicity

— Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox icity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotox icity Screening Battery (rat) ................. 870.6200b 90 - Day Neuro toxicity Screening Battery (rat) ............... 870.6300 Develop. Neuro toxicity ................................ ................. no no yes yes no --

-- no no

-- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ yes yes ye s

yes 870.7800 Immunotoxicity series ................................ ......................... yes no Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no no no --

--

-- 1 - A recent study waiver request from the registrant is being evaluated.Is oxaben D376428

Page 50 of 90 A.2. 1 Acute Toxicity P rofile for Isoxaben (95.86%) A.2.1 Acute Toxicity Profile - Test Substance Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral - rat 00132126 LD 50 > 10,000 mg/kg (both sexe s) IV 870.1200 Ac ute dermal - rabbit 00153112 LD 50 > 2000 mg/kg (both sexes) III 870.1300 Ac ute inhalation - rat 00132127 LC 50 > 1.99 mg/L (both sexes) III 870.2400 Ac ute eye irritation - rabbit 00132127 Slight irritation at 28 mg on eye III 870.2500 Ac ute dermal irritation - rabbit 00132127 Non - irritating IV 870.2600 Skin sensitization - guinea pig 00137846 Not a sensitizer (Buehler method) N/AIs oxaben D376428

Page 51 of 90 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ C lassification /Doses Results 870.3100 90 - Day

oral toxicity (rat) MRID 00153116 (1984)

Acceptable/guideline 0, 0.05, 0.14, 0.42 or 1.25% via diet ( 0/0, 32/36, 94/104, 285/312 or 853/946 mg/kg/day in males/females) LOAEL was not observed (> 853/946 mg/kg/d ay) . NOAEL = 853/946 mg/kg/day in males/females (HDT).

870.3100 90 - Day

oral toxicity (rat) MRID 00134493 (1982)

Acceptable/guideline 0, 1.25, 2.5 or 5.0% via diet (0/0, 905/964, 1813/1939 or 3701/3962 mg/kg/day in males/females) LOAEL (females) = 1939 mg/kg/day, based on slightly decreased body weight gain and food efficiency. LOAEL (males) was not observed (> 3701 mg/kg/day) . NOAEL = 964 mg/kg/day NOAEL (males = 3701 mg/kg/day (HDT). 870.3100 90 - Day

oral toxicity (mouse) MRIDs 00164549 and

00164550 (1985) Acceptable/guideline 0, 0.001, 0.01, 0.14 or 1.25% via diet (0, 1.5, 15, 210 or 1875 mg/kg/day) LOAEL was not observed (>1875 mg/kg/day) . NOAEL = 1875 mg/kg/day (HDT). Assays of hepatic enzymes showed treatment related induction that recovered aft er cessation of exposure and was considered adaptive. 870.3150 90 - Day

oral toxicity (dog) MRID 00153115 (1984)

Unacceptable/guideline; not upgradable (the dogs could have tolerated a higher dose) 0, 25, 100 or 500 mg/kg/day by

capsule LOAEL was not observ ed (>500 mg/kg/day) .

NOAEL = 500 mg/kg/day (HDT) .

870.3150 90 - Day

oral toxicity (dog) MRID 00132134 (1982)

Acceptable/guideline 0, 250, 500, or 1000 mg/kg/day by

capsule LOAEL was not observed (>1000 mg/kg/day) .

NOAEL = 1000 mg/kg/day. 870.3200 21 - Day

dermal toxicity (rat) MRID 00137849 (1983)

Acceptable/guideline 250, 500 or 1000 mg/kg/day LOAEL was not observed (1000 mg/kg/day) . NOAEL = 1000 mg/kg/day (HDT) . 870.3700a Prenatal

developmental in (rat) MRID 0015311 9 (1984)

Acceptable/guideline 0, 100, 320 or 1000 mg/kg/day by

gavage M aternal LOAEL was not observed (>1000

mg/kg/day). Maternal N OAEL = 1000 mg/kg bw/day D evelopmental LOAEL was not observed >1000 mg/kg/day). Developmental NOAEL = 1000 mg/kg / day 870.3700b Prenatal

developmental in (rabbit) MRID 00153118 (1984)

Acceptable/guideline 0, 100, 320 or 1000 mg/kg/day by

gavage Maternal LOAEL was not observed ( >1000

mg/kg/day) . Maternal NOAEL = 1000 mg/kg/day (HDT) . Developmental LOAEL was not observed (>1000 mg/kg/day) . Developmental NOAEL =Is oxaben D376428

Page 52 of 90 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ C lassification /Doses Results 1000 mg/kg/day (HDT) . 870.3800 Reproduction and

fertility effects (rat) MRID 00153529 (1984)

Acceptable/guideline 0, 0.05, 0.25 or 1.25% in the diet (0, 40, 200 or 1000 mg/kg/day) Matings conducted twice with F0 parental animals (F1a and F1b litters); three times with F1 parental animals (F2a, F2b and F2c litters) and once with F2 parental animals (F3a litters). The F2c and F3a litters were assessed in utero on GD 20 for developmental effects. All other litters were assessed following delivery according to standard reproductive toxicity study procedures. Parental LOAEL = 200 mg/kg/day , based on decreased body weights /

body w eight gains during the growth phase in F2 females; decreased body weights in F2a and F2b females during gestation and F2b females during lactation; and decreased feed efficiency in F2 females during the grow

th phase . Parental NOAEL = 4 0 mg/kg/day. Offspring LOAEL = 1000 mg/kg/day, based on decreased pup body weights during lactation (all generations), possible increased in cidence of microphthalmia , exencephaly and hydroureter, decreased gestation survival (F2b) and live fetuses/litter (F2c and F3a) . Offspring NOAEL = 200 mg/kg/day Reproductive LOAEL = 1000 mg/kg/day, based on decreased corpora lutea (F2c and F3a), implantations (F2c and F3a), mean number of live pups/litter (F2b), gestation survival (F2b) and live fetuses /litter (F2c and F3a) . Reproductive NOAEL = 200 mg/kg/day. 870.4100a Chronic toxicity

(rat)

– One year duration (also see two - year chronic toxicity/carc inogen icity study, MRID 00164553) MRID 00164552 (1984)

Acceptable/guideline 0, 0. 0125, 0.125 or 1.25% in the diet ( 0, 6.25, 62.5 or 625 mg/kg/day) LOAEL = 625 mg/kg/day, based on decreased body weight gain and food efficiency in females. NOAEL = 62.5 mg/kg/day . 870.4100b Chronic toxicity

(dog) MRID 00164551 (1985)

Acceptable/guideline 0, 10, 100 or 1000 mg/kg/day by

capsule LOAEL was not observed (>1000 mg/kg/day) .

NOAEL = 1000 mg/kg/day (HDT). 870.4200a Carcinogenicity

(rat) See 870.4300, below 8 70.4200b Carcinogenicity

(mouse) MRID 00164554 (1985)

Acceptable/guideline 0, 100, 1000 or 12,500 ppm in the diet (0, 15, 150 or 1875 mg/kg/day) LOAEL = 1875 mg/kg/day, based on decreased body weights and body weight gains in males and hepato to xicity in both sexes. NOAEL = 150 mg/kg/day At 1 875 mg/kg/day , increased incidences of hepatocellular adenoma were noted in both sexes. 870.4300 Com

bined carcinogenicity/chr MRID 00164553 (1985)

Acceptable/guideline LOAEL = 50.7 mg/kg/day in males , based on gross whole tissue alteration in the kidney and progressive glomerulonephrosis . 646.6Is oxaben D376428

Page 53 of 90 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ C lassification /Doses Results onic toxicity (rat) 0, 0.0125, 0.125 or 1.25%

in the diet ( 0/0, 5.0/6.2, 50.7/61.8 or 526.5/646.6 mg/kg/day in males/females) mg/kg/day in females, based on decreased body weig ht gain and progressive glomerulonephrosis. NOAEL = 5.0 mg/kg/day in males (61.8 mg/kg/day in females ). 870.5100 Bacterial Gene

Reverse Mutation S. typhimurium Ames Assay, strains TA 98, 100, 1535, 1537, 1538 MRID 00132136 (1984)

Acceptable/guideline 3 1, 62.5, 125, 250 or 500 μg/plate (with or without activation) Negative. There was no evidence of induced reverse mutations with or without activation up to precipitating doses.

870.5100 Bacterial Gene

Reverse Mutation S. typhimurium TA 98, 100, 1535, 1537 E. coli WP2uvrA 404 85701 (1987)

Acceptable/guideline 31 to 500 μg/plate with and without S9 activation Negative. There was no evidence of induced reverse mutation with or without activation.

870.5100 Bacterial Gene

Reverse Mutation E. coli WP2uvrA 40485702 (1987)

Accep table/guideline 31 to 500 μg/plate with and without S9 activation Negative. There was no evidence of induced reversed mutation with or without activation. 870.5300 In Vitro

Mammalian Cell Forward Gene Mutation Mouse lymphoma L5178Y cells 00132138 (198 3 )

Acceptable/guideline 1, 10, 50, 75, 100, 150, 200 or 250 μg/mL (non activated) 0.5, 1, 2, 4, 6, 8, 10 or 12 μg/mL (activated) Negative. There was no evidence of induced forward mutations with or without activation up to cy totoxic concentrations.

870.537 5 In Vitro

Mammalian Chromosome Aberration CHO cells 40435901 (1987)

Acceptable/guideline 10, 20, 40 or 80 μg/mL without S9 25, 50, 100, 200 μg/mL with S9 Negative. There was no treatment - related increase in the frequency of chromosomal aberrations up to precipitating concentrations. 870.5395 In vivo Mammalian

Micronucleus Assay Mouse (male) 00164555 (1984)

Unacceptable/guideline ( results inconclusive) 5000 mg/kg Inconclusive. Slight, significant increases in the frequency of micronucleated polychromat ic erythrocytes were noted at 24 and 48 h, but not at 72 h. 870.5395 In vivo Mammalian

Micronucleus Assay Mouse (male) 40485704 (1984)

Acceptable/guideline (results inconclusive) 800, 2000 or 5000 mg/kg Weakly positive. Slight, statistically significant increases in the frequency of micronucleated polychromatic erythrocytes were noted at 24 hrs. 870.5395 In vivo Mammalian

Micronucleus 47170002 (1992)

Acceptable/guideline 0, 1250, 2500 or 5000 Negative. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow of mice up to theIs oxaben D376428

Page 54 of 90 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ C lassification /Doses Results Assay Mouse (male and female) mg/kg limit dose . 870.5450 Rodent Dominant

Lethal Assay Rat 00164556 (1985)

Unacceptable/guideline (upgradable, pending submission of positive co ntrol data) 0, 34, 173, 932 mg/kg/day Negative. There was no evidence of a dominant lethal effect in the progeny of male rats.

870.5550 Unscheduled DNA

synthesis Rat cultured hepatocytes 00132137 (1982)

Acceptable/guideline eight concentrations ranging from 0.5 - 1000 nmoles/mL Negative. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts], was induced. Cytotoxicity was not observed. 870.5915 In Vivo Sister

Chromatid Exchang e in Chinese hamster 40485703 (1987)

Acceptable/guideline 800, 2000 or 5000 mg/kg Negative. There was no increase in sister chromatid exchange frequency up to the limit dose. 870.7485 Metabolism and

pharmacokinetics (rat) 00153114; 00164557;

00164558; 0 0164559 (1984 - 1986) Acceptable/guideline 250 mg/kg , single oral dose for expired air, excretion and metabolite identification and multiple oral dose for excretion 1000 mg/kg, single oral dose, tissue distribution After 72 hours, 90% of the dose was recove red in the feces, mostly as parent. Approximately half the absorbed dose was excreted in the urine and the other half in the feces as metabolites. The urine contained 15 - 20 metabolites. Identification of urinary metabolites led to the conclusion that th e major metabolic transformation involved oxidation of the test compound at position 2 of the alkyl side chain to produce either an alcohol or a ketone, hydroxylation of the aromatic ring adjacent to one of the methoxy substituents, and O demethylation of one of the methoxy substituents. Fecal metabolites were not identified. Generally, there were no major differences in the excretion or metabolism of the test compound between sexes. Excluding the GI tract and residual carcass , highest tissue levels were isolated in the liver at 4 and 24 hours post - dose. Tissue levels were lower at 24 hrs than 4 hrs except for the colon. Predosing of the animals with cold 25 0 mg/kg i soxaben, did not significantly change the pattern of urinary and fecal excretion of i sox aben. Significant amounts of radioactivity did not remain in the organs and tissues at 7 days post dose. Expired air accounted for <3% of the dose. 870.7485 Metabolism and

pharmacokinetics (rat) 00132131; - 32; - 33 (1982)

Acceptable/guideline 10, 100, 25 0, 500 or 1000 Most of the administered radioactivity was excreted by 24 hrs postdosing. The major route of elimination was via feces (>85%), with aIs oxaben D376428

Page 55 of 90 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ C lassification /Doses Results mg/kg, single dose excretion; 10 or 250 mg/kg, biliary excretion 250 mg/kg - tissue distribution dose - relate d decrease in urinary excretion due to poor gastrointestinal absorption. Urine and fecal excretion ranged from 70.8% - 94.9% of dose (males) and 88.2% to 106.3% (females) of dose. Biliary excretion was observed at 10 mg/kg (23.1% and 38.8% of dose in males and females, respectively) but was decreased as a percent of dose at 250 mg/kg (17.5% and 15.3%, males and females, respectively), indicating rate - limiting gastrointestinal absorption. Following a single 250 mg/kg dose, radioactivity was widely distribut ed with the highest levels seen in liver (except for the intestinal tract). Most tissue levels decreased between 4 and 24 hr postdosing except for pituitary and thyroid in females. Tissue:plasma ratios decreased by 24 hr except in the thyroid, adrenals, eyes and pituitary of both sexes, and ovaries in females. Tissue levels were not analyzed at later times. 870.7600 In Vivo Dermal

Penetration Rhesus Monkey MRID 00153113 (1983)

Acceptable/non - guideline 2 mg/kg by intravenous injection compared to 2 mg/kg by dermal application Dermal absorption was estimated to be between 7.5 and 11%.

A.3 Executive Summaries A.3.1 Subchronic Toxicity 870.3100 90 - Day Oral Toxicity - Rat (1) In a subchronic oral toxicity study (MRID 00134493), 15 Fischer 344 rats/sex/dose group were administered EL - 107 (Isoxaben technical; 92.4% a.i.; L ot No. B31 - 72C - 88) in the diet at doses of 0, 1.25, 2.5, or 5.0% (equivalent to average daily intakes of 0/0, 905/964, 1813/1939, and 3701/3962 mg/kg/ day in males/females) for 3 months. In addition to standard subchronic study parameters, hepatic p - nitroanisole O - demethylase activity was anal yz ed at necrops y. No adverse, treatment - related effects were observed on mortality , clinical signs, food consumption, hematology , clinical chemistry , organ weights, or gross or histological pathology . At 2.5% and 5.0%, mean body weight gain and food efficiency in females were decreased b y 10 - 11% (p ≤0.05%) during the last weeks of the study , but no significant ch anges were observed in males. The following differences (p ≤0.05, except as noted) were noted between the treated groups and the control groups: (i) decreased mean serum alkaline phosphatase levels in the 2.5%Is oxaben D376428

Page 56 of 90 and 5.0% groups; (ii) decreased serum creatini ne in all treated female groups; (iii) increased blood glucose in the 5.0% females; (iv) increased hepatic p - nitroanisole O - demeth yl ase activity in all treated groups (but the increase was not statistically significant in the 5.0% males); (v) increased abs olute and relative to body liver weights in all treated groups; and (vi) increased relative to body kidney weights in all treated groups (but the increase was not statistically significant at 5.0% in either sex). The effect on hepatic enz ym e induction and corresponding liver weight increase, without any corroborating clinical chemistry or pathological support for hepatotoxicity , suggests that the effect on the liver was adaptive and not adverse. The effects observed on clinical chemistry parameters were unconvincing without corroborating pathological evidence of an adverse effect. The LOAEL is 2.5% (1939 mg/kg/day in females), based on slightly decreased body

weight gain and food efficiency

in females. The LOAEL in males is >5.0% (3701 mg/kg/day). The N OAEL is 1.25% (905/964 mg/kg/day in females). The NOAEL in males is 5.0% (3701 mg/kg/day). This study

is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3100; OECD 408) for a subchronic oral toxicity study in rats. (2) In a subchronic oral toxicity study (MRID 00153116), 25 Fischer 344 rats/sex/dose group were administered EL - 107 (Isoxaben technical; 86.7 - 92.5% a.i.; Lot No. H02 - 2G6 - 118) in the diet at doses of 0, 0.05, 0.14, 0.42 or 1.25% (equivalent to 0/0, 32/36, 94/104, 285/312, and 853/946 mg/kg/day

in males/females) for 3 months. Fifteen rats/sex/dose group were terminated at this time, and subgroups of 10 rats/sex/dose group were fed control diet for 1 month to evaluate recovery . No adverse, treatment - relate d effects were observed on mortality , clinical signs, body weights, food consumption, food efficiency , hematology , organ weights, or histological pathology . The following observations were noted and were statisticall y significant (p ≤0.05), but were not considered adverse as there were onl y minor differences from controls: (i) body weights at three months were decreased by 5% in both the 0.42% and 1.25% males (females were unaffected); (ii) food efficiency

was decrease d 4% in the 1.25% males and decreased 6 - 9% in the >=0.14% females; and (iii) serum glucose increased b y 14% in both the 1.25% males and females. In creased (p ≤0.05) absolute and relative to body liver weights were noted in all treated female groups, and in creased (p ≤0.05) relative to body liver weights were observed in the 0.42% and 1.25% males. Increased (p ≤0.05) hepatic p - nitroanisole O - demeth yl ase activity was observed in the 0.42% males (incr 41%) and the >=0.14% females (incr 30 - 33%). These differenc es generall y returned to normal after the recovery period. Effects on liver weight and enzymes were considered adaptive in the absence of other evidence of hepatotoxicity . The effect on hepatic enzy me induction and corresponding liver weight increase, wi thout any corroborating clinical chemistry or pathological support for hepatotoxicity , suggests that the effect on the liver was adaptive and not adverse. The LOAEL was not observed. The NOAEL is 1.25% (HDT; equivalent to 853/946 mg/kg/day in males/femal es; approximately the limit dose).Is oxaben D376428

Page 57 of 90 This study

is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3100; OECD 408) for a subchronic oral toxicity study in rats. 870.3100 90 - Day Oral Toxicity - Mouse In a subchronic ora l toxicity study (MRID 00164549), 25 B6C3F 1 mice/sex/dose group were administered EL - 107 (Isoxaben technical; 93.7 - 94.2% a.i.; L ot No. H02 - 2G6 - 118) in the diet at doses of 0, 0.001, 0.01, 0.14, or 1.25% (approximately equivalent to 0, 1.5, 15, 210, and 187 5 mg/kg bw/day

based on a conversion factor of 1 ppm = 0.150 mg/kg bw/day). Up to 15 mice/sex/dose group were terminated after 3 months, and subgroups of 10 mice/sex/dose group were fed control diet for an additional month prior to sacrifice in order to e valuate recovery . No adverse treatment - related effects were observed on mortality , clinical signs, body weights, body weight gains, ophthalmology , hematology , clinical chemistry , organ weights, or gross or histological pathology . Food consumption was no t measured in this study. At 0.14% and 1.25%, increased (p ≤0.05) absolute liver weights were observed in males, and increased (p ≤0.01) relative to body liver weights were noted in both sexes. An increased incidence of minimal hepatic hy pertrophy was note d in males at 0.14% (3/15 treated vs. 0/15 controls) and 1.25% (9/15 treated). Increased (p ≤0.05) hepatic p - nitroanisole O - demeth yl ase activity was observed in the 0.14% and 1.25% dose groups. Without further evidence of toxicity , these changes were cons idered adaptive and not adverse. These differences generally returned to normal after the recovery period. The LOAEL was not observed. The NOAEL is 1.25% (approximately equivalent to 1875 mg/kg bw/day). This study

is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3100; OECD 408) for a subchronic oral toxicity study in the rodent. An acceptable study in the rat is also available (MRID 00153116; TXR#s 005372, 0051626). 870.3150 90 - Day Oral Toxicity – Dog (1) In a subchronic oral toxicity study (MRID 00132134), 4 beagle dogs/sex/dose group were administered EL - 107 (Isoxaben technical, 93.3% a.i., L ot No. H02 - 2G6 - 021) in gelatin capsules at doses of 0 (capsule only), 250, 500 or 1000 mg/kg bw/day for 3 months. In addition to s tandard subchronic study parameters, hepatic p - nitroanisole - O - demethylase activity was anal yz ed at necrops y. No adverse, treatment - related effects were observed on mortality , clinical signs, body weights, body weight gains, food consumption, ophthalmology , hematology , clinical chemistry , urinaly sis, organ weights, or gross or histological pathology . One 1000 mg/kg/day

male lost 10% of its initial body weight during the study , but had regained some of the loss by

the end of the test. As no other dogs ha d significant body weight changes and no other evidence of toxicity was noted, this effect was considered incidental (in addition, noIs oxaben D376428

Page 58 of 90 body weight effects were reported in the one year dog study at 1000 mg/kg/day ; MRID 00164551). Increased hepatic p - nitroanisole O - demethylase activity was observed in all treated groups (between about +60% to +100% of control values), indicating induction of hepatic microsomal enzy

me activity . Minimal hepatocellular centrilobular h yp ertrophy was observed in one male at 500 mg/kg/day and one at 1000 mg/kg/day . The effects on the liver were considered adaptive rather than adverse in the absence of other clinical chemistry and microscopic findings. It was reported that man y dogs in the 500 and 1000 mg/kg/day groups intermitte ntly vomited food and/or test compound. These findings were attributed to the large volume of test compound administered (up to the limit dose via capsule dosing). The LOAEL was not observed. The NOAEL is 1000 mg/kg bw/day (the limit dose). This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3150; OECD 409) for a subchronic oral toxicity study in dogs. (2) In a subchronic oral toxicity study (MRID 00153115), 4 beagle dogs/sex/dose group were administered E L - 107 (Isoxaben technical; 95.5%; L ot No. Z10025) in gelatin capsules at doses of 0 (capsules onl y) , 25, 100 or 500 mg/kg bw/day for 3 months. No adverse, treatment - related effects were observed on mortality , clinical signs, body weights, body weight gai ns, food consumption, hematology , clinical chemistry , urinaly sis, organ weights, or gross or histological pathology . Significant treatment - related changes were not found for hepatic p - nitroanisole O - demethylase activity . Absolute and relative to body liv er weights were increased (p ≤0.05) in the 500 mg/kg/day males. In the absence of corroborating evidence of hepatotoxicity , this effect was considered an adaptive response. The LOAEL was not observed. The NOAEL is 500 mg/kg bw/day . This study

is class ified un acceptable/guideline, not upgradeable and does not satisfy the guideline requirements (OPPTS 870.3150; OECD 409) for a subchronic oral toxicity study in dogs. The animals could have tolerated a higher dose, and the limit dose was not tested. The previously

conducted subchronic study in dog (MRID 00132134; see this TXR# and TXR# 003434 for DER and executive summary) indicated that the limit dose should have been selected for the high dose and satisfies the guideline requirement for a subchronic oral toxicity study in the dog. 870.3200 21 - Day Dermal Toxicity – Rabbit In a 21 - day dermal toxicity study (MRID 00137849 ) , EL - 107 (Isoxaben technical grade; 94.8% a.i.; L ot No. Z10025) was applied to the clipped skin of rabbits (5 sex/dose; New Zealand Wh ite) for 6 hours/day for 21 consecutive day s . One dose group was treated with EL - 107 technical equivalent to 1000 mg active technical EL - 107/kg bw. Group 2 (also 5 animals/sex/dose) was treated with 500 mg/kg bw suspension concentration formulation (FN - 7 033) containing 50% EL -Is oxaben D376428

Page 59 of 90 107 (250 mg/kg bw). Groups 3 and 4 were treated with 1000 mg/kg of FN - 7033 (500 mg/kg bw EL - 107). All groups were sacrificed after 21 day s, except group 4, which was maintained without treatment for an additional 2 weeks before sac rifice in order to monitor recovery . No adverse, treatment - related effects were observed on mortality , clinical signs, dermal effects, body weight, food consumption , hematology , clinical chemistry , organ weights, or gross or histological pathology . Sy ste micall y, relative to body th yroid/parath yroid weight was increased (p ≤0.01) by 77% in the 1000 mg/kg FN - 7033 group. No increase was noted in the recovery group and only

slight increases (not statistically significant) of 21 - 23% were observed in the other treated groups. Pathological examination did not corroborate th yr oid toxicity , and thy roid toxicity

was not demonstrated in the concurrentl y submitted toxicity studies. Consequentl y, the increased th yroid weights were considered an equivocal finding. Sy stemically, t he LOAEL was not observed. The systemic NOAEL was 1000 mg/kg bw/day (the limit dose). T ransient dermal irritation was observed in the 1000 mg/kg FN - 7033 group (4/20 treated vs. 0/20 controls) during the first week of treatment. This effect was not observed in the animals treated with EL - 107 technical and could have been related to some other compound in the formulation. There was no morphologic evidence of dermal irritation, and as the incidence of irritation was slight and the effect was transient, this effect was not considered adverse. The dermal LOAEL was not observed. The dermal NOAEL was 1000 mg/kg bw/day (the limit dose). This study

is classified as acceptable/guideline and satisfies the guideline requirement for a 21 - day dermal to xicity

study (OPPTS 870.3200; OECD 410) in rabbits . A.3.2 Prenatal Developmental Toxicity 870.3700a Prenatal Developmental Toxicity Study - Rat In a developmental toxicity study (MRID 00153119 ) , EL - 107 (Isoxaben technical; 95.5%; L ot No. Z10025) in 1 0% aqueous acacia oil was administered b y dail y gavage (10 mL/kg) to presumed pregnant Wistar rats (25/dose group) at dose levels of 0, 100, 320 or 1000 mg/kg bw/day on gestation day s (GD) 6 - 15 . On GD 20, all dams were euthanized. The uterus was removed via cesarean section, and its contents examined. Fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal Toxicity : No treatment - related effects were observed. At 1000 mg/kg/day , mean maternal body weight gain w as decreased b y 15% compared to controls (not analyzed statistically) during the interval GD 6 - 16 (treatment occurred on GD 6 - 15). Recovery occurred post - treatment (GD 17 - 20), with a cumulative weight gain for GD 0 - 20 of 7% (p ≤0.05). Net weight gains of 78.5, 79.6, 75.9 and 76.2 g (control to high dose, respectively) were calculated by subtraction of gravid uterine weight from total body weight gain, indicating that by GD20,Is oxaben D376428

Page 60 of 90 much of this decrease was secondary to lower gravid uterine weight. Based on th e marginal changes observed, this was not considered a treatment - related effect. The maternal LOAEL was not established (>1000 mg/kg bw/day). The maternal NO AEL is 1000 mg/kg bw/day . Developmental Toxicity : No treatment - related effects were observed. At 1000 mg/kg bw/day , slightly increased mean resorptions (control to high dose 0.7, 0.5, 1.1 and 1.6), increased postimplantation loss (8.4, 12.6, 8.4 and 16.5%) and a decreased mean number of live fetuses per litter (11.5, 11.4, 11.5 and 10.0) were obs erved. Post - implantation loss increased to 13.8% vs. 5.7% in controls. A slight increase in incidence of runts was observed (4/240 in 4 litters vs. 1/265 controls). These effects were not considered treatment - related because values for resorptions and p ostimplantation loss were within published MARTA historical control range. Decreases in fetal weights were marginal and not considered treatment - related. Male fetal weights were decreased (p ≤0.05) by 5% in all treated groups; thus, this effect was unrelat ed to dose. A similar effect was not observed in females. The developmental LOAEL was not established (>1000 mg/kg bw/day). The developmental NOAEL is 1000 mg/kg bw/day. This study is classified acceptable/guideline and satisfies the guideline requir ement for a developmental toxicity

study (OPPTS 870.3700; OECD 414) in rats . 870.3700b Prenatal Developmental Toxicity Study – Ra bbit In a developmental toxicity study (MRID 00153118 ) , EL - 107 (Isoxaben technical; 95.5%; L ot No. Z10025) in 10% aqueous acacia oil was administered b y dail y oral gavage (10 mL/kg) to inseminated Dutch Belted rabbits (20/dose group) at dose levels of 0, 100, 320, or 1000 mg/kg bw/day on gestation day s (GD) 6 - 18 . On GD 28, all dams were euthanized. The uterus was removed vi a cesarean section, and its contents examined. Fetuses were examined for external, visceral, and skeletal malformations and variations. There wer e no treatment - related effects o n survival, clinical signs, body weight, food consumption, or cesarean parame ters. One mortality

occurred on GD 28 in a 1000 mg/kg/day pregnant dam. Another 1000 mg/kg/day dam aborted on GD 22 and was sacrificed. This abortion and death were attributed to nutritional deprivation as a result of partial or complete blockage of th e digestive s ys tem by hair. The maternal LOAEL was not observed. The maternal NO AEL is 1000 mg/kg bw/day (the limit dose) . There wer e no treatment - related effects o n developmental parameters. There were no effects of treatment on numbers of litters, li ve fetuses, dead fetuses, or sex ratio. There were no treatment related external, visceral, or skeletal malformations or variations. There were no effects of treatment on fetal body weights .Is oxaben D376428

Page 61 of 90 The developmental LOAEL was not observed. The developmental NOAEL was 1000 mg/kg bw/day (the limit dose). This study is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity

study (OPPTS 870.3700; OECD 414) in rabbits. A.3.3 Reproductive Toxicity 870.3800 Reprodu ction and Fertility Effects - Rat In a three - generation reproduction study (MRID 00153529), 25 Wistar rats/sex/dose group were administered EL - 107 (Isoxaben technical; 93.7 - 94.5% a.i.; L ot Nos. H02 - 2G6 - 118 and Z10025) continuously

in the diet at doses of 0, 0.05, 0.25 or 1.25% (equivalent to 0, 40, 200 or 1000 mg/kg/day). Each generation was maintained on the test diets for a growth period of approximately

10 weeks prior to mating (1 male: 1 female). Rats from the P, F1 and F2 generations were continued on the test diets for 2, 3 and 1 breeding trial(s), respectivel y. From the F1a and F2b weanlings, 25 rats/sex/dose were selected to be parents of the F2 and F3 generations, respectivel y. Selected weanlings were fed the same test diet concentrations as th eir parents. At sacrifice, livers and reproductive organs were collected for histological examination. In addition, eyes from F2 parental animals were saved and examined histologically . Additionally

from the F2b litters, high - dose progeny with microphth almia (8 rats/sex), 10 control weanlings with linear retinal dy splasia (diagnosed during ophthalmic examinations), and 10 normal control weanlings from each sex were retained as F2 parental animals. These additional animals were also maintained on the tes t diets for approximately 10 weeks prior to mating. The study also contained a developmental assessment: F2c and F3a litters were subjected to complete teratological evaluation. Females were grossl y examined and livers and reproductive organs were colle cted for histological examination. The uterus was removed via cesarean section, and its contents examined. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. Parental toxicity : At 0.25%, dec reased (p ≤0.05) body weight gain (Day s 0 - 70) was observed in the F2 females (decr 16%) and decreased (p ≤0.05) body weights were noted in the dams on PND 21 of the F2b generation (decr 6%). Decreased (p ≤0.05) food efficiency was also observed in the F2 - generation f

emales. At 1.25%, decreased (p ≤0.05) maternal body weights were observed on gestation day (GD) 7, 14, and 20 in the F1 generation (decr 9 - 10%), resulting in a decreased (p ≤0.05) total body weight gain of 17%. Decreased (p ≤0.05) maternal body weights we re observed at PND 0, 7, and 14 in the F2 generation (decr 17 - 19%), resulting in a decreased (p ≤0.05) total body weight gain of 29%. Body weight gains (Days 0 - 70) were decreased (p ≤0.05) by 15 - 20% in the F1 and F2 parental females during pre - mating. Decr eased (p ≤0.05) food efficiency was observed in the F2 - generation females. In the dams, mean body weight gain was decreased (p ≤0.05) by 12 - 29% during gestation of the F1a, F1b, F2a, and F2b litters. Decreased (p ≤0.05) mean body weight was noted in the 1.2 5% dams on postnatal day (PND) 21 of the F1b, F2a, and F2b litters (decr 8 -Is oxaben D376428

Page 62 of 90 14%) and at 0.25 % in the F2b litter (decr 6%). There were no treatment - related effects on survival, clinical signs or histology . Slight increases (p ≤0.05) in parental mean relativ e liver weight were observed in the 0.25% females (incr 8 - 13%) and generall y in the 1.25% males and females (incr 10 - 13%) from P, F1, and F2 generations. Subchronic oral toxicity studies in rats (MRIDs 00153116 and 00134493; concurrently

submitted) indicated that the increased liver weight was an adaptive effect. No adverse treatment - related effect was observed on mortality , clinical signs or histology . The LOAEL for parental toxicity is 0.25% (200 mg/kg bw/day), based on decreased body weights, body wei ght gains and food efficiency. The NOAEL is 0.05% (40 mg/kg bw/day). Offspring Toxicity : At 1.25%, the mean number of live pups/litter was decreased (not statistically

significant [NS]) by

10 - 14% in the F1a, F1b, and F2a litters, and decreased (p ≤0.05) by 34% in the F2b litter. Gestation survival (percentage of newborn progeny alive on PND 0) was decreased (NS) in the 1.25% F2b generation (88.6% treated vs. 98.3% controls). At 1.25%, decreases (p ≤0.05) in pup body weight were observed on PND 4 in the F 1b generation (decr 12%), on PND 14 in the F1b, F2a, and F2b generations (decr 14 - 19%), and on PND 21 in the F1a, F1b, F2a, and F2b generations (decr 13 - 25%). Decreases in pup body weights were generall y also observed at 0.25%, but only obtained significance (p ≤0.05) on PND 14 in the F2a generation (decr 9%). Therefore, the effect on body weights at 0.25% was not considered adverse. In the 1.25% F2b weanlings, the incidence of uni - or bilateral microphthalmia was increased (8.6% treated vs. 0% controls). Equi vocally treatment - related slight increases in incidence of coloboma optic disc (3.4% treated vs. 0.6% controls) and uni - or bilateral linear retinal dy splasia (8.6% treated vs. 6.1% controls) were also noted. Exencephaly was observed in the F2b generation (9 fetuses in 2 litters) and in one fetus each from the F1a and F2a generations Most affected fetuses showed more than one malformation. The significance of these malformations is unclear because man y of the affected litters were associated with specif ic progenitor animals and/or cousin matings, but they are considered potentially treatment - related. An increased incidence of h ydroureter was noted at 1.25% in both F1 and F2 generations (10 - 13% fetuses; 59% litters) compared to controls (2% fetuses; 19 - 2 2% litters). In the developmental toxicity phase of the study, slightly increased incidences in hydroureter were also noted in the F1 generation at 0.05% (4% fetuses; 42% litters) and 0.25% (5% fetuses; 33% litters). Slightly i ncreased incidences of microphthalmia were noted at 1.25% in the F1 generation (2 % fetuses; 14% litters) compared to controls (0.5% fetuses; 6% litters) and in the F2 generation (3% fetuses; 11% litters) compared to controls (0% fetuses; 0% litters). The historical control ranges w ere not reported. In summary , fetal incidence was 5% or less, except for the incidence of hydroureter in the 1.25% F1 and F2 generations. Consequentl y, the increased incidence of hydroureter is conservativel y considered a possible treatment - related effec t. there was no evidence of teratogenicit y in the concurrentl y submitted developmental study in Wistar rats (MRID 00153119). It also must be noted that the latter developmental study followed the suggested guidelines for a developmental study (including daily

gavage treatment from GD 6 - 15), unlike the present study. The findings of h ydroureter at 0.05% and 0.25% and microphthalmia wereIs oxaben D376428

Page 63 of 90 considered equivocal, because the incidence was minor and there was no indication of teratogenicit y in the developmental study . The LOAEL for offspring toxicity is 1.25% (1000 mg/kg bw/day), based on decreased pup body weights, decreased live pups/litter and gestation survival in F2b litters and possibly increased incidence of malformations including microphthalmia, colo boma and/or exencephaly, and hydroureter, in some litters beginning in the F2b generation. The NOAEL is 0.25% (200 mg/kg bw/day). Reproductive Toxicity: At 1.25%, the following decreases (p ≤0.05) in cesarean section parameters were observed in the F2c and F3a generations and in the additional animals with microphthalmia that were mated and killed on GD20: (i) mean number of corpora lutea (decr 13 - 21%); (ii) mean number of implantations (decr 10 - 23%); and (iii) mean number of live fetuses (decr 20 - 41%). In the F2b litters, the mean number of live pups per litter and gestation survival were decreased ( - 35% and - 10%, respectivel y, p ≤0.05). At 1.25%, insufficient milk production was noted in at least four dams and their progeny were not thriving in the F1b, F2a, and F2b litters. The LOAEL for reproductive toxicity is 1.25% (equivalent to 1000 mg/kg bw/day), based on decreased mean number of live pups/litter, gestation survival, corpora lutea , implantations, and reduced milk production seen in some nursing dams. The NOAEL is 0.25% (equivalent to 200 mg/kg bw/day in males/females). This study

is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a multiple - generation reproduction study in the rat. A.3.4 Chronic Toxicity 870.4100a (870.4300) Chronic Toxicity – Rat Ina chronic toxicity

study (MRID 00164552; interim report on two - ye ar chronic dietary toxicity /carcinogenicit y s tudy

reported in MRID 00164553), 30 Fischer 344 rats/sex/dose group were administered EL - 107 (Isoxaben technical; 92 - 95% a.i.; Lot No. Z10025) in the diet at doses of 0, 0.0125, 0.125, or 1.25% (approximately equivalent to 0, 6.25, 62.5, and 625 mg/kg bw/day). T en rats/sex/dose group were terminated after exposure for 3, 6, and 12 months. No adverse, treatment - related effects were observed on mortality , clinical signs, ophthalmology , hematology

or gross or histological pathology . In the 1.25% females, decrea sed (p ≤0.05) mean body weight gain was observed during Months 0 - 3, 0 - 6, and 0 - 12 (decr 8 - 15%) and decreased (p ≤0.05) food efficiency was noted during Months 0 - 3 and 0 - 12 (decr 7 - 13%). During Months 0 - 3, the 0.125% females also had decreased body weight ga in and food efficiency (decr 6% each), but this effect was considered minor. In creased serum glucose was observed in the 0.125% and 1.25% groups at 6 months and males at 12 months (incr 15 - 18%); however, this slight difference was not considered adverse i n the absence of corroborating evidence of toxicity .Is oxaben D376428

Page 64 of 90 In creased (p ≤0.05) absolute and relative to body liver weights were generally noted in the 1.25% group at Months 3, 6, and 12 (incr 9 - 29%). At Months 6 and 12, increased (p ≤0.05) hepatic p nitroanisole O - demeth yl ase activity was observed in the 0.125% fem ales (incr 29 - 36%), the 1.25% males (incr 34 - 35%), and the 1.25% females (incr 57 - 88%). The effect on hepatic enzy me induction and corresponding liver weight increase, without any corroborating clinical chemistry or pathological support for hepatotoxicity , suggests that the effect on the liver was adaptive and not adverse. The LOAEL was 1.25% (approximately equivalent to 625 mg/kg bw/day), based on decreased body weight gain and food efficiency in females. The NOAEL is 0.125% (approximately equivalent to 62.5 mg/kg bw/day). This study

is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.4100; OECD 452) for a chronic toxicity study in rats. 870.4100b Chronic Toxicity – Dog In a chronic toxicity

study (MRID 00164551) , 4 beagle dogs/sex/dose group were administered EL - 107 (Isoxaben technical; 92 - 95% a.i.; Lot No. Z10025) in gelatin capsules at doses of 0, 10, 100 or 1000 mg/kg bw/day for 12 months. In addition to standard chronic study parameters, hepatic p - nitroanis ole O - demethylase activity was anal yz ed at necrops y. No adverse, treatment - related effects were observed on mortality , clinical signs, body weight, food consumption, ophthalmology , electrocardiograms, hematology , clinical chemistry , urinaly sis, organ weights, or gross or histological pathology . In creases in serum alkaline phosphatase levels relative to controls were observed at 100 and 1000 mg/kg/day

for various time periods (anal yz ed pretest, weeks 1, 2 and 4; monthly thereafter). A statistically signi ficant increase (generall y about 2 - fold; 3 - fold in last months of study) was seen in males at 1000 mg/kg/day at most analy ses, beginning on Day 118. At 100 mg/kg/day , increases of about 2 - fold were seen at later months and were not significant. In creases in females were also seen at these dose levels but were generall y less pronounced and statistical significance was only seen occasionall y at 1000 mg/kg/day during the later half of the study . In both sexes, alkaline phosphatase levels did not show an age - related decrease in the treated dogs as was seen in the control dogs. At 1000 mg/kg/day , increased (p ≤0.05) p nitroanisole O - demeth yl ase activity (+31%) was noted in males. Increased (p ≤0.05) relative to brain liver weights were observed in both sexes ( incr 27 - 38%), and increased (p ≤0.05) relative to body liver weight was noted in the females (incr 29%). There was minimal to slight hepatocellular h yp ertrophy observed in 1 male and 2 females (vs. 0 controls). Overall, the findings are considered evidence of adaptive change and are attributed to treatment, but are not considered adverse in the absence of other supporting evidence of hepatotoxicity . The LOAEL was not observed. The NOAEL is 1000 mg/kg/day (the limit dose).Is oxaben D376428

Page 65 of 90 This study

is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.4100; OECD 452) for a chronic toxicity study in dogs. A.3.5 Carcinogenicity 870.4200a Carcinogenicity Study - rat In a combined chronic toxicity /carcinogenicit y study

(MRID 00164553), 60 Fischer 344 rats/sex/dose (in study

report, stated to be two replicate test groups of 30 rats/sex/dose group that were considered as one test group), EL - 107 (Isoxaben; 92 - 95% a.i.; L ot No. Z10025) was administered in the diet at doses of 0, 0.0125%, 0. 125% or 1.25% (equivalent to 0/0, 5.0/6.2, 50.7/61.8, and 526.5/646.6 mg/kg bw in males/females). No adverse, treatment - related effects were observed on clinical signs, hematology or urinaly sis. In the 1.25% males at Month 24, decreased survival was n oted (combined study survival rates of 48% treated vs. 66% control), and an increased incidence of general thinning of the body was also observed. At 1.25%, mean weight at termination and cumulative mean weight gain over the entire treatment period were e ach decreased (p ≤0.05) by 12 - 19% in both sexes. The decreases were associated with reduced efficiency of food utilization, which was decreased (p ≤0.05) b y 15 - 23%. In males, statistically significant decreases in weight gain were primarily observed in the first and last 6 months of the study ; the decreases did not reach 10% until the last months of the study . In females, statistically significant (p ≤0.01) reductions in both bodyweight and weight gain were observed throughout most of the study , with cumulative gain generall y decreased b y 10%. At 0.125%, statistically significant reductions in mean weight gain were also observed in females for man y weeks of the study, but the decreases were marginal (between 5 - 7% below controls) and not considered adverse. Treatment - related nephrotoxicity was observed in males at 0.125% and 1.25%. At 0.125% and above, nephrotoxicity

was evident in males as an increased incidence and severit y of minimal to severe progressive glomerulonephrosis (from control to high dose, re spectively 44%, 55%, 67% and 85%; mean severity 1.8, 1.7, 2.0 and 2.5). At 1.25%, urea nitrogen levels in the terminal blood samples were increased (p ≤0.05) b y 32 - 67% at termination in the males of both replicate studies and increased (p ≤0.05) by 34% in the females of one study . In both replicate studies, relative to body kidney weights were increased (p ≤0.05) b y 25 - 39% in males and by 15 - 23% in females. Grossly , increased incidences of whole tissue alterations were noted in the kidney of the males (39 /60 vs. 16/59, controls) and females (38/60 vs. 21/61 controls), and increased incidences and severity of minimal to severe progressive glomerulonephrosis were observed in the females (from control to high dose, respectivel y 56%, 45%, 58% and 78%; mean sev erity 1.4, 1.6, 1.5 and 2.0). The LOAEL in males is 0.125% (50.7 mg/kg/day), based on increased incidence and severity of progressive glomerulonephrosis. The NOAEL is 0.0125% (equivalent to 5.0 mg/kg bw/day in males). The LOAEL in females is 1.25% (64 6.6 mg/kg/day), based on increased incidence and severit y of progressive glomerulonephrosis and decreased body weight/weight gain. The NOAEL is 0.125% (61.8 mg/kg/day).Is oxaben D376428

Page 66 of 90 At the doses tested, an increased incidence of adrenal pheochromocy tomas was observed in the 1.25% males (18/60 treated vs. 10/59 controls). The increase was not seen in females. Dosing was considered adequate based on decreased survival in males, decreased body weights, body weight gains, and food efficiency in both sexes, and nephrotox icity in both sexes. This study

is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.4300; OECD 453) for a combined chronic toxicity /carcinogenicit y study in rats. 870.4200b Carcinogenicity (feeding) - Mouse In an oral carcinogenicity study (MRID 00164554), 60 B6C3F 1 mice/sex/dose group (in study report listed as two replicate studies of 30 mice/sex/dose considered as one test group) were administered EL - 107 (Isoxaben technical, 95.5% a.i.; L ot No. Z10025) in the di et for 24 months at doses of 0, 100, 1000 or 12,500 ppm. Food consumption was not measured for this study : using in - house control food consumption data, average dail y intakes were estimated at 0, 11.5, 113.7 or 1476.4 mg/kg/day for males and 0, 12.2, 123 .9 or 1567.1 mg/kg/day in females. Because no weight loss was observed in the early weeks of the study, palatability did not appear to be affected and these surrogate food consumption values were considered acceptable for use. (Using the standard convers ion factor of 1 ppm = 0.150 mg/kg/day for mice, daily

intakes were calculated at 0, 15, 150 or 1875 mg/kg bw/day . The estimates obtained using in - house control food consumption were therefore used to provide more conservative values). The combined groups (60 mice/sex/dose group) were subjected to statistical analy ses. An interim 12 - month sacrifice cohort was not included in this study . The findings of the two replicate studies showed similar results. No adverse, treatment - related effects were observed on mortality , clinical signs, ophthalmology or hematology . Sy stemicall y in the 12,500 ppm males, decreased (p ≤0.05) mean body weights were noted at Weeks 25 - 79, and decreased (p ≤0.05) bodywei ght gains (about 10 to 15% below controls) were noted at Weeks 25 - 73. No effects on body weight or weight gain were reported in females and in high dose males, body weight/weight gain was not significantl y lower at the end of the study. Hepatotoxicity

was observed at 12,500 ppm. In the males, serum alkaline phosp hatase and alanine aminotransferase were increased (p ≤0.05) by 97 and 139%, respectively in the two - ye ar measurements (clinical chemistry was not evaluated at earlier times). Absolute and relative to body liver weights were increased (p ≤0.05) in both sexe s. Increased incidences of hepatic nodules were observed grossly in the males (35/60 treated vs. 26/60 controls) and females (16/60 treated vs. 4/60 controls). Increased incidences of the following non - neoplastic hepatic lesions were observed: (i) cy

tome gal y in the males (33/59 treated vs. 9/60 controls) and females (4/60 treated vs. 0/60 controls); (ii) hy perplasia in the males (27/59 treated vs. 19/60 controls) and females (20/60 treated vs. 3/60 controls); and (iii) minimal to moderate vacuolation in the males (22/59 treated vs. 5/60 controls) and females (40/60 treated vs. 4/60 controls). Minimal to moderate vacuolation was also noted at 1000 ppm in males (10/60 treated) and females (11/59 treated) ; however, this effect was not considered adverse at this dose level due to the nature of this lesion and the lack of corroborating evidence of toxicity . The systemic toxicity LOAEL was 12,500 ppm (approximately equivalent to 1 476/1567 mg/kg bw/day in M/F ), based onIs oxaben D376428

Page 67 of 90 decreased body weights and body weight gai ns in males and hepatoxicity (as detailed above) in both sexes. The NOAEL is 1000 ppm (approximately equivalent to 114/124 mg/kg bw/day in M/F ). At the doses tested, there was a treatment - related increase in tumor incidence when compared to controls. At 12,500 ppm, incidences of hepatocellular adenoma were increased in the males (12/59 treated vs. 3/60 controls) and females (7/60 treated vs. 0/60 controls). Increased incidence of hepatocellular carcinomas in females (2/60 treated vs. 0/60 controls) was expected to be within the range of historical controls. Dosing was considered adequate based on decreased body weights and body weight gain in males and hepatotoxicity observed in both sexes. This study

is classified as acceptable/guideline and satisfie s the guideline requirements (OPPTS 870.4300; OECD 453) for a combined chronic toxicity /carcinogenicit y study in mice. A.3.6 Mutagenicity Gene Mutation 870.5100 Bacterial Gene Reverse Mutation in S. typhimurium TA 98, 100, 1535,1537, 1538 MRID 00132136 Acceptable/guideline 31, 62.5, 125, 250 or 500 μg/plate with and without S9 activation. Negative up to precipitating concentrations. 870.5100 Bacterial Gene Reverse Mutation, S. typhimurium TA 98, 100, 1535, 1537 and E. coli WP2uvrA MRID 40485701 Acceptable/guideline 31 to 500 μg/plate with and without S9 activation. Negative up to precipitating concentrations. 870.5100 Bacterial Gene Reverse Mutation , E. coli WP2uvrA MRID 40485702 Acceptable/guideline 31 to 500 μg/plate with and without S9 activation . Negative up to precipitating concentrations. 870.5300 in Vitro Forward Mutation, Mouse Lymphoma L5178Y cells MRID 00132138 Acceptable/guideline 1 to 250 μg/mL (without activation) and 0.5 to 12 μg/mL (with activation). Negative up to cytotoxic concentrations. Cytogenetics 870.5375 In Vitro Chromosomal Aberration in CHO Cells MRID 40435901 Acceptable/guideline 10 to 80 μ g/mL (without activation) and 25 to 2 00 μg/mL (with activation). Negative up to precipitating concentrations. 870.5395 In Vivo Micronucleus Assay in Male Mice MRID 00164555 Unacceptable/guideline (results inconclusive) 5000 mg/kg Inconclusive. Slight, significant increases in frequency of micronucleated polychromatic erythrocytes at 24 and 48 hrs but not 72 h.Is oxaben D376428

Page 68 of 90 870.5395 In Vivo Micronu cleus Assay in Male Mice MRID 40485704 Acceptable/guideline (results inconclusive) 800, 2000 or 5000 mg/kg Weakly positive. Slight, statistically significant increase in the frequency of micronucleated polychromatic erythrocytes were noted at 24 h. 870.5 395 In Vivo Micronucleus Assay in Mice MRID 47140002 Acceptable/guideline 0, 1250, 2500 or 5000 mg/kg Negative up to the limit dose. 870.5450 Rodent Dominant Lethal in male rats MRID 00164556 Unacceptable/guideline (upgradeable; no positive control data provided) 0, 34, 173 or 932 mg/kg/day. Negative for dominant lethal effects in male rats Other Genotoxicity 870.5550 Unscheduled DNA Synthesis in Cultured Rat Hepatocy tes MRID 00132137 Acceptable/guideline 0.5 to 1000 nmoles/mL Negative. No cytotoxicity observed. 870.5915, In Vivo Sister Chromatid Exchange, Chinese Hamster MRID 40485703 Acceptable/guideline 800, 2000 or 5000 mg/kg Negative up to the limit dose. A.3.7 Metabolism 870.7485 Metabolism – Rat (1) In a series of three metabolism studies (MRID 00132131, - 32, - 33 ) , isoxaben ( 14 C - EL - 107 technical, lot # 553 - 02V - 094; label located on the 5 position of the isoxazole ring and radiochemical purity

100%) and unlabeled isoxaben (EL - 107 technical, 92.4%, lot B31 - 72C - 88) w ere administered to Fische r 344 rats according to the following protocols: (1) biliary excretion

- to 5 rats/sex/dose by

gavage in 10% aqueous acacia (w/v) at 10 or 250 mg/kg 14 C - EL - 107 (dosing volume 10 mL/kg bw). All rats had surgically installed exteriorized bile duct cannul ae and collection of bile was continued for 24 hrs following dosing; (2) excretion - to 5 rats/sex/dose by

gavage in 10% aqueous acacia (w/v) at 10, 100, 250, 500 or 1000 mg/kg 14 C EL - 107 (10 mL/kg dosing volume). Urine and feces were collected for 72 hours; (3) tissue distribution - to 5 rats/sex/sampling time, a single gavage dose of 250 mg/kg 14 C - EL - 107 in 10% aqueous acacia (10 mL/kg bw dosing volume). At 4 or 24 hrs postdosing, rats were sacrificed under ether anesthesia, blood samples were collected and tissues and organs collected for radioassay . Total excretion of radiolabel in urine and feces b y 72 hrs ranged from 70.8% to 94.9% in males and 88.2% to 106.3% in females. The majority of radioactivity

was excreted within the first 24 hrs. The l owest recoveries in males ( ≈71 - 74%) were observed at 10, 100 and 250 mg/kg. The major route of excretion of isoxaben was fecal, ranging from 57.2% to 81.8% of dose in malesIs oxaben D376428

Page 69 of 90 and 81.7 to 104.3% in females. Urinary excretion ranged from 2.0% at high dose lev els to about 12 - 13% of the dose at the lower doses. With increasing dose, the percent of dose excreted in the urine decreased and fecal excretion increased, suggesting oral absorption may be a rate - limiting process. At 10 mg/kg, biliary excretion was obse rved in males and females at 23.1% and 38.8% of the dose, respectivel y. At 250 mg/kg, the percent radioactivity excreted was 17.5% and 15.3%, respectively , consistent with rate - limiting oral absorption. Radioactivity was widel y distributed to tissues. At 4 hrs postdosing, the tissues with the greatest amount of radiolabel were liver, pituitary , thy

roid, kidney , adrenals and prostate, with 12/20 tissues in males and 13/20 tissues in females. At 24 hrs postdosing, the tissue to plasma ratios were increase d compared to 4 hrs in pituitary , thy

roid, ovaries and eyes of females. Males showed slightly higher levels in adrenals and pituitary . However, radioactivity in tissues was not assessed at times later than 24 hrs postdosing to evaluate levels through 72 hrs. It is not known whether the lower recoveries in males were due to increased retention in tissues or experimental artifact, such as quenching or problems with a suspension dosing solution. This metabolism study

in the rat is classified A cceptable/gui deline and satisfies the guideline requirement for a metabolism study [OPPTS 870.7485, OECD 417] in the rodent when considered together with additional metabolism studies in the rat that include repeated dosing, exhaled air excretion and identification of metabolites (TXR # 005732). (2) In a series of metabolism studies (MRID s 00153114, 00164557, - 58, - 59 ) , 14 C - EL - 107 (isoxaben technical, lot # 553 - 3N1 - 056, radiochemical purity of 98.6% - 99.9% and unlabeled EL 107, lot no. Z10025, purity 95%) was administer ed to male and female rats according to one of the following protocols: (1) single gavage dose of 250 mg/kg 14 C - EL - 107 to 5 Wistar rats/sex for evaluation of fecal and urinary excretion and analy sis of metabolites; (2) single gavage dose of 1000 mg/kg 14 C - EL - 107 to 5 Fischer 344 rats/sex/time point for analy sis of tissue levels of radioactivity

at 4 and 24 hrs postdosing; (3) repeated daily gavage doses of 250 mg/kg unlabeled EL - 107 for 14 day s, followed by a single oral dose of 250 mg/kg 14 C - EL - 107 on day 15 for assessment of excretion and carcass and tissue levels by 7 day s following the radioactive dose; and (4) single gavage doses of 250 mg/kg 14 C - EL - 107 to 5 Fischer 344 rats/sex for collection of expired air 14 CO 2 over a 48 hr period postdosing. Carca sses and cage rinses were also assay ed. Following a single dose of 250 mg/kg, radioactivity was rapidl y eliminated in both males and females, with almost all the administered dose excreted b y 48 hrs. The major route of excretion was fecal, with 81.8% and 91.8% of the dose excreted in males and females, respectivel y. Urinary excretion of radioactivity accounted for 8.5% in both sexes. About 90% of the radioactivity

present in the feces was unmetabolized EL - 107. Absorption of EL - 107 was poor, with about 8 - 10% of the dose absorbed and extensively metabolized. In the urine, 15 to 20 metabolites were recovered. The major metabolic pathway s involve oxidation at the 2 - position of the alkylside chain to yield either an alcohol or ketone, hydrox yl ation of the aromatic ring next to one of the methoxy groups, and O - demethylation of one of the methoxy groups. Radiolabel was widel y distributed among tissues by 4 hrs postdosing after administration of 1000 mg/kg. By

24 hrs most tissue levels decreased compared to 4 hrs, with the exception of the colon in both sexes. Tissues with levels of radioactivity higher than plasma at 4 and 24 hrs included the GI tract, liver, kidney s, fat, prostate, pancreas (females), adrenal glands and carcass. Levels were not assessed at later times. The ratio of red cell to plasma radioactivity was 0.4 toIs oxaben D376428

Page 70 of 90 0.8. The study

author noted that the high levels of radiocarbon at 24 hrs in the previous study (MRID 00132133) may

have been an artifact of counting small tissues than may have cau sed overestimation of radioactivity due to undetected chemiluminescence. Predosing with unlabeled isoxaben did not significantly change the pattern of urinary and fecal excretion of radioactivity. Urinary excretion was 5.6% and 7.5% and fecal excretion 7 5% and 88.6% for males and females, respectivel y, with the greatest amount excreted by 24 hrs. Combined seven day

urine and fecal recoveries were 80.6% in males and 96.1% in females. At 7 day s after the final, radiolabeled dose, residual carcass levels o f radioactivity were 0.3% and 0.4% in males and females, respectively . All tissue levels at 7 day s postdosing were less than 0.01% of dose except for liver, which was 0.01% and 0.02% in males and females, respectivel y. All tissues samples were at or belo w 0.32 μg equivalents/g tissue. Excretion of 14 CO 2 was limited to 2.4% (males) and 2.8% (females) of the dose. At 48 hrs postdosing in the expired air study , urinary and fecal excretion represented 78.1% and 73.8% of the dose and carcasses 1.5% and 14.4% of the dose in males and females, respectivel y. This series of metabolism studies in the rat is classified acceptable/guideline and satisfies the guideline requirement for a metabolism study [OPPTS 870.7485, OECD 417] in the rodent. 870.7600 Dermal A bsorption - Monkey In an in vivo dermal absorption study (MRID 00153113), two male and two female Rhesus monkey s were administered a single IV dose of 2.0 mg/kg 14 C - EL - 107 (isoxaben technical, lot # 553 - 02V - 094, radiochemical purity 100% and lot # 558 - 1X7 - 018 radiochemical purity 98.4%, radiolabel on the 5 carbon of the isoxazole ring) and samples of plasma were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 24, 48, 72, 96, 120, 144 and 168 hrs postdosing for anal ys is of levels of radioactivity . Urine and feces w ere also collected twice dail y for 7 day s and anal yz ed. One month later the same animals were treated topically for 24 hr with 2.0 mg/kg 14 C - EL - 107 (6 cm 2 on shaved are of right ventral forearm). Serum, urine and feces were collected and anal yz ed as desc ribed for the IV dosing. The results indicated limited dermal absorption of EL - 107. Comparison of IV and topical dosing plasma AUCs indicated that about 11% of the dermal dose was absorbed. A dermal absorption value of 7.5% was obtained by comparison of the urinary excretion data. EL - 107 was rapidly distributed to a second compartment (half life 1.4 hrs) with a half life for the terminal elimination phase from plasma of 30.9 hrs. Based on volume of distribution estimates, the study authors suggested th at the radioactivity was partially

bound to plasma protein. This dermal absorption study in the monkey

is classified acceptable/guideline and satisfies the guideline requirement for an in vivo dermal absorption study (OPPTS 870.7600).Is oxaben D376428

Page 71 of 90 A.4 Rationale for Toxicology Data Requirements Table A.4.1 Guideline Number: 870.3465 Study Title: 90 - Day Inhalation Toxicity Rationale for Requiring the Data This study is required if there is the likelihood o f significant repeated inhalation exposure to the pesticide as a gas, vapor or aerosol. The Agency has determined that there are potential inhalation exposures to mixers, loaders and applicators, as well as potential postapplication exposures, associated w ith isoxaben applications. T he inhalation study may potentially be shortened (i.e., 28 - day exposure) as appropriate to exposures from current use patterns. Because toxicity via the inhalation route may differ from that observed following oral dosing, the study is required to better assess potential effects resulting from inhalation exposure and provide a refined assessment of risk from inhalation exposure. Practical Utility of the Data How did the Agency make its re - registration decision without these data? In the absence of inhalation toxicity studies for any given pesticide active ingredient, The Agency estimates occupational risk from inhalation exposure by using the most sensitive oral endpoint appropriate for a given exposure scenario. To acco unt for route - to - route extrapolation, 100% absorption is assumed . How will the data be used? An inhalation study may result in changes to the endpoints and how the risks are quantified. These animal studies can be used to select endpoints and doses for use in risk assessment f or all exposure scenarios and are considered a primary data source for reliable reference dose calculation for the inhalation route of exposure. How could the data impact the Agency’s future decision - making? The Agency does not have a full picture of the potential effects which could occur as a result of exposure via the inhalation route. In some cases, toxicity observed via the inhalation route is higher than toxicity observed via oral exposure, which means that route - to - route extrapolation could result in an underestimation of risks from inhalation. The study may be used to confirm that no further mitigation is needed for uses where inhalation exposure occurs. Table A.4.2 Guideline Number: 870.6200 Study Title : Neurotoxicity Battery (Acute and Subchronic Studies) Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Neurotoxicity

Screening Batte ry

(OPPTS 870.6200) is designed to evaluate the potential adverse effects on the nervous sy stem from exposure to pesticide chemicals. The Agency believes that the guideline studies are inadequate in their assessment of behavioral effects and do not use op timal methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize these potential effects more full y, a battery of more sensitive testing is required. The objective of this neurotoxicity battery testi ng is to evaluate the incidence and severity

of the functional and/or behavioral effects, the level of motor activity , and the histopathology

of the nervous s ys tem. The acute neurotoxicity study is required toIs oxaben D376428

Page 72 of 90 detect possible effects resulting from a singl e exposure. The subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or long - term exposures. Practical Utility of the Data How will the data be used? The acute and subchronic neurotoxicity studies provide criti cal scientific information needed to characterize potential hazard to the human population on the nervous s ys tem from pesticide exposure. These studies can provide data on a wide range of functional tests for evaluating neurotoxicity

including sensory

effe cts, neuromuscular effects, learning and memory and histopathology

of the nervous sy stem For example, animal studies with organophosphorous chemicals have shown neurotoxicity to be the primary

toxic endpoints (e.g., cholinesterase inhibition) of concern in rodents and non - rodents. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., organophos p hates and carbamates) where neurotoxicity was the most sensitive endpoint of concern. How could the data impact the Agency's future decision - making? If the acute or subchronic neurotoxicity studies show that isoxaben poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessment for isoxaben may

need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency

does not have this data, a 10X database uncertaint y factor may be applied when conducting a risk assessment using the currentl y available studies.Is oxaben D376428

Page 73 of 90 Table A. 4 .3 Guideline Number: 870. 7800 Study Title: Immunotoxicity Rationale for Requiring the Data The immunotoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential immunotoxic effects. Practical Utility of the Data How will the data be used? These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary dat a source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8 - tetrachlorodibenzo -p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impact the Agency's future decision - making? I f the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potentia l risk derived from the new data. If the Agency does not have these data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.Is oxaben D376428

Page 74 of 90 Appendix B: Metabolism Assessment B.1 Metabolism Guidance and Considerations Plants: For the primary

crop grapes and tree nuts, isoxaben parent can serve as an adequate measure of misuse based on its percentage of the total radioactive residue (TRR) in the barley metabolism study

and the field trial residues observed in almond hulls and nutmeat. Inaddition, the FDA multiresidue method Section 302 completely recovers the parent (PESTDATA 06/05). Therefore, ROCKS recommends using the levels of the parent for compliance purposes. For dietary

risk assessment purposes , ROCKS concludes that the tolerance based on the parent will be adequate. In the grape metabolism study , the TRR was <0.008 ppm in the fruit, after a single appl ication of isoxaben ranging from 1.79 - 1.97 lbs ai/A (1.8 - 2.0x proposed seasonal rate). Grapes harvested 60 days following a single broadcast application of the 75% DF formulation of isoxaben to the soil at 5.0 lb ai/A (5x the proposed rate) had residues b elow the L OQ (0.01 ppm) in/on all samples of grapes and raisins. Therefore, use of the LOQ (0.01 ppm) for the parent in grapes represents a conservative estimate of dietary exposure. Although radiolabeled data have not been provided for tree nuts to make a similar comparison with field trial results, it is unlikely that significant uptake of residues from a soil - directed application into the edible nutmeat would occur. Three h ydrox yl ated metabolites ( 1 - hydroxyl , 2 - hy drox yl , 3 - hydroxyl ) were major residu es in the barley metabolism study . Structure - activity relationship ( SAR) analy sis (DEREK) did not reveal any alerts for the parent compound or the 1 - hydroxyl metabolite. Due to structural similarity , all of the hydroxylated metabolites are assumed to hav e comparable toxicity to the parent; therefore, for an y future uses on grains or grasses, the petitioner is advised to include residue data on the three h ydrox yl ated metabolites as they are likel y t o be included for at least risk assessment purposes on tho se crops. Livestock : Although the goat metabolism study identified low percentages of the TRR in most matrices, it is adequate for the proposed uses based on the very low dietary burden for cattle. Only one commodity

associated with the proposed uses, a lmond hulls, is a cattle feed item. There are no poultry

or swine feed items associated with the proposed uses. HED/RAB2 review of the livestock metabolism study indicates that a cattle feeding study , and tolerances for livestock commodities are not need ed. A ROCKS decision on the residues of concern is thus not required at this time. However, another goat metabolism study with better identification and characterization of the residues will be needed for any additional uses of isoxaben that result in si gnificantl y higher dietary burdens.

Table B.1 . DEREK Alerts for Major Biodegradates . Compound Alerts Isoxaben Nothing to report Hydroxy isoxaben Methoxyphenyl pyrimidinol 121 Substituted pyrimidine or purine. Carcinogenicity. Number of matches = 1 440 Resorcinol or precursor. Skin sensitization. Number of matches = 1 AEM hexenoyl isoxaben 444 Imine or alpha, beta - unsaturated imine. Skin sensitization. Number of matches = 1Is oxaben D376428

Page 75 of 90 Table B.1 . DEREK Alerts for Major Biodegradates . Compound Alerts Dimethoxy benzamide Nothing to report Drinking Water: Major degradates (>10% of total residues) detected during aerobic and anaerobic soil metabolism studies and aerobic and anaerobic aqueous metabolism studies include hydrox y isoxaben, dimethox y benzamide, methoxy phenyl py rimidinol, and AEM hexenoyl isoxaben. SAR analy sis (DEREK) did not reveal any alerts for the parent compound but did produce alerts for the methoxy phen ylpy rimidinol ( carcinogenicit y , skin sensitization ) and AEM hexenoyl isoxaben ( skin sensitization ) metabolites. ROCKS is not concerned for these alerts be cause substituted p yri midine/ purine carcinogenicity is only seen at very

high doses (as a result of bladder calculi) and dermal exposure to metabolites is not expected to be significant. None of these environmental degradates are thus expected to be more toxic than the parent compound, but data are not available to exclude them as residues of concern. Four major photol yt ic degradates (Unk 3, Unk 3i, Unk 5a, and Unk 5b) were detected but not conclusively

identified. SAR analy sis triggered an alert for Unk 3 (carcinogenicity), but was based on bladder tumors from saturating urinary levels of p yrimidines, considered an unlikel y occurrence in humans. SAR analy sis triggered an alert for Unk 3i for mutagenicity based on the presence of an oxime moiety . The mutagenicit y discussion indicated that some oximes were positive in Ames and mouse ly mphoma tests, but that results were often conflicting depending on which labo ratory

performs the test. Unk3i also had a carbox ylgroup that will be ionized under environmental and most physiological conditions. The presence of the group was likel y to enhance excretion and interfere with an y potential mutagenic activity. In the absence of other data that might support the mutagenicity alert, ROCKS was not concerned with thi s mutagenicity alert for Unk 3i. Lastly , SAR analy sis triggered alerts for Unk 3i, Unk 5a, and 5b for skin sensitivity . ROCKS was not concerned with these alerts because dermal exposure of metabolites was not expected to be significant. Therefore, becau se aqueous photol ys is was not expected to be a dominant degradation pathway of isoxaben and these degradates were not observed in an y other study , the formation of the photodegradates was considered minimal, and none of these degradates were expected to be more toxic than the parent compound, these major degradates were excluded as residues of concern. Recommended Tolerance Expression: The ROCKS recommends the following language for the tolerance expression for plant commodities: Tolerances are establish ed for residues of the herbicide isoxaben, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined b y measuring only isoxaben, N - [3 - (1 - ethyl - 1 - methylprop yl ) - 5 - isoxazolyl] - 2,6 - dimethoxy benzamide .Is oxaben D376428

Page 76 of 90 B.2 Tabular Summary of Metabolites and Major Degradates Figure 1. Isoxaben Metabolism in/on Grape.Is oxaben D376428

Page 77 of 90 Figure 2. Isoxaben Metabolism in/on Barley .Is oxaben D376428

Page 78 of 90 FI GURE 3. Proposed Metabolic Profile of Isoxaben in the Lactating Goat

APPENDIX B.2.1 Chemical Names and Structures of Isoxaben and Plant Metabolites. Common name; Com pany code Chemical name Chemical structure Isoxaben N - [3 - (1 - ethyl - 1 - methylpropyl) - 5 - isoxazolyl] - 2,6 - dimethoxybenzamide

O C H 3 N H O O N C H 3 C H 3 C H

3 O C H 3Is oxaben D376428

Page 79 of 90 APPENDIX B.2.1 Chemical Names and Structures of Isoxaben and Plant Metabolites. Common name; Com pany code Chemical name Chemical structure Metabolite I 1 2,6 - dimethoxybenzoic acid O C H 3

O C H

3 O H O

Isoxaben - 2 - hydroxy/ Metabolite II (mixture of two diastereomers) N - [3 - (1 - ethyl - 2 - hydroxy - 1 - methylpropyl) - 5 - isoxazolyl] - 2,6 - dimethoxybenzamide O C H 3

O C H

3 N H O O N C H 3 C H 3 C H

3 O H

Isoxaben - 3 - hydroxy/ Metabolite III N - [3 - (3 - hydroxy - 1 - ethyl - 1 - methylpropyl) - 5 - isoxazolyl] - 2,6 - dimethoxybenzamide O C H3

O C H3 N H O O N C H3

C H3 O H

Isoxaben - 1 - hydroxy/ Metabolite IV N - [3 - (1 - hydroxy - 1 - methylpropyl) - 5 - isoxazolyl] - 2,6 - dimethoxybenzamide

O C H 3 N H O O N C H 3 O H C H 3 O C H 3

2 - OH - 6 - OMe benzamide 2 - hydroxy - 6 - methoxy benzamide O C H 3 N H 2 O

O H 2,6 - dimethoxy benzamide O C H 3

O C H 3 N H 2 O

1 Suspected to be an artifact formed during acid h ydrolysis.Is oxaben D376428

Page 80 of 90 Appendix B. 2. 2 Chemical Names and Structures of Isoxaben and Livestock Metaboli tes . Common name/code Figure C.3.1 ID No. Chemical name Chemical structure Isoxaben N - (3 - (1 - ethyl - 1 - methylpropyl) - 5 - isoxazolyl) - 2,6 - dimethoxybenzamide

3 - Hydroxy isoxaben N - (3 - (1 - hydroxy - 1 - ethyl - 1 - methypropyl) - 5 - isoxazolyl) - 2,6 - dimethoxybenzamide

2,6 Dimethoxybenzamide 2,6 Dimethoxybenzamide

2,6 Dimethoxyb enzoic acid 2,6 Dimethoxybenzoic acid

Isoxaben Desmethyl metabolite Benzamide, N - [3 - (1 - ethyl - 1 - methypropyl) - 5 - isoxazolyl] - 2 - hydroxy 6 - methoxyIs oxaben D376428

Page 81 of 90 2 - Hydroxy - 6 - methoxybenzamide 2 - Hydroxy - 6 - methoxybenzamide

Oxime Metabolite

Carboxylic Acid Metabolite

Hydroxylated IsoxabenIs oxaben D376428

Page 82 of 90 Appendix B. 2. 3 Chemical Names and Structures of Isoxaben and Rat Metaboli tes (copied from EL - 107 Metabolic Study

In Rats, Accession # 073293) .Page 83 of 90

B.3 Environmental Fate Summary

Table B.3.1 . Summary of Maximum Degradate Amo unts in Environmental Fate Studies of Isoxaben Degradate 1 Max. Degradate % of Applied (Time of Peak) Analyzed Degradates

Hydrolysis Aqueous

Photolysis Soil

Photolysis Aerobic Soil Anaerobic Soil Aerobic Aquatic Anaerobic

Aquatic TFD PGW Source MRID 47 140003 47428403 47140004 41106302 46393202 46393201 No study Dimethoxy benzamide - 21.9 % (12 days) 8.5% (30 days) - - 10.7 % (44 days) 12.9 % (30 days) Hydroxy i soxaben

- - - 10.8 % (122 days) 16.8 % (60 days) 1.1% (84 days) - 8.6% (224 days) Methoxyph enyl pyrimidinol - - - - - 0.1% (61 days) 33.1 % (93 days) AEM hexenoyl isoxaben - - - - - 8.4% (30 days) 60.1 % (14 days) Unk1 - 27.6 % (36 days) - - - - - Unk3 - 24.2 % (36 days) - - - - - Unk3i - 14.8 % (14 days) - - - - - Unk 4a/4b - 8.0% (14 days) - - - - - Unk5a - 23.2 % (1 days) - - - - - Unk5b - 17.6 % (14 days) - - - - - Oxypropyl isoxaben

- - - 7.3% (90 days) 4.4% (30 days) 1.6% (30 days) 1.4% (121 days) Desmethyl isoxaben

- - - 1.6% (122 days) 2.2% (60 days) - 2.5% (7 days) Hydroxyethyl isoxaben - - - 0.4% (90 days) 1.9% (60 days) - - 3.9% (602 days) Hydroxymethoxy benzamide - - - - - 1.1% (84 days) 7.7% (61 days) CO 2 - 11.5% (36 days) 15.9% (23 days) 8.6% (122 days) - 18.7% (103 days) - 1 - 2,6 - DMB - 2,6 - dimethoxy benzamide (127992); Unk3 - 6 - (1 - ethyl - 1 - methylpropyl)pyrimidine - 2,4(1H,3H) - dione; Unk3i - 4 - ethyl - 3 - (hydroxyimino) - 4 - methylhexanoic acid; Unk5a - 2 - (2,6 - dimethoxybenzoyl) - 5 - (1 - ethyl - 1 - methylpropyl)1,2 - dihydro - 3H - pyrazol - 3 - one; Unk5b - 4,6 - diethyl - 4a,8 - dime thoxy- 4 - methyl - 4a,8a - dihydropyrazolo[1,5 - b]isoquinoline - 2,9(1H,4H) - dione; Unk1 and Unk 4a/4b

– composites of several minor transformation products , each < 6.5% of applied . Unk4a - N - (2,6 - dimethoxybenzoy1) - 3 - (1 - ethyl - 1 - methylpropyl) - 2H - azirene - 2 - carboxamid e; Unk4b

- N - [2 - (1 - ethyl - 1 - methylpropy1) - 1,3 - oxazo1 - 5 - yl] - 2,6 - dimethoxybenzamideIs oxaben D376428

Page 84 of 90 Table B.3.2 Maximum Reported Amounts of Isoxaben Degradation Products 1 Degradate Maximum % of Applied % of Applied at Study Termination Study Type MRID Monitoring Data Isoxa ben (parent) Not applicable 96.5 - 98 (30 d, pH4,7,9) 1.2 (36 days) 83.8 - 89.5 (30 days) 54.3 - 70.4 (122 days) 55.8 (60 days) 0.2 - 2.4 (103 days) 0.5 (121 days) 3 (313 days, 0 - 6”, autumn FL app) 5 (127 days, 0 - 6”, spring FL app) 18 (127 days, 0 - 6”, spring I N app) 35 (182 days, 0 - 6”, autumn TX app) 2.9 (299 days, 0 - 15 cm, FL app) 5.8 (322 days, 0 - 15 cm, I

N app) 14.4 (483 days, 0 - 15 cm, TX app) 9.1 (700 days, 0 - 15 cm) Hydrolysis Aqueous Photolysis Soil Photolysis Aerobic Soil Metabolism Anaerobic Soil Metabolism Aerobic Aquatic Metabolism Anaerobic Aquatic Metabolism Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field D issipation Terrestrial Field Dissipation 00250449 47140003 47428403 47140004 41106302 46393202 46393201 40059508 40059508 40059508 40059508 40532101 40532101 40532101 00250449 No

Dimethoxy benzamide 21.9 (12 days) 8.5 (30 days) 10.7 (44 days) 12.9 (30 day s) 14.1 (36 days) 8.5 (30 days) 2.5 - 5.7 (103 days) 5.2 (121 days) Aqueous Photolysis Soil Photolysis Aerobic Aquatic Metabolism Anaerobic Aquatic Metabolism 47140003 47428403 46393202 46393201 No Hydoxy isoxaben 10.8 (122 days) 16.8 (60 days) 1.1 (84 day s) 5 (36 days, 0 - 6”, autumn FL app) 9 (60 days, 0 - 6”, spring FL app) 7 (41 days, 0 - 6”, spring IN app) 3 (182 days, 0 - 6”, autumn TX app) 4.2 (299 days, 0 - 15 cm, FL app) 3.2 (322 days, 0 - 15 cm, I

N app) 2.1 (375 days, 0 - 15 cm, TX app) 11 (66 days, 0 - 6”, IL ap p) 8.6 (224 days, 0 - 7.5 cm) 7.6 (539 days, 0 - 15 cm) 10.8 (122 days) 18.8 (60 days) 0.1 - 0.3 (103 days) 3 (313 days, 0 - 6”, autumn FL app) 5 (127 days, 0 - 6”, spring FL app) 3 (127 days, 0 - 6”, spring I N app) 3 (182 days, 0 - 6”, autumn TX app) 4.2 (299 days, 0 - 1 5 cm, FL app) 3.2 (322 days, 0 - 15 cm, I

N app) 1.0 (483 days, 0 - 15 cm, TX app) 2.0 (211 days, 0 - 6”, IL app) 4.6 (700 days, 0 - 15 cm) 4.6 (700 days, 0 - 15 cm) Aerobic Soil Metabolism Anaerobic Soil Metabolism Aerobic Aquatic Metabolism Terrestrial Field Dissip ation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestrial Field Dissipation Terrestria l Field Dissipation 47140004 41106302 46393202 40059508 40059508 40059508 40059508 40532101 40532101 40532101 40532102 00250449 00250449 No

Methoxyphenyl pyrimidinol 0.1 (61 days) 33.1 (93 days) 0 (103 days) 27.8 (121 days) Aerobic Aquatic Metabolism Anaerobic Aquatic Metabolism 46393202 46393201 No AEM hexenoyl isoxaben 8.4 (30 days) 60.1 (14 days) 2.5 (103 days) 36.0 (121 days) Aerobic Aquatic Metabolism Anaerobic Aquatic Metabolism 46393202 46393201 No Unk1 27.6 (36 days) 27.6 (36 days) Aqueous Photolysis 47140003 No Unk3 24.2 (36 days) 24.2 (36 days) Aqueous Photolysis 47140003 No Unk3i 14.8 (14 days) 11.8 (36 days) Aqueous Photolysis 47140003 No Unk 4a/4b 8.0 (14 days) 1.2 (36 days) Aqueous Photolysis 47140003 No Unk5a 23.2 (1 days) 0.0 (36 days) Aqueous Photolysis 47140003 NoIs oxaben D376428

Page 85 of 90 Degradate Maximum % of Applied % of Applied at Study Termination Study Type MRID Monitoring Data Unk5b 17.6 (14 days) 13.6 (36 days) Aqueous Photolysis 47140003 No Oxypropyl isoxaben 7.3 (90 days) 4.4 (30 days) 1.6 (30 days) 1.4 (121 days) 3.3 - 5.7 (122 days) 4.2 (60 days) 0.4 (103 days) 1.4 (121 days) Aerobic Soil Met abolism Anaerobic Soil Metabolism Aerobic Aquatic Metabolism Anaerobic Aquatic Metabolism 47140004 41106302 46393202 46393201 No Desmethyl isoxaben 1.6 (122 days) 2.2 (60 days) 2.5 (7 days) 0.5 - 1.6 (122 days) 2.2 (60 days) 0.0 (121 days) Aerobic Soil Meta bolism Anaerobic Soil Metabolism Anaerobic Aquatic Metabolism 47140004 41106302 46393201 No Hydroxyethyl isoxaben 0.4 (90 days) 1.9 (60 days) 2.3 (350 days, 0 - 7.5 cm) 3.9 (602 days, 0 - 15 cm) <0.1 - 0.3 (122 days) 1.9 (60 days) 3.8 (700 days, 0 - 15 cm) 3.8 (7 00 days, 0 - 15 cm) Aerobic Soil Metabolism Anaerobic Soil Metabolism Terrestrial Field Dissipation Terrestrial Field Dissipation 47140004 41106302 00250449 00250449 No Hydroxymethoxy benzamide 1.1 (84 days) 7.7 (61 days) 0.1 - 0.6 (103 days) 6.8 (121 days) A erobic Aquatic Metabolism Anaerobic Aquatic Metabolism 46393202 46393201 No 1 - Major degradates and maximum amounts >10% are in bold. Unacceptable data were not reported.Page 86 of 90

Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies Name(s) Structure Occurrence Fate Properties 1 Isoxaben (parent) Pseudonyms - EL - 107 IUPAC name N - [3 - (methylpent - 3 - yl)isoxazol - 5 - yl] - 2,6 - dimethoxy - benzamide CAS # - 82558 - 50 - 7 See Table 2.3

Dimethoxy benzamide 2,6 - Dimethoxybenzamide Aqueous photolysis (major) Aerobic Aquatic Metabolism (major) Anaerobic Aquatic Metabolism (major) Soil Photoly sis (minor) VP = 1.6x10 - 5 torr Sol = 8.4x10 4 mg/L Log KOW = - 0.22 KOC = 4.9

– 10 mL/g

Hydroxy isoxaben Pseudonyms - AA - 045 N - [3 - (1 - hydroxyl - 1 - methylpropyl) - 5 - isoxazoyl] - 2,6 - dimethoxy - benzamide Aerobic Soil Metabolism (major) Anaerobi c Soil Metabolism (major) Aerobic Aquatic Metabolism (minor) Terrestrial Field Dissipation (minor) VP = 9.8x10 - 12 torr Sol = 462 mg/L Log KOW = 1.53 KOC = 17

– 31 mL/g KOC = 21

– 73 (MRID 4110603) Methoxyphenol pyrimidinol 6 - (1 - ethyl - 1 - methylpropyl) - 2 - (2 - hydroxy - 6 - methoxyphenyl) - 4 - pyrimidinol Anaerobic Aquatic Metabolism (major) Aerobic Aquatic Metabolism (minor) VP = 4x10 - 10 torr Sol = 41.2 mg/L Log KOW = 3.56 KOC = 4800

– 38,000 mL/gIs oxaben D376428

Page 87 of 90 Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies Name(s) Structure Occurrence Fate Properties 1 AEM hexenoyl isoxaben N - [3 - amino - 4 - ethyl - 4 - methyl - 2 - hexenoyl] - 2,6 - dimethoxybenzamide Anaerobic Aquatic Metabolism (major) Aerobic Aquatic Metabolism (minor) VP = 3.1x10 - 13 torr Sol = 265 mg/L Log KOW = 1.71 KOC = 21 - 102 mL/g Oxypropyl isoxaben N - [3 - (1 - ethyl - methyl - 2 - oxopropyl) - isoxazolyl - 5 - yl] - 2,6 - dimethoxybenzamide Aerobic Soil Metabolism (minor) Anaerobic Soil Metabolism (minor) Aerobic Aquatic Metabolism (minor) Anaerobic Aquatic Metabolism (minor) VP = 5x10 - 10 torr Sol = 148 mg/L Log KOW = 1.93 KOC = 1 12 - 148 mL/g

Desmethyl isoxaben N - [3 - (1 - ethyl - 1 - methylpropyl) - 5 - isoxazolyl] - 2 - hydroxy - 6 - methoxybenzamide Aerobic Soil Metabolism (minor) Anaerobic Soil Metabolism (minor) Anaerobic Aquatic Metabolism (minor) VP = 1.6x10 - 10 torr Sol = 5.32 mg/L Log KOW = 4.5 KOC = 2400 - 2500 mL/g Hydroxyethyl isoxaben N - [3 - (1 - hydroxyethyl) - 5 - isoxazolyl] - 2,6 - dimethoxybenzamide Aerobic Soil Metabolism (minor) Anaerobic Soil Metabolism (minor) Terrestrial Field Dissipation (minor) VP = 2.9x10 - 11 torr Sol = 4322 mg/L Log KOW = 0.58 KOC = 5

– 11 mL/gIs oxaben D376428

Page 88 of 90 Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies Name(s) Structure Occurrence Fate Properties 1 Hydroxymethoxybenzamide 2 - hydroxy - methoxy benzamide Aerobic Aquatic Metabolism (minor) Anaerobic Aquatic Metabolism (minor) VP = 1.7x10 - 6 torr Sol = 7.7x10 4 mg/L Lo g KOW = 0.58 KOC = 15

– 17 mL/g 6 - (1 - ethyl - 1 - methylpropyl)pyrimidine 2,4(1H,3H) - dione Aqueous Photolysis (major) VP = 5.6x10 - 8 torr Sol = 853 mg/L Log KOW = 2.0 KOC = 80

– 113 mL/g

4 - ethyl - 3 - (hydroxyimino) - 4 - methylhexanoic acid Aqueous Photoly sis (major) VP = 3.8x10 - 6 torr Sol = 698 mg/L Log KOW = 2.8 KOC = 51

– 126 mL/g N - (2,6 - dimethoxybenzoy1) - 3 - (1 - ethyl - 1 - methylpropyl) - 2H - azirene - 2 - carboxamide Aqueous Photolysis (minor) VP = 6.6x10 - 12 torr Sol = 1.1 mg/L Log KOW = 4.5 KOC = 362

– 2014 mL/g N - [2 - (1 - ethyl - 1 - methylpropy1) - 1,3 - oxazo1 - 5 - yl] - 2,6 - dimethoxybenzamide Aqueous Photolysis (minor) VP = 2.5x10 - 9 torr Sol = 3.2 mg/L Log KOW = 4.0 KOC = 972

– 1262 mL/gIs oxaben D376428

Page 89 of 90 Table B.3.3. Chemical Names and Structures of isoxaben and degradation products detected in submitted environmental fate studies Name(s) Structure Occurrence Fate Properties 1 2 - (2,6 - dimethoxybenzoyl) - 5 - (1 - ethyl - 1 - methylpropyl)1,2 - di hydro - 3H - py razol - 3 - one Aqueous Photolysis (major) VP = 2.0x10 - 10 torr Sol = 29 mg/L Log KOW = 2.85 KOC = 222

– 228 mL/g

4,6 - diethyl - 4a,8 - dimethoxy - 4 - methyl 4a,8a - dihydropyrazolo[1,5 - b]isoquinoline - 2,9(1H,4H) - dione Aqueous Photolysis (major) VP = 1.3x10 - 10 torr Sol = 2221 mg/L Log KOW = 0.65 KOC = 12

– 331 mL/g

CO 2 Carbon dioxide C O O Aqueous Photolysis (major) Soil Photolysis (major) Aerobic Soil Metabolism (minor) Aerobic Aquatic Metabolism (major) 1. Fate properties for degradates estimated using EPISuite 4.0.Page 90 of 90

Appendix C: Tolerance Summary Table Appendix C . Tolerance Summary for Isoxaben. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodit y Definition Grape 0.01 0.01 Grape, juice 0.01 Remove A separate tolerance for grape juice is not needed. Grape, raisin 0.01 Remove A separate tolerance for raisin is not needed. Nut, tree, Group 14 0.03 0.02 Nut, tree, Group 14 Pistachio 0.03 0.02 Almond, hulls 0.35 0. 40 Tolerance should be 0. 40 ppm and not 0.35 ppm, based on evaluation using the NAFTA Tolerance Spreadsheet. No Codex, Canadian, or Mexican MRL s have been established for isoxaben. Appendix D: R eview of Human Research This risk assessment rel ies in part on data from studies in which adult human subjects were intentionally

exposed to determine their dermal and inhalation exposures. Many such studies , involving exposure to many diffe rent pesticides comprise generic pesticide exposure databases such as Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task F orce (ORETF) database and the Agricultural Reentry Task Force (ARTF) database. EPA has reviewed all the studies in these multi - pesticide generic exposure databases, and on the basis of available evidence has found them to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no regulatory

barrier to continued reliance on these studies, and all applicable requirements of EPA's Rule for the Protection of Human Subjects for Research (40 CFR part 26) have been satisfied.