### Page 1 of 50 UNITED STATES ENVIRONMENTA L PROTECTION AGENCY WA SHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFET Y AND POLLU T ION PREVENTION 

### Date: September 16 , 2010 MEMORANDUM SUBJECT: Indaziflam : Human Health Risk Assessment for Use in Citrus, Stone , and

Pome Fruits ; Grapes ; Tree Nuts ; Pistachios ; Olives ; and Sugar Cane (Imported Refined Sugar) . PC Code: 080818 DP Barcode: D36 7 4 51 Decision No.: 416570 Registration No.: 432 - 1 501 Petition No.: 9F7589, 9E7588 Regulatory Action: Section 3 Assessment Type: Sing le Chemical Aggregate Case No.: NA TXR No.: None CAS No.: 730979 - 19 - 8 MRID No.: See Below 40 CFR: None (New Active Ingredient) 

### FROM: Margarita Collantes, Risk Assessor

Elizabeth Holman, Chemist William Drew, Chemist Michael Doherty , Ph.D., Chemi st Linnea Hansen, Toxicologist Edward Scollon, Ph.D., Toxicologist Risk Assessment Branch 2 Health Effects Division (7509P) THROUGH : Richard A. Loranger, Ph.D., Senior Scientist

Christina Swartz, Branch Chief Risk Assessment Branch 2 Health Effects Div ision (7509P) TO: Bethany Benbow/ James Tompkins , RM 25

Herbicide Branch Registration Division (7505P) The Registration Division (RD) requested that the Health Effects Divis i on (HED) conduct a risk assessment for proposed uses of the active in gredient indaziflam to estimate the risk to human health that will result from the proposed use of indaziflam to control weeds in citrus, stone, and pome fruits ; grapes ; tree nut s ; pistachios ; and olives ; and the requested tolerance without a U.S. registration on processed cane sugar .

### Page 2 of 50

Summary of Submitted Residue Chemistry Studies OPPTS 860 Series Guideline MRID

Number Title 1300

– Nature of the Residue 477 43272 Krolski, M. ; Nguyen, T. (2008) The Metabolism of [Indane - 3 - 14C] and [Triazine 2,4 - 14C] AE 1170437 in Sugarcane. Project Number: M/302672/01/1, MEDHP005. Unpublished study prepared by Bayer CropScience. 64 p. 47743318 Nguyen, T.; Krolski, M. (2009) The Metabolism of [Indane - 3 - (Carbon 14)] and

[Triazine - 2,4 - (Carbon 14)] AE 1170437 in Apples. Project Number: M/344398/01/1/OCR, MEDHP008, MEDHP010. Unpublished study prepared by Bayer CropScience. 71 p. 47743319 Krolski, M.; Nguyen, T. (2009) The Metabolism of [Indane - 3 - (Carbon 14)] and

[Triazine - 2,4 - (Carbon 14)] AE 1170437 in Grapes. Project Num ber: M/344727/01/1/OCR, MEDHP007, MEDHP009. Unpublished study prepared by Bayer CropScience. 70 p. 47743320 Fisher, D. (2009) The Metabolism of [Triazine - 2,4 - (Carbon 14)] AE 1170437 in

the Lactating Goat. Project Number: M/347312/01/1/OCR, MEDHP027. Un published study prepared by Bayer CropScience. 204 p. 47743321 Fischer, D. (2009) The Metabolism of [Indane - 3 - (Carbon 14)] AE 1170437 in the

Lactating Goat. Project Number: M/347315/01/1/OCR, MEDHP028. Unpublished study prepared by Bayer CropScience and Southwest Bio - Labs, Inc. 172 p. 47743322 Mislankar, S. (2009) Waiver of the Requirement for a Poultry Metabolism Study

for Indaziflam. Project Number: MEDHP077. Unpublished study prepared by Bayer CropScience. 6 p. 1340

– Analytical Methods 47743323 T imberlake, B. (2009) Validation of Bayer CropScienceMethod DH - 003 - P07 - 01 and DH - 003 - P07 - 02 - An Analytical Method for the Determination of Residues of AE1170437 in Fruit and Tree Nut Matrices Using LC/MS/MS - Revised. Project Number: M/349201/01/1/OCR, RADHP 040. Unpublished study prepared by Bayer CropScience. 297 p. 47743324 Dallstream, K. (2009) Radiovalidation of Bayer Method DH - 003 - P07 - 01 - An

Analytical Method for the Determination of Residues of AE 1170437 in Crop Matricies Using LC/MS/MS. Project Num ber: M/347745/01/1/OCR, RADHP047. Unpublished study prepared by Bayer CropScience. 35 p. 47743325 Merdian, H. (2009) Independent Laboratory Validation of Bayer Method DH - 003 -

P07 - 01 for the Determination of Residues of Indaziflam (AE 1170437) and its Metabolite 1 - Fluoroethyl Triazinediamine in Plant Materials, Using LC/MS/MS. Project Number: M/342267/01/2/OCR, P612097523, P/B/1633/G. Unpublished study prepared by PTRL Europe Gmbh. 49 p. 47743326 Simpson, R.; Bennett, R. (2009) Independent Laboratory Vali dation of Method

DH - 003 - P07 - 02 for the Determination of Residues of AE1170437 and its Diaminotriazine Metabolites in Crop Matrices Using LC/MS/MS - Revised: Final Report. Project Number: M/349152/01/1/OCR, RADHP079, KP/2009/32. Unpublished study prepared by JRF America. 244 p. 1360

– Multiresidue Method 47743327 Rockwell, D. (2009) PAM I Multiresidue Protocol Testing of AE 1170437 (Indaziflam) and its Metabolite 1 - Fluoroethyl Triazinediamine. Project Number: M/346696/01/1/OCR, RADHP072, 2008. Unpublished study prepared by Pyxant Labs, Inc. 107 p. 1380

– Storage Stability 47743329 Tim berlake, B. (2009) Storage Stability of AE 1170437 and 1 - Fluoroethyl Triazinediamine in / on Fruit and Nut Matrices. Project Number: M/348221/01/1/OCR, RADHP039. Unpublished study prepared by Bayer CropScience. 138 p. 1480

– Meat, Milk, Poultry, and Eggs 477434 01 Mislankar, S. (2009) Waiver of the Requirement for a Livestock Feeding Study for Indaziflam. Project Number: MEDHP074, M/347958/01/1. Unpublished study prepared by Baye r CropScience. 9 p.

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1500

– Crop Field Trials 47743402 Desmarteau, D.; Fischer, D. (2009) AE 1170437 500 SC - Magnitude of the Residue in/on Pome Fruit (CG 11). Project Number: M/348053/01/1, RADHP029, M/348053/01/1/OCR. Unpublished study prepared by Bayer CropScience. 199 p. 47743403 Krolski, M.; Brungardt, J.; Stoughton, S. (2009) AE 1170437 500 SC - Magnitude

of the Residue in/on Stone Fruit (CG 12). Project Number: M/347950/01/1, RADHP030, M/347950/01/1/OCR. Unpublished study prepared by Bayer CropSci ence. 246 p. 47743404 Brungardt, J.; Krolski, M. (2009) AE 1170437 500 SC - Magnitude of the Residue

in/on Tree Nuts (CG 14). Project Number: M/347601/01/1, RADHP028, M/344601/01/1/OCR. Unpublished study prepared by Bayer CropScience. 197 p. 47743405 F ischer, D.; Harbin, A. (2009) AE 1170437 500 SC - Magnitude of the Residue

in/on Citrus (CG 10). Project Number: M/348968/01/1, RADHP027, M/348968/01/1/OCR. Unpublished study prepared by Bayer CropScience. 273 p. 47743406 Sturdivant, D.; Fischeer, D. (20 09) AE 1170437 500 SC - Magnitude of the

Residue in/on Grapes. Project Number: M/348344/01/1, RADHP033, M/348344/01/1/OCR. Unpublished study prepared by Bayer CropScience. 143 p. 47743407 Tim

berlake, B.; Fischer, D. (2009) AE 1170437 500 SC - Magnitude o f the Residue in/on Olives. Project Number: M/348345/01/1, RADHP037, M/348345/01/1/OCR. Unpublished study prepared by Bayer CropScience. 93 p. 47743432 Mislankar, S. (2009) Proposed Tolerance (Maximum Residue Levels) for

Indaziflam in Grapes, Citrus, Pome Fruits, Stone Fruits, Tree Nuts, and Olives. Project Number: RADHP078, M/348689/01/1. Unpublished study prepared by Bayer CropScience. 24 p. 1520

– Processed Food and Feed 47743408 Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue in/on Sugar cane Processed Commodities. Project Number: M/348217/01/1, RADHP018, M/348217/01/1/OCR. Unpublished study prepared by Bayer CropScience and GLP Technologies. 89 p. 47743409 Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue in/on Apple

Processe d Commodities. Project Number: M/348056/01/1, RADHP011, M/348056/01/1/OCR. Unpublished study prepared by Bayer CropScience and University of Idaho. 81 p. 47743410 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue

in/on Plum Proc essed Commodities. Project Number: M/347951/01/1, RADHP012, M/347951/01/1/OCR. Unpublished study prepared by Bayer CropScience and GLP Technologies. 80 p. 47743411 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue

in/on Orange P rocessed Commodities. Project Number: M/347960/01/1, RADHP013, M/347960/01/1/OCR. Unpublished study prepared by University of Idaho and Bayer CropScience. 85 p. 47743412 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue

in/on Gr ape Processed Commodities. Project Number: M/348051/01/1, RADHP014, M/348051/01/1/OCR. Unpublished study prepared by Bayer CropScience and University of Idaho, Cooperative Extension. 118 p. 47743413 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue

in/on Olive Processed Commodities. Project Number: M/348052/01/1, RADHP015, M/348052/01/1/OCR. Unpublished study prepared by Bayer CropScience and GLP Technologies. 78 p. 1850

– Confined Accumulation in Rotational Crops 47743431 Mislankar, S. (2009) Waiver of the Requirement for a Confined Rotational Crop Study for Indaziflam (MRID 47743414). Project Number: MEDHP072, M/347957/01/1. Unpublished study prepared by Bayer CropScience. 6 p.

### Page 4 of 50 Table of Contents 1.0 Executive Su mmary ................................ ................................ ................................ .......... 6 2.0 Ingredient Profile ................................ ................................ ................................ .............. 8 2.1 Summary

of Proposed Uses ................................ ................................ .................... 8 2.2 Structure and Nomenclature ................................ ................................ ................... 9 3.0 Hazard Characterization/Assessment ................................ ................................ ........... 11 3.1 Hazard and Dose - Response Characterization ................................ ....................... 11 3.1.1 Database Summary ................................ ................................ ................... 11 3 .1.2 Toxicological Effects ................................ ................................ ................ 12 3.1.3 Dose - response ................................ ................................ ........................... 13 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) ................................ . 14 3.3 FQPA Considerations ................................ ................................ ........................... 14 3.3.1 Adequacy

of the Toxicity

Database ................................ .......................... 14 3.3.2 Ev idence of Neurotoxicity ................................ ................................ ........ 15 3.3.3 Developmental Toxicity Studies................................................16 3.3.4 Reproductive Toxicity Studies ..................................................16 3.3.5 Additional Information from Literature Sources ................................ ...... 16 3.3.6 Pre - and/or Postnatal Toxicity ................................ ................................ ... 16 3.4 FQPA Safety Factor for Infants and Children .........................................17 3.5 Hazard Identification and Toxicity Endpoint Selection ................................ ........ 17 3.5.1 Acute Re ference Dose (aRfD) - Females age 13 - 49 ................................ . 17 3.5. 2 Chronic Reference Dose (cRfD) ................................ ............................... 18 3.5. 3 In cidental Oral Exposure (Short - and Intermediate - Term) ....................... 18 3.5. 4 Dermal Absorp tion ................................ ................................ .................... 18 3.5.5 Dermal Exposure (Short - and Intermediate - Term) ........................ 19 3.5.6 Dermal Exposure (L ong - term) ..................................................19 3.5.7 Inhalation Exposure (Short - and Intermediate - Term) ........................19 3.5.8 Inhalation Exposure (Long - term) ..............................................20 3.5. 9 Level of Concern for Margin of Exposure ................................ ................ 20 3.5. 10 Recommendation for Combining Routes of Exposure ............................. 20 3.5.1 1 Classification of Carcinogenic Potential ................................ ................... 20 3.5.12 Acute Toxicity

....................................................................21 3.5.13 Summary

of Toxicological Doses and Endpoints ...........................21 3.6 Endocrine disruption ................................ ................................ ............................. 22 4.0 Public Health and Pesticide Epi demiology Data ................................ .......................... 23 5.0 Dietary Exposure/Risk Characterization ................................ ................................ ..... 23 5.1 Pesticide Metabolism and Environmental Degradation ................................ ...... 26 3 5.2 Dietary

Exposure and Risk ................................ ................................ ................... 29 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ............................ 30 6.1 Residential Handler Exposure ................................ ................................ ............... 30 6.2 Spray

Drift .................................................................................31 6.3 Combine d Residential Exposure ........................................................32 7.0 Aggregate Risk Assessments and Risk Characterization ................................ ............ 32 7.1 Acute Aggregate Risk ................................ ................................ ........................... 32 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ..................... 32

### Page 5 of 50

7.3 Long - Term Aggregate Risk ................................ ................................ .................. 33 7.4 Cancer Risk ................................ ................................ ................................ ........... 33 8.0 Cumulative Risk Characterization/Assessment ................................ ................................ 33 9.0 Occupational Exposure/Risk Pathway ................................ ................................ .......... 34 9.1 Handler Risk ...............................................................................35 9.2 Occupational/Commercial Postapplication Exposure ................................36 10.0 Data Needs and Label Recommendations ................................ ................................ .... 36 10.1 Toxicology ................................ ................................ ................................ ............ 36 10.2 Residue Chemistry ................................ ................................ ................................ 37 10.3 Occupational and Residential Exposure ................................ ............................... 38 11.0 References ................................ ................................ ................................ ........................ 38 Appendix A: Toxicology Assessment ................................ ................................ ....................... 39 A.1 Toxicology

Data Requirements ................................ ................................ ............ 39 A.2 Toxicity

Profiles ...........................................................................40 Appendix B : Table o f Structures ...... ......... .......................................................... 48

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1.0 Executive Summary Indaziflam ([1, 3,5 - triazine - 2,4 - diamine,N - [(1R , 2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - (1 - flu o roethyl )]) is registered as a s elective, pre - emergent and post - emergent alkylazine herbicide for control of many annual grasses and broadleaf weeds in l awns, golf course, sod farms, recreational turf, ornamentals, non - crop areas, Christmas tree farms and forested areas. It is also registered for use as a pre - emergent herbicide for weed control in parks, railroads, utility , industrial and municipal sites. Baye r CropScience has submitted petitions proposing new uses for indaziflam formulated as a 19.05% and 45.05% soluble concentrates (Indaziflam 200 SC and Indaziflam 500 SC) for control of annual grasses and broadleaf weeds in citrus, stone, and pome fruits, grapes, tree nuts, pistachios and olives. Th is is the first food use assessment for this chemical. HED has sufficient information to complete a human health risk assessment . The toxicology

database is considered adequate for conducting a Food Quality Protection Act (FQPA) risk assessment. The scientific quality is relativel y high, and the toxicity is well characterized for all ty

pes of effects, including potential developmental, reproductive, immunologic and neurologic toxicity . The nervous sy st em is a target for indaziflam and neurotoxic effects are being used to assess risks from indazi flam exposure . In daziflam is classified as “Not likely

to be carcinogenic to humans,” and, therefore, is not a concern for cancer effects. HED has evaluated the available data with respect to the F ood Q uality P rotection A ct (FQPA) safety factor and recommends that the FQPA safety factor be reduced to 1X. The submitted residue chemistry data are relatively

complete . HED is recommending for the establishment of permanent tolerances for all of the requested crops. The registration of indaziflam should be conditional pending receipt of acceptable final storage stability and citrus processing studies. Suitable anal ytical methods are available to enforce tolerance s for residues of indaziflam. HED has assessed dietary , residential, and occupational exposures. Risks from these exposures, including aggregate exposures are below the level of concern. Indaziflam contains a s ymmetrical triazine moiety . Based on a comparative review of its structure and toxicological profile , HED determined that indaziflam does not belong in the triazine cumulative assessment group . Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Exposure Database (PHED), and the Outdoor Residential Exposure Task Force (ORETF) Database, have been determined to re quire a review of their ethical conduct, have received that review, and have been determined to be ethicall y conducted. Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered for this human health risk asses sment, in accordance with US Executive Order 12898, Federal Actions to

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Address Environmental Justice in Minority Populations 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 variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exp osures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by USDA under the CSFII, and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Whenever appropriate, non - dietary expos ures based on home use of pesticide products, associated risks for adult applicators, and for toddlers, yo uths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. Proposed Tolerances At this time , tolerances are not required for livestock commodities. For plant commodities, the tolerance expression for indaziflam should read as follows: Tolerances are established for residues of the herbicide indaziflam, including its metabolites and degradates, in or on the commodities in the table below as a result of application of indaziflam. Compliance with the tolerance levels specified below is to be determined b y measuring only indaziflam { 1,3,5 - triazine - 2,4 - diamine, N - [(1 R ,2 S ) - 2,3 - dihydro - 2,6 - dimethyl - 1 H - inden - 1 - yl ] - 6 - [(1 R ,1 S

) - 1 - fluoroethyl ] - } and 1 - fluoroethyl diaminotri azine { 6 - [(1 R ,1 S ) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine} , calculated in terms of indaziflam stoichiometric equivalents , in or on the commodity . A summary

of the petitioned - for tol erances and HED’s recommendations is provided in Table 1 below. With the exception of almond hulls, all residue levels from field trials were below the L imit O f Q uanti t ation (LOQ) and the Tolerance/Maximum Residue L evel ( MRL) Harmonization Spreadsheet was not used to obtain a recommended tolerance level. Table 1 . Tolerance Summary for Indaziflam Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments (correct commodity definition) Fruit, citrus, Group 10 0.01 0.01 -- Fruit, pome, Gro up 11 0.01 0.01 -- Fruit, stone, Group 12 0.01 0.01 -- Nut, tree, Group 14 0.01 0.01 -- Pistachio 0.01 0.01 -- Almond, hulls 0.20 0.15 Spreadsheet - recommended change Grape 0.01 0.01 -- Olive 0.01 0.01 -- Sugarcane, sugar, refined 0.01 0.01 Sugarcane , refined sugar; tolerance without a corresponding U.S. registration

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2.0 Ingredient Profile 2.1 Summary of Proposed Uses Indaziflam is a s elective, pre - emergent alkyl azine herbicide proposed for control of annual grasses and broadleaf weeds in citrus, stone, and pome fruits, grapes, tree nuts, pistachios and olives. This assessment include s two i ndaziflam end - use agricultural products; Indaziflam 200 SC and 500 SC. Both products are formulated as soluble concentrates and contain 19.05 and 45.05% of the active ingredient, indaziflam , respectively . They may b e applied , by

ground equipment only , to the soil as a uniform broadcast or band application . Indaziflam may not be applied by aerial equipment or chemigation. Application may be at anytime throughout the year when the ground is not frozen or covered with snow. It is most effective when adequate moisture is present and the application is followed by rain or an irrigation event p rior to weed seed germination . Table 2.1 provides a summary of the proposed use s . Table 2.1. Summ ary of Directions for Use of Indaziflam . Product EPA Reg. No. Applic ations ,

Timing, Type, and Equip. Applic ation .

Rate (lb ai/A) Max. No.

Applic ations . pe r Season Max.

Seasonal Applic ation . Rate (lb ai/A) PHI

(days) Use Directions and

Limitations Indaziflam 200 SC Herbicide (Soluble Concentrate) 19.05% ai Airblast,

broadcast or b and application to soil; ground equipment only (no chemigation) 0.065 (coars e

soil) 0.085 (fine soil) 2 0.134 (0.089 Grape) 7 (Citrus) a

14 (Others) Avoid direct or indirect

spray contact with crop foliage, green bark, roots, or fruits. Citrus trees must be established for at least 1 year prior to use. Trees/vines other than citr us must be established for at least 3 years prior to use. Do not use on soils with > 40% gravel content. Do not use on soils with open channels or cracks. Allow at least 30 days between applications (90 days in FL and GA). Grapes must be planted at least 1 2 inches deep. Allow at least 12 months between the last application of indaziflam and replanting with a labeled tree or vine Indaziflam 500 SC He rbicide (Soluble Concentrate) 45.05% ai

### Page 9 of 50 crop. Allow at least 24 months between the last indaziflam application and replanting with non labeled crop. Sugarcane (Non - Domestic - Im ported) Broadcast spray, pre - or post - crop emergence, pre - emergence for weeds; ground or aerial equipment 0.107 lb

a.i./A (120 g a.i./ha) 1 0.107 lb a.i./A (120 g a.i./ha) 90 No ne that are relevant

a Note that Citrus field trials were conducted at 14 - day PHI or longer. See Section 5.1.9 ( Crop Field Trials and Processing) for further discussion. 

### 2.2 Structure and Nomenclature Table 2.2 N omenclature Com pound AE 1170437

C H 3 C H 3

N H N N N N H 2 F C H 3

Common name Indaziflam Com pany experimental name AE 1170437 IUPAC name N - [(1 R ,2 S ) - 2,6 - Dimethyl - 2,3 - dihydro - 1 H - inden - 1 - yl] - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine CAS name 1,3,5 - triazine - 2,4 - diamine, N - [(1 R ,2 S ) - 2,3 - dihydro - 2,6 - dimethyl - 1 Hinden - 1 - yl] - 6 - [(1 R ) - 1 - fluoroethyl] - CAS # 730979 - 19 - 8 Com pound AE 117043 8 N N N N H N H 2

C H 3 C H 3

C H 3 F

Common name Indaziflam Com pany experimental name AE 117043 8 IUPAC name N - [(1 R ,2 S ) - 2,6 - Dimethyl - 2,3 - d ihydro - 1 H - inden - 1 - yl] - 6 - [(1 S

) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine CAS name 1,3,5 - triazine - 2,4 - diamine, N - [(1 R ,2 S ) - 2,3 - dihydro - 2,6 - dimethyl - 1 Hinden - 1 - yl] - 6 - [(1 S

) - 1 - fluoroethyl] -

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CAS # 730979 - 32 - 5 Com pound 1 - Fluoroethyl diaminotriazine (FDAT) N N N N H 2 N H 2

F C H 3

Common name Indaziflam - diaminotriazine Com pany experimental name AE 1170437 - diaminotriazine IUPAC name 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine CAS name 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine CAS # Unavailable 

### Due to the presence of three chiral carbons in the indaziflam structure, there are eight possible isomers for this herbicide. Based on the product chemistry review of the manufacturing use product (MUP) b y RD (H. Mukhoty, 12/1/2008, D356393), the registr ant is declaring the active ingredient to consist of only isomers “A” (AE 1170437) and “B” (AE 1170438) with concentrations of about 92% and 3%, respectivel y. Two later RD reviews (S. Malak, 9/22/09, D367608 and 3/18/10, D372513) report additional statements of formula with similar levels of isomer A (92 - 93%) and isomer B (2.4 - 2.9%). The first chemical name appearing above in Table 2.2 (N - [(1R,2S)...] - 6 - [(1R) ....diamine) represents that of the A isomer. The second name is for isomer B and is identical to A with the exception of the stereochemistry at the fluorine - bearing carbon (i.e., ... - 6 - [(1S)...diamine). The remaining six isomers are present at significantl y lower levels and are considered to be impurities. The batches used for dosing in the toxicology s tudies had >90% isomer A, about 1 - 3% isomer B, and negligible (<1%) levels of the remaining six isomers. These isomer contents are appropriate for the above described composition of indaziflam 2.3 Physical and Chemical Properties Table 2. 3 Physicochemical Properties of Indaziflam (TGAI Unless Otherwise Noted) Parameter Value Reference Melting point/range 183 - 184 o C indaziflam (pure substance) Petition Administrative Materials pH (23 °C) pH = 6.5 indaziflam (pure substance) pH = 5.1 indazifl am

(technical substance) Density 1.23 g/cm3 at 20 °C (both pure and technical substance) Water solubility ( g/L at 20 °C) pH 4: 0.00 44 pH 9: 0.00 28 Distilled water (pH 6.6 - 6. 9): 0.00 28 Solvent solubility (g/L at 20 °C) Acetone: 55 Acetonitrile: 7.6 Dichloromethane: 150 Dimethyl sulfoxide: >250 Ethanol: 13.0 Ethyl acetate: 47 Heptane: 0.032 Toluene: 4.3

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Table 2. 3 Physicochemical Properties of Indaziflam (TGAI Unless Otherwise Noted) Parameter Value Reference Vapor pressure 2.5 x 10 - 8 P a at 20 °C or 1.875 x 10 - 10 mm Hg 6.8 x 10 - 8 P a at 25 °C or 5.1 x 10 - 10 mm Hg 6.9 x 10 - 6 P a at 50 °C or 5.2 x 10 - 8 mm Hg Henry’s la w constant 2.69 x 10 - 6 [Pa x m3/mol] at 20 °C Dissociation constant (pKa) 3.5 Octanol/water partition coefficient Log (KOW) pH 2: 2.0 pH4, pH7 and pH9: 2.8 UV/visible absorption spectrum methanol (nm)  max1 = 213 nm / A = 1.428  max2 = 268 nm / A = 0.197  max3 = 291 nm / A = 0.019 

### 3.0 Hazard Characterization/Assessment 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary Studies considered for this assessment included acute lethality (oral, dermal and inhalation routes); primary

eye and dermal irritation, dermal sensitization, subc hronic oral toxicity (rat, mouse and dog), rat 28 - day dermal toxicity , rat acute and subchronic neurotoxicity, dog chronic toxicity, rat chronic toxicity /carcinogenicity, mouse carcinogenicity, developmental toxicity (rat and rabbit), rat two - generation reproductive toxicity (with an additional special non - guideline study evaluating sexual maturation in rats exposed during earl y development to the triazine - ring metabolite BCS - AA10365, or FDAT ), rat developmental neurotoxicity, rat immunotoxicity, genotoxici ty , rat general metabolism (Tier 1 and Tier 2), in vivo rat dermal absorption and in vitro human and rat dermal absorption. The database is considered complete with the possible exception of a 28 - or 90 - day inhalation toxicity study in the rat. The Agency

is in the process of evaluating expert advice and input on issues related to volatilization of pesticides and route - to - route extrapolation using oral studies for inhalation exposure assessment from its Federal Insecticide, Fungicide, and Rodenticide Ac t Scientific Advisory

Panel (SAP) in December, 2009 (final report of March 2, 2010; http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ) and determining the approp riate toxicity

data needed to assess inhalation exposure. The requirement of an inhalation toxicity study will be determined once scientific guidance and policies on inhalation toxicity have been established. 3.1.1.1 Mode of action, metabolism, toxicokinetic data Indaziflam is a broad - spectrum, pre - and/or post - emergent herbicide of the fluoroalkyltriazine class. It affects germination of seeds of grasses and broadleaf weeds by inhibitin g cell wall biosy nthesis and affecting meristematic stem growth. The exact mode of toxicity in mammals is unknown. Metabolism in the rat is discussed below in Section 3.2.

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3.1.2 Toxicological Effects The nervous sy stem is a target for toxicity in rats and dogs . In repeated - dose studies, the dog was the more sensitive species, showing the lowest NOAELs among all available studies, based on neuropathology

(degenerative nerve fibers in the brain, spinal cord and sci atic nerve). In the rat, focal/multifocal vacuolation of the median eminence of the brain and the pituitary pars nervosa was observed at higher doses. Clinical signs of neurotoxicity were observed in both species in several studies, which included rat adult and developmental neurotoxicity studies, including the rat acute neurotoxicity study . Ophthalmologic effects were also seen in the rat. In the developmental neurotoxicity study , decreased motor activity was observed in 21 - day

old male pups but was n ot observed in females at later times. Additional details on neurotoxic effects are found in Section 3.3.2. In the rat and mouse, effects on the kidney were observed following chronic exposure. Female rats had an increased incidence of dark kidney and basophilic renal tubules. Males in the reproductive toxicity

study showed increased kidney weights and incidence of hyaline degeneration and tubular regeneration. In the mouse, males showed decreased kidney weights and increased incidences of collecting duct and pelvic epithelial hy perplasia, papillary

necrosis and intratubular yellow - brown material. Liver cell hypertrophy was observed in the rat following chronic exposure but was considered an adaptive response. In males, white foci were also observ ed. In females, livers were enlarged and showed an increased incidence of macrovacuolation and multinucleated hepatocy tes with aniso karyosis. The thy roid was affected by

treatment only

in male rats. Increased follicular cell hypertrophy and colloid alteration were observed. Statistically significant increases in TSH were observed at Week 3, but not at Week 13. There were no significant changes in levels of T3 or T4. Although treatment - related, the thyroid changes were not considered of concern for d evelopment because they appeared to be secondary to liver effects (and induction of liver metabolic enzy mes), they were seen at high doses relative to the endpoints selected for risk assessment, and other thy roid hormone levels (T3, T4) did not show change s. Additional effects observed following chronic exposure included atrophied or small seminal vesicles in male rats and glandular erosion/necrosis in the stomach and blood - filled ovarian cy sts/follicles in female mice. However, these effects occurred at higher doses than those at which neurotoxicity

was observed in the dog. Decreased body weight gain was observed in most studies following exposure to indaziflam. There was no evidence of immunotoxicity in the available studies, which included a guideline immunotoxicity study in the rat. No sy stemic effects were observed in the rat following a 28 - day dermal exposure period. In the rat developmental toxicity study , decreased fetal weight was observed in the presence of maternal effects that included d ecreased body weight and clinical signs of toxicity . No developmental effects were observed in rabbits up to maternally toxic dose levels. Decreased pup weight and delay s in sexual maturation (preputial separation in males and vaginal patency in females) were observed in the rat two - generation reproductive toxicity study , along with clinical

### Page 13 of 50

signs of toxicity, at a dose causing parental toxicity that included clinical signs and decreased weight gain. In the developmental neurotoxicity study , transiently decreased motor activity (PND 21 only) in male offspring was observed and was considered a potential neurotoxic effect. It was ob served at a dose that also caused clinical signs of neurotoxicity along with decreased body weight in maternal animals. Indaz iflam showed no evidence of carcinogenicity in the two - ye ar dietary rat and mouse bioassay s. All genotoxicity studies that were conducted on indaziflam were negative. 3.1.3 Dose - response For acute dietary

exposure, an acute reference dose (aRfD) of 0.50 mg/kg/day was selected for assessment of all populations, based on a NOAEL of 50 mg/kg/day in the rat acute neurotoxicity study with decreased motor and locomotor activities in females observed at 100 mg/kg/day . This endpo int is a single - dose effect and is appropriate for the populations of concern. Although the rat developmental toxicity study had a lower developmental NOAEL (25 mg/kg/day), the acute neurotoxicity

NOAEL of 50 mg/kg/day , with a LOAEL of 100 mg/kg/day, is c onsidered protective for all populations including potentially pregnant females because of the large spread in the dose spacing in the rat developmental study (i.e., NOAEL = 25 and the LOAEL = 200 mg/kg/day). Furthermore, our confidence in the use of the neurotoxicity endpoint is supported by the observed mild effects at the rat developmental LOAEL (200 mg/kg/day), which were limited to pup body

weight decrements of <10%. For chronic dietary

exposure, a chronic reference dose (cRfD) of 0.02 mg/kg/day was selected for assessment of all populations, based on a NOAELof 2.0 mg/kg/day with evidence of nervous sy stem microscopic effects observed at the LOAEL of 6 and 7 mg/kg/day in males and females respectivel y in the dog chronic dietary study . This provided the most sensitive endpoint available for chronic dietary exposure: rat and mouse chronic exposure NOAEL s were ≥12 mg/kg/day . For short - and intermediate - term residential and occupational exposure scenarios involving incidental oral and inhalation exp osure, the NOAEL of 7.5 mg/kg/day from the dog oral subchronic toxicity

study was selected. The LOAELof 15 mg/kg/day was based on nervous sy stem microscopic degenerative effects. Developmental toxicity studies in the rat and rabbit were also available f

or short - term exposure, but had higher NOAELs (25 mg/kg/day) and, therefore were not considered protective of potential neurotoxicity . The rat subchronic neurotoxicity

study also had a significantl y higher NOAEL (244 mg/kg/day), as did the developmental n eurotoxicity study (maternal and developmental 84 mg/kg/day). The chronic dog study was considered for intermediate - term exposure due to greater incidence and severity of lesions at lower doses with continued exposure, but was not selected because, at one ye ar, the neuropathology

at the L OAEL was minimal. Furthermore, based on the proposed use patterns, continu ous daily

exposures occurring for more than 90 day s are not expected to occur. Although a 28 - day

dermal toxicity

study in the rat was available and showed no toxicity up to the limit dose, including neuropathology or clinical signs, it was not selected for dermal risk assessment because the dog showed considerabl y greater sensitivity for neuropathology

than the

### Page 14 of 50

rat in the oral studies. The NOAEL from the subchronic dog study was therefore selected to be protective of potential neurotoxicity, but is considered a conservative endpoint due to the bolus (gavage) dosing method employed in the dog subchronic study (similarly , in the chronic dog study an imals would consume their treated diets in a relativel y short time period). Long - term dermal and inhalation exposure are not expected; therefore, endpoints were not selected. 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) The metabolism of indaziflam has been evaluated in the rat using indaziflam labeled with 14 

### C at either the indane or the triazine ring. Indaziflam is rapidly and completel y absorbed. Radioactivity

wa s detected in the blood within 5 minutes of dosing. Absorption was estimated at 90% or greater of administered dose, based on bile cannulation experiments. Absorption was slightly more rapid in females than males. Radioactivity was rapidl y excreted (app roximately 90% of dose b y 24 hrs postdosing). Excretion was predominantly fecal at the high dose (1:10 urine:feces). However, at the low dose, urinary excretion was also prominent (1:1 to 1:2 urine:feces), indicating absorption from the gastrointestinal tract was overwhelmed at the higher oral doses. Radioactivity was not retained at significant levels in the tissues by 3 day s’ postdosing (less than 0.2 to 0.3% of dose), with the highest levels found in the gastrointestinal tract, liver, skin and thyr oid . Metabolism was extensive with only 2 - 12% of the dose excreted in feces as unchanged parent, and occurred primarily via oxidative processes. The major metabolite in the rat was the carbox yl ic acid metabolite of indaziflam, which was largel y excreted in the bile but also found in urine. Other compounds that were identified as major metabolites in combined excreta in one or more groups were 3 - hydrox yi ndane acid, 3 - hydroxyindane acid epimer, dihydroxy , hydrox y glucuronic acid, 3 - ketoindane acid, and hydrox ye thyl acid metabolites. The fluoroethyl diaminotriazine (FDAT) metabolite was identified at low levels (1.18 to 1.69% of administered dose) in the triazine - labeled groups. Some metabolite profile differences were observed depending on the site of the radiolabel. For example, the dihydrox y and hydrox ye thyl acid and acid conjugate metabolites were found in the indane - labeled group, but not the triazine - labeled group. In the bile - duct - cannulated group, the 3 - ketohydroxy

methyl metabolite was identified in feces but was not found in the mass balance groups. Parent compound was found at higher levels in the triazine - labeled mass balance group than the indane - labeled group, but was present at higher levels in the indane - labeled group in the bile - duct - cannulation experiments. Metabolite profiles in males and females were comparable, with some minor qualitative differences, but females excreted significantl y less unchanged parent compound. 3.3 FQ PA Considerations 3.3.1 Ade quacy of the Toxicity Database The database is considered adequate for assessment of potential sensitivity of infants and children to the effects of indaziflam. Acceptable rat and rabbit developmental tox icity , rat two generation reproductive toxicity, rat developmental neurotoxicity, rat acute and subchronic neurotoxicity

screening and immunotoxicity studies have been submitted .

### Page 15 of 50

3.3.2 Evidence of Neurotoxicity Neurotoxicity

was observed in the dog and the rat. In the dog, axonal nerve fiber degeneration was observed in the brain, spinal cord and sciatic nerve following subchronic and chronic exposure at the LOAELs ( 15 mg/kg/day in both sexes in the subchronic stu dy and 6 and 7 in males and females, respectively in the chronic study). The study NOAELs were 7.5 mg/kg/day for the subchronic and 2 mg/kg/day for the chronic study . No clinical signs of toxicity were observed at doses up to 11 and 15 mg/kg/day (chronic/subchronic studies). High dosed dogs in the sub chronic study (30 mg/kg/day) were prematurely terminated due to excessive clinical signs including ataxia, tremors, decreased pupil response , seizures and other findings. In the rat, a marginal decrease in motor/locomotor activity was observed in females in the acute neurotoxicity

study at 100 mg/kg (NOAEL = 50 mg/kg). Additional findings at higher doses include tremors, increased reactivity, decreased activity, and urine, oral or perianal staining. Male s also showed nerve fiber degeneration of the gasserian ganglion, sciatic nerves and tibial nerves. Similar clinical and motor activity changes were observed in the subchronic neurotoxicity

study , although no neuropathology was observed. Decreased motor and locomotor activity in females and clinical signs in both sexes (including tremors, repetitive chewing movements and perianal/lacrimal staining) were reported in the subchronic neurotoxicity study at a higher dose (about 580 mg/kg/day with a NOAEL of 24 4 mg/kg/day) than the acute study , probably as a result of gavage vs. dietary exposure. The clinical signs were consistent with neurotoxicity, but also could have been due to sy stemic toxicity . In addition, similar clinical findings were seen in P and F1 generation animals in the reproductive toxicity study , at doses ≥318 mg/kg/day . Clinical signs of neurotoxicity following chronic dietary exposure to the rat at dietary concentrations ≥12 mg/kg/day were numerous and included dilated pupil, reduced motor activity , movement and posture abnormalities, soiling and staining, tremors, reduced alertness, labored, rapid or noisy

respiration, piloerection and ophthalmological abnormalities, including mydriasis, absent papillary reflex and pale fundus. At terminal sacrifice, focal/multifocal vacuolation of the median eminence in the brain and of the pars nervosa was seen in males and females and peripheral or bilateral retinal atrophy in females. Neurotoxicity was not observed in the mouse. In a developmental n eurotoxicity study on indaziflam, pregnant rats were administered indaziflam at dietary

concentrations of 0, 150, 1000 or 7000 ppm ; equivalent to average daily intakes of 0, 13, 83.8 or 432 mg/kg/day . The high dose, originally at 7000 ppm, was reduced to 4000 ppm on LD 4. Maternal and offspring toxicity were observed onl y at the high dose of 432 mg/kg/day . Maternal clinical signs (daily observations and/or FOB) include coarse tremor, dilated pupils or dilated pupils that were unresponsive to penlight, n asal staining and repetitive chewing movements. Maternal body weight and weight gain were decreased during gestation and lactation. The number of litters was reduced by 17%. In the offspring, body weights were also decreased in both sexes from PND 1 through lactation; postweaning males also had lower body weights. A statistically

significant decrease in motor activity (29%) on PND 21 was observed in males onl y athigher doses; although no changes were seen at other assessment times or in females, it was considered treatment - related because it was statistically significant and outside the laboratory

historical control range.

### Page 16 of 50

3.3.3 Developmental Toxicity Studies Acceptable developmental toxicity studies in the rat and rabbit are available . In the rat, matern al body weight gain and food consumption w ere decreased at 200 mg/kg/day . Decreased fetal body weight was observed at 200 mg/kg/day . The maternal and developmental NOAEL was 25 mg/kg/day . In the rabbit, decreased maternal body weight gain and food consumption, and macroscopic liver changes in one doe (pallor, white foci) were observed at 60 mg/kg/day , but no developmental effects were observed. The maternal NOAEL was 25 mg/kg/day and the developmental NOAEL was 60 mg/kg/day . The developmental neurotoxi city study is described above in Section 3.3.2. 3.3.4 Reproductive Toxicity Studies In the reproductive study parental toxicity was observed onl y at the high dose (≥317 mg/kg/day) and includes coarse tremors in females during premating, gestatio n and lactation , decreased body weight gain and food consumption in both sexes and kidney effects in males (increased absolute and relative weight and hyaline degeneration/regeneration). Offspring toxicity was also observed onl y at the high dose. Clinical signs of toxi city in F1 pups included perianal, urine and nasal stains, tremors, increased reactivity and activity , myoclonus, and diarrhea but no signs were seen in F2 pups. F1 pup weights were decreased through the postnatal period for males and females. Reproductiv e toxicity was observed as delay s in achieving sexual maturation at the high dose, as measured b y preputial separation (males) and vaginal opening (females), in the F1 and F2 offspring. The NOAELfor parental, offspring and reproductive toxicity was 69.3 mg/kg/day . 3.3.5 Additional Information from Literature Sources No published studies, relevant to human hazard resulting from use of indaziflam, were identified. 3.3.6 Pre - and/or Postnatal Toxicity 3.3.6.1 Determination of Susceptibility There was no evidence of increased susceptibility (qualitative or quantitative) for pre - and/or postnatal effects in developmental toxicity studies in the rat and rabbit , the rat developmental neurotoxicity

study or the rat two - generation reproductive toxicity study . There is no concern and there are no residual uncertainties for qualitative or quantitative p re - and/or postnatal susceptibility

to indaziflam. This is based on the completeness of the database, lack of evidence of increased susceptibility, and the selection of endpoints with low NOAELs that are adequatel y protective of potential developmental ef fects. Delayed sexual maturation in offspring was observed at the highest dose of the reproductive toxicity study in the presence of maternal toxicity . Effects in offspring in the developmental neurotoxicity study (decreased motor activity in males on PND 21 ) were well characterized and were onl y observed at doses that caused maternal neurotoxicity . Although treatment - related thy roid histological changes (following subchronic or chronic exposure) and transiently increased TSH (at Week 3 but not Week 14) were observed in male rats, they are not of concern for developmental effects because they were only observed in the males, were observed at a high dose relative to the selected regulatory

### Page 17 of 50

endpoints, and appear to be secondary to liver effects. 3.4 FQ PA Saf

ety Factor for Infants and Children HED recommends reduction of the FQPA safety factor to 1X . The toxicity database for indaziflam is complete, including the required studies that characterize potential susceptibility of infants and children. There was n o evidence of increased quantitative or qualitative pre - and/or postnatal susceptibility ; developmental effects in the rat were observed only at high doses in the presence of maternal/parental toxicity . Although indaziflam causes neurotoxicity, the effect s are well characterized and served as the basis for endpoint selection. Therefore, the risk assessment is protective of potential neurotoxicity and other effects which occurred at higher doses. Conservative, upper - bound assumptions were used to determin e exposure through food, drinking water and residential sources, such that these exposures have not been underestimated. Although the dog is the more sensitive species, the results of the rat developmental neurotoxicity study , which thoroughl y examined po tential effects to the developing nervous sy stem following pre - and post - natal exposure, showed onl y marginal effects in offspring (slightl y decreased motor activity , absolute brain weight) at relativel y high (and maternally toxic) doses and indicates that increased susceptibility does not occur. 3.5 Hazard Identification and Toxicity Endpoint Selection 3.5.1 Acute Reference Dose (aRfD) – All Populations Including Infants and Children an d Females Age 13 - 49 Stud y Selected : Acute Neurotoxicity

– Rat MRID Nos : 4 7443310 Dose and Endpoint for Risk Assessment : NOAEL= 50 mg/kg, based on decreased motor and locomotor activity in females at 100 mg/kg. Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intraspecies variability) Acute RfD = )

( 100 / 50 UF kg mg = 0.50 m g/kg 

### Comments about Study/Endpoint/Uncertainty Factors: The selected NOAEL of 50 mg/kg is from a study of the appropriate route and duration. The decreases in motor and locomotor activity

are considered potential single - dose effects because they were observed within the first hours following dosing. The endpoint is protective of the decreases in m aternal body weight gains seen within the first three day s of exposure in the developmental rat (25/200 mg/kg/day , NOAEL/LOAE L) and rabbit (25/60 mg/kg/day , NOAEL/L OAEL) toxicity studies, but which were considered questionable as an endpoint due to variabi lity in the data. No other acute effects were observed in the database. The endpoint is also protective of potential developmental effects, based on the lack of observed increased pre - and/or postnatal susceptibility and higher LOAELs observed in develop mental, reproductive, neurotoxicity, developmental neurotoxicity and immunotoxicity

studies. Although the rat developmental toxicity study ’s developmental NOAEL was lower (25 mg/kg/day), the neurotoxicity NOAEL of 50 mg/kg/day is

### Page 18 of 50

considered protective be cause the rat developmental L OAEL ( 7 - 9% decrease in fetal body weight) was significantly greater (200 mg/kg/day) and the effects were relatively mild at that dose and unlikely to occur after a single dose. 3.5.2 Chronic Reference Dose (cRfD ) Study Selected : Chronic Toxicity (Dietary)

– Dog MRID No : 4 7743294 Dose and Endpoint for Risk Assessment : NOAEL= 2.0 mg/kg/day , based on nerve fiber degeneration in the brain, spinal cord and sciatic nerve at 6 and 7 mg/kg/day (M and F respectivel y). Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intraspecies variability)

Chronic RfD = ) ( 100 / / 0 . 2 UF day kg mg = 0.0 2 mg/kg/day 

### Comments about Study/Endpoint/Uncertainty Factors: The NOAEL selected fo r this risk assessment represents the lowest available NOAEL for effects of indaziflam following long - term dietary administration. The RfD is protective of potential developmental effects, based on the lack of observed increased pre - and/or postnatal susceptibility

and significantly

higher NOAELs observed in developmental, reproductive, neurotoxicity, developmental neurotoxicity and immunotoxicity

studies. 3.5.3 Incidental Oral Exposure (Short- and Intermediate - Term) Study Selected : Subchronic Toxicity (Gavage)

– Dog MRID No : 47743289 Dose and Endpoint for Risk Assessment : NOAEL= 7.5 mg/kg/day , based on brain, spinal cord and sciatic nerve degenerative lesions at 15 mg/kg/day . Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the most sensitive NOAELavailable from an oral study of appropriate exposure duration (90 - day s) for short - term (up to 30 days) and intermediate - term (up to 6 months) exposure via the oral route. The selected endpoint is protective of potential postnatal developmental toxicity, based on the lack of observed postnatal susceptibility and signific antl y higher NOAEL s for postnatal toxicity in the developmental neurotoxicity and the two - generation reproductive toxicity studies. 3.5.4 Dermal Absorption In addition to a 28 - day

study evaluating dermal toxicity in the rat, an in vivo dermal absorption study

in the rat and in vitro dermal absorption studies in the rat and human were submitted. The data demonstrated an inverse relationship between dosing concentration and percent absorption. Based on in vivo dermal abs orption observed in the rat and in vitro comparative rat:human absorption data, an estimated human dermal absorption factor (DAF) of 7.3% was obtained.

### Page 19 of 50

The human DAF was calculated as follows (all absorption values adjusted for recovery): (1) in the rat in vivo dermal absorption study , 27.39% of the applied dose was absorbed at 24 hrs postexposure (actual exposure time 8 hrs) using an application of 0.0005 mg/cm2 

### ; (2) in vitro exposure of microtomed rat skin under the same exposure and assessment conditi ons gave a dermal absorption of 22.40%; (3) the ratio of the in vitro to the in vivo absorption is 0.82 (22.4/27.39) and therefore is close to 1, indicating that the in vitro data is predictive of in vivo absorption; (4) based on this ratio, a DAF for hum ans may be calculated using in vitro human dermal absorption (5.975%, adjusted for recovery) observed in vitro under the same exposure conditions. The DAF for humans is therefore 5.975%/0.82 = 7.3%. 3.5.5 Dermal Exposure (Short- Term, 1 - 30 days, and Intermedia te - Term, 1 - 6 months ) Study Selected : Subchronic Toxicity- Dog MRID No : 47743289 Dose and Endpoint for Risk Assessment : NOAEL= 7.5 mg/kg/day , based on degenerative brain, spinal cord and sciatic nerve fiber lesions at 15 mg/kg/day . Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the most sensitive NOAELavailable from a study of appropriate exposure duration (90 day s) for short - and inter

mediate - term exposure. The subchronic oral dog study was selected over other studies because the dog was the most sensitive species for neurotoxicity and had the lowest overall NOAEL. Although a 28 - day dermal toxicity

study in the rat showed no effects at the limit dose (including neuropathology), it was not selected as an endpoint for this exposure scenario due to the significantly greater sensitivity

for neurotoxicity

seen in the dog relative to the rat. Neurotoxic effects in the dog were identified at doses that were 10 - 20 times lower than in the rat. The endpoint is nonetheless considered conservative because the effects in the dog were observed following gavage dosing, in contrast to a relativel y slower dermal absorption rate. For route - to - route extrapolation, dermal absorption of 7.3% relative to oral absorption was used, estimated from human and rat in vitro and rat in vivo dermal absorption. 3.5.6 Dermal Exposure (Long - Term, >1 year) Long - term dermal exposures are not anticipated from occupational ac tivities. 3.5.7 Inhalation Exposure (Short- Term, 1 - 30 days and Intermediate - Term, 1 - 6 months) Study Selected : Subchronic Toxicity- Dog MRID No : 47743289 Dose and Endpoint for Risk Assessment : NOAEL= 7.5 mg/kg/day , based on degenerative brain, spinal cord and sciatic nerve fiber lesions at 15 mg/kg/day . Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the most sensitive NOAELavailable from a study of appropriate exposure duration (90 - day s)

### Page 20 of 50

for short - and intermediate - term exposure. The subchronic oral dog study was selected over other studies because the dog was the most sensitive species for neurotoxicity and overall lowest NOAEL. For rout e - to - route extrapolation, inhalation absorption of 100% is assumed relative to oral absorption because there are no data on inhalation absorption and a route - specific inhalation study is not available. 3.5.8 Inhalation Exposure (Long - Term) Long - term inhalatio n exposure scenarios are not anticipated for occupational exposures. 3.5.9 Level of Concern for Margin of Exposure Table 3.5. 9. Summary of Levels of Concern for Risk Assessment. Route Short- Term (1 - 30 Days) Intermediate - Term

(1 - 6 Months) Long - Term

(> 6 Months) Occupational (Worker) Exposure Dermal 100 100 NA Inhalation 100 100 NA Residential Exposure Dermal 100 100 NA Inhalation 100 100 NA Oral 100 100 NA NA = not applicable 3. 5.10 Recommendation for Combining Routes of Exposure for Risk Assessments When there are potential occupational and residential exposures to the pesticide, the risk assessment must address exposures from three major sources: oral, dermal and inhalation exposures and determine whether the individual exposures can be combined if they have the same toxicological effects. Since the dermal , inhalation and oral endpoints are based on the sam e effects (neurotoxicity) these routes of exposure may be combined for purposes of this risk assessment. 3.5.11 Classification of Carcinogenic Potential There was no evidence of carcinogenicity observed in the two - ye ar dietary rat or mouse carcinogenicity

bioassays. Genotoxicity studies (reverse gene mutation in bacteria, forward gene mutation in mammalian cells and in vitro and in vivo chromosomal aberration assay s) were negative. Based on the lack of evidence of carcinogenicity or genotoxicity , HED classified indaziflam as “Not likely to be carcinogenic to humans.”

### Page 21 of 50

3.5.12 Acute Toxicity Indaziflam shows low acute toxicity by all routes of exposure (Toxicity Category I II, oral and dermal and Category

IV, inhalation) and is not an ocular or dermal irritant or a dermal sensitizer. 3.5.13 Summary of Toxicological Doses and Endpoints for Use in Human Risk Assessments of Indaziflam Table 3.5.13. Summary of Toxicological Doses and Endpoints fo r Indaziflam for Use in Dietary and Non - Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects Ac ute Dietary (All Po pulations, including Infants and Children and Females 13 - 49 years of age) NOAEL =

50 mg/kg/day UF A= 10X

UF H= 10X FQPA SF= 1X Ac ute RfD =

0.5 mg/kg/day aPAD = 0.5 mg/kg/day Ac ute oral neurotoxicity in the rat

LOAEL = 100 mg/kg/day, based on decreased mo tor and locomotor activity in females. Chronic Dietary (All Populations) NOAEL = 2

mg/kg/day UF A= 10X

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

0.02 mg/kg/day cPAD = 0.02 mg/kg/day Chronic oral (dietary) toxicity in the dog

LOAEL = 6/7 mg/kg/day M/F, based o n nerve fiber degenerative lesions in the brain, spinal cord and sciatic nerve. Incidental Oral, Short - term

(1 to 30 days) and Intermediate - term (1 to 6 months) NOAEL =

7.5 mg/kg/day UF A=10X

UF H=10X FQPA SF = 1X Residential

LOC for MOE = 100 Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings in the brain, spinal cord and sciatic nerve. Dermal, Short - term (1 to 30 days) and Intermediate - term (1 to 6 months) NOAEL =

7.5 mg/kg/day DAF = 7.3% UF A=10X

UF H=10X FQPA SF = 1X Residential

LOC for MOE = 100 Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings in the brain, spinal cord and sciatic nerve. Dermal, Long Term (>6 months) Not required for this assessment (exposure is seasonal; long - term dermal exposure scenarios

are not anticipated). Inhalation, Short term (1 to 30 days) and Intermediate term (1 to 6 mo nths) NOAEL =

7.5 mg/kg/day Inhalation absorption assumed to be 100% (default) relative to o ral. UF A=10X

UF H=10X FQPA SF = 1X Residential

LOC for MOE = 100 Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings in the brain, spinal cord and sciatic nerve. Inhalation, Long term (>6 months) Not required for this assessment (exposure is seasonal; long - term inhalation exposure scenarios

are not anticipated). Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans”

### Page 22 of 50

Point of Departure (POD) = A data point or an e stimated 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 obs erved 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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor 

### Table 3.5.13 Summary of Toxicological Doses and Endpoints for Indaziflam 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) NOAEL =

7.5 mg/kg/day DAF = 7.3% UF A=10X

UF H=10X Occupational

LOC for MOE = 100 Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings in the brain, spinal cord and sciatic nerve. Dermal, Long Term (>6 months) Not required for this assessment (exposure is seasonal; long - term occupational exposure scenarios are not anticipated).

Inhalation Short Term (1 to 30 days) and Intermediate Term (1 to 6 mo nths) NOAEL=

7.5 mg/kg/day

. Inhalation absorption assumed to be 100% (default) relative to oral. UF A=10X

UF H=10X Occupational LOC

for MOE = 100 Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings in the brain, spinal cord and sciatic nerve. Inhalation Long Term (> 6 mo nths) Not required for this assessment (exposure is seasonal; long - term occupational exposure scenarios are not anticipated). Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” Point of Departure (POD) = A dat a 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). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor. 

### 3.6 Endocrine disruption As required under FFDCA section 408(p) , EPA has develop ed 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 employs 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

### Page 23 of 50

chemical substance to interact with the estrogen, androgen, or thyroid (E , A , or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the 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 designed to identity 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. EPA is issuing test order s/data call - ins for the first group of 67 chemicals, which 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 scenarios. This list should not be construed as a list of known or likely

endocrine disruptors. Indaziflam 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 screen 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 There are no public health , pesticide epidemiology or incident data to report at this time . 5.0 Dietary Exposure/Risk Characterization ( Indaziflam. Petition for the Establishment of Permanent Tolerances and Registration for Use on Pome Fruits, Stone Fruits, Citrus, Tree Nuts (including Pistachios), Grapes, and Olives (PP 9F7589); and a Tolerance without a Domestic Registration for Sugarcane (PP 9E7588). Summary of Analytical Chemistry and Residue Data; D374105; E. Holman ; September 9 , 2010) 

### 5.1 Pesticide Metabolism and Environmental Degradation 5.1.1 Metabolism in Primary Crops Metabolism studies were performed in three primary crops, apples, grapes and sugarcan e. In plants, the metabolism of indaziflam is relatively uncomplicated with parent indaziflam and the fluoroethyldiaminotriazine ( FDAT ) metabolite being the onl y indentified compounds . The metabolism data are sufficient to support the requested uses; ho wever, if uses in other crops are sought in the future, additional studies depicting the nature of the residue may be necessary

( e.g. , root/tuber vegetables, small grain). The residue definitions based on the available data are summarized in Table 5.1.7 .

### Page 24 of 50

5.1.2 Metabolism in Livestock M etabolism data depicting the residue profile in the lactating goat w ere submitted reflecting indaziflam labeled with 14 

### C at either the indane or the triazine ring , with separate studies being submitted for each specific ring. Based on the available information, indaziflam appear s to undergo significant oxidative metabolism in ruminants. There are a number of significant (> 10% TRR) metabolites, depending on the commodity being examined, with most consisting of some leve l of increased hydroxylation relative to the parent compound . 5.1.3 Metabolism in Rotational Crops Baye r Crop Science has requested a waiver for the requirement of a confined rotational crop study for indaziflam. Given that none of the target crops are rotated, HED waives the need for a confined rotational crop study at this time. Should uses for indaziflam on rotated crops be sought in the future, a confined rotational crop study will likely

be required to support such uses. 5.1. 4 Environmental Degrad ation Field and laboratory

data indicate that indaziflam and its degradates have a potential to leach to ground water, particularly FDAT. Indaziflam is classified as moderately mobile; however, transformation products of indaziflam are mobile to highly m obile and were detected in field studies at depth. Further, data show that indaziflam is persistent in anaerobic soil and anaerobic aquatic s ys tems. There are no data available on the anaerobic degradation of the transformation products of indaziflam. Key lines of evidence show that residues of indaziflam, and degradate products (e.g., FDAT) are a concern for exposure via ground water. A prospective ground water study could help reduce the uncertainty regarding the exposure via ground water. 5.1.5 Co mparative Metabolic Profile The metabolism of indaziflam is complex, with a few major metabolites (fluoroethyl diaminotriazine = FDAT, and indaziflam carbox yl ic acid) found in plants, goat, rat, soil and water and numerous minor metabolites. Table 5.1.5 provides a profile of the major residues from metabolism and environmental fate studies. In determining metabolism OPP performed a preliminary review of the available metabolism and environmental fate data for purposes of determining the residues of conce rn for drinking water by the Residues of Concern Knowledgebase Subcommittee (ROCKS) (G. Kramer, D371659, February 18, 2010). The metabolism of indaziflam has been evaluated in the rat using indaziflam labeled with 14 

### C at either the indane or the triazine ring. Indaziflam is rapidly and completel y absorbed. Radioactivity

was rapidly

excreted (approximately 90% of dose by

24 hrs postdosing). Metabolism was extensive with only 2 - 12% of the dose excreted in feces as unchanged parent, and occurred primarily via oxidative processes. The major metabolite in the rat was the carbox yl ic acid metabolite of indaziflam, which was largel y excreted in the bile but also found in urine. Other compounds that were identified as major metabolites in combined excreta in on e or more groups were 3 - hydroxyindane acid, 3 - hydroxyindane acid epimer, dihydrox y, h ydrox y

### Page 25 of 50

glucuronic acid, 3 - ketoindane acid, and hydrox yethyl acid metabolites. The fluoroethyl diaminotriazine (FDAT) metabolite was identified at low levels (1.18 to 1.69 % of administered dose) in the triazine - labeled groups. Conclusions regarding residues of concern for metabolites in proposed crops and livestock are that while the residue profile in crops is comprised of indaziflam and FDAT being the onl y indentified compounds; however, in the goat indaziflam appears to undergo significant oxidative metabolism. There are a number of significant (> 10% TRR) metabolites, depending on the commodity

(i.e., milk, liver, muscle, fat) being examined, with most consisting of some level of increased hydrox yl ation relative to the parent compound. Residues of concern for metabolites in soil consist of the parent, FDAT, carbox yl ic acid, i ndaziflam ketone, and f

luoroethyltriazinane - 2,4 - dione . Several environmental degradates are of concern for drinking water risk assessment. Drinking water residues of concern for this purpose include triazine indanone, indaziflam carbox yl ic acid, FDAT, dihydroamino triazine, indaziflam hydroxyethyl, and indaziflam olefin . Table 5.1.5. Summary of Major 1 Residues from Metabolism and Environmental Fate Studies. Compound Sugarcan e Apples Grapes Goat

– Milk Goat - Liver Goat - Muscle Goat -

Fat Goat - Kidney Rat

Excreta Soil 2 Water3 Indaziflam 24 13 24 9 2 - 20 - 38 56 21 Fluoroethyl diaminotriazine 30 72 47 13 - 15 3 2 2 39 13 Indaziflam carboxylic acid - - - 9 24 6 19 20 67 22 21 Indaziflam- 4 - hydroxyhydroxymethyl - - - 18 4 15 7 4 - - - Indaziflam- dihydroxy - - - 18 2 18 4 11 13 - - Indaziflam- 4 - hydroxy acid - - - - 5 - 12 14 - - - Indaz iflam- 3 - ketohydroxymethyl 4 - - - 28 2 5 4 6 1 - - Indaxiflam- 3 - hydroxyindane 4 - - - 18 24 14 9 17 13 - - Indaziflam ketone - - - - - - - - - 16 21 Fluoroethyltriazinane - 2,4 - dione - - - - - - - - - 26 - Indaziflam hydroxyethyl - - - - - - - - 9 - 21 In daziflam olefin - - - - - - - - - - 54 Yellow = greater than 10% TRR, Blue = between 1 and 10% TRR, White = less than 1% TRR; dash ( - ) = not detected. 1 Only metabolites that appeared in at least one study at > 10% of the TRR or total applied radioactivity are included in this table. Maximum reported values for each matrix are provided. 2 The maximum value from all soil studies is reported ( i.e. , aerobic and anaerobic study results are combined). 3 The maximum value from all aquatic studies is reported, including aquatic photolysis and aerobic aquatic metabolism. 4 Including the glucuronic acid conjugate 

### 5.1.6 Toxicity Profile of Major Metabolites and Degradate s With the exception of FDAT and dihydroamino triazine, all of the major metabolites are assume d to have comparable toxicity to the parent due to structural similarity (i.e., both rings

### Page 26 of 50

intact). FDAT is not expected to be more toxic than the parent indaziflam based on FDAT’s non - neurotoxic mode of action (E. Scollon, D371661, April 21, 2010). Therefore, the neurotoxic endpoints selected for this risk assessment will be protective of potential FDAT toxicity . Dihydroamino triazine (ROI 1) is assumed to have comparable toxicity to FDAT. 5.1 . 7 Pesticide Metabolism and Degradates of Concern Based on the available metabolism studies, HED concluded that for these uses, the nature of the residue has been adequately delineated for tolerance enforcement and risk assessment (Table 5.1.7). Str

uctures of these compounds are shown in Appendix C. Table 5 .1. 7 : Residue Definition for Indaziflam . Matrix Risk Assessment Compliance Monitoring Plants Primary Crop Indaziflam + Fluoroethyl Diaminotriazine (FDAT) Indaziflam + FDAT Rotational Crop No t applicable at this time (no data

available) Not applicable at this time (no data available) Livestock Ruminant Indaziflam + FDAT + Indaziflam - 3 - ketohydroxymethyl + Indaziflam carboxylic acid + Indaz iflam - 3 - hydroxyindane Indaziflam + FDAT + Indaziflam - 3 - ketohydroxymethyl + Indaziflam carboxylic acid + Indaz iflam - 3 - hydroxyindane * Poultry Not applicable at this time (no data

available) Not applicable at this time (no data available) Drinking Water Indaziflam + FDAT + Triazine indanone + Indaziflam carboxylic acid + Indaziflam hydroxyethyl + Indaziflam olefin + dihydro - amino triazine Not Applicable

Indaziflam = N

- [(1 R ,2 S ) - 2,3 - dihydro - 2,6 - dimethyl - 1 H - inden - 1 - yl] - 6 - (1 - fluoroethyl) - 1,3,5 - triazine - 2,4 - diamine (CAS) FDAT = 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin e - 2,4 - diamine Indaziflam carboxylic acid = (2 S,3 R ) - 3 - [[4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl]amino) - 2,3 - dihydro - 2 - methyl - 1 Hindene - 5 - carboxylic acid Indaziflam- 3 - ketohydroxym ethyl = (2 S,3 R ) - 3 - [[4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl] amino) - 5 - hydroxymethyl - 2 - methylindane - 1 - one Indaz iflam- 3 - hydroxyindane = (2R ,3 R ) - 3 - ({4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl}amino) - 2 - methylindan - 1 - ol - 5 - carboxylic acid Triazine i ndanone = N

- [(1 R ,2 S ) - 2,3 - Dihydro - 2,6 - dimethyl - 3 - oxo - 1 H - inden - 1 - yl] - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine Indaziflam hydroxyethyl = 1 - {4 - Amino - 6 - [(1R,2S) - 2,6 - dimethyl - 2,3 - dihydro - 1 H - inden - 1 - ylamino] - 1,3,5 - triazin - 2 - yl}ethanol Indaziflam olefin = N

- [(1 R ,2 S ) - 2,6 - dimethyl - 2,3 - dihydro - 1 H - inden - 1 - yl] - 6 - vinyl - 1,3,5 - triazine - 2,4 - diamine * tentative , these residues should be included in the feeding study (if required) . 

### 5.1. 8 Analytical Methodology Baye r CropScience method DH - 003 - P07 - 02 was developed to determine the residues of AE 1170437 in fruit and tree nut matrice s. Method DH - 003 - P07 - 02 is based on high performance liquid chromatography with tanden mass spectrometry (LC/MS/MS), has been sufficiently

validated and is suitable as an enforcement method for crops. The method is able to determine, separatel y, residues of indaziflam and FDAT. The method has been adequatel y radiovalidated using samples from the apple and grape metabolism studies. The method has been sent to the Anal ytical Chemistry Branch of the Biological and Economic Analy sis Division (AC B /BEAD) as w ell as to the Food and Drug Administration (FDA) as an official enforcement

### Page 27 of 50

method. The anal ytical standards, including the stable - isotope internal standard, for the method will need to be forwarded by the petitioner to ACB prior to registration. Use of the proper stable - isotope - labeled internal standards is critical to the method ’ s accuracy and effectiveness. 5.1.9 Food Residue Profile Crop Field Trials and Processing Studies: Baye r Crop Science has conducted and submitted adequate field trial data on citru s, pome , and stone fruits ; tree nuts ; grapes ; and olives and processing studies to support tolerances in plant commodities. With the exception of almond hulls, total residues (indaziflam + FDAT) were below the limit of quantitation (LOQ; < 0.01 ppm) in al l raw agricultural commodities (RACs), even at exaggerated rates. Although adjuvants were not included in the field trials, a label restriction prohibiting their addition to spray mixtures is not required based on the nature of this use (i.e., application targeted to soil with very little uptake of residues into harvested crop). Residues in all processed commodities except grape juice and raisins were not measured due to the lack of quantifiable residues in the RACs at exaggerated rates. In grapes, total residues of indaziflam concentrated upon processing b y 1.5X in juice and 2.8X in raisins. Total residues in almond hulls ranged from <0.01 ppm to 0.153 ppm (mean = 0.05 ppm, standard deviation = 0.06 ppm). Using the NAFTA - harmonized tolerance/MRL calcul ator with maximum likelihood estimation (MLE) resulted in a recommended tolerance of 0.15 ppm for residues in almond hulls. With the exception of almond hulls, which may

be fed to cattle, the proposed uses do not involve any significant livestock feed items. Although citrus RACs from submitted field trials and a processing study have total residues below the LOQ at a 5X exaggerated rate, data for citrus oil are required due to the extremely high potential concentration factor (1000X) for that processed c ommodity . Citrus oil was not anal yz ed during the originally submitted processing study . The petitioner has been made aware of this issue and provided data from a preliminary anal ys is of citrus oil. Although this interim report suggests that indaziflam residues are concentrated approximately 11.7X compared to those observed in citrus RACs, the total residues in citr us oil are still less than L OQ (0.01 ppm). Therefore, HED does not believe that a tolerance for citrus oil is required, as no finite residues would be expected even at exaggerated rates. However, the final study report from this citrus oil anal ys is should be required as a condition of registration. The petitioner is requesting a 7 - day PHI for citrus whereas all citrus field trials were con ducted at 14 day s or longer. All 14 - day PHI citrus field trials had total indaziflam residues that were less than both the L OQ and the LOD. With a total indaziflam residue LOD of 0.0011 ppm, even if the 14 day

PHI total residue was equal to the LOD and the residue assumed to be ten times more concentrated at a 7 - day PHI , then the total residue should still not exceed the LOQ and proposed tolerance of 0.01 ppm. The field trial design was intended to estimate the “worst case” scenario for long - term exposure and translocation from root uptake of the soil - applied herbicide, with the 14 - day

PHI used to simulate any possible short - term uptake. Finally , the field trial results suggest that the highest total residues are observed in those with the longest PHI’s, with the FDAT metabolite being the primary residue detected above the LOD (but still less than the LOQ). Therefore, HED believes that the existing data support a 7 - day PHI and no additional citrus field trials are needed.

### Page 28 of 50

For sugarcane, s amples from the processing study showed no quantifiable residues of indaziflam or FDAT following a 2X application rate, and the processed commodities of molasses and refined sugar were not analyzed. Ty pically , HED requires that no residues of concern be found in a RAC following at least a 5X exaggerated application rate to make a finding that tolerances are not necessary

in the processed commodity . Based on information in the metabolism study, quantifiable residues of indaziflam or FDAT would not be expected in sugarcane even at a 5X treatment rate, with the highest observed TRR of 0.005 ppm in the 2X metabolism study . Therefore, HED does not believe that residues of indaziflam and FDAT in refined sugar will exceed those in the sugarcane RAC (i.e., <0.01 ppm) . Nevertheless, in this instance HED recommends the tolerance be set on the refined sugar since that is the commodity to be imported. HED notes that a metabolism trial at a 10X exaggerated treatment rate was initiated and subsequently

terminated due to treatment - related phy totoxicity . It should be noted that all of the processing studies were conducted at long PHI ’s (174 - 287 day s) relative to the label PHI of 7 and 14 day s. However, based on the crop field trial results, there was a general trend toward s longer PHI having higher observed residues. Therefore, the use of samples with longer PHI should actually have increased the probability of finding quantifiable residues in the RAC and processed commodities. Meat, Milk, Poultry and Eggs: Based on re sidue levels observed in the goat metabolism studies and the residues in almond hulls, finite residues are not expected in ruminant meat, meat by product, fat, or milk and tolerances are not required for these commodities. Rotational Crops: Limited field rotational crop studies are not needed to support the proposed uses since the target crops are not rotated. The proposed label currentl y specifies a plant - back restriction of 2 years due to phyt otoxicity concerns. Storage Stability: The available storage stability data indicate that residues of indaziflam and FDAT are stable in frozen storage for up to approximately 12 months. Samples from the citrus, olive, and tree nut crop field trials, and the grape processing study were stored for over one year and are not fully

supported by

the available storage stability data. Since the available data demonstrate that residues have some long - term stability, HED will use the available study to support the tolerance petition. The petitioner has indicated that while the final report has not been through quality assurance review, preliminary findings show that the residue s have remained stable over a 25 - 26 month period. S ubmission of the ongoing storage stability study covering the full duration of sample storage sh ould be made a condition of registration. 5.1. 10 Drinking Water Residue Profile (Tier 2 Drinking Water Exposure Assessment for the Section 3 New Chemical Registration of Indaziflam; R. Baris, D356141; February 2, 2010) 

### Based on a review of the available environmental fate data, the ROCKS determined that the four major transformation products that maintain the dual ring structure of indaziflam should be included in the drinking water exposure assessment since they may be of toxicological concern (i.e., they are assumed to be of equal or lower toxicity to the parent in the absence of toxicological data). These transformation products include: triazine indanone, indaziflam carbox yl ic acid, indaziflam - olefin, and indaziflam - hydroxyethyl . In order to account for residues

### Page 29 of 50

of these transformation products, the Environmental Fate and Effects Division (EFED) calculated drinking water concentrations for total indaziflam residues which included indaziflam and similarly

s tructured degradates. EFED also calculated separate concentration estimates for FDAT plus dihydroamino triazine (ROI 1; a degradate of FDAT). Drinking water concentrations were based on maximum seasonal application rates for citrus (0.134 lb ai/A), which i s higher than turf application rates (0.094 lb ai./A) and thus protective of drinking water scenarios and populations. As noted above, HED has included the residue estimates for FDAT and ROI1 directly in the indaziflam assessment due to the available toxi city data indicating the neurotoxic endpoints for indaziflam are protective of toxicity from these degradates. The drinking water concentrations used to estimate exposure via drinking water are included in Table 5.1. 10 . Table 5.1. 10 Summary of Estimate d Surface Water and Groundwater Concentrations

for Indaziflam Exposure Duration Indaziflam FDAT + ROI1 Combined * Surface, ppb a Ground,

ppb b Surface,

ppb a Ground,

ppb b Surface, ppb Ground, ppb Ac ute 48 1.6 19 1.1 84 3.7 Chronic (non - cancer) 14 1.6 6 1.1 26 3.7 * Residue estimates for FDAT and ROI1 have been converted to indaziflam equivalents (molecular weight ratio = 301÷157 = 1.92) and included directly in the indaziflam concentration estimates. a From the PRZM and EXAMS b From the SCI - GROW mode l assuming a maximum seasonal use rate of 0.134 lb ai/A for citrus. 

### 5.1.1 1 International Residue Limits At this time, there are no Canadian, Mexican, or Codex MRL s for indaziflam and, therefore, there are no international harmonization issues with this action. 5.2 Dietary Exposure and Risk (Indaziflam: Acute and Chronic Aggregate Dietary Exposure (Food and Drinking Water) and Risk Assessment for the Section 3 Registration on Pome Fruits, Stone Fruits, Citrus, Tre e Nuts (including Pistachios), Grapes, Olives, and Sugarcane; E. Holman; D376909; July 28, 2010) 

### Acute and chronic aggregate dietary risk assessment s (food and drinking water) were conducted using the Dietary

Exposure Evaluation Model (DEEM - FCID, Version 2.03), which uses food consumption data from the U.S. Department of Agriculture (USDA’s) Continuing Survey s of Food Intakes by

Individuals (CSFII) from 1994 - 1996 and 1998. The acute and chronic anal ys es are based on tolerance - level residues and 100% crop treated assumptions. Default processing factors were used for all commodities, with exception of the empirically derived raisin processing factor of 2.8 X . For acute and chronic assessments, HED is concerned when dietary risk exceeds 100% of the PAD. Th e acute and chronic dietary exposure analy sis results are reported in Table 5 .2 and show all population exposures are well below HED’s level of concern . The acute dietary

risk estimate for the general U.S. population is <1 % of the aPAD. The most highl y e xposed population subgroup is all infants (<1 y r old), w ith a risk estimate of 3% of the aPAD.

### Page 30 of 50

The chronic dietary

risk estimate for the general U.S. population is 3% of the cPAD. The most highl y exposed population subgroup is all infants (<1 y r old), w ith a risk estimate of 10 % of the cPAD. Table 5.2 Summary of Dietary Exposure and Risk for I ndaziflam 1

Population Subgroup* Acute Dietary Chronic Dietary Cancer Dietary Exposure (m g/kg/day) %

aPAD Dietary

Exposure (m g/kg/day) %

cPAD Diet ary

Exposure (m g/kg/day) Risk General U.S. Population 0.00448 <1 0.00060 0 3 N/A N/A All Infants (< 1 year old) 0.0166 74 3 0.00192 2 10 Children 1 - 2 years old 0.0071 4 8 1 0.0010 61 5 Children 3 - 5 years old 0.00645 9 1 0.0009 29 5 Children 6 - 12 years old 0.0044 47 <1 0.00060 6 3 Youth 13 - 19 years old 0.0036 48 <1 0.00043 8 2 Adults 20 - 49 years old 0.00410 3 <1 0.00054 2 3 Adults 50+ years old 0.00371 2 <1 0.00057 1 3 Females 13 - 49 years old 0.0041 18 <1 0.00054 3 3 1 The value for the highest expos ed population in the acute and chronic risk assessment is bolded. 

### 5.2.1 C ancer Dietary Risk HED has classified indaziflam as “not likely to be carcinogenic to humans.” Based upon this classification, HED has determined there is no cancer risk associat ed with the proposed uses. 6.0 Residential (Non - Occupational) Exposure/Risk Characterization (Occupational and Residential Exposure Assessment for Use of the New Active Ingredient Indaziflam on Turf, Golf Courses, Sod Farms, Christmas Tree Farms, Non - Crop Areas and Forestry; M. Collantes: April 2010; D372538) 

### 6.1 Residential Handler Exposure A residential assessment for use of indazifl am on turf was previously conducted in D372538 (M. Collantes; 4/21/10). No new residential uses are being requested at this time . Handler MOEs were significantly

greater than 100 (ranging from 3,000 to 510,000) and are not of concern. The postapplication scenarios resulting from commercial and residential applications were assessed for adults and children using the HED Draft Standard Operating Procedures (SOP’s) for Residential Exposure Assessments, 2000 . All adult and children residential lawn and g olf dermal exposures and oral non - dietary ingestion exposures for children (i.e. soil ingestio n, and hand - /object - to - mouth) were assessed . S cenarios resulted in MOEs greater than the level of concern (ranging from 2,800 to 2,100,000 ) for short - term exposure and are not of concern to HED. Furthermore, the episodic oral MOE for i ncidental ingestion of granules among young children (3 to 6 ye ars of age) is 5,000 and therefore is not of concern to HED .

### Page 31 of 50

The short - and intermediate - term dermal endpoints are the same, and onl y short - term dermal exposures were assessed for adults and children. HED estimates short - term dermal postapplication exposure based on day- 0 residues. Using day- 0 residues to assess intermediate term exposure does not take into account dissipation of residues over time and thus results in a conservative estimation. Therefore, the short - term dermal postapplication exposure assessment represents the worst case scenario and is protective of intermediate - term dermal exposure. Based on the A gency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for indaziflam at this time primarily because it has a very

low vapor pressure (vapor pressure 5 x 10 - 10 

### mmHg at 25oC ), it is applied at low application rates (maximum rates range from 0.089 - 0.125 lbs ai/A depending on use site), and it is not projected to be applied via typically high inhalation exposure application equipment (e.g., airblast and aerial equipment). However, v olatilization of pestici des may be a potential 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 Rod enticide 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 exposure assessment for indaziflam. 6.2 Spray Drift Spray drift is a potential source of exposure for residents living in close proximity to spraying operations. This situation is particularly the case with aerial application. However, to a lesser extent, spray

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

the Spray

Drift Task Force, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assess ments 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 practices to reduce off - target drift, and risks associated with pesticid e application. Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. It is noted that the 0.094 lb ai/acre application rate for turf was modeled to estimate postapplication residential exposure of children (ag es 1 to 6 ye ars of age) . As this rate is equal to or higher than many of the commercial application rates, this scenario is protective of any exposure of children via spray drift from commercial indaziflam applications.

### Page 32 of 50

6.3 Combined Residential Exp osure HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneousl y based on the use - pattern and the behavior associated with the exposed population. HED evaluated the following combined residential e xposures of indaziflam, 1.) adult dermal and inhalation handler (lawns only) exposure, and 2.) child postapplication dermal and oral exposures. Since HED does not generally combine adult handler and dermal postapplication exposure, such a combined quantit ative residential exposure estimate was not provided. However, combined residential scenario assessments for children which could occur simultaneously

were performed and did not result in risks of concern. Table 6 .3: Combined Residential Exposure and Risk Product Use Site Handler Total MOE 1 Post - application

Derm al MOE 2 Hand - to - Mouth

MOE 3 Combined

MOE 4 Adult Lawn 3FL Concentrate /Ready to spray 72155 - IO Lawns, hardscapes and ornamentals 3,000 4,700 NA NA

Child Lawn 3 FL (72155 - IO) Lawns, hardscapes and ornamentals NA 2,800 5,300 1,800 1. See Table 4.1.2: Indaziflam Residential Handler Exposure and Risk (Hand Held Pump) ; M. Collantes: April 2010; D372538 2. See Table 4.2.2b Dermal Postapplication Exposure and Risk (DFR data) ) ; M. Collante s: April 2010; D372538 3. See Table 4.2.3 Hand - To - Mouth Exposure and Risk) ; M. Collantes: April 2010; D372538 4. Adult Combined MOE = NA = HED does not combine adult handler and postapplication exposure Child Combined MOE = NOAEL (7.5 mg/kg/day)/dermal postappli cation dose (0.00266) + HTM dose (0.00141) 

### HED did not combine risk resulting from adult homeowner handler, postapplication , and golfer exposure to treated turf because HED considers the probability of co - occurrence for these scenarios to be low . 7.0 Ag gregate Risk Assessments and Risk Characterization 7.1 Acute Aggregate Risk Other than dietary

exposure, there are no other sources of exposure that constitute an acute exposure scenario; therefore, acute aggregate exposure and risk estimates are equivalent to the acute dietary

exposure and risk estimates summarized in Table 5.2 and are below HED’s level of concern. 7.2 Short- and Intermediate - Term Aggrega te Risk HED combined risk values resulting from chronic dietary (food + drinking water) and residential scenarios. When estimating adult residential exposure, HED does not generally combine handler

### Page 33 of 50

and dermal postapplication exposure as it would result in an over estimate of exposure. All short term combined exposures resulted in MOEs greater than 100 for all populations and are not of concern. Short - term risks are summarized in Table 7 .2 below. Table 7.2. Summ ary of the Short - and Intermediate - Term Aggregate Exposure and Risk Estimates for Indaziflam . Population Subgroup Total Residential Exposure, mg/kg/day Chronic Dietary Exposure, mg/kg/day Aggregate

Exp osure 1 , mg/kg/day MOE 2 U.S. Population (total) 0.00 254 0.00 060 0 0.00 314 2400 All infants (< 1 year) 0.00 407 0.0 0 1 92 2 0.005 99 1300 Children 1 - 2 y

rs 0.004 0 7 0.0 010 61 0.0 0514 1500 Children 3 - 5 y

rs 0.00 40 7 0.0 009 29 0.0 04 99 1 5 0 0 Children 6 - 12 y

rs 0.00 407 0 .00 060 6 0.00 4 6 78 1 6 00 Youth 13 - 19 y

rs 0.00 254 0.00 043 8 0.00 2979 2 5 00 Adults 20 - 49 y

rs 0.00 254 0.00 054 2 0.00 308 2 2 4 00 Adults 50+ yrs 0.00 254 0.00 057 1 0.00 3112 2400 Females 13 - 49 y

rs 0.00 254 0.00 054 3 0.00 3084 2 4 00 The population subgroup with the highes t estimated exposure/risk is bolded . 1 Aggregate Exposure = Residential Exposure + Chronic Dietary Exposure 2 Aggregate MOE = NOAEL ( 7 . 5 mg/kg/day) ÷ Aggregate Exposure (mg/kg/day) 

### 7.3 Long - Term Aggregate Risk Other than dietary

exposure, there are no other sources of exposure that constitute a long - term exposure scenario; therefore, long - term aggregate exposure and risk estimates are equivalent to the chronic dietary

exposure and risk estimates summarized in Table 5. 2 and are below HED’s level of concern. 7.4 Cancer Risk Indaziflam has been classified as “not likely to be carcinogenic to humans.” Therefore, cancer risk is not a concern for this chemical. 8.0 Cumulative Risk Characterizati on/Assessment FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available info rmation concerning the cumulative effects to human health that may result from dietary , residential, or other non - occupational exposure to other substances that have 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 health 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 common toxic effect b y a mechanism common with that of the subject pesticide, even if the indi vidual exposure levels to the other substances are also considered safe.

### Page 34 of 50

Several triazine herbicides were determined to have a common mechanism of toxicity based on their ability

to disrupt the hy

pothalamic - pituitary- gonadal axis (US EPA, 2002 ). The triaz ine common mechanism group (TCMG) includes atrazine, simazine, propazine, and the metabolites desethyl - s - atrazine (DEA), deisopropyl - s - atrazine (DIA), and diaminochlorotriazine (DACT). Indaziflam and its metabolite FDAT were considered for incorporation into the TCMG by the HED ToxSAC committee based on structure; indaziflam, FDAT, and the TCMG members contain a common triazine moiety (E. Scollon, D371661, April 21, 2010 ). However, HED determined that it would not be appropriate to include indaziflam and FDAT in the TCMG for the following reasons: 1) The structure s of indaziflam and FDAT are unique in that they contain a fluoroethylgroup at the 2 - position of the triazine ring; whereas, the TCMG members contain a chlorine substituent at the 2 - position of the triazine ring and; 2) Indaziflam and FDAT do not elicit the same toxicological responses shared b y the TCMG members. The TCMG members cause an increase in mammary gland tumors in rats and multiple developmental effects such as attenuation of the lute inizing hormone surge, altered pregnancy outcome, and delayed preputial separation. None of these effects were observed in the carcinogenicity or developmental guideline studies for indaziflam. Delayed maturation was observed in the rat reproduction study , however, the effect occurred at the highest dose and was attributed to significant clinical toxicity rather than a perturbation of the hy pothalamic - pituitary- gonadal axis . Ina non - guideline study, FDAT delayed vaginal potency in a dose dependent manner. However, none of the other characteristic developmental effects of the TCMG members were observed . 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 mechanis m of toxicity finding for indaziflam or its metabolite FDAT and any other substances, and indaziflam does not appear to produce a toxic metabolite produced b y other substances. Therefore, for the purposes of this risk assessment, EPA has not assumed that indaziflam or its metabolite FDAT 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 (Occupational and Residential Exposure Assessment for Use of Indaziflam on Citrus Fruit, Stone Frui t, Pome Fruit, Grapes, Tree Nuts, Pistachios and Olives ; M. Collantes: June 7, 2010; D37 6907 ) 

### The proposed domestic uses of indaziflam are for control of annual grasses and broadleaf weeds in citrus fruit, stone fruit, pome fruit, grapes, tree nuts, pistachios and olives. This document assesses occupational exposures and risks from the proposed uses of Indaziflam 200 SC Herbicide (suspension concentrate, 19.05% ai) and Indaziflam 500 SC Herbicide (suspension concentrate, 45.05% ai). Based on the proposed uses, exposures to indaziflam are anticipated to occur for short - and intermediate - term durations.

### Page 35 of 50

9.1 Handler Risk No chemical - specific data were available with which to assess potential exposure for pesticide handlers. The estimates of exposure for p esticide handlers are based upon surrogate study data available in the PHED (v. 1.1, 1998) and from the Outdoor Residential Exposure Task Force (ORETF). Table 9 .1 presents the results of the occupational handler exposure and risk assessment indicating that short - and intermediate - term dermal, inhalation and total MOEs were greater than the level of concern (MOEs ≥ 100) at the baseline clothing level ( i.e. single layer clothing and no respirator), when baseline data are available. There are no baseline dermal data to ass ess the mixing/loading/appl yi ng handgun scenario. The proposed product label involved in this assessment directs handlers to wear long sleeved shirt and long pants, shoes plus socks, and chemical resistant gloves. When baseline attire plus ch emical - resistant gloves are used for this scenario, short - and intermediate - term dermal and total MOEs were greater than the level of concern (MOEs ≥ 100). Handler MOEs ranged from 370 to 43,000 and are not of concern . Table 9 .1. Occupational Handler Exposures and Risks a Exposure Scenario Crop or Target App. Rate b (lb ai/A) Area T reated Daily c (acres) Unit Exposure d Dose e (μg/kg/day) MOE f,g Dermal (mg/lb ai) Inhalation

(μg/lb ai) Dermal Inhalation Dermal Inhalation Total Mixer/Loader Groundboom Equipment (PHED data) Citrus Fruit, Pome

Fruit, Stone Fruit, Grapes, Tree Nuts, Pistachios, Olives 0.085 80 2.9 1.2 0.021 0.0001 16 3 6 0 6 5, 000 3 7 0 Applicator Groundboom Equipment (PHED data) Citrus Fruit, Pome

Fruit, Stone Fruit, Grapes, Tree Nuts, Pistachios, Olives 0.085 80 0.014 0.74 0.000099 0.000072 76 , 000 100 , 000 4 3, 000 Mixer/Loader/Applicator Handgun Sprayer (ORETF data) Citrus Fruit, Pome

Fruit, Stone Fruit, Grapes, Tree Nuts, Pistachios, Olives 0.085 2 5 0.45 (with gloves) 1.8 0.001 (with gloves) 0.000055 7,600

(with gloves) 140,000 7,200

(with gloves) a Risks repres ent baseline attire ( l ong - sleeve shirt, long pants, no respirator), except where indicate d (i.e. addition of chemical - resistant gloves for the mixer/loader/applicator handgun scenario). b Application rates = maximum application rates from labels. c Amount handled per day values are HED estimates of acres treated applied per day based on Exposure SAC SOP #9 .1 “Standard Values for Dai ly Acres Treated in Agriculture ” and professional judgment . d. Unit Exposures based on PHED Version 1.1 or ORETF data. e Dos e (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x % Absorption (7.3% dermal and 100% inhalation) / Body weight (70 kg). f Dermal and Inhalation MOE = NOAEL (7.5 mg/kg/day) / Dose (mg/kg/d ay) g Total MOE = 1 / (1/ Dermal MOE) + (1/ Inhalation MOE).

### Page 36 of 50

9 .2 Occupational/Commercial Postapplication Exposure 9.2.1 Postapplicati o n Inhalation Exposure Based on the Agency's current practices, a quantitative postapplication inhalation exposure asse ssment was not performed for indaziflam at this time primarily because it has a very

low vapor pressure (vapor pressure 5 x 10 - 10 

### mmHg at 25oC ), it is applied at low application rates (maximum rates range from 0.089 - 0.1 34 lbs ai/A depending on use site), it is not projected to be applied via typicall y high inhalation exposure application equipment (e.g., airblast and aerial equipment). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing postappl ication activities in previously 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 by the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for an d, 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 assessment for indaziflam. 9.2.2 Postapplication Dermal Exposure The proposed uses for indaziflam are ground - directed uses where no crop foliage is treated. Currently , HED has no data to assess postapplication dermal exposures to treated soil by occupational workers. In general, such exposures are considered to be negligible. Therefore, for the proposed soil - directed uses, postapplication exposures and risks to occupational workers were not quantitativel y assessed but are not considered t o be of concern . Restricted Entry Interval The restricted entry

interval (REI) is based on the acute toxicity of indaziflam technical material. Active ingredients classified as category III or IV for acute dermal toxicity, eye irritation potential, an d skin irritation potential are assigned a default REI of 12 hours under the Worker Protection Standard for Agricultural Pesticides . Based on the acute toxicity profile for indaziflam, the 12 - hour REIwhich appears on the proposed labels is adequate . 10 .0 Data Needs and Label Recommendations 10.1 Toxicology Based on the available toxicity database and the Agency's current practices, the inhalation risk for indaziflam was asse ssed using an oral toxicity study . The Agency

sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, an d Rodenticide

### Page 37 of 50

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, re - examine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may revisit the nee d for an inhalation toxicity study for indaziflam and/or a re examination of the inhalation toxicity risk assessment. 10.2 Residue Chemistry The residue chemistry

data set is complete with the exception of a final storage stability report and a final anal ys is report for the processed commodity of citrus oil. HED recommends that submission of acceptable storage stability and processing study

reports be made a condition of registration. In addition, anal ytical referenc e st andards need to be provided prior to registration (see item 3 below). 1. Citrus oil tolerance - Although citrus RACs from submitted field trials and a processing study have total residues below the L OQ at a 5X exaggerated rate, data for the processed comm odity of citrus oil is required due to the extremely high potential concentration factor (1000X). Citrus oil was not analyzed during the originall y submitted processing study. The petitioner has been made aware of this issue and provided data from a prel iminary anal ys is of citrus oil. Although this interim report suggests that indaziflam residues are concentrated approximately 11.7X compared to those observed in citrus RACs, the total residues in citrus oil are still less than LOQ (0.01 ppm). Therefore, HED does not believe that a tolerance for citrus oil is required, as no finite residues would be expected even at exaggerated rates. However, the final study report from this citrus oil analy sis should be required as a condition of registration. 2. S torage stability

studies - The storage stability study submitted to support the petition was conducted for a duration of approximately 12 months. All residues were shown to be stable in frozen storage during that time frame. Samples from various studies were stored, frozen, for up to approximately

17 months. The petitioner has indicated that while the final report has not been through quality

assurance review, preliminary findings show that the residue have remained stable over a 25 - 26 month period. How ever, submission of the ongoing storage stability study covering the full duration of sample storage should be submitted as a condition of registration. 3 . Standards - Prior to registration, the petitioner should ensure that analy tical standards of in daziflam and FDAT, as well as the stable - isotope - labeled internal standards, have been sent to the pesticide repository

at the Analy

tical Chemistry

Branch (ACB). It should be emphasized with ACLthat use of the proper stable - isotope - labeled internal stand ards is critical to the method accuracy . The reference standards should be sent to the Analy tical Chemis try

Branch, which is located at Fort Meade, to the attention of either Theresa Cole or Thuy Nguyen at the following address: US EPA National Pesti cide Standards Repository /Anal ytical Chemistry

Branch/OPP

### Page 38 of 50

701 Mapes Road Fort George G. Meade, MD 20755 - 5350 (Note: mail will be returned if the extended zip code is not used.) 10.3 Occupational and Residential Exposure None 11. 0 References 1. Indaziflam : Occupational/Residential Exposure Assessment for Use of Indaziflam on Turf, Golf Courses, Sod Farms, Christmas Tree Farms, Non - Crop Areas and Forestry (M.Collantes, D372538; April 2010) 2. Tier 2 Drinking Water Assessment for the Section 3 New Chemical Registration of Indaziflam; Rueben Baris; D3 56141; and D3 67447; February 2, 2010. 3. Indaziflam. Petition for the Establishment of Permanent Tolerances and Registration for Use on Pome Fruits, Stone Fruits, Citrus, Tree Nuts (including Pistachios), Grapes, and Olives (PP 9F7589); and a Tolerance without a Domestic Registration for Sugarcane (PP 9E7588). Summary

of Analy tical Chemistry

and Residue Data. ( E. Holman et al , D374105; S ept. 9, 2010) 4. Indaziflam: Acute and Chronic Aggregate Dietary Exposure (Food and Drinking Water) and Risk Assessment for the Section 3 Registration on Pome Fruits, Stone Fruits, Citrus, Tree Nuts (including Pistachios), Grapes, Olives, and Processed Cane Sugar (Import). (E. Holman et al , D376909; July 28, 2010)

### Page 39 of 50

Appendix A: Toxicology Assessment A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for turf and food use for indaziflam are shown below in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Test Technical Indaziflam Required Satisfied 870.1100 Acute Oral Toxic ity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Su

bchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21/28 - Day Dermal ................................ ......................... 870.3250 90 - Day

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

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

yes yes

-

- 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxi city (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

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

yes yes 1 yes yes 870.5100 Mutagenicity

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

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

— Structural Chromosomal 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 me ntal Neuro to xicity ................................ ........ no no yes yes yes --

-- yes yes yes 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity............................................... yes yes yes ye s

yes yes Special Studies for Ocular Effects

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

--

-- 1 Satisfied by 870.4300.

### Page 40 of 50

A.2 Toxicity Profiles Table A.2.1 Acute Toxicity Profile - Indaziflam technical Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral - rat 47443281 LD 50 > 2000 mg/kg (both sexes) III 870.1200 Ac ute dermal - rabbit 47443282 LD 50 > 2000 mg/kg (both sexes) III 870.1300 Ac ute inhalation - rat 47443283 LC 50 > 2.3 mg/L (both sexes) IV 870.2400 Ac ute eye irritation - rabbit 47443284 Non - irritant IV 870.2500 Ac ute dermal irritation - rabbit 47443285 Non - irritant IV 870.2600 Skin sensitization - guinea pig 47443286 Not a sensitizer (Buehler method) N/A

### Page 41 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90 - Day

oral toxicity (rat) 47443287 (2005)

Acceptable/Guideline 0, 200, 5000 or 10,000 ppm in diet for 13 weeks M: 0, 14, 338 or 689 mg/kg/day F: 0, 16, 410 or 806 mg/kg/day 98.7% a.i. NOAEL = 14/410 mg/kg/day M/F LOAEL = 338/806 mg/kg/day M/F, based on: in males at 338 mg/kg/day, increased TSH at Week 3 and diffuse thyroid follicular cell hypertrophy at Week 13; in females at 806 mg/kg/day, mortality (one female, sacrificed in extremis with clini cal signs, decreased motor activity and gastric red foci), marginally decreased body weights and decreased food consumption. 870.3100 90 - Day

oral toxicity (mouse) 47443288 (2005)

Acceptable/Guideline 0, 100, 500 or 1200 ppm in diet for 13 weeks M: 0, 1 9, 91 or 218 mg/kg/day; F: 0, 23, 118 or 256 mg/kg/day 96.5% a.i. NOAEL = 91/118 mg/kg/day M/F LOAEL = 218/256 mg/kg/day M/F, based on increased mortality and wasted appearance (females), hunched posture in males and females, decreased body weight/weight gain and food consumption in males and females.

870.3150 90 - Day

oral toxicity (dog) 47443289 (2008)

Acceptable/Guideline 0, 7.5, 15 or 30 mg/kg/day by gavage 94.5 - 99.4% a.i. NOAEL = 7.5 mg/kg/day M/F LOAEL = 15 mg/kg/day, based on axonal d egeneration in the brain, spinal cord and sciatic nerve in males and females. At 30 mg/kg/day, 3 animals were sacrificed with seizures by Day 30; all remaining group animals were sacrificed on Day 36. Decreased body weight gain and neuropathology were ob served. 870.3200 28 - Day

dermal toxicity (rat) 47443290 (2006)

Acceptable/Guideline 0, 40, 200 or 1000 mg/kg/day applied to skin 5 days/week for 4 weeks (22/23 total applications in M/F) 90.32% a.i. Systemic NOAEL = 1000 mg/kg/day LOAEL = not determined ( >1000 mg/kg/day) Local derm al NOAEL = 1000 mg/kg/day LOAEL = not determined (>1000 mg/kg/day). Some indication of local dermal irritation was observed at all doses but the findings were transient and observed only in females, and therefore were not consid ered adverse. 870.3700a Prenatal

developmental in (rat) 47443291 (2006)

Acceptable/Guideline 0, 10, 25 or 200 mg/kg/day by gavage in 0.5% aqueous methylcellulose, GD 6 through 20 Maternal NOAEL = 25 mg/kg/day LOAEL = 200 mg/kg/day based on dec reased body weight gain and food consumption. Developm ental NOAEL = 25 mg/kg/day LOAEL = 200 mg/kg/day based on decreased fetal body weights.

### Page 42 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 94.5% a.i. 870.3700b Prenatal

developmental in (rabbit) 47443292 (2008)

Acceptable/Guideline 0, 10, 25 or 60 mg/kg/day by gavage in 0.5% aqueous methylcellulose, GD 6 through 28 93.14% a.i. Materna l NOAEL = 25 mg/kg/day LOAEL = 60 mg/kg/day based on decreased maternal body weight gain and food consumption and macroscopic changes in the liver in one doe. Developm enta l NOAEL = 60 mg/kg/day LOAEL = not established (>60 mg/kg/day). 870.3800 Reproduction and

fertility effects (rat) 47443293 (2008)

Acceptable/Guideline 0, 150, 1000 or 8000 ppm in the diet; F1 high dose reduced to 4000 ppm at 5 - 17 days’ postweaning Average P/F 1 co nsumption (note: high dose not averaged due to F1 dose reduction) M: 0, 10.4, 69.3 or 560.1 mg/kg/day (P males) and 317.6 mg/kg/day (F 1 males, due to reduction in dietary dose) F: 0, 12.9, 85.2 or 656.2 mg/kg/day (P females) and 355.2 mg/kg/day (F 1 fema les, due to reduction in dietary dose) 93.14 - 94.5% a.i. Parental NOAEL = 69.3/85.2 mg/kg/day M/F LOAEL = 560.1/656.2 mg/kg/day M/F, based on coarse tremors in females from Weeks 6 - 17 and in gestation and lactation, decreased body weight/weight gain and foo d consumption and renal toxicity (tubular degeneration/ regeneration and increased weight) in males. Offspring NOAEL = 69.3/85.2 mg/kg/day M/F LOAEL = 317.6/355.2 mg/kg/day M/F, based on clinical signs (perianal, urine or nasal staining, diarrhea or soft s tool, distended abdomen, weakness, tremors, myoclonus, increased activity and reactivity) and decreased pup body weights throughout postnatal period. Reproductive NOAEL = 69.3/85.2 mg/kg/day M/F (based on F1 intakes) LOAEL = 317.6/355.2 mg/kg/day M/F, bas ed on delayed sexual maturation in males and females (% pups reaching criterion unaffected). 870.4100a Chronic toxicity

(rat) 47443296 (2007)

Acceptable/Guideline 0, 300, 3000 or 10,000 ppm in the diet (6000 in females after Day 280) equivalent to averag e daily intake of M: 0, 14, 136 or 474 mg/kg/day; F: 0, 19, 185 or 589 mg/kg/day 93.14% a.i. NOAEL = 19 mg/kg/day F, 136 mg/kg/day M; LOAEL = 185 mg/kg/day F, based on increased mo rtality, clinical signs of toxicity, mydriasis and absence of papillary re flex; 474 mg/kg/day M, based on decreased body weight/weight gain and food consumption.

870.4100b Chronic toxicity

(dog) 47443294 (2008; main

study);47443295 (2007; dietary stability) NOAEL = 2.0 mg/kg/day LOAEL = 6/7 mg/kg/day M/F, based on axonal degeneration of nerve fibers in the brain, spinal cord and sciatic nerve in males and females.

### Page 43 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results Acceptable/Guideline 0, 60, 225 or 450 ppm in the diet M: 0, 2, 6 or 12 mg/kg/day; F: 0, 2, 7 or 11 mg/kg/day 93.16% a.i. Marginal body weight decreases early in study seen at 12/11 mg/kg/day M/F.

870.4200a Carcinogenicity

(rat) See 870.4300, below 870.4200b Carcinogenicity

(mouse) 47743416 (2008)

Acceptable/Guideline 0, 50, 250 or 1000 ppm in diet M: 0, 6.8, 34 or 142 mg/kg/day; F: 0, 8.4, 42 or 168 mg/kg/day 93.14% a.i. NOAEL = 34/42 mg/kg/day M/F LOAEL = 142/168 mg/kg/day M/F, based on decreased body weight/weight gain and food consumption, M/F; renal and hepatotoxicity in males; stomach and ovarian toxicity in females. No evidence of carcinogenicity

870.4300 Com

bined carcinogenicity/ chronic toxicity (rat) 47743417 (2009)

Acceptable/Guideline 0, 300, 3000 or 10,000 ppm in the diet M: 0, 12, 118 or 414 mg/kg/day; F: 0, 17, 167 or 452 mg/kg/day 93.14% a.i. NOAEL = 12/17 mg/kg/day M/F LOAEL = 118/167 mg/kg/day M/F, based on decreased body weight/weight gain, signs of neurotoxicity (various symptoms, including dilated pupils, tremors, limb/movement effects, reduced activity/alertness) and renal toxicity in females, liver toxicity in males and females and atrophic seminal vesicles and increased TSH (Week 3 only) and thyroid colloid alteration in males. Thyroid alterations in males appeared to be secondary to liver effects. Decreased survival was observed at 452 mg/kg/day in females and both males and fem ales showed mo re pronounced clinical signs of toxicity. No evidence of carcinogenicity Gene Mutation 870.5100 Bacterial reverse

gene mutation assay ( S. typhimurium ) 47443297 (2006)

Acceptable/Guideline 0, 16, 50, 158, 500, 1581 or 5000 μg/plate in presenc e or absence of S9 activation. Trial 1

– plate incorporation method and Trial 2, pre - incubation method 90.32% a.i. Negative +/ - S9 activation in S. typhimurium strains TA98, TA100, TA 102, TA1535, TA 1537 for increased frequency of revertant colonies up to cy

totoxic (500 μg/plate) and precipitating concentrations (5000 μg/plate).

### Page 44 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results Gene Mutation 870.5100 Bacterial reverse

gene mutation assay ( S. typhimurium ) 47443301 (2007)

Acceptable/Guideline Trial 1: 0, 15, 50, 158, 500, 1502 or 5000 μg/plate in the prese nce or absence of S9 activation, plate - incorporation method Trial 2: 0, 100, 200, 400, 800, 1600 or 3200 μg/plate in the presence or absence of S9 activation, pre - incubation method 95.7% a.i. Negative +/ - S9 activation in S. typhimurium strains TA98, TA100 , TA102, TA1535, TA 1537 for incr eased frequency of revertant colonies up to cytotoxic ( ≥800 μg/plate) and precipitating (3200 μg/plate) concentrations.

Gene Mutation 870.5300 Mammalian cell

in vitro forward gene mutation (cultured V79 cells, HGPRT locus) 47443302 (2006)

Acceptable/Guide line 0, 10, 100 or 1000 μg/mL in presence or absence of S9 activation 90.32% a.i. Negative for increased frequency of mutation in CHO cells (not cytotoxic).

Cy togenetics 870.5375 Mammalian in

vitro cy togenetic assay (Chinese hamster V79 lung cells) 4744 3305 (2006)

Acceptable/Guideline 4 hr exposure, 14 hr recovery period: 0, 15, 30, 60, 90 or 120 μg/mL in the absence of S9 activation; 0, 50, 100, 160, 200 and 240 μg/mL in the presence of S9 activation. 4 hr exposure, 26 hr recovery period: 0, 60, 90 and 120 in the absence of S9 activation; 0, 160, 200 and 240 μg/mL 18 hr exposure, no recovery period in the absence of S9 activation: 0, 4, 8, 16, 20 and 24 μg/mL 90.32% a.i. Negative for induction of chromosomal aberrations above background in the prese nce or absence of S9 metabolic activation. Tested up to the limit of solubility (160 μg/mL, - S9)

Cy togenetics 870.5395 Mammalian in

vivo micronucleus assay (mouse) 47443308 (2006)

Acceptable/Guideline Two doses of 0, 10, 20 or Negative for induction of increased frequency of micronucleated polychromatic erythrocytes in bone marrow at any treatment time.

### Page 45 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 40 mg/kg by IP injection in 0.5% aqueous Cremaphor vehicle administered 24 hrs apart; harvested 24 hrs after second dose 90.32% a.i. 870.6200a Ac ute

n eurotoxicity screening battery (rat) 47443310 (2008)

Acceptable/Guideline 0, 50, 100 or 2000 mg/kg by gavage in corn oil. Time of peak effect estimated at 50 min postdosing. 93.14% a.i. NOAEL = 50 mg/kg LOAEL = 100 mg/kg based on decreased mo tor and locomotor activity in females (threshold effect level). Lower NOAEL/LOAEL relative to subchronic study likely due to gavage vs. dietary administration.

870.6200b Subchronic

neurotoxicity screening battery (rat) 47443309 (2008)

Acceptable/Guideline 0, 200, 400 0 or 8000/10,000 ppm (M/F) equivalent to average daily intake in the diet of M: 0, 12.2, 243.6 or 585.7 mg/kg/day F: 0, 15.1, 306.9 or 580.9 mg/kg/day 93.14% a.i. NOAEL = 243.6/306.9 mg/kg/day M/F LOAEL = 585.7/580.9 mg/kg/day M/F, based on decreased to tal session motor and locomotor activity in females, clinical signs/FOB effects in males and females (tremors, repetitive chewing motion and perianal and lacrimal staining), decreased body weights (females ) and cumulative body weight gain in males and fema les.

870.6300 Developmental

neurotoxicity (rat) 47443311 (2008)

Acceptable/Nonguideline 0, 150, 1000 or 7000 ppm in the diet (high dose reduced to 4000 ppm on LD4) equivalent to average daily intake in the diet of 0, 13, 83.8 or 432 mg/kg/day 93.14% a.i. Maternal NOAEL = 83.8 mg/kg/day LOAEL = 432 mg/kg/day, based on clinical signs at daily observation and FOB assessment (coarse tremors, dilated pupils and dilated pupils unresponsive to penlight, nasal staining, repetitive chewing movements), decreased b ody weights/weight gain and reduced number of litters ( - 17%). Offspring NOAEL = 83.8 mg/kg/day LOAEL = 432 mg/kg/day, based on decreased body weight through PND 21 in males and females. Males postweaning had slightly decreased body weights. Decreased mot or activity ( - 29%) on PND 21 in males was considered treatment - related, but was not seen at other measurement times nor in females. 870.7485 Metabolism and

pharmacokinetics 47443312 (2008)

Acceptable/Guideline Absorption was complete (>90% bioavailability) and rapid, with radioactivity

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results (rat)

– tier 1 Male rats given single

gava ge dose of either 14 C indane labeled or - triazine labeled indaziflam at 11.5 - 14.98 mg/kg. Mass balance groups

– excreta collected for 3 days postdosing. Bile - duct cannulated groups

– bile and excreta collected for 2 days postdosing. 99 - 100% radiochemic al purity found in bile by 1 hr postdosing and most radioactivity (generally around 90%) excreted by 24 hrs. Tissue levels of radioactivity were low (0.2% of administered dose by 3 days) with highest levels observed in the GIT, liver, kidney, skin and thyroid. In the bile duct cannulated animals, tissue levels were about 2 - 4 times greater in the triazine - labeled group than the indane - labeled group but levels in other groups were s imilar. Excretion was largely fecal (62 - 70%), with significant biliary excretion observed. CO 2 exhalation was negligible. Parent com

pound was identified at between 2 - 16% of dose in urine and feces. Major routes of metabolism were oxidative pathways; glucuronide conjugation also observed. Major metabolite was carboxylic acid, found in urine, bile and feces. Numerous other metabolites identified or characterized; profile varied among dose groups. Other metabolites identified at low levels included the 3 - hydroxyindane acid epimer, diaminotriazine and 3 - ketohydroxymethyl metabolites. 870.7485 Metabolism and

pharmacokinetics (rat)

– tier 2 47743418 (2009)

Acceptable/Guideline Single gavage doses as follows: (1) low

dose mass balance studies in females giv en 14 C - indane labelled indaziflam at 4.8 mg/kg or 14

- triazine labelled indaziflam at 8.8 mg/kg; (2) high dose mass balance studies in males given 14 C - indane - labelled indaziflam at 559 mg/kg or 14

- triazine - labelled indaziflam at 723 mg/kg; (3) plasma pharma cokinetic experiments with indane label at 2.9 mg/kg (females) or 13.7 mg/kg (males) or triazine - label at 13.2 mg/kg (females) or 16.3 mg/kg (males). Radiochemical purity 99% Absorption was rapid (radioactivity detected in blood by 5 minutes and peak blood concentrations observed between 40 - 60 - minutes postdosing; rapidly decreasing thereafter) Females showed slightly higher absorption than males. Excretion was rapid (>87% by 24 hrs) and was equally distributed between urine and feces in females but was greater in feces in males (10:1). CO 2 excretion wa s negligible. Radioactivity was not retained at significant levels in tissues; the GIT, liver and skin showed the highest residues. The carboxylic acid metabolite was the major metabolite in both high dose males and low dose females, which was found in urine and feces. Additional metabolites present at >5% of dose included 3 - hydroxyindane acid metabolite in low dose females, dihydroxy metabolite in low dose females and hydroxyethyl acid metabolite in the high dose males (indane - label).

870.7600 Dermal 47743420 (2008) Absorption was inversely proportional to dose,

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results absorption, in vivo (rat) Acceptable/Guideline

0.5, 2 or 5000 μg ai/ cm 2 on 12 cm

2 skin for 8 hrs to male rats; absorption evaluated after 8, 24, 72 and 168 hr postdosing Radiochemical purity >98% indicating saturation of skin penetration with increasing dose. Between 0.4 - 20.4% of the applied dose was recovered in combined residual carcass, excreta, blood and non - treated skin. Based on decreased radioactivity at the application site, the most conservative value for risk assessment is a dermal absorption of 42.7% observed at 0.5 μg ai/ cm 2 at 8 hr postapplication. 870.7800 Immunotoxicity -

rat 47443313 (2008)

Acceptable/Guideline 0, 300, 3000 or 6000 (females) or 10,000/6000 (males) ppm in the diet equivalent to average daily intake in the diet of M: 0, 27.7, 258 or 528 mg/kg/day F; 0, 31, 334.2 or 737.9 mg/kg/day 93.12% a.i. Systemic NOAEL = 258.8/334.2 mg/kg/day M/F LOAEL = 528/737.9 mg/kg/day M/F, based on mo rtality (one male sacrificed in extremis) , clinical signs of toxicity in males and females (including tremor, abnormal gait, pallor, hunched back), decreased food and water consumption in males and decreased body weight/weight gain in male s and females. Immunotoxicity NOAEL = 528/737.9 mg/kg/day M/F LOAEL = not established (>528/737.9 mg/kg/day M/F) Non guideline In vitro dermal

absorption

– rat and human skin 47743419 (2007)

Acceptable/Nonguideline Application of a 10μL/ volume of concentrated 500 mg/mL formulation and representative spray dilutions of 0.5, 0.2 or 1.0 mg/mL to excised human and rat dermatomed skin. Exposure duration was 24 hr. Radiochemical purity >98% Total absorbed dose decreased with increasing concentration, indicating saturation of skin penetration with increasing dose. Rat skin was 3.8 to 10.7 times more permeable than human skin over 24 hr at the concentrations tested.

Toxicity Profile - FDAT Nonguideline Study Sexual maturation

supplemental study (rat) 474433 14 (2008)

Accetable/Nonguideline 0, 18.0, 36.5, 72.9 or 145.8 mg/kg/day by gavage to LD21 offspring and timed -pregnant female Wistar rats: administered daily until PND 41 NOAEL = 36.5 mg/kg/day LOAEL = 72.9 mg/kg/day, based on delays in vaginal patency (+2 .3 days, increasing to 3.9 days at 145.8 mg/kg/day). Also at high dose, body weight was decreased and salivation and urine staining were observed.

### Page 48 of 50

Appendix B. 

### Table of Structures Table 1: Major Chemicals Identified in Metabolismand Fate Studies Com pound/Code Chemical Name Chemical Structure Indaziflam 1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S) - 2,3 - dihydro 2,6 - dimethyl - 1H - inden - 1 - yl] - 6 - [(1R) - 1 - fluoroethyl] - N N N N H N H 2

F C H 3 C H 3

C H 3 Fluoro ethyl diaminotriazine 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine

N N N N H 2 C H 3 F

N H 2 Indaziflam carboxylic acid (2 S,3 R ) - 3 - [[4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl]amino) - 2,3 - dihydro - 2 - methyl - 1 H

indene - 5 - carboxylic acid N N N C H 3 N H C H 3 F

N H 2 H O 2 C Indaziflam - 4 - hydroxyhydroxymethyl (2 S,3 R ) - 3 - [[4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl]amino) - 5 - hydroxymethyl - 2,3 - dihydro - 2 - methyl - 1 H

indene - 7 - ol N N N C H 3 N H C H 3 F

N H 2 O H

O H Indaziflam - dihydroxy (2R ,3 R ) - 3 - ({4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1 ,3,5 - triazin - 2 - yl}amino) - 5 - hydroxymethyl - 2 - methylindan - 1 - ol N N N C H 3 N H C H 3 F

N H 2 O H

O H

### Page 49 of 50

Indaziflam - 4 - hydroxy acid (2 S,3 R ) - 3 - [[4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl]amino) - 2,3 - dihydro - 2 - methyl - 1 H

indene - 7 - ol - 5 - carboxylic acid N N N C H 3 N H C H 3 F

N H 2 O H

H O 2 C Indaziflam - 3 - ketohydroxymethyl (2 S,3 R ) - 3 - [[4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl]amino) - 5 - hydroxymethyl - 2 - methylindane - 1 - one N N N C H 3 N H C H 3 F

N H 2 O

O H Indaxiflam - 3 - hydroxyindane (2R ,3 R ) - 3 - ({4 - amino - 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazin - 2 - yl}amino) - 2 - methylindan - 1 - ol - 5 - carboxylic acid N N N C H 3 N H C H 3 F

N H 2 O H

H O 2 C Indaziflam ketone N - [(1R,2S) - 2,3 - Dihydro 2,6 - dimethyl - 3 - oxo - 1H inden - 1 - yl] - 6 - [(1R) - 1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine Fluoroethyltriazinane - 2,4 - dione 6 - [(1R) - 1 - fluoroethyl] - 1,3,5 - triazinane - 2,4 - dione

Indaziflam hydroxyethyl 1 - {4 - Amino - 6 - [(1R,2S) - 2,6 - dimethyl - 2,3 - dihydro 1H - inden - 1 - ylamino] - 1,3,5 - triazin - 2 - yl}ethanol

### Page 50 of 50

Indaziflam olefin N - [(1R,2S) - 2,6 - dimethyl 2,3 - dihydro - 1H - inden - 1 - yl] - 6 - vinyl - 1,3,5 - triazine 2,4 - diamine