I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 1 of 52 UNITED STA

TES ENVIRONMENTA L PROTECTION AGENCY WA SHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION 

### MEMORANDUM Date: 9 Sept 2010 Sub ject: In daziflam. 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 S ugarcane (PP 9E7588) . Summary of Analy tical Chemistry

and Residue Data. PC Code: 080818 DP Barcode: D374105, D376908 Decision No.: 416570 Registration No. : 432 - RLNR Petition No.: 9F7589, 9E7588 Regulatory Action: Section 3 Assessment Type: Singl e Chemical Registration Case No.: NA T XR No.: None CAS No.: 730979 - 19 - 8 MRID No.: See Below 40 CFR 180. New Active Ingredient 

### FROM: Elizabeth Holman, Chemist Michael A. Doherty , Ph.D., Senior Chemist William T. Drew, Chemist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Richard A. L oranger, Ph.D., Senior Scientist

Risk Assessment Branch II Health Effects Division (7509P) TO: Bethany

Benbow/James Tompkins (RM25) Herbicide Branch Registration Division (7505P)I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 2 of 52 Summary of Submitted Residue Chemistry Studies OPPTS 860 Series Guideline MRID

Number Title 1300

– Nature of the Residue 47743272 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 Unpublished study prepared by Bayer CropScience. 64 p. 47743318 Nguyen, T.; Krolski, M. (2009) The Metabolism of [Indane - 3 - (Carbon 14)] and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 Unpublished study prepared by Bayer CropScience. 71 p. 47743319 Krolski, M.; Nguyen, T. (2009) The Metabolism of [Indane - 3 - (Carbon 14)] and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 Number: 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 Unpublished study prepared by Bayer CropScience. 70 p. 47743320 Fisher, D. (2009) The Metabolism of [Triazine - 2,4 - (Carbon 14)] AE 1170437 in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. Unpublished study prepared by Bayer CropScience. 204 p. 47743321 Fischer, D. (2009) The Metabolism of [Indane - 3 - (Carbon 14)] AE 1170437 in the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 p repared 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. 134 0

– Analytical Methods 47743323 Tim berlake, 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, RADHP040. 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 Number: 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 Ind aziflam (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 Validation 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/2009/3 2. 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 47443279 Netzband, D. (2008) Stability of AE1170437 and its Metabolites (AE1170437 Acid, AE1170437 ketone, AE1170437 Hydroxy, AE1170437 Olefin, AE1170437 Diaminotriazine) in Soil During Frozen Storage (Reported Through a Maximum of 433 Days Storage). Project Number: M/302527/01/1, RADHP041. Unpublished study prepared by Bayer CropScience. 56 p.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 3 of 52 47743328 Netzeband, D. (2009) Stability of AE1170437 and its Met abolites (AE1170437

Acid, AE1170437 Ketone, AE1170437 Hydroxy, AE1170437 Olefin, AE1170437 Diaminotriazine) in Soil During Frozen Storage (Reported Through a Maximum of 736 Days Storage). Project Number: M/302527/02/1/OCR, RADHP041/1. Unpublished study prepared by Bayer CropScience. 56 p. 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 CropScienc e. 138 p. 1480

– Meat, Milk, Poultry, and Eggs 47743401 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 Bayer CropScience. 9 p. 1500

– Cro p 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 CropScience. 246 p. 47743404 Brungar dt, 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 Fischer, 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. (2009) 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 of the Residue in/on Olives. Pro ject 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 Sugarcane Processed Commodities. Pro ject 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

Processed 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 Processed Commodities. Project Numb er: 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 Processed 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.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 4 of 52 47743412 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue

in/on Grape Processed Commodities. Proj ect 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 Oliv e 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.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 5 of 52 Table of Contents E xecutive Summary ................................ ................................ ................................ ...................... 6 Residue Chemistry Deficiencies ................................ ................................ ................................ ... 7 Background ................................ ................................ ................................ ................................ ... 8 860.1200 Directions for Use ................................ ................................ ................................ ....... 11 860.1300 Nature of the Residue - Plants ................................ ................................ ................... 12 860.1300 Nature of the Residue - Livestock ................................ ................................ .............. 18 860.1340 Residue Analytical Methods ................................ ................................ ....................... 25 860.1360 Multiresidue Methods ................................ ................................ ................................ . 26 860.1380 Storage Stability ................................ ................................ ................................ .......... 26 860.1400 Water, Fish, and Irrigated Crops ................................ ................................ .............. 27 860.1460 Food Handling ................................ ................................ ................................ ............. 27 860.1480 Meat, Milk, Poultry, and Eggs ................................ ................................ ................... 27 860.1500 Crop Field Trials ................................ ................................ ................................ ......... 28 860.1520 Processe d Food and Feed ................................ ................................ ........................... 37 860.1850 Confined Accumulation in Rotational Crops ................................ ........................... 43 860.1900 Field Accumulation in Rotational Crops ................................ ................................ .. 43 860.1550 Proposed Tolerances ................................ ................................ ................................ ... 44I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 6 of 52 Executive Summary In daziflam { 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 S,1 R ) - fluoroethyl) - } is a new alkylazine herbicide being developed by Bayer for non - selective pre - emergent and early

post - emergent control of annual grass and dicot species in trees, nuts, vines, and turf. This herbicide is a cellulose biosy nthesis inhibitor and is activ e at rates of 50 to 100 g ai/ha. The technical - grade a.i. (TGAI) is made up of at least 95% of the 1 R - fluorethyl isomer and no more than 5% of the 1 S - fluoroethyl isomer. Although the company name AE 1170437 refers specifically to the 1 R - fluoroethyl isome r, it has been used interchangeably with the TGAIduring the data review process. Both isomers have equal herbicidal activity . In daziflam 200 SC and Indaziflam 500 SC are suspension concentrate formulation s of ind aziflam , contain ing 200 and 500 g activ e ingredient (a.i.)/L (1.67 lb a . i . /gallon and 4.16 lb a . i . /gallon) , respectively . The product s are intended for ground - directed application for preemergent weed control in orchards of pome fruits, stone fruits, citrus, tree nuts (including pistachios), grapes, and olives . Use rates for both formulations are dependent, to some extent, on the soil ty pe within the use area. Seasonal maximum application rates are 0.089 lb a.i./A for grapes and 0.134 lb a.i./A for all other crops. In daziflam is not to be ap plied through any ty pe of irrigation system or by

aerial equipment. The pre - harvest intervals (PHI s) on the proposed labels are 7 days for citrus crops and 14 days for other crops. The residue chemistry

database is relatively

complete and there are no re sidue chemistry issues that would preclude conditionally granting the requested registrations and establishing permanent tolerances. The petitioner has submitted data depicting the nature of the residue in apple, grape, sugarcane, and lactating goat. The profile of residues in crops is relatively uncomplicated, with indaziflam and fluoroethyl diaminotriazine (a.k.a. FDAT, AE 1170437 - diaminotriazine) being the only identified compounds. In the goat, the residue profile is far more complex with numerous ma

jor species [> 10% total radioactive residue (TRR)] . R esidue levels (including those of major residues) in crop and goat commodities are in the parts - per - billion (ppb) range, even at exaggerated application/feeding rates. The residue definition for tolerance enforcement and risk assessment for crops is indaziflam + FDAT. An analy tical method using solvent extraction and High Performance Liquid Chromatography- Mass Spectrometry /Mass Spectrometry

( HPL C - MS/MS ) has been developed to assay the residues of conc ern for tolerance enforcement and risk assessment. Adequate crop field trials and processing studies have been conducted to support tolerances in plant commodities. With the exception of almond hulls, total residues (indaziflam + FDAT) were below the lim it of quantitation (L OQ; < 0.01 ppm) in all 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 RA Cs at exaggerated rates. Ingrapes, total residues of indaziflam concentrated upon processing by 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 North American Free Trade Agreement (NAFTA ) - harmonized tolerance/Maximum Residue L imit ( MRL) calculator with maximumI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 7 of 52 likelihood estimation (MLE) resulted in a recommended tolerance of 0. 1 5 ppm for residues in almond hulls. With the exception of almon d hulls, which may be fed to cattle, the proposed uses do not involve any

significant livestock feed items. Based on residue 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 crop studies are not needed to support the proposed uses since the target crops are not rotated . The proposed label currently specifies a plant - back restriction of 2 years due to phy totoxicity concerns. Insupport of the requested tolerance without a U.S. registration for indaziflam on refined sugar , the petitioner has submitted studies examining the nature of the residue in sugarcane and a sugar processing s tudy . The samples from the processing study showed no quantifiable residues of indaziflam or FDAT fo llowing a 2X application rate , and the processed commodities of molasses and refined sugar were not analy zed. 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 ; therefore, HED does not believe that a processing factor is needed to assess residues of indaziflam and FDAT in refined sugar . A tolerance should be set on the latter as an imported commodity at th e level of the method’s L OQ. HED notes that a metabolism trial at a 10X exaggerated treatment rate was initiated and subsequently terminated due to treatment - related phy totoxicity . Residue Chemistry Deficiencies The residue chemistry

data set is complet e with the exception of a final storage stability report and a final analysis report for the processed commodity of citrus oil. This assessment will be amended appropriately once these final reports become available and have undergone HED review. Despite the deficiencies denoted 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 commodity of citrus oil is required due to the extremely high potential concentration factor (1000X). Citrus oil was not analy

zed during the originally

submitted processing study . The petitioner has been made aware of this issue and provided data from a preliminary analysis of citrus oil. Although this interim report suggest s that indaziflam residues are concentrated approximately 11.7X compared to those observed in citrus R ACs, the total residues in citru s oil are still less than L OQ (0.01 ppm). Therefore, HED does not believe that a toleran ce 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 analysis should be required as a condition of registration. 2. 7 - day PHIfor citrus - T he petitioner is requesting a 7 - day PHIfor citrus whereas all citrus field trials were conducted at 14 days or longer. All 14 - day PHIcitrus field trials had total indaziflam residues that were less than both the L OQ and the LOD. With a total indaziflam residue L OD of 0.0011 ppm, even if the 14 day PHItotal residue was equal to the L OD and the residue assumedI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 8 of 52 to be ten times more concentrated at a 7 - day PHI , then the total residue should still not exceed the L OQ 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 PHIused 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 L OQ). Therefore, HED believes that the existing data support a 7 - day PHIand no additional citrus field trials are needed. 3 . Storage 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 froze n storage during that time frame. Samples from various studies were stored, frozen, for up to approximately

17 months. The petitioner has continue d the storage stability study to encompass 24 months of frozen storage , but the final report has not been re ceived yet . Submittal of a valid study

depicting storage stability for 24 months should be a condition of registration. 4 . Apple metabolism study (MRID 47743318) - HED notes a concern regarding the apple metabolism study . At issue is the unexplained los s of radioactivity during extraction of the apple samples. This loss ranges from 18 to 45%. The petitioner attributes the loss of radioactivity to measurement variability

due to low residue levels, noting that the high est losses were observed in samples with the lowest TRR’s (less than 0.01 ppm). Given that the results of this study are supported by

similar metabolic profiles in the sugarcane and grape studies, HED will accept the apple metabolism study

as acceptable despite the apparent loss of radioactivity . 5 . Standards - Prior to registration, the petitioner should ensure that analy tical standards of indaziflam and FDAT, as well as the stable - isotope - labeled internal standards, have been sent to the pesticide repository

at the Analy

tical Chemistry Branch (AC B ). Itshould be emphasized with ACLthat use of the proper stable - isotope - labeled internal standards is critical to the method accuracy . The reference standards should be sent to the Analy tical Chemistry

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

Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755 - 5350 (Note: mail will be returned if the extended zip code is not used.) Background The petitioner, Bayer Crop Science, has developed a new herbicide, indaziflam, for control of grass and broadleaf weeds in orchard crops and non - food sites ( e.g. , turfgrass, ornamentals, etc.). In daziflam inhib its cellulose biosy nthesis in germinating seedlings and is efficacious atI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 9 of 52 relatively low use rat es. OPP has recently assessed and recommended for the non - food uses of this herbicide (M. Collantes, et al ., D 356142, 22 April 2010). Nomenclature and the physicochemical properties of indaziflam are summarized in Tables 1 and 2, below. T able 1. Nomenclature Compound AE 1170437 Isomer A

C H 3 C H 3

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

Common name Indaziflam Company 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 Compound AE 117043 8 Isomer B N N N N H N H 2

C H 3 C H 3

C H 3 F

Common name Indaziflam Company experimental name AE 117043 8 IUPAC name N - [(1 R ,2 S ) - 2,6 - Dimethyl - 2,3 - dihydro - 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] - CAS # 730979 - 32 - 5 Compound 1 - Fluoroethyl diaminotriazine (FDAT) N N N N H 2 N H 2

F C H 3

Common name Indaziflam- diaminotriazine Company 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 # UnavailableI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 10 of 52 T able 2. Physicochemical Properties of the Technical Grade AE 1170437 Parameter Value Reference Molecular weight 301.37 Melting point/range 183 - 184 o C AE 1170437 pure substance H. Mukhoty, 1 Dec 2008, D356393. pH (23 °C) pH = 6.5 AE 1170437 pure substance pH = 5.1 AE 1170437

technical substance Density (g/mL at 2 0  C) (relative density compared to water at 4  C, D 4 20 ) 1.23 AE 1170437 pure substance 1.23 AE 1170437 technical substance Water solubility (at 20 °C) pH 4: 4.4 mg/L, pH 9: 2.8 mg/L, Distilled water (pH 6.6 - 6.9): 2.8 mg/L Solvent solubility (g/L at 20 °C) Acetone: Acetonitrile: Dichloromethane: Dimethyl sulfoxide: Ethanol: Ethyl acetate: Heptane: Toluene: 55 g/L

7.6 g/L 150 g/L >250 g/L 13.0 g/L 47 g/L 0.032 g/L 4.3 g/L Vapor pressure 2.5 x 10 - 8 PA at 20 °C 6.8 x 10 - 8 PA at 25 °C 6.9 x 10 - 6 PA at 50 °C Henry’s law constant 2.69 x 10E - 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 abs orption spectrum methanol (nm)  max1 = 213 nm / A = 1.428  max2 = 268 nm / A = 0.197  max3 = 291 nm / A = 0.019 

### Due to the presence of three chiral carbons in the indaziflam structure, there are eight possible isomers for this herbicide. Based on the p roduct chemistry review of the manufacturing use product (MUP) by

R egistration D ivision (H. Mukhoty , 12/1/2008, D356393), the registrant is declaring the active ingredient to consist of only isomers “A” (AE 1170437) and “B” (AE 1170438) with concentrations of about 92% and 3%, respectively . 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%). As shown in Table 1, the names for isomer A (N - [(1R,2S)...] - 6 - [( 1R) ....diamine) and iso mer B (... - 6 - [( 1S )...diamine) are identical with the exception of the stereochemistry at the fluorine - bearing carbon. The remaining six isomers are present at significantly lower levels and are considered to be imp urities.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 11 of 52 860.1200 Directions for Use Table 3 . Summary of Directions for Use of Indaziflam . These directions are identical for the Indaziflam 200 SC and 500 SC formulations. a Applic. Timing, Ty pe, and Equip. Applic. Rate

(lb ai/A) Max. No.

App lic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and Limitations Pre - emergent application on annual grasses and weeds in Citrus Fruits, Pome Fruits, Stone Fruits, Tree Nuts (Including Pistachio), Grapes Airblast, b roadcast o r Band application to soil ; ground equipment only (no chemigation) 0.065 (coarse soil)

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

14 (Others) Avoid direct or indirect spray

contact with crop foliage, green bark, roots, or fruits. Citrus trees mu st be established for at least 1 year prior to use . Trees/vines other than citrus 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 12 inches deep . Allow at least 12 months between the last application of indaziflam and replanting with a labeled tree or vine crop. Allow at least 24 months between the last ind aziflam application and replanting with non - labeled crop . Sugarcane (Non - Domestic Use) Broadcast spray, pre - or post - crop emergence, pre emergence for we eds; 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 Indaziflam 200 SC Herbicide (Soluble Concentrate) 19.05% ai Indaziflam 500 SC Herbicide (Soluble Concentrate) 45.05% ai b Note that Citrus field trials conducted at 14 day PHI or longer. See Section 860.1500 ( Crop Field Trials ) for further discussion. 

### Conclusions . The proposed labels are adequate to evaluate the residue data relative to the proposed uses.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 12 of 52 860.1300 Nature of the Residue - Plants 47743318 .der.doc

– Apple metabolism 47743319 .der.doc

– Grape metabolism 4744 3272 .der.doc

– Sugarcane metabolism 

### Apple . The metabolism of 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 - fluoroethyl] - ; CAS Number 730979 - 19 - 8 ) was studied in apples following two applications of e ither [indane - 3 - 14 

### C] indaziflam or [triazine - 2,4 - 14 

### C] indaziflam to the soil at the base of the apple trees. Two target application rates were used in each study, corresponding to approximately 2X and 10X the anticipated annual maximum use rate of 150g ai/ha. The total target was split between a spray at flowering comprising 67% (200 g ai/ha and 1000 g ai/ha) of the total applied material and a second spray at a 30 - day pre - harvest interval (PHI) comprising 33% of the total applied material (100 g ai/ha an d 500 g ai/ha). At maturity, apple fruit was harvested and radioassayed to determine the total radioactive residues (TRRs). TRR values in apple fruit from trees treated with [indane - 3 - 14 

### C] indaziflam at approximately 2X and 10X the maximum seasonal use rate of 150 g ai/ha were 0.004 ppm and 0.011 ppm, respectively. TRR values in apple fruit from trees treated with [triazine - 2,4 - 14 

### C] indaziflam at approximately 2X and 10X the maximum seasonal use rate of 150 g ai/ha were 0.011 ppm and 0.054 ppm, respectively. When corrected for the exaggerated application rates, all anticipated TRR values at a 1X rate were <0.01 ppm. Apples from the 2X and 10X [indane - 3 - 14 

### C] indaziflam experiments had extractable residues of 43% and 62%, respectively. While there were several polar compounds formed, the only identified residue in the [indane - 3 - 14 

### C] indaziflam study was unmetabolized parent accounting for 13 % of the TRR (<0.001 ppm) in the 2X experiment and 8 % of the TRR ( <0.001 ppm) in the 10X experiment. Apples from the 2X and 10X [triazine - 2,4 - 14 

### C] indaziflam experiments had extractable residues of 79% and 80%, respectively. The major residue detected, and the only metabolite identified, in the [triazine - 2,4 - 14 

### C] indaziflam study was fluoroethyldiaminotriazine , a ccounting for 72% of the TRR (0.008 ppm) in the 2X experiment and 62% of the TRR (0.033 ppm) in the 10X experiment. 

### Grape . The metabolism of AE 1170437 or 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 - fluoroethyl]; CAS Number 730979 - 19 - 8 ) was studied in grapes following two applications of either [indane - 3 - 14 

### C] indaziflam or [triazine 2,4 - 14 

### C] indaziflam to the soil at the base of the grape vines. Two target application rates were used in each stu dy , corresponding to 2X and 10X the anticipated annual maximum use rate of 150 grams of active ingredient per hectare (g ai/ha) . The total target application was split between a spray

at flowering, comprising 67% (200 g ai/ha and 1000 g ai/ha) of the total applied material, and a second spray at a 30 - day

pre - harvest interval (PHI), comprising 33% of the total applied material (100 g ai/ha and 500 g ai/ha). The pots containing the grape vines (eight total) were maintained in an outdoor area (patio outside of the greenhouse) during the course of the study and were only moved into the greenhouse for spray treatment. 

### Grapes were harvested and radioassayed to determine the total radioactive residues (TRR). Grapes were harvested at full maturity from plants in the 2X dose groups. However,I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 13 of 52 phy totoxicity forced harvest of immature grapes from plants in the 10X dose groups prior to the second treatment, resulting in the plants receiving a 7X overdose with harvest 59 days ([indane 3 - 14 

### C] indaziflam) or 45 days ([triazine - 2,4 - 14 

### C] indaziflam) after treatment. TRR values in fruit from plants treated with [indane - 3 - 14 

### C] indaziflam at 2X and 7X the maximum seasonal use rate of 150 g ai/ha were 0.006 ppm and 0.019 ppm, respectively . TRR values in grapes from plants treated with [triazine - 2,4 - 14 

### C] indaziflam at 2X and 7X the maximum seasonal use rate of 150 g ai/ha were 0.015 ppm and 0.040 ppm, respectively . The petitioner has not provided any specific dates for extraction and analysis. Petitioner materials indicate that samples were analyzed no more than 150 days after harvest. 

### Grapes from the 2X and 7X [indane - 3 - 14 

### C] indaziflam experiments had extractable residues of 71% and 66%, respectively . While there were several polar compounds formed, the only identified residue in the [indane - 3 - 14 

### C] indaziflam study was unmetabolized parent, accounting for 19% of the TRR (0.001 ppm) in the 2X experiment and 24% of the TRR (0.005 ppm) in the 7X experiment. Grapes from the 2X and 7X [triazine - 2,4 - 14 

### C] indaziflam experime nts had extractable residues of 81% and 96%, respectively. The major residue detected, and the only metabolite identified, in the [triazine - 2,4 - 14 

### C] indaziflam study was fluoroethyldiaminotriazine (FDAT) , accounting for 43% of the TRR (0.006 ppm) in the 2X experiment and 47% of the TRR (0.019 ppm) in the 7X experiment. 

### The majority

of radioactivity

was accounted for, with overall accountability (based on theoretical radioactivity

) ranging from 85 to 99%. Sugarcane . The metabolism of 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 - fluoroethyl]; CAS Number 730979 - 19 - 8 ) was studied in sugarcane following two applications of either [indane - 3 - 14 

### C] indaziflam or [triazine - 2,4 - 14 

### C] indaziflam. Two appl ication rates were used in each study, corresponding to 2X and 10X the anticipated annual maximum use rate of 150 grams of active ingredient per hectare (g ai/ha). I n the 2X experiments, the total application was split between a spray to both the plant an d the surrounding soil when the plants were 10 - to 12 - inches tall, comprising 67% (200 g ai/ha) of the total applied material, and a second spray made to the base of the stalk and soil at the base of the mature sugarcane at a 30 - day pre - harvest interval (P HI), comprising 33% of the total applied material (100 g ai/ha). Plants in the 10X experiments received a single treatment to both the plant and the surrounding soil when the plants were 10 - to 12 - inches tall comprising 67% (1000 g ai/ha) of the total target rate. All experiments were carried out in a greenhouse environment. Due to extreme phy

totoxicity following the initial treatments to plants at the 10X rate, those experiments were terminated without sample collection. At maturity , sugarcane from the 2X experiments was harvested and radioassayed to determine the total radioactive residues (T RR). TRR values in sugarcane from plants treated with [indane 3 - 14 

### C] indaziflam and [triazine - 2,4 - 14 

### C] indaziflam at 2X the maximum seasonal use rate of 150 g ai/ha were 0.004 ppm and 0.005 ppm, respectively .I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 14 of 52 Sugarcane from the 2X [indane - 3 - 14 

### C] indaziflam experiment had extractable residues of 65%. While there were several polar compounds formed, the only identified residue in the [indane - 3 - 14 

### C] indaziflam study

was unmetabolized parent accounting for 2 4 % of the TRR (<0.001 ppm). Sugarcane from the 2X [triazine - 2,4 - 14 

### C] indaziflam experiment had extractable residues of 6 8 %. The major residue detected, and the only metabolite identified, in the [triazine - 2,4 - 14 

### C] indaziflam study

was fluoroethyldiaminotriazine (FDAT) , accounting for 30% of the TRR (0.002 ppm). Additionally , 17% of the TRR (<0.001 ppm) was tentatively identified as parent indaziflam in sugarcane from the 2X [triazine - 2,4 - 14 

### C] indaziflam experiment. The majority

of radioactivity

was accounted for, with overall accountability (based on theoretical radioactivity

) of 91 - 100%. Conclusions . Inplants, the metabolism of indaziflam is relatively uncomplicated. The only identified terminal residues in any of the plant studies were parent indaziflam and the FDAT metabolite ( Table s 4a, 4b, 4c , Figure 1). The metabolism data are sufficient to support the requested uses; however, 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 6 . HED does note a concern regarding the apple metabolism study . At issue is the unexplained loss of radioactivity during extraction of the apple samples. This loss ranges from 18 to 45%. The petitioner attributes the loss of radioactivity to measurement variability due to low residue levels, noting that the high est losses were observed in samples with the lowest TRR’s (less than 0.01 ppm). Given that the results of this study are supported by

similar metabolic profiles in the sugarcane and grape studies, HED will accept the apple metabolism study as acceptable despite the apparent loss of radioactivity .I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 15 of 52 Table 4 a . Summary of Characterization and Identification of Radioactive Residues in Apples Following Application of [Indane - 3 - 14 C] or [Triazine - 2,4 - 14 C] Indaziflam Harvested 30 Days Following the Last of Two Soil Applicati ons at the Base of the Tree Compound [Indane - 3 - 14 C] IndaziflamTreated Apples [Triazine - 2,4 - 14 C] IndaziflamTreated Apples 2 .2 x ( 0.29 lb ai/A) 1 2.8 x (1 .7 lb ai/A) 2 .3 x ( 0.31 lb ai/A) 10 .5 x ( 1.4 lb ai/A) TRR = 0.004 ppm TRR = 0.011 ppm TRR = 0.011 ppm TRR = 0.054 ppm % TRR ppm % TRR ppm % TRR ppm % TRR ppm Indaziflam 13 <0.001 8 <0.001 -- -- -- -- Fluoroethyl Diaminotriazine -- -- -- 72 0.008 62 0.033 ROI 1 (Polar) 46 0.002 76 0.008 -- -- -- -- ROI 2 (Moderately polar) 15 <0.001 -- -- -- -- - - -- ROI 3 (Polar) -- -- -- -- 25 0.003 32 0.017 Diffuse -- -- -- -- -- -- 3 0.002 Total identified 13 <0.001 8 <0.001 72 0.008 62 0.033 Total characterized 61 <0.003 76 0.008 25 0.003 35 0.019 Total uncharacterized 1 4 -- 1 -- 0 -- 0 -- Total extract able 78 0.003 85 0.009 97 0.011 97 0.052 Unextractable (PES) 2 22 0.001 15 0.002 3 <0.001 3 0.002 Accountability3 ~100 ~100 ~100 ~100 1 Total uncharacterized = Total extractable

– Total characterized

– Total Identified. The Total Extractable information comes from the reported values in the registrant study profile template. 2 Residues remaining after exhaustive extractions. 3 Accountability = Total extractable + Total unextractable. Accountabilities were ~100% because results were normalized.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 16 of 52 Table 4 b . Summary of Characterization and Identification of Radioactive Residues in Grapes Treated with [Indane 3 - 14 C] or [Triazine - 2,4 - 14 C] Indaziflam (Spray Application to Soil at the Base of the Vine) Compound [Indane - 3 - 14 C] IndaziflamTreated Grapes 1 [Tria zine - 2,4 - 14 C] IndaziflamTreated Grapes 1 1.8x ( 0.24 lb ai/A) 7.4 x ( 0.98 lb ai/A) 2.0 x ( 0.27 lb ai/A) 7.2 x ( 0.96 lb ai/A) TRR = 0.006 ppm TRR = 0.019 ppm TRR = 0.015 ppm TRR = 0.040 ppm % TRR ppm % TRR ppm % TRR ppm % TRR ppm Indaziflam 19 0.001 2 4 0.005 -- -- -- -- Fluoroethyl Diaminotriazine -- -- -- -- 43 0.006 47 0.019 ROI 1 (Polar) 22 0.001 5 0.001 -- -- -- -- ROI 2 (Moderately polar) 27 0.002 23 0.004 -- -- -- -- ROI 3 (Moderately polar) -- -- -- -- 9 0.001 47 0.019 ROI 4 (Non - polar) -- -- 10 0.002 28 0.004 Total identified 19 0.001 24 0.005 43 0.006 47 0.019 Total characterized 49 0.003 38 0.007 37 0.005 47 0.019 Total uncharacterized2 3 -- 4 -- 1 -- 2 -- Total extractable 71 0.004 66 0.013 81 0.012 96 0.038 Unextractable (PES) 3 2 9 0.002 34 0.006 19 0.003 4 0.002 Accountability

4 ~100 ~100 ~100 ~100 1 In the 2x studies, there were 2 applications

– the first at flowering (67% of total application), the second at a 30 day PHI (33% of total). In the 10x studies, there was a single a pplication at flowering. 2 Total uncharacterized = Total extractable

– Total characterized

– Total Identified. The Total Extractable information comes from the reported values in the registrant study profile template. 3 Residues remaining after exhausti ve extractions. 4 Accountability = Total extractable + Total unextractable. Accountabilities were ~100% because results were normalized.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 17 of 52 Table 4c . Summary of Characterization and Identification of Radioactive Residues Sugarcane Following Application of [Indane - 3 - 14 C] or [Triazine - 2,4 - 14 C] Indaziflam Harvested 30 Days After the Last of Two Soil and Base of Stalk Applications at a total rate of 0.29 lb a.i./A (2.2 times the Proposed maximum seasonal field application rate) 1 Compound [Indane - 3 - 14 C] Indazif lam Treated Sugarcane [Triazine - 2,4 - 14 C] Indaziflam Treated Sugarcane TRR = 0.004 ppm TRR = 0.005 ppm % TRR ppm % TRR ppm Indaziflam 24 <0.001 17 <0.001 Fluoroethyl Diaminotriazine -- -- 30 0.001 ROI 1 (Polar) 6 <0.001 -- -- ROI 2 (Moderately Polar) 35 0.001 -- -- ROI 3 (Polar) -- -- 10 <0.001 ROI 4 (Non - Polar) -- -- 11 <0.001 Total identified 24 <0.001 47 <0.002 Total characterized 41 <0.002 21 <0.002 Total uncharacterized2 1 -- 0 -- Total extractable 66 0.003 68 0.003 Unextractable (PES) 3 34 0.001 32 0.002 Accountability

4 ~100 ~100 1 A similar study was also carried out using 10x the proposed maximum seasonal field application rate. However, due to phytotoxicity, no sugarcane plants survived the experiment. 2 Total uncharacterized = Tot al extractable

– Total characterized

– Total Identified. The Total Extractable information comes from the reported values in the registrant study profile template. 3 Residues remaining after exhaustive extractions. 4 Accountability = Total extractable + Total unextractable. Accountabilities were ~100% because results were normalized.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 18 of 52 Figure 1. Proposed Metabolic Profile of Indaziflam in Sugarcane, Apples, and Grapes (Note: This figure was taken f

rom the petitioner’s study profile without modification .)

C H 3 

### C H 3



### N H N N N N H 2 

### F C H 3



### N H 2 

### N N N N H 2 

### F C H 3 

### AE 1170437

AE 1170437 - Diaminotriazine Polar Metabolites Moderately Polar Metabolites



### 860.1300 Nature of the Residue - Livestock 47743320 .der.doc /47743321 .der.doc

– Goat metabolism D371659

– Report of the Residues of Concern Knowledgebase Subcommittee. G. Kramer. 18 February 2010 

### Indane Label Two lactating go ats were dosed orally, via capsule, with [indane - 3 - 14 

### C ] - AE 1170437 at a rate of 2.14 milligrams of active ingredient per kilogram (mg ai/kg) of body weight (approximately

57 ppm in feed) once daily for five consecutive days. The dose rate wa s 2558X the anticipated maximum reasonably balanced dietary

burden of AE 1170437 (indaziflam) residues in ruminant feed. Milk was collected twice daily during the treatment period. Approximately 23 hours after the last dose, the goats were sacrificed, and edible tis sues ( liver, kidney, perirenal fat, omental fat, round muscle, and loin muscle ) were collected for analysis. The total radioactive residue s (TRR) in the milk and tissues w ere determined using a liquid scintillation counter. I dentification and quantitation of the residues in the milk and tissueI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 19 of 52 extracts were accomplished by using reverse - phase high - performance liquid chromatography ( HPL C ) , and liquid chromatography with tandem mass - spectrometric detection ( LC /MS/MS ). Tissues and milk were extracted , and the results summarized in Table 5a (below) . The majority of the residues (85% to 98 % of the TRR) in the milk and tissues w as extractable, while only 2% to 15% of the TRR (<0.001 to 0.023 ppm) in milk and tissues were unextractable. The TRR (expressed in AE 1170437 equivalents) in the milk samples ranged from 0.011 ppm in the Day- 1 morning, Day- 3 morning, and Day- 5 morning milk to 0.048 ppm in the Day- 2 evening milk. The TRR found in the tissue samples was 0.368, 0.006, 0.007, 0.013, 0.015, and 0.153 ppm in liver, loin muscle, round muscle, perirenal fat, omental fat, and kidney, respectively . TABLE 5a Extractability of [indane - 3 - 14 C] - AE 1170437 Residues in Edible Tissues and Milk. Matrix Total

Residues (ppm) Extractable Residues Unextractable Re sidues %TRR 1 ppm % TRR ppm Liver 0.368 97 0.362 2 0.006 Kidney 0.153 85 0.131 15 0.023 Muscle (Loin) 0.006 NE 2

- - - Muscle (Round) 0.007 NE - - - Fat (Perirenal) 0.013 98 0.013 2 <0.001 Fat (Omental) 0.015 NE Day- 1 Milk 0.120 96 0.116 4 0.0 05 Day- 3 Milk 0.123 92 0.113 8 0.010 Day- 5 Milk 0.164 86 0.141 14 0.023 3 1 %TRR = percent Total Radioactive Residues. 2 NE = Not Extracted. Muscle samples were not extracted due to the low TRR values. Results are reported from the extraction of peri renal fat, which was used to represent the residue profile in fat. 3 The D ay- 5 milk solids solublized during reflux with 1 N HCl, so there were no solids remaining after this step. 

### The major residues found in the milk and tissues were parent AE 117043 7 (2% to 20% of the TRR; 0.003 to 0.011 ppm), AE 1170437 - 4 - hydroxy- hydroxy methyl (2% to 16% of the TRR; <0.001 to 0.020 ppm), AE 1170437 - dihydroxy (11% to 14% of the TRR; 0.016 to 0.020 ppm), AE 1170437 - 3 - ketohydroxy methyl (2% to 13% of the TRR; <0.001 to 0.017 ppm), AE 1170437 - 3 - ketohydroxy

methyl GA (2% to 28% of the TRR; 0.002 to 0.105 ppm), AE 1170437 - 3 - hydroxyindane GA (12% to 19% of the TRR; 0.002 to 0.017 ppm), 3 - hydroxyindane (12% to 18% of the TRR; 0.018 to 0.021 ppm), and AE 1170437 - carboxylic acid (6% to 26% of the TRR; 0.008 to 0.089 ppm). The minor residues found in the milk and tissues were AE 1170437 - 4 - hydroxy acid (2% to 7% of the TRR; <0.001 to 0.006 ppm) and AE 1170437 - 3 - keto - 4 - hydroxy (3% to 5% of the TRR; 0.004 to 0.007 ppm). Metabolic degradation of AE 1170437 is rapid and nearly complete, with between 2% and 20% of the TRR being observed in the milk and tissues as unmetabolized parent (AE 1170437). Oxidation products , including AE 1170437 - 4 - hydroxy- hydroxy methyl, AE 1170437 - dihydroxy , AE 1170437 - 3 - ketohydroxy methyl, 3 - hydroxyindane, and AE 1170437 - carboxylic acid , were observed in milk and tissue samples, indicating that oxidation is the main route of metabolism for the parent compound. Glucuronic acid (GA) conjugates AE 1170437 - 3 - hydroxyindane GAI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 20 of 52 and AE 1170437 - 3 - ketohydroxy methyl GA were also observed. T riazine Label . Two lactating goats were dosed orally, via capsule, with [triazine - 2,4 - 14 

### C ] - A E 1170437 at a rate of 2.24 milligrams of active ingredient per kilogram (mg ai/kg) of body weight (approximately

47 ppm in feed) once daily for five consecutive days. The dose rate wa s 2125X the anticipated maximum reasonably balanced dietary

burden of AE 1170437 residues in ruminant feed. Milk was collected twice daily during the treatment period. Approximately 23 hours after the last dose, the goats were sacrificed, and edible tissues ( liver, kidney, perirenal fat, omental fat, round muscle, and loin muscle ) were collected for analysis. The total radioactive residue s (TRR) in th e milk and tissues w ere determined using a liquid scintillation counter. I dentification and quantitation of the residues in the milk and tissue extracts were accomplished by using reverse - phase high - performance liquid chromatography ( HPL C ) , and liquid chromatography with tandem mass - spectrometric detection ( LC /MS/MS ) . The TRR (expressed in AE 1170437 equivalents) in the milk samples ranged from 0.037 ppm in the Day- 1 morning milk to 0.067 ppm in the Day- 3 evening milk. The TRR found in the tissue sampl es was 0.816, 0.022 , 0.025, 0.044, 0.032, and 0.405 ppm in liver, loin muscle, round muscle, perirenal fat, omental fat, and kidney, respectively . The residues extrapolated to 1X the anticipated maximum reasonably balanced dietary

burden would be <0.001 p pm in all tissues and milk. Tissues and milk were extracted , and the results summarized in Table 5b (below) . The majority of the residues (95% to 100% of the TRR) in the milk and tissues was extractable, while only <1% to 4% of the TRR (<0.001 to 0.012 ppm) in milk and tissues w ere unextractable. TABLE 5b . Extractability of [triazine - 2,4 - 14 C] - AE 1170437 Residues in Edible Tissues and Milk. Matrix Total

Residues (ppm) Extractable Residues Unextractable Residues %TRR 1 ppm % TRR ppm Liver 2 0.8 16 99 0.812 <1 0.003 Kidney 2 0.405 97 0.392 3 0.012 Muscle (Loin) 2 0.022 95 0.021 4 <0.001 Muscle (Round) 0.025 NE 3

- - - Fat (Perirenal) 2 0.044 97 0.042 3 0.001 Fat (Omental) 0.032 NE - - - Day- 1 Milk 0.274 99 0.271 1 0.003 Day- 3 Milk 0.400 99 0.397 <1 0.003 Day- 5 Milk 0.378 100 0.377 <1 0.001 1 %TRR = percent Total Radioactive Residues. TRR were detemined by oxidation, unless otherwise noted. 2 The TRR values reported for the liver, kidney, loin muscle, and perirenal fat were calculated as the sum of the extracted radioactive residues and the radioactive residues remaining in the extracted solids. 3 NE = Not Extracted. Muscle samples were not extracted due to the low TRR values. Results are reported from the extraction of perirenal fat, w hich was used to represent the residue profile in fat. 

### The major residues found in the milk and tissues were AE 1170437 - diaminotriazine (2% to 15%I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 21 of 52 of the TRR; 0.001 to 0.049 ppm), AE 1170437 - 4 - hydroxy- hydroxy methyl (4% to 18% of the TRR; 0.003 to 0.066 ppm), AE 1170437 - dihydroxy (2% to 18% of the TRR; 0.002 to 0.067 ppm), AE 1170437 - 4 - hydroxy acid (5% to 14% of the TRR; 0.005 to 0.058 ppm), AE 1170437 - 3 - ketohydroxy

methyl (2% to 28% of the TRR; 0.001 to 0.089 ppm), AE 1170437 - 3 - hydroxyindane GA (9% to 24% of the TRR; 0.004 to 0.199 ppm), 3 - hydroxyindane (3% to 14% of the TRR; 0.003 to 0.022 ppm), and AE 1170437 - carboxylic acid (2% to 20% of the TRR; 0.001 to 0.130 ppm). The minor residues found in the milk and tissues were AE 1170437 - 3 - hydroxyindane acid (2% to 7% of the TRR; 0.002 to 0.028 ppm), AE 1170437 - 3 - keto - 4 - hydroxy (4% to 6% of the TRR; <0.001 to 0.020 ppm), and AE 1170437 - 3 - ketohydroxy methyl GA (<1% to 4% of the TRR; <0.001 to 0.032 ppm). Only a minor amount of parent AE 1170437 was identified i n any

of the milk and tissues (1% to 9% of the TRR; 0.004 to 0.015 ppm). Metabolic degradation of AE 1170437 is rapid and nearly complete, with between 1% and 9% of the TRR being observed in the milk and tissues as unmetabolized parent (AE 1170437). Ox idation products , including AE 1170437 - 4 - hydroxy- hydroxy methyl, AE 1170437 - dihydroxy , AE 1170437 - 4 - hydroxy

acid, AE 1170437 - 3 - ketohydroxy methyl, 3 - hydroxyindane, and AE 1170437 - carboxylic acid were observed in milk and tissue samples, indicating that oxidation is the main route of metabolism for the parent compound. Glucuronic acid (GA) conjugates AE 1170437 - 3 - hydroxyindane GA and AE 1170437 - 3 - ketohydroxy methyl GA were also observed. Conclusions . Based on the available information, indaziflam appear s t o undergo significant oxidative metabolism in ruminants. The metabolic pathways observed in the s e studies w ere similar , with the exception of the label specific diaminotriazine metabolite found in the triazine label study . T he same was true for the [ 14 

### C ] - AE 1170437 rat metabolism study ( MRID 47443312, 47743418 ) with only minor differences (two additional metabolites, AE 1170437 - 4 - hydroxy- hydroxy

methyl and AE 1170437 - 3 - keto - 4 - hydroxy , were found in the goat metabolism studies) . Table s 5c and 5d summariz e the characterization and identification of residues in goat matrices from the indane and triazine label studies. There are a number of significant (> 10% TRR) metabolites, depending on the commodity being examined , with most consisting of some level of increased hydroxylation relative to the parent compound (Figure 2). The residue definitions for tolerance enforcement and risk assessment are summarized in Table 6 .I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 22 of 52 Table 5 c . Summary of Characterization and Identification of Radioactive Resi dues in Goat Matrices Following the Oral Administration of [Indane - 34 - 14 C] AE 1170437 at a Rate of 2.14 mg ai/kg Body Weight/Day for Five Consecutive Days. Compound Milka TRR = 0.120 to 0.164 ppm Liver

TRR = 0.368 ppm Fatb

TRR = 0.013 ppm Kidney

TRR = 0.153 ppm %TRR ppm %TRR ppm %TRR ppm %TRR ppm AE 1170437 3 to 9 0.005 to 0.011 2 0.008 20 0.003 ND c ND c AE 1170437 - 4 - hydroxy- hydroxymethyl 11 to 16 0.013 to 0.020 2 0.006 5 <0.001 4 0.006 AE 1170437 - dihydroxy 12 to 14 0.016 to 0.020 ND c ND c ND c ND c 11 0.016 AE 1170437 - 4 - hydroxy acid ND c ND c 2 0.006 7 <0.001 ND c ND c AE 1170437 - 3 - keto - 4 - hydroxy 3 to 5 0.004 to 0.006 ND c ND c ND c ND c 5 0.007 AE 1170437 - 3 - ketohydroxymethyl 11 to 13 0.014 to 0.017 2 0.008 4 <0.001 3 0.004 AE 1170437 - 3 - ketohydroxymethyl GA 3 0.003 28 0.105 ND c ND c 2 0.002 AE 1170437 - 3 - hydroxyindane GA ND c ND c ND c ND c 19 0.002 12 d 0.017 d 3 - hydroxyindane 12 to 18 0.018 to 0.021 ND c ND c ND c ND c ND c ND c AE 1170437 - carboxylic acid 6 to 9 0.008 to 0.011 24 0.089 16 0.002 26 0.04 0 M3 - 2, M5 - 2 2 0.002 to 0.003 ND c ND c ND c ND c ND c ND c M5 - 3 2 0.003 ND c ND c ND c ND c ND c ND c M1 - 5, M3 - 7, M5 - 8, L - 3, F - 3, K - 4 5 to 7 0.008 2 0.009 4 <0.001 7 0.010 L - 4, F - 4 ND c ND c 4 0.013 7 <0.001 ND c ND c M1 - 2, M3 - 3, M5 - 4 3 to 4 0.004 to 0.006 ND c ND c ND c ND c ND c ND c M3 - 4 2 0.002 ND c ND c ND c ND c ND c ND c M5 - 5 2 0.004 ND c ND c ND c ND c ND c ND c M3 - 10, M5 - 11 2 to 3 0.003 to 0.004 ND c ND c ND c ND c ND c ND c M1 - 9, M3 - 11, M5 - 12, K - 8 5 0.006 to 0.008 ND c ND c ND c ND c 1 0.002 K - 1 ND c ND c ND c ND c ND c ND c 2 0.003 M 1 - 1, M3 - 1, M5 - 1 2 0.002 to 0.003 ND c ND c ND c ND c ND c ND c K - 10 ND c ND c ND c ND c ND c ND c 2 0.003 F - 7 ND c ND c ND c ND c 3 <0.001 ND c ND c K - 11 ND c ND c ND c ND c ND c ND c 1 0.002 F - 9 ND c ND c ND c ND c 10 0.001 ND c ND c K - 13 ND c ND c ND c ND c ND c ND c 2 0.002 F - 11 ND c ND c ND c ND c 3 <0.001 ND c ND c Total Identified 60 to 81 0.083 to 0.097 60 0.222 71 0.009 63 0.092 Total Characterized 16 to 28 0.021 to 0.045 38 0.141 27 0.004 23 0.035 Total Extractable 92 to 100 0.113 to 0.164 97 0.362 98 0.013 85 0.131 Unextracted 4 to 8 0.005 to 0.010 2 0.006 2 <0.001 15 0.023 Accountability 97 to 106 103 82 121 aResults are reported as ranges of values for the composite day- 1, day- 3, and day- 5 milk. bResults are reported from the extraction of perirenal fat, which was used to rep resent the residue profile in fat. cND = Not detected. dThe amount of AE 1170437 - 3 - hydroxyindane GA reported in kidney (12% of the TRR and 0.017 ppm) was the sum of K - 9 (4% of the TRR and 0.005 ppm) and K - 14 (8% of the TRR and 0.012 ppm).I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 23 of 52 Table 5 d . Summary of Characterization and Identification of Radioactive Residues in Goat Matrices Following the Oral Administration of [Triazine - 2,4 - 14 C] AE 1170437 at a Rate of 2.24 mg ai/kg Body Weight/Day for Five Consecutive Days. Compound Milka TRR = 0.274 to 0.40 0 ppm Liver TRR = 0.816 ppm Muscle b

TRR = 0.022 ppm Fat c

TRR = 0.044 ppm Kidney

TRR = 0.405 ppm %TRR ppm %TRR ppm %TRR ppm %TRR ppm %TRR ppm AE 1170437 1 0.004 2 0.015 ND d ND d 9 0.004 ND d ND d AE 1170437 - diaminotriazine 12 to 13 0.036 to 0.049 ND d ND d 1 5 0.003 3 0.001 2 0.009 AE 1170437 - 4 - hydroxyhydroxymethyl 15 to 18 0.042 to 0.066 4 0.036 15 0.003 7 0.003 4 0.016 AE 1170437 - dihydroxy 17 to 18 0.048 to 0.067 2 0.015 18 0.040 4 0.002 6 0.026 AE 1170437 - 4 - hydroxy acid ND d ND d 5 0.038 ND d ND d 12 0.005 14 0.058 AE 1170437 - 3 - hydroxyindane acid 2 to 3 0.005 to 0.010 ND d ND d ND d ND d 5 0.002 7 0.028 AE 1170437 - 3 - keto - 4 - hydroxy 5 to 6 0.017 to 0.020 ND d ND d 4 <0.001 ND d ND d ND d ND d AE 1170437 - 3 - ketohydroxymethyl 22 to 28 0.076 to 0.089 2 0.020 5 0.001 4 0. 002 6 0.024 AE 1170437 - 3 - ketohydroxymethyl GA <1 0.003 4 0.032 3 <0.001 2 0.001 ND d ND d AE 1170437 - 3 - hydroxyindane GA ND d ND d 24 e 0.199 e ND d ND d 9 0.004 17 0.068 3 - hydroxyindane 3 to 6 0.012 to 0.022 ND d ND d 14 0.003 ND d ND d ND d ND d AE 1170437 - carboxyl ic acid 2 to 3 0.007 to 0.014 16 0.130 6 0.001 19 0.008 20 0.082 M1 - 4, M3 - 4, M5 - 4 <1 to 1 0.002 to 0.005 ND d ND d ND d ND d ND d ND d ND d ND d M - 2, K - 3 ND d ND d ND d ND d 2 <0.001 ND d ND d 1 0.005 L - 4, M - 6 ND d ND d 4 0.030 2 <0.001 ND d ND d ND d ND d F - 7, K - 8 ND d ND d ND d ND d ND d ND d 4 0.002 5 0.022 M1 - 5, M3 - 5, M5 - 5, F - 2 5 to 6 0.014 to 0.022 ND d ND d ND d ND d 2 <0.001 ND d ND d M5 - 6 <1 0.003 ND d ND d ND d ND d ND d ND d ND d ND d M5 - 12, F - 9, K - 10 <1 0.002 ND d ND d ND d ND d 3 0.001 7 0.028 M - 3 ND d ND d ND d ND d 5 0.001 ND d ND d ND d ND d M1 - 11, M3 - 12, M5 - 13, M 10, F - 11, K - 11 1 to 2 0.003 to 0.008 ND d ND d 2 <0.001 2 0.001 2 0.007 M3 - 13, M5 - 14 <1 to 3 0.003 to 0.013 ND d ND d ND d ND d ND d ND d ND d ND d M1 - 1, M3 - 1, M5 - 1 1 0.003 to 0.005 ND d ND d ND d ND d ND d ND d ND d ND d M1 - 3, M3 - 3, M5 - 3, K - 2 1 to 2 0.003 to 0.006 ND d ND d ND d ND d ND d ND d 2 0.006 F - 13, M - 12 ND d ND d ND d ND d 4 <0.001 4 0.002 ND d ND d F - 14 ND d ND d ND d ND d ND d ND d 2 <0.001 ND d ND d M3 - 16, L - 9, F - 16, K - 14 2 0.008 2 0.017 ND d ND d 2 <0.001 3 0.011 F - 18 ND d ND d ND d ND d ND d ND d 4 0 .002 ND d ND d Total Identified 85 to 89 0.246 to 0.345 59 0.485 80 0.051 74 0.032 76 0.311 Total Characterized 8 to 14 0.025 to 0.060 40 0.326 15 0.001 23 0.010 20 0.079 Total Extractable 99 to 100 0.271 to 0.397 99 0.800 95 0.021 97 0.042 97 0.392 Unextracted <1 to 1 0.001 to 0.003 <1 0.003 4 <0.001 3 0.001 3 0.012 Accountability 94 to 105 99 86 105 100 aResults are reported as ranges of values for the composite day- 1, day- 3, and day- 5 milk. bResults are reported from the extraction of loin muscle, wh ich was used to represent the residue profile in muscle. c Results are reported from the extraction of perirenal fat, which was used to represent the residue profile in fat. d ND = Not detected. e The amount of AE 1170437 - 3 - hydroxyindane GA reported in liver (24% of the TRR and 0.199 ppm) was the sum of L - 7 (5% of the TRR and 0.042 ppm) and L - 10 (19% of the TRR and 0.157 ppm).I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 24 of 52 Figure 2. Proposed Metabolic Profile for Indaziflam in the L actating Goat (Note: This figure was taken f

rom the petitioner’s study p rofile without modification .)

N N N

C H 3 C H 3

N H C H 3 F

N H 2 AE 1170437

N N N

C H 3 C H 3

N H C H 3 F

N H 2 O O O H O H O H O H O

3-Hy

droxyindane GA N N N C H 3 N H C H 3 F

N H 2 O H Hydroxymethyl N N N N H 2 C H 3 F

N H 2 AE 1170437-diaminotriazine

N N N

C H 3 C H 3

N H C H 3 F

N H 2 O H O H

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

N H 2 O H

O H N N N

C H 3 C H 3

N H C H 3 F

N H 2 O H

AE 1170437-3-hy droxyindane

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

N H 2 O H

O H AE 1170437-dihy droxy

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

N H 2 O

O H AE 1170437-3-ketohydroxy methyl O N N

N C H 3 N H C H 3 F

N H 2 O

O O H

O O H O H

O H

AE 1170437-3-ketohydroxymethy l GA N N N C H 3 N H C H 3 F

N H 2 O H O

AE 1170437-3-keto-4-hy droxy N N N C H 3 N H C H 3 F

N H 2 H O 2 C AE 1170437-carboxylic acid

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

N H 2 O H

H O 2 C AE 1170437-3-hydroxyindane acid N N N C H 3 N H C H 3 F

N H 2 O H

H O 2 C AE 1170437-4-hy droxy acid AE 1170437-4-hy

droxyhydroxymethylI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 25 of 52 Table 6 . Compounds to be Included in the Risk Assessment and Tolerance Expression. Matrix Residues included in Risk Assessment Residues included in Tolerance Expression for Compliance Monitoring Plants Primary Crop Indaziflam + Fluoroethyl Diaminotriazine (FDAT) Indaziflam + FDAT Rotational Crop Not applicable at this time (no data

available) Not applicable at this time (no data available) Livestock Ruminant Indaziflam + FDAT + Indaziflam- 3 - ketohydroxymethyl + Indazif lam 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 av ailable) Drinking Water Indaziflam + FDAT + Triazine i ndanone + Indaziflam carboxylic acid + Indaziflam hydroxyethyl + Indaziflam olefin 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 - d iamine (CAS) FDAT = 6 - [(1 R ) - 1 - fluoroethyl] - 1,3,5 - triazine - 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) . 

### 860.1340 Residue Analytical Methods 47743323 .der.doc 

### Bayer CropScience method DH - 003 - P07 - 02 wa s developed to determine the residues of AE 1170437 in fruit and tree nut matrices. The method was successfully validated in almond hulls, almonds nutmeat, apple fresh fruit, cherries (sweet), cherries (tart), grape fresh fruit, grapefruit, lemon, olive, orange fresh fruit, peach fresh fruit, pear fresh fruit, pecan nutmeat, plum and sugarcane matrices. Additional validation was performed as part of the magnitude of the residue studies. A 5.0 - g aliquot of the crop matrix was extracted by blending with a mixture of ACN/water, filtered and analy

zed by high performance liquid chromatography / electrospray

ionization / tandem mass spectrometry (LC/MS/MS). The method was validated to a limit of quantitation (LOQ) of 0.005 ppm in crop matrices. These data s upport a total method L OQ of 0.01 ppm in all fruit and tree nut matrices [combined residues of parent (0.005 ppm) and metabolite (0.005 ppm)]. In addition, method limits ofI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 26 of 52 detection (L ODs) were calculated from the data. A previous version DH - 003 - P07 - 01 was validated to a limit of quantitation of 0.01 ppm in crops matrices. All analy tical steps, including the extraction, are identical in DH - 003 - P07 - 02 which effectively replaces the previous version. The independent laboratory validation showed that the individual recoveries for both analy tes lie between 70 % and 120%, and the individual average recoveries had a relative standard deviation (RSD) below 20%. The method has been shown to be specific for the target analy tes. The method used HPL C MS/MS for de tection and quantitation of the indaziflam and fluoroethyl diaminotriazine . Conclusions . Method DH - 003 - P07 - 02 has been sufficiently validated and is suitable as an enforcement method for crops. The method is able to determine, separately, residues of indaziflam and FDAT. The method has been adequately radiovalidated using samples from the apple and grape metabolism studies. The method has been sent to the Analy tical Chemistry Branch of the Biological and Economic Analysis Division (AC B /BEAD) as well as to the Food and Drug Administration (FDA) as an official enforcement method. The analy tical standards, including the stable - isotope internal standard, for the method will need to be forwarded by the petitioner to AC B prior to registration. Use of the proper stable - isotope - labeled internal standards is critical to the methods accuracy and effectiveness. 860.1360 Multiresidue Methods 47743327.der.doc 

### Bayer CropScience tested the suitability of the Food and Drug Administration ’s (FDA ’s ) multi residu e methods for regulatory analysis of i ndaziflam (CAS name 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, and CAS number 950782 - 86 - 2 ) and its metabolite , 1 - fluoroethyldiaminotriazine . None of the method pro tocols were suitable for the analysis of i ndaziflam or its metabolite in crop matrices. Conclusions . FDA’s multiresidue methods are not suitable for analysis or enforcement of indaziflam residues. This information has been forwarded to FDA. 860.1380 Storage Stability 477433329.der.doc 

### This study

was initiated to evaluate the freezer storage stability of indaziflam and 1 - fluoroethyldiaminotriazine in various crop matrices. Samples (approximately

5.00 grams each) of almond hulls, almond nutmeat, ap ples (fresh fruit), cherries (fresh fruit), and orange s (fresh fruit) were prepared. Samples were fortified individually at 0.100 ppm each of indaziflam or 1 - fluoroethyldiaminotriazine. Triplicate fortified samples of each matrix were analy

zed immediately after fortification (zero days). Stored samples were analy zed for residues of indaziflam and 1 - fluoroethyldiaminotriazine at nominal intervals of 1, 3, 6, 9 and 12 months. Throughout these intervals, all fortified samples were stored at a maximumI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 27 of 52 daily average temperature of < - 20°C. Sampl e analyses for indaziflam and 1 - fluoroethyldiaminotriazine were performed using the analy tical method for determining the total residues of indaziflam and 1 - fluoroethyl diamino triazine in crop matrices ( see Reference s 1 and 2 ). Indaziflam and 1 - flurorethyldiaminotriazine were stable in all crop matrices studied for up to 12 months . Conclusions . The available storage stability data indicate that residues of indaziflam and FDAT are stable in frozen storage for up t o approximately 1 2 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. However, s ubmission of an acceptable storage stability study covering the full duration of sample storage should be submitted as a conditi on of registration. 860.1400 Water, Fish, and Irrigated Crops There are no proposed uses for indaziflam that are germane to this guideline. No evaluation is necessary at this time. 860.1460 Food Handling There are no proposed uses for indaziflam that are germane to this guideline. No evaluation is necessary at this time. 860.1480 Meat, Milk, Poultry, and Eggs 47743401 .der.doc 

### Bayer CropScience has requested a waiver of the requirement for a livestock feeding study with indaziflam. B ayer ha s submi tted acceptable ruminant ( goat) metabolism studies with indaziflam, performed at exaggerated rates (>2100X) relative to the expected dietary burden . Section (b) of EPA’s OPPTS Residue Chemistry Guideline 860.1480 (Meat/Milk/Poultry /Eggs) states that “[w]he never pesticide residues are detected in feed items, data on the transfer of residues to meat, milk, poultry , and eggs are required.” Similarly, Section 8.2 of the PMRA Residue Chemistry Guidelines (Meat/Milk/Poultry /Eggs) states that “[w]henever pesticid e residues are detected in feed items, data on the transfer of residues to meat, milk, poultry, and eggs are required.” The revised Table 1 of OPPTS Residue Chemistry Guideline 860.1000 shows that, from the target crops for indaziflam, the only Raw Agricu ltural Commodity (RAC) which is used as a feed item for ruminants is almond hulls. Analysis of samples from the tree nuts field trial study showed that the highest residue in almond hulls was 0.15 ppm. Since the target crops for indaziflam are all orchard crops, there will be no rotation to a crop that could be used for animal feed, and, therefore, rotational crops are of no concern. None of the target crop commodities are used in poultry feeds to any

significant degree.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 28 of 52 When the highest residues in e ach matrix from the goat metabolism studies are used to calculate anticipated maximum residues in cattle, all calculated tissue residues are less than 0.004 ppm, and milk residues are less than 0.0003 ppm, at a 10X feeding level. Conclusions . Using inf

ormation in the goat metabolism studies, residues of indaziflam (as defined by

the livestock residue definition) are expected to be below the limit of quantitation of a reasonable livestock analy tical method. Hence a 40 CFR 180.6(a)(3) situation (no expec tation of finite residues) exists. Neither feeding studies nor tolerances for livestock commodities are required at this time. Feeding studies and analy tical methods may

be required to support future uses of indaziflam that involve significant livestock feed items. 860.1500 Crop Field Trials 47743405.der.doc (citrus) 47743402.der.doc (pome fruit) 47743403.der.doc (stone fruit) 47743404.der.doc (tree nuts) 47743406.der.doc (grapes) 47743407.der.doc (olive) Table 7 . Summary of Residues from the Crop Fi eld Trials with Indaziflam Crop Matrix Applic. Rate , lb a . i . /A (kg a.i./ha) PHI , days Residues , ppm 1 n M i n Max HAFT Median Mean Std. Dev Citrus (proposed use = 0.134 lb ai/A total application rate, 7 - day PHI ) Orange 0.129 - 0.141

(0.145 - 0.159) 12 - 2 8 24 <0.01 <0.01 <0.01 0.010 0.010 0 Orange 0.129 - 0.141

(0.145 - 0.159) 43 - 45 24 <0.01 <0.01 <0.01 0.010 0.010 0 Orange 0.129 - 0.141

(0.145 - 0.159) 234 - 240 24 <0.01 <0.01 <0.01 0.010 0.010 0 Grapefruit 0.129 - 0.139

(0.144 - 0.156) 13 - 28 12 <0.01 <0.01 <0.01 0.010 0.010 0 Grapefruit 0.129 - 0.139

(0.144 - 0.156) 43 - 45 12 <0.01 <0.01 <0.01 0.010 0.010 0 Grapefruit 0.129 - 0.139

(0.144 - 0.156) 231 - 240 12 <0.01 <0.01 <0.01 0.010 0.010 0 Lemon 0.133 - 0.136

(0.149 - 0.153) 14 10 <0.01 <0.01 <0.01 0.010 0.010 0 Lemon 0.133 - 0.136

(0.149 - 0.153) 45 10 <0.01 <0.01 <0.01 0.010 0.010 0 Lemon 0.133 - 0.136

(0.149 - 0.153) 231 - 240 10 <0.01 <0.01 <0.01 0.010 0.010 0 Pom e Fruit (proposed use = 0.134 lb ai/A total application rate, 14 - day PHI ) Apple 0.131 - 0.138

(0.147 - 0.155) 13 - 14 24 <0.01 <0.01 <0.01 0.010 0.010 0 Apple 0.131 - 0.137

(0.146 - 0.154) 43 - 46 24 <0.01 <0.01 <0.01 0.010 0.010 0 Apple 0.131 - 0.140

(0.147 - 0.157) 157 - 209 24 <0.01 <0.01 <0.01 0.010 0.010 0I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 29 of 52 Table 7 . Summary of Residues from the Crop Fi eld Trials with Indaziflam Crop Matrix Applic. Rate , lb a . i . /A (kg a.i./ha) PHI , days Residues , ppm 1 n M i n Max HAFT Median Mean Std. Dev Pear 0.134 - 0.137

(0.150 - 0.154) 13 - 14 11 <0.01 <0.01 <0.01 0.010 0.010 0 Pear 0.133 - 0.144

(0.149 - 0.161) 39 - 45 11 <0.01 <0.01 <0.01 0.010 0.010 0 Pear 0.129 - 0.139

(0.145 - 0.155) 157 - 184 11 <0.01 <0.01 <0.01 0.010 0.010 0 Stone Fruit (proposed use = 0.134 lb ai/A total application rate, 14 - day PHI ) Cherries 0.134 - 0 .141

(0.150 - 0.158) 14 - 20 12 <0.010 <0.010 <0.010 0.010 0.010 0 Cherries 0.132 - 0.145

(0.148 - 0.162) 45 12 <0.010 <0.010 <0.010 0.010 0.010 0 Cherries 0.132 - 0.142

(0.148 - 0.159) 83 - 115 12 <0.010 <0.010 <0.010 0.010 0.010 0 Peaches 0.129 - 0.140

(0.145 - 0.15 7) 13 - 14 18 <0.010 <0.010 <0.010 0.010 0.010 0 Peaches 0.129 - 0.135

(0.144 - 0.152) 43 - 45 18 <0.010 <0.010 <0.010 0.010 0.010 0 Peaches 0.133 - 0.139

(0.149 - 0.156) 120 - 211 18 <0.010 <0.010 <0.010 0.010 0.010 0 Plums 0.132 - 0.136

(0.148 - 0.152) 14 12 <0.010 <0.010 <0.010 0.010 0.010 0 Plums 0.132 - 0.139

(0.148 - 0.156) 45 12 <0.010 <0.010 <0.010 0.010 0.010 0 Plums 0.131 - 0.136

(0.146 - 0.153) 160 - 210 12 <0.010 <0.010 <0.010 0.010 0.010 0 Tree Nuts (proposed use = 0.134 lb ai/A total application rate, 14 - day P HI ) Almond nutmeat 0.132 - 0.135

(0.148 - 0.152) 14 10 <0.010 <0.010 <0.010 0.010 0.010 0 Almond hull 0.132 - 0.135

(0.148 - 0.152) 14 10 <0.010 <0.153 <0.149 0.023 0.050 0.059 Pecan nutmeat 0.130 - 0.134

(0.146 - 0.150) 12 - 13 10 <0.010 <0.010 <0.010 0.010 0.010 0 Grape (proposed use = 0.089 lb ai/A total application rate, 14 - day PHI ) Fresh Fruit 0.130 - 0.140

(0.145 - 0.157) 13 - 14 24 <0.01 <0.01 <0.01 0.01 0.01 0 Fresh Fruit 0.131 - 0.139

(0.147 - 0.155) 43 - 45 24 <0.01 <0.01 <0.01 0.01 0.01 0 Fresh Fruit 0.1 32 - 0.142

(0.148 - 0.159) 143 - 240 24 <0.01 0.0115 0.0113 0.01 0.01 0.0029 Olive (proposed use = 0.134 lb ai/A total application rate, 14 - day PHI ) Fresh Fruit 0.133 - 0.155

(0.149 - 0.151) 14 6 <0.01 <0.01 <0.01 0.01 0.01 0 Fresh Fruit 0.133 - 0.136

(0.149 - 0. 152) 45 6 <0.01 <0.01 <0.01 0.01 0.01 0 Fresh Fruit 0.132 - 0.137

(0.148 - 0.153) 287 - 300 6 <0.01 <0.01 <0.01 0.01 0.01 0 1 Total indaziflam residues (indaziflam + FDAT) are reported. For all samples, residues of FDAT were below the LOQ (< 0.005 ppm). For determination of the median, mean, and standard deviation, all residues reported as < LOQI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 30 of 52 we re assumed to be equal to the single - analyte LOQ of 0.005 ppm. 

### Citrus Twenty- three harvest trials (twelve orange, six grapefruit, and five lemon trials) were condu cted to measure the magnitude of indaziflam {1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - [1 - fluoroethyl]} residues in/on citrus fruits following a single bro adcast application of Indaziflam 500 SC to bare soil, mown or chemically burned - down ground cover, directed to the base of trees and extending to the row centers at a target rate of 0.134 lb ai/A (150 g ai/ha). In daziflam 500 SC is a suspension concentrate formulation containing 500 g ai/L . Application rates ranged from 0.129 to 0.141 lb ai/A (145 to 159 g ai/ha) in orange, from 0.129 to 0.139 lb ai/A (144 to 156 g ai/ha) in grapefruit, and from 0.132 to 0.137 lb ai/A (148 to 153 g ai/ha) in lemon. Spray

volumes ranged from 10 to 20 gal/A (93 to 187 L /ha) for all trials. There were no adjuvants added to the spray mixture. All applications were made using ground - based equipment . All trials had two treated plots that received an application of In daziflam 500 SC; samples were collected from the TRT45 plot at targe t pre - harvest - intervals (PHI ’s) of 14 and 45 days (actual 12 to 14 days and 43 to 45 days, with the exception of three trials where the 14 - day PHIsamples were collected two weeks late due to field investigator oversight) and from the TR240 plot at a targe t PHIof 240 days (actual 231 to 240 days). Inorange plots, application to the TRT45 plots (sampled at target PHI s of 14 and 45 days) was made between BBCH 81 and 85 (BBCH 81: beginning of fruit coloring; BBCH 85: advanced ripening) and application to the TR240 plots (target PHI of 240 days) was made between BBCH 55 and 89 (BBCH 55: flowers visible but still closed, BBCH 89: fruit ripe for consumption). Ingrapefruit plots, application to the TRT45 plots (14 - and 45 - day target PHI s) was made between BBCH 81 to 89 (BBCH 81: beginning of fruit coloring, BBCH 89: fruit ripe for consumption) and application to the TR240 plots (240 - day target PHI) was made between BBCH 60 and 89 (BBCH 60: first flowers open, BBCH 89: fruit ripe for consumption) Inlemon p lots, application to the TRT45 plots (14 - and 45 - day target PHI s) was made between BBCH 79 to 89 (BBCH 79: fruits are about 90% of final size, BBCH 89: fruit ripe for consumption) and application to the TR240 plots (240 - day target PHI) was made between BBC H 07 and 74 (BBCH 07: beginning of bud burst, BBCH 74: fruits are about 40% of final size). Duplicate composite samples of oranges, grapefruit, and lemons were collected from the treated plots at target PHI s of 14, 45, and 240 days after application, and a single composite sample was collected from the control plot at the same time the 45 - day PHIsamples were collected. The residues of indaziflam and its metab olite fluoroethyldiaminotriazine were quantitated by high pressure liquid chromatography /triple stage quadrupole mass spectrometry (LC/MS/MS) using stable isotopically

labeled internal standards. The limit of quantitation (L OQ) for total indaziflam residue (the sum of indaziflam and fluoroethyldiaminotriazine ) was 0.01 ppm inI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 31 of 52 oranges, grapefruit, an d lemons. Freezer storage stability

studies indicate that indaziflam and fluoroethyldiaminotriazine residues would have been stable in orange, grapefruit, and lemon raw agricultural commodities (RACs) during frozen storage (11.5 months) prior to analysis. The orange, grapefruit, and lemon analy zed in this study

were held in frozen storage for a maximum of 1 6.6 months (497 days ) prior to extraction. Inorange, grapefruit, and lemon, the HAFT (highest average field trial) and maximum total indaziflam resid

ues at all three PHI ’s (14 - day , 45 - day , and 240 - day ) were less than the L OQ (<0.01 ppm). Pome Fruit . Eighteen field trials (twelve on apples, and six on pears) were conducted to measure the magnitude of indaziflam (CAS name N - [(1 R ,2 S ) - 2,3 - dihydro - 2,6 - dim ethyl - 1 Hinden - 1 - yl ] - 6 - [1 - fluoroethyl] - 1,3,5 - triazine - 2,4 - diamine, and CAS number 950782 - 86 - 2) residues in pome fruit following a single broadcast application of indaziflam, formulated as the end - use product (EP) , In daziflam 500 SC. Applications were made to bare soil, or mown or chemically

burned - down ground cover, and directed to the base of apple and pear trees (extending to the row centers), at a target rate of 0.134 pounds of active ingredient per acre (lb ai/A), the equivalent of 150 grams ai per hec tare (g ai/ha). The actual use rates were 0.131 - 0.140 lb ai/A (146 - 157 g ai/ha) o n apple s , and 0.129 - 0.144 lb ai/A (145 - 161 g ai/ha) o n pear s . In daziflam 500 SC is a suspension concentrate (SC) formulation containing 500 g ai per liter (g ai/L). There w ere no adjuvants added to the spray mixture. All applications were made using ground - based equipment. All trials had three treated plots that received an application of indaziflam at target 14 - day , 45 - day , or 150 - to 210 - day (5 - to 7 - month) pre - harvest i ntervals (PHI s). Inapple plots, the 14 - day target PHIapplication was made between BBCH 78 and 87 (BBCH 78 = fruit about 80% of final size; BBCH 87 = fruit ripe for picking). The 45 - day target PHI application was made between BBCH 74 and 81 (BBCH 74 = fruit diameter up to 40 mm ; BBCH 81 = beginning of ripening). The 150 - to 210 - day target PHIapplication was made between BBCH 00 and 57 (BBCH 00 = dormancy ; BBCH 57 = pink bud stage). Duplicate composite samples of apples were collected at target PHI s of 14, 45 and 150 - 210 days after application. A single composite sample of apple, whole fresh fruit, was collected from the control plot of each trial at the same time the 14 - day samples were collected from the treated plot. Inpear plots, the 14 - day

t arget PHIapplication was made between BBCH 78 and 85 (BBCH 78 = fruit about 80% of final size; BBCH 85 = advanced ripening). The 45 - day target PHIapplication was made between BBCH 75 and 78 (BBCH 75 = fruit about half of final size). The 150 - to 210 - day target PHIapplication was made between BBCH 00 and 57 (BBCH 00 = dormancy ; BBCH 57 = pink bud stage). Duplicate composite samples of pears were collected at target PHI s of 14, 45 and 150 - 210 days after application with the exception of trial DH092 - 06HA , which had only single treated samples collected. A single composite sample of pear, whole fresh fruit, was collected from the control plot of each trial at the same time the 14 - day samples were collectedI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 32 of 52 from the treated plot. The residues of indazif

lam and its metabolite , 1 - fluoroethyldiaminotriazine, were quantitated by high - pressure liquid chromatography with triple - stage quadrupole m ass spectrometric detection (LC/MS/MS) , using stable isotopically labeled internal standards. The limit of quantitation (LOQ) for total indaziflam residue s (the sum of indaziflam and 1 - fluoroethyldiaminotriazine ) was 0.010 ppm in apples and pears. Freezer storage stability

studies indicate that the indaziflam and 1 - fluoroethyldiaminotriazine residues would be stable in apple and pear raw agricultural commodities (RACs) during frozen storage prior to analysis. The apples and pears analy zed in this study

were held in frozen storage for a maximum of 6.7 months (201 days) prior to extraction. The storage stability studies indicate that indaziflam and 1 - fluoroethyldiaminotriazine are stable for intervals of at least 12.1 months in apple fresh fruit. Inboth apples and pears, the HAFT (highest average field trial) and maximum total indaziflam residues at all three PHI s (14 - day , 45 - day , and 150 - to 210 - day ) were less than the LOQ ( 0.010 ppm). Stone Fruit . T wenty- one field trials (three tart cherry, three sweet cherry , nine peach , and six plum) were conducted to measure the magnitude of indaziflam (CAS name 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, and CAS number 950782 - 86 - 2) residues in stone fruit following a single broadcast application of indaziflam, formulated as the end - use product (EP) , In daziflam 500 SC. Applications were made to bare soil, or mown or chemically burned - down ground cover , and directed to the base of cherry , peach and plum trees (extending to the row centers), at a target rate of 0.134 pounds of active ingredient per acre (lb ai/A), the equiv alent of 150 grams ai per hectare (g ai/ha) . The actual use rates were 0.132 to 0.145 lb ai/A (148 to 162 g ai/ha) o n cherries, 0.129 to 0.14 0 lb ai/A (145 to 157 g ai/ha) o n peaches , and 0.131 to 0.139 lb ai/A (146 to 156 g ai/ha) o n plums. In daziflam 5 00 SC is a suspension concentrate (SC) formulation containing 500 g ai per liter (g ai/L). There were no adjuvants added to the spray mixture. All applications were made using ground - based equipment. All trials had three treated plots (TRT14, TRT45, and either TR150 or TR210) 

### that received an application of indaziflam at target 14 - day , 45 - day , or 150 - to 210 - day (5 - to 7 - month) pre - harvest intervals (PHI s) , respectively . Incherry plots, the application was made on plot TR150 at dormancy, on plot TRT1 4 at a PHIof 14 days, and on plot TRT45 at a PHI of 45 days. Duplicate composite samples of cherries were collected at target 14 - day , 45 - day , and 3 - 5 month (150 - day ) PHI s from treated plots TRT14, TRT45 and TR150, respectively . A single composite sample was collected from the control plot of each trial at the same time the 14 - day PHI samples were collected from the treated plot. Inpeach plots, the application was made on plot TR210 at dormancy, on plot TRT14 at a PHIof 14 days, and on plot TRT45 at a PHIof 45 days. Duplicate composite samples of peaches were collected at target 14 - day , 45 - day , and 5 - 7 month (210 - day ) PHI s from treated plots TRT14, TRT45 and TR210, respectively . A single composite sample was collected from the control plotI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 33 of 52 of each trial at the same time the 14 - day PHI samples were collected from the treated plot. Inplum plots, the application was made on plot TR210 at dormancy, on plot TRT14 at a PHIof 14 days, and on plot TRT45 at a PHI of 45 days. Duplicate composite samples of plums were collected at target 14 - day , 45 - day , and 5 - 7 month (210 - day ) PHI s from treated plots TRT14, TRT45 and TR210, respectively . A single composite sample was collected from the control plot of each trial at the same time the 14 - day PHI samples we re collected from the treated plot. The residues of indaziflam and its metabolite , 1 - fluoroethyldiaminotriazine, were quantitated by high - pressure liquid chromatography with triple - stage quadrupole mass spectrometric detection (LC/MS/MS) , using stable i sotopically labeled internal standards. The limit of quantitation (LOQ) for total indaziflam residue s (the sum of indaziflam and 1 - fluoroethyldiaminotriazine ) was 0.010 ppm in cherries, peaches and plums. Freezer storage stability

studies indicate that the indaziflam and 1 - fluoroethyldiaminotriazine residues would be stable in cherry, peach and plum raw agricultural commodities (RACs) during frozen storage for at least 11.5 months prior to analysis. The cherry, peach and plum fruit analy zed in this stu dy

were held in frozen storage for a maximum duration of 9 months (269 days) prior to extraction. The continuation of the storage stability studies will provide more information when additional time intervals through 24 months are analy zed. Incherries (sweet and tart), the highest average field trial s ( HAFTs) , and maximum total indaziflam residues at target 14 - day , 45 - day , and 150 - day PHI s were all less than the LOQ ( 0.010 ppm). Inpeaches and plums , the HAFTs and maximum total indaziflam residues at target 14 - day , 45 - day , and 210 - day PHI s were all less than the LOQ ( 0.010 ppm). Tree Nuts . T en field trials (five almond and five pecan) were conducted to measure the magnitude of indaziflam (CAS name 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, and CAS number 950782 - 86 - 2) residues in almond nutmeat, almond hulls, and pecan nutmeat following a single broadcast application of indaziflam, formulated as the end - use product (EP) , In daziflam 500 SC. Applic ations were made to bare soil, or mown or chemically burned - down ground cover , and directed to the base of almond and pecan trees , at a target rate of 0.134 pounds of active ingredient per acre (lb ai/A), the equivalent of 150 grams ai per hectare (g ai/ha). The actual use rates were 0.132 to 0.13 5 lb ai/A (148 to 152 g ai/ha) o n almond s, and 0.130 to 0.13 4 lb ai/A (146 to 150 g ai/ha) o n pecan s . In daziflam 500 SC is a suspension concentrate (SC) formulation containing 500 g ai per liter (g ai/L). There were no adjuvants added to the spray mixture. All applications were made using ground - based equipment. All trials had one treated plot (TRTD) that received an application of In daziflam 500 SC. Inalmond plots, the application was made between BBCH 79 and 87 (BBCH 79 = fruit about 90% of fin al size; BBCH 87 = fruit ripe for picking). Duplicate composit e samples of almond nutmeat and almond hulls were collected at a target 14 - day pre - harvest interval (PHI) after application. A single composite sample w as collected from the control plot of each trial at the same time the 14 - day

samples were collected from the treated plot.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 34 of 52 Inpecan plots, the application was made between BBCH 79 and 89 (BBCH 79 = fruit a bout 90% of final size; BBCH 89 = fruit ripe for consumption). Duplicate composite samples of pecans were collected at a target 14 - day PHIafter application. A single composite sample was collected from the control plot of each trial at the same time the 14 - day samples were collected from the treated plot. The residues of indaziflam and its metabolite , 1 - fluoroethyldiaminotriazine, were quantitated by high - pressure liquid chromatography with triple - stage quadrupole mass spectrometric detection (LC/MS/MS) , using stable isotopically labeled internal s tandards. The limit of quantitation (LOQ) for total indaziflam residue s (the sum of indaziflam and 1 - fluoroethyldiaminotriazine ) was 0.010 ppm in almond nutmeat, almond hulls , and pecan nutmeat. Freezer storage stability

studies indicate that the indaz iflam and 1 - fluoroethyldiaminotriazine residues would be stable in almond and pecan raw agricultural commodities (RACs) during frozen storage for intervals of at least 11.8 months prior to analysis. The nutmeat and hulls analy zed in this study

were held i n frozen storage for a maximum of 13.8 months (414 days) prior to extraction. The continuation of the storage stability studies will provide more information when additional time intervals through 24 months are analy zed. Inalmond nutmeat, the HAFT (hi ghest av erage field trial) and maximum total indaziflam residues ( at a target 14 - day PHI) were both <LOQ ( 0.010 ppm). Inpecan nutmeat, the HAFT and maximum total indaziflam residues ( at a target 14 - day PHI) were both <LOQ ( 0.010 ppm) . Inalmond hulls, the HAFT and maximum total indaziflam residues ( at a target 14 - day PHI) were 0. 149 ppm and 0.153 ppm, respectively . Grape . Field trials were conducted to measure the magnitude of Indaziflam { 1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - [1 - fluoroethyl] } residues in/on grapes following a single broadcast spray application of Indaziflam 500 SC. Indaziflam 500 SC is a suspension concentrate (SC) formulation containing 500 grams of active ingredient per liter ( 

### g ai/L) of ind aziflam. Twelve field trials were conducted on grapes in the United States, encompassing Zones 1, 10, and 11 (Zone 1 (PA)

– 2 trials, Zone 10 (CA)

– 8 trials, Zone 11 (OR)

– 2 trials) during the 2007 or 2008 growing season. There were three treated plots for each trial. Each treated plot received one broadcast application at a target rate of 0.134 lb ai/A (150 g ai/ha) to bare soil, or mown or chemically

burned - down ground cover, using backpack sprayers directed to the base of grape vines, and extending to the row centers. Applications were made at target pre - harvest intervals (PHI s) of 14 days, 45 days, and either 150 to 210 days (five to seven months) or 240 days (eight months). Application of Indaziflam 500 SC in this manner has been shown to be effi cacious for controlling dicot and annual grass weeds in grapes and is representative of the proposed use pattern. The actual rates were 0.130 to 0.142 lb ai/A (145 to 159 g ai/ha) for all trials. There were no adjuvants added to the spray mixture. All trials had three treated plots (TRT14, TRT45, and either TR210 or TR240) that received an application of Indaziflam 500 SC.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 35 of 52 Ingrape plots treated at a target 14 - day PHI , the growth stage at application ranged from BBCH 83 to BBCH 89 (BBCH 83: fruit develo ping color; BBCH 89: fruit ripe for harvest). In plots treated at a target 45 - day

PHI , the growth stage at application ranged from BBCH 77 to BBCH 85 (BBCH 77: fruit beginning to touch; BBCH 85: fruit softening). In plots treated at a target 210 - or 240 - day

PHI , the growth stage at application was BBCH 00, with the exception of one target 210 - day

PHIplot in which application was made at BBCH 01 and one target 240 - day PHI plot in which application was made at BBCH 11 (BBCH 00: dormancy - bud scales more o r less closed; BBCH 01: beginning of bud swelling: buds begin to expand inside the bud scales; BBCH 11: first leaf unfolded and spread away from shoot). Duplicate composite samples of grapes were collected in all trials from each treated plot (TRT14, TRT4 5, and either TR210 or TR240) at the target 14 - day , 45 - day , and either 210 - day or 240 - day

PHIafter application. A single composite sample was collected from the control plot of each trial at the same time the 14 - day samples were collected from the treate d plot. The residues of indaziflam and its metabolite fluoroethyldiaminotriazine (FDAT) were quantitated by

high performance liquid chromatography /electrospray

ionization/tandem mass spectrometry

(LC/MS/MS) using stable isotopically labeled internal stan dards. The limit of quantitation (L OQ) for total indaziflam residues (the sum of indaziflam and fluoroethyldiaminotriazine) was 0.01 ppm in grape (fresh fruit). Freezer storage stability

studies in representative crop matrices indicate that the indaziflam and fluoroethyldiaminotriazine residues would have been stable (<1% decomposition) in grape raw agricultural commodity

(RAC) during frozen storage for up to 11.5 months (345 days) prior to analysis. The fresh fruit analy zed in this study

was held in fro zen storage for a maximum of six months (181 days) prior to extraction. The continuation of the storage stability studies will provide more information when additional time intervals through 24 months are analy zed. Ingrape (fresh fruit), the HAFT (highes t average field trial) and maximum total indaziflam residues at target 14 - day , 45 - day , and 210 - day PHI s were less than the L OQ (<0.01 ppm). The HAFT and maximum total indaziflam residues at a target 240 - day PHIwere both 0.01 ppm. Olive . Field trials were conducted to measure the magnitude of indaziflam { 1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - [1 - fluoroethyl] } residues in/on olives following a single broadcast spray application of In daziflam 500 SC. In daziflam 50 0 SC is a suspension concentrate formulation containing 500 g ai/L of indaziflam . Three field trials were conducted on olives. There were three treated plots for each trial. Each treated plot received one broadcast application at a target rate of 0.134 lb ai/A (150 g ai/ha) to bare soil, mown, or chemically burned - down ground cover using backpack sprayers directed to the base of olive trees and extending to the row centers. Applications were made at target pre harvest - intervals (PHI s) of 14 days, 45 days, and 300 days (10 months). Application of In daziflam 500 SC in this manner has been shown to be efficacious for controlling dicot and annual grass weeds in olives and is representative of the proposed use pattern. The actual rates were 0.132 to 0.137 lb ai/A (148 to 153 g ai/ha) for all trials. There were no adjuvants added to the spray mixture. All trials had 3 treated plots (TRT14, TRT45, and TR300) that received anI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 36 of 52 application of In daziflam 500 SC. Duplicate composite samples of olives were collec ted in all trials from each treated plot (TRT14, TRT45 and TR300) at the target 14 - day , 45 - day , and 300 - days PHIafter application. A single composite sample was collected from the control plot of each trial at the same time the 14 - day samples were collec ted from the treated plot. The residues of indaziflam and its metabolite fluoroethyldiaminotriazine were quantitated by high performance liquid chromatography /electrospray

ionization/tandem mass spectrometry (LC/MS/MS) using a stable isotopically labeled internal standards. The limit of quantitation (LOQ) for total indaziflam residue (the sum of indaziflam and fluoroethyldiaminotriazine ) was 0.01 ppm in olive (fresh fruit). Freezer storage stability

studies in representative crop matrices indicate that the indaziflam and fluoroethyldiaminotriazine residues would have been stable (<1% decomposition) in olive raw agricultural commodity

(RAC) during frozen storage for up to 11.7 months (351 days) prior to analysis. The fresh fruit analy zed in this study

wa s held in frozen storage for a maximum of 16 months 28 days (515 days) prior to extraction. The continuation of the storage stability studies will provide more information when additional time intervals through 24 months are analy zed. Ino live (fresh fr

uit), the HAFT (highest average field trial) and maximum total indaziflam residues at a target 14 - day , 45 - day , and 300 - day PHIwere less than the L OQ (<0.01 ppm). Sugarcane . No data depicting residues of indaziflam in/on sugarcane following field application were submitted to support the requested tolerance. Conclusions . The submitted crop field trials are conditionally adequate to support the requested uses of indaziflam. Samples from the citrus, tree nut, and olive trials were stored longer than the duration supported by

the currently

available storage stability study . Pending submission of an acceptable final storage stability study , the data support the requested tolerances for all crops except almond hulls and sugarcane (see Section 860.1550, belo w for a discussion of tolerance levels). Itshould also be noted that the petitioner is requesting a 7 - day PHIfor citrus whereas all citrus field trials were conducted at 14 days or longer. All 14 - day PHIcitrus field trials had total indaziflam residue s 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 PHItotal residue was equal to the L OD and the residue assumed to be ten times more concentrated at a 7 - day PHI , then the total residue s hould still not exceed the L OQ 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 PHIused 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 th an the L OQ). Therefore, HED believes that the existing data support a 7 - day PHIand no additional citrus field trials are needed.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 37 of 52 860.1520 Processed Food and Feed 47743411.der.doc (citrus) 47743409.der.doc (pome fruit) 47743410.der.doc (stone fr uit) 47743412.der.doc (grape) 47743413.der.doc (olive) 47743408.der.doc (sugarcane) 

### Citrus . An orange processing trial was conducted to measure the magnitude of total AE 1170437, 1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - [1 - fluoroethyl ] - residue in oranges and orange processed commodities following an exaggerated rate application of In daziflam 500 SC to the base of orange trees. The test substance, Indaziflam 500 SC, is a suspension concentrate formulation containin g 500 g ai/L. A single broadcast spray

application was made to mowed ground cover, from tree row center to tree row center in the treated plot using ground - based equipment customarily used to apply pesticides in this manner to orange trees. The applicatio n was made at BBCH 74, when fruits are about 40% of the final size. The test substance application was made at a rate of 0.662 lb ai/A (742 g ai/ha) in a spray

volume of 18.29 GPA (171 L/ha). This single application rate is equivalent to five times (5X) the total maximum proposed label rate for a single growing season. A single composite sample of oranges was harvested at a 236 - day PHI(BBCH 83). Subsamples of the oranges were removed for analysis, and the remaining oranges were used to generate the required processed commodities of dried pulp, oil, and juice. Processing was performed using procedures that simulated commercial processing practices. The resultant orange RAC sample was analy z ed to determine total indaziflam residue. The residues of indaz iflam and its metabolite fluoroethyldiaminotriazine were quantitated by high - pressure liquid chromatography /triple stage quadrupole mass spectrometry (LC/MS/MS) using stable - labeled isotopes as internal standards. The limit of quantitation (LOQ) for total indaziflam residue (the sum of indaziflam and fluoroethyldiaminotriazine ) was 0.01 ppm in the orange fruit raw agricultural commodity (RAC). Freezer storage stability

studies indicate that total indaziflam residue would have been stable in oranges during frozen storage (at least 11 months) prior to analysis. The orange fruit analy zed in this study was held in frozen storage for less than one month (16 days) prior to extraction. No total indaziflam residues were observed above the total LOQ (0.01 ppm) in the orange fruit following a 5X exaggerated rate of application of indaziflam to oranges. In addition no total indaziflam residue above the total L OQ was observed in orange fruit collected from a citrus fruit tolerance setting study . Therefore, although oranges were processed into dried pulp, oil, and juice, no analyses were conducted on the processed commodities and no processing factors calculated and no tolerances are required for processed commodities of citrus .I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 38 of 52 Pome Fruit . An apple processing trial was conducted to measure the magnitude of total indaziflam (CAS name 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, and CAS number 950782 - 86 - 2 ) residues in apples and apple processed commodities, follo wing an exaggerated rate application of In daziflam 500 SC to the base of apple trees. The test substance, formulated as the end - use product ( EP) Indaziflam 500 SC, is a suspension concentrate (SC) formulation containing 500 grams of active ingredient per liter (g ai/L). A single broadcast spray

application was made to flail - mowed ground cover, from tree row center to tree row center in the treated plot, using ground - based equipment customarily utilized to apply pesticides in this manner. The test subst ance application was made at BBCH 0 (dormancy

). The application was made at a rate of 0.658 pounds ai per acre (lb ai/A), the equivalent of 738 grams ai per hectare (g ai/ha), in a spray volume of 17 gallons per acre (GPA), equivalent to 159 L/ha. This s ingle application rate is equivalent to five times (5X) the total maximum proposed label rate on apples for a single growing season. A single composite sample of apples was harvested at a 181 - day pre - harvest interval (PHI), corresponding to BBCH 81. Subsamples of the apples were removed for analysis, while the remaining apples were used to generate the required processed commodities, juice and wet pomace. Processing was performed using procedures that simulated commercial processing practices. The app le raw agricultural commodity

(RAC) samples were analy zed to determine total indaziflam residues. The residues of indaziflam and its metabolite, 1 - fluoroethyldiaminotriazine , were quantitated by high - pressure liquid chromatography with triple - stage quadrupole mass spectrometric detection (LC/MS/MS), using stable isotopically labeled internal standards. The individual analy te residues were summed to give a total indaziflam residue. The limit of quantitation (L OQ) for total indaziflam residues was 0.010 ppm in the apple fruit RAC. Freezer storage stability

studies indicate that total indaziflam residue s would be stable in apples during frozen storage for an interval of at least 11 months. The apple fruit analy zed in this study was held in frozen storage for a maximum duration of 38 days (1.2 months) prior to extraction. No total indaziflam residues were observed above the L OQ (0.010 ppm) in the apple fruit following a 5X exaggerated rate application of indaziflam to apples. Therefore, although apples were processed into juice and wet pomace, no analyses were conducted on the processed commodities, and no processing (concentration) factors were calculated and no tolerances are required for processed commodities of apple . Stone Fruit . A plum process ing trial was conducted to measure the magnitude of total indaziflam (CAS name 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 , and CAS number 950782 - 86 - 2) residues in plums and the plum processed commodity

(prunes), following an exaggerated rate application of In daziflam 500 SC to the base of plum trees. The test substance, formulated as the end - use product (EP) In daziflam 500 SC, is a suspension concentrate (SC) formulation containing 500 grams of active ingredient per liter (g ai/L).I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 39 of 52 A single broadcast spray

application was made to flail - mowed ground cover, from tree row center to tree row center in the treated plot, using ground - based equipment customarily used to apply pesticides in this manner. The t est substance application was made at BBCH 0 (dormancy

). The application was made at a rate of 0.668 pounds ai per acre (lb ai/A), the equivalent of 749 grams ai per hectare (g ai/ha), in a spray volume of 15.11 gallons per acre (GPA), equivalent to 141 L/ha. This single application rate is equivalent to five times (5X) the total maximum proposed label rate on plums for a single growing season. A single composite sample of plums was harvested at a 174 - day pre - harvest interval (PHI), corresponding to BBCH 89. Subsamples of the plums were removed for analysis, while the remaining plums were used to generate the required processed commodity, prunes. Processing was performed using procedures that simulated commercial processing practices. The plum raw agricultural commodity (RAC) samples were analy

zed to determine total indaziflam residues. The residues of indaziflam and its metabolite, 1 - fluoroethyldiaminotriazine, were quantitated by high - pressure liquid chromatography with triple - stage quadrupole ma ss spectrometric detection (LC/MS/MS), using stable isotopically labeled internal standards. The individual analy te residues were summed to give a total indaziflam residue. The limit of quantitation (L OQ) for total indaziflam residues was 0.010 ppm in th e plum fruit RAC. Freezer storage stability

studies indicate that total indaziflam residue would be stable in plums during frozen storage for an interval of at least 11 months . The plum fruit analy zed in this study was held in frozen storage for a maxi mum duration of less than one month (21 days) prior to extraction. No total indaziflam residues were observed above the L OQ (0.010 ppm) in the plum fruit following a 5X exaggerated rate application of indaziflam to plum s. Therefore, although plum s were processed into prunes , no analyses were conducted on the processed commodity , and no processing (concentration) factors were calculated and no tolerances are required for processed commodities of plum . Grape . A grape processing trial was conducted to measure the magnitude of total indaziflam (1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - [1 - fluoroethyl]) residue in grapes and grape processed commodities following an exaggerated rate application of In daziflam 500 SC to the base of grape vines. The test substance, Indaziflam 500 SC, is a suspension concentrate (SC) formulation containing 500 grams of active ingredient per liter (g ai/L) of indaziflam. A single broadcast spray

application was made to flail mowed ground c over, to the base of grape vines in the treated plot using ground - based equipment customarily used to apply

pesticides in this manner to grape vines. The application was made at BBCH 0, dormancy . The test substance application was made at a rate of 0.67 lb ai/A (754 g ai/ha) in a spray volume of 15.12 gallons per acre (GPA, 141 L/ha). This single application rate is equivalent to five times (5X) the totalI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 40 of 52 maximum proposed label rate for a single growing season. A single composite sample of grapes (growth stage BBCH 89) was harvested at a 223 - day pre - harvest interval (PHI). Subsamples of the grapes were removed for analysis, and the remaining grapes were used to generate the required processed commodities of juice and raisins. Processing was performed usi ng procedures that simulated commercial processing practices. The resultant grape raw agricultural commodity

(RAC) sample and processed commodities were analy zed to determine total indaziflam residues. The residues of indaziflam and its metabolite fluoro ethyldiaminotriazine were quantitated by high - pressure liquid chromatography /triple stage quadrupole mass spectrometry (LC/MS/MS) using stable - labeled isotopes as internal standards. The individual analy te - derived residues were summed to give a total indaziflam residue. The limit of quantitation (L OQ) for total indaziflam residues (the sum of indaziflam and fluoroethyldiaminotriazine) was 0.01 ppm in the grape fresh fruit RAC and in the processed commodities of juice and raisins. Total indaziflam residue s were found to concentrate in juice (1.5X) and in raisins (2.8X). Freezer storage stability

studies indicate that total indaziflam residues would have been stable in grapes during frozen storage (at least 11 months) prior to analysis. The grape fresh fruit analy zed in this study

was held in frozen storage for a maximum of 569 days (19 months) prior to extraction. The processing factor determined for total indaziflam residues in raisins is less than the theoretical concentration factor based on loss of water of 4.7X cited in Table 2 of EPA’s OPPTS Residue Chemistry

Test Guideline 860.1520. However, the processing factor determined for total indaziflam residues in grape juice is slightly greater than the theoretical concentration factor based on separation into components of 1.2X cited in Table 3 of the EPA’s OPPTS Residue Test Guideline 860.1520. Table 8 . Residue Data from Grape Processing Study Conducted on Indaziflam. Matrix Total Rate lb

a.i./A (kg a.i./ha) PHI

(days) Indaziflam

Residue (ppm) c FDAT Residue

(ppm) Total

Indaziflam Residue b Total

Indaziflam Processing Factor Grape fresh fruit 0.673

(754 ) 223 <LOD <LOD <LOD 0.0012

0.0014 0.0016 0.0019

0.0020 0.0023 Avg 0.0021 NA a Juice <LOD <LOD <LOD 0.0023

0.0025 0.0024 0.0030

0.0032 0. 0031 Avg 0.0031 1.5X Raisins <LOD <LOD <LOD 0.0050

0.0056 0.0051 0.0056

0.0062 0.0058 Avg 0.0059 2.8X

a NA = Not applicable.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 41 of 52 b The average total indaziflam residue in grape fresh fruit and grape commodites were less than the total LOQ (<0.01 ppm) however, detected residue values below the LOQ are reported in order to calculate a processing factor. c Residues below the LOD are reported as <LOD and summed into the Total Residue value as 1⁄2 the LOD (1⁄2 LOD = 0.00065) ppm. 

### Olive . An olive processing tri al was conducted to measure the magnitude of total indaziflam 

### (1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - [1 - fluoroethyl]) residue in olives and olive processed commodities following an exaggerated rate application of Indaziflam 500 SC to the base of olive trees. The test substance, Indaziflam 500 SC, is a suspension concentrate formulation containing 500 g ai/L. A single broadcast spray application was made to disked soil, from tree row center to tree row center in the treated plot using ground - based equipment customarily used to apply pesticides in this manner to olive trees. The application was made at BBCH 55, first individual flowers visible (still closed). The test substance application was made at a rate of 0.6 77 lb ai/A (759 g ai/ha) in a spray volume of 15.21GPA (142 L/ha). This single application rate is equivalent to five times (5X) the total maximum proposed label rate for a single growing season. A single composite sample of olives was harvested at a 287 - day PHI (BBCH 89). Subsamples of the olives were removed for analysis, and the remaining olives were used to generate the required processed commodity of oil. Processing was performed using procedures that simulated commercial processing practices. The resultant olive RAC sample was analyzed to determine total AE 1170437 residue. The residues of indaziflam and its metabolite 

### fluoroethyldiaminotriazine were quantitated by high pressure liquid chromatography/triple stage quadrupole mass spectrometry (LC/M S/MS) using stable labeled isotopes as internal standards. The limit of quantitation (LOQ) for total indaziflam residue (the sum of indaziflam and 

### fluoroethyldiaminotriazine ) was 0.01 ppm in the olive fruit raw agricultural commodity (RAC). Freezer stora ge stability studies indicate that total indaziflam residue would have been stable in olives during frozen storage (at least 11 months) prior to analysis. The olive fruit analyzed in this study was held in ambient/frozen storage for a maximum of 38 days ( 1 month) prior to extraction. No total AE 1170437 residues were observed above the total LOQ (0.01 ppm) in the olive fruit following a 5X exaggerated rate of application of indaziflam to olives. In addition no total indaziflam residue above the total LOQ was observed in olive fruit collected from an olive fruit tolerance setting study. Therefore, although olives were processed into oil, no analyses were conducted on the processed commodities and no processing factors calculated , and no tolerances are required for processed commodities of olives . Sugarcane . A sugarcane processing trial was conducted to measure the magnitude of total indaziflam 

### { 1,3,5 - triazine - 2,4 - diamine, N - [(1R,2S ) - 2,3 - dihydro - 2,6 - dimethyl - 1H - inden - 1 - yl ] - 6 - [1 - fluoroethyl] residue in s ugarcane and sugarcane processed commodities following an exaggerated rate application of Indaziflam 500 SC to ratooned sugarcane. The test substance, Indaziflam 500 SC , is a suspension concentrate formulation (SC) containing 500 grams of active ingredient per liter (g ai/L).I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 42 of 52 A single broadcast foliar spray application was applied as an early season pre - emergence (prior to lay by) herbicide to a ratooned crop of sugarcane. The application was made at pre - emergence, BBCH 8, shoot growing toward soil surface . The test substance application was made at a rate of 0.18 lb ai /A (206 g ai/ha) in a spray volume of 21 gallons per acre (GPA, 193 L/ha) to a treated plot. This single application rate is equivalent to two times (2X) the proposed label rate for a singl e growing season. A single composite sample of sugarcane was harvested at BBCH 39, nine or more nodes present, plant actively growing. Subsamples of the sugarcane were removed for analysis, and the remaining sugarcane were used to generate the required processed commodities of blackstrap molasses and refined sugar. Processing was performed using procedures that simulated commercial processing practices. The resultant sugarcane raw agricultural commodity (RAC) sample was analyzed to determine total indaziflam residue. The residues of indaziflam and its metabolite 

### fluoroethyldiaminotriazine were quantitated by high pressure liquid chromatography/triple stage quadrupole mass spectrometry ( LC - MS/MS ) using stable labeled isotopes as internal standards. The individual analyte - derived residues were summed to give a total indaziflam residue. The limit of quantitation (LOQ) for total indaziflam residues was 0.01 ppm in the sugarcane RAC. Freezer storage stability studies indicate that total indaziflam residue would have been stable in sugarcane during frozen storage (at least 11 months) prior to analysis. The sugarcane analyzed in this study was held in frozen storage for a maximum of 107 days (3.5 months) prior to extraction. No total indaziflam residues we re observed above the LOQ (0.01 ppm) in the sugarcane RAC following a 2X exaggerated rate of application of indaziflam to sugarcane. Therefore, although sugarcane was processed into blackstrap molasses and refined sugar, no analyses were conducted on the processed commodities and no processing factors were calculated. 

### Conclusions . Based on the available data, the only processed commodities pertinent to the subject of the requested petition that potentially require tolerances are grape juice and raisins . Studies with citrus, pome fruit, stone fruit, and olive demonstrated that residues of concern were below the limit of quantitation at e xaggerated rates appropriate for waiving analysis of the processed foods and feeds ( i.e. , residues were < LOQ at 5X ex aggerated application rates) . The grape processing study relied on residue estimates between the L OD and LOQ in order to calculate processing factors. The calculated factor for grape juice (1.5X) is slightly greater than the theoretical maximum factor of 1.2X). The calculated factor for raisins (2.8X) less than the theoretical maximum (4.6X). Given the high variability inherent in quantifying residues below the L OQ and the assumptions made regarding residues below the LOD, it is not surprising that the juice factor slightly

exceeded the theoretical maximum. The petitioner has reduced the maximum application rate for grapes from 0.134 lb a.i./A to 0.089 lb a.i./A. Based on the residue values reported in the study conducted at ca. 0.134 lb a.i./A, the re duction in the application rate, and the processing factors discussed above, HED does not believe that residues in processed commodities will exceed the total indaziflam L OQ of 0.01 ppm; therefore, separate tolerances are not necessary

for residues of indaziflam in grape juice and raisins as these are covered by the proposed tolerance for residues in/on grapes.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 43 of 52 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 commodity of citrus oil is required due to the extremely high potential concentration factor (1000X). Citrus oil was not analy zed during the originally

submitted processing study . The petitioner has been made aware of this issue and provided data from a preliminary analysis of citrus oil. Although this interim report suggest s 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 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 analysis should be required as a condition of registrati on. Itshould be noted that all of the processing studies were conducted at long PHI ’s (174 - 287 days) relative to the label PHI

of 7 and 14 days. However, based on the crop field trial results, there was a general trend towards longer PHI having highe r observed residues. Therefore, the use of samples with long er PHIshould actually have increased the probability of finding quantifiable residues in the RAC and processed commodities. For sugarcane, s amples from the processing study showed no quantif

iable residues of indaziflam or FDAT following a 2X application rate, and the processed commodities of molasses and refined sugar were not analy zed. 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 sugarc ane even at a 5X treatment rate, with the highest observed TRR of 0.005 ppm in the 2X metabolism study . T herefore, 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 . 860.1850 C onfined Accumulation in Rotational Crops 47743414.der.doc 

### Bayer 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 confin ed 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. 860.1900 Field Accumulation in Rotational Crops There are no rotational crop tolerance issues associated with this petition.I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 44 of 52 860.1550 Proposed Tolerances At this time, tolerances are not required for livestock commodities. For plant commodities, the tolerance expression for indaziflam should read as follows: Toleranc es 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 dete rmined by

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

of the petitioned - for tolerances and HED’s recommendations is provided in Table 9, below. With the exception of almond hulls, all residue levels from field trials were below the LOQ and the Tolerance/MRLHarmonization Spreadsheet was not used to obtain a recommended tolerance level. A discussion of the recommended almond hull tolerance is provided in Attachment 3 . At this time, there are no Canadian, Mexican, or Codex MRL s for indaziflam and, the refore, there are no international harmonization issues with this action (Attachment 4).I ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 45 of 52 Table 9 . 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, Group 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 -- Oli ve 0.01 0.01 -- Sugarcane, sugar, refined 0.01 0.01 Sugarcane, refined sugar ; tolerance without a corresponding U.S. registrationI ndaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D3 74105



### 46 of 52 Attachment 1. Summary of Major Residues in Metabolism and Environmental Fate Studies. Table A1. Summary of Major 1 Residues from Metabolism and Environmental Fate Studies.

Compound Sugarcane Apples Grapes Goat

– Milk Goat -

Liver Goat -

Muscle Goat -

Fat Goat - Kidney Rat

Excreta Soil 2 Water 3 Indaziflam 24 13 24 9 2 - 20 - 38 56 21 Fluoroethyl diaminotri azine 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 - - - Indazi flam- 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 Ind aziflam 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, in cluding aquatic photolysis and aerobic aquatic metabolism. 4 

### In cluding the glucuronic acid conjugateIndaziflam (080818) Summary of Analytical Chemistry and Residue Data Barcode: D374105



### Page 47 of 52 Attachment 2. Compounds I dentified in metabolism and environmental fate studies. Table A2. Major Chemicals Identified in Metabolism and Fate Studies Co mp ound/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 Fluoroethyl 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 - amin o - 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 HIndaziflam (080818) Summary of Analytical Chemistry and Residue Data Barcode: D374105



### Page 48 of 52 Table A2. Major Chemicals Identified in Metabolism and Fate Studies Co mp ound/Code Chemical Name Chemical Structure 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}ethanolIndaziflam (080818) Summary of Analytical Chemistry and Residue Data Barcode: D374105



### Page 49 of 52 Table A2. Major Chemicals Identified in Metabolism and Fate Studies Co mp ound/Code Chemical Name Chemical Structure Indaziflam olefin N - [(1R,2S) - 2,6 - dimethyl 2,3 - dihydro - 1H - inden - 1 - yl] - 6 - vinyl - 1,3,5 - triazine 2,4 - diamineIndaziflam (080818) Summary of Analytical Chemistry and Residue Data Barcode: D374105



### Page 50 of 52 Attachment 3. Determination of the Recommended Tolerance for Alm ond Hulls. The dataset used to obtain a tolerance recommendation for residues of indaziflam + FDAT in almond hulls consists of field trial data depicting residues following a single application of indaziflam to almonds per the proposed label use pattern at rates ranging from 0.132 to 0.135 lb a.i./A. Total residues (indaziflam + FDAT) on almond hulls, presumably as contamination from contact with treated ground during harvesting, ranged from <0.01 ppm to 0.153 ppm, with five of the 10 values being below the LOQ. Given the left - censoring of the dataset, a maximum likelihood estimation (MLE) algorithm was applied to the data to provide “fill - in” values for the <LOQ data. The data used to calculate the recommended tolerance are summarized in Table A3.1. No te that the fill - in values derived by HED are different from those estimated by the petitioner and result in a different tolerance recommendation tha n that given by

the petitioner. HED surmises that the different values may be due to the petitioner not re calculating the fill - in values provided by

the MLE spreadsheet. The lognormal probability plot (Figure A3.1) and the analysis summary

(Table A3.2) both indicate a good log - normal fit for the data. The recommended tolerance lev el is 0.15 ppm. Table A3.1. Summary of Residue Values for the Determination of the Recommended Tolerance for Residues in Almond Hulls. Regulator: EPA Chemical: Indaziflam Crop: Almond Hulls PHI: 14 Days App. Rate: Submitter: Residues < LOQ; MLE Fill - in 0.001 < LOQ; MLE Fill - in 0.002 < LOQ; MLE Fill - in 0.003 < LOQ; MLE Fill - in 0.004 < LOQ; MLE Fill - in 0.007 0.078 0.063 0.145 0.153 0.038Indaziflam (080818) Summary of Analytical Chemistry and Residue Data Barcode: D374105



### Page 51 of 52 Figure A3.1. Lo gnormal Probability Plot for Residues in/on Almond Hulls Following Treatment with Indaziflam. Lognormal Probability Plot

99.9 99 98 95 90 80 70 50 30 20 10 5 2 1 0.1 1.0000 0.5000 0.2500 0.1250 0.0625 0.0313 0.0156 0.0078 0.0039 0.0020 0.0010 0.0005 y = 2.0376x - 4.2364 R 2 = 0.9326

PercentilesConcentrations EPA Indaziflam Almond Hulls 14 Days

Table A3 .2. Summary of the Tolerance/MRL Harmonization Spreadsheet Results for Indaziflam in/on Almond Hulls. Regulator: EPA Chemical: Indaziflam Crop: Almond Hulls PHI: 14 Days n: 10 min: 0.00 1 max: 0.15 3 median: 0.02 2 average: 0.0 49 95th Percentile 99th Percentile 99.9th Percentile EU Method I Normal 0.15 0.20 0.25 (0.25) (0.30) ( -- ) 95/99 Rule 0.40 1.5 7.0 (5.0) (40) ( -- ) EU Method II Distribution - Free 0.20 Mean+3SD 0.25 UCLMedian9 5th 0.15 Approximate Shapiro - Francia Normality Test Statistic 0.9326 p - value > 0.05 : Do not reject lognormality assumption Would you like the above values rounded? (Y or N)==> YIndaziflam (080818) Summary of Analytical Chemistry and Residue Data Barcode: D374105



### Page 52 of 52 Attachment 4. International Residue Limit Summary . 

# INTERNATIONAL RESIDUE LIMIT STATUS Chemical Name 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 - fluoroethyl] - 

### Common Name: Indaziflam X Proposed tolerance  Reevaluated tolerance  Other Date: 5 May 2010 

# Co dex Status (Maximum Residue L imits) 

# U. S. Tolerances √ No Codex proposal step 6 or above  No Codex proposal step 6 or above for the crops requested Petition Number: PP# 9F7589, 9E7588 DP Barcode: D374105 Other Identifier: Residue definition (step 8/CXL): N/A Reviewer/Branch: M. Doherty/RAB2 Residue def

inition: Indaziflam + fluoroethyldiaminotriazine 

### Crop (s) MRL (mg/kg) Crop(s) Tolerance (ppm) Fruit, citrus, Group 10 0.01 Fruit, pome, Group 11 0.01 Fruit, stone, Group 12 0.01 Nut, tree, Group 14 0.01 Pistachio 0.01 Almond, hulls 0. 1 5 Grape 0.01 Olive 0.01 Sugarcane, refined sugar 0.01 

# Limits for Canada Limits for Mexico √ No Limits  No Limits for the crops requested  No Limits  No Limits for the crops requested Residue definition: N/A Residue definition: 

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

### Crop(s) MRL(mg/kg) Crop(s) MRL(mg/kg) Notes/Special Instructions: S Funk/M Negussie