Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

Date: 9 Sept 2010

Subject: Indaziflam. Petition for the Establishment of Permanent Tolerances and Registration 

for Use on Pome Fruits, Stone Fruits, Citrus, Tree Nuts (including Pistachios), 

Grapes, and Olives (PP 9F7589); and a Tolerance without a Domestic Registration 

for Sugarcane (PP 9E7588). Summary of Analytical Chemistry and Residue Data.

PC Code: 080818 DP Barcode: D374105, D376908

Decision No.: 416570 Registration No.: 432-RLNR

Petition No.: 9F7589, 9E7588 Regulatory Action: Section 3

Assessment Type: Single Chemical Registration Case No.: NA

TXR 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. Loranger, Ph.D., Senior Scientist

Risk Assessment Branch II

Health Effects Division (7509P)

TO: Bethany Benbow/James Tompkins (RM25)

Herbicide Branch

Registration Division (7505P)
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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 [Triazine2,4-14C] 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 Unpublished study prepared by Bayer CropScience. 64 p.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 Unpublished study prepared by 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 Unpublished study prepared by 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Unpublished study prepared by Bayer CropScience. 204 p.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 prepared by Bayer CropScience and Southwest Bio-Labs, Inc. 172 p.

47743322 Mislankar, S. (2009) Waiver of the Requirement for a Poultry Metabolism Study 

for Indaziflam. Project Number: MEDHP077. Unpublished study prepared by 

Bayer CropScience. 6 p.

1340 –

Analytical 

Methods

47743323 Timberlake, 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 Indaziflam (AE 1170437) and its 

Metabolite 1-Fluoroethyl Triazinediamine in Plant Materials, Using LC/MS/MS. 

Project Number: M/342267/01/2/OCR, P612097523, P/B/1633/G. Unpublished 

study prepared by PTRL Europe Gmbh. 49 p.

47743326 Simpson, R.; Bennett, R. (2009) Independent Laboratory 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/2009/32. 

Unpublished study prepared by JRF America. 244 p.

1360 –

Multiresidue 

Method

47743327 Rockwell, D. (2009) PAM I Multiresidue Protocol Testing of AE 1170437 

(Indaziflam) and its Metabolite 1-Fluoroethyl Triazinediamine. Project Number: 

M/346696/01/1/OCR, RADHP072, 2008. Unpublished study prepared by Pyxant 

Labs, Inc. 107 p.

1380 – Storage 

Stability

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.
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47743328 Netzeband, D. (2009) 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 

736 Days Storage). Project Number: M/302527/02/1/OCR, RADHP041/1. 

Unpublished study prepared by Bayer CropScience. 56 p.

47743329 Timberlake, B. (2009) Storage Stability of AE 1170437 and 1-Fluoroethyl 

Triazinediamine in / on Fruit and Nut Matrices. Project Number: 

M/348221/01/1/OCR, RADHP039. Unpublished study prepared by Bayer 

CropScience. 138 p.

1480 – Meat, 

Milk, Poultry, 

and Eggs

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 – Crop 

Field Trials

47743402 Desmarteau, D.; Fischer, D. (2009) AE 1170437 500 SC - Magnitude of the 

Residue in/on Pome Fruit (CG 11). Project Number: M/348053/01/1, RADHP029, 

M/348053/01/1/OCR. Unpublished study prepared by Bayer CropScience. 199 p.

47743403 Krolski, M.; Brungardt, J.; Stoughton, S. (2009) AE 1170437 500 SC - Magnitude 

of the Residue in/on Stone Fruit (CG 12). Project Number: M/347950/01/1, 

RADHP030, M/347950/01/1/OCR. Unpublished study prepared by Bayer 

CropScience. 246 p.

47743404 Brungardt, J.; Krolski, M. (2009) AE 1170437 500 SC - Magnitude of the Residue 

in/on Tree Nuts (CG 14). Project Number: M/347601/01/1, RADHP028, 

M/344601/01/1/OCR. Unpublished study prepared by Bayer CropScience. 197 p.

47743405 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 Timberlake, B.; Fischer, D. (2009) AE 1170437 500 SC - Magnitude of the 

Residue in/on Olives. Project Number: M/348345/01/1, RADHP037, 

M/348345/01/1/OCR. Unpublished study prepared by Bayer CropScience. 93 p.

47743432 Mislankar, S. (2009) Proposed Tolerance (Maximum Residue Levels) for 

Indaziflam in Grapes, Citrus, Pome Fruits, Stone Fruits, Tree Nuts, and Olives. 

Project Number: RADHP078, M/348689/01/1. Unpublished study prepared by 

Bayer CropScience. 24 p.

1520 – Processed 

Food and Feed

47743408 Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue in/on Sugarcane 

Processed Commodities. Project Number: M/348217/01/1, RADHP018, 

M/348217/01/1/OCR. Unpublished study prepared by Bayer CropScience and 

GLP Technologies. 89 p.

47743409 Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue in/on Apple 

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 Number: M/347951/01/1, 

RADHP012, M/347951/01/1/OCR. Unpublished study prepared by Bayer 

CropScience and GLP Technologies. 80 p.

47743411 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue 

in/on Orange 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.
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47743412 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue 

in/on Grape Processed Commodities. Project Number: M/348051/01/1, 

RADHP014, M/348051/01/1/OCR. Unpublished study prepared by Bayer 

CropScience and University of Idaho, Cooperative Extension. 118 p.

47743413 Stoughton, S.; Lenz, C. (2009) AE 1170437 500 SC - Magnitude of the Residue 

in/on Olive Processed Commodities. Project Number: M/348052/01/1, 

RADHP015, M/348052/01/1/OCR. Unpublished study prepared by Bayer 

CropScience and GLP Technologies. 78 p.

1850 – Confined 

Accumulation in 

Rotational Crops

47743431 Mislankar, S. (2009) Waiver of the Requirement for a Confined Rotational Crop 

Study for Indaziflam (MRID 47743414). Project Number: MEDHP072, 

M/347957/01/1. Unpublished study prepared by Bayer CropScience. 6 p.
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Table of Contents

Executive 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 Processed Food and Feed ........................................................................................... 37

860.1850 Confined Accumulation in Rotational Crops........................................................... 43

860.1900 Field Accumulation in Rotational Crops.................................................................. 43

860.1550 Proposed Tolerances................................................................................................... 44
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Executive Summary

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

[(1S,1R)-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 biosynthesis inhibitor and is active at rates of 50 to 

100 g ai/ha. The technical-grade a.i. (TGAI) is made up of at least 95% of the 1R-fluorethyl 

isomer and no more than 5% of the 1S-fluoroethyl isomer. Although the company name AE 

1170437 refers specifically to the 1R-fluoroethyl isomer, it has been used interchangeably with 

the TGAI during the data review process. Both isomers have equal herbicidal activity. 

Indaziflam 200 SC and Indaziflam 500 SC are suspension concentrate formulations of

indaziflam, containing 200 and 500 g active ingredient (a.i.)/L (1.67 lb a.i./gallon and 4.16 lb 

a.i./gallon), respectively. The products 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 type 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. Indaziflam is not to be applied through any type of 

irrigation system or by aerial equipment. The pre-harvest intervals (PHIs) 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 residue 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 major species [> 10% total radioactive residue (TRR)]. Residue 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 analytical method using solvent 

extraction and High Performance Liquid Chromatography-Mass Spectrometry/Mass 

Spectrometry (HPLC-MS/MS) has been developed to assay the residues of concern 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 limit of quantitation (LOQ; < 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 RACs at exaggerated 

rates. In grapes, 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 Limit (MRL) calculator with maximum 
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likelihood estimation (MLE) resulted in a recommended tolerance of 0.15 ppm for residues in 

almond hulls. With the exception of almond hulls, which may be fed to cattle, the proposed uses 

do not involve any significant livestock feed items. 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 byproduct, 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 

phytotoxicity concerns.

In support 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 study. The samples from the processing study showed no quantifiable residues of 

indaziflam or FDAT following a 2X application rate, and the processed commodities of molasses 

and refined sugar were not analyzed. Typically, 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 the level of the method’s LOQ. HED notes that a 

metabolism trial at a 10X exaggerated treatment rate was initiated and subsequently terminated 

due to treatment-related phytotoxicity.

Residue Chemistry Deficiencies

The residue chemistry data set is complete 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 LOQ 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 analyzed 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 suggests that indaziflam residues are concentrated approximately 11.7X compared 

to those observed in citrus RACs, the total residues in citrus oil are still less than LOQ (0.01 

ppm). Therefore, HED does not believe that a tolerance for citrus oil is required, as no finite 

residues would be expected even at exaggerated rates. However, the final study report from this 

citrus oil analysis should be required as a condition of registration. 

2. 7-day PHI for citrus - The petitioner is requesting a 7-day PHI for citrus whereas all citrus field 

trials were conducted at 14 days or longer. All 14-day PHI citrus field trials had total indaziflam 

residues that were less than both the LOQ and the LOD. With a total indaziflam residue LOD of 

0.0011 ppm, even if the 14 day PHI total residue was equal to the LOD and the residue assumed 
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to be ten times more concentrated at a 7-day PHI, then the total residue should still not exceed 

the LOQ and proposed tolerance of 0.01 ppm. The field trial design was intended to estimate the 

“worst case” scenario for long-term exposure and translocation from root uptake of the soilapplied herbicide, with the 14-day PHI used to simulate any possible short-term uptake. Finally, 

the field trial results suggest that the highest total residues are observed in those with the longest 

PHI’s, with the FDAT metabolite being the primary residue detected above the LOD (but still 

less than the LOQ). Therefore, HED believes that the existing data support a 7-day PHI and no 

additional citrus field trials are needed. 

 

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 

frozen storage during that time frame. Samples from various studies were stored, frozen, for up 

to approximately 17 months. The petitioner has continued the storage stability study to 

encompass 24 months of frozen storage, but the final report has not been received 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 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 highest 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 analytical standards of

indaziflam and FDAT, as well as the stable-isotope-labeled internal standards, have been sent to

the pesticide repository at the Analytical Chemistry Branch (ACB). It should be emphasized

with ACL that use of the proper stable-isotope-labeled internal standards is critical to the method

accuracy. 

The reference standards should be sent to the Analytical 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/Analytical 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.). 

Indaziflam inhibits cellulose biosynthesis in germinating seedlings and is efficacious at 
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relatively low use rates. OPP has recently assessed and recommended for the non-food uses of 

this herbicide (M. Collantes, et al., D356142, 22 April 2010). Nomenclature and the 

physicochemical properties of indaziflam are summarized in Tables 1 and 2, below.

Table 1. Nomenclature

Compound

AE 1170437

Isomer A

H3C

CH3

N

H

N

N N

NH2

F CH3

Common name Indaziflam

Company experimental name AE 1170437

IUPAC name N-[(1R,2S)-2,6-Dimethyl-2,3-dihydro-1H-inden-1-yl]-6-[(1R)-1-

fluoroethyl]-1,3,5-triazine-2,4-diamine

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

CAS # 730979-19-8

Compound

AE 1170438

Isomer B N

N

N

N

H

NH2

CH3

CH3

H3C

F

Common name Indaziflam

Company experimental name AE 1170438

IUPAC name N-[(1R,2S)-2,6-Dimethyl-2,3-dihydro-1H-inden-1-yl]-6-[(1S)-1-

fluoroethyl]-1,3,5-triazine-2,4-diamine

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

CAS # 730979-32-5

Compound

1-Fluoroethyl diaminotriazine

(FDAT) N

N

N

H2N NH2

H C F 3

Common name Indaziflam-diaminotriazine

Company experimental name AE 1170437-diaminotriazine

IUPAC name 6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine

CAS name 6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine

CAS # Unavailable
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Table 2. Physicochemical Properties of the Technical Grade AE 1170437 

Parameter Value Reference

Molecular weight 301.37

Melting point/range 183 -184 oC 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 20 C)

(relative density compared to water 

at 4 C, D4

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 10-8PA at 20 °C

6.8 x 10-8PA at 25 °C

6.9 x 10-6PA 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 absorption 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 product chemistry review of the manufacturing use 

product (MUP) by Registration Division (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 isomer 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 impurities. 
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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, 

Type, and Equip.

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. 

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, broadcast 

or 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 must 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 indaziflam 

application and replanting 

with non-labeled crop.

Sugarcane (Non-Domestic Use)

Broadcast spray, 

pre- or post-crop 

emergence, preemergence for 

weeds; ground or 

aerial equipment

0.107 lb a.i./A

(120 g a.i./ha) 1

0.107 lb a.i./A

(120 g a.i./ha) 90 None 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. 
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860.1300 Nature of the Residue - Plants

47743318.der.doc – Apple metabolism

47743319.der.doc – Grape metabolism

47443272.der.doc – Sugarcane metabolism

Apple. The metabolism of 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]-; CAS Number 730979-19-8) was studied in apples 

following two applications of either [indane-3-

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

14C] 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-

14C] 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-

14C] 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-

14C] 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-

14C] indaziflam experiments had extractable residues of 

79% and 80%, respectively. The major residue detected, and the only metabolite identified, in the 

[triazine-2,4-

14C] indaziflam study was fluoroethyldiaminotriazine, accounting 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-[(1R,2S)-

2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl]; CAS Number 730979-19-8) 

was studied in grapes following two applications of either [indane-3-

14C] indaziflam or [triazine2,4-

14C] indaziflam to the soil at the base of the grape vines. Two target application 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). 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, 
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phytotoxicity 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 ([indane3-

14C] indaziflam) or 45 days ([triazine-2,4-14C] indaziflam) after treatment. TRR values in fruit 

from plants treated with [indane-3-

14C] 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-

14C] 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-

14C] 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-

14C] 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-

14C] indaziflam experiments had extractable residues of 

81% and 96%, respectively. The major residue detected, and the only metabolite identified, in the 

[triazine-2,4-

14C] 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-[(1R,2S)-2,3-dihydro2,6-dimethyl-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl]; CAS Number 730979-19-8) was studied in 

sugarcane following two applications of either [indane-3-

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

indaziflam. Two application 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). In 

the 2X experiments, the total application was split between a spray to both the plant and 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 (PHI), 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 phytotoxicity 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 (TRR). TRR values in sugarcane from plants treated with [indane3-

14C] indaziflam and [triazine-2,4-14C] indaziflam at 2X the maximum seasonal use rate of 150 

g ai/ha were 0.004 ppm and 0.005 ppm, respectively. 
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Sugarcane from the 2X [indane-3-

14C] indaziflam experiment had extractable residues of 65%. 

While there were several polar compounds formed, the only identified residue in the [indane-3-

14C] indaziflam study was unmetabolized parent accounting for 24% of the TRR (<0.001 ppm). 

Sugarcane from the 2X [triazine-2,4-

14C] indaziflam experiment had extractable residues of 68%. 

The major residue detected, and the only metabolite identified, in the [triazine-2,4-

14C] 

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-

14C] indaziflam experiment.

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

radioactivity) of 91-100%. 

Conclusions. In plants, 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 (Tables 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 highest 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.
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Table 4a. Summary of Characterization and Identification of Radioactive Residues in Apples Following Application

of [Indane-3-

14C] or [Triazine-2,4-14C] Indaziflam Harvested 30 Days Following the Last of Two Soil Applications 

at the Base of the Tree 

Compound [Indane-3-

14C] Indaziflam Treated 

Apples

[Triazine-2,4-

14C] Indaziflam Treated 

Apples

2.2x (0.29 lb ai/A) 12.8x (1.7 lb ai/A) 2.3x (0.31 lb ai/A) 10.5x (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 uncharacterized14 -- 1 -- 0 -- 0 --

Total extractable 78 0.003 85 0.009 97 0.011 97 0.052

Unextractable (PES)222 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. 

2Residues remaining after exhaustive extractions.

3Accountability = Total extractable + Total unextractable. Accountabilities were ~100% because results were normalized.
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Table 4b. Summary of Characterization and Identification of Radioactive Residues in Grapes Treated with [Indane3-

14C] or [Triazine-2,4-14C] Indaziflam (Spray Application to Soil at the Base of the Vine)

Compound [Indane-3-

14C] Indaziflam Treated 

Grapes1

[Triazine-2,4-

14C] Indaziflam Treated 

Grapes1

1.8x (0.24 lb ai/A) 7.4x (0.98 lb ai/A) 2.0x (0.27 lb ai/A) 7.2x (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 24 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 uncharacterized23 -- 4 -- 1 -- 2 --

Total extractable 71 0.004 66 0.013 81 0.012 96 0.038

Unextractable (PES)329 0.002 34 0.006 19 0.003 4 0.002

Accountability4~100 ~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 application at flowering. 

2Total uncharacterized = Total extractable – Total characterized – Total Identified. The Total Extractable information comes 

from the reported values in the registrant study profile template. 

3Residues remaining after exhaustive extractions.

4Accountability = Total extractable + Total unextractable. Accountabilities were ~100% because results were normalized.
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Table 4c. Summary of Characterization and Identification of Radioactive Residues Sugarcane Following 

Application of [Indane-3-

14C] or [Triazine-2,4-14C] 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-

14C] Indaziflam 

Treated Sugarcane

[Triazine-2,4-

14C] 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 uncharacterized21 -- 0 --

Total extractable 66 0.003 68 0.003

Unextractable (PES)334 0.001 32 0.002

Accountability4~100 ~100

1A 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. 

2Total uncharacterized = Total extractable – Total characterized – Total Identified. The Total Extractable information comes 

from the reported values in the registrant study profile template. 

3Residues remaining after exhaustive extractions.

4 Accountability = Total extractable + Total unextractable. Accountabilities were ~100% because results were normalized.
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Figure 1. Proposed Metabolic Profile of Indaziflam in Sugarcane, Apples, and Grapes (Note: 

This figure was taken from the petitioner’s study profile without modification.) 

H3C

CH3

N

H

N

N N

NH2

F CH3

H2N N

N N

NH2

F CH3

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 goats were dosed orally, via capsule, with [indane-3-

14C]-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 was 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 tissues (liver, kidney, perirenal fat, omental fat, 

round muscle, and loin muscle) were collected for analysis. 

The total radioactive residues (TRR) in the milk and tissues were determined using a liquid 

scintillation counter. Identification and quantitation of the residues in the milk and tissue 
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extracts were accomplished by using reverse-phase high-performance liquid chromatography

(HPLC), 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 was 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-

14C]-AE 1170437 Residues in Edible Tissues and Milk. 

Matrix Total

Residues (ppm)

Extractable Residues Unextractable Residues

%TRR 1ppm % 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 0.005

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 perirenal fat, which was used to represent the residue profile in fat. 

3 The Day-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 1170437 (2% to 20% of the 

TRR; 0.003 to 0.011 ppm), AE 1170437-4-hydroxy-hydroxymethyl (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-ketohydroxymethyl (2% to 13% of the TRR; <0.001 to 0.017 ppm), AE 1170437-

3-ketohydroxymethyl 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-hydroxymethyl, AE 1170437-dihydroxy, 

AE 1170437-3-ketohydroxymethyl, 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 
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and AE 1170437-3-ketohydroxymethyl GA were also observed. 

Triazine Label. Two lactating goats were dosed orally, via capsule, with [triazine-2,4-

14C]-AE 

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 was 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 residues (TRR) in the milk and tissues were determined using a liquid 

scintillation counter. Identification and quantitation of the residues in the milk and tissue 

extracts were accomplished by using reverse-phase high-performance liquid chromatography

(HPLC), 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 

samples 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 ppm 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 were unextractable. 

TABLE 5b. Extractability of [triazine-2,4-

14C]-AE 1170437 Residues in Edible Tissues and Milk. 

Matrix Total

Residues (ppm)

Extractable Residues Unextractable Residues

%TRR 1ppm % TRR ppm

Liver 2

0.816 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, which 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% 
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of the TRR; 0.001 to 0.049 ppm), AE 1170437-4-hydroxy-hydroxymethyl (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-ketohydroxymethyl (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-ketohydroxymethyl GA (<1% 

to 4% of the TRR; <0.001 to 0.032 ppm). Only a minor amount of parent AE 1170437 was 

identified in 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). 

Oxidation products, including AE 1170437-4-hydroxy-hydroxymethyl, AE 1170437-dihydroxy, 

AE 1170437-4-hydroxy acid, AE 1170437-3-ketohydroxymethyl, 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-ketohydroxymethyl GA were also observed. 

Conclusions. Based on the available information, indaziflam appears to undergo significant 

oxidative metabolism in ruminants. The metabolic pathways observed in these studies were

similar, with the exception of the label specific diaminotriazine metabolite found in the triazine 

label study. The same was true for the [

14C]-AE 1170437 rat metabolism study (MRID 

47443312, 47743418) with only minor differences (two additional metabolites, AE 1170437-4-

hydroxy-hydroxymethyl and AE 1170437-3-keto-4-hydroxy, were found in the goat metabolism 

studies). 

Tables 5c and 5d summarize 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.
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Table 5c. Summary of Characterization and Identification of Radioactive Residues in Goat Matrices Following the Oral 

Administration of [Indane-34-

14C] 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 NDc NDc

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 NDc NDc NDc NDc11 0.016

AE 1170437-4-hydroxy acid NDc NDc2 0.006 7 <0.001 NDc NDc

AE 1170437-3-keto-4-hydroxy 3 to 5 0.004 to 0.006 NDc NDc NDc NDc5 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 NDc NDc2 0.002

AE 1170437-3-hydroxyindane GA NDc NDc NDc NDc19 0.002 12d0.017d

3-hydroxyindane 12 to 18 0.018 to 0.021 NDc NDc NDc NDc NDc NDc

AE 1170437-carboxylic acid 6 to 9 0.008 to 0.011 24 0.089 16 0.002 26 0.040

M3-2, M5-2 2 0.002 to 0.003 NDc NDc NDc NDc NDc NDc

M5-3 2 0.003 NDc NDc NDc NDc NDc NDc

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 NDc NDc4 0.013 7 <0.001 NDc NDc

M1-2, M3-3, M5-4 3 to 4 0.004 to 0.006 NDc NDc ND

c NDc NDc NDc

M3-4 2 0.002 NDc NDc NDc NDc NDc NDc

M5-5 2 0.004 NDc NDc NDc NDc NDc NDc

M3-10, M5-11 2 to 3 0.003 to 0.004 NDc NDc NDc NDc NDc NDc

M1-9, M3-11, M5-12, K-8 5 0.006 to 0.008 NDc NDc NDc NDc1 0.002

K-1 NDc NDc NDc NDc NDc NDc2 0.003

M1-1, M3-1, M5-1 2 0.002 to 0.003 NDc NDc NDc NDc NDc NDc

K-10 NDc NDc NDc NDc NDc NDc2 0.003

F-7 NDc NDc NDc NDc3 <0.001 NDc NDc

K-11 NDc NDc NDc NDc NDc NDc1 0.002

F-9 NDc NDc NDc NDc10 0.001 NDc NDc

K-13 NDc NDc NDc NDc NDc NDc2 0.002

F-11 NDc NDc NDc NDc3 <0.001 NDc NDc

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 represent 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).
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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Table 5d. Summary of Characterization and Identification of Radioactive Residues in Goat Matrices Following the Oral Administration of 

[Triazine-2,4-

14C] AE 1170437 at a Rate of 2.24 mg ai/kg Body Weight/Day for Five Consecutive Days.

Compound

Milka

TRR = 0.274 to 0.400 ppm

Liver

TRR = 0.816 

ppm

Muscleb

TRR = 0.022 ppm

Fatc

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 NDd NDd9 0.004 NDd NDd

AE 1170437-diaminotriazine 12 to 13 0.036 to 0.049 NDd NDd15 0.003 3 0.001 2 0.009

AE 1170437-4-hydroxyhydroxymethyl15 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 NDd NDd5 0.038 NDd NDd12 0.005 14 0.058

AE 1170437-3-

hydroxyindane acid

2 to 3 0.005 to 0.010 NDd NDd NDd NDd5 0.002 7 0.028

AE 1170437-3-keto-4-

hydroxy

5 to 6 0.017 to 0.020 NDd NDd4 <0.001 NDd NDd NDd NDd

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 NDd NDd

AE 1170437-3-

hydroxyindane GA

NDd NDd24e0.199e NDd NDd9 0.004 17 0.068

3-hydroxyindane 3 to 6 0.012 to 0.022 NDd NDd14 0.003 NDd NDd NDd NDd

AE 1170437-carboxylic 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 NDd NDd NDd NDd NDd NDd NDd NDd

M-2, K-3 NDd NDd NDd NDd2 <0.001 NDd NDd1 0.005

L-4, M-6 NDd NDd4 0.030 2 <0.001 NDd NDd NDd NDd

F-7, K-8 NDd NDd NDd NDd NDd NDd4 0.002 5 0.022

M1-5, M3-5, M5-5, F-2 5 to 6 0.014 to 0.022 NDd NDd NDd NDd2 <0.001 NDd NDd

M5-6 <1 0.003 NDd NDd NDd NDd NDd NDd NDd NDd

M5-12, F-9, K-10 <1 0.002 NDd NDd NDd NDd3 0.001 7 0.028

M-3 NDd NDd NDd NDd5 0.001 NDd NDd ND

d NDd

M1-11, M3-12, M5-13, M10, F-11, K-111 to 2 0.003 to 0.008 NDd NDd2 <0.001 2 0.001 2 0.007

M3-13, M5-14 <1 to 3 0.003 to 0.013 NDd NDd NDd NDd NDd NDd NDd NDd

M1-1, M3-1, M5-1 1 0.003 to 0.005 NDd NDd NDd NDd NDd NDd NDd NDd

M1-3, M3-3, M5-3, K-2 1 to 2 0.003 to 0.006 NDd NDd NDd NDd NDd NDd2 0.006

F-13, M-12 NDd NDd NDd NDd4 <0.001 4 0.002 NDd NDd

F-14 NDd NDd NDd NDd NDd NDd2 <0.001 NDd NDd

M3-16, L-9, F-16, K-14 2 0.008 2 0.017 NDd NDd2 <0.001 3 0.011

F-18 NDd NDd NDd NDd NDd NDd4 0.002 NDd NDd

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, which was used to represent the residue profile in muscle.

cResults are reported from the extraction of perirenal fat, which was used to represent the residue profile in fat.

dND = Not detected.

eThe 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).
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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Figure 2. Proposed Metabolic Profile for Indaziflam in the Lactating Goat (Note: This figure 

was taken from the petitioner’s study profile without modification.)

N

N N

H3C

CH3

N

H

CH3

F

NH2

AE 1170437

N

N N

H3C

CH3

N

H

CH3

F

NH2

O

O

HO

HO

HO

HO

O

3-Hydroxyindane GA

N

N N

CH3

N

H

CH3

F

NH2

OH

Hydroxymethyl

N

N N

H2N

CH3

F

NH2

AE 1170437-diaminotriazine

N

N N

H3C

CH3

N

H

CH3

F

NH2

HO

HO

N

N N

CH3

N

H

CH3

F

NH2

HO

OH

N

N N

H3C

CH3

N

H

CH3

F

NH2

HO

AE 1170437-3-hydroxyindane

N

N N

CH3

N

H

CH3

F

NH2

HO

OH

AE 1170437-dihydroxy

N

N N

CH3

N

H

CH3

F

NH2

O

OH

AE 1170437-3-ketohydroxymethyl

O

N

N N

CH3

N

H

CH3

F

NH2

O

O

OH

O

OH

OH

OH

AE 1170437-3-ketohydroxymethyl GA

N

N N

CH3

N

H

CH3

F

NH2

HO

O

AE 1170437-3-keto-4-hydroxy

N

N N

CH3

N

H

F CH3

NH2

HO2C

AE 1170437-carboxylic acid

N

N N

CH3

N

H

CH3

F

NH2

HO

HO2C

AE 1170437-3-hydroxyindane acid

N

N N

CH3

N

H

CH3

F

NH2

HO

HO2C

AE 1170437-4-hydroxy acid

AE 1170437-4-hydroxyhydroxymethyl
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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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 + Indaziflam 

carboxylic acid + Indaziflam-3-

hydroxyindane

Indaziflam + FDAT + Indaziflam-3-

ketohydroxymethyl + Indaziflam 

carboxylic acid + Indaziflam-3-

hydroxyindane*

Poultry Not applicable at this time (no data 

available)

Not applicable at this time (no data 

available)

Drinking Water Indaziflam + FDAT + Triazine indanone

+ Indaziflam carboxylic acid + 

Indaziflam hydroxyethyl + Indaziflam 

olefin

Not Applicable

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

FDAT = 6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine

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

Indaziflam-3-ketohydroxymethyl = (2S,3R)-3-[[4-amino-6-[(1R)-1-fluoroethyl]-1,3,5-triazin-2-yl]amino)-5-hydroxymethyl-2-

methylindane-1-one

Indaziflam-3-hydroxyindane = (2R,3R)-3-({4-amino-6-[(1R)-1-fluoroethyl]-1,3,5-triazin-2-yl}amino)-2-methylindan-1-ol-5-

carboxylic acid

Triazine indanone = 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

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

Indaziflam olefin = N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-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 was 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 analyzed 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 support a total method LOQ 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 of 
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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detection (LODs) 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 analytical 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 analytes 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 analytes. The method used HPLCMS/MS for detection 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 Analytical Chemistry

Branch of the Biological and Economic Analysis Division (ACB/BEAD) as well as to the Food 

and Drug Administration (FDA) as an official enforcement method. The analytical standards, 

including the stable-isotope internal standard, for the method will need to be forwarded by the 

petitioner to ACB prior to registration. Use of the proper stable- isotope-labeled internal 

standards is critical to the 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) multiresidue methods for regulatory analysis of indaziflam (CAS name N-[(1R,2S)-2,3-dihydro-2,6-

dimethyl-1H-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 protocols were 

suitable for the analysis of indaziflam 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, apples (fresh fruit), 

cherries (fresh fruit), and oranges (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 analyzed immediately after fortification (zero days). Stored samples were 

analyzed 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 maximum 
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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daily average temperature of <-20°C. Sample analyses for indaziflam and 

1-fluoroethyldiaminotriazine were performed using the analytical method for determining the 

total residues of indaziflam and 1-fluoroethyldiaminotriazine in crop matrices (see References 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 to approximately 12 months. Samples from the citrus, olive, 

and tree nut crop field trials, and the grape processing study were stored for over one year and are 

not fully supported by the available storage stability data. Since the available data demonstrate 

that residues have some long-term stability, HED will use the available study to support the 

tolerance petition. However, submission of an acceptable storage stability study covering the full 

duration of sample storage should be submitted as a condition 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. Bayer has submitted 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]henever 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 pesticide 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 Agricultural 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. 
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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When the highest residues in each 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 information 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 analytical method. Hence a 40 CFR 180.6(a)(3) situation (no expectation of 

finite residues) exists. Neither feeding studies nor tolerances for livestock commodities are 

required at this time. Feeding studies and analytical 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 Field Trials with Indaziflam

Crop Matrix

Applic. Rate,

lb a.i./A

(kg a.i./ha)

PHI, days

Residues, ppm1

n Min 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) 12-28 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

Pome 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 0
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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Table 7. Summary of Residues from the Crop Field Trials with Indaziflam

Crop Matrix

Applic. Rate,

lb a.i./A

(kg a.i./ha)

PHI, days

Residues, ppm1

n Min 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

(0.145-0.157) 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 PHI)

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 0.132 - 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 < LOQ 
Indaziflam Summary of Analytical Chemistry and Residue Data DP Barcode D374105

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were 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 

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 citrus fruits following a 

single broadcast 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). Indaziflam 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 Indaziflam 500 SC; samples were 

collected from the TRT45 plot at target 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 PHI samples 

were collected two weeks late due to field investigator oversight) and from the TR240 plot at a 

target PHI of 240 days (actual 231 to 240 days). 

In orange plots, application to the TRT45 plots (sampled at target PHIs 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). 

In grapefruit plots, application to the TRT45 plots (14- and 45-day target PHIs) 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)

In lemon plots, application to the TRT45 plots (14- and 45-day target PHIs) 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 BBCH 

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 PHIs 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 PHI samples were collected. 

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 isotopically labeled internal standards. The limit of quantitation (LOQ) for total 

indaziflam residue (the sum of indaziflam and fluoroethyldiaminotriazine) was 0.01 ppm in 
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oranges, grapefruit, and 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

analyzed in this study were held in frozen storage for a maximum of 16.6 months (497 

days) prior to extraction.

In orange, grapefruit, and lemon, the HAFT (highest average field trial) and maximum total 

indaziflam residues at all three PHI’s (14-day, 45-day, and 240-day) were less than the LOQ 

(<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-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1Hinden-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), Indaziflam 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 hectare (g ai/ha). The actual use rates were 0.131-

0.140 lb ai/A (146-157 g ai/ha) on apples, and 0.129-0.144 lb ai/A (145-161 g ai/ha) on pears. 

Indaziflam 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 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 intervals 

(PHIs). 

In apple plots, the 14-day target PHI application 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 PHI application was made 

between BBCH 00 and 57 (BBCH 00 = dormancy; BBCH 57 = pink bud stage). Duplicate 

composite samples of apples were collected at target PHIs 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. 

In pear plots, the 14-day target PHI application was made between BBCH 78 and 85 (BBCH 78 =

fruit about 80% of final size; BBCH 85 = advanced ripening). The 45-day target PHI application 

was made between BBCH 75 and 78 (BBCH 75 = fruit about half of final size). The 150- to 

210-day target PHI application was made between BBCH 00 and 57 (BBCH 00 = dormancy; 

BBCH 57 = pink bud stage). Duplicate composite samples of pears were collected at target PHIs

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 collected 
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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 standards. The limit of quantitation 

(LOQ) for total indaziflam residues (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 analyzed 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. 

In both apples and pears, the HAFT (highest average field trial) and maximum total indaziflam

residues at all three PHIs (14-day, 45-day, and 150- to 210-day) were less than the LOQ (0.010 

ppm). 

Stone Fruit. Twenty-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-[(1R,2S)-2,3-

dihydro-2,6-dimethyl-1H-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), Indaziflam 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 equivalent 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) on cherries, 0.129 to 0.140 lb 

ai/A (145 to 157 g ai/ha) on peaches, and 0.131 to 0.139 lb ai/A (146 to 156 g ai/ha) on plums. 

Indaziflam 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 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 (PHIs), respectively. 

In cherry plots, the application was made on plot TR150 at dormancy, on plot TRT14 at a PHI of 

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) PHIs 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. 

In peach plots, the application was made on plot TR210 at dormancy, on plot TRT14 at a PHI of 

14 days, and on plot TRT45 at a PHI of 45 days. Duplicate composite samples of peaches were 

collected at target 14-day, 45-day, and 5-7 month (210-day) PHIs from treated plots TRT14, 

TRT45 and TR210, respectively. A single composite sample was collected from the control plot 
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of each trial at the same time the 14-day PHI samples were collected from the treated plot. 

In plum plots, the application was made on plot TR210 at dormancy, on plot TRT14 at a PHI of 

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) PHIs 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 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 standards. The limit of quantitation 

(LOQ) for total indaziflam residues (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 

analyzed in this study 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 analyzed. 

In cherries (sweet and tart), the highest average field trials (HAFTs), and maximum total 

indaziflam residues at target 14-day, 45-day, and 150-day PHIs were all less than the LOQ (0.010 

ppm). In peaches and plums, the HAFTs and maximum total indaziflam residues at target 14-

day, 45-day, and 210-day PHIs were all less than the LOQ (0.010 ppm). 

Tree Nuts. Ten field trials (five almond and five pecan) were conducted to measure the 

magnitude of indaziflam (CAS name N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-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), Indaziflam 500 SC. Applications 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 0.135 lb ai/A (148 to 

152 g ai/ha) on almonds, and 0.130 to 0.134 lb ai/A (146 to 150 g ai/ha) on pecans. Indaziflam

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 Indaziflam

500 SC. 

In almond plots, the application was made between BBCH 79 and 87 (BBCH 79 = fruit about 

90% of final size; BBCH 87 = fruit ripe for picking). Duplicate composite samples of almond 

nutmeat and almond hulls were collected at a target 14-day pre-harvest interval (PHI) after 

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. 
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In pecan plots, the application was made between BBCH 79 and 89 (BBCH 79 = fruit about 90% 

of final size; BBCH 89 = fruit ripe for consumption). Duplicate composite samples of pecans 

were collected at a target 14-day PHI after 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 standards. The limit of quantitation 

(LOQ) for total indaziflam residues (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 indaziflam 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 

analyzed in this study were held in 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 analyzed. 

In almond nutmeat, the HAFT (highest average field trial) and maximum total indaziflam

residues (at a target 14-day PHI) were both <LOQ (0.010 ppm). In pecan nutmeat, the HAFT 

and maximum total indaziflam residues (at a target 14-day PHI) were both <LOQ (0.010 ppm). 

In almond 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 indaziflam.

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 

(PHIs) 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 efficacious 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.
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In grape plots treated at a target 14-day PHI, the growth stage at application ranged from BBCH 

83 to BBCH 89 (BBCH 83: fruit developing 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 PHI plot 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 or 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, TRT45, and either TR210 or TR240) 

at the target 14-day, 45-day, and either 210-day or 240-day PHI after 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 fluoroethyldiaminotriazine (FDAT) were 

quantitated by high performance liquid chromatography/electrospray ionization/tandem mass 

spectrometry (LC/MS/MS) using stable isotopically labeled internal standards. The limit of 

quantitation (LOQ) 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 analyzed in this study was held in frozen 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 analyzed.

In grape (fresh fruit), the HAFT (highest average field trial) and maximum total indaziflam 

residues at target 14-day, 45-day, and 210-day PHIs were less than the LOQ (<0.01 ppm). The 

HAFT and maximum total indaziflam residues at a target 240-day PHI were 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 Indaziflam 500 SC. Indaziflam 500 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 preharvest-intervals (PHIs) of 14 days, 45 days, and 300 days (10 months). Application of 

Indaziflam 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 an 
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application of Indaziflam 500 SC.

Duplicate composite samples of olives were collected in all trials from each treated plot (TRT14, 

TRT45 and TR300) at the target 14-day, 45-day, and 300-days PHI after 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 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 analyzed in this study was 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 analyzed.

In olive (fresh fruit), the HAFT (highest average field trial) and maximum total indaziflam residues 

at a target 14-day, 45-day, and 300-day PHI were less than the LOQ (<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, below for a discussion of tolerance 

levels).

It should also be noted that the petitioner is requesting a 7-day PHI for citrus whereas all citrus 

field trials were conducted at 14 days or longer. All 14-day PHI citrus field trials had total 

indaziflam residues that were less than both the LOQ and the LOD. With a total indaziflam 

residue LOD of 0.0011 ppm, even if the 14 day PHI total residue was equal to the LOD and the 

residue assumed to be ten times more concentrated at a 7-day PHI, then the total residue should 

still not exceed the LOQ and proposed tolerance of 0.01 ppm. The field trial design was intended

to estimate the “worst case” scenario for long-term exposure and translocation from root uptake 

of the soil-applied herbicide, with the 14-day PHI used to simulate any possible short-term 

uptake. Finally, the field trial results suggest that the highest total residues are observed in those 

with the longest PHI’s, with the FDAT metabolite being the primary residue detected above the 

LOD (but still less than the LOQ). Therefore, HED believes that the existing data support a 7-

day PHI and no additional citrus field trials are needed. 
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860.1520 Processed Food and Feed

47743411.der.doc (citrus)

47743409.der.doc (pome fruit)

47743410.der.doc (stone fruit)

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 Indaziflam 500 SC to the base of orange 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 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 application 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 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 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 analyzed 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 LOQ 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. 
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Pome Fruit. An apple processing trial was conducted to measure the magnitude of total 

indaziflam (CAS name N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-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, following an exaggerated rate application of Indaziflam 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 substance 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 single 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 apple raw agricultural 

commodity (RAC) samples were analyzed 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 analyte 

residues were summed to give a total indaziflam residue. The limit of quantitation (LOQ) for 

total indaziflam residues was 0.010 ppm in the apple fruit RAC.

Freezer storage stability studies indicate that total indaziflam residues would be stable in apples 

during frozen storage for an interval of at least 11 months. The apple fruit analyzed 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 LOQ (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 processing trial was conducted to measure the magnitude of total 

indaziflam (CAS name N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-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 Indaziflam 500 SC 

to the base of plum 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). 
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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 test 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 analyzed 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 analyte 

residues were summed to give a total indaziflam residue. The limit of quantitation (LOQ) for 

total indaziflam residues was 0.010 ppm in the 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 analyzed in this study

was held in frozen storage for a maximum duration of less than one month (21 days) prior to 

extraction. 

No total indaziflam residues were observed above the LOQ (0.010 ppm) in the plum fruit 

following a 5X exaggerated rate application of indaziflam to plums. Therefore, although plums 

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 Indaziflam 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 cover, 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 total 
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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 

using procedures that simulated commercial processing practices. The resultant grape raw 

agricultural commodity (RAC) sample and processed commodities were analyzed to determine 

total indaziflam residues.

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 (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 residues 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 analyzed 

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

Residueb

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

NAa

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.
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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 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 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 0.677 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 highpressure liquid chromatography/triple stage quadrupole mass spectrometry (LC/MS/MS) using stablelabeled 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 storage 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 sugarcane 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).
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A single broadcast foliar spray application was applied as an early season pre-emergence (prior to layby) 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 single 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 highpressure liquid chromatography/triple stage quadrupole mass spectrometry (LC-MS/MS) using stablelabeled 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 were 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 exaggerated rates appropriate for waiving analysis of the 

processed foods and feeds (i.e., residues were < LOQ at 5X exaggerated application rates).

The grape processing study relied on residue estimates between the LOD 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 LOQ 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 reduction in the application rate, 

and the processing factors discussed above, HED does not believe that residues in processed 

commodities will exceed the total indaziflam LOQ 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.
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Although citrus RACs from submitted field trials and a processing study have total residues 

below the LOQ 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 

analyzed 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 suggests that indaziflam residues are concentrated approximately 11.7X compared to those 

observed in citrus RACs, the total residues in citrus oil are still less than LOQ (0.01 ppm). 

Therefore, HED does not believe that a tolerance for citrus oil is required, as no finite residues 

would be expected even at exaggerated rates. However, the final study report from this citrus oil 

analysis should be required as a condition of registration. 

It should 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 higher observed residues. Therefore, the use of 

samples with longer PHI should actually have increased the probability of finding quantifiable 

residues in the RAC and processed commodities. 

For sugarcane, samples from the processing study showed no quantifiable residues of indaziflam 

or FDAT following a 2X application rate, and the processed commodities of molasses and 

refined sugar were not analyzed. Typically, HED requires that no residues of concern be found 

in a RAC following at least a 5X exaggerated application rate to make a finding that tolerances 

are not necessary in the processed commodity. Based on information in the metabolism study, 

quantifiable residues of indaziflam or FDAT would not be expected in sugarcane even at a 5X 

treatment rate, with the highest observed TRR of 0.005 ppm in the 2X metabolism study. 

Therefore, HED does not believe that residues of indaziflam and FDAT in refined sugar will 

exceed those in the sugarcane RAC (i.e., <0.01 ppm). Nevertheless, in this instance HED 

recommends the tolerance be set on the refined sugar since that is the commodity to be imported.

HED notes that a metabolism trial at a 10X exaggerated treatment rate was initiated and 

subsequently terminated due to treatment-related phytotoxicity.

860.1850 Confined 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 

confined rotational crop study at this time. Should uses for indaziflam on rotated crops be sought 

in the future, a confined rotational crop study will likely be required to support such uses.

860.1900 Field Accumulation in Rotational Crops

There are no rotational crop tolerance issues associated with this petition.
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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:

Tolerances are established for residues of the herbicide indaziflam, including its 

metabolites and degradates, in or on the commodities in the table below as a result of 

application of indaziflam. Compliance with the tolerance levels specified below is to be 

determined by measuring only indaziflam {1,3,5-triazine-2,4-diamine, N-[(1R,2S)-2,3-

dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1R,1S)-1-fluoroethyl]-} and 1-fluoroethyl 

diaminotrizine {6-[(1R,1S)-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/MRL Harmonization 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 MRLs for indaziflam and, 

therefore, there are no international harmonization issues with this action (Attachment 4).
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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 --

Olive 0.01 0.01 --

Sugarcane, sugar, refined 0.01 0.01 Sugarcane, refined sugar; tolerance 

without a corresponding U.S. registration
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Attachment 1. Summary of Major Residues in Metabolism and Environmental Fate Studies.

Table A1. Summary of Major1 Residues from Metabolism and Environmental Fate Studies.

Compound Sugarcane Apples Grapes Goat –

Milk

Goat - 

Liver

Goat -

Muscle

Goat -

Fat

Goat -

Kidney

Rat 

Excreta

Soil2 Water3

Indaziflam 24 13 24 9 2 - 20 - 38 56 21

Fluoroethyl diaminotriazine 30 72 47 13 - 15 3 2 2 39 13

Indaziflam carboxylic acid - - - 9 24 6 19 20 67 22 21

Indaziflam-4-hydroxyhydroxymethyl - - - 18 4 15 7 4 - - -

Indaziflam-dihydroxy - - - 18 2 18 4 11 13 - -

Indaziflam-4-hydroxy acid - - - - 5 - 12 14 - - -

Indaziflam-3-ketohydroxymethyl4- - - 28 2 5 4 6 1 - -

Indaxiflam-3-hydroxyindane4- - - 18 24 14 9 17 13 - -

Indaziflam ketone - - - - - - - - - 16 21

Fluoroethyltriazinane-2,4-dione - - - - - - - - - 26 -

Indaziflam hydroxyethyl - - - - - - - - 9 - 21

Indaziflam olefin - - - - - - - - - - 54

Yellow = greater than 10% TRR, Blue = between 1 and 10% TRR, White = less than 1% TRR; dash (-) = not detected.

1 Only metabolites that appeared in at least one study at > 10% of the TRR or total applied radioactivity are included in this table. 

Maximum reported values for each matrix are provided.

2 The maximum value from all soil studies is reported (i.e., aerobic and anaerobic study results are combined).

3 The maximum value from all aquatic studies is reported, including aquatic photolysis and aerobic aquatic metabolism.

4 Including the glucuronic acid conjugate
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Attachment 2. Compounds Identified in metabolism and environmental fate studies.

Table A2. Major Chemicals Identified in Metabolism and Fate Studies

Compound/Code Chemical Name Chemical Structure

Indaziflam 1,3,5-triazine-2,4-diamine, 

N-[(1R,2S)-2,3-dihydro2,6-dimethyl-1H-inden-1-

yl]-6-[(1R)-1-fluoroethyl]-

N

N

N

N

H

NH2

H C F 3

CH3

H3C

Fluoroethyl diaminotriazine 6-[(1R)-1-fluoroethyl]-

1,3,5-triazine-2,4-diamine

N

N N

H2N

CH3

F

NH2

Indaziflam carboxylic acid (2S,3R)-3-[[4-amino-6-

[(1R)-1-fluoroethyl]-1,3,5-

triazin-2-yl]amino)-2,3-

dihydro-2-methyl-1Hindene-5-carboxylic acid N

N N

CH3

N

H

CH3

F

NH2

HO2C

Indaziflam-4-

hydroxyhydroxymethyl (2S,3R)-3-[[4-amino-6-

[(1R)-1-fluoroethyl]-1,3,5-

triazin-2-yl]amino)-5-

hydroxymethyl-2,3-

dihydro-2-methyl-1Hindene-7-ol

N

N N

CH3

N

H

CH3

F

NH2

HO

OH

Indaziflam-dihydroxy (2R,3R)-3-({4-amino-6-

[(1R)-1-fluoroethyl]-1,3,5-

triazin-2-yl}amino)-5-

hydroxymethyl-2-

methylindan-1-ol N

N N

CH3

N

H

CH3

F

NH2

HO

OH
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Table A2. Major Chemicals Identified in Metabolism and Fate Studies

Compound/Code Chemical Name Chemical Structure

Indaziflam-4-hydroxy acid (2S,3R)-3-[[4-amino-6-

[(1R)-1-fluoroethyl]-1,3,5-

triazin-2-yl]amino)-2,3-

dihydro-2-methyl-1Hindene-7-ol-5-carboxylic 

acid N

N N

CH3

N

H

CH3

F

NH2

HO

HO2C

Indaziflam-3-

ketohydroxymethyl

(2S,3R)-3-[[4-amino-6-

[(1R)-1-fluoroethyl]-1,3,5-

triazin-2-yl]amino)-5-

hydroxymethyl-2-

methylindane-1-one

N

N N

CH3

N

H

CH3

F

NH2

O

OH

Indaxiflam-3-

hydroxyindane

(2R,3R)-3-({4-amino-6-

[(1R)-1-fluoroethyl]-1,3,5-

triazin-2-yl}amino)-2-

methylindan-1-ol-5-

carboxylic acid

N

N N

CH3

N

H

CH3

F

NH2

HO

HO2C

Indaziflam ketone N-[(1R,2S)-2,3-Dihydro2,6-dimethyl-3-oxo-1Hinden-1-yl]-6-[(1R)-1-

fluoroethyl]-1,3,5-triazine2,4-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-dihydro1H-inden-1-ylamino]-1,3,5-

triazin-2-yl}ethanol
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Table A2. Major Chemicals Identified in Metabolism and Fate Studies

Compound/Code Chemical Name Chemical Structure

Indaziflam olefin N-[(1R,2S)-2,6-dimethyl2,3-dihydro-1H-inden-1-

yl]-6-vinyl-1,3,5-triazine2,4-diamine
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Attachment 3. Determination of the Recommended Tolerance for Almond 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. Note that the fill-in values derived by HED are different from those estimated by the 

petitioner and result in a different tolerance recommendation than that given by the petitioner. 

HED surmises that the different values may be due to the petitioner not recalculating 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 level 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

0.038
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Figure A3.1. Lognormal Probability Plot for Residues in/on Almond Hulls Following Treatment 

with Indaziflam.

Lognormal Probability Plot

0.1 1 2 5 10 20 30 50 70 80 90 95 98 99 99.9

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

Percentiles

Concentrations

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: 0.001

max: 0.153

median: 0.022

average: 0.049

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

UCLMedian95th 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)==> Y
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Attachment 4. International Residue Limit Summary.

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name

1,3,5-triazine-2,4-diamine, N-

[(1R,2S)-2,3-dihydro-2,6-

dimethyl-1H-inden-1-yl]-6-

[(1R)-1-fluoroethyl]-

Common Name: 

Indaziflam

X Proposed tolerance

 Reevaluated tolerance

 Other

Date: 5 May 2010

Codex Status (Maximum Residue Limits) 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 definition: 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 0.15

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