Page 1 of 50

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

Date: September 16, 2010

MEMORANDUM

SUBJECT: Indaziflam: Human Health Risk Assessment for Use in Citrus, Stone, and 

Pome Fruits; Grapes; Tree Nuts; Pistachios; Olives; and Sugar Cane (Imported 

Refined Sugar).

PC Code: 080818 DP Barcode: D367451

Decision No.: 416570 Registration No.: 432-1501

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

Assessment Type: Single Chemical Aggregate Case No.: NA

TXR No.: None CAS No.: 730979-19-8

MRID No.: See Below 40 CFR: None (New Active Ingredient)

FROM: Margarita Collantes, Risk Assessor 

Elizabeth Holman, Chemist 

William Drew, Chemist

Michael Doherty, Ph.D., Chemist 

Linnea Hansen, Toxicologist

Edward Scollon, Ph.D., Toxicologist

Risk Assessment Branch 2

Health Effects Division (7509P)

THROUGH: Richard A. Loranger, Ph.D., Senior Scientist

Christina Swartz, Branch Chief

Risk Assessment Branch 2

Health Effects Division (7509P)

TO: Bethany Benbow/ James Tompkins, RM 25

Herbicide Branch

Registration Division (7505P)

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a risk 

assessment for proposed uses of the active ingredient indaziflam to estimate the risk to human 

health that will result from the proposed use of indaziflam to control weeds in citrus, stone, and 

pome fruits; grapes; tree nuts; pistachios; and olives; and the requested tolerance without a U.S. 

registration on processed cane sugar. 
Page 2 of 50

Summary of Submitted Residue Chemistry Studies

OPPTS 860 

Series Guideline

MRID 

Number

Title

1300 – Nature of 

the Residue

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 Unpublished study prepared by Bayer CropScience. 64 p.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 Unpublished study prepared by 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 Unpublished study prepared by 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 

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.
Page 3 of 50

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.

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.
Page 4 of 50

Table of Contents

1.0 Executive Summary.......................................................................................................... 6

2.0 Ingredient Profile.............................................................................................................. 8

2.1 Summary of Proposed Uses.................................................................................... 8

2.2 Structure and Nomenclature ................................................................................... 9

3.0 Hazard Characterization/Assessment........................................................................... 11

3.1 Hazard and Dose-Response Characterization....................................................... 11

3.1.1 Database Summary ................................................................................... 11

3.1.2 Toxicological Effects................................................................................ 12

3.1.3 Dose-response ........................................................................................... 13

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................................. 14

3.3 FQPA Considerations ........................................................................................... 14

3.3.1 Adequacy of the Toxicity Database.......................................................... 14

3.3.2 Evidence of Neurotoxicity ........................................................................ 15

3.3.3 Developmental Toxicity Studies................................................16

3.3.4 Reproductive Toxicity Studies ..................................................16

3.3.5 Additional Information from Literature Sources...................................... 16

3.3.6 Pre-and/or Postnatal Toxicity ................................................................... 16

3.4 FQPA Safety Factor for Infants and Children .........................................17

3.5 Hazard Identification and Toxicity Endpoint Selection........................................ 17

3.5.1 Acute Reference Dose (aRfD) - Females age 13-49................................. 17

3.5.2 Chronic Reference Dose (cRfD)............................................................... 18

3.5.3 Incidental Oral Exposure (Short- and Intermediate-Term)....................... 18

3.5.4 Dermal Absorption.................................................................................... 18

3.5.5 Dermal Exposure (Short- and Intermediate-Term) ........................ 19

3.5.6 Dermal Exposure (Long-term) ..................................................19

3.5.7 Inhalation Exposure (Short- and Intermediate-Term) ........................19

3.5.8 Inhalation Exposure (Long-term) ..............................................20

3.5.9 Level of Concern for Margin of Exposure................................................ 20

3.5.10 Recommendation for Combining Routes of Exposure ............................. 20

3.5.11 Classification of Carcinogenic Potential................................................... 20

3.5.12 Acute Toxicity ....................................................................21

3.5.13 Summary of Toxicological Doses and Endpoints ...........................21

3.6 Endocrine disruption............................................................................................. 22

4.0 Public Health and Pesticide Epidemiology Data.......................................................... 23

5.0 Dietary Exposure/Risk Characterization ..................................................................... 23

5.1 Pesticide Metabolism and Environmental Degradation...................................... 263

5.2 Dietary Exposure and Risk ................................................................................... 29

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 30

6.1 Residential Handler Exposure............................................................................... 30

6.2 Spray Drift .................................................................................31

6.3 Combined Residential Exposure ........................................................32

7.0 Aggregate Risk Assessments and Risk Characterization............................................ 32

7.1 Acute Aggregate Risk........................................................................................... 32

7.2 Short- and Intermediate-Term Aggregate Risk..................................................... 32
Page 5 of 50

7.3 Long-Term Aggregate Risk .................................................................................. 33

7.4 Cancer Risk........................................................................................................... 33

8.0 Cumulative Risk Characterization/Assessment ................................................................ 33

9.0 Occupational Exposure/Risk Pathway.......................................................................... 34

9.1 Handler Risk ...............................................................................35

9.2 Occupational/Commercial Postapplication Exposure ................................36

10.0 Data Needs and Label Recommendations.................................................................... 36

10.1 Toxicology ............................................................................................................ 36

10.2 Residue Chemistry................................................................................................ 37

10.3 Occupational and Residential Exposure ............................................................... 38

11.0 References........................................................................................................................ 38

Appendix A: Toxicology Assessment ....................................................................................... 39

A.1 Toxicology Data Requirements ............................................................................ 39

A.2 Toxicity Profiles ...........................................................................40 

Appendix B: Table of Structures.........................................................................48
Page 6 of 50

1.0 Executive Summary

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

(1-fluoroethyl)]) is registered as a selective, pre-emergent and post-emergent alkylazine 

herbicide for control of many annual grasses and broadleaf weeds in lawns, golf course, sod 

farms, recreational turf, ornamentals, non-crop areas, Christmas tree farms and forested areas. It 

is also registered for use as a pre-emergent herbicide for weed control in parks, railroads, utility, 

industrial and municipal sites. Bayer CropScience has submitted petitions proposing new uses 

for indaziflam formulated as a 19.05% and 45.05% soluble concentrates (Indaziflam 200 SC and 

Indaziflam 500 SC) for control of annual grasses and broadleaf weeds in citrus, stone, and pome 

fruits, grapes, tree nuts, pistachios and olives. This is the first food use assessment for this 

chemical. HED has sufficient information to complete a human health risk assessment.

The toxicology database is considered adequate for conducting a Food Quality Protection Act 

(FQPA) risk assessment. The scientific quality is relatively high, and the toxicity is wellcharacterized for all types of effects, including potential developmental, reproductive, 

immunologic and neurologic toxicity. The nervous system is a target for indaziflam and 

neurotoxic effects are being used to assess risks from indaziflam exposure. Indaziflam is 

classified as “Not likely to be carcinogenic to humans,” and, therefore, is not a concern for 

cancer effects. HED has evaluated the available data with respect to the Food Quality

Protection Act (FQPA) safety factor and recommends that the FQPA safety factor be reduced to 

1X.

The submitted residue chemistry data are relatively complete. HED is recommending for the 

establishment of permanent tolerances for all of the requested crops. The registration of 

indaziflam should be conditional pending receipt of acceptable final storage stability and citrus 

processing studies. Suitable analytical methods are available to enforce tolerances for residues 

of indaziflam. 

HED has assessed dietary, residential, and occupational exposures. Risks from these exposures, 

including aggregate exposures are below the level of concern. 

Indaziflam contains a symmetrical triazine moiety. Based on a comparative review of its 

structure and toxicological profile, HED determined that indaziflam does not belong in the 

triazine cumulative assessment group.

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which comprise the 

Pesticide Handlers Exposure Database (PHED), and the Outdoor Residential Exposure Task 

Force (ORETF) Database, have been determined to require a review of their ethical conduct, 

have received that review, and have been determined to be ethically conducted.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered for this 

human health risk assessment, in accordance with US Executive Order 12898, Federal Actions to 
Page 7 of 50

Address Environmental Justice in Minority Populations and Low-Income Populations, 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by USDA under the CSFII, and are used in pesticide risk assessments for all registered food uses 

of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Whenever appropriate, non-dietary exposures 

based on home use of pesticide products, associated risks for adult applicators, and for toddlers, 

youths, and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Proposed Tolerances

At this time, tolerances are not required for livestock commodities. For plant commodities, the 

tolerance expression for indaziflam should read as follows:

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

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

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

determined 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 

diaminotriazine {6-[(1R,1S)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine}, calculated in 

terms of indaziflam stoichiometric equivalents, in or on the commodity. 

A summary of the petitioned-for tolerances and HED’s recommendations is provided in Table 1

below. With the exception of almond hulls, all residue levels from field trials were below the 

Limit Of Quantitation (LOQ) and the Tolerance/Maximum Residue Level (MRL) Harmonization 

Spreadsheet was not used to obtain a recommended tolerance level. 

Table 1. Tolerance Summary for Indaziflam

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments (correct commodity definition)

Fruit, citrus, Group 10 0.01 0.01 --

Fruit, pome, 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
Page 8 of 50

2.0 Ingredient Profile

2.1 Summary of Proposed Uses

Indaziflam is a selective, pre-emergent alkylazine herbicide proposed for control of annual 

grasses and broadleaf weeds in citrus, stone, and pome fruits, grapes, tree nuts, pistachios and 

olives. This assessment includes two indaziflam end-use agricultural products; Indaziflam 200 

SC and 500 SC. Both products are formulated as soluble concentrates and contain 19.05 and 

45.05% of the active ingredient, indaziflam, respectively. They may be applied, by ground 

equipment only, to the soil as a uniform broadcast or band application. Indaziflam may not be 

applied by aerial equipment or chemigation. Application may be at anytime throughout the year 

when the ground is not frozen or covered with snow. It is most effective when adequate 

moisture is present and the application is followed by rain or an irrigation event prior to weed 

seed germination. Table 2.1 provides a summary of the proposed uses.

Table 2.1. Summary of Directions for Use of Indaziflam.

Product 

EPA Reg. No. Applications,

Timing, Type, 

and Equip.

Application. 

Rate 

(lb ai/A)

Max. No. 

Applications. 

per Season

Max. 

Seasonal 

Application. 

Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Indaziflam

200 SC 

Herbicide

(Soluble 

Concentrate)

19.05% ai 

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)a

14 

(Others)

Avoid direct or indirect 

spray contact with 

crop foliage, green 

bark, roots, or fruits.

Citrus trees must be 

established for at 

least 1 year prior to 

use.

Trees/vines other than 

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 

Indaziflam

500 SC 

Herbicide

(Soluble 

Concentrate)

45.05% ai 
Page 9 of 50

crop.

Allow at least 24 months 

between the last 

indaziflam application 

and replanting with nonlabeled crop.

Sugarcane (Non-Domestic - Imported)

Broadcast 

spray, pre- or 

post-crop 

emergence, 

pre-emergence 

for weeds; 

ground or 

aerial 

equipment

0.107 lb 

a.i./A

(120 g 

a.i./ha)

1

0.107 lb 

a.i./A

(120 g 

a.i./ha)

90 None that are relevant

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

Processing) for further discussion. 

2.2 Structure and Nomenclature

Table 2.2 Nomenclature

Compound

AE 1170437

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

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]-
Page 10 of 50

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

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 RD (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%). The first chemical name appearing above in Table 

2.2 (N-[(1R,2S)...]-6-[(1R) ....diamine) represents that of the A isomer. The second name is for 

isomer B and is identical to A with the exception of the stereochemistry at the fluorine-bearing 

carbon (i.e., ...-6-[(1S)...diamine). The remaining six isomers are present at significantly lower 

levels and are considered to be impurities. The batches used for dosing in the toxicology studies 

had >90% isomer A, about 1-3% isomer B, and negligible (<1%) levels of the remaining six 

isomers. These isomer contents are appropriate for the above described composition of 

indaziflam

2.3 Physical and Chemical Properties

Table 2.3 Physicochemical Properties of Indaziflam (TGAI Unless Otherwise Noted)

Parameter Value Reference

Melting point/range 183 -184 oC indaziflam (pure substance) Petition 

Administrative 

Materials

pH (23 °C) pH = 6.5 indaziflam (pure substance)

pH = 5.1 indaziflam (technical substance)

Density 1.23 g/cm3at 20 °C (both pure and technical 

substance)

Water solubility (g/L at 20 °C) pH 4: 0.0044 

pH 9: 0.0028

Distilled water (pH 6.6-6.9): 0.0028 

Solvent solubility (g/L at 20 °C) Acetone: 55 

Acetonitrile: 7.6 

Dichloromethane: 150 

Dimethyl sulfoxide: >250 

Ethanol: 13.0 

Ethyl acetate: 47 

Heptane: 0.032 

Toluene: 4.3 
Page 11 of 50

Table 2.3 Physicochemical Properties of Indaziflam (TGAI Unless Otherwise Noted)

Parameter Value Reference

Vapor pressure 2.5 x 10-8Pa at 20 °C or 1.875 x 10-10 mm Hg

6.8 x 10-8Pa at 25 °C or 5.1 x 10-10 mm Hg

6.9 x 10-6Pa at 50 °C or 5.2 x 10-8 mm Hg

Henry’s law constant 2.69 x 10-6[Pa x m3/mol] at 20 °C

Dissociation constant (pKa) 3.5 

Octanol/water partition coefficient 

Log (KOW)

pH 2: 2.0

pH4, pH7 and pH9: 2.8

UV/visible absorption spectrum

methanol (nm)

max1 = 213 nm / A = 1.428

max2 = 268 nm / A = 0.197

max3 = 291 nm / A = 0.019

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

Studies considered for this assessment included acute lethality (oral, dermal and inhalation 

routes); primary eye and dermal irritation, dermal sensitization, subchronic oral toxicity (rat, 

mouse and dog), rat 28-day dermal toxicity, rat acute and subchronic neurotoxicity, dog chronic 

toxicity, rat chronic toxicity/carcinogenicity, mouse carcinogenicity, developmental toxicity (rat 

and rabbit), rat two-generation reproductive toxicity (with an additional special non-guideline 

study evaluating sexual maturation in rats exposed during early development to the triazine-ring 

metabolite BCS-AA10365, or FDAT), rat developmental neurotoxicity, rat immunotoxicity, 

genotoxicity, rat general metabolism (Tier 1 and Tier 2), in vivo rat dermal absorption and in 

vitro human and rat dermal absorption. 

The database is considered complete with the possible exception of a 28- or 90-day inhalation 

toxicity study in the rat. The Agency is in the process of evaluating expert advice and input on 

issues related to volatilization of pesticides and route-to-route extrapolation using oral studies for 

inhalation exposure assessment from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December, 2009 (final report of March 2, 2010; 

http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and determining the 

appropriate toxicity data needed to assess inhalation exposure. The requirement of an inhalation 

toxicity study will be determined once scientific guidance and policies on inhalation toxicity

have been established. 

3.1.1.1 Mode of action, metabolism, toxicokinetic data

Indaziflam is a broad-spectrum, pre- and/or post-emergent herbicide of the fluoroalkyltriazine 

class. It affects germination of seeds of grasses and broadleaf weeds by inhibiting cell wall 

biosynthesis and affecting meristematic stem growth. The exact mode of toxicity in mammals is 

unknown. Metabolism in the rat is discussed below in Section 3.2. 
Page 12 of 50

3.1.2 Toxicological Effects

The nervous system is a target for toxicity in rats and dogs. In repeated-dose studies, the dog 

was the more sensitive species, showing the lowest NOAELs among all available studies, based 

on neuropathology (degenerative nerve fibers in the brain, spinal cord and sciatic nerve). In the 

rat, focal/multifocal vacuolation of the median eminence of the brain and the pituitary pars 

nervosa was observed at higher doses. Clinical signs of neurotoxicity were observed in both 

species in several studies, which included rat adult and developmental neurotoxicity studies, 

including the rat acute neurotoxicity study. Ophthalmologic effects were also seen in the rat. In 

the developmental neurotoxicity study, decreased motor activity was observed in 21-day old 

male pups but was not observed in females at later times. Additional details on neurotoxic 

effects are found in Section 3.3.2. 

In the rat and mouse, effects on the kidney were observed following chronic exposure. Female 

rats had an increased incidence of dark kidney and basophilic renal tubules. Males in the 

reproductive toxicity study showed increased kidney weights and incidence of hyaline 

degeneration and tubular regeneration. In the mouse, males showed decreased kidney weights 

and increased incidences of collecting duct and pelvic epithelial hyperplasia, papillary necrosis 

and intratubular yellow-brown material. 

Liver cell hypertrophy was observed in the rat following chronic exposure but was considered an 

adaptive response. In males, white foci were also observed. In females, livers were enlarged and 

showed an increased incidence of macrovacuolation and multinucleated hepatocytes with 

anisokaryosis. 

The thyroid was affected by treatment only in male rats. Increased follicular cell hypertrophy 

and colloid alteration were observed. Statistically significant increases in TSH were observed at 

Week 3, but not at Week 13. There were no significant changes in levels of T3 or T4. Although 

treatment-related, the thyroid changes were not considered of concern for development because 

they appeared to be secondary to liver effects (and induction of liver metabolic enzymes), they

were seen at high doses relative to the endpoints selected for risk assessment, and other thyroid 

hormone levels (T3, T4) did not show changes. 

Additional effects observed following chronic exposure included atrophied or small seminal 

vesicles in male rats and glandular erosion/necrosis in the stomach and blood-filled ovarian 

cysts/follicles in female mice. However, these effects occurred at higher doses than those at 

which neurotoxicity was observed in the dog. Decreased body weight gain was observed in most 

studies following exposure to indaziflam. There was no evidence of immunotoxicity in the 

available studies, which included a guideline immunotoxicity study in the rat. No systemic 

effects were observed in the rat following a 28-day dermal exposure period. 

In the rat developmental toxicity study, decreased fetal weight was observed in the presence of 

maternal effects that included decreased body weight and clinical signs of toxicity. No 

developmental effects were observed in rabbits up to maternally toxic dose levels. Decreased 

pup weight and delays in sexual maturation (preputial separation in males and vaginal patency in 

females) were observed in the rat two-generation reproductive toxicity study, along with clinical 
Page 13 of 50

signs of toxicity, at a dose causing parental toxicity that included clinical signs and decreased 

weight gain. In the developmental neurotoxicity study, transiently decreased motor activity

(PND 21 only) in male offspring was observed and was considered a potential neurotoxic effect. 

It was observed at a dose that also caused clinical signs of neurotoxicity along with decreased 

body weight in maternal animals.

Indaziflam showed no evidence of carcinogenicity in the two-year dietary rat and mouse 

bioassays. All genotoxicity studies that were conducted on indaziflam were negative. 

3.1.3 Dose-response

For acute dietary exposure, an acute reference dose (aRfD) of 0.50 mg/kg/day was selected for 

assessment of all populations, based on a NOAEL of 50 mg/kg/day in the rat acute neurotoxicity

study with decreased motor and locomotor activities in females observed at 100 mg/kg/day. This 

endpoint is a single-dose effect and is appropriate for the populations of concern. Although the 

rat developmental toxicity study had a lower developmental NOAEL (25 mg/kg/day), the acute 

neurotoxicity NOAEL of 50 mg/kg/day, with a LOAEL of 100 mg/kg/day, is considered 

protective for all populations including potentially pregnant females because of the large spread 

in the dose spacing in the rat developmental study (i.e., NOAEL = 25 and the LOAEL = 200 

mg/kg/day). Furthermore, our confidence in the use of the neurotoxicity endpoint is supported 

by the observed mild effects at the rat developmental LOAEL (200 mg/kg/day), which were 

limited to pup body weight decrements of <10%.

For chronic dietary exposure, a chronic reference dose (cRfD) of 0.02 mg/kg/day was selected 

for assessment of all populations, based on a NOAEL of 2.0 mg/kg/day with evidence of nervous 

system microscopic effects observed at the LOAEL of 6 and 7 mg/kg/day in males and females 

respectively in the dog chronic dietary study. This provided the most sensitive endpoint 

available for chronic dietary exposure: rat and mouse chronic exposure NOAELs were ≥12 

mg/kg/day. 

For short- and intermediate-term residential and occupational exposure scenarios involving 

incidental oral and inhalation exposure, the NOAEL of 7.5 mg/kg/day from the dog oral 

subchronic toxicity study was selected. The LOAEL of 15 mg/kg/day was based on nervous 

system microscopic degenerative effects. Developmental toxicity studies in the rat and rabbit 

were also available for short-term exposure, but had higher NOAELs (25 mg/kg/day) and, 

therefore were not considered protective of potential neurotoxicity. The rat subchronic 

neurotoxicity study also had a significantly higher NOAEL (244 mg/kg/day), as did the 

developmental neurotoxicity study (maternal and developmental 84 mg/kg/day). The chronic 

dog study was considered for intermediate-term exposure due to greater incidence and severity

of lesions at lower doses with continued exposure, but was not selected because, at one year, the 

neuropathology at the LOAEL was minimal. Furthermore, based on the proposed use patterns, 

continuous daily exposures occurring for more than 90 days are not expected to occur. 

Although a 28-day dermal toxicity study in the rat was available and showed no toxicity up to 

the limit dose, including neuropathology or clinical signs, it was not selected for dermal risk 

assessment because the dog showed considerably greater sensitivity for neuropathology than the 
Page 14 of 50

rat in the oral studies. The NOAEL from the subchronic dog study was therefore selected to be 

protective of potential neurotoxicity, but is considered a conservative endpoint due to the bolus 

(gavage) dosing method employed in the dog subchronic study (similarly, in the chronic dog 

study animals would consume their treated diets in a relatively short time period). 

Long-term dermal and inhalation exposure are not expected; therefore, endpoints were not 

selected. 

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

The metabolism of indaziflam has been evaluated in the rat using indaziflam labeled with 14C at 

either the indane or the triazine ring. Indaziflam is rapidly and completely absorbed. 

Radioactivity was detected in the blood within 5 minutes of dosing. Absorption was estimated at 

90% or greater of administered dose, based on bile cannulation experiments. Absorption was 

slightly more rapid in females than males. Radioactivity was rapidly excreted (approximately

90% of dose by 24 hrs postdosing). Excretion was predominantly fecal at the high dose (1:10 

urine:feces). However, at the low dose, urinary excretion was also prominent (1:1 to 1:2 

urine:feces), indicating absorption from the gastrointestinal tract was overwhelmed at the higher 

oral doses. Radioactivity was not retained at significant levels in the tissues by 3 days’ 

postdosing (less than 0.2 to 0.3% of dose), with the highest levels found in the gastrointestinal 

tract, liver, skin and thyroid. Metabolism was extensive with only 2-12% of the dose excreted in 

feces as unchanged parent, and occurred primarily via oxidative processes. The major 

metabolite in the rat was the carboxylic acid metabolite of indaziflam, which was largely 

excreted in the bile but also found in urine. Other compounds that were identified as major 

metabolites in combined excreta in one or more groups were 3-hydroxyindane acid, 

3-hydroxyindane acid epimer, dihydroxy, hydroxy glucuronic acid, 3-ketoindane acid, and 

hydroxyethyl acid metabolites. The fluoroethyl diaminotriazine (FDAT) metabolite was 

identified at low levels (1.18 to 1.69% of administered dose) in the triazine-labeled groups. 

Some metabolite profile differences were observed depending on the site of the radiolabel. For 

example, the dihydroxy and hydroxyethyl acid and acid conjugate metabolites were found in the 

indane-labeled group, but not the triazine-labeled group. In the bile-duct-cannulated group, the 

3-ketohydroxymethyl metabolite was identified in feces but was not found in the mass balance 

groups. Parent compound was found at higher levels in the triazine-labeled mass balance group 

than the indane-labeled group, but was present at higher levels in the indane-labeled group in the 

bile-duct-cannulation experiments. Metabolite profiles in males and females were comparable, 

with some minor qualitative differences, but females excreted significantly less unchanged 

parent compound. 

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

The database is considered adequate for assessment of potential sensitivity of infants and 

children to the effects of indaziflam. Acceptable rat and rabbit developmental toxicity, rat twogeneration reproductive toxicity, rat developmental neurotoxicity, rat acute and subchronic 

neurotoxicity screening and immunotoxicity studies have been submitted.
Page 15 of 50

3.3.2 Evidence of Neurotoxicity

Neurotoxicity was observed in the dog and the rat. In the dog, axonal nerve fiber degeneration 

was observed in the brain, spinal cord and sciatic nerve following subchronic and chronic 

exposure at the LOAELs (15 mg/kg/day in both sexes in the subchronic study and 6 and 7 in 

males and females, respectively in the chronic study). The study NOAELs were 7.5 mg/kg/day

for the subchronic and 2 mg/kg/day for the chronic study. No clinical signs of toxicity were 

observed at doses up to 11 and 15 mg/kg/day (chronic/subchronic studies). High dosed dogs in 

the subchronic study (30 mg/kg/day) were prematurely terminated due to excessive clinical signs 

including ataxia, tremors, decreased pupil response, seizures and other findings. 

In the rat, a marginal decrease in motor/locomotor activity was observed in females in the acute 

neurotoxicity study at 100 mg/kg (NOAEL = 50 mg/kg). Additional findings at higher doses 

include tremors, increased reactivity, decreased activity, and urine, oral or perianal staining. 

Males also showed nerve fiber degeneration of the gasserian ganglion, sciatic nerves and tibial 

nerves. Similar clinical and motor activity changes were observed in the subchronic 

neurotoxicity study, although no neuropathology was observed. Decreased motor and locomotor 

activity in females and clinical signs in both sexes (including tremors, repetitive chewing 

movements and perianal/lacrimal staining) were reported in the subchronic neurotoxicity study at 

a higher dose (about 580 mg/kg/day with a NOAEL of 244 mg/kg/day) than the acute study, 

probably as a result of gavage vs. dietary exposure. The clinical signs were consistent with 

neurotoxicity, but also could have been due to systemic toxicity. In addition, similar clinical 

findings were seen in P and F1 generation animals in the reproductive toxicity study, at doses 

≥318 mg/kg/day. Clinical signs of neurotoxicity following chronic dietary exposure to the rat at 

dietary concentrations ≥12 mg/kg/day were numerous and included dilated pupil, reduced motor 

activity, movement and posture abnormalities, soiling and staining, tremors, reduced alertness, 

labored, rapid or noisy respiration, piloerection and ophthalmological abnormalities, including 

mydriasis, absent papillary reflex and pale fundus. At terminal sacrifice, focal/multifocal 

vacuolation of the median eminence in the brain and of the pars nervosa was seen in males and 

females and peripheral or bilateral retinal atrophy in females. Neurotoxicity was not observed in 

the mouse. 

In a developmental neurotoxicity study on indaziflam, pregnant rats were administered 

indaziflam at dietary concentrations of 0, 150, 1000 or 7000 ppm; equivalent to average daily

intakes of 0, 13, 83.8 or 432 mg/kg/day. The high dose, originally at 7000 ppm, was reduced to

4000 ppm on LD 4. Maternal and offspring toxicity were observed only at the high dose of 432 

mg/kg/day. Maternal clinical signs (daily observations and/or FOB) include coarse tremor, 

dilated pupils or dilated pupils that were unresponsive to penlight, nasal staining and repetitive 

chewing movements. Maternal body weight and weight gain were decreased during gestation 

and lactation. The number of litters was reduced by 17%. In the offspring, body weights were 

also decreased in both sexes from PND 1 through lactation; postweaning males also had lower 

body weights. A statistically significant decrease in motor activity (29%) on PND 21 was 

observed in males only at higher doses; although no changes were seen at other assessment times 

or in females, it was considered treatment-related because it was statistically significant and 

outside the laboratory historical control range. 
Page 16 of 50

3.3.3 Developmental Toxicity Studies

Acceptable developmental toxicity studies in the rat and rabbit are available. In the rat, maternal 

body weight gain and food consumption were decreased at 200 mg/kg/day. Decreased fetal body

weight was observed at 200 mg/kg/day. The maternal and developmental NOAEL was 25 

mg/kg/day. In the rabbit, decreased maternal body weight gain and food consumption, and 

macroscopic liver changes in one doe (pallor, white foci) were observed at 60 mg/kg/day, but no 

developmental effects were observed. The maternal NOAEL was 25 mg/kg/day and the 

developmental NOAEL was 60 mg/kg/day. The developmental neurotoxicity study is described 

above in Section 3.3.2.

3.3.4 Reproductive Toxicity Studies

In the reproductive study parental toxicity was observed only at the high dose (≥317 mg/kg/day)

and includes coarse tremors in females during premating, gestation and lactation, decreased body 

weight gain and food consumption in both sexes and kidney effects in males (increased absolute 

and relative weight and hyaline degeneration/regeneration). Offspring toxicity was also 

observed only at the high dose. Clinical signs of toxicity in F1 pups included perianal, urine and 

nasal stains, tremors, increased reactivity and activity, myoclonus, and diarrhea but no signs 

were seen in F2 pups. F1 pup weights were decreased through the postnatal period for males and 

females. Reproductive toxicity was observed as delays in achieving sexual maturation at the high 

dose, as measured by preputial separation (males) and vaginal opening (females), in the F1 and 

F2 offspring. The NOAEL for parental, offspring and reproductive toxicity was 69.3 mg/kg/day.

3.3.5 Additional Information from Literature Sources

No published studies, relevant to human hazard resulting from use of indaziflam, were identified. 

3.3.6 Pre-and/or Postnatal Toxicity

3.3.6.1 Determination of Susceptibility

There was no evidence of increased susceptibility (qualitative or quantitative) for pre- and/or 

postnatal effects in developmental toxicity studies in the rat and rabbit, the rat developmental 

neurotoxicity study or the rat two-generation reproductive toxicity study. There is no concern 

and there are no residual uncertainties for qualitative or quantitative pre- and/or postnatal 

susceptibility to indaziflam. This is based on the completeness of the database, lack of evidence 

of increased susceptibility, and the selection of endpoints with low NOAELs that are adequately 

protective of potential developmental effects. Delayed sexual maturation in offspring was 

observed at the highest dose of the reproductive toxicity study in the presence of maternal 

toxicity. Effects in offspring in the developmental neurotoxicity study (decreased motor activity 

in males on PND 21) were well characterized and were only observed at doses that caused 

maternal neurotoxicity. Although treatment-related thyroid histological changes (following 

subchronic or chronic exposure) and transiently increased TSH (at Week 3 but not Week 14) 

were observed in male rats, they are not of concern for developmental effects because they were 

only observed in the males, were observed at a high dose relative to the selected regulatory
Page 17 of 50

endpoints, and appear to be secondary to liver effects. 

3.4 FQPA Safety Factor for Infants and Children

HED recommends reduction of the FQPA safety factor to 1X. The toxicity database for 

indaziflam is complete, including the required studies that characterize potential susceptibility of 

infants and children. There was no evidence of increased quantitative or qualitative pre- and/or 

postnatal susceptibility; developmental effects in the rat were observed only at high doses in the 

presence of maternal/parental toxicity. Although indaziflam causes neurotoxicity, the effects are 

well characterized and served as the basis for endpoint selection. Therefore, the risk assessment 

is protective of potential neurotoxicity and other effects which occurred at higher doses. 

Conservative, upper-bound assumptions were used to determine exposure through food, drinking 

water and residential sources, such that these exposures have not been underestimated.

Although the dog is the more sensitive species, the results of the rat developmental neurotoxicity

study, which thoroughly examined potential effects to the developing nervous system following 

pre- and post-natal exposure, showed only marginal effects in offspring (slightly decreased 

motor activity, absolute brain weight) at relatively high (and maternally toxic) doses and 

indicates that increased susceptibility does not occur.

3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1 Acute Reference Dose (aRfD) – All Populations Including Infants and Children and 

Females Age 13-49 

Study Selected: Acute Neurotoxicity – Rat 

MRID Nos: 47443310

Dose and Endpoint for Risk Assessment: NOAEL = 50 mg/kg, based on decreased 

motor and locomotor activity in females at 100 mg/kg. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability)

Acute RfD = 

100 ( )

50 /

UF

mg kg = 0.50 mg/kg

Comments about Study/Endpoint/Uncertainty Factors: The selected NOAEL of 50 

mg/kg is from a study of the appropriate route and duration. The decreases in motor and 

locomotor activity are considered potential single-dose effects because they were 

observed within the first hours following dosing. The endpoint is protective of the 

decreases in maternal body weight gains seen within the first three days of exposure in 

the developmental rat (25/200 mg/kg/day, NOAEL/LOAEL) and rabbit (25/60 

mg/kg/day, NOAEL/LOAEL) toxicity studies, but which were considered questionable 

as an endpoint due to variability in the data. No other acute effects were observed in the 

database. The endpoint is also protective of potential developmental effects, based on the 

lack of observed increased pre- and/or postnatal susceptibility and higher LOAELs 

observed in developmental, reproductive, neurotoxicity, developmental neurotoxicity and 

immunotoxicity studies. Although the rat developmental toxicity study’s developmental 

NOAEL was lower (25 mg/kg/day), the neurotoxicity NOAEL of 50 mg/kg/day is 
Page 18 of 50

considered protective because the rat developmental LOAEL (7-9% decrease in fetal 

body weight) was significantly greater (200 mg/kg/day) and the effects were relatively

mild at that dose and unlikely to occur after a single dose. 

3.5.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic Toxicity (Dietary) – Dog

MRID No: 47743294

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/day, based on nerve 

fiber degeneration in the brain, spinal cord and sciatic nerve at 6 and 7 mg/kg/day (M and 

F respectively). 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability)

Chronic RfD = 

100 ( )

2.0 / /

UF

mg kg day = 0.02 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: The NOAEL selected for 

this risk assessment represents the lowest available NOAEL for effects of indaziflam 

following long-term dietary administration. The RfD is protective of potential 

developmental effects, based on the lack of observed increased pre- and/or postnatal 

susceptibility and significantly higher NOAELs observed in developmental, reproductive, 

neurotoxicity, developmental neurotoxicity and immunotoxicity studies. 

3.5.3 Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: Subchronic Toxicity (Gavage) – Dog

MRID No: 47743289

Dose and Endpoint for Risk Assessment: NOAEL = 7.5 mg/kg/day, based on brain, 

spinal cord and sciatic nerve degenerative lesions at 15 mg/kg/day. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the 

most sensitive NOAEL available from an oral study of appropriate exposure duration 

(90-days) for short-term (up to 30 days) and intermediate-term (up to 6 months) exposure 

via the oral route. The selected endpoint is protective of potential postnatal 

developmental toxicity, based on the lack of observed postnatal susceptibility and 

significantly higher NOAELs for postnatal toxicity in the developmental neurotoxicity

and the two-generation reproductive toxicity studies.

3.5.4 Dermal Absorption

In addition to a 28-day study evaluating dermal toxicity in the rat, an in vivo dermal 

absorption study in the rat and in vitro dermal absorption studies in the rat and human 

were submitted. The data demonstrated an inverse relationship between dosing 

concentration and percent absorption. Based on in vivo dermal absorption observed in 

the rat and in vitro comparative rat:human absorption data, an estimated human dermal 

absorption factor (DAF) of 7.3% was obtained.
Page 19 of 50

The human DAF was calculated as follows (all absorption values adjusted for recovery): 

(1) in the rat in vivo dermal absorption study, 27.39% of the applied dose was absorbed at 

24 hrs postexposure (actual exposure time 8 hrs) using an application of 0.0005 mg/cm2; 

(2) in vitro exposure of microtomed rat skin under the same exposure and assessment 

conditions gave a dermal absorption of 22.40%; (3) the ratio of the in vitro to the in vivo

absorption is 0.82 (22.4/27.39) and therefore is close to 1, indicating that the in vitro data 

is predictive of in vivo absorption; (4) based on this ratio, a DAF for humans may be 

calculated using in vitro human dermal absorption (5.975%, adjusted for recovery) 

observed in vitro under the same exposure conditions. The DAF for humans is therefore 

5.975%/0.82 = 7.3%.

3.5.5 Dermal Exposure (Short-Term, 1-30 days, and Intermediate-Term, 1-6 months)

Study Selected: Subchronic Toxicity-Dog

MRID No: 47743289

Dose and Endpoint for Risk Assessment: NOAEL = 7.5 mg/kg/day, based on 

degenerative brain, spinal cord and sciatic nerve fiber lesions at 15 mg/kg/day. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the 

most sensitive NOAEL available from a study of appropriate exposure duration (90 days) 

for short- and intermediate-term exposure. The subchronic oral dog study was selected 

over other studies because the dog was the most sensitive species for neurotoxicity and 

had the lowest overall NOAEL. Although a 28-day dermal toxicity study in the rat 

showed no effects at the limit dose (including neuropathology), it was not selected as an 

endpoint for this exposure scenario due to the significantly greater sensitivity for 

neurotoxicity seen in the dog relative to the rat. Neurotoxic effects in the dog were 

identified at doses that were 10-20 times lower than in the rat. The endpoint is 

nonetheless considered conservative because the effects in the dog were observed 

following gavage dosing, in contrast to a relatively slower dermal absorption rate. For 

route-to-route extrapolation, dermal absorption of 7.3% relative to oral absorption was 

used, estimated from human and rat in vitro and rat in vivo dermal absorption.

3.5.6 Dermal Exposure (Long-Term, >1 year)

Long-term dermal exposures are not anticipated from occupational activities. 

3.5.7 Inhalation Exposure (Short-Term, 1-30 days and Intermediate-Term, 1-6 months)

Study Selected: Subchronic Toxicity-Dog

MRID No: 47743289

Dose and Endpoint for Risk Assessment: NOAEL = 7.5 mg/kg/day, based on 

degenerative brain, spinal cord and sciatic nerve fiber lesions at 15 mg/kg/day. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the 

most sensitive NOAEL available from a study of appropriate exposure duration (90-days) 
Page 20 of 50

for short- and intermediate-term exposure. The subchronic oral dog study was selected 

over other studies because the dog was the most sensitive species for neurotoxicity and 

overall lowest NOAEL. For route-to-route extrapolation, inhalation absorption of 100% 

is assumed relative to oral absorption because there are no data on inhalation absorption 

and a route-specific inhalation study is not available.

3.5.8 Inhalation Exposure (Long-Term)

Long-term inhalation exposure scenarios are not anticipated for occupational exposures. 

3.5.9 Level of Concern for Margin of Exposure

Table 3.5.9. Summary of Levels of Concern for Risk Assessment.

Route

Short-Term

(1 - 30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 NA

Inhalation 100 100 NA

Residential Exposure

Dermal 100 100 NA

Inhalation 100 100 NA

Oral 100 100 NA 

 NA = not applicable 

3.5.10 Recommendation for Combining Routes of Exposure for Risk Assessments

When there are potential occupational and residential exposures to the pesticide, the risk 

assessment must address exposures from three major sources: oral, dermal and inhalation 

exposures and determine whether the individual exposures can be combined if they have the 

same toxicological effects. Since the dermal, inhalation and oral endpoints are based on the 

same effects (neurotoxicity) these routes of exposure may be combined for purposes of this risk 

assessment. 

3.5.11 Classification of Carcinogenic Potential

There was no evidence of carcinogenicity observed in the two-year dietary rat or mouse 

carcinogenicity bioassays. Genotoxicity studies (reverse gene mutation in bacteria, forward gene 

mutation in mammalian cells and in vitro and in vivo chromosomal aberration assays) were 

negative. Based on the lack of evidence of carcinogenicity or genotoxicity, HED classified 

indaziflam as “Not likely to be carcinogenic to humans.”
Page 21 of 50

3.5.12 Acute Toxicity

Indaziflam shows low acute toxicity by all routes of exposure (Toxicity Category III, oral and 

dermal and Category IV, inhalation) and is not an ocular or dermal irritant or a dermal sensitizer. 

3.5.13 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments of Indaziflam 

Table 3.5.13. Summary of Toxicological Doses and Endpoints for Indaziflam for Use in 

Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary (All 

Populations, 

including Infants 

and Children and 

Females 13-49 

years of age)

NOAEL = 

50 

mg/kg/day

UFA= 10X

UFH= 10X

FQPA SF= 1X 

Acute RfD = 

0.5

mg/kg/day

aPAD = 0.5 

mg/kg/day

Acute oral neurotoxicity in the rat

LOAEL = 100 mg/kg/day, based on 

decreased motor and locomotor activity in 

females.

Chronic Dietary 

(All Populations)

NOAEL = 2 

mg/kg/day

UFA= 10X

UFH= 10X

FQPA SF= 1X 

Chronic RfD = 

0.02

mg/kg/day

cPAD = 0.02 

mg/kg/day

Chronic oral (dietary) toxicity in the dog

LOAEL = 6/7 mg/kg/day M/F, based on 

nerve fiber degenerative lesions in the 

brain, spinal cord and sciatic nerve. 

Incidental Oral, 

Short-term (1 to 30 

days) and 

Intermediate-term

(1 to 6 months)

NOAEL = 

7.5 

mg/kg/day

UFA=10X

UFH=10X

FQPA SF = 1X

Residential 

LOC for MOE 

= 100

Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal 

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Dermal, Short-term

(1 to 30 days) and 

Intermediate-term

(1 to 6 months)

NOAEL = 

7.5 

mg/kg/day

DAF = 7.3%

UFA=10X

UFH=10X

FQPA SF = 1X

Residential 

LOC for MOE 

= 100

Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal 

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Dermal, LongTerm (>6 months)

Not required for this assessment (exposure is seasonal; long-term dermal exposure scenarios 

are not anticipated).

Inhalation, Shortterm (1 to 30 days) 

and Intermediateterm (1 to 6 

months)

NOAEL = 

7.5 

mg/kg/day

Inhalation 

absorption 

assumed to 

be 100% 

(default) 

relative to 

oral.

UFA=10X

UFH=10X

FQPA SF = 1X

Residential 

LOC for MOE 

= 100

Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal 

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Inhalation, Longterm (>6 months)

Not required for this assessment (exposure is seasonal; long-term inhalation exposure scenarios 

are not anticipated).

Cancer (oral, 

dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans”
Page 22 of 50

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable. DAF = dermal absorption factor

Table 3.5.13 Summary of Toxicological Doses and Endpoints for Indaziflam for Use in

Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal, ShortTerm (1 to 30 days) 

and Intermediateterm (1 to 6 

months)

NOAEL = 

7.5

mg/kg/day

DAF = 7.3%

UFA=10X

UFH=10X

Occupational 

LOC for MOE 

= 100

Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal 

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Dermal, LongTerm (>6 months)

Not required for this assessment (exposure is seasonal; long-term occupational exposure 

scenarios are not anticipated).

Inhalation ShortTerm (1 to 30 days) 

and IntermediateTerm (1 to 6 

months)

NOAEL= 

7.5 

mg/kg/day

. 

Inhalation 

absorption 

assumed 

to be 

100%

(default) 

relative to 

oral.

UFA=10X

UFH=10X

Occupational LOC 

for MOE = 100

Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal 

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Inhalation LongTerm (> 6 months)Not required for this assessment (exposure is seasonal; long-term occupational exposure 

scenarios are not anticipated).

Cancer (oral, 

dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable. DAF = dermal absorption factor.

3.6 Endocrine disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including all pesticide 

active and other ingredients) “may have an effect in humans or wildlife similar to an effect 

produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 
Page 23 of 50

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identity any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

EPA is issuing test orders/data call-ins for the first group of 67 chemicals, which contains 58 

pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on 

the potential for human exposure through pathways such as food and water, residential activity, 

and certain post-application agricultural scenarios. This list should not be construed as a list of 

known or likely endocrine disruptors.

Indaziflam is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408 (p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients.

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 Public Health and Pesticide Epidemiology Data and Incident Reports

There are no public health, pesticide epidemiology or incident data to report at this time.

5.0 Dietary Exposure/Risk Characterization

(Indaziflam. Petition for the Establishment of Permanent Tolerances and Registration for Use on Pome Fruits, Stone 

Fruits, Citrus, Tree Nuts (including Pistachios), Grapes, and Olives (PP 9F7589); and a Tolerance without a 

Domestic Registration for Sugarcane (PP 9E7588). Summary of Analytical Chemistry and Residue Data; D374105;

E. Holman; September 9, 2010)

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

Metabolism studies were performed in three primary crops, apples, grapes and sugarcane. In

plants, the metabolism of indaziflam is relatively uncomplicated with parent indaziflam and the 

fluoroethyl diaminotriazine (FDAT) metabolite being the only indentified compounds. 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 5.1.7. 
Page 24 of 50

5.1.2 Metabolism in Livestock

Metabolism data depicting the residue profile in the lactating goat were submitted reflecting 

indaziflam labeled with 14C at either the indane or the triazine ring, with separate studies being 

submitted for each specific ring. Based on the available information, indaziflam appears to 

undergo significant oxidative metabolism in ruminants. There are a number of significant (> 

10% TRR) metabolites, depending on the commodity being examined, with most consisting of 

some level of increased hydroxylation relative to the parent compound.

5.1.3 Metabolism in Rotational Crops

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.

5.1.4 Environmental Degradation

Field and laboratory data indicate that indaziflam and its degradates have a potential to leach to 

ground water, particularly FDAT. Indaziflam is classified as moderately mobile; however, 

transformation products of indaziflam are mobile to highly mobile and were detected in field 

studies at depth. Further, data show that indaziflam is persistent in anaerobic soil and anaerobic 

aquatic systems. There are no data available on the anaerobic degradation of the transformation 

products of indaziflam. Key lines of evidence show that residues of indaziflam, and degradate 

products (e.g., FDAT) are a concern for exposure via ground water. A prospective ground water 

study could help reduce the uncertainty regarding the exposure via ground water. 

5.1.5 Comparative Metabolic Profile

The metabolism of indaziflam is complex, with a few major metabolites (fluoroethyl 

diaminotriazine = FDAT, and indaziflam carboxylic acid) found in plants, goat, rat, soil and 

water and numerous minor metabolites. Table 5.1.5 provides a profile of the major residues 

from metabolism and environmental fate studies.

In determining metabolism OPP performed a preliminary review of the available metabolism and 

environmental fate data for purposes of determining the residues of concern for drinking water 

by the Residues of Concern Knowledgebase Subcommittee (ROCKS) (G. Kramer, D371659, 

February 18, 2010).

The metabolism of indaziflam has been evaluated in the rat using indaziflam labeled with 14C at 

either the indane or the triazine ring. Indaziflam is rapidly and completely absorbed. 

Radioactivity was rapidly excreted (approximately 90% of dose by 24 hrs postdosing). 

Metabolism was extensive with only 2-12% of the dose excreted in feces as unchanged parent, 

and occurred primarily via oxidative processes. The major metabolite in the rat was the 

carboxylic acid metabolite of indaziflam, which was largely excreted in the bile but also found in 

urine. Other compounds that were identified as major metabolites in combined excreta in one or 

more groups were 3-hydroxyindane acid, 3-hydroxyindane acid epimer, dihydroxy, hydroxy 
Page 25 of 50

glucuronic acid, 3-ketoindane acid, and hydroxyethyl acid metabolites. The fluoroethyl

diaminotriazine (FDAT) metabolite was identified at low levels (1.18 to 1.69% of administered 

dose) in the triazine-labeled groups. 

Conclusions regarding residues of concern for metabolites in proposed crops and livestock are 

that while the residue profile in crops is comprised of indaziflam and FDAT being the only 

indentified compounds; however, in the goat indaziflam appears to undergo significant oxidative 

metabolism. There are a number of significant (> 10% TRR) metabolites, depending on the 

commodity (i.e., milk, liver, muscle, fat) being examined, with most consisting of some level of 

increased hydroxylation relative to the parent compound.

Residues of concern for metabolites in soil consist of the parent, FDAT, carboxylic acid, 

indaziflam ketone, and fluoroethyltriazinane-2,4-dione.

Several environmental degradates are of concern for drinking water risk assessment. Drinking 

water residues of concern for this purpose include triazine indanone, indaziflam carboxylic acid, 

FDAT, dihydroamino triazine, indaziflam hydroxyethyl, and indaziflam olefin. 

Table 5.1.5. Summary of Major1 Residues from Metabolism and Environmental Fate Studies.

Compound Sugarcan

e

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

5.1.6 Toxicity Profile of Major Metabolites and Degradates

With the exception of FDAT and dihydroamino triazine, all of the major metabolites are 

assumed to have comparable toxicity to the parent due to structural similarity (i.e., both rings 
Page 26 of 50

intact). FDAT is not expected to be more toxic than the parent indaziflam based on FDAT’s 

non-neurotoxic mode of action (E. Scollon, D371661, April 21, 2010). Therefore, the neurotoxic 

endpoints selected for this risk assessment will be protective of potential FDAT toxicity. 

Dihydroamino triazine (ROI1) is assumed to have comparable toxicity to FDAT.

5.1.7 Pesticide Metabolism and Degradates of Concern 

Based on the available metabolism studies, HED concluded that for these uses, the nature of the 

residue has been adequately delineated for tolerance enforcement and risk assessment (Table 

5.1.7). Structures of these compounds are shown in Appendix C. 

Table 5.1.7: Residue Definition for Indaziflam.

Matrix Risk Assessment Compliance Monitoring

Plants Primary Crop Indaziflam + Fluoroethyl 

Diaminotriazine (FDAT)

Indaziflam + FDAT

Rotational Crop 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 + dihydro- amino triazine

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).

5.1.8 Analytical Methodology

Bayer CropScience method DH-003-P07-02 was developed to determine the residues of 

AE 1170437 in fruit and tree nut matrices. Method DH-003-P07-02 is based on high 

performance liquid chromatography with tanden mass spectrometry (LC/MS/MS), has been 

sufficiently validated and is suitable as an enforcement method for crops. The method is able to 

determine, 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 
Page 27 of 50

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 method’s accuracy and effectiveness.

5.1.9 Food Residue Profile

Crop Field Trials and Processing Studies: Bayer Crop Science has conducted and submitted 

adequate field trial data on citrus, pome, and stone fruits; tree nuts; grapes; and olives and 

processing studies to support tolerances in plant commodities. With the exception of almond 

hulls, total residues (indaziflam + FDAT) were below the limit of quantitation (LOQ; < 0.01 

ppm) in 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 NAFTA-harmonized 

tolerance/MRL calculator with maximum likelihood estimation (MLE) resulted in a 

recommended tolerance of 0.15 ppm for residues in almond hulls. With the exception of almond 

hulls, which may be fed to cattle, the proposed uses do not involve any significant livestock feed 

items. 

Although citrus RACs from submitted field trials and a processing study have total residues 

below the LOQ at a 5X exaggerated rate, data for citrus oil are required due to the extremely

high potential concentration factor (1000X) for that processed commodity. 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. 

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. 
Page 28 of 50

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.

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. 

Meat, Milk, Poultry and Eggs: 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 Crops: Limited field 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.

Storage Stability: The available storage stability data indicate that residues of indaziflam and 

FDAT are stable in frozen storage for up to approximately 12 months. Samples from the citrus, 

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

and are not fully supported by the available storage stability data. Since the available data 

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

support the tolerance petition. The petitioner has indicated that while the final report has not 

been through quality assurance review, preliminary findings show that the residues have 

remained stable over a 25-26 month period. Submission of the ongoing storage stability study

covering the full duration of sample storage should be made a condition of registration.

5.1.10 Drinking Water Residue Profile

(Tier 2 Drinking Water Exposure Assessment for the Section 3 New Chemical Registration of Indaziflam; R. Baris, 

D356141; February 2, 2010)

Based on a review of the available environmental fate data, the ROCKS determined that the four 

major transformation products that maintain the dual ring structure of indaziflam should be 

included in the drinking water exposure assessment since they may be of toxicological concern 

(i.e., they are assumed to be of equal or lower toxicity to the parent in the absence of 

toxicological data). These transformation products include: triazine indanone, indaziflamcarboxylic acid, indaziflam-olefin, and indaziflam-hydroxyethyl. In order to account for residues 
Page 29 of 50

of these transformation products, the Environmental Fate and Effects Division (EFED) 

calculated drinking water concentrations for total indaziflam residues which included indaziflam 

and similarly structured degradates. EFED also calculated separate concentration estimates for 

FDAT plus dihydroamino triazine (ROI1; a degradate of FDAT). Drinking water concentrations 

were based on maximum seasonal application rates for citrus (0.134 lb ai/A), which is higher 

than turf application rates (0.094 lb ai./A) and thus protective of drinking water scenarios and 

populations. As noted above, HED has included the residue estimates for FDAT and ROI1 

directly in the indaziflam assessment due to the available toxicity data indicating the neurotoxic 

endpoints for indaziflam are protective of toxicity from these degradates. The drinking water 

concentrations used to estimate exposure via drinking water are included in Table 5.1.10. 

Table 5.1.10 Summary of Estimated Surface Water and Groundwater Concentrations 

for Indaziflam

Exposure Duration Indaziflam FDAT + ROI1 Combined*

Surface, 

ppb a

Ground, 

ppb b

Surface, 

ppb a

Ground, 

ppb b

Surface, ppb Ground, ppb

Acute 48 1.6 19 1.1 84 3.7

Chronic (non-cancer) 14 1.6 6 1.1 26 3.7

* Residue estimates for FDAT and ROI1 have been converted to indaziflam equivalents (molecular weight ratio = 

301÷157 = 1.92) and included directly in the indaziflam concentration estimates.

a

From the PRZM and EXAMS 

b

From the SCI-GROW model assuming a maximum seasonal use rate of 0.134 lb ai/A for citrus.

5.1.11 International Residue Limits

At this time, there are no Canadian, Mexican, or Codex MRLs for indaziflam and, therefore, 

there are no international harmonization issues with this action. 

5.2 Dietary Exposure and Risk

(Indaziflam: Acute and Chronic Aggregate Dietary Exposure (Food and Drinking Water) and Risk Assessment for 

the Section 3 Registration on Pome Fruits, Stone Fruits, Citrus, Tree Nuts (including Pistachios), Grapes, Olives, 

and Sugarcane; E. Holman; D376909; July 28, 2010)

Acute and chronic aggregate dietary risk assessments (food and drinking water) were conducted 

using the Dietary Exposure Evaluation Model (DEEM-FCID, Version 2.03), which uses food 

consumption data from the U.S. Department of Agriculture (USDA’s) Continuing Surveys of 

Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. The acute and chronic analyses 

are based on tolerance-level residues and 100% crop treated assumptions. Default processing 

factors were used for all commodities, with exception of the empirically derived raisin

processing factor of 2.8X. For acute and chronic assessments, HED is concerned when dietary

risk exceeds 100% of the PAD. The acute and chronic dietary exposure analysis results are 

reported in Table 5.2 and show all population exposures are well below HED’s level of concern.

The acute dietary risk estimate for the general U.S. population is <1% of the aPAD. The most 

highly exposed population subgroup is all infants (<1 yr old), with a risk estimate of 3% of the 

aPAD. 
Page 30 of 50

The chronic dietary risk estimate for the general U.S. population is 3% of the cPAD. The most 

highly exposed population subgroup is all infants (<1 yr old), with a risk estimate of 10% of the 

cPAD. 

Table 5.2 Summary of Dietary Exposure and Risk for Indaziflam1

Population Subgroup*

Acute Dietary Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% 

aPAD

Dietary 

Exposure

(mg/kg/day)

% 

cPAD

Dietary 

Exposure

(mg/kg/day) Risk

General U.S. Population 0.00448 <1 0.000600 3 N/A N/A

All Infants (< 1 year old) 0.016674 3 0.001922 10

Children 1-2 years old 0.007148 1 0.001061 5

Children 3-5 years old 0.006459 1 0.000929 5

Children 6-12 years old 0.004447 <1 0.000606 3

Youth 13-19 years old 0.003648 <1 0.000438 2

Adults 20-49 years old 0.004103 <1 0.000542 3

Adults 50+ years old 0.003712 <1 0.000571 3

Females 13-49 years old 0.004118 <1 0.000543 3

1The value for the highest exposed population in the acute and chronic risk assessment is bolded. 

5.2.1 Cancer Dietary Risk

HED has classified indaziflam as “not likely to be carcinogenic to humans.” Based upon this 

classification, HED has determined there is no cancer risk associated with the proposed uses.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

(Occupational and Residential Exposure Assessment for Use of the New Active Ingredient Indaziflam on Turf, Golf 

Courses, Sod Farms, Christmas Tree Farms, Non-Crop Areas and Forestry; M. Collantes: April 2010; D372538)

 

6.1 Residential Handler Exposure

A residential assessment for use of indaziflam on turf was previously conducted in D372538 (M. 

Collantes; 4/21/10). No new residential uses are being requested at this time. Handler MOEs 

were significantly greater than 100 (ranging from 3,000 to 510,000) and are not of concern. 

The postapplication scenarios resulting from commercial and residential applications were 

assessed for adults and children using the HED Draft Standard Operating Procedures (SOP’s) for 

Residential Exposure Assessments, 2000. All adult and children residential lawn and golf 

dermal exposures and oral non-dietary ingestion exposures for children (i.e. soil ingestion, and 

hand-/object-to-mouth) were assessed. Scenarios resulted in MOEs greater than the level of 

concern (ranging from 2,800 to 2,100,000) for short-term exposure and are not of concern to 

HED. Furthermore, the episodic oral MOE for incidental ingestion of granules among young 

children (3 to 6 years of age) is 5,000 and therefore is not of concern to HED. 
Page 31 of 50

The short- and intermediate-term dermal endpoints are the same, and only short-term dermal 

exposures were assessed for adults and children. HED estimates short-term dermal 

postapplication exposure based on day-0 residues. Using day-0 residues to assess intermediateterm exposure does not take into account dissipation of residues over time and thus results in a 

conservative estimation. Therefore, the short-term dermal postapplication exposure assessment 

represents the worst case scenario and is protective of intermediate-term dermal exposure.

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

assessment was not performed for indaziflam at this time primarily because it has a very low 

vapor pressure (vapor pressure 5 x 10-10 mmHg at 25oC), it is applied at low application rates 

(maximum rates range from 0.089 - 0.125 lbs ai/A depending on use site), and it is not projected 

to be applied via typically high inhalation exposure application equipment (e.g., airblast and 

aerial equipment). However, volatilization of pesticides may be a potential source of 

postapplication inhalation exposure to individuals nearby pesticide applications. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative postapplication inhalation exposure assessment 

for indaziflam.

6.2 Spray Drift

Spray drift is a potential source of exposure for residents living in close proximity to spraying 

operations. This situation is particularly the case with aerial application. However, to a lesser 

extent, spray drift resulting from the ground application of indaziflam could also be a potential 

source of exposure. The Agency has been working with the Spray Drift Task Force (a 

membership of US pesticide registrants), EPA Regional Offices, State Lead Agencies for 

pesticide regulation, and other parties to develop the best spray drift management practices. The 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, and is developing a policy on how to appropriately 

apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied 

by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off-target drift, 

and risks associated with pesticide application. 

Spray drift is always a potential source of exposure to residents nearby to spraying operations. It

is noted that the 0.094 lb ai/acre application rate for turf was modeled to estimate postapplication 

residential exposure of children (ages 1 to 6 years of age). As this rate is equal to or higher than 

many of the commercial application rates, this scenario is protective of any exposure of children 

via spray drift from commercial indaziflam applications. 
Page 32 of 50

6.3 Combined Residential Exposure

HED combines risk values resulting from separate exposure scenarios when it is likely they can 

occur simultaneously based on the use-pattern and the behavior associated with the exposed 

population. HED evaluated the following combined residential exposures of indaziflam, 1.) 

adult dermal and inhalation handler (lawns only) exposure, and 2.) child postapplication dermal 

and oral exposures. Since HED does not generally combine adult handler and dermal 

postapplication exposure, such a combined quantitative residential exposure estimate was not 

provided. However, combined residential scenario assessments for children which could occur 

simultaneously were performed and did not result in risks of concern. 

Table 6.3: Combined Residential Exposure and Risk 

Product Use Site Handler 

Total

MOE 1

Post-application 

Dermal MOE 2

Hand-to-Mouth 

MOE 3

Combined 

MOE 4

Adult 

Lawn 3FL Concentrate 

/Ready to spray

72155-IO

Lawns, 

hardscapes 

and 

ornamentals

3,000 4,700 NA NA

Child

Lawn 3 FL (72155-IO) Lawns,

hardscapes 

and 

ornamentals

NA 2,800 5,300 1,800

1. See Table 4.1.2: Indaziflam Residential Handler Exposure and Risk (Hand Held Pump); M. Collantes: April 2010; 

D372538

2. See Table 4.2.2b Dermal Postapplication Exposure and Risk (DFR data) ); M. Collantes: April 2010; D372538

3. See Table 4.2.3 Hand-To-Mouth Exposure and Risk); M. Collantes: April 2010; D372538

4. Adult Combined MOE = NA = HED does not combine adult handler and postapplication exposure

Child Combined MOE = NOAEL (7.5 mg/kg/day)/dermal postapplication dose (0.00266) + HTM dose (0.00141)

HED did not combine risk resulting from adult homeowner handler, postapplication, and golfer 

exposure to treated turf because HED considers the probability of co-occurrence for these 

scenarios to be low.

7.0 Aggregate Risk Assessments and Risk Characterization

7.1 Acute Aggregate Risk

Other than dietary exposure, there are no other sources of exposure that constitute an acute 

exposure scenario; therefore, acute aggregate exposure and risk estimates are equivalent to the 

acute dietary exposure and risk estimates summarized in Table 5.2 and are below HED’s level of 

concern.

7.2 Short- and Intermediate-Term Aggregate Risk

HED combined risk values resulting from chronic dietary (food + drinking water) and residential 

scenarios. When estimating adult residential exposure, HED does not generally combine handler 
Page 33 of 50

and dermal postapplication exposure as it would result in an over estimate of exposure. All shortterm combined exposures resulted in MOEs greater than 100 for all populations and are not of 

concern. Short-term risks are summarized in Table 7.2 below.

Table 7.2. Summary of the Short- and Intermediate-Term Aggregate Exposure and Risk Estimates for 

Indaziflam.

Population Subgroup Total Residential 

Exposure, mg/kg/day

Chronic Dietary 

Exposure, 

mg/kg/day

Aggregate 

Exposure1, 

mg/kg/day

MOE2

U.S. Population (total) 0.00254 0.000600 0.00314 2400

All infants (< 1 year) 0.00407 0.001922 0.00599 1300

Children 1-2 yrs 0.00407 0.001061 0.00514 1500

Children 3-5 yrs 0.00407 0.000929 0.00499 1500

Children 6-12 yrs 0.00407 0.000606 0.004678 1600

Youth 13-19 yrs 0.00254 0.000438 0.002979 2500

Adults 20-49 yrs 0.00254 0.000542 0.003082 2400

Adults 50+ yrs 0.00254 0.000571 0.003112 2400

Females 13-49 yrs 0.00254 0.000543 0.003084 2400

The population subgroup with the highest estimated exposure/risk is bolded.

1 Aggregate Exposure = Residential Exposure + Chronic Dietary Exposure

2 Aggregate MOE = NOAEL (7.5 mg/kg/day) ÷ Aggregate Exposure (mg/kg/day)

7.3 Long-Term Aggregate Risk

Other than dietary exposure, there are no other sources of exposure that constitute a long-term 

exposure scenario; therefore, long-term aggregate exposure and risk estimates are equivalent to 

the chronic dietary exposure and risk estimates summarized in Table 5.2 and are below HED’s 

level of concern.

7.4 Cancer Risk

Indaziflam has been classified as “not likely to be carcinogenic to humans.” Therefore, cancer 

risk is not a concern for this chemical.

8.0 Cumulative Risk Characterization/Assessment

FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base 

its assessment of the risk posed by the chemical on, among other things, available information 

concerning the cumulative effects to human health that may result from dietary, residential, or 

other non-occupational exposure to other substances that have a common mechanism of toxicity. 

The reason for consideration of other substances is due to the possibility that low-level exposures 

to multiple chemical substances that cause a common toxic effect by a common mechanism 

could lead to the same adverse health effect as would a higher level of exposure to any of the 

other substances individually. A person exposed to a pesticide at a level that is considered safe 

may, in fact, experience harm if that person is also exposed to other substances that cause a 

common toxic effect by a mechanism common with that of the subject pesticide, even if the 

individual exposure levels to the other substances are also considered safe.
Page 34 of 50

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

their ability to disrupt the hypothalamic-pituitary-gonadal axis (US EPA, 2002). The triazine 

common mechanism group (TCMG) includes atrazine, simazine, propazine, and the metabolites 

desethyl-s-atrazine (DEA), deisopropyl-s-atrazine (DIA), and diaminochlorotriazine (DACT). 

Indaziflam and its metabolite FDAT were considered for incorporation into the TCMG by the 

HED ToxSAC committee based on structure; indaziflam, FDAT, and the TCMG members 

contain a common triazine moiety (E. Scollon, D371661, April 21, 2010). However, HED 

determined that it would not be appropriate to include indaziflam and FDAT in the TCMG for 

the following reasons: 1) The structures of indaziflam and FDAT are unique in that they contain 

a fluoroethyl group at the 2-position of the triazine ring; whereas, the TCMG members contain a 

chlorine substituent at the 2-position of the triazine ring and; 2) Indaziflam and FDAT do not 

elicit the same toxicological responses shared by the TCMG members. The TCMG members 

cause an increase in mammary gland tumors in rats and multiple developmental effects such as 

attenuation of the luteinizing hormone surge, altered pregnancy outcome, and delayed preputial 

separation. None of these effects were observed in the carcinogenicity or developmental 

guideline studies for indaziflam. Delayed maturation was observed in the rat reproduction study,

however, the effect occurred at the highest dose and was attributed to significant clinical toxicity

rather than a perturbation of the hypothalamic-pituitary-gonadal axis. In a non-guideline study, 

FDAT delayed vaginal potency in a dose dependent manner. However, none of the other 

characteristic developmental effects of the TCMG members were observed. 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 

indaziflam or its metabolite FDAT and any other substances, and indaziflam does not appear to 

produce a toxic metabolite produced by other substances. Therefore, for the purposes of this risk 

assessment, EPA has not assumed that indaziflam or its metabolite FDAT has a common 

mechanism of toxicity with other substances.

For information regarding EPA’s efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

(Occupational and Residential Exposure Assessment for Use of Indaziflam on Citrus Fruit, Stone

Fruit, Pome Fruit, Grapes, Tree Nuts, Pistachios and Olives; M. Collantes: June 7, 2010; D376907)

The proposed domestic uses of indaziflam are for control of annual grasses and broadleaf weeds 

in citrus fruit, stone fruit, pome fruit, grapes, tree nuts, pistachios and olives. This document 

assesses occupational exposures and risks from the proposed uses of Indaziflam 200 SC 

Herbicide (suspension concentrate, 19.05% ai) and Indaziflam 500 SC Herbicide (suspension 

concentrate, 45.05% ai). Based on the proposed uses, exposures to indaziflam are anticipated to 

occur for short- and intermediate-term durations.
Page 35 of 50

9.1 Handler Risk

No chemical-specific data were available with which to assess potential exposure for pesticide 

handlers. The estimates of exposure for pesticide handlers are based upon surrogate study data 

available in the PHED (v. 1.1, 1998) and from the Outdoor Residential Exposure Task Force 

(ORETF). Table 9.1 presents the results of the occupational handler exposure and risk 

assessment indicating that short- and intermediate-term dermal, inhalation and total MOEs were 

greater than the level of concern (MOEs ≥ 100) at the baseline clothing level (i.e. single layer 

clothing and no respirator), when baseline data are available. There are no baseline dermal data 

to assess the mixing/loading/applying handgun scenario. The proposed product label involved in 

this assessment directs handlers to wear long sleeved shirt and long pants, shoes plus socks, and 

chemical resistant gloves. When baseline attire plus chemical-resistant gloves are used for this 

scenario, short- and intermediate-term dermal and total MOEs were greater than the level of 

concern (MOEs ≥ 100). Handler MOEs ranged from 370 to 43,000 and are not of concern.

Table 9.1. Occupational Handler Exposures and Risksa

Exposure 

Scenario Crop or Target

App. 

Rateb

(lb 

ai/A)

Area 

Treated 

Dailyc

(acres)

Unit Exposured Dosee

(μg/kg/day) MOEf,g

Dermal 

(mg/lb ai)

Inhalation 

(μg/lb ai) Dermal Inhalation Dermal Inhalation Total 

Mixer/Loader

Groundboom 

Equipment

(PHED data)

Citrus Fruit, Pome 

Fruit, Stone Fruit, 

Grapes, Tree Nuts, 

Pistachios, Olives

0.085 80 2.9 1.2 0.021 0.000116 360 65,000 370

Applicator

Groundboom 

Equipment

(PHED data)

Citrus Fruit, Pome 

Fruit, Stone Fruit, 

Grapes, Tree Nuts, 

Pistachios, Olives

0.085 80 0.014 0.74 0.000099 0.000072 76,000 100,000 43,000

Mixer/Loader/Applicator

Handgun 

Sprayer 

(ORETF data)

Citrus Fruit, Pome 

Fruit, Stone Fruit, 

Grapes, Tree Nuts, 

Pistachios, Olives

0.085 25

0.45

(with 

gloves)

1.8

0.001

(with 

gloves)

0.000055

7,600

(with 

gloves)

140,000

7,200

(with 

gloves)

a Risks represent baseline attire (long-sleeve shirt, long pants, no respirator), except where indicated (i.e. addition of 

chemical-resistant gloves for the mixer/loader/applicator handgun scenario).

b Application rates = maximum application rates from labels.

c Amount handled per day values are HED estimates of acres treated applied per day based on Exposure SAC SOP #9.1

“Standard Values for Daily Acres Treated in Agriculture” and professional judgment.

d. Unit Exposures based on PHED Version 1.1 or ORETF data. 

e Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x %

Absorption (7.3% dermal and 100% inhalation) / Body weight (70 kg). 

f Dermal and Inhalation MOE = NOAEL (7.5 mg/kg/day) / Dose (mg/kg/day) 

g Total MOE = 1 / (1/ Dermal MOE) + (1/ Inhalation MOE).
Page 36 of 50

9.2 Occupational/Commercial Postapplication Exposure 

9.2.1 Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

assessment was not performed for indaziflam at this time primarily because it has a very low 

vapor pressure (vapor pressure 5 x 10-10 mmHg at 25oC), it is applied at low application rates 

(maximum rates range from 0.089 - 0.134 lbs ai/A depending on use site), it is not projected to 

be applied via typically high inhalation exposure application equipment (e.g., airblast and aerial 

equipment). However, there are multiple potential sources of postapplication inhalation 

exposure to individuals performing postapplication activities in previously treated fields. These 

potential sources include volatilization of pesticides and resuspension of dusts and/or particulates 

that contain pesticides. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report as well as available postapplication 

inhalation exposure data generated by the Agricultural Reentry Task Force and may, as 

appropriate, develop policies and procedures, to identify the need for and, subsequently, the way

to incorporate occupational postapplication inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational postapplication inhalation exposure assessment for indaziflam.

9.2.2 Postapplication Dermal Exposure

The proposed uses for indaziflam are ground-directed uses where no crop foliage is treated. 

Currently, HED has no data to assess postapplication dermal exposures to treated soil by

occupational workers. In general, such exposures are considered to be negligible. Therefore, for 

the proposed soil-directed uses, postapplication exposures and risks to occupational workers 

were not quantitatively assessed but are not considered to be of concern. 

Restricted Entry Interval

The restricted entry interval (REI) is based on the acute toxicity of indaziflam technical material. 

Active ingredients classified as category III or IV for acute dermal toxicity, eye irritation 

potential, and skin irritation potential are assigned a default REI of 12 hours under the Worker 

Protection Standard for Agricultural Pesticides. Based on the acute toxicity profile for 

indaziflam, the 12-hour REI which appears on the proposed labels is adequate.

10.0 Data Needs and Label Recommendations

10.1 Toxicology

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for indaziflam was assessed using an oral toxicity study. The Agency sought expert advice and 

input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity

studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide 
Page 37 of 50

Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final 

report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 

The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine 

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

route to route extrapolation of toxicity data. If any new policies or procedures are developed, the 

Agency may revisit the need for an inhalation toxicity study for indaziflam and/or a reexamination of the inhalation toxicity risk assessment.

10.2 Residue Chemistry

The residue chemistry data set is complete with the exception of a final storage stability report 

and a final analysis report for the processed commodity of citrus oil. HED recommends that 

submission of acceptable storage stability and processing study reports be made a condition of 

registration. In addition, analytical reference standards need to be provided prior to registration 

(see item 3 below).

1. Citrus oil tolerance - Although citrus RACs from submitted field trials and a processing study

have total residues below the 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. 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 indicated that while the final report has not been 

through quality assurance review, preliminary findings show that the residue have remained 

stable over a 25-26 month period. However, submission of the ongoing storage stability study

covering the full duration of sample storage should be submitted as a condition of registration. 

3. Standards - Prior to registration, the petitioner should ensure that 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
Page 38 of 50

701 Mapes Road

Fort George G. Meade, MD 20755-5350

(Note: mail will be returned if the extended zip code is not used.)

10.3 Occupational and Residential Exposure

None

11.0 References

1. Indaziflam: Occupational/Residential Exposure Assessment for Use of Indaziflam on 

Turf, Golf Courses, Sod Farms, Christmas Tree Farms, Non-Crop Areas and Forestry

(M.Collantes, D372538; April 2010)

2. Tier 2 Drinking Water Assessment for the Section 3 New Chemical Registration of 

Indaziflam; Rueben Baris; D356141; and D367447; February 2, 2010.

3. Indaziflam. Petition for the Establishment of Permanent Tolerances and Registration for 

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

Olives (PP 9F7589); and a Tolerance without a Domestic Registration for Sugarcane (PP 

9E7588). Summary of Analytical Chemistry and Residue Data. (E. Holman et al,

D374105; Sept. 9, 2010)

4. Indaziflam: Acute and Chronic Aggregate Dietary Exposure (Food and Drinking Water) 

and Risk Assessment for the Section 3 Registration on Pome Fruits, Stone Fruits, Citrus, 

Tree Nuts (including Pistachios), Grapes, Olives, and Processed Cane Sugar (Import). 

(E. Holman et al, D376909; July 28, 2010) 
Page 39 of 50

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for turf and food use for indaziflam are shown below in Table 1. Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical Indaziflam

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21/28-Day Dermal .........................................................

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

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes1

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5550 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Developmental Neurotoxicity........................................

no

no

yes

yes

yes

--

--

yes

yes

yes

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity...............................................

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

--

--

--

1 Satisfied by 870.4300.
Page 40 of 50

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Indaziflam technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - rat 47443281 LD50 > 2000 mg/kg 

(both sexes)

III

870.1200 Acute dermal - rabbit 47443282 LD50 > 2000 mg/kg 

(both sexes)

III

870.1300 Acute inhalation - rat 47443283 LC50 > 2.3 mg/L 

(both sexes)

IV

870.2400 Acute eye irritation - rabbit 47443284 Non-irritant IV

870.2500 Acute dermal irritation - rabbit 47443285 Non-irritant IV

870.2600 Skin sensitization - guinea pig 47443286 Not a sensitizer 

(Buehler method)

N/A
Page 41 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

47443287 (2005)

Acceptable/Guideline

0, 200, 5000 or 10,000 

ppm in diet for 13 weeks

M: 0, 14, 338 or 689 

mg/kg/day

F: 0, 16, 410 or 806 

mg/kg/day

98.7% a.i.

NOAEL = 14/410 mg/kg/day M/F

LOAEL = 338/806 mg/kg/day M/F, based on: 

in males at 338 mg/kg/day, increased TSH at 

Week 3 and diffuse thyroid follicular cell 

hypertrophy at Week 13; in females at 806 

mg/kg/day, mortality (one female, sacrificed in 

extremis with clinical signs, decreased motor 

activity and gastric red foci), marginally 

decreased body weights and decreased food 

consumption. 

870.3100 90-Day oral 

toxicity (mouse)

47443288 (2005)

Acceptable/Guideline 

0, 100, 500 or 1200 ppm 

in diet for 13 weeks

M: 0, 19, 91 or 218 

mg/kg/day; 

F: 0, 23, 118 or 256 

mg/kg/day

96.5% a.i.

NOAEL = 91/118 mg/kg/day M/F

LOAEL = 218/256 mg/kg/day M/F, based on 

increased mortality and wasted appearance 

(females), hunched posture in males and 

females, decreased body weight/weight gain 

and food consumption in males and females.

870.3150 90-Day oral 

toxicity (dog)

47443289 (2008)

Acceptable/Guideline

0, 7.5, 15 or 30 mg/kg/day 

by gavage

94.5-99.4% a.i.

NOAEL = 7.5 mg/kg/day M/F

LOAEL = 15 mg/kg/day, based on axonal 

degeneration in the brain, spinal cord and 

sciatic nerve in males and females. At 30 

mg/kg/day, 3 animals were sacrificed with 

seizures by Day 30; all remaining group 

animals were sacrificed on Day 36. Decreased 

body weight gain and neuropathology were 

observed.

870.3200 28-Day dermal 

toxicity (rat)

47443290 (2006)

Acceptable/Guideline

0, 40, 200 or 1000 

mg/kg/day applied to skin 

5 days/week for 4 weeks 

(22/23 total applications 

in M/F)

90.32% a.i.

Systemic NOAEL = 1000 mg/kg/day

LOAEL = not determined (>1000 mg/kg/day)

Local dermal NOAEL = 1000 mg/kg/day

LOAEL = not determined (>1000 mg/kg/day). 

Some indication of local dermal irritation was 

observed at all doses but the findings were 

transient and observed only in females, and 

therefore were not considered adverse.

870.3700a Prenatal 

developmental in 

(rat)

47443291 (2006)

Acceptable/Guideline

0, 10, 25 or 200 

mg/kg/day by gavage in 

0.5% aqueous 

methylcellulose, GD 6 

through 20

Maternal NOAEL = 25 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased 

body weight gain and food consumption. 

Developmental NOAEL = 25 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased 

fetal body weights.
Page 42 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

94.5% a.i.

870.3700b Prenatal 

developmental in 

(rabbit)

47443292 (2008)

Acceptable/Guideline

0, 10, 25 or 60 mg/kg/day 

by gavage in 0.5% 

aqueous methylcellulose, 

GD 6 through 28

93.14% a.i.

Maternal NOAEL = 25 mg/kg/day

LOAEL = 60 mg/kg/day based on decreased 

maternal body weight gain and food 

consumption and macroscopic changes in the 

liver in one doe.

Developmental NOAEL = 60 mg/kg/day

LOAEL = not established (>60 mg/kg/day).

870.3800 Reproduction and 

fertility effects

(rat)

47443293 (2008)

Acceptable/Guideline

0, 150, 1000 or 8000 ppm 

in the diet; F1 high dose 

reduced to 4000 ppm at 5-

17 days’ postweaning

Average P/F1

consumption (note: high 

dose not averaged due to 

F1 dose reduction)

M: 0, 10.4, 69.3 or 560.1 

mg/kg/day (P males) and 

317.6 mg/kg/day (F1

males, due to reduction in 

dietary dose)

F: 0, 12.9, 85.2 or 656.2 

mg/kg/day (P females) 

and 355.2 mg/kg/day (F1

females, due to reduction 

in dietary dose)

93.14-94.5% a.i.

Parental NOAEL = 69.3/85.2 mg/kg/day M/F

LOAEL = 560.1/656.2 mg/kg/day M/F, based 

on coarse tremors in females from Weeks 6-17 

and in gestation and lactation, decreased body 

weight/weight gain and food consumption and 

renal toxicity (tubular degeneration/ 

regeneration and increased weight) in males.

Offspring NOAEL = 69.3/85.2 mg/kg/day M/F

LOAEL = 317.6/355.2 mg/kg/day M/F, based 

on clinical signs (perianal, urine or nasal 

staining, diarrhea or soft stool, distended 

abdomen, weakness, tremors, myoclonus, 

increased activity and reactivity) and decreased 

pup body weights throughout postnatal period.

Reproductive NOAEL = 69.3/85.2 mg/kg/day 

M/F (based on F1 intakes)

LOAEL = 317.6/355.2 mg/kg/day M/F, based 

on delayed sexual maturation in males and 

females (% pups reaching criterion unaffected).

870.4100a Chronic toxicity

(rat)

47443296 (2007)

Acceptable/Guideline

0, 300, 3000 or 10,000 

ppm in the diet (6000 in 

females after Day 280)

equivalent to average 

daily intake of

M: 0, 14, 136 or 474 

mg/kg/day;

F: 0, 19, 185 or 589 

mg/kg/day

93.14% a.i.

NOAEL = 19 mg/kg/day F, 136 mg/kg/day M;

LOAEL = 185 mg/kg/day F, based on increased 

mortality, clinical signs of toxicity, mydriasis 

and absence of papillary reflex; 474 mg/kg/day 

M, based on decreased body weight/weight 

gain and food consumption.

870.4100b Chronic toxicity 

(dog)

47443294 (2008; main 

study);47443295 (2007; 

dietary stability)

NOAEL = 2.0 mg/kg/day

LOAEL = 6/7 mg/kg/day M/F, based on axonal 

degeneration of nerve fibers in the brain, spinal 

cord and sciatic nerve in males and females. 
Page 43 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Acceptable/Guideline

0, 60, 225 or 450 ppm in 

the diet

M: 0, 2, 6 or 12 

mg/kg/day;

F: 0, 2, 7 or 11 

mg/kg/day

93.16% a.i.

Marginal body weight decreases early in study 

seen at 12/11 mg/kg/day M/F.

870.4200a Carcinogenicity

(rat) See 870.4300, below

870.4200b Carcinogenicity

(mouse)

47743416 (2008)

Acceptable/Guideline

0, 50, 250 or 1000 ppm in 

diet

M: 0, 6.8, 34 or 142 

mg/kg/day;

F: 0, 8.4, 42 or 168 

mg/kg/day

93.14% a.i.

NOAEL = 34/42 mg/kg/day M/F

LOAEL = 142/168 mg/kg/day M/F, based on 

decreased body weight/weight gain and food 

consumption, M/F; renal and hepatotoxicity in 

males; stomach and ovarian toxicity in females. 

No evidence of carcinogenicity

870.4300 Combined 

carcinogenicity/ 

chronic toxicity 

(rat)

47743417 (2009)

Acceptable/Guideline

0, 300, 3000 or 10,000 

ppm in the diet

M: 0, 12, 118 or 414 

mg/kg/day;

F: 0, 17, 167 or 452 

mg/kg/day

93.14% a.i.

NOAEL = 12/17 mg/kg/day M/F

LOAEL = 118/167 mg/kg/day M/F, based on 

decreased body weight/weight gain, signs of 

neurotoxicity (various symptoms, including 

dilated pupils, tremors, limb/movement effects, 

reduced activity/alertness) and renal toxicity in 

females, liver toxicity in males and females and

atrophic seminal vesicles and increased TSH 

(Week 3 only) and thyroid colloid alteration in 

males. Thyroid alterations in males appeared to 

be secondary to liver effects. Decreased 

survival was observed at 452 mg/kg/day in 

females and both males and females showed 

more pronounced clinical signs of toxicity.

No evidence of carcinogenicity

Gene 

Mutation

870.5100

Bacterial reverse 

gene mutation 

assay (S. 

typhimurium)

47443297 (2006)

Acceptable/Guideline

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate in 

presence or absence of S9 

activation. Trial 1 – plate 

incorporation method and 

Trial 2, pre-incubation 

method

90.32% a.i.

Negative +/-S9 activation in S. typhimurium

strains TA98, TA100, TA 102, TA1535, 

TA1537 for increased frequency of revertant 

colonies up to cytotoxic (500 μg/plate) and 

precipitating concentrations (5000 μg/plate).
Page 44 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Gene 

Mutation

870.5100

Bacterial reverse 

gene mutation 

assay (S. 

typhimurium)

47443301 (2007)

Acceptable/Guideline

Trial 1: 0, 15, 50, 158, 

500, 1502 or 5000 

μg/plate in the presence or 

absence of S9 activation, 

plate-incorporation 

method

Trial 2: 0, 100, 200, 400, 

800, 1600 or 3200 

μg/plate in the presence or 

absence of S9 activation, 

pre-incubation method

95.7% a.i.

Negative +/-S9 activation in S. typhimurium 

strains TA98, TA100, TA102, TA1535, 

TA1537 for increased frequency of revertant 

colonies up to cytotoxic (≥800 μg/plate) and 

precipitating (3200 μg/plate) concentrations.

Gene 

Mutation 

870.5300

Mammalian cell 

in vitro forward 

gene mutation 

(cultured V79 

cells, HGPRT 

locus)

47443302 (2006)

Acceptable/Guideline 

0, 10, 100 or 1000 μg/mL 

in presence or absence of 

S9 activation

90.32% a.i.

Negative for increased frequency of mutation 

in CHO cells (not cytotoxic).

Cytogenetics 

870.5375

Mammalian in 

vitro cytogenetic 

assay (Chinese 

hamster V79 lung 

cells)

47443305 (2006)

Acceptable/Guideline

4 hr exposure, 14 hr 

recovery period: 0, 15, 

30, 60, 90 or 120 μg/mL 

in the absence of S9 

activation; 0, 50, 100, 

160, 200 and 240 μg/mL 

in the presence of S9 

activation.

4 hr exposure, 26 hr 

recovery period: 0, 60, 90 

and 120 in the absence of 

S9 activation; 0, 160, 200 

and 240 μg/mL 

18 hr exposure, no 

recovery period in the 

absence of S9 activation: 

0, 4, 8, 16, 20 and 24 

μg/mL 

90.32% a.i.

Negative for induction of chromosomal 

aberrations above background in the presence 

or absence of S9 metabolic activation. Tested 

up to the limit of solubility (160 μg/mL, -S9)

Cytogenetics 

870.5395

Mammalian in 

vivo micronucleus 

assay (mouse)

47443308 (2006)

Acceptable/Guideline

Two doses of 0, 10, 20 or 

Negative for induction of increased frequency 

of micronucleated polychromatic erythrocytes 

in bone marrow at any treatment time.
Page 45 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

40 mg/kg by IP injection 

in 0.5% aqueous 

Cremaphor vehicle 

administered 24 hrs apart; 

harvested 24 hrs after 

second dose

90.32% a.i.

870.6200a Acute 

neurotoxicity 

screening battery 

(rat)

47443310 (2008)

Acceptable/Guideline

0, 50, 100 or 2000 mg/kg 

by gavage in corn oil. 

Time of peak effect 

estimated at 50 min 

postdosing.

93.14% a.i.

NOAEL = 50 mg/kg

LOAEL = 100 mg/kg based on decreased 

motor and locomotor activity in females 

(threshold effect level). Lower 

NOAEL/LOAEL relative to subchronic study 

likely due to gavage vs. dietary administration.

870.6200b Subchronic 

neurotoxicity 

screening battery 

(rat)

47443309 (2008)

Acceptable/Guideline

0, 200, 4000 or 

8000/10,000 ppm (M/F) 

equivalent to average 

daily intake in the diet of

M: 0, 12.2, 243.6 or 

585.7 mg/kg/day

F: 0, 15.1, 306.9 or 580.9 

mg/kg/day 

93.14% a.i.

NOAEL = 243.6/306.9 mg/kg/day M/F

LOAEL = 585.7/580.9 mg/kg/day M/F, based 

on decreased total session motor and locomotor 

activity in females, clinical signs/FOB effects 

in males and females (tremors, repetitive 

chewing motion and perianal and lacrimal 

staining), decreased body weights (females)

and cumulative body weight gain in males and 

females.

870.6300 Developmental 

neurotoxicity (rat)

47443311 (2008)

Acceptable/Nonguideline

0, 150, 1000 or 7000 ppm 

in the diet (high dose 

reduced to 4000 ppm on 

LD4) equivalent to 

average daily intake in the 

diet of

0, 13, 83.8 or 432 

mg/kg/day

93.14% a.i.

Maternal NOAEL = 83.8 mg/kg/day 

LOAEL = 432 mg/kg/day, based on clinical 

signs at daily observation and FOB assessment 

(coarse tremors, dilated pupils and dilated 

pupils unresponsive to penlight, nasal staining, 

repetitive chewing movements), decreased 

body weights/weight gain and reduced number 

of litters (-17%).

Offspring NOAEL = 83.8 mg/kg/day

LOAEL = 432 mg/kg/day, based on decreased 

body weight through PND 21 in males and 

females. Males postweaning had slightly 

decreased body weights. Decreased motor 

activity (-29%) on PND 21 in males was 

considered treatment-related, but was not seen 

at other measurement times nor in females. 

870.7485 Metabolism and 

pharmacokinetics

47443312 (2008)

Acceptable/Guideline

Absorption was complete (>90% 

bioavailability) and rapid, with radioactivity 
Page 46 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

(rat) – tier 1 Male rats given single 

gavage dose of either 14Cindane labeled or -triazine 

labeled indaziflam at 

11.5-14.98 mg/kg. Mass 

balance groups – excreta 

collected for 3 days 

postdosing. Bile-duct 

cannulated groups – bile 

and excreta collected for 2 

days postdosing. 

99-100% radiochemical 

purity

found in bile by 1 hr postdosing and most 

radioactivity (generally around 90%) excreted 

by 24 hrs. Tissue levels of radioactivity were 

low (0.2% of administered dose by 3 days) with 

highest levels observed in the GIT, liver, 

kidney, skin and thyroid. In the bile ductcannulated animals, tissue levels were about 2-

4 times greater in the triazine-labeled group 

than the indane-labeled group but levels in 

other groups were similar. Excretion was 

largely fecal (62-70%), with significant biliary 

excretion observed. CO2 exhalation was 

negligible. Parent compound was identified at 

between 2-16% of dose in urine and feces. 

Major routes of metabolism were oxidative 

pathways; glucuronide conjugation also 

observed. Major metabolite was carboxylic 

acid, found in urine, bile and feces. Numerous 

other metabolites identified or characterized; 

profile varied among dose groups. Other 

metabolites identified at low levels included the 

3-hydroxyindane acid epimer, diaminotriazine 

and 3-ketohydroxymethyl metabolites.

870.7485 Metabolism and 

pharmacokinetics 

(rat) – tier 2

47743418 (2009)

Acceptable/Guideline

Single gavage doses as 

follows: (1) low dose 

mass balance studies in 

females given 14C-indanelabelled indaziflam at 4.8 

mg/kg or 14-triazinelabelled indaziflam at 8.8 

mg/kg; (2) high dose mass 

balance studies in males 

given 14C-indane-labelled 

indaziflam at 559 mg/kg 

or 14-triazine-labelled 

indaziflam at 723 mg/kg; 

(3) plasma 

pharmacokinetic 

experiments with indanelabel at 2.9 mg/kg 

(females) or 13.7 mg/kg 

(males) or triazine-label at 

13.2 mg/kg (females) or 

16.3 mg/kg (males).

Radiochemical purity 

99%

Absorption was rapid (radioactivity detected in 

blood by 5 minutes and peak blood

concentrations observed between 40-60-

minutes postdosing; rapidly decreasing 

thereafter) Females showed slightly higher 

absorption than males. Excretion was rapid 

(>87% by 24 hrs) and was equally distributed 

between urine and feces in females but was 

greater in feces in males (10:1). CO2 excretion 

was negligible. Radioactivity was not retained 

at significant levels in tissues; the GIT, liver 

and skin showed the highest residues. The 

carboxylic acid metabolite was the major 

metabolite in both high dose males and low

dose females, which was found in urine and 

feces. Additional metabolites present at >5% 

of dose included 3-hydroxyindane acid 

metabolite in low dose females, dihydroxy 

metabolite in low dose females and 

hydroxyethyl acid metabolite in the high dose 

males (indane-label).

870.7600 Dermal 47743420 (2008) Absorption was inversely proportional to dose, 
Page 47 of 50

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

absorption, in vivo 

(rat)

Acceptable/Guideline

0.5, 2 or 5000 μg ai/ cm2

on 12 cm2skin for 8 hrs to 

male rats; absorption 

evaluated after 8, 24, 72 

and 168 hr postdosing

Radiochemical purity 

>98% 

indicating saturation of skin penetration with 

increasing dose. Between 0.4-20.4% of the 

applied dose was recovered in combined 

residual carcass, excreta, blood and non-treated 

skin. Based on decreased radioactivity at the 

application site, the most conservative value for 

risk assessment is a dermal absorption of 42.7% 

observed at 0.5 μg ai/ cm2at 8 hr 

postapplication.

870.7800 Immunotoxicity -

rat

47443313 (2008)

Acceptable/Guideline

0, 300, 3000 or 6000 

(females) or 10,000/6000 

(males) ppm in the diet

equivalent to average 

daily intake in the diet of

M: 0, 27.7, 258 or 528 

mg/kg/day

F; 0, 31, 334.2 or 737.9 

mg/kg/day

93.12% a.i.

Systemic NOAEL = 258.8/334.2 mg/kg/day 

M/F

LOAEL = 528/737.9 mg/kg/day M/F, based on 

mortality (one male sacrificed in extremis), 

clinical signs of toxicity in males and females 

(including tremor, abnormal gait, pallor, 

hunched back), decreased food and water 

consumption in males and decreased body 

weight/weight gain in males and females.

Immunotoxicity NOAEL = 528/737.9 

mg/kg/day M/F

LOAEL = not established (>528/737.9 

mg/kg/day M/F)

NonguidelineIn vitro dermal 

absorption – rat 

and human skin

47743419 (2007)

Acceptable/Nonguideline

Application of a 10μL/ 

volume of concentrated 

500 mg/mL formulation 

and representative spray 

dilutions of 0.5, 0.2 or 1.0 

mg/mL to excised human 

and rat dermatomed skin. 

Exposure duration was 24 

hr.

Radiochemical purity 

>98%

Total absorbed dose decreased with increasing 

concentration, indicating saturation of skin 

penetration with increasing dose. Rat skin was 

3.8 to 10.7 times more permeable than human 

skin over 24 hr at the concentrations tested. 

Toxicity Profile - FDAT

Nonguideline 

Study

Sexual maturation 

supplemental study 

(rat)

47443314 (2008) 

Accetable/Nonguideline 0, 18.0, 

36.5, 72.9 or 145.8 mg/kg/day 

by gavage to LD21 offspring and 

timed-pregnant female Wistar 

rats: administered daily until 

PND 41

NOAEL = 36.5 mg/kg/day

LOAEL = 72.9 mg/kg/day, based on 

delays in vaginal patency (+2.3 days, 

increasing to 3.9 days at 145.8 

mg/kg/day). Also at high dose, body 

weight was decreased and salivation 

and urine staining were observed.
Page 48 of 50

Appendix B. Table of Structures 

Table 1: Major Chemicals Identified in 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
Page 49 of 50

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-

triazine-2,4-diamine

Fluoroethyltriazinane-2,4-

dione

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

1,3,5-triazinane-2,4-dione

Indaziflam hydroxyethyl 1-{4-Amino-6-[(1R,2S)-

2,6-dimethyl-2,3-dihydro1H-inden-1-ylamino]-

1,3,5-triazin-2-yl}ethanol
Page 50 of 50

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

yl]-6-vinyl-1,3,5-triazine2,4-diamine