Indaziflam Human Health Risk Assessment DP Barcode 408033 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: September 27, 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Indaziflam. Human Health Risk Assessment to Support Proposed New Import 

Tolerances (Without a U.S. Registration) on Banana, Coffee, and Palm Oil. 

PC Code: 080818 

Decision No.: 472679 

Petition No.: 2£8125 

Risk Assessment Type: Single Chemical Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D408033 

Registration No.: 264-1129 

Regulatory Action: Tolerance Without US 

Registration 

CaseNo.: NA 

CAS No.: 730979-19-8 

40 CFR: 180.653 

FROM: Elizabeth Holman, Physical Scientist/Risk 

Zaida Figueroa, Industrial Hygienist 

Jaime D' Agostino, Toxicologist 

Risk Assessment Branch II (RABII) 

Health Effects Division (7509P) ~ 

THROUGH: Christina 

Risk 

Health 

Assessment 

Effects 

Swartz, 

Division 

Branch 

Branch 

(7509P) 

II 

Chief 

(RABII) 

~ 

TO: Maggie Ruddick/Kable Davis, RM Team 25 

Herbicide Branch 

Registration Division (7505P) 

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

assessment for the active ingredient indaziflam to estimate the risk to human health that will 

result from the proposed new import tolerances on banana, coffee, and palm oil. 

The attached human health risk assessment addresses exposure and risk associated with the 

proposed tolerances, as well as the existing agricultural and residential uses. The exposures 

assessed include dietary (food and water), residential exposure durations and scenarios involving 

incidental oral, dermal and inhalation exposure, and aggregate exposure and risk for residential 

handlers resulting from use on turf. There were no risks of concern identified for any route or 

duration of exposure. 

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Indaziflam Human Health Risk Assessment DP Barcode 408033 

Table of Contents 

1.0 Executive Summary .................................................................. ........ ................................. 4 

2.0 HED Recommendations .................................................................................................... 6 

2.1 Data Deficiencies/Conditions of Registration .............................................................. 6 

2.2 Tolerance Considerations .............................................................................................. 6 

2.2.1 Enforcement Analytical Method ............................................................................... 6 

2.2.2 International Harmonization ..................................................................................... 6 

2.2.3 Recommended Tolerances ........................................................................................ 6 

2.2.4 Revisions to Petitioned-For Tolerances .................................................................... 7 

2.3 Label Recommendations From Residue Review ......................................................... 7 

3.0 Introduction ........................................................................................................................ 7 

3.1 Chemical Identity ................................................................... ........................................ 7 

3.2 Physical/Chemical Characteristics ................................................................................ 8 

3.3 Pesticide Use Pattern .................... ~ ................................................................................. 8 

3.4 Anticipated Exposure Pathways ........................................... ........ ............................... 10 

3.5 Consideration of Environmental Justice .................................................................... 10 

4.0 Hazard Characterization and Dose-Response Assessment.. ........................................ 11 

4.1 Toxicology Studies Available for Analysis ................................................................. 11 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ............................. 11 

4.2.1 Dermal Absorption .................................................................................................. 12 

4.3 Toxicological Effects .................................................................................................... 12 

4.4 Safety Factor for Infants and Children (FQP A Safety Factor) ............................... 13 

4.4.2 Evidence ofNeurotoxicity ...................................................................................... 14 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 14 

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 14 

4. 5 .1 Dose-Response Assessment .................................................................................... 14 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment. ....... 17 

4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 17 

5.0 Dietary Exposure and Risk Assessment.. ....................................................................... 19 

5.1 Metabolite/Degradate Residue Profile ......................................................... .............. 19 

5.1.1 Summary of Plant and Animal Metabolism Studies ............................................... 19 

5.1.2 Summary of Environmental Degradation ............................................................... 20 

5.1.3 Comparison of Metabolic Pathways ....................................................................... 20 

5.1.4 Residues of Concern Summary and Rationale ........................................................ 20 

5.2 Food Residue Profile .................................................................................................... 22 

5.4 Dietary Risk Assessment. ............................................................................................. 24 

5.4.1 Description of Residue Data Used in Dietary Assessment.. ................................... 24 

5.4.2 Percent Crop Treated Used in Dietary Assessment.. .............................................. 24 

5.4.3 Acute Dietary Risk Assessment .............................................................................. 24 

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5.4.4 Chronic Dietary Risk Assessment .......................................................................... 25

5.4.5 Cancer Dietary Risk Assessment............................................................................ 26

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 26

6.1 Residential Handler Exposure .................................................................................... 26

6.2 Dermal Post-application Exposure ............................................................................. 27

6.5 Spray Drift.................................................................................................................... 28

7.0 Aggregate Exposure/Risk Characterization.................................................................. 29

7.1 Acute Aggregate Risk................................................................................................... 29

7.2 Short-Term Aggregate Risk ........................................................................................ 29

7.3 Chronic Aggregate Risk .............................................................................................. 30

8.0 Cumulative Exposure/Risk Characterization ............................................................... 30

9.0 Occupational Exposure/Risk Characterization ............................................................ 31

10.0 References......................................................................................................................... 31

Appendix A. Toxicology Profile and Executive Summaries .................................................. 32

Appendix B. Physical/Chemical Properties........................................................................... 47

Appendix C. Review of Human Research................................................................................ 47
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1.0 Executive Summary

The Agency has received a petition from the registrant, Bayer CropScience, for import tolerances 

associated with the use of the herbicide indaziflam {1,3,5-triazine-2,4-diamine, N-[(1R,2S)-2,3-

dihydro-2,6-dimethyl-1H-inden-1-yl]-6-[(1S,1R)-fluoroethyl)-} outside the U.S. on coffee, 

banana, and palm oil. The end use product used in the submitted crop field trials and processing 

studies is the currently registered Indaziflam 500 SC formulation, a suspension concentrate 

formulation of indaziflam, containing 500 g active ingredient (a.i.)/L (4.16 lb a.i./gallon). 

Indaziflam is registered for control of many annual grasses and broadleaf weeds in lawns, golf 

course/turf, 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. Registered agricultural use sites for preemergent control of annual grasses and broadleaf weeds include citrus, stone, and pome fruits, 

grapes, tree nuts (including pistachio), and olives, with permanent tolerances established under 

40 CFR §180.653 ranging from 0.01 ppm to 0.15 ppm in plant commodities. The residue 

definition for both tolerance enforcement and risk assessment for crops is indaziflam and the 

fluoroethyl diaminotriazine metabolite, FDAT. Acceptable analytical methods are available to 

enforce tolerances for residues of indaziflam in plant and livestock commodities.

The toxicology database is considered adequate for conducting a human health risk assessment 

in accordance with the Food Quality Protection Act (FQPA). The scientific quality is relatively 

high, and the toxicity is well-characterized 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 has reduced the required 10X FQPA 

safety factor to 1X, based on the following considerations: the toxicity data base is complete; 

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; the endpoints selected 

for risk assessment are protective of the observed neurotoxicity; and the residential and dietary 

exposure estimates are considered to be upper bound and will not underestimate exposure. 

The residue chemistry database is complete and there are no residue chemistry issues that would 

preclude granting the requested registrations and establishing permanent import tolerances. 

Adequate crop field trials and processing studies have been conducted to support import 

tolerances in plant commodities (coffee, banana, and palm oil). HED is recommending for the 

establishment of permanent import tolerances (without U.S. registrations) for all of the requested 

crops. 

HED used modeling to assess acute and chronic dietary exposure to indaziflam. In combination 

with an extensive database of food consumption patterns for the U.S. population and population 

subgroups, this modeling used conservative upper-bound assumptions regarding residues of 

indaziflam and its breakdown products in food and drinking water. Specifically, the dietary 
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assessments included tolerance-level residues from the existing and proposed uses, the 

assumption of 100% crop treated (CT) for all crops, and drinking water residues derived from 

modeling the maximum application rate in vulnerable areas. The highest potential drinking 

water exposure is from surface water sources. The acute and chronic dietary exposure and risk 

estimates are below HED’s level of concern (LOC) of 100% of the acute population adjusted 

dose (aPAD) or chronic population adjusted dose (cPAD) for the general U.S. population and all 

population subgroups, including those of infants and children. The highest exposed population 

subgroup was infants <1 year old, with dietary risk estimates of 19% aPAD and 8% cPAD; all 

other population subgroups had lower risk estimates, including the general U.S. population at 6% 

aPAD and 3% cPAD.

There are no new indaziflam residential uses associated with this regulatory action. However, 

there are existing residential uses - home lawn/turf and gardens/trees uses – that have been 

reassessed to reflect updates to HED’s 2012 Residential SOPs1along with policy changes for 

body weight assumptions. Short-term dermal and inhalation handler exposures are expected for 

those making applications at their homes and short-term dermal, inhalation, and incidental oral 

exposures are expected via contact with residues following applications in outdoor home 

environments. No risks of concern were identified for any scenario – all MOEs were greater 

than 100.

In accordance with the FQPA, in evaluating human health risks from exposure to pesticides, 

HED aggregates exposure from various routes, i.e., residential exposure is added to dietary 

exposure from food and drinking water. For adults, the highest residential exposure estimate was 

from dermal high-contact (playing) with treated turf, and it was combined with the chronic 

dietary exposure from the mostly highly exposed adult (General U.S. Population) sub-population

to determine aggregate exposure and risk. For children, the highest post-application dermal and 

incidental oral risk estimates on turf associated with children 1<2 years old were combined with 

the chronic dietary exposure for the most highly exposed child (Infants <1 year old), to 

determine aggregate exposure and risk. The resulting aggregate MOEs for both adults and 

children are above the LOC of 100, and therefore the aggregate risk estimates are not of concern.

As there are no occupational exposures associated with the proposed import tolerances, a new 

occupational exposure assessment was not conducted for this risk assessment. Occupational 

exposures from the existing registered uses of indaziflam were previously assessed and no risks 

of concern were identified. 

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

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

in the triazine cumulative assessment group (E. Scollon, D371661, 04/21/2010). 

The risk assessment is based, in part, on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies are compliant with 

applicable ethical requirements (refer to Appendix C).

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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2.0 HED Recommendations

HED recommends in favor of the proposed import tolerances (i.e., without a U.S. registration) 

for indaziflam on banana, coffee, and palm oil as summarized in Table 2.2.3.

2.1 Data Deficiencies/Conditions of Registration

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Approved tolerance enforcement methods for crops are available for indaziflam using high 

performance liquid chromatography with tandem mass spectrometry detection (LC/MS/MS; 

Method DH-003-P07-02) for fruit and tree nut matrices. The method 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. Use of the proper stable- isotopelabeled internal standards is critical to the methods accuracy and effectiveness. 

This LC/MS/MS method uses extraction, by blending with a mixture of acetonitrile and water. 

The limit of quantitation (LOQ) for vegetables and non-citrus fruits is 0.01 ppm. The method 

was validated to a limit of quantitation (LOQ) of 0.005 ppm in fruit and tree nut crop matrices. 

These data support a total method LOQ of 0.01 ppm in all fruit and tree nut matrices [combined 

residues of parent (0.005 ppm) and FDAT metabolite (0.005 ppm)]. 

2.2.2 International Harmonization

There are currently no established Codex, Canadian, or Mexican maximum residue limits 

(MRLs) for indaziflam on banana, coffee, or palm oil; therefore, there are no issues of 

harmonization. Codex has no tolerances established for indaziflam on any commodity, whereas 

Canada has established tolerances for indaziflam on other commodities not currently under 

review. For existing uses of indaziflam, tolerances are harmonized for all commodities where 

both the U.S. and Canada have established tolerances. 

2.2.3 Recommended Tolerances

Table 2.2.3. Tolerance Summary for Indaziflam.

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments (correct commodity definition)

Banana 0.01 0.01 Tolerance without a corresponding U.S. 

registration

Coffee 0.01 0.01 Tolerance without a corresponding U.S. 

registration

Palm oil 0.03 0.03 Palm, oil; Tolerance without a 

corresponding U.S. registration
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2.2.4 Revisions to Petitioned-For Tolerances

With the exception of revising the palm oil commodity listing as given in Table 2.2.3 above, 

there are no revisions to the petitioned-for tolerances. 

2.3 Label Recommendations From Residue Review

None. 

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Nomenclature.

Compound

AE 1170437

Isomer A

H3C

CH3

N

H

N

N N

NH2

F CH3

Common name Indaziflam

Company experimental name AE 1170437

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

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

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

CAS # 730979-19-8

Compound

AE 1170438

Isomer B

N

N

N

N

H

NH2

CH3

CH3

H3C

F

Common name Indaziflam

Company experimental name AE 1170438

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

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

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

CAS # 730979-32-5
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Table 3.1. Nomenclature.

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 the Registration Division (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 3.1 (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.

3.2 Physical/Chemical Characteristics

The information regarding physical chemical characteristics of indaziflam does not indicate that 

there are any special concerns in terms of bioaccumulation, exposure or other risk assessment 

considerations. A table of physical and chemical properties for indaziflam is included in 

Appendix B.

3.3 Pesticide Use Pattern

Indaziflam is an alkylazine herbicide registered for non-selective pre-emergent and early postemergent control of annual grass and dicot species in trees, nuts, vines, and turf. This herbicide

is a cellulose biosynthesis inhibitor and is active at rates of 50 to 100 g ai/ha. The technicalgrade a.i. (TGAI) is made up of at least 95% of the 1R-fluorethyl isomer and no more than 5% of 

the 1S-fluoroethyl isomer. Although the company name AE 1170437 refers specifically to the 

1R-fluoroethyl isomer, it has been used interchangeably with the technical grade active 

ingredient (TGAI). Both isomers have equal herbicidal activity. 
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Currently registered end use products include Indaziflam 200 SC and Indaziflam 500 SC, which

are suspension concentrate formulations of indaziflam, containing 200 and 500 g active 

ingredient (a.i.)/L (1.67 lb a.i./gallon and 4.16 lb a.i./gallon), respectively. The products are 

registered for use in ground-directed application for pre-emergent weed control in orchards of 

pome fruits, stone fruits, citrus, tree nuts (including pistachios), grapes, and olives. Use rates for 

both formulations are dependent, to some extent, on the soil type within the use area. For 

existing uses, seasonal maximum application rates are 0.089 lb a.i./A for grapes and 0.134 lb 

a.i./A for all other crops. Indaziflam is not to be applied through any type of irrigation system or 

by aerial equipment for the registered uses. However, aerial applications are permitted on the 

overseas labels associated with the import tolerances. 

The pre-harvest intervals (PHIs) on the labels associated with the import tolerances are 0 days 

for banana, 0-30 days for palm oil, and 19-20 days for coffee. All of the submitted crop field 

trials and processing studies used the 500 SC formulation. For the proposed uses on various 

labels in other countries, the use rates range from 0.049 to 0.098 lb ai/A on palm oil, 0.079 lb 

ai/A on banana, and from 0.088 to 0.098 lb ai/A on coffee.

Table 3.3 provides a summary of the labels supporting the proposed import tolerances. 

Table 3.3. Summary of Directions for Use of Indaziflam (On Proposed Labels for Registration Outside the U.S.).

a

Applic. Timing, 

Type, and Equip.

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. 

per Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days) Use Directions and Limitations

Banana (Non-Domestic Use)

Broadcast spray, 

pre- or post-crop 

emergence, preemergence for 

weeds; ground or 

aerial equipment

0.079 lb a.i./A

(80 g a.i./ha) 1

0.079 lb a.i./A

(80 g a.i./ha) 0 None that are relevant.

Coffee (Non-Domestic Use)

Broadcast spray, 

pre- or post-crop 

emergence, preemergence for 

weeds; ground or 

aerial equipment

0.088-0.098 lb 

a.i./A

(90-100 g a.i./ha)b

1

0.088-0.098 lb 

a.i./A

(90-100 g 

a.i./ha)

19-20 None that are relevant.

Palm Oil (Non-Domestic Use)

Broadcast spray, 

pre- or post-crop 

emergence, preemergence for 

weeds; ground or 

aerial equipment

0.049-0.098 lb 

ai/A 

(50-100 g a.i./ha)c

1

0.049-0.098 lb 

ai/A 

(50-100 g 

a.i./ha)

0-30 None that are relevant.

a

All submitted crop field trials and processing studies were conducted using the Indaziflam 500 SC Herbicide 

(Soluble Concentrate, 45.05% a.i.) formulation. 

b The proposed label (Alion 50SC) is proposed for use on coffee at 90 g a.i./ha in Belize, Cuba, Dominican 

Republic, El Salvador, Guatemala, Honduras, Jamaica, Nicaragua, and Panama. The proposed label (Alion) is 

proposed for us at 100 g a.i./ha in Brazil. 
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c Multiple proposed labels for use on oil palm at a maximum single application rate at 50, 60, 75, 80, and 100 g 

a.i./ha in various countries, with the maximum application rate varying by country. The low value of 50 g a.i./ha is 

for the proposed Alion 50 SC label for use in Thailand, with the high value of 100 g a.i./ha coming from the 

proposed Alion 500 SC label in Peru. 

3.4 Anticipated Exposure Pathways

As a result of the registered and proposed uses of the insecticide indaziflam, humans may be 

exposed through food and drinking water, since the chemical may be applied directly to growing 

crops and may reach surface and ground water sources of drinking water. In an occupational 

setting, applicators may be exposed while handling the pesticide prior to application (i.e., 

mixing/loading), as well as during application. There is also potential for post-application 

exposure for workers re-entering treated fields. 

Since indaziflam is also registered for use on lawns/turf and gardens/tree uses, there is likely to 

be exposure in residential and non-occupational settings. Short-term dermal and inhalation 

handler exposures are expected for those making applications at their homes and short-term 

dermal, inhalation, and incidental oral exposures are expected via contact with residues 

following applications in outdoor home environments. 

This risk assessment considers all of the relevant exposure pathways, combining them as 

appropriate, to estimate overall exposure and risk. 

3.5 Consideration of Environmental Justice

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

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority 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 the U.S. Department of 

Agriculture under the National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA). These food consumption patterns 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. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for children, 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.
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4.0 Hazard Characterization and Dose-Response Assessment

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 toxic action in 

mammals is unknown. 

4.1 Toxicology Studies Available for Analysis

The toxicology data for indaziflam are sufficient and are of good quality for selecting toxicity 

endpoints and points of departure for risk assessment. The available toxicology studies include:

(1) subchronic oral toxicity studies in rats, mice and dogs; (2) a 28 day dermal toxicity study in 

rats; (3) developmental toxicity studies in rats and rabbits; (4) a 2-generation reproduction study 

in rats; (5) chronic toxicity studies in rats and dogs; (6) carcinogenicity studies in mice and rats; 

(7) a battery of genotoxicity studies; (8) two metabolism studies in rats; (9) a dermal penetration 

study in rats; (10) acute, subchronic and developmental neurotoxicity studies in rats; and (11) an 

immunotoxicity study in mice. The requirement of the subchronic inhalation toxicity study has 

been waived by HED’s Hazard and Science Policy Council (HASPOC, Rury, K. 3/20/2013, 

TXR 0056608).

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The metabolism of indaziflam has been evaluated in the rat. Indaziflam is rapidly and 

completely absorbed. Radioactivity was detected in the blood within 5 minutes of dosing with 

peak blood concentrations between 40-60 minutes. Absorption was estimated at 90% or greater 

of administered dose, based on bile cannulation experiments. Absorption was slightly more 

rapid in females than males. Indaziflam was distributed to multiple tissues with the highest 

levels found in the gastrointestinal tract, liver, skin and thyroid. Radioactivity was not retained 

at significant levels in the tissues by 3 days’ post dosing (less than 0.2 to 0.3% of dose). 

Metabolism was extensive with only 2-16% 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 (37-39% AD in bile cannulated rats and 63-67% AD in 

non-cannulated rats), which was largely excreted in the bile but also found in urine and feces. 

Other compounds that were identified as major metabolites (>5% AD) in combined excreta in 

one or more groups were 3-hydroxyindane acid (11-12% AD), 3-hydroxyindane acid epimer

(11% AD), dihydroxy (6-13% AD), hydroxy glucuronic acid (11-13% AD), 3-ketoindane acid

(5-6% AD), and hydroxyethyl acid metabolite (5% AD). Metabolite profiles in males and 

females were comparable, with some minor qualitative differences, but females excreted 

significantly less unchanged parent compound. 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. 
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4.2.1 Dermal Absorption

An in vivo dermal absorption study in the rat and in vitro dermal absorption study in 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.

The human DAF was calculated as follows (all absorption values adjusted for recovery): (1) in 

the rat in vivo dermal absorption study, a dermal absorption of 27.39% (directly absorbed plus 

absorbable) was found at 24 hrs post-exposure (actual exposure time 8 hrs) using an application 

of 0.05 mg/cm2; (2) in vitro exposure of microtomed rat skin under the same exposure and 

assessment conditions gave a dermal absorption of 22.40% (directly absorbed plus absorbable); 

(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 under the same exposure conditions. The DAF for humans is therefore 

5.975%/0.82 = 7.3%.

4.3 Toxicological Effects

The nervous system is the major target for toxicity in rats and dogs. Evidence of neurotoxicity 

(e.g., decreased motor activity, clinical signs, and/or neuropathology) was observed in both 

species throughout the database, which included the dog subchronic and chronic toxicity studies, 

the rat acute, subchronic, and developmental neurotoxicity studies, the rat two-generation 

reproduction study, the rat chronic toxicity study, and the rat combined carcinogenicity/chronic 

toxicity study. In repeated-dose studies, the dog was the more sensitive species, showing the 

lowest NOAELs and LOAELs among all available studies, based on neuropathology 

(degenerative nerve fibers in the brain, spinal cord and sciatic nerve). At higher doses, three 

dogs in the subchronic study 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. Decreases in motor/locomotor activity were also seen in the subchronic 

neurotoxicity study in females and in the developmental neurotoxicity study in male offspring at 

PND 21. Clinical signs of neurotoxicity were observed in the acute, subchronic, and 

developmental neurotoxicity studies and consisted primarily of tremors, changes in activity and 

reactivity, repetitive chewing, dilated pupils, and oral, perianal, and nasal staining. Similar 

clinical signs of neurotoxicity were observed in the 2-generation reproduction study, the rat 

chronic toxicity study, and the combined rat carcinogenicity/chronic toxicity study. 

Neuropathology findings were also observed in the rat manifested as focal/multifocal 

vacuolation of the median eminence of the brain and the pituitary pars nervosa and degenerative 

nerve fibers in the gasserian ganglion, sciatic nerve, and tibial nerve. Evidence of neurotoxicity 

was not seen in the mouse. 

Other organs affected by indaziflam in mice and rats included the kidney, liver, thyroid, stomach, 
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seminal vesicles and ovaries. Effects on the kidney were observed following chronic exposure in 

rats and mice while effects on the liver were observed following chronic exposure in the rat. 

Effects on the thyroid were only observed in multiple dose rat studies. Chronic exposures also 

lead to 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. In rats, effects 

observed on the liver, thyroid, kidney, and seminal vesicles occurred at doses that were similar to 

those that produced neurotoxicity. Decreased body weight gain was also 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. 

No evidence of increased quantitative or qualitative susceptibility was seen in developmental 

toxicity studies in rats and rabbits or in a reproduction study in rats. In the rat developmental 

toxicity study, decreased fetal weight was observed in the presence of maternal effects that 

included decreased body weight gain and food consumption. 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 signs of toxicity, at a 

dose causing parental toxicity that included coarse tremors, renal toxicity 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. 

Testing in acute lethality studies with indaziflam resulted in low toxicity via the oral (Category 

III), dermal (Category III), and inhalation (Category IV) routes of exposure. Indaziflam was not 

an irritant to eyes (Toxicity Category IV) or skin (Toxicity Category IV) and was not a skin 

sensitizer.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The toxicology and the exposure databases support a reduction of the required 10X FQPA safety 

factor to 1X for the following reasons, based on the following considerations: The toxicology 

data based is complete; there is no evidence of qualitative or quantitative susceptibility; the 

endpoints selected for risk assessment are based on and protective of the neurotoxic effects seen 

in the guideline studies; and exposure will not be underestimated because the assessment was 

based on tolerance-level residues in food, upper-bound estimates of potential residues in drinking 

water, the updated Residential SOPs, and chemical-specific data for post-application exposure.
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4.4.1 Completeness of the Toxicology Database

The toxicology database is considered complete and is adequate for the purpose of assessing preand postnatal susceptibility. Acceptable/guideline developmental toxicity studies in rats and 

rabbits and a reproduction study in rats, as well as acute, subchronic, and developmental 

neurotoxicity studies in rats were available for FQPA assessment. There is no concern for 

increased susceptibility in the developing young. 

4.4.2 Evidence of Neurotoxicity

Evidence of neurotoxicity was observed in dogs and rats throughout the database, which 

included the dog subchronic toxicity study, the rat subchronic toxicity, the rat acute, subchronic, 

and developmental neurotoxicity screening batteries, the rat two-generation reproduction study, 

the rat chronic toxicity study, and the rat combined carcinogenicity/chronic toxicity study. 

Evidence of neurotoxicity was manifested as neuropathology in dogs and as decreased motor 

activity and clinical signs (e.g., tremors) in rats. Evidence of neurotoxicity was the most 

consistent effect (seen in dogs and rats), the most sensitive toxicological finding (based on 

neuropathology in dogs), and the basis for the risk assessment.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No developmental effects were observed in rabbits up to maternally toxic dose levels. Offspring 

effects in the developmental toxicity study in rats, DNT, and multigeneration toxicity studies 

only occurred in the presence of maternal toxicity and were not considered more severe than the 

parental effects. In addition, clear NOAELs/LOAELs were identified for these studies. 

Therefore, HED concluded that there is no evidence of increased quantitative or qualitative 

susceptibility to rat or rabbit fetuses exposed in utero and/or post-natally to indaziflam. 

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. There are no exposure data gaps and 

the current dietary assessment is based on high-end assumptions such as tolerance-level residue 

values, 100% crop treated, and modeled estimates of drinking water residues. New 2012 

Residential SOPs and chemical-specific data were used to assess post-application exposure to 

children including incidental oral exposure. The residential post-application assessment assumes 

that maximum application rates are applied and that hand-to-mouth activities occur on the day of 

application. All of the exposure estimates are based on conservative, health-protective 

assumptions and are not likely to underestimate risk.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The toxicity endpoints and points of departure are presented in Table 4.5.4.1 and Table 4.5.4.2, 

and the details for selecting toxicity endpoints and points of departure for various exposure 

scenarios are presented in Appendix A.
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A comprehensive risk assessment for indaziflam was conducted in 2010 (Collantes, M. 16 

September 2010, D367451). In the last risk assessment the point of departure (POD) for acute 

dietary exposure was chosen from the acute neurotoxicity study in the rat, based on a NOAEL of 

50 mg/kg. In this study, evidence of neurotoxicity in females (marginal decreases in motor and 

locomotor activity) was seen within the first hour following dosing at the LOAEL of 100 mg/kg. 

However, following subchronic and chronic exposures, the dog was the most sensitive species 

with the lowest NOAELs among all of the available studies. The apparent increased sensitivity 

of the dog is still present following allometric scaling using the 3⁄4 power of body weight. While 

the greater sensitivity of dogs compared to rats is based on subchronic and chronic exposures and 

may not apply to acute exposure, increased sensitivity cannot be ruled out due to the absence of 

data for acute exposures in dogs. The magnitude of sensitivity is greater than the 10x 

interspecies uncertainty factor used in the previous risk assessment for calculation of the aRfD.

Thus, there is a concern that using the NOAEL from the rat acute neurotoxicity battery may be 

under protective despite being from a study of the appropriate route and duration.

In addition to a potential sensitivity issue between rats and dogs, there is evidence that supports 

that the effects observed in the subchronic oral study in dogs could have been the result of a 

single dose. In the acute neurotoxicity (ACN) study in rats, nerve fiber degeneration of the 

gasserian ganglion, sciatic nerve, and the tibial nerve, were observed following a single exposure 

to indaziflam at the limit dose (neuropathology examination was conducted 14 days after 

exposure, at the end of the study). Similar effects (axonal nerve fiber degeneration in the brain, 

spinal cord, and sciatic nerve) were observed following treatment of dogs with indaziflam for 90 

days. Since nerve degeneration was only visible following sacrifice of the animals at the end of 

the study, it is impossible to determine if nerve fiber degeneration was present following a single 

dose in the subchronic dog study as was the case in the rat ACN. 

Following the observation of seizures and clinical signs of neurotoxicity in two dogs of the high 

dose group (30 mg/kg/day) of the subchronic oral study in dogs (study days 15 and 22), the study 

investigators attempted to split the dose into two 15 mg/kg/day doses 7-8 hours apart to 

determine if lowering the Cmax would prevent further seizures. This dosing regimen was 

instituted following a two day break from the 30 mg/kg/day dosing regimen and was followed 

for ten days before seizures and clinical signs of neurotoxicity were observed in another female 

dog (study day 35). Based on the description of the dosing, there were 16 hours between the 

second dose on a given study day and the first dose on the next day. Metabolism data in rats 

indicate that indaziflam is excreted rapidly. It is estimated that >90% of the administered dose 

is excreted after 24 hours in male bile cannulated rats dosed with 13.35 or 14.00 mg/kg 

indaziflam with the majority (~76%) of the excretion in bile and urine occurring within 12 hours. 

Although metabolism data in dogs are not available, the rat metabolism data support the concept

that a large portion of the absorbed dose is likely eliminated within the 16 hours between doses. 

Furthermore, the seizures and clinical signs of neurotoxicity observed following the conversion 

to the split dosing occurred ~2 hours after the first dose in the morning. This is similar to the 

estimated time of peak of effect in the rat acute neurotoxicity battery (~50 mins) and the time to 

peak plasma concentration in the rat metabolism study (~40-60 mins). The study did not indicate 

how long after dosing the seizures and clinical signs of neurotoxicity were observed in the two 

dogs that received the single 30 mg/kg/day dose of indaziflam and had seizures on study days 15 

and 22.
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In addition, in a range-finding study (MRID 49073701) for the subchronic oral study in dogs, 

seizures in three dogs were observed on day 0-1 following exposure to indaziflam in the diet at 

50 (two dogs) or 200 (one dog) mg/kg/day indicating that neurotoxicity in dogs could occur from 

an acute exposure. The NOAEL for this study was 15 mg/kg/day and the LOAEL was 50 

mg/kg/day based on seizures. While the 90-day range finding study supports the conclusion that 

seizures in dogs could result from a single dose, the 90-day range finding study itself with a 

NOAEL of 15 mg/kg/day was not considered appropriate for selection of an acute endpoint and 

dose for risk assessment due to the limited number of dogs used (n=2/dose group) and because 

no neuropathology was conducted. However, HED considers it likely that nerve degeneration 

occurred in these animals because neuropathology was seen at a dose (15 mg/kg/day) that was 

below the dose (30 mg/kg/day) that caused seizures in the subchronic oral study in dogs and 

nerve degeneration was found in rats following a single dose in the rat acute neurotoxicity study. 

A summary of all seizures observed in the multiple dose dog studies is provided in appendix A 

(Table A.3).

Based on a weight of evidence approach, HED has concluded that the subchronic oral toxicity 

study in dogs should be used as basis for endpoint and dose selection for the acute dietary 

exposure scenario. While the rat acute neurotoxicity study is of the appropriate duration, the 

increased sensitivity of the dog following subchronic and chronic exposure to indaziflam 

suggests that the rat acute neurotoxicity study may be under protective of risk from an acute 

exposure. Furthermore, the observation of similar effects in the acute neurotoxicity study at 

higher doses, the rapid excretion of indaziflam in rat metabolism studies, and the timing of the 

observation of seizures and clinical signs of neurotoxicity in the subchronic oral toxicity study

and the range-finding study in dogs suggest that signs of neurotoxicity could result from a single 

dose in dogs. Similar neuropathology (axonal nerve fiber degeneration in the brain, spinal cord, 

and sciatic nerve) was also observed in the chronic oral study in dogs, which could have been the 

result of an acute exposure. Although a lower NOAEL (2 mg/kg/day) and LOAEL (6 

mg/kg/day) were identified in the chronic oral study in dogs, it was not selected for the acute 

dietary risk assessment since a clear NOAEL of 7.5 mg/kg/day was identified in the subchronic 

toxicity study in dogs which is a more appropriate duration for the acute dietary exposure 

scenario. HED acknowledges that selecting an endpoint from the subchronic toxicity study in 

dogs is likely conservative. However, given the severity of observed effects in the dog, the 

apparent increased sensitivity of dogs to the neurotoxic effects of indaziflam relative to rats, and 

absence of an acute neurotoxicity study in dogs, the Agency concluded that it was prudent to 

adopt this conservative approach.

The POD for chronic dietary exposure was chosen from the chronic study in dogs, based on a 

NOAEL of 2 mg/kg/day with axonal degeneration of nerve fibers in the brain, spinal cord and 

sciatic nerve 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 since rat and mouse chronic 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 axonal 
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degeneration of nerve fibers in the brain, spinal cord and sciatic nerve. 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.

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 

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.

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

selected. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For short- and intermediate-term aggregate risk assessments, incidental oral, dermal and 

inhalation routes can be combined due to the selection of a common toxicological endpoint of 

concern (axonal nerve degeneration). Long-term dermal and inhalation exposure are not 

expected for the currently registered uses of indaziflam.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Increased tumor incidence was not seen in acceptable carcinogenicity studies in rats and mice, 

and indaziflam is classified as “Not likely to be Carcinogenic to Humans.” Cancer risk is not an 

issue for the chemical.
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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Use in Indaziflam Dietary and NonOccupational 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 

(General 

population, 

including 

Infants and 

Children and 

females 13-49)

NOAEL = 7.5 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

1X

Acute RfD = 0.075 

mg/kg/day

aPAD = 

0.075mg/kg/day

Subchronic Gavage Toxicity 

Study in Dogs

LOAEL = 15 mg/kg/day, 

based on axonal degenerative 

microscopic findings in the 

brain, spinal cord and sciatic 

nerve.

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 Dietary Toxicity 

Study in Dogs

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 

Intermediateterm (1 to 6 

months)

NOAEL = 7.5 

mg/kg/day

UFA=10X

UFH=10X

FQPA SF = 

1X

Residential LOC for 

MOE = 100

Subchronic Gavage Toxicity 

Study in Dogs

LOAEL = 15 mg/kg/day, 

based on axonal degenerative 

microscopic findings in the 

brain, spinal cord and sciatic 

nerve.

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

FQPA SF = 

1X

Residential LOC for 

MOE = 100

Subchronic Gavage Toxicity 

Study in Dogs

LOAEL = 15 mg/kg/day, 

based on axonal degenerative 

microscopic findings in the 

brain, spinal cord and sciatic 

nerve.

Inhalation, 

Short-term (1 to 

30 days) and 

Intermediateterm (1 to 6 

months)

NOAEL = 7.5 

mg/kg/day

UFA=10X

UFH=10X

FQPA SF = 

1X

Residential LOC for 

MOE = 100

Subchronic Gavage Toxicity 

Study in Dogs

LOAEL = 15 mg/kg/day, 

based on axonal degenerative 

microscopic findings in the 

brain, spinal cord and sciatic 

nerve.

Cancer (oral, 

dermal, 

inhalation) 

No Evidence of Carcinogenicity. Classified as “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 = 
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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. N/A = not applicable.

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Use in Indaziflam Occupational Human 

Health Risk Assessments.

Exposure

Scenario

Point of Departure Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment

Study and Toxicological 

Effects

Dermal 

Short-Term (1 -

30 days) and 

IntermediateTerm (1-6 

months)

NOAEL = 7.5

mg/kg/day

UFA=10X

UFH=10X

Occupational LOC 

for MOE = 100

Subchronic Gavage Toxicity 

Study in Dogs

LOAEL = 15 mg/kg/day, 

based on axonal degenerative 

microscopic findings in the 

brain, spinal cord and sciatic 

nerve.

Inhalation 

Short-Term

(1 - 30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL = 7.5 

mg/kg/day

UFA=10X

UFH=10X

Occupational LOC 

for MOE = 100

Subchronic Gavage Toxicity 

Study in Dogs

LOAEL = 15 mg/kg/day, 

based on axonal degenerative 

microscopic findings in the 

brain, spinal cord and sciatic

nerve.

Cancer (oral, 

dermal, 

inhalation) 

No Evidence of Carcinogenicity. Classified as “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.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue for indaziflam is considered to be adequately understood for registered 

and proposed crops and appropriate livestock (ruminant only). 

Plant and livestock metabolism data were reviewed in greater detail in a recent chemistry 

summary document (D383415, E. Holman, 2/28/11). Radiolabeled metabolism studies are 

available for apple, sugarcane, grape, lactating goat, and rat. In plants, the metabolism of 

indaziflam is relatively uncomplicated. The only identified terminal residues in any of the plant 

studies were parent indaziflam and the FDAT metabolite. The metabolism data are sufficient to 

support the requested import tolerances; however, if uses in other crops are sought in the future, 
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additional studies depicting the nature of the residue may be necessary (e.g., root/tuber 

vegetables, small grain). 

Based on the available information, indaziflam appears to undergo significant oxidative 

metabolism in ruminants. The metabolic pathways observed in these studies were similar, with 

the exception of the label specific diaminotriazine metabolite found in the triazine label study.

The same was true for the [

14C]-AE 1170437 rat metabolism study (MRID 47443312, 47743418)

with only minor differences (two additional metabolites, AE 1170437-4-hydroxy-hydroxymethyl

and AE 1170437-3-keto-4-hydroxy, were found in the goat metabolism studies). 

5.1.2 Summary of Environmental Degradation

Memo, K. Milians, Ph.D., Chemist, 8/17/2011, D388876

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. 

5.1.3 Comparison of Metabolic Pathways

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. 

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 

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. 

5.1.4 Residues of Concern Summary and Rationale

D371659 – Report of the Residues of Concern Knowledgebase Subcommittee. G. Kramer. 18 February 2010

With the exception of FDAT and dihydroamino triazine, all of the major metabolites are 
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assumed to have comparable toxicity to the parent due to structural similarity (i.e., both rings 

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.

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, 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.

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. 

The toxicological and residue chemistry databases for indaziflam have been examined to 

determine residue definitions for the purposes of setting tolerances and risk assessments. The 

residue definitions are summarized in Table 5.1.4.

Table 5.1.4. Compounds to be Included in the Risk Assessment and Tolerance Expression.

Matrix Residues included in Risk Assessment

Residues included in Tolerance 

Expression for Compliance 

Monitoring

Plants Primary Crop Indaziflam + Fluoroethyl 

Diaminotriazine (FDAT)

Indaziflam + FDAT

Rotational Crop Not applicable at this time (no data 

available)

Not applicable at this time (no data 

available)

Livestock Ruminant Indaziflam + FDAT + Indaziflam-3-

ketohydroxymethyl + Indaziflam 

carboxylic acid + Indaziflam-3-

hydroxyindane

Indaziflam + FDAT + Indaziflam-3-

ketohydroxymethyl + Indaziflam 

carboxylic acid + Indaziflam-3-

hydroxyindane*

Poultry Not applicable at this time** (no data 

available)

Not applicable at this time (no data 

available)

Drinking Water Indaziflam + FDAT + Triazine indanone

+ Indaziflam carboxylic acid + 

Indaziflam hydroxyethyl + Indaziflam 

olefin

Not Applicable

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

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

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

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

methylindane-1-one

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

carboxylic acid

Triazine indanone = N-[(1R,2S)-2,3-Dihydro-2,6-dimethyl-3-oxo-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-

diamine

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

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

**None of the target crop commodities are used in poultry feeds to any significant degree. 

5.2 Food Residue Profile

Memo, E. Holman, 09/26/2013, D408151

Acceptable crop field trial data are available to support import tolerances on banana, coffee, and 

palm oil, and to establish tolerances for residues in the associated commodities. No quantifiable 

residues were observed in/on all crop commodities. Due to the unquantifiable residues at each 

sampling interval, residue decline could not be evaluated; however, because no individual value 

approached the LOQ for either analyte in/on any sample, there was no evidence that residues 

increase over time. The available data are adequate for risk assessment and tolerance 

assessment. The results from these field trials are summarized in Table 5.2.

Because there are no processed commodities for bananas, processing studies were not required 

for this raw agricultural commodity (RAC). The coffee processing study demonstrated that 

residues of concern were below the limit of quantitation at exaggerated rates appropriate for 

waiving analysis of the processed foods and feeds (i.e., residues were < LOQ at 5X exaggerated 

application rates). The submitted palm oil processing study is adequate, supporting a palm oil 

tolerance of 0.03 ppm. 

The available storage stability data are adequate, and support the storage conditions and 

durations for samples from the submitted banana, coffee, and palm oil field trials, and the palm 

oil processing study.

 

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

livestock residue definition) are expected to be below the limit of quantitation of the livestock 

analytical method. Hence a 40 CFR 180.6(a)(3) situation (i.e., no reasonable expectation of 

finite residues) exists. Furthermore, none of the proposed import tolerances have associated 

livestock commodities. Neither feeding studies nor tolerances for livestock commodities are 

required at this time. Feeding studies and analytical methods may be required to support future 

uses of indaziflam that involve significant livestock feed items. 
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Table 5.2. Summary of Residue Data from Crop Field Trials with Indaziflam.

Commodity

Total 

Applic. Rate

(lb ai/A)

[kg ai/ha]

PHI 

(days) Analyte

Residue Levels1

(ppm)

n

Sample

Min.

Sample

Max. LAFT2 HAFT2 Median Mean Std. Dev.

Banana (proposed use = 0.079 lb ai/A total application rate, 0-day PHI)

Banana 

whole fruit

(bagged)

0.086-0.095

[0.096-

0.107]

0

Indaziflam 14 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

AE 1170437-

diaminotriazine 14 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Combined 14 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Banana 

whole fruit 

(unbagged)

0.086-0.095

[0.096-

0.107]

0

Indaziflam 14 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

AE 1170437-

diaminotriazine 14 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Combined 14 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Coffee (proposed use = 0.098 lb ai/A maximum total application rate, 19-20 day PHI)

Coffee bean, 

green

0.087-0.099

[0.098-

0.111]

18-20

Indaziflam 7 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

AE 1170437-

diaminotriazine 7 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Combined 7 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Oil Palm Fruit (proposed use = 0.098 lb ai/A maximum total application rate, 0-30 day PHI)

Oil palm fruit

0.067-0.072

[0.075-

0.080]

0

Indaziflam 3 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

AE 1170437-

diaminotriazine 3 <0.005 <0.005 <0.005 <0.005 0.005 0.005 N/A

Combined 3 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ (0.005 ppm for each analyte and 0.010 ppm for combined residues) was used for results reported as 

nondetectable in Table 7. N/A = Not Applicable.

2

 LAFT = lowest average field trial; HAFT = highest average field trial.

5.3 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 

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 the maximum seasonal application rate for citrus (0.134 lb ai/A), which is higher 

than the turf application rate (0.094 lb ai./A) and thus is protective of all other drinking water 

scenarios. 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 
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concentrations used to estimate exposure via drinking water have not changed since the last risk 

assessment, and are included in Table 5.3. 

Table 5.3. 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 assuming a maximum seasonal use rate of 0.134 lb ai/A for citrus.

b

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

5.4 Dietary Risk Assessment

Memo, E. Holman, 09/2013, D408152

5.4.1 Description of Residue Data Used in Dietary Assessment

For this analysis existing and recommended tolerance levels were used, as well as 100% CT 

assumptions for all commodities. DEEM (Version 7.81) default processing factors were used for 

most processed commodities that do not have individual tolerances, except in cases where 

available processing data indicate that no concentration of residues occurs in processed 

commodities. In these cases where no concentration occurred, the processing factor was reduced 

to 1. 

HED has selected the most conservative drinking water residue estimates in order to be 

protective of all possible exposures through drinking water. The above residue estimates for 

FDAT and ROI1 were stoichiometrically converted to indaziflam equivalents and included 

directly in the indaziflam concentration estimates (Table 5.3). Thus, following this 

stoichiometric conversion, the combined maximum surface water concentration was 84 ppb for 

the acute analysis and 26 ppb for the chronic analysis. These values were used in the acute and 

chronic dietary analyses, respectively.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary exposure assessments, based on food and drinking water, include 

the assumption of 100% CT for all existing and proposed uses.

5.4.3 Acute Dietary Risk Assessment

An unrefined acute dietary analysis for indaziflam was conducted using tolerance level residues 

and 100% CT for all existing and proposed primary crop import uses. The DEEM-FCIDTM 

analyses estimate the dietary exposure of the U.S. population and various population subgroups. 

The results reported in Table 5.4.4 are for the general U.S. population, all infants (<1 year old), 

children 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, adults 20-49, and adults 

50-99 years. The acute results summarized in Table 5.4.4 are for the 95th percentile of exposure. 
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Based on highly conservative assumptions, acute dietary (food and water) risk estimates at the 

95th percentile of exposure are less than or equal to 19% of the acute population-adjusted dose 

(aPAD) for all population subgroups. Generally, HED is concerned when risk estimates exceed 

100% of the PAD; therefore, all acute dietary risk estimates are below HED’s level of concern 

(LOC). The most highly exposed population subgroup is all infants <1 year old.

The results of the acute dietary exposure analysis are reported in the Summary Table 5.4.4.

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary analysis for indaziflam was conducted using tolerance level 

residues and 100% CT for all existing and proposed primary crop import uses. Indaziflam

chronic dietary (food + drinking water) exposure estimates using the DEEM-FCIDTM software 

are below HED’s level of concern for the U.S. population and each of the population subgroups. 

Chronic dietary exposure was 3% of the cPAD for the U.S. population. The chronic dietary 

exposure for the highest reported exposed population subgroup, Infants <1 year old, was 8% of 

the cPAD. The results of the analysis indicate that chronic risk from the dietary (food + drinking 

water) exposure to indaziflam will not exceed HED’s LOC for the general U.S. population, nor 

any other population subgroups. Based on the very conservative assumptions used, actual 

dietary exposure to indaziflam from food and drinking water is expected to be significantly lower 

than the exposures presented in Table 5.4.4. 

The results of the chronic dietary exposure analysis are reported in the Summary Table 5.4.4.

Table 5.4.4. Summary of Dietary Exposure and Risk for Indaziflam.

1

Population Subgroup*

Acute Dietary

(95th percentile) 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 0.004648 6 0.000586 3 N/A N/A

All Infants (< 1 year old) 0.014510 19 0.001545 8

Children 1-2 years old 0.007509 10 0.001014 5

Children 3-5 years old 0.005873 8 0.000807 4

Children 6-12 years old 0.004480 6 0.000540 3

Youth 13-19 years old 0.003838 5 0.000425 2

Adults 20-49 years old 0.004526 6 0.000568 3

Adults 50+ years old 0.004056 5 0.000565 3

Females 13-49 years old 0.004615 6 0.000567 3

1The value for the highest exposed population in the acute and chronic risk assessment is bolded. 
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5.4.5 Cancer Dietary Risk Assessment

HED classified indaziflam as “not likely to be carcinogenetic to humans” and, therefore, cancer 

risk is not of concern for indaziflam.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Memo, Z. Figueroa 09/2013; D415431

There are no new indaziflam residential uses associated with this regulatory action. However, 

there are existing residential uses - home lawn/turf and gardens/trees uses – that have been 

reassessed to reflect updates to HED’s 2012 Residential SOPs2along with policy changes for 

body weight assumptions. In order to incorporate residential exposure into the short-term 

aggregate risk assessment, a summary of the residential exposure and risk estimates resulting 

from the residential use of indaziflam is provided below.

6.1 Residential Handler Exposure

The existing residential uses include a liquid concentrate for use on home lawn/turf and 

gardens/trees (Reg. No. 72155-89) and a granule for use on home lawn/turf (Reg. No. 72155-91). 

The following use scenarios and sources of unit exposures were used to assess residential handler 

exposures:

Mixing/Loading/Applying for Sprays Using Manually-pressurized Handwand,

Mixing/Loading/Applying for Sprays with Backpack Sprayer,

Mixing/Loading/Applying for Sprays with Hose-end Sprayer,

Mixing/Loading/Applying for Granule with Rotary/push-type Spreader, and

Mixing/Loading/Applying for Granule Belly Grinder.

HED’s LOC is a MOE greater than or equal to 100 for residential exposure. Handler MOEs 

from either inhalation or dermal exposure were significantly greater than 100 (ranging from 

13,000 to 71,000,000) and are not of concern. Although a point of departure from an oral study 

was used to assess the handler inhalation risks, the calculated MOEs are all >570,000, thus 

providing an ample margin of safety to account for any uncertainties in route-to-route 

extrapolation. Combined inhalation and dermal MOEs ranged from 12,000 to 440,000 and are 

also not of concern. Handler exposure and risk estimates are summarized in Table 6.1. 

Table 6.1. Residential Handler Non-cancer Exposure and Risk Estimates for Existing Residential Uses of Indaziflam.

Scenario Formulation Equipment

Dose

(mg/kg/day) MOE

Dermal Inhalation Dermal Inhalation Combined

Lawns/Turf Liquid

Manually-pressurized 

Handwand 0.00016 0.00000062 47,000 12,000,000 47,000

Backpack 0.00033 0.0000048 23,000 1,600,000 23,000

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Table 6.1. Residential Handler Non-cancer Exposure and Risk Estimates for Existing Residential Uses of Indaziflam.

Scenario Formulation Equipment

Dose

(mg/kg/day) MOE

Dermal Inhalation Dermal Inhalation Combined

Hose-end Sprayer 0.00059 0.000013 13,000 570,000 12,000

Granule

Rotary/push-type 

Spreader 0.00002 0.0000007 460,000 10,000,000 440,000

Belly Grinder 0.00039 0.0000006 19,000 13,000,000 19,000

Gardens/Trees Liquid

Manually-pressurized 

Handwand 0.00016 0.00000062 47,000 12,000,000 47,000

Hose-end Sprayer 0.00032 0.00000011 23,000 71,000,000 23,000

Backpack 0.00033 0.0000048 23,000 1,600,000 23,000

6.2 Dermal Post-application Exposure

An existing indaziflam TTR study (“Determination of Transferable Residues from Turf”, D. 

Fisher, EPA MRID 47443316) was used to assess post-application exposures from treated turf. 

The study was first reviewed by HED in 2010 (M. Collantes; D372538; 04/21/2010). Based on 

current practices and updated policies, HED assumed first-order dissipation kinetics to generate 

dissipation curves for indaziflam. HED conducted linear regression analyses for each state 

evaluated in the TTR study using the natural logarithm of the individual turf residue values 

collected immediately after the application through the last day of sampling. Based on linear 

regression of the natural log transformed data, the calculated half-lives for indaziflam dislodged 

from treated turf were 1.2 days (R2= 0.848) for the Florida site, 9.6 days (R2= 0.710) for the 

Kansas site, and 2.6 days (R2= 0.846) for the California site. The predicted day 0 residue value 

of 0.019 ug/cm2from the Florida site (reflecting an adjustment for the maximum application rate 

of 0.096 lb ai/A) was used in this assessment to estimate residential post-application exposure 

and risk. A complete summary of the study is presented in Memo, Z. Figueroa 09/26/2013; 

D415431. 

 

For post-application exposures from treated turf, both registered formulations (liquid vs.

granular) were assessed; however, only the exposure scenarios with the highest risk estimates 

were presented below. Risks from liquid spray applications are considered protective of granule 

formulation uses which would result in lower exposures. Since there is an acute dietary 

endpoint, a post-application episodic incidental ingestion of granules/pellets assessment for 

children was also conducted.

Table 6.2 summarizes the post-application risk estimates for the existing residential uses of 

indaziflam. No risks of concern were identified.

Table 6.2. Post-application Non-cancer Exposure and Risk Estimates for Existing Residential Uses of Indaziflam.

Use/Target Lifestage Post-application 

Exposure Scenario

Dose

(mg/kg/day) MOE

Combined Routes

(X indicates included 

in Combined MOE)

Combined 

MOE

Turf

(Spray 

Application)1

Adult Dermal

High-contact 

(playing) 0.00468 1,600 --

NA Mowing 0.00010 77,000 --

Golfing 0.00037 20,000 --

Child 11<16

yrs

Dermal Mowing 0.00011 68,000 NA Golfing 0.00043 18,000 --
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Table 6.2. Post-application Non-cancer Exposure and Risk Estimates for Existing Residential Uses of Indaziflam.

Use/Target Lifestage Post-application 

Exposure Scenario

Dose

(mg/kg/day) MOE

Combined Routes

(X indicates included 

in Combined MOE)

Combined 

MOE

Child 6<11 yrs Dermal Golfing 0.00050 15,000 -- NA

Child 1<2 yrs

Dermal (High-contact;

playing)

0.00927 810 X

Hand to Mouth 0.00260 2,900 X 630

Object to Mouth 0.00008 95,000 --

Incidental Soil Ingestion 0.0000032 2,300,000 --

Turf

(Granules) Child 1<2 yrs

Incidental Ingestion of 

Granules/Pellets 0.01 550 -- NA

Gardens/Trees Adult Dermal 0.00459 1,700 -- NA

Child 6<11 yrs Dermal 0.00308 2,400 -- NA

1 Risk estimates are based on the predicted day-of-application residue value from a submitted turf transferable residue study 

(MRID 47443316). Risks from liquid spray applications are presented above and are considered health-protective of granule 

formulation uses for the following reasons: 1) the AR for the liquid formulation is higher than the AR for the granular 

formulation, therefore, the liquid TTR data is a conservative representation of granular TTR data (with a lower AR); and 2) 

granular formulations have lower transferability when compare to liquid formulations.

6.3 Residential Bystander Post-Application Inhalation Exposure 

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed at this time for the agricultural indaziflam uses primarily because 

of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure (5.1 x 10-10

mmHg at 25°). However, volatilization of pesticides may be a source of post-application 

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, and 

received the SAP’s final report on March 2, 20103. 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 post-application inhalation exposure into the Agency's 

risk assessments. If new policies or procedures are developed, the Agency may revisit the need 

for a quantitative post-application inhalation exposure assessment for the existing uses of 

indaziflam.

6.5 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for indaziflam. The Agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the Agency’s Spray 

Drift website for more information). The Agency is also taking means to qualitatively and 

qualitatively address spray drift as a potential source of exposure in risk assessments for 

pesticides through existing programs such as Ag Drift and chemical specific properties of 

 

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. In the case of indaziflam, acute and chronic aggregate risks result from 

exposure through food and water only. For short-term risk, adult and child post-application

exposure was combined with background exposure from food and water. 

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 5.4.4 and are below HED’s level 

of concern.

7.2 Short-Term Aggregate Risk

When estimating adult residential exposure, HED does not generally combine handler and 

dermal post-application exposure as it would result in an overestimate of exposure. For adults, 

the highest post-application exposure from high-contact (playing) on turf where indaziflam was 

applied (Table 6.2) was combined with the chronic dietary exposure from the mostly highly 

exposed adult (General U.S. Population) sub-population, to determine aggregate exposure and 

risk as shown in Table 7.2. For children, the highest post-application dermal and oral exposure 

risk estimates on turf associated with children 1-2 years old (Table 6.2) were combined with the 

chronic dietary exposure for the most highly exposed children’s sub-population (Infants <1 year 

old), to determine aggregate exposure and risk as shown in Table 7.2. The aggregate MOEs are 

above the LOC of 100, and therefore aggregate risk estimates are not of concern.

Table 7.2. Short-Term Aggregate Risk Calculations for Indaziflam.

Population NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult (Postapplication)7.5 100 0.075 0.000586 0.00468 0.005266 1400

Child (Postapplication) 7.5 100 0.075 0.001545 0.01187 0.013415 560

1

The LOC is based on the standard inter- and intra- species uncertainty factors totaling 100. The FQPA Safety Factor has been 

reduced to 1X.
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2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC.

3 Residential Exposure (Adult Post-application) = Turf High-contact (Playing, Table 6.2). Residential Exposure (Child PostApplication) = Combined Dermal and Oral Exposure from Turf Spray Application for Child 1<2 Years Old.

4 Total Exposure = (Avg. Food & Water Exposure + Residential Exposure).

5 Aggregate MOE = [NOAEL 7.5mg/kg/day/Total Exposure mg/kg/day].

7.3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary exposure and risk, which is not of 

concern. Refer to Section 5.4.4.

8.0 Cumulative Exposure/Risk Characterization

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/.
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9.0 Occupational Exposure/Risk Characterization

As there are no occupational exposures associated with the proposed import tolerances, a new 

occupational exposure assessment was not conducted for this import tolerance petition on 

banana, coffee, and palm oil. Occupational exposures from the existing registered uses of 

indaziflam were previously assessed and no risks of concern were identified. 

10.0 References

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)

Indaziflam: Revised Residential Exposure Assessment to Support Import Tolerances for 

Banana, Coffee, and Palm Oil. (Z. Figueroa, D415431, 09/26/2013)

Tier 2 Drinking Water Assessment for the Section 3 New Chemical Registration of Indaziflam; 

Rueben Baris; D356141; and D367447; February 2, 2010.

Indaziflam. Petition for the Establishment of Import Tolerance Use on Banana, Coffee, and 

Palm Oil. Summary of Analytical Chemistry and Residue Data. (E. Holman, D408151;

09/26/2013)

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

Risk Assessment for the Section 3 Registration (Import Use Only) on Banana, Coffee, and Palm 

Oil. (E. Holman, D408152; 09/26/2013) 
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for indaziflam food and turf uses are presented below. 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.
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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
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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.

cord and sciatic nerve in males and females. 

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

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).
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

90.32% a.i.

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 

47443308 (2006) Negative for induction of increased frequency 

of micronucleated polychromatic erythrocytes 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

assay (mouse) Acceptable/Guideline

Two doses of 0, 10, 20 or 

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.

in bone marrow at any treatment time.

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). 

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, an increased incidence of 

minimal spinal nerve degeneration, 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. 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics

(rat) – tier 1

47443312 (2008)

Acceptable/Guideline

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

Absorption was complete (>90% 

bioavailability) and rapid, with radioactivity 

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 

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).
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – Indaziflam technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

99%

870.7600 Dermal 

absorption, in vivo 

(rat)

47743420 (2008)

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% 

Absorption was inversely proportional to dose, 

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. 

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - General Population including females age 13-49

Study Selected: Subchronic gavage toxicity study in dogs. 
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MRID No: 47443289

EXECUTIVE SUMMARY: In a subchronic oral toxicity study in dogs (MRID 47443289), 

BCS-AA10717 (AE 1170437, indaziflam tech.; 94.5-99.4% a.i.; Batch Nos. EFIM000511 and 

NLL 7482-5A, respectively) in 0.5% aqueous methyl cellulose was administered via daily oral 

gavage in a dose volume of 1 or 5 mL/kg to four beagle dogs/sex/dose group at doses of 0, 7.5 15

or 30 mg/kg/day for at least 90 days. On Day 23, dosing was halted in the 30 mg/kg/day group 

due to a seizure in one female, and resumed on Day 25 at 15 mg/kg given twice daily 

approximately 7-8 hours apart. The 30 mg/kg/day animals were terminated on Day 36 due to 

seizures.

No adverse, treatment-related effects were observed on food consumption, ophthalmoscopic 

examinations, hematology, clinical chemistry, urinalysis, organ weights, or gross pathology.

At 15 mg/kg/day, treatment-related histopathological findings were observed in the nervous 

system (brain, spinal cord, sciatic nerve). In the males, slight multifocal axonal degeneration of 

the sciatic nerve was observed in 1/4 dogs, and minimal multifocal axonal degeneration of the 

spinal cord was noted in 1/4 dogs, both compared to 0 controls. In the females, minimal 

multifocal axonal degeneration was observed in the brain in 1/4 dogs, minimal focal/multifocal 

axonal degeneration was observed in the sciatic nerve in 2/4 dogs, and minimal to moderate 

multifocal axonal degeneration of the spinal cord was noted in 2/4 dogs, all compared to 0 

controls. No clinical signs of toxicity were observed.

At 30 mg/kg/day, three dogs presented with seizures on Days 15, 22, and 35, respectively, and 

were killed on the day the seizures were observed. Treatment-related clinical findings observed 

in these dogs included the following: seizures in the male; aggressive, tremors, ataxia 

(unsteady), labored breathing, pupil no reaction to light or sluggish, decreased activity, circling, 

seizures, and sores due to seizures in the females. Due to the seizures, dosing of the 30 

mg/kg/day group was halted on Day 35, and the surviving dogs of this group were euthanized on 

Day 36 for humane reasons. Additionally at this dose, male dogs displayed decreased body 

weight gains for Days 0-35 compared to all other groups, while females lost weight during this 

period compared to the other groups. Treatment-related histopathologic findings were observed 

in the nervous system (brain, spinal cord and sciatic nerve). In the males, slight multifocal 

axonal degeneration of the sciatic nerve was observed in 1/4 dogs, and minimal to moderate 

multifocal axonal degeneration of the spinal cord was noted in 4/4 dogs (mean severity 1.8), both 

compared to 0 controls. In the females, minimal to slight multifocal axonal degeneration was 

observed in the brain in 2/4 dogs, minimal to slight focal/multifocal axonal degeneration was 

observed in the sciatic nerve in 2/4 dogs, and minimal to moderate multifocal axonal 

degeneration of the spinal cord was noted in 4/4 dogs (mean severity 2.3), all compared to 0 

controls. Although the dogs affected by seizures all showed neurohistopathology, there did not 

appear to be an association with the severity of these findings.

The LOAEL is 15 mg/kg/day, based on axonal degeneration in the nervous system of both 

sexes. The NOAEL is 7.5 mg/kg/day.
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This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3150; OECD 409) for a subchronic oral toxicity study in dogs.

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

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

Acute RfD = 

100( )

7.5 / /

UF

mg kg day = 0.075 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factor: 

The results of the subchronic toxicity study in dogs were used to select the dose and endpoints 

for establishing the aRfD of 0.075 mg/kg for the general population based on axonal nerve fiber 

degeneration seen at the LOAEL of 15 mg/kg. The nerve fiber degeneration is considered a 

potential single-dose effect because similar nerve fiber degeneration was seen in the acute 

neurotoxicity study in rats following a single dose, the majority (~90%) of indaziflam is excreted 

within 24 hours in rat metabolism studies, the timing of the observation of seizures (occurring on 

day 0 at 50 mg/kg/day in 2 dogs in a range finding subchronic dog study), and clinical signs of 

neurotoxicity in the subchronic dog study were observed ~2 hours following dosing of 

indaziflam. While there was an acute neurotoxicity study in rats available, this study had a much 

higher LOAEL of 586/581 mg/kg (M/F). Based on the 39-fold increased sensitivity of the dog 

compared to the rat for subchronic exposure, the acute neurotoxicity study was determined to 

likely be under protective of potential neurotoxicity. The 90-day range-finding study (with 

seizures occurring at day 0 at 50 mg/kg/day) with a NOAEL of 15 mg/kg/day, however, was 

not considered appropriate for acute endpoint and dose selection due to the limited number of 

dogs used (n=2/dose group) and because no neuropathology was conducted in that study. In 

combination with the potential of the effects observed in the subchronic toxicity study in dogs to 

be a single dose effect, the subchronic dog study was chosen in the absence of an acute study in 

dogs. 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. 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.

A.3.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic dietary toxicity study in dogs. 

MRID No: 47443294

EXECUTIVE SUMMARY: In a chronic oral toxicity study (MRID 47443294), BCSAA10717 technical (AE 1170437; Indaziflam; 94.5% a.i.; Batch No. EFIM000511) was 

administered to four beagle dogs/sex/dose group in the diet at doses of 0, 60, 225 or 450 ppm 
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(equivalent to 0/0, 2/2, 6/7 or 12/11 mg/kg/day in males/females) for at least 12 months. In 

addition to evaluation of standard chronic toxicity study parameters, a neurological examination 

was performed monthly from months 7 through 11 and just prior to termination.

No adverse, treatment-related effects were observed on mortality, clinical signs of toxicity, 

neurological or ophthalmoscopic examinations, hematology, clinical chemistry, urinalysis, organ 

weights or gross pathology. One high dose male was sacrificed on Day 190 due to seizures that 

were not considered treatment-related: this animal had dilatation of the lateral ventricles and no 

seizures were observed in the subchronic dog study with bolus dosing at 15 mg/kg/day. 

Although body weights of the 450 ppm group were not significantly different from controls, 

body weight gains (calculated by reviewers) were decreased by treatment in the early months of 

the study. Male dogs lost 1.7 g during Days 0-91 compared to a gain of 534.5 g in the controls, 

and female dogs body weight gains were decreased by 66% compared to controls during this 

period. Overall (Day 0-364) body weight gains were decreased by 12% in the males and by 21% 

in the females. Additionally at 450 ppm, decreased food consumption was generally observed in 

both males and females throughout the study (Days 1-368), resulting in an overall mean decrease 

of 20% in both sexes (calculated by reviewers). Although these decreases infrequently attained 

statistical significance, the magnitude was generally greater than 10%, and correlated with the 

decreased body weight gains observed in this group. 

Treatment-related microscopic findings were primarily observed within the dorsal funiculi 

(primarily the funiculus cuneatus) of the spinal cord at 225 and 450 ppm. The lesion was 

characterized by axonal degeneration of individual nerve fibers, consisting of fragmented and 

lysed axonal fibers, sometimes associated with phagocytic macrophages forming a digestion 

chamber. Secondary subtle demyelination was also noted. At 225 ppm, multifocal axonal 

degeneration was observed in the spinal cord of 3/4 males (minimal) and 1/4 females (slight), 

both compared to 0 controls. At 450 ppm in the males: minimal axonal degeneration was 

observed in the brain of 1/4 dogs; minimal perivascular multifocal lymphocytic inflammation 

was noted in the brain of 1/4 dogs; minimal multifocal axonal degeneration of the sciatic nerve 

was observed in 1/4 dogs; and minimal to moderate multifocal axonal degeneration of the spinal 

cord was noted in 3/4 dogs, all compared to 0 controls. In the females, minimal axonal 

degeneration was observed in the brain of 1/4 dogs, minimal to moderate multifocal axonal 

degeneration of the spinal cord was observed in 4/4 dogs (p≤0.05), all compared to 0 controls 

and minimal multifocal axonal degeneration of the sciatic nerve was observed in 1/4 females.

The LOAEL is 225 ppm (equivalent to 6/7 mg/kg/day in males/females), based on 

microscopic lesions of the nervous system of both sexes as described above. The NOAEL is 

60 ppm (equivalent to 2/2 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.4100b; OECD 452) for a chronic oral toxicity study in dogs.

Dose and Endpoint for Risk Assessment: NOAEL= 2.0 mg/kg/day 
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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 Factor: 

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.

A.3.3 Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: Subchronic gavage toxicity study in dogs. 

MRID No: 47443289

Dose and Endpoint for Risk Assessment: NOAEL= 7.5 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.

A.3.4 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.

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%.
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A.3.5 Dermal Exposure (Short-and Intermediate-Term)

Study Selected: Subchronic gavage toxicity study in dogs. 

MRID No: 47443289

Dose and Endpoint for Risk Assessment: NOAEL= 7.5 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 shortand 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.

A.3.6 Inhalation Exposure (Short-and Intermediate-Term)

Study Selected: Subchronic gavage toxicity study in dogs. 

MRID No: 47443289

Dose and Endpoint for Risk Assessment: NOAEL= 7.5 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 shortand 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.

A.3 Summary table for the observation of seizures in dog toxicity studies.

Study # of animals with 

finding

Day of observation 

(dose in mg/kg/day

and sex)

Timing after dose

Subchronic oral 

(gavage)-dog (MRID 

3 15 (30, M), 22 (30, F), 

and 35 (15x2a, F)

~2 hours after 

dosing with 15 
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Study # of animals with 

finding

Day of observation 

(dose in mg/kg/day

and sex)

Timing after dose

47443289) mg/kg/day for the 

day 35 dog, timing 

was not reported for 

the other dogs.

Chronic oral (diet)-

dog (MRID 

47443289)

1 190 (12, M) Timing not reported.

Subchronic oral 

(gavage) rangefinding study (MRID 

49073701)

8 0 (50, 1M and 1F), 1 

(200, 2Mb), 2 (100, 

M

c

), 3 (100, Fb), 7 

(100, M), and 9 (100, 

F)

Timing not reported.

Subchronic rangefinding study (not 

submitted)d

2 5 (600, F and 800, M) 24 hours for the 

female and 1-1.5 

hours for the male.

Subchronic rangefinding study (not 

submitted)d

1 5 (400, F) Timing not reported.

a After the observation of seizures in the two animals dosed with 30 mg/kg/day, the dosing was stopped for two days 

and then started again as two 15 mg/kg/day doses given 7-8 hours apart.

b Described as “vibratory shake of the head and shoulders”.

c This dog also had a “seizure” on day 9.

d This study was referenced in the subchronic oral (gavage) range finding study (MRID 49073701).
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Appendix B. Physical/Chemical Properties.

Physicochemical Properties of the Technical Grade AE 1170437 (Indaziflam)

Parameter Value Reference

Molecular weight 301.37

Melting point/range 183 -184 oC AE 1170437 

 pure substance

H. Mukhoty, 1 Dec 2008, 

D356393.

pH (23 °C) pH = 6.5 AE 1170437 

 pure substance

pH = 5.1 AE 1170437

 technical substance

Density (g/mL at 20 C)

(relative density compared to water 

at 4 C, D4

20)

1.23 AE 1170437 pure substance

1.23 AE 1170437 technical grade active 

ingredient

Water solubility (at 20 °C) pH 4: 4.4 mg/L, 

pH 9: 2.8 mg/L, 

Distilled water (pH 6.6-6.9): 2.8 mg/L

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

Acetonitrile:

Dichloromethane: 

Dimethyl 

sulfoxide: 

Ethanol: 

Ethyl acetate: 

Heptane: 

Toluene: 

55 g/L

7.6 g/L

150 g/L

>250 g/L

13.0 g/L

47 g/L

0.032 g/L

4.3 g/L

Vapor pressure 2.5 x 10-8PA at 20 °C

6.8 x 10-8PA at 25 °C

6.9 x 10-6PA at 50 °C

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

Dissociation constant (pKa) 3.5 

Octanol/water partition coefficient 

Log (KOW)

pH 2: 2.0

pH4, pH7 and pH9: 2.8

UV/visible absorption spectrum 

methanol (nm)

max1 = 213 nm / A = 1.428

max2 = 268 nm / A = 0.197

max3 = 291 nm / A = 0.019

Appendix C. 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 data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force 

(ORETF) database; are subject to ethics review pursuant to 40 CFR 26, have received that 

review, and are compliant with applicable ethics requirements. For certain studies that review 

may have included review by the Human Studies Review Board. Descriptions of data sources as 

well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handlerexposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.