UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: April 13, 2010

MEMORANDUM

SUBJECT: Indaziflam: Human Health Risk Assessment for Use of Indaziflam on Turf, 

Golf Courses, Sod Farms, Christmas Tree Farms, Non-Crop Areas and Forestry.

PC Code: 080818 DP Barcode: D356142

MRID No.: 47443316; 47443317;and 

47443319

Decision No.: 398884

Petition No.: NA Registration No.: 432-1483

Assessment Type: Single Chemical Aggregate Regulatory Action: Section 3

TXR No.: None Registration Case No.: None

CAS No.: 68359-37-5

FROM: Margarita Collantes, Risk Assessor 

Linnea Hansen, Toxicologist

Alan Levy Ph.D., Toxicologist

Edward Scollon, Ph.D., Toxicologist

Karlyn Middleton, Toxicologist

Michael Doherty, Ph.D., Chemist

Elizabeth Holman, Chemist

Risk Assessment Branch 2

Health Effects Division (7509P)

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

Risk Assessment Branch 2

Health Effects Division (7509P)

TO: Erik Kraft/ James Tompkins RM 25

Product Registration Branch

Registration Division (7505P)

The Registration Division (RD) of the Office of Pesticide Programs (OPP) has requested that the 

Health Effects Division (HED) conduct a risk assessment to estimate the risk to human health 

that will result from the proposed use of indaziflam on turf in both commercial and residential 

uses. 
Page 2 of 52

Table of Contents

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

2.0 Ingredient Profile.............................................................................................................. 6

2.1 Summary of Registered/Proposed Uses.................................................................. 6

2.2 Structure and Nomenclature ................................................................................... 8

2.3 Physical and Chemical Properties.........................................................9

3.0 Hazard Characterization/Assessment........................................................................... 10

3.1 Hazard and Dose-Response Characterization....................................................... 10

3.1.1 Database Summary ................................................................................... 10

3.1.1.1 Mode of action, metabolism, toxicokinetic data........................ 10

3.1.2 Toxicological Effects................................................................................ 10

3.1.3 Dose-Response................................................................ ....12

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)..................................13

3.3 FQPA Considerations.....................................................................13

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

3.3.2 Evidence of Neurotoxicity ........................................................................ 14

3.3.3 Developmental Toxicity Studies.................................................15

3.3.4 Resproductive Toxicity Studies........................................ ........15

3.3.5 Additional Information from Iterature Sources...............................15

3.3.6 Pre-and/or Postnatal Toxicity ................................................................... 15

3.3.6.1 Determination of Susceptibility........................................15

3.4 FQPA Safety Factor for Infants and Children ......................................................... 16

3.5 Hazard Identification and Toxicity Endpoint Selection...............................16

3.5.1 Acute Reference Dose............................................................16

3.5.2 Chronic Reference Dose.........................................................17

3.5.3 Incidental Oral Exposure.........................................................17

3.5.4 Dermal Absorption.................................................................17

3.5.5 Dermal Exposure..................................................................18

3.5.7 Inhalation Exposure...............................................................18

3.5.9 Level of Concern for Margin of Exposure................................................ 19

3.5.10 Recommendation for Combining Routes of Exposure..............................19

3.5.11 Classification of Carcinogenic Potential.......................................19

3.5.12 Acute Toxicity............................................................... ...20

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

Assessment.........................................................................20

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

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

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

5.1 Pesticide Metabolism and Degradates of Concern ............................................... 23

5.1.1 Drinking Water Residue Profile................................................................ 24

5.2 Dietary Exposure and Risk ................................................................................... 24

5.2.1 Cancer Dietary Risk...............................................................25

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

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

6.2. Residential Postapplication Exposure................................................................... 28
Page 3 of 52

6.2.1 Inhalation Postapplication Exposures....................................................... 28

6.2.2 Dermal Postapplication Exposure...............................................28

6.2.3 Oral Postapplication Exposure.................................................................... 30

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

7.0 Combined Risk Assessments and Risk Characterization............................................ 33

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

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

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

9.2 Postapplication Exposure and Risk......................................................40

10.0 Data Needs and Label Recommendations....................................................41

10.1 Toxicology..................................................................................41

10.2 Residue Chemistry.........................................................................41

10.3 Occupational and Residential Exposure................................................41

References:................................................................................................................................... 42

Appendix A:Toxicology Assessment ........................................................................................... 43

A.1 Toxicology Data Requirements..........................................................43

A.2 Toxicity Profiles............................................................................ 44

Appendix B: Input Values for Drinking Water Exposure Assessment..............................52
Page 4 of 52

1.0 Executive Summary

Indaziflam ([1,3,5-triazine-2,4-diamine,N-[(1R2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-

(1-fluroethyl)]) is proposed as a selective, pre-emergent and post-emergent alkylazine herbicide 

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

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

proposed for use as a pre-emergent herbicide for weed control in parks, rail roads, utility, 

industrial and municipal sites. Indaziflam is proposed for use by commercial and professional 

applicators (formulated as a water soluble packet and turf fertilizers) as well as residential 

homeowners (formulated as Lawn 3 FL granules and liquid). It may be applied through a variety 

of application methods ranging from aerial to hand held equipment. Proposed uses are 

anticipated to result in short- and intermediate-term durations of exposure. There are currently no 

registered food uses associated with indaziflam and this is OPP’s first human health risk 

assessment for this chemical. 

The toxicology database is considered adequate for selecting toxicity endpoints for this risk 

assessment. 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. Although at this time the database is considered complete, the Agency is currently

evaluating issues related to volatilization of pesticides including the use of route-to-route 

extrapolation and assessment of inhalation exposure using oral studies, based on the December, 

2009 FIFRA Scientific Advisory Panel recommendations. The requirement of a 28- or 90-day

inhalation toxicity study will be determined when the Agency has completed its review. 

The nervous system is a target for indaziflam in rats and dogs. Degenerative neuropathology of 

the brain, spinal cord and sciatic nerve was reported in the dog following both subchronic and 

chronic oral exposure. Neuropathology in the dog was the most sensitive effect and was selected 

as the endpoint for all exposure scenarios involving repeated exposure. In the rat, histopathology

of the brain and pituitary pars nervosa was observed following chronic exposure. Clinical signs 

of neurotoxicity were observed in both species in several studies, which included rat adult and 

developmental neurotoxicity studies. Decreased motor activity observed in the rat acute 

neurotoxicity study was selected as the appropriate endpoint for acute oral toxicity. 

Degenerative renal effects were observed in the rat and mouse following chronic exposure. 

Liver hypertrophy was observed in rats and females showed liver histopathology. Thyroid 

effects were observed in male rats following subchronic and chronic exposure but were 

considered secondary to liver stimulation and occurred at significantly higher doses than those 

selected for risk assessment (15-fold or greater), and therefore are not considered to be of 

concern for pre- and/or postnatal development. Other effects observed following chronic 

exposure were an increased incidence of atrophied or small seminal vesicles in male rats and in 

female mice, an incidence of stomach erosions and blood-filled ovarian cysts. Decreased body 

weight gains were generally observed in the available studies. No systemic toxicity was 

observed in a 28-day dermal toxicity study in the rat. Based on the lack of evidence of 

carcinogenicity or genotoxicity, HED classified indaziflam as “Not likely to be carcinogenic to 

humans.” 
Page 5 of 52

Although no food uses are associated with the current request, a food-use petition has been 

received by the Agency and HED has evaluated the available data with respect to the FQPA 

safety factor. HED recommends that the FQPA safety factor be reduced to 1X, based on (1) lack 

of evidence of increased quantitative or qualitative pre- and/or postnatal susceptibility in a 

complete database that includes adult and developmental, reproductive, developmental 

neurotoxicity, and immunotoxicity studies, (2) the developmental effects in the rat that were 

observed only at high doses in the presence of maternal/parental toxicity, (3) the selection of 

endpoints and doses are protective of potential developmental toxicity, and (4) since there are no 

food uses associated with this action the only potential exposure pathways included drinking 

water and residential exposure assessments which resulted in no risks of concern. 

HED has retained the traditional uncertainty factors for inter-species extrapolation (10X) and 

intra-species variability (10X) remain. Therefore, HED’s level of concern (LOC) is an MOE of 

100 and exposure scenarios resulting in MOEs greater than or equal to 100 are not of concern.

HED has assessed residential application and post-application scenarios and determined that 

risks for these exposures are below the level of concern. HED has also examined the impact of 

potential residues in drinking water alone and in combination with the residential exposures and 

found them to be below the level of concern.

HED has also assessed occupational exposures associated with the proposed turf uses. All risk 

estimates are below HED’s level of concern.

Indaziflam contains a symmetrical triazine moiety and has been reviewed for possible inclusion 

in the triazine cumulative assessment group of chemicals which include atrazine, simazine, 

propazine and metabolites diaminochlorotriazine (DACT), desethyl-s-atrazine (DEA), and 

deisopropyl-s-atrazine (DIA). Based on a comparative review of its structure and toxicological 

profile indicating that the toxicological effects of indaziflam do not fit the triazine characteristics, 

HED did not include indaziflam in the triazine cumulative assessment.

Review of Human Research

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

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

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

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

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

Environmental Justice

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

human health risk assessment, in accordance with US Executive Order 12898, Federal Actions to 

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 
Page 6 of 52

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

pesticide use in a residential setting. Since the proposed uses of indaziflam are classified as nonfood uses and indaziflam is unlikely to contaminate drinking water, no dietary or drinking water 

exposure is expected for indaziflam. 

However, post-application inhalation exposure in the general population can occur as a result of 

the registered uses. This inhalation exposure may not be limited to occupational workers, but 

may occur for bystanders located in proximity to treated fields. Whenever appropriate, nondietary exposures based on home use of pesticide products, associated risks for adult applicators, 

and for children (3 to 6 years of age), youths, and adults entering or playing on treated areas 

post-application are evaluated.

Based on the exposure pattern, an analysis of residential bystander inhalation exposure has been 

performed as part of the indaziflam risk assessment. This analysis takes into account individuals 

who may live directly next to a field/area treated with indaziflam as well as those individuals 

who may live in an area with multiple indaziflam treated fields/areas. Inputs used in the 

assessment (e.g., breathing rates, air concentration levels, body weights, etc.) were chosen to 

assure that the inhalation component of the aggregate exposure assessment will be protective of 

all potential exposed populations, including populations specifically targeted for possible 

environmental justice concerns such as low income residents and minorities. 

The analysis also considers the potential for increased exposure to children which might occur 

due to different breathing rates and body weights. Also, risk assessment endpoints were selected 

considering the potential susceptibility of infants, children, and pregnant women to assure 

protection of these populations.

Since (a) dermal risks will drive this assessment and will be protective of all populations, (b) 

food and drinking water exposure will not occur, and (c) no additional unique exposures are 

anticipated for this chemical, the aggregate indaziflam assessment will be protective of potential 

exposures and risks to all populations.

Further considerations are currently under evaluation as OPP has committed resources and 

expertise to the development of specialized software/models and the refinement of current 

methodologies and policies that consider exposure to bystanders and farm workers, as well as, 

lifestyle and traditional dietary patterns among specific subgroups. To ensure that this risk 

assessment is consistent with scientific standards/policies under development, HED may refine 

the risk assessment components for all the registered uses in the future.

2.0 Ingredient Profile

2.1 Summary of Proposed Uses

Indaziflam is a selective, pre-emergent and post-emergent alkylazine herbicide proposed for 

control of many annual grasses and broadleaf weeds in turf (lawns, sod farms, golf courses, 

recreational fields, etc), ornamentals and trees. It is also proposed for use as a pre-emergent 

herbicide for weed control in parks, railroads, utility, industrial and municipal sites. Indaziflam 
Page 7 of 52

is proposed for use by commercial and professional applicators (formulated as a water-soluble 

packet and turf fertilizers) as well as residential homeowners (formulated as Lawn 3 FL granules 

and liquid). It may be applied through a variety of application methods including: aerial, ground 

equipment, right of way handgun, backpack, broadcast and push type spreader, hand held 

equipment (low pressure, high pressure, pump and trigger sprayer) and hose end sprayer. The 

herbicide requires rainfall or irrigation within several weeks after application to be activated and 

effective. The personal protective equipment (PPE) for all proposed commercial labels consists 

of baseline clothing (i.e., long-sleeved shirt and long pants) and use of chemical resistant gloves. 

It should be noted that the residential products (i.e., Lawn 3 FL) contain additional active 

ingredients. This assessment only addresses exposure resulting from the use of indaziflam. 

Therefore the Registration Division (RD) should ensure that all residential label requests are 

intended for Lawn 3 FL products and recommendations are appropriate for other active 

ingredients. Table 2.1 provides a summary of the proposed uses.

Table 2.1: Proposed Commercial and Residential Products and Uses of Indaziflam

Product 

EPA Reg. No.

Use Site Application 

Method

Application 

Rate

Comments

Commercial Products

Esplanade

200 SC

(Soluble 

Concentrate)

19% ai 

Annual grasses and weeds 

in non-crop areas (utilities, 

industrial, municipal and 

government sites, roadsides) 

ornamental perennial 

plantings, around farm 

buildings, educational 

facilities, parking lots

ground 

equipment

0.089 lb ai/A

Pre-emergent

right of way

0.089 lb ai/A

or 0.0178

lb ai/gal

handgun

low pressure 

handwand

back pack

Esplanade F 

(Flowable 

Concentrate)

19% ai 

Forestry aerial

0.125 lb ai/A

Preemergent

groundboom 1 application

backpack 0.125 lb ai/A 

or 0.0248 lb ai 

/gal

BCSAA10717

20 WSP 

(Water Soluble 

Packet)

Annual grasses and weeds 

in turfgrass, golf courses, 

sod farms; ornamentals, 

nurseries, Christmas trees, 

landscapes forestry, noncrop areas

groundboom 0.088 lb ai/A 

groundboom,

hand held 

equipment

0.071 lb ai/A –

non-crop areas

Single application in 

spring, summer and 

fall; 3 month interval 

between applications; 

not to exceed 0.088 

lb ai/A per year

BCSAA10717

0.0142% Plus 

Turf Fertilizer 

(granule)

Annual grasses and weeds 

in turfgrass, (golf courses 

and sod farms; lawns, 

cemeteries)

Tractor-drawn 

spreader and 

push type 

spreader and 

belly grinder for 

use on lawns and 

parks

0.071 lb ai/A Not to exceed 0.088 

lb ai/A per year

BCSAA10717
Page 8 of 52

Table 2.1: Proposed Commercial and Residential Products and Uses of Indaziflam

Product 

EPA Reg. No.

Use Site Application 

Method

Application 

Rate

Comments

0.0213% Plus 

Turf Fertilizer

(granule)

BCSAA10717

0.0284% Plus 

Turf Fertilizer

(granule)

Residential Products

Lawn 3FL 

Concentrate 

/Ready to 

spray

Residential lawns, hard 

scapes and ornamentals

Pump style tank 

sprayer

0.00063 lb ai/ 

gallon

hose-end 

sprayer 

concentrate; prepacked hose-end 

ready to spray; 

low pressure 

handwand

0.044 – 0.094 

lb ai/A

Lawn 3FL 

Granule

Push type 

spreader and 

belly grinder

0.044 lb ai/A Do not repeat 

applications within 6 

months

Lawn 3FL 

Concentrate 

Ready to Use

Trigger sprayer 0.00026 lb ai 

/gallon

As needed

2.2 Structure and Nomenclature

Table 2.2. Indaziflam Nomenclature

Compound Chemical Structure

Common name Indaziflam (ISO proposed)

Company experimental names AE 1170437, BCS-AA10717

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 registry number 730979-19-8

End-use product (EP) Indaziflam 200 SC Herbicide

Indaziflam 500 SC Herbicide

N

N

N

N

H

NH2

H C F 3

CH3

H3C
Page 9 of 52

Table 2.2. Indaziflam Nomenclature

Esplanade 200 SC Herbicide

Esplanade F 200 SC Herbicide

Lawn 3FL Herbicide Concentrate/Ready-to-Spray

Lawn 3FL Herbicide Granule

Lawn 3FL Herbicide Ready-to-Use

AA10717 Herbicide Technical

AA10717 2% MUP Herbicide

AA10717 20WSP Herbicide

AA10717 Herbicide 0.0284% Plus Turf Fertilizer

AA10717 Herbicide 0.0213% Plus Turf Fertilizer

AA10717 Herbicide 0.0142% Plus Turf Fertilizer

Due to the presence of three chiral carbons in the indaziflam structure, there are eight possible 

isomers for this herbicide. Based on the product chemistry review of the manufacturing use 

product (MUP) by RD (H. Mukhoty, 12/1/2008, D356393), the registrant is declaring the active 

ingredient to consist of only isomers “A” (AE 1170437) and “B” (AE 1170438) with 

concentrations of about 92% and 3%, respectively. The chemical name appearing above in 

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

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

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

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

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

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

indaziflam

2.3 Physical and Chemical Properties

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

Parameter Value Reference

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

Administrative 

Materials

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

pH = 5.1 indaziflam (technical substance)

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

substance)

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

pH 9: 0.0028

Distilled water (pH 6.6-6.9): 0.0028 

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

Acetonitrile: 7.6 

Dichloromethane: 150 

Dimethyl sulfoxide: >250 

Ethanol: 13.0 

Ethyl acetate: 47 

Heptane: 0.032 

Toluene: 4.3 

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

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

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

Henry’s law constant 2.69 x 10-6[Pa x m3/mol] at 20 °C
Page 10 of 52

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

Parameter Value Reference

Dissociation constant (pKa) 3.5 

Octanol/water partition coefficient 

Log (KOW)

pH 2: 2.0

pH4, pH7 and pH9: 2.8

UV/visible absorption spectrum 

methanol (nm)

max1 = 213 nm / A = 1.428

max2 = 268 nm / A = 0.197

max3 = 291 nm / A = 0.019

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

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

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

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

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

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

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

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

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

vitro human and rat dermal absorption. 

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

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

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

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

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

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

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

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

have been established. 

3.1.1.1 Mode of action, metabolism, toxicokinetic data

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

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

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

unknown. Metabolism in the rat is discussed below in Section 3.2. 

3.1.2 Toxicological Effects

The nervous system is a target for toxicity in rats and dogs. In repeated-dose studies, the dog 
Page 11 of 52

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

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

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

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

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

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

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

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

effects are found in Section 3.3.2. 

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

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

reproductive toxicity study showed increased kidney weights and incidence of hyaline 

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

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

and intratubular yellow-brown material. 

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

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

showed an increased incidence of macrovacuolation and multinucleated hepatocytes with 

anisocaryosis. 

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

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

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

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

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

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

hormone levels did not show changes. 

Additional effects observed following chronic exposure included atrophied or small seminal 

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

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

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

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

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

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

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

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

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

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

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

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

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

(PND 21 only) in male offspring was observed and was considered a potential neurotoxic effect. 
Page 12 of 52

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

body weight in maternal animals.

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

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

3.1.3 Dose-response

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

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

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

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

is protective of the decreases in maternal body weight gains seen in the rat developmental and 

rabbit developmental toxicity studies, potential developmental effects based on lack of observed 

increased pre- and/or postnatal susceptibility and higher LOAELs observed in developmental, 

reproductive, neurotoxicity, developmental neurotoxicity and immunotoxicity studies. Although 

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

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

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

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

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

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

limited to pup body weight decrements of <10%.

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

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

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

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

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

mg/kg/day. 

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

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

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

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

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

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

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

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

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

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

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

continual daily exposures occurring for more than 90 days (i.e., intermediate-term exposure) are 

not expected to occur. 

Although a 28-day dermal toxicity study in the rat was available and showed no toxicity up to 
Page 13 of 52

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 (similarly, in the chronic dog 

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

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

selected. 

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

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

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

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

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

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

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

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

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

oral doses which followed. Radioactivity was not retained at significant levels in the tissues by 3 

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

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

dose excreted in feces as unchanged parent, and occurred primarily via oxidative processes. The 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

parent compound. 

3.3 FQPA Considerations

An FQPA assessment is not required for the proposed turf uses of indaziflam. However, because 

there are proposed food uses pending that will be evaluated subsequent to the turf evaluation, an 

FQPA assessment has been performed.
Page 14 of 52

3.3.1 Adequacy of the Toxicity Database

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

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

neurotoxicity screening and immunotoxicity studies have been submitted. Executive summaries 

for all of these studies are provided as a separate attachment.

3.3.2 Evidence of Neurotoxicity

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

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

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

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

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

observed at doses up to 11 and15 mg/kg/day (chronic/subchronic studies). High dosed dogs in 

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

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

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

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

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

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

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

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

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

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

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

probably as a result of gavage vs. dietary exposure. In addition, similar clinical findings were 

seen in P and F1 generation animals in the reproductive toxicity study, at doses ≥318 mg/kg/day. 

Clinical signs of neurotoxicity following chronic dietary exposure to the rat at dietary

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

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

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

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

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

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

the mouse. 

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

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

of 0, 13, 83.8 or 432 mg/kg/day. The high dose, originally at 7000 ppm, was reduced to 4000 

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

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

dilated pupils or dilated pupils that were unresponsive to penlight, nasal staining and repetitive 
Page 15 of 52

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

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

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

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

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

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

outside the laboratory historical control range. 

3.3.3 Developmental Toxicity Studies

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

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

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

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

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

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

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

above in Section 3.3.2.

3.3.4 Reproductive Toxicity Studies

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

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

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

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

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

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

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

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

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

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

3.3.5 Additional Information from Literature Sources

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

3.3.6 Pre-and/or Postnatal Toxicity

3.3.6.1 Determination of Susceptibility

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

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

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

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

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

of increased susceptibility, and the selection of endpoints with low NOAELs that are adequately 
Page 16 of 52

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

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

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

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

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

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

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

only observed in the males, were observed at a high dose relative to the selected regulatory

endpoints, and appear to be secondary to liver effects. 

3.4 FQPA Safety Factor for Infants and Children

HED recommends reduction of the FQPA safety factor to 1X, based on (1) lack of evidence of 

increased quantitative or qualitative pre- and/or postnatal susceptibility in a complete database 

that includes adult and developmental, reproductive, developmental neurotoxicity and 

immunotoxicity studies, (2) the developmental effects in the rat observed at relatively high doses 

in the presence of maternal/parental toxicity, (3) the selection of endpoints that are protective of 

potential developmental toxicity, and (4) the estimates of exposure from drinking water and 

residential uses are not likely to underestimate potential exposure to indaziflam. Although the 

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

thoroughly examined potential effects to the developing nervous system following pre- and postnatal exposure, showed only marginal effects in offspring (slightly decreased motor activity, 

absolute brain weight) at relatively high (and maternally toxic) doses and indicates that 

increased susceptibility does not occur.

3.5 Hazard Identification and Toxicity Endpoint Selection

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

Females Age 13-49 

Study Selected: Acute Neurotoxicity – Rat 

MRID Nos: 47443310

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

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

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

Acute RfD = 

100 ( )

50 /

UF

mg kg = 0.50 mg/kg

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

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

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

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

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

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

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

as an endpoint due to variability in the data. No other acute effects were observed in the 
Page 17 of 52

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

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

observed in developmental, reproductive, neurotoxicity, developmental neurotoxicity and 

immunotoxicity studies. Although the rat developmental toxicity developmental 

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

protective because the rat developmental LOAEL (7-9% decrease in fetal body weight) 

was significantly greater (200 mg/kg/day) and the effects were relatively mild at that dose 

and unlikely to occur after a single dose. 

3.5.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic Toxicity (Dietary) – Dog

MRID No: 47743294

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

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

F respectively). 

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

Chronic RfD = 

100 ( )

2.0 / /

UF

mg kg day = 0.02 mg/kg/day

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

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

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

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

susceptibility and significantly higher NOAELs observed in developmental, reproductive, 

neurotoxicity, developmental neurotoxicity and immunotoxicity studies. 

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

Study Selected: Subchronic Toxicity (Gavage) – Dog

MRID No: 47743289

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

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

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

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

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

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

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

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

significantly higher NOAELs for postnatal toxicity in the developmental neurotoxicity

and the two-generation reproductive toxicity studies.

3.5.4 Dermal Absorption

In addition to a 28-day study evaluating dermal toxicity in the rat, an in vivo dermal 
Page 18 of 52

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 vitrohuman dermal absorption (5.975%, adjusted for recovery) 

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

5.975%/0.82 = 7.3%.

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

Study Selected: Subchronic Toxicity-Dog

MRID No: 47743289

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

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

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

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

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

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

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

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

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

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

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

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

nonetheless considered conservative because the effects in the dog were observed 

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

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

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

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

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

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

Study Selected: Subchronic Toxicity-Dog

MRID No: 47743289
Page 19 of 52

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

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

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

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

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

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

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

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

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

and a route-specific inhalation study is not available.

3.5.8 Inhalation Exposure (Long-Term)

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

3.5.9 Level of Concern for Margin of Exposure

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

Route

Short-Term

(1 - 30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 NA

Inhalation 100 100 NA

Residential Exposure

Dermal 100 100 NA

Inhalation 100 100 NA

Oral 100 100 NA 

 NA = not applicable 

3.5.10 Recommendation for Combining Routes of Exposure for Risk Assessments

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

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

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

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

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

risk assessment. 

3.5.11 Classification of Carcinogenic Potential

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

carcinogenicity bioassays. Genotoxicity studies (reverse gene mutation in bacteria, forward gene 
Page 20 of 52

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

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

indaziflam as “Not likely to be carcinogenic to humans.”

3.5.12 Acute Toxicity

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

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

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

Assessments of Indaziflam 

Acute and chronic dietary endpoints are not needed for this risk assessment on turf, but were 

selected for proposed food uses.

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

Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(All 

Populations, 

including 

Infants and 

Children and 

Females 13-49 

years of age)

NOAEL = 

50 

mg/kg/day

UFA= 10X

UFH= 10X

FQPA SF= 1X 

Acute RfD = 

0.5

mg/kg/day

aPAD = 0.5 

mg/kg/day

Acute oral neurotoxicity in the rat

LOAEL = 100 mg/kg/day, based on 

decreased motor and locomotor activity in 

females.

Chronic 

Dietary (All 

Populations)

NOAEL = 2 

mg/kg/day

UFA= 10X

UFH= 10X

FQPA SF= 1X 

Chronic RfD = 

0.02

mg/kg/day

cPAD = 0.02 

mg/kg/day

Chronic oral (dietary) toxicity in the dog

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

nerve fiber degenerative lesions in the 

brain, spinal cord and sciatic nerve. 

Incidental 

Oral, Shortterm (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 oral (gavage) in the dog

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

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Dermal, 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 oral (gavage) in the dog

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

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Dermal, LongTerm (>6 

months)

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

are not anticipated).
Page 21 of 52

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

Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Inhalation, 

Short-term (1 

to 30 days) 

and 

Intermediateterm (1 to 6 

months)

NOAEL = 

7.5 

mg/kg/day

Inhalation 

absorption 

assumed to 

be 100% 

(default) 

relative to 

oral.

UFA=10X

UFH=10X

FQPA SF = 1X

Residential 

LOC for MOE 

= 100

Subchronic oral (gavage) in the dog

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

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Inhalation, 

Long-term (>6 

months)

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

are not anticipated).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans”

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

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

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

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

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

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

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

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

Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal, ShortTerm (1 to 30 

days) and 

Intermediateterm (1 to 6 

months)

NOAEL = 

7.5 

mg/kg/day

DAF = 7.3%

UFA=10X

UFH=10X

Occupational LOC 

for MOE = 100

Subchronic oral (gavage) in the dog

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

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Dermal, LongTerm (>6 

months)

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

are not anticipated).
Page 22 of 52

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

Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Inhalation 

Short-Term (1 

to 30 days) and 

IntermediateTerm (1 to 6 

months)

NOAEL= 

7.5 

mg/kg/day. 

Inhalation 

absorption 

assumed to 

be 100% 

(default) 

relative to 

oral.

UFA=10X

UFH=10X

Occupational LOC 

for MOE = 100

Subchronic oral (gavage) in the dog

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

degenerative microscopic findings in the 

brain, spinal cord and sciatic nerve.

Inhalation 

Long-Term (> 

6 months)

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

are not anticipated).

Cancer (oral, 

dermal, 

inhalation)

Classification: “Not likely to be Carcinogenic to Humans” 

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

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

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

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

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

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

3.6 Endocrine disruption

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

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

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

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

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

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

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

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

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

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

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

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

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

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

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

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 
Page 23 of 52

pesticide active ingredients.

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

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

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

4.0 Public Health and Pesticide Epidemiology Data and Incident Reports

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

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Degradates of Concern 

OPP performed a preliminary review of the available metabolism and environmental fate data for 

purposes of determining the residues of concern for drinking water by the Residues and Concern 

Knowledgebase Subcommittee (ROCKS) (G. Kramer, D371659, January 2010). Conclusions 

regarding residues of concern for metabolites in proposed crops and livestock are not pertinent to 

this assessment and will be addressed in a future, separate risk assessment for indaziflam.

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

Drinking water residues of concern include triazine indanone, indaziflam carboxylic acid, FDAT, 

dihydroamino triazine, indaziflam hydroxyethyl, and indaziflam olefin. A similar list of 

degradates are included as residues of concern for risk assessment; indaziflam, triazine indanone, 

indaziflam carboxylic acid, indaziflam hydroxyethyl, FDAT, and indaziflam olefin. With the 

exception of FDAT, all of the ring-intact metabolites are assumed to have comparable toxicity to 

the parent due to structural similarity. FDAT is not expected to be more toxic than the parent 

indaziflam based on FDAT’s non-neurotoxic mode of action (Non-guideline study MRID 

47443314; E. Scollon, D371661, draft). Therefore, the neurotoxic endpoints selected for this 

risk assessment will be protective of potential FDAT toxicity. A summary of the metabolites and 

degradates are provided in Table 5.1.

Table 5.1. Summary of Metabolites and Degradates to be included in the Indaziflam Risk Assessment 

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Drinking Water Indaziflam + FDAT + 

Triazine idanone + Indaziflam 

carboxylic acid + Indaziflam 

hydroxyethyl + Inaziflam 

olefin

Not Applicable
Page 24 of 52

5.1.1 Drinking Water Residue Profile

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

D356141; February 2, 2010)

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

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

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

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

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

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 fluoroethyl-triazinedione (ROI1; a degradate of FDAT). Drinking water 

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

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

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

and ROI1 directly in the indaziflam assessment due to lack of toxicity data for FDAT. The 

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

5.1.1. 

Table 5.1.1 Summary of Estimated Surface Water and Groundwater Concentrations 

for Indaziflam*

Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 48 1.6

Chronic (non-cancer) 14 1.6

* Residue estimates for FDAT and ROI1 have been stoichiometrically converted to indaziflam equivalents and 

included directly in the indaziflam concentration estimates.

a

From the PRZM and EXAMS 

b

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

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. However, there is 

uncertainty regarding the toxicity of indaziflam transformation products. A prospective ground 

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

5.2 Dietary Exposure and Risk

A screening level drinking water exposure risk assessment was conducted using the Dietary

Exposure Evaluation Model Database (DEEM-FCID TM). While there are currently no food 

exposures associated with the proposed new use (i.e., turf), discussion of acute and chronic 
Page 25 of 52

dietary exposure via drinking water is provided for purposes of completing the combined 

assessment. For acute and chronic drinking water assessments, the risk is expressed as a 

percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in 

no unreasonable adverse health effects). For food-use pesticides, this dose is referred to as the 

population-adjusted dose (PAD) typically reserved for food uses. As indicated previously, the 

Agency is currently reviewing new proposed food uses associated with a separate action. For the 

purposes of facilitating the future indaziflam food uses (under current review), HED has 

incorporated the use of the PAD in this assessment. The PAD is equivalent to the reference dose 

(RfD) divided by the FQPA Safety Factor. For acute and chronic exposures, HED is concerned 

when estimated dietary risk exceeds 100% of the PAD. 

Acute and chronic drinking water risk estimates are not of concern for general population or 

other population subgroups. The subgroup with the highest risk estimate was infants less than 

one year old with an aPAD of 6.6% and a cPAD of 9.0%. The aPAD for the general population 

was 1.8% and the cPAD was 2.7%. The results of the acute and chronic dietary exposure 

analysis are reported in Table 5.2.

Table 5.2. Result of Chronic Dietary Exposure and Risk Estimates for 

Indaziflam

Population Subgroup Acute Dietary Exposure (mg/kg/day) 1 % aPAD 2 MOE 3

General U.S. Population 0.004388 1.8 5700

All Infants < 1 yr old 0.016544 6.6 1500

Children 1-2 yrs old 0.006885 2.8 3600

Children 3-5 yrs old 0.006290 2.5 4000

Children 6-12 yrs old 0.004379 1.8 5700

Youth 13-19 yrs old 0.003560 1.4 7000

Adults 20-40 yrs old 0.004066 1.6 6100

Adults 50+ yrs old 0.003671 1.5 6800

Females 13-49 yrs old 0.004089 1.6 6100

Population Subgroup Chronic Dietary Exposure % cPAD MOE

General U.S. Population 0.000548 2.7 3700

All Infants < 1 yr old 0.001797 9.0 1100

Children 1-2 yrs old 0.000814 4.1 2500

Children 3-5 yrs old 0.000762 3.8 2600

Children 6-12 yrs old 0.000525 2.6 3800

Youth 13-19 yrs old 0.000396 2.0 5100

Adults 20-40 yrs old 0.000512 2.6 3900

Adults 50+ yrs old 0.000538 2.7 3700

Females 13-49 yrs old 0.000510 2.5 3900

1. Output from dietary exposure (drinking water only) assessment

2. % PAD = Exposure (mg/kg/day)/(aPAD = 0.25 mg/kg/day or cPAD = 0.02 mg/kg/day)

3. Acute Dietary MOE = Acute Dietary NOAEL (50 mg/kg/day)/acute dietary exposure (mg/kg/day))

 Chronic Dietary MOE = Chronic Dietary NOAEL (2 mg/kg/day)/chronic dietary exposure (mg/kg/day)

5.2.1 Cancer Dietary Risk

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

classification, HED has determined there is no cancer risk associated with the proposed uses.
Page 26 of 52

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

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

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

 

6.1 Residential Handler Exposure

Three indaziflam residential turf products (i.e., Lawn 3 FL Concentrate/Ready-to-Spray, Lawn 3 

FL Granule, and Lawn 3 FL Ready-To- Use) are proposed for use by home owners. These 

products are to be applied using hand held sprayers (pump style tank, hose end, and trigger) or 

push-type spreaders. No chemical-specific unit exposure data were provided in support of this 

submission; therefore, the Pesticide Handlers Exposure Database (PHED) Surrogate Exposure 

Guide and Outdoor Residential Exposure Task Force (OREFT) study (MRID 44972201) unit 

exposures were used to estimate handler exposure. Exposures are expected to be short- and 

intermediate-term in duration.

HED’s level of concern for risks (i.e., margin of concern (MOE))for indaziflam is 100 for 

residential exposure. Handler dermal, inhalation and total (dermal + inhalation) MOEs were 

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

HED. Handler exposure and risk is summarized in Table 6.1.2.
Page 27 of 52

Table 6.1.2: Indaziflam Residential Handler Exposure and Risk

Turf 

Exposure 

Scenarios

Use Site Dermal 

Unit 

Exposure 

(mg/lb) a

Inhalation 

Unit 

Exposure 

(mg/lb) a

Application 

Rate b

(lb ai/acre)

Area 

Treated 

(A/day)

Dermal 

Dose c

(mg/kg/day)

Dermal 

MOE d

Inhalation 

Dose e

(mg/kg/day)

Inhalation

MOEf

Total 

MOE g

Mixer/Loader/Applicator

1. Hose-end 

Sprayer “Mix 

Your Own” 

(ORETF –

OMA004))

lawns, 

hardscapes 

and 

ornamentals

11 0.017 0.094

0.5

0.000539 14,000 1.14E-5 660,000 14,000

2. Belly 

Grinder

(PHED)

72155-OR

110 0.062 0.044 0.00252 3000 1.95E-5 380,000 3000

0.023 0.00011 68,000 8.96E-7 8,000,000 67,000

3. Hand-Held 

Pump Sprayer 

(ORETFOMA005)

72155-IO

56 0.0038 0. 00063 5 

gallons

0.000184 41,000 1.71E-7 44,000,000 40,000

Applicator

4. Trigger 

sprayer

Ready to Use 

(ORETF –

OMA006)

72155-ON

54 0.0019 0.00026 

lbai/gal

1 gallon 0.000014 510,000 7.0E-9 100,000,000 510,000

5. Granular 

Push 

Spreader 

(ORETF –

OMA003)

72155-OR

lawns

0.67 0.00088 0.044

0.5

0.0000154 490,000 2.77e-7 27,000,000 480,000

6. Hose End 

Sprayer 

Ready to Use 

(ORETF –

OMA004) 

72155-IO

lawns, 

hardscapes 

and 

ornamentals

11 0.011 0. 094 0.000127 59,000 7.39E-6 1,000,000 56,000
Page 28 of 52

a. Application Rate based on proposed labels

b. Dermal Dose = Unit Exposure (mg/lb) x Application Rate (lb ai/acre or lb ai/gal. ) x Area Treated (acre/day or gal./day) x 

7.3% dermal absorption factor/BW

c. Dermal MOE = NOAEL (7.5 mg/kg/day)/Dermal Dose (mg/kg/day)

d. Inhalation Dose = Unit Exposure (mg/lb) x Application Rate (lb ai/acre or lb ai/gal. ) x Area Treated (acre/day or 

gal./day)/BW

e. Inhalation MOE = NOAEL (7.5 mg/kg/day)/Inhalation Dose (mg/kg/day)

g. Total MOE = NOAEL (7.5 mg/kg/day)/ (dermal dose + inhalation dose) mg/kg/day

6.2 Residential Postapplication Exposure

Indaziflam residential postapplication scenarios include children (3 to 6 years) playing on treated 

turf, adults performing yard work on treated turf and adults playing golf on treated turf. As a 

result, a wide array of individuals of varying ages can potentially be exposed when they do 

activities in areas that have been treated. Postapplication dermal exposures for adults and 

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

hand-/object-to-mouth) resulting from commercial and residential applications were assessed. 

Although a chemical specific turf transferable residue (TTR) study was submitted and reviewed 

by HED (AE 1170437 20WP Determination of transferable Residues from Turf; D. Fischer, 

June 2008; MRID #47443316), all dermal and oral postapplication exposures were assessed 

using default assumptions and transfer coefficients from the HED Draft Standard Operating 

Procedures (SOP’s) for Residential Exposure Assessments, 2000. Residential postapplication

exposures resulting in MOEs greater than or equal to 100 are not of concern. 

6.2.1 Inhalation Postapplication Exposure

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

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

vapor pressure (vapor pressure less than 1 x 10-10 mmHg), it is applied at low application rates 

(maximum rates range from 0.089 - 0.125 lbs ai/A depending on use site), and except for forestry

uses, it is not projected to be applied via typically high inhalation exposure application 

equipment (e.g., airblast and aerial equipment). However, volatilization of pesticides may be a 

potential source of postapplication inhalation exposure to individuals nearby to pesticide 

applications. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 

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

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

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

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

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

for indaziflam.

6.2.2 Dermal Postapplication Exposure

All adult and children residential lawn and golf dermal scenarios resulted in MOEs greater than 

the level of concern (ranging from 2,800 to 90,000) for short-term exposure. A quantitative 

dermal postapplication assessment was not performed for the Trigger Pump scenario as the 

amount used is so small that the other scenarios are considered protective of this one use. As 
Page 29 of 52

these exposure values were determined using default assumptions (5% of the application rate 

available as transferable turf residue) it should be noted that exposure would only be lower 

(greater MOEs) if calculated using actual chemical specific TTR data. Thus use of default 

assumptions is protective of all postapplication dermal exposure scenarios. Additional details 

regarding the TTR data are provided in the Indaziflam Occupational and Residential Exposure 

Assessment (M.Collantes, D372538, April 2010). 

Furthermore, since the short- and intermediate-term dermal endpoints are the same, only shortterm dermal exposures were assessed for adults and children. HED estimates dermal 

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

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

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

summary of the adult and children short-term dermal exposures are summarized in Tables 6.2.2.

Table 6.2.2: Postapplication Short-term Dermal Exposure and Risk Using Default Assumptions 

Scenario Application 

Rate

(lb ai/A)

TTR 1

(μg/cm2)

CF Short-Term 

Tc 

(cm2/hr)

ET 

(hrs)

BW 

(kg)

Dose 2 

(mg/kg/day)

MOE 3

Adults

Hose-end 

Sprayer

0.094 

(ornamentals & 

lawn)

0.047

(lawn)

0.071 *

0.05264

0.02632

0.03976

0.001 14500 -

lawn

2 70 0.001592

0.000796

0.0012

4,700

9,400

6,000

Hand-held 

Pump Sprayer

0.094 

(ornamentals & 

lawn)

0.05264 0.001592 4,700

Belly Grinder 

& Granular 

Push Spreader

0.044

0.071

0.02464

0.03976

0.000745

0.0012

10,000

6,000

Golfer

Hose-end 

Sprayer or 

Granular Push 

Spreader

0.071 * 0.03976 0.001 500 4 70 0.0000829 90,000

Children (3 to 6 years)

Hose-end 

Sprayer

0.094

0.047

0.071 *

0.05264

0.02632

0.03976

0.001 5200 - lawn 2 15 0.00266

0.0013

0.0020

2,800

5,800

3,700

Hand-held 

Pump Sprayer

0.094 0.05264 0.00266 2,800
Page 30 of 52

Table 6.2.2: Postapplication Short-term Dermal Exposure and Risk Using Default Assumptions 

Scenario Application 

Rate

(lb ai/A)

TTR 1

(μg/cm2)

CF Short-Term 

Tc 

(cm2/hr)

ET 

(hrs)

BW 

(kg)

Dose 2 

(mg/kg/day)

MOE 3

Belly Grinder

& Granular 

Push Spreader

0.044

0.071 *

0.02464

0.03976

0.001247

0.0020

6,000

3,700

1. Turf Transferable Residues (TTR) = Application Rate x 0.05% x 11.2

2. Dermal Dose (mg/kg/day) = TTR (μg/cm2) x 0.001 (mg/μg) x short-term TC (cm2/hr) x ET (hr/day) x DAF (7.3%)

BW (kg) 

3. Short-term Dermal MOE = NOAEL (7.5 mg/kg/day)/Dermal Dose (mg/kg/day)

* = commercially applied

6.2.3 Oral Exposure

The hand-to-mouth transfer scenario was assessed using the HED Draft Standard Operating 

Procedures (SOP’s) for Residential Exposure Assessments (12/18/97), and the Revisions to the 

Standard Operating Procedures (SOP’s) for Residential Exposure Assessment (Science Advisory

Council for Exposure Policy 12, Revised February 22, 2001). This scenario assumes pesticide 

residues are transferred to the skin of children (ages 3-6 years) during postapplication contact 

with treated turf areas and are subsequently ingested as a result of hand-to-mouth transfer. 

Residential postapplication oral exposure and risk resulting in MOEs greater than or equal to 100 

are not of concern to HED. 

6.2.3.1 Hand-To-Mouth Exposure and Risk 

This scenario assumes that pesticide residues are transferred to the skin of children playing on 

treated areas and are subsequently ingested as a result of hand-to-mouth transfer. All short- and 

intermediate-term hand-to-mouth (HTM) scenarios result in MOEs greater than 100 and 

therefore pose no risk of concern to HED. Table 6.2.3.1 provides a summary of the short-term 

HTM exposures.

Table 6.2.3.1: Hand-To-Mouth Exposure and Risk for Children (3 to 6 years)

Product TTR 1 

(ug/cm2)

SA 

(cm2/event)

FQ SE ET 

(hr/day)

CF BW 

(kg)

Dose 2

(mg/kg/day)

MOE 3

Short-term

BCS AA10717 

Turf Fertilizer 

(432-RUOL; 432-

RUOA; and 432-

RUOT) and 20 

WSP (432-RUOO)

3.98E-2 20 20 0.5 2 0.001 15 1.06E-3 7,000

Lawn 3FL

(72155-IO)

5.27E-2 1.41E-3 5,300

1. Turf Transferable Residues = (TTR) = 

AR (0.071 or 0.094 lb ai/A) x F (0.05) x (1-D)0x CF2 (4.54E8 μg/lb) x CF3 (2.47E-8 acre /cm2) = 03.98E-2 or 5.27E-2 

ug/cm2

2. Dose = TTRt x SA x FQ x ET x SE x CF1 

 BW

3. MOE = NOAEL (7.5 mg/kg/day)/HTM Dose (mg/kg/day)
Page 31 of 52

6.2.3.2 Object-to-Mouth (Ingestion of Treated Turf) Assumptions and Equations

This scenario estimates doses among young children (3 to 6 years of age) from incidental 

ingestion of pesticide and/or residential turf grass that has been treated with pesticides. It 

assumes that pesticide from a treated object or turf is ingested by young children (3 to 6 years of 

age) who play on treated areas. The object-to-mouth (OTM) scenario results in a MOE greater 

than 100 and therefore poses no risk of concern to HED. Table 6.2.3.2 provides a summary of 

the object-to-mouth exposure and risk.

 

Table 6.2.3.2: Object–to-Mouth Exposure and Risk for Children (3 to 6 years)

Product GR 1 

(ug/cm2)

CF 

(mg/μg)

IgR 

(cm2/day) 

BW 

(kg)

Dose 2 

(mg/kg/day)

MOE 3

BCS AA10717 Turf Fertilizer 

(432-RUOL; 432-RUOA; and 

432-RUOT) and 

20 WSP (432-RUOO)

1.59E-1 0.001 25 15 2.65E-4 28,000

Lawn 3FL

(72155-IO)

2.11E-1 0.001 25 15 3.51E-4 21,000

1. GR (grass residue) = AR x F x (1-D)0x CF2 x CF3 

2. Dose = GR 0 x IgR x CF1

3. MOE = NOAEL (7.5 mg/kg/day)/Dose (mg/kg/day)

6.2.3.3 Incidental Ingestion of Soil Assumptions, Exposure and Risk

This scenario assumes children who play on treated areas ingest pesticide residues in soil as a 

result of normal mouthing activities. The soil-ingestion scenario results in a MOE much greater 

than 100 and therefore poses no risk of concern to HED. This assessment should be considered

conservative in that it assumes no dissipation of soil residues would occur over the exposure 

period. Table 6.2.3.3 provides a summary of the soil ingestion exposure and risk.

Table 6.2.3.3: Soil Ingestion Exposure and Risk Risk for Children (3 to 6 years)

Product SR 1 

(ug/g)

CF 

(g/μg)

IgR 

(mg/day) 

BW 

(kg)

Dose 2 

(mg/kg/day)

MOE 3

BCS AA10717 Turf Fertilizer 

(432-RUOL; 432-RUOA; and 

432-RUOT) and 

20 WSP (432-RUOO)

5.33E-1 0.000001 25 15 3.56E-6 2.11E6

Lawn 3FL

(72155-IO)

7.06E-1 0.000001 25 15 4.71E-6 1.59E6

1. SR0 (soil residue) = AR(lb ai/A) x F(1) x (1-D)0x 0.67 x (4.54x108μg/lg)x (2.47 x 10-8 A/cm2)

2. Dose (mg/kg/day) = SR0 (μg/g) x IgR (mg/day) x CF1 (g/μg)/BW (kg)

3. MOE = NOAEL (7.5 mg/kg/day)/ Dose (mg/kg/day)

6.2.3.4 Episodic Ingestion of Granules

This scenario was assessed using the Residential SOP and provides a standard method for 

estimating postapplication exposure among young children (3 to 6 years of age) from incidental 

ingestion of pesticide granules. The episodic oral MOE for incidental ingestion of granules is

5,000 and therefore is not of concern to HED. Table 6.2.3.4 provides a summary or exposure 

risk.
Page 32 of 52

Table 6.2.3.4: Postapplication Exposure and Risk for Incidental Ingestion of Granules

Scenario IgR 

(g/day)

F CF1 

(mg/g)

Dose a

(mg/kg/day)

MOEb

Lawn 3FL Granule Reg No 72155-OR 0.3 0.0005 1000 0.001 5,000

a. Dose = IgR x F x CF1  BW

b. MOE = acute dietary NOAEL (50 mg/kg/day)/Dose 

Ingestion of granules is considered an episodic event and not a routine behavior. Because HED 

does not believe that this would occur on a regular basis, our concern for human health is related 

to acute poisoning (thus using the acute dietary endpoint) rather than short -term residue 

exposure. It should also be noted that the proposed label does indicate that granules should be 

watered in for proper activation. Watering in granules could further reduce the availability of 

granules to be potentially ingested.

6.3 Combined Residential Risk Estimates

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

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

population. In evaluating combined residential uses of indaziflam, HED reviewed all nondietary sources of exposure which consisted of 1.) adult dermal and inhalation handler (lawns 

only) exposure, 2.) adult and child dermal postapplication exposure and 3.) child postapplication 

oral exposures. The oral postapplication exposure resulted from hand-to-mouth exposure only, 

since it represents the worst case of oral exposure. To include exposure from object-to-mouth 

and soil ingestion in addition to hand-to-mouth could result in a very conservative estimation of 

exposure as it would overestimate the potential of oral exposure. Similarly, HED does not 

generally combine adult handler and dermal postapplication exposure as it would result in an 

over estimate of exposure. Table 6.3 identifies the combined residential scenarios and MOEs for 

children simply for use in performing an aggregate exposure assessment in the indaziflam human 

health risk assessment. There are no risks of concern 

Table 6.3: Combined Residential Exposure and Risk 

Product Use Site Handler 

Total

MOE 1

Post-application 

Dermal MOE 2

Hand-to-Mouth 

MOE 3

Combined 

MOE 4

Adult 

Lawn 3FL Concentrate 

/Ready to spray

72155-IO

Lawns, 

hardscapes 

and 

ornamentals

3,000 4,700 NA NA

Child

Lawn 3 FL (72155-IO) Lawns, 

hardscapes 

and 

ornamentals

NA 2,800 5,300 1,800

1. See Table 4.1.2: Indaziflam Residential Handler Exposure and Risk (Hand Held Pump)

2. See Table 4.2.2a Dermal Postapplication Exposure and Risk (DFR data)

3. See Table 4.2.3 Hand-To-Mouth Exposure and Risk

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

Child Combinded MOE = NOAEL (7.5 mg/kg/day)/dermal postapplication dose (0.00266) + HTM dose (1.41E-3)
Page 33 of 52

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

exposure to treated turf because HED considers it unlikely that these exposures would co-occur.

7.0 Combined Risk Assessments and Risk Characterization

HED conducted screening level combined risk estimates for short-term exposure durations to 

ensure that residential and drinking water exposure would not exceed HED’s level of concern. 

In conducting these estimates for indaziflam, HED combined risk values resulting from drinking 

water and residential scenarios. 

To estimate short-term combined risk, HED combined the chronic dietary (water) exposures (as 

a measure of average dietary exposure) with the short-term residential exposure. HED does not 

generally combine adult handler and dermal postapplication exposure as it would result in an 

over estimate of exposure. All short-term combined exposures resulted in MOEs greater than 100 

for all populations and are not of concern. Short-term risks are summarized in Table 7 below.

Table 7: Short-Term Combined Risk Calculations

Population LOC for 

Aggregate

Risk1

MOE

drinking 

water2

MOE

Total 

Handler 3

MOE 

Dermal 

Postapplication 4

MOE 

Oral 5

Combined MOE

(drinking water + 

residential) 6

US Population 100 3700 3,000 4,700 NA 1700

Child (3-6 yrs) 100 2500 NA 2,800 5,300 1100

1 see Table 3.5.8 - basis for the LOC.

2 MOE drinking water = See Table 5.2

3 MOE total handler = See Table 6.1.2

4. MOE dermal postapplication = See Table 

5 MOE oral = See Table 6.2.1 Hand-To-Mouth Exposure and Risk

6. Adult Combined MOE = (drinking water +total handler) = ____________1________ 

1/MOE w + 1/MOEIH 

5 Child Combined MOE = (drinking water + dermal postapplication + oral postapplication) = ____________1________

1/MOE w + 1/MOED + /MOEO 

8.0 Cumulative Risk Characterization/Assessment

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

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

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

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

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

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

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

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

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

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

individual exposure levels to the other substances are also considered safe.
Page 34 of 52

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, Draft). However, HED determined 

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

reasons: 1) The structure 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 and this effect only

occurred at higher doses compared to DACT. 

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

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

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

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

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

mechanism of toxicity with other substances.

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

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

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

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

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

9.0 Occupational Exposure/Risk Pathway

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

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

The proposed use of indaziflam is for control of many annual grasses and broadleaf weeds in turf 

(lawns, sod farms, golf courses, recreational fields, etc), ornamentals and trees. It is also 

proposed for use as a pre-emergent herbicide for weed control in parks, rail roads, utility, 

industrial and municipal sites. Indaziflam is available for use by commercial and professional 

applicators (formulated as a water soluble packet and turf fertilizers). Therefore, the potential for 

occupational handler and postapplication exposure does exist. Based on the proposed uses, 

exposures to indaziflam are anticipated to occur for short- and intermediate-term durations.
Page 35 of 52

9.1 Handler Risk

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

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

available in the PHED (v. 1.1, 1998) and from the ORETF data. Table 9.1 presents the 

estimated risks for workers based on the short- and intermediate-term dermal, inhalation, and 

total exposures at baseline levels and in few cases the additional use of gloves with the exception 

of aerial application which included engineering controls. Short- and intermediate-term risks for 

handlers are not of concern (i.e., MOEs are above 100) and resulted in MOEs ranging from 100 

to 840,000. HED used standard assumptions with respect to body weight, areas treated, and use 

of maximum application rates in assessing occupational exposure.
Page 36 of 52

Table 9.1. Occupational Handler Exposures and Risks

Exposure Scenario and 

Product

Target 

site 

Application 

Ratea

Area 

Treated b

Dermal 

Unit 

Exposure

(mg/lb)

Inhalation 

Unit 

Exposure

(mg/lb)

Dermal 

Dose c

(mg/kg/day)

Dermal 

MOE d

Inhalation 

Dose c 

(mg/kg/day)

Inhalation 

MOE d

Total 

MOE g

Mixer/Loader

Liquids for Aerial 

Applications (PHED) 

Esplanade F

forestry

0.125 lb ai/A 1200 A

0.023

single layer/

gloves

0.0012 

0.003598 2100 0.002571 2900 1200

Liquids for Ground 

Applications (PHED)

Esplanade F

forestry 0.125 lb ai/A 200 A 0.0006 13,000 0.000429 10,000 7,300

Liquids for

Ground, and Right-ofWay, Applications 

(PHED)

Esplanade 200SC

non-crop 

areas * 

0.089 lb ai/A 25 A 2.9 0.00673 1100 3.81E-5 196,000 1100

Water Soluble Packets

Ground Applications 

(PHED)

BCS-AA10717

20 WSP

Non-crop 

areas, turf 

grass, 

nurseries, 

landscapes

0.071 lb ai/A 

(non-crop)

5 A

0.021 0.00024 

7.77E-6 960,000 1.22E-6 6,000,000 830,000

Golf course 

and fields 

grown for 

ornamentals

40 A 6.22E-5 120,000 9.74E-6 770,000 100,000

sod farm 

and ,

Christmas 

tree farms

80 A 0.000124 60,000 1.95E-5 390,000 52,000

forestry 0.088 lb ai/A 200 A 0.000385 19,000 0.000060E-5 120,000 17,000

Loading Granulars 

for Tractor Drawn 

Spreader Applications 

(PHED)

BCS-AA10717 plus turf 

fertilizer (0.0142%, 

0.0213%, and 0.0284%)

Lawns, 

recreational 

fields and 

parks

0.071 lb ai/A

5 A

0.0084 0.0017 

3.11E-6 2,400,000 8.62E-6 870,000 640,000

golf course

40 A 2.49E-5 300,000 6.9E-5 100,000 80,000

sod farm

80 A 4.98E-5 150,000 0.000138 54,000 40,000

Applicators
Page 37 of 52

Table 9.1. Occupational Handler Exposures and Risks

Exposure Scenario and 

Product

Target 

site 

Application 

Ratea

Area 

Treated b

Dermal 

Unit 

Exposure

(mg/lb)

Inhalation 

Unit 

Exposure

(mg/lb)

Dermal 

Dose c

(mg/kg/day)

Dermal 

MOE d

Inhalation 

Dose c 

(mg/kg/day)

Inhalation 

MOE d

Total 

MOE g

Applying Sprays via 

Aerial Equipment 

(PHED)

forestry 0.125 lb ai/A

Esplanade F

1200 A 0.005

Eng controlf

0.000068

Eng controlf

0.00078 9,600 0.000146 51,000 8,100

Applying Sprays via 

Groundboom Equipment 

(PHED)

forestry

0.125 lb ai/A

Esplanade F

200 A

0.014 0.00074 

0.000365 21,000 0.000264 28,000 12,000

0.088 lb ai/A

BCSAA10717

20 WSP

0.000257 30,000 0.000186 40,000 17,000

non-crop 

areas * 

0.089 lb ai/A

Esplanade 

200SC

40 A 0.000052 140,000 3.76E-5 200,000 84,000

Non-crop 

sites, turf 

and 

recreation 

fields 0.071 lb ai/A 

BCSAA10717

20 WSP

5 A 0.00000518 1,400,000 3.75E-6 2,000,000 840,000

Golf course 

and field 

grown for 

ornamentals 

and 

nurseries

40 A 0.0000415 180,000 3.0E-5 250,000 100,000

Sod and 

Christmas 

tree farms,

80 A 0.0000829 90,000 6.0E-5 120,000 52,000

Applying Sprays via 

Right-of-Way 

Equipment (PHED)

non-crop 

areas *

0.089 lb ai/A

Esplanade 

200SC

25 A 0.0039 0.0000325 230,000 0.000124 60,000 48,000

Applying Granules using 

Solid Broadcast 

Spreader (PHED)

Lawns, turf, 

sports and 

recreation 

parks

0.071 lb ai/A

BCSAA10717 plus 

turf fertilizer 

(0.0142%, 

0.0213%, and 

0.0284%)

5 A

0.0099 0.0063

0.00000367 2,000,000 0.000032 230,000 210,000

golf courses 40 A 0.0000293 260,000 0.000256 29,000 26,000

sod farms 80 A .0000586 130,000 0.00051 15,000 13,000
Page 38 of 52

Table 9.1. Occupational Handler Exposures and Risks

Exposure Scenario and 

Product

Target 

site 

Application 

Ratea

Area 

Treated b

Dermal 

Unit 

Exposure

(mg/lb)

Inhalation 

Unit 

Exposure

(mg/lb)

Dermal 

Dose c

(mg/kg/day)

Dermal 

MOE d

Inhalation 

Dose c 

(mg/kg/day)

Inhalation 

MOE d

Total 

MOE g

LCO Push Cyclone 

Granular Spreader 

(OMA001)ORETF

Lawns, turf, 

sports and 

recreation 

parks

0.071 lb ai/A

5 A

0.35 0.0073

0.00013 56,000 0.000037 200,000 45,000

golf courses 40 A 0.0010 7,200 0.000296 25,000 5,600

sod farms 80 A 0.0020 3,600 0.00532 12,000 2,800

Belly Grinder (PHED)

Lawns, turf, 

sports and 

recreation 

parks

1 A 10 0.062 0.00074 10,000 6.29E-5 120,000 9,300

Flaggers

Flagging for Aerial 

Sprays Applications 

(PHED)

Esplanade F

forestry 0.125 lb ai/A 350 A 0.011 0.00035 0.00050 15,000 0.000219 34,000 10,000

Mixer/Loader/Applicator

Mixing/Loading/ 

Applying Liquids with 

Low Pressure Handwand 

(PHED)

Forestry

Esplanade 

F

0.125 lb ai/A 5 A 100

0.03

0.0652 120 0.000268 28,000 110

0.0248

lb ai/gal

40 gals 0.43

0.000445 17,000 0.000425 18,000 8,600

non-crop 

areas *

Esplanade 

200SC

0.089 lb ai/A 5 A

100

0.0464 160 0.000191 39,000 160

0.0178 lb 

ai/gal

40 gals

0.07425 100 0.000305 25,000 100

Mixing/Loading/ 

Applying Liquids with 

Back Pack

(PHED)

Forestry

Esplanade 

F

0.125 lb ai/A 5 A

2.5

0.00163 4600 0.000268 28,000 4,000

0.0248 40 gals

0.00258 3,000 0.000425 18,000 2,500

non-crop 

areas*

Esplanade 

200SC

0.089 lb ai/A 5 A 0.00116 6,500 0.000191 39,000 5,600

0.0178 lb ai/A 40 gals 0.00185 4,000 0.000305 25,000 3,500
Page 39 of 52

Table 9.1. Occupational Handler Exposures and Risks

Exposure Scenario and 

Product

Target 

site 

Application 

Ratea

Area 

Treated b

Dermal 

Unit 

Exposure

(mg/lb)

Inhalation 

Unit 

Exposure

(mg/lb)

Dermal 

Dose c

(mg/kg/day)

Dermal 

MOE d

Inhalation 

Dose c 

(mg/kg/day)

Inhalation 

MOE d

Total 

MOE g

Mixing/Loading/ 

Applying Liquid 

Concentrates with a 

Handgun Sprayer (LCO 

ORETF)

Non-crop 

sites, turf, 

recreation 

fields, 

Christmas 

tree farms, 

ornamentals 

and 

nurseries

0.071

BCS-A10717

20 WSP

5 A

0.64 0.0072 0.000237 32,000 0.0000365 200,000 27,000

0.089

Esplanade 

200SC 0.45 0.0018 0.000209 36,000 0.000014E-5 650,000 34,000

a Application rates = maximum application rates from labels.

b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” industry sources, and 

HED estimates.

c Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x %Absorption (7.3% dermal and 100% inhalation) / Body weight (70 kg). 

d MOE = NOAEL (7.5 mg/kg/day) / Dose (mg/kg/day) 

e All scenarios were run at Baseline (dermal - single layer clothing; Inhalation - no respirator) unless otherwise specified.

f. Eng Con: Engineering control is enclosed cab, or enclosed cockpit.

g. Total MOE = NOAEL (7.5 mg/kg/day) / Dermal Dose + Inhalation Dose (mg/kg/day)

*non crop areas = rail road yards, roadsides, ornamental and perennial plantings, fence rows, utilities, hardscapes, industrial, municipal and government site
Page 40 of 52

9.2 Occupational/Commercial Postapplication Exposure 

9.2.1 Postapplicatin Inhalation Exposure

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

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

vapor pressure (vapor pressure less than 1 x 10-10 mmHg), it is applied at low application rates 

(maximum rates range from 0.089 - 0.125 lbs ai/A depending on use site), and except for forestry

uses, it is not projected to be applied via typically high inhalation exposure application 

equipment (e.g., airblast and aerial equipment). However, volatilization of pesticides may be a 

potential source of postapplication inhalation exposure to individuals nearby to pesticide 

applications. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 

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

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

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

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

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

for indaziflam.

9.2.2 Postapplication Dermal Exposure

Exposures during postapplication activities were estimated using dermal transfer coefficients 

from the Science Advisory Council for Exposure Policy Number 3.1: Agricultural Transfer 

Coefficients, August 2000, and default assumptions (5% of application rate available as 

transferable residue). Since the short- and intermediate-term dermal endpoints are the same, 

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

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

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

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

short-term postapplication dermal exposures resulted in MOEs greater than 100 (ranging from 

3,400 to 110,000) and therefore were not of concern. Table 9.2.2 provides a summary of the 

postapplication exposures and risk for indaziflam.

Table 9.2.2: Postapplication Exposure and Risk for Indaziflam Using Default 

Assumptions 

Scenario Tc 1

(cm2/hr)

DAT 2 DFR 3 

(ug/cm2)

DOSE 4

(mg/kg/day)

MOE 5

Sod farm & Golf 

Course Mowing

500 0 0.016 0.000066 110,000

hand weeding &, 

transplant of turf

16,500 0 0.002 3,400
Page 41 of 52

Outdoor 

ornamentals

110 0 0.159 0.000145 51,000

Moving 

ornamentals in 

pots to trucks 

and reorganizing

400 0 0.001 14,000

Christmas Trees 

thinning

3000 0 0.016 0.00040 19,000

1. DAT = Days after treatment

2. DFR = Dislodgeable Foliar Residue = application rate (0.071 lb ai/A) x (1- daily dissipation rate) t x 4.54E8 ug/lb x 

24.7E-9 A/cm2 x % TTR (5% for turn and 2% for ornamentals) after initial treatment.

3. Dermal Dose = [TTR (ug/cm2) x Tc (cm2/hr) x 0.001 mg/ug x 8 hrs/day x 7.3%DA] ÷ body weight (70 kg)

4. MOE = NOAEL (7.5 mg/kg/day)/Dermal Dose 

Restricted Entry Interval

The restricted entry interval (REI) listed on proposed labels is based on the acute toxicity of the 

technical material. Indaziflam has low acute dermal toxicity (Toxicity Category III) and is not 

an ocular nor dermal irritant nor a dermal sensitizer (Category IV). Acute toxicity Category III 

and IV chemicals require a 12- hour REI. Furthermore, all short -term postapplication dermal 

exposures resulted in MOEs greater than the level of concern (MOE>100) and therefore were not 

of concern. Therefore the 12-hour REI which appears on the proposed labels is adequate and not 

of concern to HED.

10.0 Data Needs and Label Recommendations

10.1 Toxicology

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

for indaziflam was assessed using an oral toxicity study. The Agency sought expert advice and 

input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity

studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide 

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

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

The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine 

and develop new policies and procedures for conducting inhalation risk assessments, including 

route to route extrapolation of toxicity data. If any new policies or procedures are developed, the 

Agency may revisit the need for an inhalation toxicity study for indaziflam and/or a reexamination of the inhalation toxicity risk assessment.

10.2 Residue Chemistry

None

10.3 Occupational and Residential Exposure

None
Page 42 of 52

References:

1. Indaziflam: Occupational/Residential Exposure Assessment for Use of Indaziflam on 

on Turf, Golf Courses, Sod Farms, Christmas Tree Farms, Non-Crop Areas and Forestry

(M.Collantes, D372538; February 2010)

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

Indaziflam; Rueben Baris; D356141; and D367447; February 2, 2010.
Page 43 of 52

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for turf and food use for indaziflam are shown below in Table 1. Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical Indaziflam

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21/28-Day Dermal .........................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes1

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5550 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen).....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotox. Screening Battery (rat) .......................

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

870.6300 Develop. Neuro..............................................................

no

no

yes

yes

yes

--

--

yes

yes

yes

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity...............................................

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

--

--

--

1 Satisfied by 870.4300.
Page 44 of 52

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Indaziflam technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - rat 47443281 LD50 > 2000 mg/kg 

(both sexes)

III

870.1200 Acute dermal - rabbit 47443282 LD50 > 2000 mg/kg 

(both sexes)

III

870.1300 Acute inhalation - rat 47443283 LC50 > 2.3 mg/L 

(both sexes)

IV

870.2400 Acute eye irritation - rabbit 47443284 Non-irritant IV

870.2500 Acute dermal irritation - rabbit 47443285 Non-irritant IV

870.2600 Skin sensitization - guinea pig 47443286 Not a sensitizer 

(Buehler method)

N/A
Page 45 of 52

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

47443287 (2005)

Acceptable/Guideline

0, 200, 5000 or 10,000 

ppm in diet for 13 weeks

M: 0, 14, 338 or 689 

mg/kg/day

F: 0, 16, 410 or 806 

mg/kg/day

98.7% a.i.

NOAEL = 14/410 mg/kg/day M/F

LOAEL = 338/806 mg/kg/day M/F, based on: 

in males at 338 mg/kg/day, increased TSH at 

Week 3 and diffuse thyroid follicular cell 

hypertrophy at Week 13; in females at 806 

mg/kg/day, mortality (one female, sacrificed in 

extremis with clinical signs, decreased motor 

activity and gastric red foci), marginally 

decreased body weights and decreased food 

consumption. 

870.3100 90-Day oral 

toxicity (mouse)

47443288 (2005)

Acceptable/Guideline 

0, 100, 500 or 1200 ppm 

in diet for 13 weeks

M: 0, 19, 91 or 218 

mg/kg/day; 

F: 0, 23, 118 or 256 

mg/kg/day

96.5% a.i.

NOAEL = 91/118 mg/kg/day M/F

LOAEL = 218/256 mg/kg/day M/F, based on 

increased mortality and wasted appearance 

(females), hunched posture in males and 

females, decreased body weight/weight gain 

and food consumption in males and females.

870.3150 90-Day oral 

toxicity (dog)

47443289 (2008)

Acceptable/Guideline

0, 7.5, 15 or 30 mg/kg/day 

by gavage

94.5-99.4% a.i.

NOAEL = 7.5 mg/kg/day M/F

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

degeneration in the brain, spinal cord and 

sciatic nerve in males and females. At 30 

mg/kg/day, 3 animals were sacrificed with 

seizures by Day 30; all remaining group 

animals were sacrificed on Day 36. Decreased 

body weight gain and neuropathology were 

observed.

870.3200 28-Day dermal 

toxicity (rat)

47443290 (2006)

Acceptable/Guideline

0, 40, 200 or 1000 

mg/kg/day applied to skin 

5 days/week for 4 weeks 

(22/23 total applications 

in M/F)

90.32% a.i.

Systemic NOAEL = 1000 mg/kg/day

LOAEL = not determined (>1000 mg/kg/day)

Local dermal NOAEL = 1000 mg/kg/day

LOAEL = not determined (>1000 mg/kg/day). 

Some indication of local dermal irritation was 

observed at all doses but the findings were 

transient and observed only in females, and 

therefore were not considered adverse.

870.3700a Prenatal 

developmental in 

(rat)

47443291 (2006)

Acceptable/Guideline

0, 10, 25 or 200 

mg/kg/day by gavage in 

0.5% aqueous 

methylcellulose, GD 6 

through 20

Maternal NOAEL = 25 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased 

body weight gain and food consumption. 

Developmental NOAEL = 25 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased 

fetal body weights.
Page 46 of 52

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

94.5% a.i.

870.3700b Prenatal 

developmental in 

(rabbit)

47443292 (2008)

Acceptable/Guideline

0, 10, 25 or 60 mg/kg/day 

by gavage in 0.5% 

aqueous methylcellulose, 

GD 6 through 28

93.14% a.i.

Maternal NOAEL = 25 mg/kg/day

LOAEL = 60 mg/kg/day based on decreased 

maternal body weight gain and food 

consumption and macroscopic changes in the 

liver in one doe.

Developmental NOAEL = 60 mg/kg/day

LOAEL = not established (>60 mg/kg/day).

870.3800 Reproduction and 

fertility effects

(rat)

47443293 (2008)

Acceptable/Guideline

0, 150, 1000 or 8000 ppm 

in the diet; F1 high dose 

reduced to 4000 ppm at 5-

17 days’ postweaning

Average P/F1

consumption (note: high 

dose not averaged due to 

F1 dose reduction)

M: 0, 10.4, 69.3 or 560.1 

mg/kg/day (P males) and 

317.6 mg/kg/day (F1

males, due to reduction in 

dietary dose)

F: 0, 12.9, 85.2 or 656.2 

mg/kg/day (P females) 

and 355.2 mg/kg/day (F1

females, due to reduction 

in dietary dose)

93.14-94.5% a.i.

Parental NOAEL = 69.3/85.2 mg/kg/day M/F

LOAEL = 560.1/656.2 mg/kg/day M/F, based 

on coarse tremors in females from Weeks 6-17 

and in gestation and lactation, decreased body 

weight/weight gain and food consumption and 

renal toxicity (tubular degeneration/ 

regeneration and increased weight) in males.

Offspring NOAEL = 69.3/85.2 mg/kg/day M/F

LOAEL = 317.6/355.2 mg/kg/day M/F, based 

on clinical signs (perianal, urine or nasal 

staining, diarrhea or soft stool, distended 

abdomen, weakness, tremors, myoclonus, 

increased activity and reactivity) and decreased 

pup body weights throughout postnatal period.

Reproductive NOAEL = 69.3/85.2 mg/kg/day 

M/F (based on F1 intakes)

LOAEL = 317.6/355.2 mg/kg/day M/F, based 

on delayed sexual maturation in males and 

females (% pups reaching criterion unaffected).

870.4100a Chronic toxicity

(rat)

47443296 (2007)

Acceptable/Guideline

0, 300, 3000 or 10,000 

ppm in the diet (6000 in 

females after Day 280)

equivalent to average 

daily intake of

M: 0, 14, 136 or 474 

mg/kg/day;

F: 0, 19, 185 or 589 

mg/kg/day

93.14% a.i.

NOAEL = 19 mg/kg/day F, 136 mg/kg/day M;

LOAEL = 185 mg/kg/day F, based on increased 

mortality, clinical signs of toxicity, mydriasis 

and absence of papillary reflex; 474 mg/kg/day 

M, based on decreased body weight/weight 

gain and food consumption.

870.4100b Chronic toxicity 

(dog)

47443294 (2008; main 

study);47443295 (2007; 

dietary stability)

NOAEL = 2.0 mg/kg/day

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

degeneration of nerve fibers in the brain, spinal 

cord and sciatic nerve in males and females. 
Page 47 of 52

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Acceptable/Guideline

0, 60, 225 or 450 ppm in 

the diet

M: 0, 2, 6 or 12 

mg/kg/day;

F: 0, 2, 7 or 11 

mg/kg/day

93.16% a.i.

Marginal body weight decreases early in study 

seen at 12/11 mg/kg/day M/F.

870.4200a Carcinogenicity

(rat) See 870.4300, below

870.4200b Carcinogenicity

(mouse)

47743416 (2008)

Acceptable/Guideline

0, 50, 250 or 1000 ppm in 

diet

M: 0, 6.8, 34 or 142 

mg/kg/day;

F: 0, 8.4, 42 or 168 

mg/kg/day

93.14% a.i.

NOAEL = 34/42 mg/kg/day M/F

LOAEL = 142/168 mg/kg/day M/F, based on 

decreased body weight/weight gain and food 

consumption, M/F; renal and hepatotoxicity in 

males; stomach and ovarian toxicity in females. 

No evidence of carcinogenicity

870.4300 Combined 

carcinogenicity/ 

chronic toxicity 

(rat)

47743417 (2009)

Acceptable/Guideline

0, 300, 3000 or 10,000 

ppm in the diet

M: 0, 12, 118 or 414 

mg/kg/day;

F: 0, 17, 167 or 452 

mg/kg/day

93.14% a.i.

NOAEL = 12/17 mg/kg/day M/F

LOAEL = 118/167 mg/kg/day M/F, based on 

decreased body weight/weight gain, signs of 

neurotoxicity (various symptoms, including 

dilated pupils, tremors, limb/movement effects, 

reduced activity/alertness) and renal toxicity in 

females, liver toxicity in males and females and 

atrophic seminal vesicles and increased TSH 

(Week 3 only) and thyroid colloid alteration in 

males. Thyroid alterations in males appeared to 

be secondary to liver effects. Decreased 

survival was observed at 452 mg/kg/day in 

females and both males and females showed 

more pronounced clinical signs of toxicity.

No evidence of carcinogenicity

Gene 

Mutation

870.5100

Bacterial reverse 

gene mutation 

assay (S. 

typhimurium)

47443297 (2006)

Acceptable/Guideline

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate in 

presence or absence of S9 

activation. Trial 1 – plate 

incorporation method and 

Trial 2, pre-incubation 

method

90.32% a.i.

Negative +/-S9 activation in S. typhimurium

strains TA98, TA100, TA 102, TA1535, 

TA1537 for increased frequency of revertant 

colonies up to cytotoxic (500 μg/plate) and 

precipitating concentrations (5000 μg/plate).
Page 48 of 52

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Gene 

Mutation

870.5100

Bacterial reverse 

gene mutation 

assay (S. 

typhimurium)

47443301 (2007)

Acceptable/Guideline

Trial 1: 0, 15, 50, 158, 

500, 1502 or 5000 

μg/plate in the presence or 

absence of S9 activation, 

plate-incorporation 

method

Trial 2: 0, 100, 200, 400, 

800, 1600 or 3200 

μg/plate in the presence or 

absence of S9 activation, 

pre-incubation method

95.7% a.i.

Negative +/-S9 activation in S. typhimurium 

strains TA98, TA100, TA102, TA1535, 

TA1537 for increased frequency of revertant 

colonies up to cytotoxic (≥800 μg/plate) and 

precipitating (3200 μg/plate) concentrations.

Gene 

Mutation 

870.5300

Mammalian cell 

in vitro forward 

gene mutation 

(cultured V79 

cells, HGPRT 

locus)

47443302 (2006)

Acceptable/Guideline 

0, 10, 100 or 1000 μg/mL 

in presence or absence of 

S9 activation

90.32% a.i.

Negative for increased frequency of mutation 

in CHO cells (not cytotoxic).

Cytogenetics 

870.5375

Mammalian in 

vitro cytogenetic 

assay (Chinese 

hamster V79 lung 

cells)

47443305 (2006)

Acceptable/Guideline

4 hr exposure, 14 hr 

recovery period: 0, 15, 

30, 60, 90 or 120 μg/mL 

in the absence of S9 

activation; 0, 50, 100, 

160, 200 and 240 μg/mL 

in the presence of S9 

activation.

4 hr exposure, 26 hr 

recovery period: 0, 60, 90 

and 120 in the absence of 

S9 activation; 0, 160, 200 

and 240 μg/mL 

18 hr exposure, no 

recovery period in the 

absence of S9 activation: 

0, 4, 8, 16, 20 and 24 

μg/mL 

90.32% a.i.

Negative for induction of chromosomal 

aberrations above background in the presence 

or absence of S9 metabolic activation. Tested 

up to the limit of solubility (160 μg/mL, -S9)

Cytogenetics 

870.5395

Mammalian in 

vivo micronucleus 

assay (mouse)

47443308 (2006)

Acceptable/Guideline

Two doses of 0, 10, 20 or 

Negative for induction of increased frequency 

of micronucleated polychromatic erythrocytes 

in bone marrow at any treatment time.
Page 49 of 52

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

40 mg/kg by IP injection 

in 0.5% aqueous 

Cremaphor vehicle 

administered 24 hrs apart; 

harvested 24 hrs after 

second dose

90.32% a.i.

870.6200a Acute 

neurotoxicity 

screening battery 

(rat)

47443310 (2008)

Acceptable/Guideline

0, 50, 100 or 2000 mg/kg 

by gavage in corn oil. 

Time of peak effect 

estimated at 50 min 

postdosing.

93.14% a.i.

NOAEL = 50 mg/kg

LOAEL = 100 mg/kg based on decreased 

motor and locomotor activity in females 

(threshold effect level). Lower 

NOAEL/LOAEL relative to subchronic study 

likely due to gavage vs. dietary administration.

870.6200b Subchronic 

neurotoxicity

screening battery 

(rat)

47443309 (2008)

Acceptable/Guideline

0, 200, 4000 or 

8000/10,000 ppm (M/F) 

equivalent to average 

daily intake in the diet of

M: 0, 12.2, 243.6 or 

585.7 mg/kg/day

F: 0, 15.1, 306.9 or 580.9 

mg/kg/day 

93.14% a.i.

NOAEL = 243.6/306.9 mg/kg/day M/F

LOAEL = 585.7/580.9 mg/kg/day M/F, based 

on decreased total session motor and locomotor 

activity in females, clinical signs/FOB effects 

in males and females (tremors, repetitive 

chewing motion and perianal and lacrimal 

staining), decreased body weights (females and 

cumulative body weight gain in males and 

females.

870.6300 Developmental 

neurotoxicity (rat)

47443311 (2008)

Acceptable/Nonguideline

0, 150, 1000 or 7000 ppm 

in the diet (high dose 

reduced to 4000 ppm on 

LD4) equivalent to 

average daily intake in the 

diet of

0, 13, 83.8 or 432 

mg/kg/day

93.14% a.i.

Maternal NOAEL = 83.8 mg/kg/day 

LOAEL = 432 mg/kg/day, based on clinical 

signs at daily observation and FOB assessment 

(coarse tremors, dilated pupils and dilated 

pupils unresponsive to penlight, nasal staining, 

repetitive chewing movements), decreased 

body weights/weight gain and reduced number 

of litters (-17%).

Offspring NOAEL = 83.8 mg/kg/day

LOAEL = 432 mg/kg/day, based on decreased 

body weight through PND 21 in males and 

females. Males postweaning had slightly 

decreased body weights. Decreased motor 

activity (-29%) on PND 21 in males was 

considered treatment-related, but was not seen 

at other measurement times nor in females. 

870.7485 Metabolism and 

pharmacokinetics

47443312 (2008)

Acceptable/Guideline

Absorption was complete (>90% 

bioavailability) and rapid, with radioactivity 
Page 50 of 52

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

(rat) – tier 1 Male rats given single 

gavage dose of either 14Cindane labeled or -triazine 

labeled indaziflam at 

11.5-14.98 mg/kg. Mass 

balance groups – excreta 

collected for 3 days 

postdosing. Bile-duct 

cannulated groups – bile 

and excreta collected for 2 

days postdosing. 

99-100% radiochemical 

purity

found in bile by 1 hr postdosing and most 

radioactivity (generally around 90%) excreted 

by 24 hrs. Tissue levels of radioactivity were 

low (0.2% of administered dose by 3 days) with 

highest levels observed in the GIT, liver, 

kidney, skin and thyroid. In the bile ductcannulated animals, tissue levels were about 2-

4 times greater in the triazine-labeled group 

than the indane-labeled group but levels in 

other groups were similar. Excretion was 

largely fecal (62-70%), with significant biliary 

excretion observed. CO2 exhalation was 

negligible. Parent compound was identified at 

between 2-16% of dose in urine and feces. 

Major routes of metabolism were oxidative 

pathways; glucuronide conjugation also 

observed. Major metabolite was carboxylic 

acid, found in urine, bile and feces. Numerous 

other metabolites identified or characterized; 

profile varied among dose groups. Other 

metabolites identified at low levels included the 

3-hydroxyindane acid epimer, diaminotriazine 

and 3-ketohydroxymethyl metabolites.

870.7485 Metabolism and 

pharmacokinetics 

(rat) – tier 2

47743418 (2009)

Acceptable/Guideline

Single gavage doses as 

follows: (1) low dose 

mass balance studies in 

females given 14C-indanelabelled indaziflam at 4.8 

mg/kg or 14-triazinelabelled indaziflam at 8.8 

mg/kg; (2) high dose mass 

balance studies in males 

given 14C-indane-labelled 

indaziflam at 559 mg/kg 

or 14-triazine-labelled 

indaziflam at 723 mg/kg; 

(3) plasma 

pharmacokinetic 

experiments with indanelabel at 2.9 mg/kg 

(females) or 13.7 mg/kg 

(males) or triazine-label at 

13.2 mg/kg (females) or 

16.3 mg/kg (males).

Radiochemical purity 

99%

Absorption was rapid (radioactivity detected in 

blood by 5 minutes and peak blood 

concentrations observed between 40-60-

minutes postdosing; rapidly decreasing 

thereafter) Females showed slightly higher 

absorption than males. Excretion was rapid 

(>87% by 24 hrs) and was equally distributed 

between urine and feces in females but was 

greater in feces in males (10:1). CO2 excretion 

was negligible. Radioactivity was not retained 

at significant levels in tissues; the GIT, liver 

and skin showed the highest residues. The 

carboxylic acid metabolite was the major 

metabolite in both high dose males and low

dose females, which was found in urine and 

feces. Additional metabolites present at >5% 

of dose included 3-hydroxyindane acid 

metabolite in low dose females, dihydroxy 

metabolite in low dose females and 

hydroxyethyl acid metabolite in the high dose 

males (indane-label).

870.7600 Dermal 47743420 (2008) Absorption was inversely proportional to dose, 
Page 51 of 52

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

absorption, in vivo 

(rat)

Acceptable/Guideline

0.5, 2 or 5000 μg ai/ cm2

on 12 cm2skin for 8 hrs to 

male rats; absorption 

evaluated after 8, 24, 72 

and 168 hr postdosing

Radiochemical purity 

>98% 

indicating saturation of skin penetration with 

increasing dose. Between 0.4-20.4% of the 

applied dose was recovered in combined 

residual carcass, excreta, blood and non-treated 

skin. Based on decreased radioactivity at the 

application site, the most conservative value for 

risk assessment is a dermal absorption of 42.7% 

observed at 0.5 μg ai/ cm2at 8 hr 

postapplication.

870.7800 Immunotoxicity -

rat

47443313 (2008)

Acceptable/Guideline

0, 300, 3000 or 6000 

(females) or 10,000/6000 

(males) ppm in the diet

equivalent to average 

daily intake in the diet of

M: 0, 27.7, 258 or 528 

mg/kg/day

F; 0, 31, 334.2 or 737.9 

mg/kg/day

93.12% a.i.

Systemic NOAEL = 258.8/334.2 mg/kg/day 

M/F

LOAEL = 528/737.9 mg/kg/day M/F, based on 

mortality (one male sacrificed in extremis), 

clinical signs of toxicity in males and females 

(including tremor, abnormal gait, pallor, 

hunched back), decreased food and water 

consumption in males and decreased body 

weight/weight gain in males and females.

Immunotoxicity NOAEL = 528/737.9 

mg/kg/day M/F

LOAEL = not established (>528/737.9 

mg/kg/day M/F)

NonguidelineIn vitro dermal 

absorption – rat 

and human skin

47743419 (2007)

Acceptable/Nonguideline

Application of a 10μL/ 

volume of concentrated 

500 mg/mL formulation 

and representative spray 

dilutions of 0.5, 0.2 or 1.0 

mg/mL to excised human 

and rat dermatomed skin. 

Exposure duration was 24 

hr.

Radiochemical purity 

>98%

Total absorbed dose decreased with increasing 

concentration, indicating saturation of skin 

penetration with increasing dose. Rat skin was 

3.8 to 10.7 times more permeable than human 

skin over 24 hr at the concentrations tested. 

Toxicity Profile - FDAT

Nonguideline 

Study

Sexual maturation 

supplemental study 

(rat)

47443314 (2008) 

Accetable/Nonguideline 0, 18.0, 

36.5, 72.9 or 145.8 mg/kg/day 

by gavage to LD21 offspring and 

timed-pregnant female Wistar 

rats: administered daily until 

PND 41

NOAEL = 36.5 mg/kg/day

LOAEL = 72.9 mg/kg/day, based on 

delays in vaginal patency (+2.3 days, 

increasing to 3.9 days at 145.8 

mg/kg/day). Also at high dose, body 

weight was decreased and salivation 

and urine staining were observed.
Page 52 of 52

Appendix B. Input Values for the Drinking Water Exposure Assessment

Filename: C:\Documents and Settings\mdoherty\My 

Documents\Chemistry Reviews\!DEEM Runs\Indaziflam\Indaziflam 

Water Acute.R98

Chemical: Indaziflam

RfD(Chronic): .02 mg/kg bw/day NOEL(Chronic): 2 mg/kg bw/day

RfD(Acute): .25 mg/kg bw/day NOEL(Acute): 25 mg/kg bw/day

Date created/last modified: 03-02-2010/12:04:17/8 

Program ver. 2.03

----------------------------------------------------------------

----------------

 EPA Crop Def Res 

Adj.Factors Comment

 Code Grp Commodity Name (ppm) #1 

#2 

-------- ---- ------------------------------- ---------- -----

- ------ -------

86010000 O Water, direct, all sources 0.084000 

1.000 1.000 

86020000 O Water, indirect, all sources 0.084000 

1.000 1.000 

Filename: C:\Documents and Settings\mdoherty\My 

Documents\Chemistry Reviews\!DEEM Runs\Indaziflam\Indaziflam 

Water Chronic.R98

Chemical: Indaziflam

RfD(Chronic): .02 mg/kg bw/day NOEL(Chronic): 2 mg/kg bw/day

RfD(Acute): .25 mg/kg bw/day NOEL(Acute): 25 mg/kg bw/day

Date created/last modified: 03-02-2010/12:04:44/8 

Program ver. 2.03

----------------------------------------------------------------

----------------

 EPA Crop Def Res 

Adj.Factors Comment

 Code Grp Commodity Name (ppm) #1 

#2 

-------- ---- ------------------------------- ---------- -----

- ------ -------

86010000 O Water, direct, all sources 0.026000 

1.000 1.000 

86020000 O Water, indirect, all sources 0.026000 1.000 1.000