Document ID: EPA-HQ-OPP-2009-0636-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-06-01T04:00Z

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.  

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc247605174 \h  4 

2.0	Ingredient Profile	  PAGEREF _Toc247605176 \h  6 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc247605177 \h  6 

2.2	Structure and Nomenclature	  PAGEREF _Toc247605178 \h  8 

2.3	Physical and Chemical
Properties…………………………………………………9

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc247605180 \h  10 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc247605181 \h
 10 

3.1.1	Database Summary	  PAGEREF _Toc247605182 \h  10 

3.1.1.1	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc247605183 \h  10 

3.1.2	Toxicological Effects	  PAGEREF _Toc247605185 \h  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……………………………………………………...1
8

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	  PAGEREF
_Toc247605194 \h  23 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc247605195 \h 
23 

5.1	Pesticide Metabolism and Degradates of Concern	  PAGEREF
_Toc247605196 \h  23 

5.1.1	Drinking Water Residue Profile	  PAGEREF _Toc247605197 \h  24 

5.2	Dietary Exposure and Risk	  PAGEREF _Toc247605198 \h  24 

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

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc247605199 \h  26 

6.1	Residential Handler Exposure	  PAGEREF _Toc247605200 \h  26 

6.2.	Residential Postapplication Exposure	28

	6.2.1    Inhalation Postapplication Exposures	28

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

6.2.3  Oral Postapplication Exposure	  PAGEREF _Toc247605205 \h  30 

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

7.0	Combined Risk Assessments and Risk Characterization	  PAGEREF
_Toc247605206 \h  33 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc247605212
\h  33 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc247605213 \h  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

 1.0	Executive Summary  TC \l1 "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.”  

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

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Since the proposed uses
of indaziflam are classified as non-food 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,
non-dietary 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  TC \l1 "2.0	Ingredient Profile 

2.1	Summary of Proposed Uses  TC \l2 "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 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

1 application

groundboom

backpack	0.125 lb ai/A or 0.0248 lb ai /gal

	BCS-AA10717

20 WSP (Water Soluble Packet)

	Annual grasses and weeds in turfgrass, golf courses, sod farms;
ornamentals, nurseries, Christmas trees, landscapes forestry, non-crop
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

BCS-AA10717

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

BCS-AA10717

0.0213% Plus Turf Fertilizer

(granule)

BCS-AA10717

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; pre-packed 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

Structure and Nomenclature

  TC \l2 "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-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl
]-

CAS registry number	730979-19-8

End-use product (EP)	Indaziflam 200 SC Herbicide

Indaziflam 500 SC Herbicide

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

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/cm3 at 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 10-8 PA at 20 °C or 1.875 x 10-10 mm Hg

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

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

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

	Dissociation constant (pKa)	3.5 

	Octanol/water partition coefficient  Log (KOW)	pH 2: 2.0

pH4, pH7 and pH9: 2.8

	UV/visible absorption spectrum methanol (nm)	(max1 = 213 nm / A = 1.428

(max2 = 268 nm / A = 0.197

(max3 = 291 nm / A = 0.019

	

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

3.1.1	Database Summary  TC \l3 "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;   HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html" 
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  TC \l4 "3.1.1.2
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  TC \l3 "3.1.2	Toxicological Effects 

The nervous system is a target for toxicity in rats and dogs.  In
repeated-dose studies, the dog was the more sensitive species, showing
the lowest NOAELs among all available studies, based on neuropathology
(degenerative nerve fibers in the brain, spinal cord and sciatic nerve).
 In the rat, focal/multifocal vacuolation of the median eminence of the
brain and the pituitary pars nervosa was observed at higher doses.  
Clinical signs of neurotoxicity were observed in both species in several
studies, which included rat adult and developmental neurotoxicity
studies, including the rat acute neurotoxicity study.  Ophthalmologic
effects were also seen in the rat.  In the developmental neurotoxicity
study, decreased motor activity was observed in 21-day old male pups but
was not observed in females at later times.  Additional details on
neurotoxic effects are found in Section 3.3.2.  

In the rat and mouse, effects on the kidney were observed following
chronic exposure.  Female rats had an increased incidence of dark kidney
and basophilic renal tubules. Males in the reproductive toxicity study
showed increased kidney weights and incidence of hyaline degeneration
and tubular regeneration.  In the mouse, males showed decreased kidney
weights and increased incidences of collecting duct and pelvic
epithelial hyperplasia, papillary necrosis and intratubular yellow-brown
material.   

Liver cell hypertrophy was observed in the rat following chronic
exposure but was considered an adaptive response.  In males, white foci
were also observed.  In females, livers were enlarged and showed an
increased incidence of macrovacuolation and multinucleated hepatocytes
with 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.
 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  TC \l3 "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 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)  TC \l2 "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  TC \l2 "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.

3.3.1	Adequacy of the Toxicity Database  TC \l3 "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 two-generation
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  TC \l3 "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.  

han 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 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. 

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.

Reproductive Toxicity Studies

(≥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  TC \l3 "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  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

3.3.6.1	   Determination of Susceptibility  TC \l4 "3.3.6.1
Determination of Susceptibility 

There was no evidence of increased susceptibility (qualitative or
quantitative) for pre- and/or postnatal effects in developmental
toxicity studies in the rat and rabbit, the rat developmental
neurotoxicity study or the rat two-generation reproductive toxicity
study.  There is no concern and there are no residual uncertainties for
qualitative or quantitative pre- and/or postnatal susceptibility to
indaziflam.  This is based on the completeness of the database, lack of
evidence of increased susceptibility, and the selection of endpoints
with low NOAELs that are adequately protective of potential
developmental effects.  Delayed sexual maturation in offspring was
observed at the highest dose of the reproductive toxicity study in the
presence of maternal toxicity.  Effects in offspring in the
developmental neurotoxicity study (decreased motor activity in males on
PND 21 were well characterized and were only observed at doses that
caused maternal neurotoxicity.  Although treatment-related thyroid
histological changes (following subchronic or chronic exposure) and
transiently increased TSH (at Week 3 but not Week 14) were observed in
male rats, they are not of concern for developmental effects because
they were only observed in the males, were observed at a high dose
relative to the selected regulatory endpoints, and appear to be
secondary to liver effects.  

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 post-natal exposure, showed only
marginal effects in offspring (slightly decreased motor activity,
absolute brain weight) at relatively high (and maternally toxic)  doses
and indicates that increased susceptibility does not occur.

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "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   TC \l3 "3.5.1	Acute Reference Dose
(aRfD) - 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)

  = 0.50 mg/kg

Comments about Study/Endpoint/Uncertainty Factors:   The selected NOAEL
of 50 mg/kg is from a study of the appropriate route and duration.  The
decreases in motor and locomotor activity are considered potential
single-dose effects because they were observed within the first hours
following dosing.  The endpoint is protective of the decreases in
maternal body weight gains seen within the first three days of exposure
in the developmental rat (25/200 mg/kg/day, NOAEL/LOAEL) and rabbit
(25/60 mg/kg/day, NOAEL/LOAEL) toxicity studies, but which were
considered questionable as an endpoint due to variability in the data. 
No other acute effects were observed in the database.  The endpoint is
also protective of potential developmental effects, based on the lack of
observed increased pre- and/or postnatal susceptibility and higher
LOAELs observed in developmental, reproductive, neurotoxicity,
developmental neurotoxicity and immunotoxicity studies.   Although the
rat developmental toxicity 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)

  TC \l3 "3.5.3	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)

  = 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) 

  TC \l3 "3.5.4	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  TC \l3 "3.5.5	Dermal Absorption 

In addition to a 28-day study evaluating dermal toxicity in the rat, an
in vivo dermal absorption study in the rat and in vitro dermal
absorption studies in the rat and human were submitted.   The data
demonstrated an inverse relationship between dosing concentration and
percent absorption.  Based on in vivo dermal absorption observed in the
rat and in vitro comparative rat:human absorption data, an estimated
human dermal absorption factor (DAF) of 7.3% was obtained.

The human DAF was calculated as follows (all absorption values adjusted
for recovery):  (1) in the rat in vivo dermal absorption study, 27.39%
of the applied dose was absorbed at 24 hrs postexposure (actual exposure
time 8 hrs) using an application of 0.0005 mg/cm2;  (2) in vitro
exposure of microtomed rat skin under the same exposure and assessment
conditions gave a dermal absorption of 22.40%;  (3) the ratio of the in
vitro to the in vivo absorption is 0.82 (22.4/27.39) and therefore is
close to 1, indicating that the in vitro data is predictive of in vivo
absorption; (4) based on this ratio, a DAF for humans may be calculated
using in 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%.

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.

Dermal Exposure (Long-Term, >1 year)

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

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

Study Selected:  Subchronic Toxicity-Dog

MRID No:  47743289

Dose and Endpoint for Risk Assessment:  NOAEL = 7.5 mg/kg/day, based on
degenerative brain, spinal cord and sciatic nerve fiber lesions at 15
mg/kg/day. 

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

Comments about Study/Endpoint/Uncertainty Factors:  The selected
endpoint is the most sensitive NOAEL available from a study of
appropriate exposure duration (90-days) 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.

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  TC \l3 "3.5.8	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  TC \l3 "3.5.9	Recommendation for Aggregate Exposure 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  TC \l3 "3.5.10
Classification of Carcinogenic Potential 

There was no evidence of carcinogenicity observed in the two-year
dietary rat or mouse carcinogenicity bioassays.  Genotoxicity studies
(reverse gene mutation in bacteria, forward gene mutation in mammalian
cells and in vitro and in vivo chromosomal aberration assays) were
negative.  Based on the lack of evidence of carcinogenicity or
genotoxicity, HED classified indaziflam as “Not likely to be
carcinogenic to humans.”

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, Short-term (1 to 30 days) and Intermediate-term (1 to 6
months)	NOAEL = 7.5 mg/kg/day	UFA=10X

UFH=10X

FQPA SF = 1X	Residential LOC for MOE = 100	 Subchronic oral (gavage) in
the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Dermal, Short-term (1 to 30 days) and Intermediate-term (1 to 6 months)
NOAEL = 7.5 mg/kg/day

DAF = 7.3%	UFA=10X

UFH=10X

FQPA SF = 1X	Residential LOC for MOE = 100	Subchronic oral (gavage) in
the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Dermal, Long-Term (>6 months)	Not required for this assessment (exposure
is seasonal; long-term occupational exposure scenarios are not
anticipated).

Inhalation, Short-term (1 to 30 days) and Intermediate-term (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, Short-Term (1 to 30 days) and Intermediate-term (1 to 6 months)
NOAEL = 7.5 mg/kg/day

DAF = 7.3%	UFA=10X

UFH=10X	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, Long-Term (>6 months)	Not required for this assessment (exposure
is seasonal; long-term occupational exposure scenarios are not
anticipated).

Inhalation Short-Term (1 to 30 days) and Intermediate-Term (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  TC \l2 "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
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 
TC \l1 "4.0	Public Health and Pesticide Epidemiology Data 

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

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

5.1	Pesticide Metabolism and Degradates of Concern   TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation 

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

5.1.1	Drinking Water Residue Profile TC \l3 "5.1.9	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, indaziflam-carboxylic 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 TC \l2 "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 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.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "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 TC \l2 "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. 

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)	 InhalationMOE f	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 (ORETF- OMA005)

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

Application Rate based on proposed labels

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

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

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

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.  

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 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 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 intermediate-term 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

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 tc \l3 "4.2.3  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)0 x 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)

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

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

Dose = GR 0 x IgR x CF1

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

SR0 (soil residue) = AR(lb ai/A) x F(1) x (1-D)0 x 0.67 x (4.54x108
µg/lg)x (2.47 x 10-8 A/cm2)

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

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.

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)	

MOE b

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 non-dietary
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

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

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

See Table 4.2.3 Hand-To-Mouth Exposure and Risk

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)

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  TC \l1 "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.  

 TC \l2 "7.2	Short-Term Combined Risk 

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  TC \l1 "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.

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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

9.0	Occupational Exposure/Risk Pathway  TC \l1 "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.

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.

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-of-Way, 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

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

BCS-AA10717

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 BCS-AA10717

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

BCS-AA10717 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

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

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	  SEQ CHAPTER \h \r 1 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

9.2	Occupational/Commercial Postapplication Exposure 

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.

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 intermediate-term 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

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  TC \l1 "10.0	Data Needs and
Label Recommendations 

     Toxicology  TC \l2 "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 re-examination of the inhalation toxicity
risk assessment.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

None

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure 

None

References:  TC \l1 "References: 

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)

Tier 2 Drinking Water Assessment for the Section 3 New Chemical
Registration of Indaziflam; Rueben Baris; D356141; and D367447; February
2, 2010.

Appendix A:	Toxicology Assessment  TC \l1 "Appendix A:	Toxicology
Assessment 

 A.1	Toxicology Data Requirements TC \l2 "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.

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

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

94.5% a.i.	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.

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)

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.	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. 
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).

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 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.	Negative for induction of increased frequency of
micronucleated polychromatic erythrocytes in bone marrow at any
treatment time.

870.6200a

	Acute neurotoxicity screening battery (rat)	47443310 (2008)

Acceptable/Guideline

0, 50, 100 or 2000 mg/kg by gavage in corn oil.  Time of peak effect
estimated at 50 min postdosing.

93.14% a.i.	NOAEL = 50 mg/kg

LOAEL = 100 mg/kg based on decreased motor and locomotor activity in
females (threshold effect level).  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

(rat) – tier 1	47443312 (2008)

Acceptable/Guideline

Male rats given single gavage dose of either 14C-indane labeled or
-triazine labeled indaziflam at 11.5-14.98 mg/kg.  Mass balance groups
– excreta collected for 3 days postdosing.  Bile-duct cannulated
groups – bile and excreta collected for 2 days postdosing.  

99-100% radiochemical purity	Absorption was complete (>90%
bioavailability) and rapid, with radioactivity found in bile by 1 hr
postdosing and most radioactivity (generally around 90%) excreted by 24
hrs. Tissue levels of radioactivity were low (0.2% of administered dose
by 3 days) with highest levels observed in the GIT, liver, kidney, skin
and thyroid.  In the bile duct-cannulated 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-indane-labelled indaziflam at 4.8 mg/kg or
14-triazine-labelled 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 indane-label 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 absorption, in vivo (rat)	47743420 (2008)

Acceptable/Guideline

0.5, 2 or 5000 µg ai/ cm2 on 12 cm2 skin for 8 hrs to male rats;
absorption evaluated after 8, 24, 72 and 168 hr postdosing

Radiochemical purity >98% 	Absorption was inversely proportional to
dose, indicating saturation of skin penetration with increasing dose. 
Between 0.4-20.4% of the applied dose was recovered in combined residual
carcass, excreta, blood and non-treated skin.  Based on decreased
radioactivity at the application site, the most conservative value for
risk assessment is a dermal absorption of 42.7% observed at 0.5 µg ai/
cm2 at 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)

Non-guideline	In 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.

  TC \l1 "Appendix A:	Toxicology Assessment 

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

------------------------------------------------------------------------
--------

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  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

 PAGE   

Page   PAGE  20  of   NUMPAGES  52