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

<IP_ADDRESS>	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

			<IP_ADDRESS>	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.

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data  TC \l4 "<IP_ADDRESS> 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

<IP_ADDRESS>	   Determination of Susceptibility  TC \l4 "<IP_ADDRESS> 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.

<IP_ADDRESS>	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 <IP_ADDRESS> provides a summary of the short-term HTM exposures.

Table <IP_ADDRESS>: 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)

<IP_ADDRESS>	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 <IP_ADDRESS> provides a summary of the object-to-mouth exposure and risk.

Table <IP_ADDRESS>: 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)

<IP_ADDRESS>	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 <IP_ADDRESS> provides a summary of the soil ingestion exposure and risk.

Table <IP_ADDRESS>:  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)

<IP_ADDRESS>	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 <IP_ADDRESS> provides a summary or exposure risk.

Table <IP_ADDRESS>: 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

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