### UNITED STATES ENVIRONMENTA L PROTECTION AGENCY WA SHINGTON, D.C. 20460
OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES 

### Date: April 1 3 , 2010 MEMORANDUM SUBJECT: Indaziflam : Human Health Risk Assessment for Use of Indaziflam on Turf,

Golf C ourses, Sod Farms, Christmas Tree Farms, Non
- Crop Areas and Forestry
. PC Code: 080818 DP Barcode: D3 5 6 142 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 Lev y Ph.D., Toxicologist Edward Scollon, Ph.D., Toxicologist Karl yn 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 assessm ent to estimate the risk to human health that will result from the proposed use of indaziflam on turf in both commercial and residential uses.

### Page 2 of 52 Table of Contents 1.0 Executive Summary
................................ ................................ ................................ .......... 4 2.0 Ingredient Profile
................................ ................................ ................................ .............. 6 2.1 Summary

of Registered/Proposed Uses
................................ ................................ .. 6 2.2 Structure and Nomenclature
................................ ................................ ................... 8 2.3 Phy sical and Chemical Properties......................................................... 9 3.0 Hazard Characterization/Assessm ent ................................ ................................ ........... 10 3.1 Hazard and Dose
- Response Characterization
................................ ....................... 10 3.1.1 Database Summary
................................ ................................ ................... 10 3.1.1.1 Mode of action, metabolism, toxicokinetic data
........................ 10 3.1.2 Toxicological Effects
................................ ................................ ................ 10 3.1.3 Dose
- Response................................................................ ....1 2 3. 2 Absorption, Distribution, Metabolism, Excretion (ADME) ..................................1 3 3.3 FQPA Considerations..................................................................... 1 3 3. 3 .1 Adequacy

of the Toxicity

Database
................................ .......................... 1 4 3. 3 .2 Evidence of Neurotoxicity
................................ ................................ ........ 1 4 3.3.3 Developmental Toxicity Studies.................................................1 5 3.3.4 Resproductive Toxicity Studies........................................ ........1 5 3.3.5 Additional Information from Iterature Sources......... ......................1 5 3. 3.6 Pre
- and/or Postnatal Toxicity
................................ ................................ ... 1 5 3.3.6.1 Determination of Susceptibility ........................................1 5 3. 4 FQPA Safety Factor for Infants and Children
................................ ......................... 1 6 3.5 Hazard Identification and Toxicity Endpoint Selection...............................1 6 3. 5.1 Acute Reference Dose............................................................1 6 3.5.2 Chronic Reference Dose.........................................................1 7 3.5.3 In cidental Oral Exposure.........................................................1 7 3.5.4 Dermal Absorption.................................................................1 7 3.5.5 Dermal Exposure..................................................................1 8 3.5.7 Inhalation Exposure...............................................................1 8 3.5.9 Level of Concern for Margin of Exposure
................................ ................ 1 9 3. 5.10 Recommendation for Combining Routes of Exposure ..............................1 9 3.5.11 Classification of Carcinogenic Potential.......................................1 9 3.5.12 Acute Toxicity
............... ................................................ ... 20 3.5.13 Summary

of Toxicological Doses and Endpoints for Use in Human Risk Assessment......................................................................... 20 3. 6 Endocrine disruption
................................ ................................ ............................. 22 4.0 Public Health and Pesticide Epidemiology Data
................................ .......................... 23 5.0 Dietary Exposure/Risk Characterization
................................ ................................ ..... 23 5.1 Pesticide Metabolism and D egradat es of Concern
................................ ............... 23 5.1. 1 Drinking Water Residue Profile
................................ ................................ 24 5.2 Dietary

Exposure and Risk
................................ ................................ ................... 24 5.2.1 Cancer Dietary

Risk...............................................................2 5 6.0 Residential (Non - Occupational) Exposure/Risk Characterization
............................ 26 6.1 Residential Handler Exposure
................................ ................................ ............... 26 6.2. Residential Postapplication Exposure
................................ ................................ ... 2 8

### Page 3 of 52 6.2.1 Inhalation Postapplication Exposures
................................ ....................... 2 8 6.2.2 Dermal Postapplication Exposure...............................................2 8 6.2.3 Oral Postapplication Exposure
................................ ................................ .... 30 6.3 Combined Residential Exposure
............ .............................................. 32 7.0 Combined Risk Assessments and Risk Characterization
................................ ............ 33 8.0 Cumulative Risk Characterization/Assessment
................................ ........................... 33 9.0 Occupational Exposure/Risk Pathway
................................ ................................ .......... 34 9. 1 Handler Risk
................................ ................................ ................................ ......... 35 9.2 Postapplication Exposure and Risk...................................................... 40 10.0 Data Needs and Label Recommendations
... ........................ .........................41 10.1 Toxicology
.................................................................................. 41 10.2 Residue Chemistry
......................................................................... 41 10.3 Occupati onal and Residential Exposure ................................................41 References:
................................ ................................ ................................ ................................ ... 42 Appendix A:Toxicology

Assessment
................................ ................................ ........................... 4 3 A. 1 Toxicology

Data Requirements.......................................................... 4 3 A.2 Toxicity Profiles
............................................................................ 4 4 Appendix B: Input Values for Drinking Water Expos ure Assessment.............................. 5 2

### Page 4 of 52

1.0 Executive Summary Indaziflam ([1, 3,5
- triazine
- 2,4
- diamine,N
- [(1R2S)
- 2,3
- dihydro
- 2,6
- dimethyl
- 1H
- inden
- 1
- yl ]
- 6
- (1
- fluroeth yl )]) is proposed as a s elective, 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 fo r 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 (formulat ed 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 currentl y 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 ty pes 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 require ment of a 28
- or 90
- day inhalation toxicity

study will be determined when the Agency has completed its review. The nervous s ys tem 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 b rain 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 h ypertroph y was observed in rats and females showed liver histopathology . Th yroid 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 incid ence of stomach erosions and blood
- filled ovarian cysts. Decreased body weight gains were generally observed in the available studies. No sy stemic toxicity was observed in a 28
- day

dermal toxicity

study in the rat. Based on the lack of evidence of carci nogenicity

or genotoxicity, HED classified indaziflam as “Not likely to be carcinogenic to humans.”

### Page 5 of 52

Although no food uses are associated with the current request, a food
- use petition has been received b y 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 onl y 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 s ymmetrical 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 inclu de 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 ethicall y 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 L o w - Income Populations, http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf
. As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups acc ording to well
- established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that

### Page 6 of 52

subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Since the proposed uses of indaziflam are classified as non
food uses and indaziflam is unlikely to contaminate drinking water, no dietary or drinking water exposure is expected for indaziflam. However, post
- a

pplication 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 by standers located in proximity to treated fields. Whenever appro priate, 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 exp osure pattern, an anal ys is of residential by stander inhalation exposure has been performed as part of the indaziflam risk assessment. This analy sis takes into account individuals who may live directl y next to a field/area treated with indaziflam as well a s 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 aggre gate exposure assessment will be protective of all potential exposed populations, including populations specificall y targeted for possible environmental justice concerns such as low income residents and minorities. The anal ys is also considers the potent ial 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 protectio n 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 by standers and farm workers, as well as, lifestyle and traditional dietary patterns among specific subgroups. To ensure that this risk assessment is consistent with scientific standards/policies under development, HED may refine the risk assessment components for all the registered uses in the future. 2.0 Ingredient Profile 2.1 Summary of Proposed Uses Indazi flam is a s elective, pre
- emergent and post
- emergent alkyl azine herbicide proposed for control of many annual grasses and broadleaf weeds in turf (lawns, sod farms, golf courses, recreational fields, etc), ornamentals and trees. It is also proposed for use as a pre - emergent herbicide for weed control in parks, railroads, utility , industrial and municipal sites. Indaziflam

### Page 7 of 52

is proposed for use b y commercial and professional applicators (formulated as a water
- soluble packet and turf fertilizers) as well as re sidential homeowners (formulated as L awn 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 ty pe 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., L awn 3 FL) contain additional active ingredients. This assessment only addresse s 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 pro vides a summary of the proposed use s . Table 2.1 : Proposed Commercial and Residential Products and Uses of Indaziflam Product EPA Reg. No. Use Site Application Me thod 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
- emerge nt 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

o r 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 h eld 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 w eeds

in turfgrass, (golf courses and sod farms; lawns, cemeteries) Tractor
- draw n 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

### Page 8 of 52

Table 2.1 : Proposed Commercial and Residential Products and Uses of Indaziflam Product EPA Reg. No. Use Site Application Me thod Application

Rate Comments 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 Pum p style tank sprayer 0.00063 lb ai/

gallon hose
- end sprayer conce ntrate; 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 mo nths Lawn 3FL Concentrate Ready to Use Trigger sprayer 0.00026 lb ai /gallon As needed



### 2.2 Structure and Nomenclature Table 2 .2 . IndaziflamNomenclature Com pound Chemical Structure

Common name Indaziflam (ISO proposed) Com pany experimental names AE 1170437, BCS
- AA10717 IUPAC name N
- [(1 R ,2 S )
- 2,6
- Dimethyl
- 2,3
- dihydro
- 1 H
- inden
- 1
- yl]
- 6
- [(1 R )
- 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 7 30979
- 19
- 8 End
- use product (EP) Indaziflam 200 SC Herbicide Indaziflam 500 SC Herbicide N N N N H N H 2

F C H 3 C H 3

C H 3

### Page 9 of 52

Table 2 .2 . IndaziflamNomenclature 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 AA1071 7 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 carbon s in the indaziflam structure, there are eight possible isomers for this herbicide. Based on the product chemistry review of the manufacturing use product (MUP) b y RD (H. Mukhoty, 12/1/2008, D356393), the registrant is declaring the active ingredient to c onsist of only isomers “A” (AE 1170437) and “B” (AE 1170438) with concentrations of about 92% and 3%, respectivel y. 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 i s 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 significantl y lower levels and are considered to be impurities. The batches used for dosing in the toxicology studies had >90% isomer A, about 1
- 3% isomer B, and negligible (<1%) levels of the remaining six isomers. These isomer contents are appropriate for the above described composition of indaziflam 2.3 Physical and Chemical Properties Table 2. 3 P hysicochemical Properties of Indaziflam(TGAI Unless Otherwise Noted) Parameter Value Reference Melting point/range 183
- 184 o C 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: 0.00 44 pH 9: 0.00 28 Distilled w ater (pH 6.6
- 6.9): 0.00 28 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 la w constant 2.69 x 10 - 6 [Pa x m3/mol] at 20 °C

### Page 10 of 52

Table 2. 3 P hysicochemical Properties of Indaziflam(TGAI Unless Otherwise Noted) Parameter Value Reference Dissociation constant (pKa) 3.5 Octanol/water partition coefficient Log (KOW) pH 2: 2.0 pH4, pH7 and pH9: 2.8 UV/visible abso rption spectrum methanol (nm)  max1 = 213 nm / A = 1.428  max2 = 268 nm / A = 0.197  max3 = 291 nm / A = 0.019 

### 3.0 Hazard Characterization/Assessment 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary Studies considered for this assessment included acute lethality (oral, dermal and inhalation routes); primary

eye and dermal irritation, dermal sens itization, 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 tw o - generation reproductive toxicity (with an additional special non
- guideline study evaluating sexual maturation in rats exposed during earl y development to the triazine
- ring metabolite BCS
- AA10365, or FDAT ), rat developmental neurotoxicity, rat immunotoxic ity, genotoxicity , rat general metabolism (Tier 1 and Tier 2), in vivo rat dermal absorption and in vitro human and rat dermal absorption. The database is considered complete with the possible exception of a 28 or 90
- day inhalation toxicity study in the rat. The Agency

is in the process of evaluating expert advice and input on issues related to volatilization of pesticides and route
- to - route extrapolation using oral studies for inhalation exposure assessment from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December, 2009 (final report of March 2, 2010; http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ) and determin ing the appropriate toxicity

data needed to assess inhalation exposure. The requirement of an inhalation toxicity study will be determined once scientific guidance and policies on inhalation toxicity have been established. 3.1.1.1 Mode of action, metab olism, 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 weed s by inhibiting cell wall biosy nthesis and affecting meristematic stem growth. The exact mode of toxicity in mammals is unknown. Metabolism in the rat is discussed below in Section 3.2. 3.1.2 Toxicological Effects The nervous s ys tem is a target for toxicity in rats and dogs . In repeated
- dose studies, the dog

### Page 11 of 52

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

(degenerative nerve fibers in the brain, spinal cord and sciatic nerve). In the rat, focal/multifocal vacuolation of the median eminence of the brain and the pituitary pars nervosa was observed at higher doses. Clinical signs of neurotoxicity were observed in both species in several studies, which included rat adult and developmental neurotoxicity studies, including the rat acute neurotoxicity study . Ophthalmologic effects were also seen in the rat. In the developmental neurotoxicity study , decreased motor activity was observed in 21
- day

old male pups but was not observed in females at later times. Additional details on neurotoxic effects are found in Section 3.3.2. In the rat and mouse, effects on the kidney were observed following chronic exposure. Female rats had an increased incidence of d ark 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 hy perplasia, papillary

necrosis and intratubular yellow
- brown material. Liver cell hypertroph y was observed in the rat following chronic exposure but was considered an adaptive response. In males, white foci we re also observed. In females, livers were enlarged and showed an increased incidence of macrovacuolation and multinucleated hepatocy tes with anisocaryosis. The thy roid was affected by

treatment only

in male rats. Increased follicular cell hypertroph y 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 enzy mes), they were seen at high doses relative to the endpoints selected for risk assessment, and other thy roid hormone levels did not show c hanges. 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 cy sts/follicles in female mice. However, these effects occur red 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 sy stemic 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 delay s in sexual maturation (preputial separation in males and vaginal patency in fem ales) were observed in the rat two
- generation reproductive toxicity study , along with clinical signs of toxicity, at a dose causing parental toxicity that included clinical signs and decreased weight gain. In the developmental neurotoxicity study , transiently

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

### Page 12 of 52

It was ob served 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
- ye ar dietary rat and mouse bioassay s. All genotoxicity studies that were conducted on indaziflam were negative. 3.1.3 Dose - response For acute dietary

exposure, an acute reference dose (aRfD) of 0.50 mg/kg/day was selected for assessment of all populations, based on a NOAEL of 50 mg/kg/day in the rat acute neurotoxicity study with decreased motor and locomotor activities in females observed at 100 mg/kg/day . This endpoint is a single
- dose effect and is appropriate for the populations of concern. The endpoint is protective of the decreases in maternal body weight gains seen in the rat developmental and rabbit developmental toxicity studies , potential developmental effects based on lack of observed increased pre
- and/or postnatal susceptibility and higher LOAELs observed in developmental, reproductive, neurotoxicity , developmental neurotoxicity and immunotoxicity

studies. Although the rat developmental toxicity stu dy had a lower developmental NOAEL (25 mg/kg/day), the acute neurotoxicity

NOAELof 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 spa cing 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 NOAELof 2.0 mg/kg/day with evidence of nervous sy stem microscopic effects observed at the LOAEL of 6 and 7 mg/kg/day in males and females respectivel y in the dog chronic dietary study . This provided the most sensitive endpoint available for chronic dietary exposure: rat and mouse chronic exposure NOAEL s 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 LOAELof 15 mg/kg/day was based on nervous sy stem 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 significantl y 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 e xposure due to greater incidence and severity of lesions at lower doses with continued exposure, but was not selected because, at one ye ar, the neuropathology

at the L OAEL was minimal. Furthermore, based on the proposed use patterns, continual daily

expos ures occurring for more than 90 days ( i.e. , intermediate
- term exposure) are not expected to occur. Although a 28
- day

dermal toxicity

study in the rat was available and showed no toxicity up to

### Page 13 of 52

the limit dose, including neuropathology or clinical signs, it was not selected for dermal risk assessment because the dog showed considerabl y 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 relativel y short time period). Long
- term dermal and inhalation exposure are not expected; therefore, endpoints were not selected. 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) The metabolism of indaziflam has b een evaluated in the rat using indaziflam labeled with 14 

### C at either the indane or the triazine ring. Indaziflam is rapidly and completel y 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 rapidl y excreted (approximately 90% of dose b y 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 re tained at significant levels in the tissues by 3 day s’ postdosing (less than 0.2 to 0.3% of dose), with the highest levels found in the gastrointestinal tract, liver, skin and thy roid. Metabolism was extensive with only 2
- 12% of the dose excreted in feces as unchanged parent, and occurred primaril y via oxidative processes. The major metabolite in the rat was the carbox yl ic acid metabolite of indaziflam, which was largely excreted in the bile but also found in urine. Other compounds that were identified a s major metabolites in combined excreta in one or more groups were 3
- hydrox yi ndane acid, 3
- hydroxyindane acid epimer, dihydroxy , hydrox y glucuronic acid, 3
- ketoindane acid, and hydrox ye thyl acid metabolites. The fluoroethyl diaminotriazine (FDAT) metaboli te 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 dihydrox y and hydrox ye thyl acid and acid conj ugate metabolites were found in the indane
- labeled group, but not the triazine
- labeled group. In the bile
- duct
- cannulated group, the 3
- ketohydroxy

methyl 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 comparab le, with some minor qualitative differences, but females excreted significantl y less unchanged parent compound. 3.3 FQ PA Considerations An FQPA assessment is not required for the proposed turf uses of indaziflam. However, because there are proposed food uses pending that will be evaluated subsequent to the turf evaluation, an FQPA assessment has been performed.

### Page 14 of 52

3.3.1 Adequacy of the Toxicity Database The database is considered adequate for assessment of potential sensitivity of infants and children to the effects of indaziflam. Acceptable rat and rabbit developmental toxicity , rat 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 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 sub chronic study (30 mg/kg/day) were prematurely terminated due to excessive clinical signs including ataxia, tremors, decreased pupil response , seizures and other findings. In the rat, a marginal decrease in motor/locomo tor activity was observed in females in the acute neurotoxicity

study at 100 mg/kg (NOAEL = 50 mg/kg). Additional findings at higher doses include tremors, increased reactivity, decreased activity, and urine, oral or perianal staining. Males also showed nerve fiber degeneration of the gasserian ganglion, sciatic nerves and tibial nerves. Similar clinical and motor activity changes were observed in the subchronic neurotoxicity

study , although no neuropathology was observed. Decreased motor and locomotor activity in females and clinical signs in both sexes (including tremors, repetitive chewing movements and perianal/lacrimal staining) were reported in the subchronic neurotoxicity study at a higher dose (about 580 mg/kg/day with a NOAEL of 244 mg/kg/day) than the acute study , probably as a result of gavage vs. dietary exposure. In addition, similar clinical findings were seen in P and F1 generation animals in the reproductive toxicity study , at doses ≥318 mg/kg/day
. Clinical signs of neurotoxicity followi ng 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 an d 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 dail y intakes of 0, 13, 83.8 or 432 mg/kg/day . The high dose, originall y at 7000 ppm, was reduced to 4000 ppm on LD 4. Maternal and offspring toxicity were observed onl y at the high dose of 432 mg/kg/day . Maternal clinical signs (daily observations and/or FOB) include coarse tremor, dilated pupils or dilated pupils that were unresponsive to penlight, nasal staining and repetitive

### Page 15 of 52

chewing movements. Maternal body weight and weight gain were decreased during gestation and lac tation. 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 onl y athigher doses; although no changes were seen at other assessment times or in females, it was considered treatment
- related because it was statistically significant and outside the laboratory

historical control range. 3.3.3 Developmental Toxicity Studies Acceptable developmental toxicity studies in the rat and rabbit are available . In the rat, maternal body weight gain and food consumption w ere 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 eff

ects were observed. The maternal NOAEL was 25 mg/kg/day and the developmental NOAEL was 60 mg/kg/day
. The developmental neurotoxicity study is described above in Section 3.3.2. 3.3.4 Reproductive Toxicity Studies In the reproductive study parental toxicity w as observed onl y at the high dose ( ≥317 mg/kg/day) and includes coarse tremors in females during premating, gestatio n 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/re generation). Offspring toxicity was also observed onl y 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 pup s. F1 pup weights were decreased through the postnatal period for males and females. Reproductive toxicity was observed as delay s in achieving sexual maturation at the high dose, as measured b y preputial separation (males) and vaginal opening (females), in the F1 and F2 offspring. The NOAELfor parental, offspring and reproductive toxicity was 69.3 mg/kg/day
. 3.3.5 Additional Information from Literature Sources No published studies, relevant to human hazard resulting from use of indaziflam, were identified. 3.3.6 Pre - and/or Postnatal Toxicity 3.3.6.1 Determination of Susceptibility There was no evidence of increased susceptibility (qualitative or quantitative) for pre
- and/or postnatal effects in developmental toxicity studies in the rat and rabbit , the rat developmental neurotoxicity

study or the rat two - generation reproductive toxicity study. There is no concern and there are no residual uncertainties for qualitative or quantitative pre
- and/or postnatal susceptibility

to indaziflam. This is based on the completeness of the database, lack of evidence of increased susceptibility, and the se lection of endpoints with low NOAELs that are adequatel y

### Page 16 of 52

protective of potential developmental effects. Delayed sexual maturation in offspring was observed at the highest dose of the reproductive toxicity study in the presence of maternal toxicity . Effec ts in offspring in the developmental neurotoxicity study (decreased motor activity in males on PND 21 were well characterized and were onl y observed at doses that caused maternal neurotoxicity . Although treatment
- related thy roid histological changes (foll owing 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 relativ e to the selected regulatory endpoints, and appear to be secondary to liver effects. 3.4 FQ PA 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 qualit ative pre - and/or postnatal susceptibility in a complete database that includes adult and d evelopmental , reproductive, developmental neurotoxicity and immunotoxicity

studies , (2) the devel opmental effects in the rat observed at relativel y 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 thoroughl y examined potential effects to the developing nervous system following pre
- and post
natal exposure, showed only margi nal effects in offspring (slightl y decreased motor activity, absolute brain weight) at relativel y high (and maternally toxic) doses and indicates that increased susceptibility

does not occur. 3.5 Hazard Identification and Toxicity Endpoint Selection 3.5.1 Acute Reference Dose (aRfD)

– All Populations Including Infants and Children and Females Age 13 - 49 Stud y Selected : Acut e Neurotoxicity

– Rat MRID Nos : 4 7443310 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 variabi lity)
Acute RfD = )

( 100 / 50 UF kg mg = 0.50 m g/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 day s of exposure in the developmental rat (25/200 mg/kg/day , NOAEL/LOAE L) and rabbit (25/60 mg/kg/day , NOAEL/L OAEL) toxicity studies, but which were considered questionable as an endpoint due to variability in the data. No other acute effects were observed in the

### Page 17 of 52

database. The endpoint is also protective of potential developmental effects, based on the lack of observed increased pre
- and/or postnatal susceptibility and higher LOAELs observed in developmental, reproductive, neurotoxicity, developmental neurotoxicity and immunotoxicity

studies. Although th e rat developmental toxicity developmental NOAEL was lower (25 mg/kg/day), the neurotoxicity NOAEL of 50 mg/kg is considered protective because the rat developmental LOAEL ( 7
- 9% decrease in fetal body weight) was significantly

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

to occur after a single dose. 3.5.2 Chronic Reference Dose (cRfD ) Study Selected : Chronic Toxicity (Dietary)

– Dog MRID No : 4 7743294 Dose and End point 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 respectivel y). Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intraspecies variabi lity)

Chronic RfD = ) ( 100 / / 0
. 2 UF day kg mg = 0.0 2 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 adm inistration. 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 neurot oxicity and immunotoxicity

studies. 3.5.3 Incidental Oral Exposure (Short- and Intermediate - Term) Study Selected : Subchronic Toxicity (Gavage)

– Dog MRID No : 47743289 Dose and E ndpoint 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 NOAELavailable from an oral study of appropriate exposure duration (90
- day s) 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 significantl y higher NOAEL s for postnatal toxicity in the developmental neurotoxicity and the two
- generation reproductive toxi city studies. 3.5.4 Dermal Absorption In addition to a 28
- day

study evaluating dermal toxicity in the rat, an in vivo dermal

### Page 18 of 52

absorption study

in the rat and in vitro dermal absorption studies in the rat and human were submitted. The data demonstrated an inverse relationship between dosing concentration and percent absorption. Based on in vivo dermal absorption observed in the rat and in vitro comparative rat:human absorption data, an estimated human dermal absorption f

actor (DAF) of 7.3% was obtained. The human DAF was calculated as follows (all absorption values adjusted for recovery): (1) in the rat in vivo dermal absorption study , 27.39% of the applied dose was absorbed at 24 hrs postexposure (actual exposure time 8 hrs) using an application of 0.0005 mg/cm2 

### ; (2) in vitro exposure of microtomed rat skin under the same exposure and assessment conditions gave a dermal absorption of 22.40%; (3) the ratio of the in vitro to the in vivo absorption is 0.82 (22.4/27.39) and therefore is close to 1, indicating that the in vitro data is predictive of in vivo absorption; (4) based on this ratio, a DAF for humans may be calculated using in vitro human dermal absorption (5.975%, adjusted for recovery) observed in vitro under the same exposure conditions. The DAF for humans is therefore 5.975%/0.82 = 7.3%. 3.5.5 Dermal Exposure (Short - Term, 1 - 30 days, and Intermediate - Term, 1 - 6 months ) Study Selected : Subchronic Toxicity
- Dog MRID No : 47743289 Dose and Endpoint for Risk Assessment : NOAEL= 7.5 mg/kg/day , based on degenerative brain, spinal cord and sciatic nerve fiber lesions at 15 mg/kg/day
. Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the most sensitive NOAELavailable from a study of appropriate exposure duration (90 day s) for short
- and intermediate
- term exposure. The subchronic oral dog study was selected over other studies because the dog was the most sens itive 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 s ignificantly 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 ef fects in the dog were observed following gavage dosing, in contrast to a relativel y slower dermal absorption rate. For route - to - route extrapolation, dermal absorption of 7.3% relative to oral absorption was used, estimated from human and rat in vitro and rat in vivo dermal absorption. 3.5.6 Dermal Exposure (Long - Term, >1 year) Long
- term dermal exposures are not anticipated from occupational activities. 3.5.7 Inhalation Exposure (Short- Term, 1 - 30 days and Intermediate - Term, 1 - 6 months) Study Selected : Subchronic Toxicity
- Dog MRID No : 47743289

### Page 19 of 52

Dose and Endpoint for Risk Assessment : NOAEL= 7.5 mg/kg/day , based on degenerative brain, spinal cord and sciatic nerve fiber lesions at 15 mg/kg/day
. Uncertainty Factor : 100X (10X interspecies extrapolation, 10X intrasp ecies variability) Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint is the most sensitive NOAELavailable from a study of appropriate exposure duration (90
- day s) for short
- and intermediate
- term exposure. The subchronic oral dog s tudy 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 dat a on inhalation absorption and a route
- specific inhalation study is not available. 3.5.8 Inhalation Exposure (Long - Term) Long
- term inhalation exposure scenarios are not anticipated for occupational exposures. 3.5.9 Level of Concern for Margin of Exposure Table 3.5. 9. Summary of Levels of Concern for Risk Assessment. Route Short - Term (1 - 30 Days) Intermediate - Term

(1 - 6 Months) Long - Term

(> 6 Months) Occupational (Worker) Exposure Dermal 100 100 NA Inhalation 100 100 NA Residential Exposure Dermal 100 100 NA Inhalation 100 100 NA Oral 100 100 NA NA = not applicable 3.5.10 Recommendation for Combining Routes of Exposure for Risk Assessments When there are potential occupational and residential exposures to the pesticide, the risk assessment must address exposures from three major sources: oral, dermal and inhalation exposures and determine whether the individual exposures can be combined if they have the same toxicological effects. Since the dermal , inhalation and oral endpoints are based on the same effects (neuropathology) these routes of exposure may be combined for purposes of this risk assessment. 3.5.11 Cl assification of Carcinogenic Potential There was no evidence of carcinogenicity observed in the two
- ye ar dietary rat or mouse carcinogenicity

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

### Page 20 of 52

mutation in mammalian cells and in vitro and in vivo chromosomal aberration assay s) 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 I II, oral and dermal and Category

IV, inhalation) and is not an ocular or dermal irritant or a dermal sensitizer. 3.5.13 Summary of Toxicol ogical 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 En dpoints 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 Ac ute Dietary (All Populations, including Infants and Children and Females 13
- 49 years of age) NOAEL =

50 mg/kg/day UF A= 10X

UF H = 10X FQPA SF= 1X Ac ute RfD =

0.5 mg/kg/day aPAD = 0.5 mg/kg/day Ac ute oral neurotoxicity in the rat

LOAEL = 100 mg/kg/day, based on dec reased motor and locomotor activity in females.

Chronic Dietary (All Populations) NOAEL = 2

mg/kg/day UF A= 10X

UF H = 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 mo nths) NOAEL =

7.5 mg/kg/day UF A=10X

UF H =10X FQPA SF = 1X Residential

LOC for MOE = 100 Su

bchronic 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 mo nths) NOAEL =

7.5 mg/kg/day DAF = 7.3% UF A=10X

UF H =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 mo nths) Not required for this assessment (exposure is seasonal; long
- term occupational exposure scenarios are not anticipated).

### Page 21 of 52

Table 3.5.13. Summary of Toxicological Doses and En dpoints for Indaziflam for Use in Dietary and Non - Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects
Inhalation, Short
- term

(1 to 30 days) and Intermediate
term (1 to 6 mo nths) NOAEL =

7.5 mg/kg/day Inhalation absorption assumed to be 100% (default) relative to oral. UF A=10X

UF H =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 mo nths) 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 d ata 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. L OAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 mo nths) NOAEL =

7.5 mg/kg/day DAF = 7.3% UF A=10X

UF H =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 mo nths) Not required for this assessment (exposure is seasonal; long
- term occupational exposure scenarios are not anticipated).

### Page 22 of 52

Table 3.5.13 Summary of Toxicological Doses and Endpoints for Indaziflam for Use in Occupational Human Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Inhalation Short
- Term

(1 to 30 days) and Intermediate
Term (1 to 6 mo nths) NOAEL=

7.5 mg/kg/day. Inhalation absorption a ssumed to be 100% (default) relative to oral. UF A=10X

UF H =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.
Inhalatio n 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 e ffect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor. 

### 3.6 Endocrine disruption As required under FFDCA section 408(p) , EPA has develop ed the Endocrine Disruptor Screening Program (E DSP) 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 b y a naturall y 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 assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, o r th yroid (E<A<or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E,A, or T hormonal sy stems 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 Oc tober 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 pathway s 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. Accordingl y, EPA anticipates issuing future EDSP test orders/data call
- ins for all

### Page 23 of 52

pesticide active ingredients. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/. 4.0 Public Health and Pesticide Epidemio logy Data and Incident Reports There are no public health , pesticide epidemiology or incident data to report at this time
. 5.0 Dietary Exposure/Risk Characterization 5.1 Pesticide Metabolism and Degradates of Concern OPP performed a preliminary review of the available metabolism and environmental fate data for purposes of dete rmining the residues of concern for drinking water b y 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 pertine nt 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, indazi flam carbox yl ic acid, FDAT, dihydroamino triazine, indaziflam hydrox yeth yl , and indaziflam olefin . A similar list of degradates are included as residues of concern for risk assessment; indaziflam, triazine indanone, indaziflam carbox yl ic acid, indaziflam hydrox yethyl, 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 metaboli tes 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 Indazif lam + FDAT + Triazine idanone + Indaziflam carboxylic acid + Indaziflam hydroxyethyl + Inaziflam olefin Not Applicable

### Page 24 of 52

5.1.1 Drinking Water Residue Profile (Tier 2 Drinking Water Exposure Assessment for th e 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
carbox yl ic acid, indaziflam
- olefin, and indaziflam
- hydroxyeth yl . 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 (ROI 1; 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 estimat es 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 Ac ute 48 1.6 Chronic (non
- cancer) 14 1.6 * Residue estimates for FDAT and ROI1 have been stoichiometrically converted to indaziflam equivalents and inc luded 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 indazifl am is persistent in anaerobic soil and anaerobic aquatic s ys tems. There are no data available on the anaerobic degradation of the transformation products of indaziflam. Key lines of evidence show that residues of indaziflam, and degradate products (e.g., FDAT) are a concern for exposure via ground water. However, there is uncertainty regarding the toxicity of indaziflam transformation products. A prospective ground water study could help reduce the uncertainty regarding the exposure via ground water. 5.2 Dietary Exposure and Risk A screening level drinking water exposure risk assessment was conducted using the Dietary Exposure Evaluation Model Database (DEEM
- FCID TM 

### ). While there are currentl y no food exposures associated with the proposed new use (i.e., turf), discussion of acute and chronic

### Page 25 of 52

dietary exposure via drinking water is provided for purposes of completing the combined assessment. For acute and chronic drinking water assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects). For food
- use pesticides, this dose is referred to as the population
- adjusted dose (PAD) ty picall y reserved for fo od uses. As indicated previousl y, the Agency is currentl y 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 b y 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 estim ates 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 anal ys is are reported in Table 5.2
. Table 5.2. Result of Chronic Dietary Exposure and Risk Estimates for Indaziflam Population Subgroup Acute Dietary Exposure (m g/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 y

rs old 0.006885 2.8 3600 Children 3
- 5 y

rs old 0.006290 2.5 4000 Children 6
- 12 y

rs old 0.004379 1.8 5700 Youth 13
- 19 y

rs old 0.003560 1.4 7000 Adults 2 0
- 40 y

rs old 0.004066 1.6 6100 Adults 50+ yrs old 0.003671 1.5 6800 Females 13
- 49 y

rs 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 y

rs old 0.000814 4.1 2500 Children 3
- 5 y

rs old 0.000762 3.8 2600 Children 6
- 12 y

rs old 0.000525 2.6 3800 Youth 13
- 19 y

rs old 0.000396 2.0 5100 Adults 20
- 40 y

rs old 0.000512 2.6 3900 Adults 50+ yrs old 0.000538 2.7 3700 Females 13
- 49 y

rs o ld 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 C ancer Dietary Risk HED has classified indaziflam as “not likely to be carcinogenic to humans.” Based upon this classification, HED has de termined there is no cancer risk associated with the proposed uses.

### Page 26 of 52

6.0 Residential (Non - Occupational) Exposure/Risk Characterization (Occupational and Residential Exposure Asses sment for Use of the New Active Ingredient Indaziflam on Turf, Golf Courses, Sod Farms, Christmas Tree Farms, Non
- Crop Areas and Forestry; M. Collantes: April 2010; D372538) 

### 6.1 Residential Handler Exposure Three indaziflam residential turf products (i.e., Lawn 3 FL Concentrate/Ready
- to - Spray , Lawn 3 FL Granule, and Lawn 3 FL Ready- To
- Use) are proposed for use by home owners. These products are to be applied using hand held sprayers (pump style tank, hose end, and trigger) or push
- ty pe spreaders. N o chemical
- specific unit exposure data w ere provided in support of this submission ; therefore, the Pesticide Handlers Exposure Database (PHED) Surrogate Exposure Guide and Outdoor Residential Exposure Task Force (ORE FT) 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 significantl y greater than 100 (rang ing from 3,000 to 510,000 ) and therefore not of concern to HED. Handler exposure and risk is summarized in Table 6.1.2
.

### Page 27 of 52

Table 6 .1.2: IndaziflamReside nt ial Handler Exposure and Risk Turf Exposure Scenarios Use Site Derm al Unit Exposure (m g/lb) a Inhalation

Unit Exposure (m g/lb ) a Application

Rate b (lb ai/acre) Area

Treated (A/day) Derm al

Dose c (m g/kg/day) Derm al

MOE d Inhalation

Dose e (m g/kg/day) Inhalation

MOE 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. Bel ly 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 Pum p 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

### Page 28 of 52

a. A pplication Rate based on proposed lab els b. Dermal Dose = Unit Exposure (mg/lb) x Application Rate (lb ai/acre or lb ai/gal. ) x Area Treated (acre/day or gal./day) x 7.3% dermal absorption factor/BW c. Dermal MOE = NOAEL (7.5 mg/kg/day)/Dermal Dose (mg/kg/day) d. Inhalation Dose = Unit Exposure (mg/lb) x Application Rate (lb ai/acre or lb ai/gal. ) x Area Treated (acre/day or gal./day)/BW e. Inhalation MOE = NOAEL (7.5 mg/kg/day)/ Inhalation Dose (mg/kg/day) g. Total MOE = NOAEL (7.5 mg/kg/day)/ (dermal dose + inhalation dose) mg/kg/day 

### 6 .2 Resid ential 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 in dividuals of varying ages can potentiall y be exposed when they do activities in areas that have been treated. Postapplication d ermal 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 fro m 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, 2 000
. Residential postapplication exposure s resulting in MOEs greater than or equal to 100 are not of concern. 6.2.1 Inhalation Postapplication Exposure Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for indaziflam at this time primarily because it has a very

low vapor pressure (vapor pressure less than 1 x 10 - 10 

### mmHg), it is applied at low application rates (maximum rates range from 0.089
- 0.125 lbs ai/A depending on use site), and exc ept for forestry uses, it is not projected to be applied via typicall y high inhalation exposure application equipment (e.g., airblast and aerial equipment). However, volatilization of pesticides may be a potential source of postapplication inhalation expo sure 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 identif y 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 inhalatio n 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
- t erm exposure. A qu antitative dermal postapplication assessment was not performed for the Trigger Pump scenario as the amount used is so small that the other scenarios are considered protective of this one use. As

### Page 29 of 52

these exposure values were determined using default assumptions (5% of the application rate available as transferable turf residue) it should be noted that exposure would only be lower (greater MOEs) if calculated using actual chemical specific TTR data
. Thus use of default assumptions is protective of all postapplication dermal exposure scenarios. Additional details regarding the TTR data are provided in the Indaziflam Occupational and Residential Exposure Assessment (M.Collantes, D372538, April 2010). Furthermore, s ince the short
- and intermediate
- term dermal endpoints are the same, onl y 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 - termDermal Exposure and Risk Using Default Assumptions Scenario Application

Rate (lb ai/A) TTR 1

(μg/cm2 ) CF Short - Term

Tc (cm2 /hr) E T

(hrs) BW (kg) Dose 2 (m g/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 0.0 01592

0.00 0796 0.0 012 4,700

9,400 6 , 0 00 Hand
- held Pum p Sprayer 0.09 4

(ornamentals & lawn) 0.05264 0.001592 4,700 Belly Grinder & Granular Push Spreader 0.044

0.071 0.02464

0.03976 0.00 0745 0.0 012 10,000

6,000 Golfer Hose
- end Sprayer or Granular Push Spreader 0.071 * 0.03976 0.001 500 4 70 0.00 00829 90, 0 00
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 0.0 013 0.0 020 2 ,8 00

5,80 0 3,70 0 Hand
- held Pum p Sprayer 0.094 0.05264 0.00266 2,800

### Page 30 of 52

Table 6 .2.2: Postapplication Short - termDermal Exposure and Risk Using Default Assumptions Scenario Application

Rate (lb ai/A) TTR 1

(μg/cm2 ) CF Short - Term

Tc (cm2 /hr) E T

(hrs) BW (kg) Dose 2 (m g/kg/day) MOE 3 Belly Grinder & Granular Push Sprea der 0.044

0.071 * 0.02464

0.03976 0.0 01247 0.0 020 6,000

3, 70 0 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 (cm 2/hr) x ET (hr/day) x DAF (7.3% ) BW (kg) 3. Short
- term Dermal MOE = NOAEL (7.5 mg/kg/day) /Dermal Dose (mg/kg/day) * = commercially applied 

### 6.2.3 Oral Exposure The hand
- to - mouth transfer scenario was assessed using the HED Draft Standard Operating Procedures (SOP’s) for Residential Exposure Assessments (12/18/97), and the Revisions to the Standard Operating Procedures (SOP’s) for Residential Exposure Assessment (Science Advisory Council for Exposure Policy 12, Revised February 22, 2001). Th i s scenario ass ume s 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 th an or equal to 1 00 are not of concern to HED. 6.2.3.1 H and - 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 inge sted as a result of hand
- to - mouth transfer. All short
- and intermediate
- term hand
- to - mouth (HTM) scenarios result in MOEs greater than 100 and therefore pose no risk of concern to HED. Table 6.2.3.1 provides a summary of the short
- term HTM exposures. T able 6.2.3.1: Hand - To - Mou th 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 (m g/kg/day) MOE 3 Short
- term BCS AA10717 Turf Fertilizer (432
- RUOL; 432
- RUOA; and 432
- RUOT) and 20 WSP (4 32
- 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 5.2 7E
- 2 ug/cm2 2. Dose = TTR

t x SA x FQ x ET x SE x CF1 BW 3. MOE = NOAEL (7.5 mg/kg/day)/HTM Dose (mg/kg/day)

### Page 31 of 52

6.2.3.2 Object- to - Mouth (Ingestion of Treated Turf) Assumptions and Equations This scenario estimates doses among young children (3 to 6 years of age) from incidental ingestion of pesticide and/or residential turf grass that has been treated with pesticides. It assumes that pesticide from a treated object or turf is ingested b y young children (3 to 6 years of age) who play

on tre ated areas. The object
- to - mouth (OTM) scenario result s in a MOE greater than 100 and therefore poses no risk of concern to HED. Table 6 .2. 3.2 provides a summary of the object
- to - mouth exposure and risk. Table 6.2.3.2: Object

–to - Mouth Exposure and Ris k for Children (3 to 6 years)

Product GR 1

(ug/cm2 ) CF

(m g/μg 

### ) IgR

(cm2 /day) BW

(kg) Dose 2 (m g/kg/day) MOE 3 BCS AA10717 Turf Fertilizer (432
- RUOL; 432
- RUOA; and 432
- RUOT) and 20 WSP (432
- RUOO) 1.59E
- 1 0.001 25 15 2.65E
- 4 28,000

Lawn 3FL (72155
- IO) 2.11E
- 1 0.001 25 15 3.51E
- 4 21,000 1. GR (grass residue) = AR x F x (1
- D) 0 x CF2 x CF3 2. Dose = GR 0 x IgR x CF1 3. MOE = NOAEL (7.5 mg/kg/day)/Dose (mg/kg/day) 

### 6.2.3.3 Incidental Ingestion of Soil Assumptions, Exposure and Risk This scenario assumes children who play on treated areas ingest pesticide residues in soil as a result of normal mouthing activities. The soil
- ingestion scenario result s in a MOE much greater than 100 and therefore poses no risk of concern to HED. This assessment should be considered conservative in that it assumes no dissipation of soil residues would occur over the exposure period. Table 6 .2. 3.3 provides a summary of the soil ingestion exposure and risk. Table 6.2.3.3: Soil Ingestion Exposure and Risk Risk for Children (3 to 6 ye ars)

Product SR 1

(ug/g) CF

(g/μg 

### ) IgR

(m g/day) BW

(kg) Dose 2 (m g/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 4.7 1E
- 6 1.59E6 1. SR0 (soil residue) = AR(lb ai/A) x F (1) x (1
- D) 0 x 0.67 x (4.54x10 8 μ g/lg ) x (2.47 x 10 - 8 A/cm 2 ) 2. Dose (mg/kg/day) = SR0 (μg/g) x IgR (mg/day) x CF1 (g/μg)/BW (kg) 3. MOE = NOAEL ( 7.5 mg/kg/day)/ Dose (mg/kg/day) 

### 6.2.3.4 Episodic Ingestion of Gra nules This scenario was assessed using the Residential SOP and provides a standard method for estimating postapplication exposure among young children (3 to 6 ye ars of age) from incidental ingestion of pesticide granules. The episodic oral MOE for incidental ingestion of granules is 5,000 and therefore is not of concern to HED
. Table 6 .2 .3. 4 provides a summary or exposure risk.

### Page 32 of 52

Table 6 .2. 3.4 : Postapplication Exposure and Risk for Incidental Ingestion of Granules

Scenario IgR (g/day) F CF1 (m g/g) Dose a

(m g/kg/day) MOE b Lawn 3FL Granule Reg No 7 2155
- 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 propose d label does indicate that granules should be watered in for proper activation. Watering in granules could further reduce the availability of granules to be potentiall y ingested. 6.3 Combined Residential Risk Estimat es HED combines risk values res ulting from separate exposure scenarios when it is likely they can occur simultaneousl y 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 s ources 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 generall y 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

f or 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

Derm al MOE 2 Hand - to - Mouth

MOE 3 Combined

MOE 4 Adult Lawn 3FL Concentrate /Ready to spray 72155
- IO Lawns, hardscapes and ornamentals 3,00 0 4,70 0 NA NA

Child Lawn 3 FL (72155
- IO) Lawns, hardscapes and ornamentals NA 2 ,8 00 5,300 1,800
1. See Table 4.1.2: Indaziflam Residential Handler Exposure and Risk (Hand Held Pump) 2. See Table 4.2.2a Dermal Postapplication Exposure and Risk (DFR data) 3. See Table 4.2.3 Hand
- To
- Mouth Exposure and Risk 4. Adult Combined MOE = NA = HED does not combine a dult h andler and postapplic ation exposure Child Combinded MOE = NOAEL (7.5 mg/kg/day)/dermal postapplication dose (0.0 0266 ) + HTM dose (1.41E
- 3)

### Page 33 of 52

HED did not combine risk resulting from adult homeowner handler, postapplication and golf er exposure to treated turf because HED considers it unlikely that these exposures would co
- occur. 7.0 Combined Risk Assessments and Risk Characterization HED conducted screening level combined risk estimates for short
- term exposure durations to ensure that residential and drinking water exposure would not exceed HED’s level of concern. In conducting these estimates for indaziflam, HED combined risk values resulting from drinking water and residential scenarios. To estimate short
- term combined risk , HED combined the chronic dietary (water) exposures (as a measure of average dietary exposure) with the short
- term residential exposure. HED does not generall y combine adult handler and dermal postappl ication 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 Co mbined Risk Calculations Population LOC for

Aggregate Risk 1 MOE

drinking water2 MOE

Total Handler 3 MOE

Dermal Postapplication 4 MOE

Oral 5 Com

bined MOE (drinking water + residential) 6 US Population 100 3700 3,000 4,700 NA 1700 Child (3
- 6 yrs) 100 2 500 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 Ta

ble 6.1.2 4. MOE dermal postapplicat io n = S ee Table 5 MOE oral = S ee Table 6.2.1 Hand
- To
- Mouth Exposure and Risk 6. Adult C ombined MOE = (drinking water +total handler) = ____________1________ 1/MOE w + 1/MOE IH 5 Child Combined MOE = (drinking water + dermal postapplication + oral postapplication) = ____________1________ 1/MOE w + 1/MOE D + /MOE O 

### 8.0 Cumula tive 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 othe r 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 o ther 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 s ubstances 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 b y a mechanism common with that of the subject pes ticide, even if the individual exposure levels to the other substances are also considered safe.

### Page 34 of 52

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

to disrupt the hy

pothalamic
- pituitary
- gonadal axis (U S 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 b y the TCMG members. The TCMG members cause an increase in mammary

gland tumors in rats and multiple developmental effects such as attenuati on 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 repro duction study , however, the effect occurred at the highest dose and was attributed to significant clinical toxicity rather than a perturbation of the hy pothalamic
- pituitary
- gonadal axis
. Ina 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 b y other substances. Th erefore, 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 mech anism of toxicity

and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to h ave a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Pathway (Occupational and Resid ential 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. In daziflam is available for use b y 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 use s, exposures to indaziflam are anticipated to occur for short
- and intermediate
- term durations.

### Page 35 of 52

9.1 Handler Risk No chemical
- specific data were available with which to assess potential exposure for pesticide handlers. The estimates of exposure for pesti cide 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 baseli ne 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 rangin g from 100 to 840,000. HED used standard assumptions with respect to body weight, areas treated, and use of maximum application rates in assessing occupational exposure.

### Page 36 of 52

Table 9 .1. Occupational Handler Exposures and Risks Exposu re Scenario and Product Target site Application

Rate a Area

Treated b Derm al

Unit Exposure (m g/lb) Inhalation

Unit Exposure (m g/lb) Derm al

Dose c (m g/kg/day) Derm al

MOE d Inhalation

Dose c (m g/kg/day) Inhalation

MOE d Total

MOE g
Mixer/Loader Liquids fo r Aerial Applications (PHED) Esplanade F forestry 0.125 lb ai/A 1200 A 0.023 single layer/ gloves 0.0012 0.003 598 2 1 00 0.002571 2900 1200 Liquids for Ground Applications (PHED) Esplanade F forestry 0.125 lb ai/A 200 A 0.0 006 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 0.006 73 1 1 00 3.81E
- 5 196,000 1 1 00

Water Soluble Packets Ground Applications (PHED) BCS
- AA10717 20 W SP Non
- crop

areas, turf grass, nurseries, landscapes 0.071 lb ai/A

(non
- crop) 5 A 0.021 0.00024 7. 77 E
- 6 96 0,000 1.22E
- 6 6,000,000 8 3 0,000

Golf course and fields grown for ornamentals 40 A 6.22 E
- 5 1 2 0,000 9.74E
- 6 770,000 100, 000

sod farm and , Christmas tree farms 80 A 0.0001 24 6 0 ,000 1.95E
- 5 390,000 5 2 ,000
forestry 0.088 lb ai/A 200 A 0.0003 85 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 3.11 E
- 6 2, 4 00,000 8.62E
- 6 870,000 6 4 0,000 golf course 40 A 2. 4 9E
- 5 3 0 0,000 6.9E
- 5 100,000 80,000 sod farm 80 A 4. 98 E
- 5 1 5 0,000 0.000138 54,0 00 40,000 Applicators

### Page 37 of 52

Table 9 .1. Occupational Handler Exposures and Risks Exposu re Scenario and Product Target site Application

Rate a Area

Treated b Derm al

Unit Exposure (m g/lb) Inhalation

Unit Exposure (m g/lb) Derm al

Dose c (m g/kg/day) Derm al

MOE d Inhalation

Dose c (m g/kg/day) Inhalation

MOE d Total

MOE g Applying Sprays via Aerial Equipment (PHED) forestry 0.125 lb ai/A Esplanade F 1200 A 0.005 Eng control f 0.000068

Eng control f 0.0007 8 9,6 00 0.000146 51,000 8, 1 00

Applying Sprays via Groundboom Equipment (PHED) forestry 0.125 lb ai/A Esplanade F 200 A

0.014 0.00074 0.0003 6 5 21,000 0.000264 28,000 12,000 0.088 lb ai/A BCS
AA10717 20 WSP 0.0002 57 30,000 0.000186 40,000 17,000

non - crop areas * 0.089 lb ai/A

Esplanade 200SC 40 A 0.0000 52 1 4 0, 000 3.76E
- 5 200,000 8 4 ,000 Non
- crop sites, turf and recreation fields 0.071 lb ai/A

BCS
AA10717 20 WSP 5 A 0.00000 518 1, 4 00,000 3.75E
- 6 2,000,000 8 4 0,000 Golf course and field grown for ornamentals and nurseries 40 A 0.0000 415 1 8 0,0 00 3.0E
- 5 250,000 100,000
Sod and Christmas tree farms, 80 A 0.0000 829 9 0 ,000 6.0E
- 5 120,000 5 2 ,000 Applying Sprays via Right
- of
- Way Equipment (PHED) non - crop areas * 0.089 lb ai/A

Esplanade 200SC 25 A 0.0039 0.000032 5 2 3 0,000 0.000124 6 0,000 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 0.000003 67 2,000,000 0.000032 230,000 210,000 golf courses 40 A 0.00002 93 2 6 0,000 0.000256 29,000 26,000 sod farms 80 A .00005 86 130,000 0.00051 15,000 13,000

### Page 38 of 52

Table 9 .1. Occupational Handler Exposures and Risks Exposu re Scenario and Product Target site Application

Rate a Area

Treated b Derm al

Unit Exposure (m g/lb) Inhalation

Unit Exposure (m g/lb) Derm al

Dose c (m g/kg/day) Derm al

MOE d Inhalation

Dose c (m g/kg/day) Inhalation

MOE d Total

MOE g

LCO Push Cyclone Granular Spreader (OMA001)ORETF Lawns, turf, sports and recreation parks 0.071 lb ai/A 5 A 0.35 0 .0073 0.0001 3 56 ,000 0.000037 200,000 4 5 ,000 golf courses 40 A 0.00 1 0 7, 2 00 0.000296 25,000 5, 6 00 sod farms 80 A 0.00 20 3, 6 00 0.00532 12,000 2, 8 00 Belly Grinder (PHED) Lawns, turf, sports and recreation parks 1 A 10 0.062 0.0007 4 1 0 ,000 6.29E
- 5 120,000 9, 3 00 Flaggers Flagging for Aerial Sprays Applications (PHED) Esplanade F forestry 0.125 lb ai/A 350 A 0.011 0.00035 0.000 50 1 5 ,000 0.000219 34,000 1 0 ,000 Mixer/Loader/Applicator
Mixing/Loading/ Applying Liquids with Lo w Pressure Handwand (PHED) Forestry

Esplanade F 0.125 lb ai/A 5 A 100

0.03 0.0 652 120 0.000268 28,000 1 1 0

0.0248 lb ai/gal 40 gals 0.43 0.0004 45 17,000 0.000425 18,000 8, 6 00
non - crop areas * Esplanade 200SC 0.089 lb ai/A 5 A 100 0 .04 64 1 6 0 0.000191 39,000 1 6 0

0.0178 lb ai/gal 40 gals 0.07 425 100 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 0.0016 3 4 6 00 0.000268 28,000 4, 0 00

0.0248 40 gal s 0.002 5 8 3,000 0.000425 18,000 2, 5 00 non - crop areas * Esplanade 200SC 0.089 lb ai/A 5 A 0.00116 6, 5 00 0.000191 39,000 5, 6 00

0.0178 lb ai/A 40 gals 0.00185 4,000 0.000305 25,000 3,500

### Page 39 of 52

Table 9 .1. Occupational Handler Exposures and Risks Exposu re Scenario and Product Target site Application

Rate a Area

Treated b Derm al

Unit Exposure (m g/lb) Inhalation

Unit Exposure (m g/lb) Derm al

Dose c (m g/kg/day) Derm al

MOE d Inhalation

Dose c (m g/kg/day) Inhalation

MOE d Total

MOE g
Mixing/Loading/ Applying Liquid Concentrates with a Hand gun 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 0.0002 3 7 3 2 ,000 0.0000365 200,000 2 7 ,000 0.089 Esplanade 200SC 0.45 0.00 18 0.0002 09 3 6 ,000 0.000014E
- 5 650,000 3 4 ,000

a Application rates = maximum application rates from labels. b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture ,” industry sources, and

HED estimates. c Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x Area Treated (acres/day) x %Absorption (7 .3 % dermal and 100% inhalation) / Body weight (70 kg). d MOE = NOAEL (7.5 mg/kg/day) / Dose (mg/kg/day) e All scenarios were run at Baseline ( dermal
- single layer clothing; I nhalation
- 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 + I nhalation Dose (mg/kg/day) *non crop areas = rail road yards, roadsides, ornamental and perennial plantings, fence rows, utilities, hardscapes, industri al, municipal and government site

### Page 40 of 52

9 .2 Occupational/Commercial Posta pplication Exposure 9.2.1 Postapplicatin Inhalation Exposure Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for indaziflam at this time primarily because it has a very

low vapor pressure (vapor pressure less than 1 x 10 - 10 

### mmHg), it is applied at low application rates (maximum rates range from 0.089
- 0.125 lbs ai/A depending on use site), and except for forestry uses, it is not projected to be applied via typicall y high inhalation expos ure 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 i nput 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 /S AP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for indaziflam. 9.2.2 Postapplication Dermal Exposure Exposures during pos tapplication 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 transf erable 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 p rotective 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 expo sures and risk for indaziflam.
Table 9 .2 .2 : Postapplication Exposure and Risk for IndaziflamUsing Default Assu mptions Scenario Tc 1

(cm2/hr) DAT 2 DFR 3 (ug/cm2) DOSE 4

(m g/kg/day) MOE 5

Sod farm & Golf Course Mowing 500 0 0.0 16 0.000 06 6 110 ,000 hand weeding & , transplant of turf 16,500 0 0.00 2 3 ,400

### Page 41 of 52

Outdoor ornamentals 110 0 0.159 0.00014 5 5 1 ,000 Moving ornamentals in pots to trucks and reorganizing 400 0 0.001 1 4 ,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 in i tial treatment. 3. Dermal Dose = [ TTR (ug/cm2) x T c (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 I II) and is not an ocular n or dermal irritant n or a dermal sensitizer ( Category IV )
. Acute toxicity

Category I II 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 an d Label Recommendations 10.1 Toxicology Based on the available toxicity database and the Agency's current practices, the inhalation risk for indaziflam was assessed using an oral toxicity study . The Agency

sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Ac t 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 appro priate, 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 None 10.3 Occupational and Residential Exposure None

### Page 42 of 52

References: 1. Indaziflam : Occupational/Residential Exposure Assessment for Use of Indaziflam on on Turf, Golf Courses, Sod Farms, Christmas Tree Farms, Non
- Crop Areas and Forestry (M.Collantes, D372538; February 2010) 2. Tier 2 Drinking Water Assessment for the Section 3 New Chemical Registration of Indaziflam; Rueben Baris; D3 56141; and D3 67447; February 2, 2010.

### Page 43 of 52

Appendix A: Toxicology Assessment A.1 Toxicology Data Requirem ents 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 Te chnical 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 yes 1 yes yes 870.5100 Mutagenicity

—Gene Mutation
- bacterial
..................... 870.5300 Mutagenicity

—Gene Mutation
- mammalian
................ 870.5375 Mutagenicity

— Structural Chromosomal Ab errations
... 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. Scre ening 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 ye s

yes yes Special Studies for Ocular Effects

Ac ute Oral (rat)
................................ ........................... Subchronic Oral (rat)
................................ .................. Six
- mo nth Oral (dog)
................................ .................. no no no --

--

-- 1 Satisfied by 870.4300.

### Page 44 of 52

A.2 Toxicity Profiles Table A.2.1 Acute Toxicity Profile - Indaziflam technical Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral
- rat 47443281 LD 50 > 2000 mg/kg (both sexes) III 870.1200 Ac ute dermal
- rabbit 47443282 LD 50 > 2000 mg/kg (both sexes) III 870.1300 Ac ute inhalation
- rat 47443283 LC 50 > 2.3 mg/L (both sexes) IV 870.2400 Ac ute eye irritation
- rab bit 47443284 Non
- irritant IV 870.2500 Ac ute dermal irritation
- rabbit 47443285 Non
- irritant IV 870.2600 Skin sensitization
- guinea pig 47443286 Not a sensitizer (Buehler method) N/A

### Page 45 of 52

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Indazif lam 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 pos ture 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 bo dy 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 derm al NOAEL = 1000 mg/kg/day LOAEL = not determined (>1000 mg/kg/day). Some indication of local dermal irritation was observed at all doses but the findings were transient and observed only in females, and therefore were not considered adverse. 870.3700a Prenatal

developmental in (rat) 47443291 (2006)

Acceptable/Guideline 0, 10, 25 or 200 mg/kg/day by gavage in 0.5% aqueous methylcellulose, GD 6 through 20 Maternal NOAEL = 25 mg/kg/day LOAEL = 200 mg/kg/day based on decreased body weight gain and food consumption. Developm ental NOAEL = 25 mg/kg/day LOAEL = 200 mg/kg/day based on decreased fetal body weights.

### Page 46 of 52

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Indazif lam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 94.5% a.i. 870.3700b Prenatal

developmental in (rabbit) 47443292 (2008)

Acceptab le/Guideline 0, 10, 25 or 60 mg/kg/day by gavage in 0.5% aqueous methylcellulose, GD 6 through 28 93.14% a.i. Materna l NOAEL = 25 mg/kg/day LOAEL = 60 mg/kg/day based on decreased maternal body weight gain and food consumption and macroscopic changes in th e liver in one doe. Developm enta l 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/F 1 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 (F 1 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 (F 1 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 intake s) 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 fe males 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 mo rtality, clinical signs of toxici ty , mydriasis and absence of papillary reflex; 474 mg/kg/day M, based on decreased body weight/weight gain and food consumption.

870.4100b Chronic toxicity

(dog) 47443294 (2008; main

study);47443295 (2007; dietary stability) NOAEL = 2.0 mg/kg/day LOAEL = 6/7 mg/kg/day M/F, based on axonal degeneration of nerve fibers in the brain, spinal cord and sciatic nerve in males and females.

### Page 47 of 52

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Indazif lam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results Acceptable/Guideline 0, 60, 225 or 450 ppm in the diet M: 0, 2, 6 or 12 mg/kg/day; F: 0, 2, 7 or 11 mg/kg/day 93.16% a.i. Marginal body weight decreases early in study seen at 12/11 mg/kg/day M/F.

870.4200a Carcinogenicity

(rat) See 870.4300, below 870.4200b Carcinogenicity

(mouse) 47743416 (2008)

Acceptable/Guideline 0, 50, 250 or 1000 ppm in diet M: 0, 6.8, 34 or 14 2 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 fem ales. No evidence of carcinogenicity

870.4300 Com

bined 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. NOAE L = 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 mo re 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, 1 58, 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, TA 1537 for increas ed frequency of revertant colonies up to cytotoxic (500 μg/plate) and precipitating concentrations (5000 μg/plate).

### Page 48 of 52

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Indazif lam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results Gene Mutation 870.5100 Bacterial reverse

gene mutation assay ( S. typhimurium ) 47443301 (2007)

Acceptable/Guideline Trial 1: 0, 15, 50, 158 , 500, 1502 or 5000 μg/plate in the presence or absence of S9 activation, plate
- incorporation method Trial 2: 0, 100, 200, 400, 800, 1600 or 3200 μg/plate in the presence or absence of S9 activation, pre - incubation method 95.7% a.i. Negative +/
- S9 activation in S. typhimurium strains TA98, TA100, TA102, TA1535, TA 1537 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).

Cy togenetics 870.5375 M ammalian in

vitro cy togenetic 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 prese nce 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)

Cy togenetics 870.5395 Mammalian in

vivo micronucleus assay (mouse) 47443308 (2006)

Acceptable/Guideline Two doses of 0, 10, 20 or Negative for induction of increased frequency of micronucleated polychromatic erythrocytes in bone marrow at any treatment time.

### Page 49 of 52

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Indazif lam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results 40 mg/kg by IP injection in 0.5% aqueous Cremaphor vehicle administered 24 hrs apart; harvested 24 hrs after second dose 90.32% a.i. 870.6200a Ac ute

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 mo tor 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 avera ge daily intake in the diet of 0, 13, 83.8 or 432 mg/kg/day 93.14% a.i. Maternal NOAEL = 83.8 mg/kg/day LOAEL = 432 mg/kg/day, based on clinical signs at daily observation and FOB assessment (coarse tremors, dilated pupils and dilated pupils unresponsive to penlight, nasal staining, repetitive chewing movements), decreased body weights/weight gain and reduced number of litters (
- 17%). Offspring NOAEL = 83.8 mg/kg/day LOAEL = 432 mg/kg/day, based on decreased body weight through PND 21 in males and females . Males postweaning had slightly decreased body weights. Decreased motor activity (
- 29%) on PND 21 in males was considered treatment
- related, but was not seen at other measurement times nor in females. 870.7485 Metabolism and

pharmacokinetics 47443312 (2008)

Acceptable/Guideline Absorption was complete (>90% bioavailability) and rapid, with radioactivity

### Page 50 of 52

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Indazif lam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results (rat)

– tier 1 Male rats given single

gavage dose of either 14 C
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 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
- label ed group than the indane
- labeled group but levels in other groups were similar. Excretion was largely fecal (62
- 70%), with significant biliary excretion observed. CO 2 exhalation was negligible. Parent com

pound 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 amon g 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 g avage doses as follows: (1) low

dose mass balance studies in females given 14 C
- 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 14 C
- 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% Absorptio n 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). CO 2 excretion wa s negligible. Radioactivity was not retained at significant levels in tissues; the GIT, liver and skin showed the highest residues. T he carboxylic acid metabolite was the major metabolite in both high dose males and low dose females, which was found in urine and feces. Additional metabolites present at >5% of dose included 3
- hydroxyindane acid metabolite in low dose females, dihydroxy metabolite in low dose females and hydroxyethyl acid metabolite in the high dose males (indane
- label).

870.7600 Dermal 47743420 (2008) Absorption was inversely proportional to dose,

### Page 51 of 52

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Indazif lam technical Guideline No. Study Type MRID No. (year)/ Classification /Doses Results absorption, in vivo (rat) Acceptable/Guideline

0.5, 2 or 5000 μg ai/ cm 2 on 12 cm

2 skin for 8 hrs to male rats; absorpti on evaluated after 8, 24, 72 and 168 hr postdosing Radiochemical purity >98% indicating saturation of skin penetration with increasing dose. Between 0.4
- 20.4% of the applied dose was recovered in combined re sidual 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/ cm 2 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 mo rtality (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
- F DAT Nonguideline Study Sexual maturation

supplemental study (rat) 47443314 (2008)

Accetable/Nonguideline 0, 18.0, 36.5, 72.9 or 145.8 mg/kg/day by gavage to LD21 offspring and timed
-pregnant female Wistar rats: administered daily until PND 41 NOAEL = 36.5 mg/kg/day LOAEL = 72.9 mg/kg/day, based on delays in vaginal patency (+2.3 days, increasing to 3.9 days at 145.8 mg/kg/day). Also at high dose, body weight was decreased and salivation and urine staining were observed.

### Page 52 of 52

Appendix B. Input Values for the Drinking Water Exposure Assessment Filename: C: \ Documents and Settings \ mdoherty \ My Documents \ Chemistry Reviews \ !DEEM Runs \ Indaziflam \ Indaziflam Water Acute.R98 Chemical: Indaziflam RfD(Chronic): .02 mg/kg bw /day NOEL(Chronic): 2 mg/kg bw/day RfD(Acute): .25 mg/kg bw/day NOEL(Acute): 25 mg/kg bw/day Date created/last modified: 03
- 02
- 2010/12:04:17/8 Program ver. 2.03

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

---------------- EPA Crop Def Res Adj.Factors Comment Code Grp Commodity Name (ppm) #1 #2

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

- ------ ------- 86010000 O Water , direct, all sources 0.084000 1.000 1.000 86020000 O Water, indirect, all sources 0.084000 1.000 1.000
Filename: C: \ Documents and Settings \ mdoherty \ My Documents \ Chemistry Reviews \ !DEEM Runs \ Indaziflam \ Indaziflam Water Chronic. R98 Chemical: Indaziflam RfD(Chronic): .02 mg/kg bw/day NOEL(Chronic): 2 mg/kg bw/day RfD(Acute): .25 mg/kg bw/day NOEL(Acute): 25 mg/kg bw/day Date created/last modified: 03
- 02
- 2010/12:04:44/8 Program ver. 2.03

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

---------------- EPA Crop Def Res Adj.Factors Comment Code Grp Commodity Name (ppm) #1 #2

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

- ------ ------- 86010000 O Water, direct, all sources 0.026000 1.000 1.000 86020000 O Water, indirect, all sources 0 .026000 1.000 1.000