Page 1 of 8 UNITED STATES ENVIRONMENTAL PROTECTI ON AGENCY

WASHI NGTON, D.C. 20460 **OFFICE OF CHEMICAL SAFETY AND**  **POLLUTION PREVENTION MEMORANDUM**  **DATE** : 08 /27 /201 3 **SUBJECT** : **Indoxacarb** : Residential Exposure and Aggregate Human - Health Risk

Assessment for Proposed Amendment for In door Uses of Arilon (EPA reg. No 100 - 1501) Label . **PC Code:** 067710 **DP Barcode:** D413735 **Decision No.:** 481544 **Registration No. :**  EPA Reg. No. 100 - 1501 **Petition No.: Regulatory Action:**  Label Amendment/Section 3 **Risk Assessment Type** Single Chemical Aggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 173584 - 44 - 6 **MRID Nos.:** NA **40 CFR:** §180.564 **FROM:** Ana Rivera - Lupiáñez, Chemist

Risk Assessment Branch V Health Effects Division (7509P) **THROUGH:** Danette Drew, Chemist

Kelly L owe, Environmental Scientist Michael Metzger, Branch Chief Risk Assessment Branch V Health Effects Division (7509P) **TO:** Jennifer Urbanski/John Hebert , Risk Manager

Registration Division (7505P)Page 2 of 8

**1.0 E**  **XECUTIVE S**  **UMMARY** Indoxacarb, (S) - methyl 7 - chloro - 2,5 - dihydro - 2 - [[(methoxycarbonyl )[4 - (trifluoromethox y)phenyl ] amino]carbonyl]indeno[1,2 - e][1,3,4]oxadiazine - 4a(3H) - carbox yl ate, a reduced risk pesticide, is an oxadiazine class insecticide active ingredient (ai) . It is formulated as granular, impregnated materials, water dispersible granules, emulsifiable, flowable, soluble concentrates, and solution - ready- to - use. In doxacarb formulations can be used by homeowners and b y commercial applicators in agricultural and non - agricultural use sites. The last Human - Health Risk Assessment for indoxacarb ( 5/2/13, D402099 , D. Drew, et al , Indoxacarb. Human Health Risk Assessment for the Proposed New Use on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13 - 07F and Low Growing Berry Subgroup (except strawberry) 13 - 07H ; (PP# 2E8029) ) identified post application risk estimates of concern for children (hand - to - mouth oral exposure) as a result of spot - directed treatment scenarios to indoor surfaces. The Health Effects Division (HED) recommend ed amending the EPA Reg. No. 100 - 1501 label to withdraw indoor spot treatment s , and restrict indoor residential uses to only crack and crevice treatments limiting applications to areas not accessible to young children . The registrant had been notified of this and responded by submitting an amended label which, rather than restrict the use to crack and crevice onl y , reduced the maximum spray volume allowed to be applied for indoor spot treatments . The Registration Division (RD) requested that HED determine if this labeling language is acceptable . The residential exposure and risk estimates were also revised , as was the aggregate (residential plus dietary) assessment , for the amended indoor use. Proposed Use Profile Indoxacarb products are frequentl y formulated as a mixture of the insecticidally active S enantiomer and the insecticidally inactive R- enantiomer. The percentage of active ingredient and application rates listed on the product labels only reflect the S - enantiomer and not the R- enantiomer. Adjustments are made in this assessment to add in the percent of R- enantiomer in product mixtures so that the total amount of indoxacarb (both S - and R- enantiomers) applied is accounted for as both are residues of toxicological concern . Arilon Insecticide 20% ai ( EPA Reg. No. 100 - 1501 , a water - soluble packaging (WSP) formulation of indoxacarb ( 75 : 25 ratio of S - and R- enantiomers ) , is registered for insect control on households and domestic dwellings . The product registrant, Sy ngenta Crop Protection LLC , has submitted a proposed label amendment to the indoor surface use directions for crack and crevice and spot directed spray applications . The original indoor application (i.e., crack and crevice and spot directed spray treatment) allowed for a maximum application rate of 0.66 oz product (dry) per gallon of water ( i.e ., 0.011 lb ai total isomer /gal) with a maximum application volume of 4 gallons diluted product per 1000 sq ft (equivalent to a maximum application rate of 0.00004 lb ai total isomer/ft2 ). The amended label proposes to limit the maximum volume of product used for indoor applications to 1 gallon diluted product per 1000 sq ft , equivalent to a maximum application rate of 0.00001 lb ai total isomer/ft2

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Hazard Profile The toxicology database for indoxacarb is complete and is sufficient for characterizing hazard . The indoxacarb endpoints that most frequently defined the lowest - observed adverse - effect - level (LOAEL) in laboratory animals were non - specific, and included decreases in body weight, weight gain, food consumption and food efficiency. Indoxacarb also affected the hematopoietic s ys tem in animals by decreasing the red blood cell count, hemoglobin and hematocrit. The FQPA safety factor ( SF ) for indoxacarb is reduced to 1 X based on the following : 1) the hazard and exposure databases are complete; 2) there are no concerns for pre - and/or postnatal toxicity ; 3) there are no residual uncertainties with regard to pre - and/or post natal toxicity ; and 4) the acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) and developmental neurotoxicity (DNT) studies are available and all endpoints used in this risk assessment are protective of any neurotoxic effects . See the 5/2013 risk assessment (D402099) for the complete details regarding the hazard characterization and selection of toxicity endpoints and points of departure for indoxacarb. Residential Exposure/Risk The residential exposure and risk estimates were revised for the amended indoor use label since they will impact the aggregate (residential plus dietary exposures ) assessment for indoxacarb. D ermal exposures resulting from residential uses are not quantitatively assessed as a dermal toxicity endpoint is not identified for indoxacarb . Only inhalation (adult and children) and incidental oral (children) exposures are assessed . The handler and post - application exposures for this residential use are expected to be short - term in duration. Residential handler (adults) risk estimates result in inhalation MOEs that do not exceed HED's level of concern ( i.e., MOEs ≥ 100) f rom the Arilon indoor application exposure scenarios . All adult and children post - application risk estimates from the Arilon indoor surface directed spray s scenarios (crack and crevice and spot treatments ) do not exceed HED’s level of concern (MOEs are ≥ 100) at the proposed reduced maximum volume rate of 1 gallon diluted product per 1000 sq ft . Aggregate Risk The short - term aggregate (residential plus dietary food and water) risk estimates for adults and children are below HED’s level of concern when considering the post applicati on exposure to indoor spray treated surfaces assuming a reduced volume application rate of 1 gallon diluted product per 1000 sq. ft . **2 .0**  **R ISK**  **A SSESSMENT**  **C ONCLUSIONS AND**  **R ECOMMENDATIONS** Page 4 of 8

**2.1 Summary of Risk Estimates**  The residential handler scenarios assessed resulted in inhalation MOEs that do not exceed HED's level of concern ( i.e., MOEs ≥ 100 for short - term exposure durations). All adult and children inhalation and incidental oral post - application short - term risk estimates from in door surface directed sprays scenarios ( c rack and crevice and spot treatments) resulted in MOEs that do not exceed HED's level of concern ( i.e., MOEs ≥ 100 ) at the proposed reduced maximum volume rate of 1 gallon diluted product per 1000 sq ft . The short - term aggregate (residential plus dietary food and water) risk estimates for adults and children are below HED’s level of concern when considering residential exposure s from indoor surface directed spray s (spot treatments) assuming a reduced volume application rate of 1 gallon diluted product per 1000 sq. ft . **2. 2**  **Label Recommendations from Residential Assessment** HED recommends amending the “Application Directions” section of the Arilon label ( EPA Reg. No. 100 - 1501) to list the maximum spray volume allowed ( i.e ., 1 gallon diluted product per 1000 sq ft) for all indoor application scenarios . **3 .0**  **R ESIDENTIAL**  **E XPOSURE AND**  **R ISK**  **E STIMATES**  Both residential handler and post - application exposures have been previously assessed for the indoor uses of indoxacarb ( 05/01/2013, D464583, A. Rivera - Lupianez ). The residential exposures for the proposed amendment to the Arilon indoor use label are reassessed below. D ermal exposures resulting from residential uses are not quantitativel y assessed as a dermal toxicity

endpoint is not identified for indoxacarb. Only inhalation and incidental oral exposures are assessed for the indoor residential uses of indoxacarb. The handler and post - application exposures for this residential use are expected to be short - term in duration. The risk estimates from residential exposures will impact the human health aggregate risk assessment for indoxacarb. **3 .1**  **Residential Handler Exposure/R isk Estimates**  HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of e ach task. Residential handlers are addressed somewhat differentl y b y HED as homeowners are assumed to complete all elements of an application without use of any protective equipment. The quantitative exposure/risk assessment developed for residential ha ndlers for the indoxacarb indoor use is based on the following scenario : (1) Mixing/loading/appl ying water- soluble packaging formulation for indoor s prayPage 5 of 8 applications with manually-pressurized hand wand ( crack and crevice and spot directed treatments ) for insect control on households/domestic dwellings . Residential Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential post - application risk assessment for indoxacarb. Each a ssumption and factor is detailed in the previous occupational and residential assessment (D464583 ). Application Rate: 0. 0 11 lb ai total isomer/gal for indoor spray applications of water - soluble packaging formulation . Summary of Residential Handler Non - Cancer Exposure and Risk Estimates The residential handler scenarios assessed resulted in inhalation MOEs that do not exceed HED's level of concern ( i.e., MOEs ≥ 100 for short - term exposure durations). Table 3.1 presents a summary

of the residential handler scenario assessed. **Table 3.1. Residential Handler Short -**  **Term Exposure and Risk Estimates for Indoxacarb Indoor Surface Treatments of**  **Arilon 20%**  **(KN128/KN127:75:25 Isomeric Mixture). Exposure Scenario**  **Level of**

**Concern Inhalation Unit** 

**Exposure (m** **g/lb ai) Ma** **xim um** 

**Application Rate**  **a Area Treated** 

**or Amount Handled**  **Daily b**  **Inhalation**

**Dose (m** **g/k g/day)**  **c MOE**  **d** Mixer/Loader/Applicator (M/L/A) Crack and Crevice and Spot - Directed Treatments (Indoor Environments) Arilon Insecticide 20% ai - EP A Reg. No. 100 - 1501 Manually Pressurized Hand Wand (water dispersible packets) 100 1.1 0.011 lb ai/gal (0. 00001 lb ai/ft2 ) 0.5 gal 0.000076 80,000

a. . Based on registered label (EPA Reg. No. 100 - 1501 ). Application rates = maxim um application rates from label (EPA Reg. No.: 100 - 1501 ). The application rate s have been adjusted by a 4/3 factor to account for 4 parts of total (S - and R- ) indoxacarb for every 3 parts of S - indoxacarb . b. . Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html ). c . Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day

or gallons/day) ÷ Body Weight ( 80 kg). d . Inhalation MOE = Inhalation NOAEL ( 6 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). **3 .**  **2 Residential Post** **- application Exposure/Risk Estimates**  **from Indoor Surfaces Directed Spray Scenarios (Crack and Crevice and Spot**  **Treatments)** Post - application exposure can result from pesticide residue transfer to the skin of individuals who contact previously treated indoor surfaces ( e.g., carpets, floors, furniture, and other surfaces) during standard activities and/or who inhale pesticide vapors that emit from treated surfaces after application . Such exposure is assumed to occur for adults and small children. An assessment has been conducted for inhalation (adults and children 1 to < 2 years), and incidental oral (children 1 to < 2 years) exposures from the proposed amended indoor use of indoxacarb. These lifestages are not the onl y lifestages that could be potentially

exposed for these post - application scenarios; however, the assessment ofPage 6 of 8

these lifestages is health protective f or the exposures and risk estimates for any other potentially

exposed lifestages. Residential Post - application Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential post - application risk assessment for indoxacarb. Each assumption and factor is detailed in the previous occupational and residential assessment (D464583 ). Application Rate: 0. 0 11 lb ai total isomer/gal and maximum spray volume allowed of 1 gallon diluted product per 1000 sq ft equivalent to 0.00001 lb ai total isomer /ft2

. Summary of Residential Post - application Non - Cancer Exposure and Risk Estimates A summary

of the adult and children short - term exposure and risk estimates from the proposed indoor s urfaces directed spray s cenarios is shown in Table 3.2 . All adult and children inhalation risk estimates do not exceed HED’s level of concern (MOEs ≥ 100) . All children oral non - dietary ingestion risk estimates for indoor treatments do not exceed HED’s level of concern (MOEs ≥ 100). Combined inhalation and oral non - dietary ingestion risk estimates for children are not of concern to the Agency at the proposed reduced maximum volume rate of 1 gallon diluted product per 1000 sq ft . **Table 3.2**  **. Residential Post -**  **application ST (Non -**  **Cancer) Exposure and Risk Estimates for Indoxacarb**  **Indoor Surface Treatm ents of**  **Arilon 20%**  **( KN128/KN127:**  **75:25 Isom er**  **ic Mixture).** Lifestage Post - application Exposure

Scenario Application Rate a, (lb ai/ ft2 ) Dose b ,

(mg/kg/day) MOEs c Com bined Routes (X indicates included in Com bined MOE) Com

bined MOEs d Route of Exposure Use Site Crack and Crevice and Spot Directed Treatments (Indoor Surface Directed Sprays Scenario)

Arilon Insecticide 20% ai - EPA Reg. No. 100 - 1501 Adult Inhalation Surface directed sprays

0.00001 lb ai

total isomer /ft2 (0.011 lb ai/gal) 2.5 x 10 - 8 2.4 x 10 8 NA

Child 1 < 2 years old Oral Hand - to - Mouth from carpets (crack and crevice treatment) 0. 00 3 2 630

130 Hand - to - Mouth from carpets (spot directed Treatment) 0.0158 130 X Object - to Mouth from carpets (crack and crevice 0.00 04 4,800Page 7 of 8

**Table 3.2**  **. Residential Post -**  **application ST (Non -**  **Cancer) Exposure and Risk Estimates for Indoxacarb**  **Indoor Surface Treatm ents of**  **Arilon 20%**  **( KN128/KN127:**  **75:25 Isom er**  **ic Mixture).** Lifestage Post - application Exposure

Scenario Application Rate a, (lb ai/ ft2 ) Dose b ,

(mg/kg/day) MOEs c Com bined Routes (X indicates included in Com bined MOE) Com

bined MOEs d Route of Exposure Use Site Crack and Crevice and Spot Directed Treatments (Indoor Surface Directed Sprays Scenario)

Arilon Insecticide 20% ai - EPA Reg. No. 100 - 1501 treatment) Object - to Mouth from carpets (spot directed Treatment) 0.0021 950 Inhalation Surface directed

sprays 1.1 x 10 - 7 5.7 x 10 7 X Note: Assumes both spot treatment and crack and crevice directions are amended to reduce the maximum volume of product used to 1 gallon diluted product per 1000 sq. ft . a. Based on maximum application rates from proposed amended label (EPA Reg. No.: 100 - 1501). The application rate have been adjusted by a 4/3 factor to account for 4 parts of total (S - and R- ) indoxacarb for every 3 parts of S indoxacarb. b . Crack and Crevice and Spot Directed Treatment Scenarios Dose Equations Hand - to -Mouth Dose (mg/kg/day) = [(Fraction of ai on Hands (0.15) x Dermal Exposure (0.14)) ÷ (2 x Surface Area of 1 hand (150 cm 2 ) ) × Fraction of Hand Mouth ed (0.13) × Exposure Time per Day (carpet, 4; hard surfaces, 2 hours hrs/day) × # of Replenishment Intervals per Hour (4 int/hr) × (1 - ((1 - Saliva Extraction Factor (0.5)) ^ (Number of Hand - to - Mouth Events per Hour (20 events/hr) ÷ ( # of Replenishment Intervals per Hour (4)))] / Body Weight (child, 11 kg)] Object- to -Mouth Dose (mg/kg/day) = [(Deposited Residue (1.0 μg/cm 2 ) x Fraction of Residue Transferred to an Object(carpet, 0.06; hard surface, 0.08)) × Unit Conversion Factor (0.001 mg/μg) × Object Surface Area Mouthed (10 cm2/event) × Exposure Time (carpet, 4; hard surface, 2 hrs/day) × # Replenishment Intervals per Hour (4 int/hr) × (1 - ((1 - Saliva Extraction Factor (0.50)) ^ (# Object - to - Mouth Events per Hour (14 events/hr) ÷ # Replenishment Intervals per Hour (4/ hr))) ÷ Body Weight (child, 11 kg)] Inhalation Daily Dose (mg/kg/day) = [(Inhalation Rate (0.64, adult; 0.33 child m3 /hr) x Mass of Active Ingredient Applied (298 mg ai)) ÷ (Air Exchanges per Hour (0.45/hr) x Vo lume of Room (33 m3 )) ÷ [1

– ((Air Exchanges per Hour (0.45/hr) x e ^ ( - First Order Decay Rate (2.1 x 10 - 5 ) x Exposure Time (hr)))

– (First Order Decay Rate (2.1 x 10 - 5 ) x e ^ ( - Air Exchanges per Hour (0.45/hr) x Exposure Time (hr))) ÷ (Air Exchanges per H our (0.45/hr)

– First Order Decay Rate (2.1 x 10 - 5 ))] ÷ Body Weight (child, 11 kg)] c . MOEs: Inhalation MOE = Inhalation NOAEL (6 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Oral MOE = NOAEL (2 mg/kg/day) / Oral Dose (mg/kg/day) d . Combined MOE = 1 ÷ [( 1/incidental oral MOE) + (1/ Inhalation MOE )], where applicable. **3 .**  **3 Short** **- Term**  **Aggregate Assessment** The short - term aggregate risk for indoxacarb includes background contribution from dietary (food and drinking water) exposure plus the short - and/or intermediate - term post application exposure to spray- treated indoor areas. The scenarios use d in the aggreg ate assessment for indoxacarb are detailed below:Page 8 of 8

 The short - term residential exposure for use in the adult aggregate assessment reflects residential handler inhalation from indoor treatments with surface directed spray s (spot treatments) .  The short - term residential exposure for use in the child (1<2 years) aggregate assessment reflects combined post - application inhalation and incidental oral (hand - to - mouth) exposures from indoor treatments with surface directed spray s ( spot treatments) . The short - term aggregate (residential plus dietary) risk estimates for adults and children are below HED’s level of concern when considering residential exposure s from indoor surface directed spray s (spot treatments) assuming a reduced spray volume application rate of 1 gallon diluted product per 1000 sq. ft (Table 3.3 ). **Table 3.3**  **. Short -**  **Term Aggregate Risk Calculations**  **Residential (**

**Indoor Spray**

**) plus Dietary (Food and Water)**  **Exposures Population**  **Short -**  **Term Scenario**

**LOC for Aggregate**  **Risk a**  **Dietary**

**MOE b**  **MOE Oral**

**Residential Exposure**  **c MOE** 

**Inhalation Residential**  **Exposure d**  **Aggregate MOE (food,**

**water, and residential) e**  Adult 100 1 , 800 NA 80,000 1 , 800 Child (1<2 yrs) 100 840 130 5.7 x 10 7 110 a LOC=100 (10x inter - and 10x intra - species uncertainty factors) b MOE dietary = [(short - or intermediate - term oral NOAEL)/(chronic dietary exposure)]. Oral NOAEL= 2.0 mg/kg/day. Chronic dietary exposure value from D402099, 05/02/2013; Table 5.4.5 . c MOE oral = [(short - or intermediate - term oral NOAEL)/(hand - to - mo uth residential exposure)]. Oral NOAEL= 2 mg/kg/day. d MOE inhalation = [(short - or intermediate - term inhalation NO AEL)/ (high end inhalation residential exposure)]. Inhalation NOAEL= 6 .0 mg/kg/day. Adult residential handler exposure value from Table 3.1 and c hild residential exposure value from Table 3.2 . e MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE inhalation)]

**4 .**  **0 R** **EFERENCES** Rivera - Lupiáñez A., D464583 , 05 / 01 /20 13. **Indoxacarb** : Revised Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on B ean ( dry) , B ean (snap), Bean (forage), and S mall Fruit Vine Climbing Subgroup 13 - 07F and Low Growing Berry

Subgroup 13 - 07H . Drew D . et al ; D402099, 05 / 02/2013. **Indoxacarb :**  Human Health Risk Assessment for the Proposed New Use on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13 - 07F and L ow Growing Berry Subgroup (except strawberry) 13 - 07H .