Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 1 of 56 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **: November 25**  **, 2013 SUBJECT:**  **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 . PC Code: 067710 DP Barcode: D4 16367 Decision No.: 464583 Registration No. : 352 - 579 and 352 - 638 Petition No.: 2E8029 Regulatory Action: Section 3 Registration Risk Assessment T ype: Single Chemical

Aggregate Case No.: NA T XR No.: NA CAS No.: 173584 - 44 - 6 MRID No.: NA 40 CFR: §180.564 **FROM:** Danette Drew, Chemist

Id eliz Negrón - Encarnación, Ph.D., Chemist Ana Rivera - Lupiáñez, Chemist William Irwin, Ph.D., Toxicologist Risk Assessment Branch V/VII Health Effects Division (7509P) **THROUGH:** Michael Metzger, Branch Chief

Risk Assessment Branch V/VII Health Effects Division (7509P) **TO:** Laura Nollen, Risk Manager

Barbara Madden, Risk Manager Risk Integration, Minor Use & Emergency Response Branch Registration Division (7505P)Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 2 of 56 1.0 Executive Summary ................................ ................................ ................................ ............. 4 2.0 HED Recommendations ................................ ................................ ................................ ....... 7 2.1 Data Deficiencies ................................ ................................ ................................ ............. 7 2.2 Tolerance Considerations ................................ ................................ ................................ . 8 2.2.1 Enforcement Anal ytical Method ................................ ................................ .................. 8 2.2.2 Recommended Tolerances ................................ ................................ ............................ 8 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ ........ 9 2.2.4 International Harmonization ................................ ................................ ......................... 9 2.3 Label Recommendations ................................ ................................ ................................ 10 2. 3.1 Recommendations from Residue Reviews ................................ ................................ . 10 2.3.2 Recommendations from Occupational Assessment ................................ ................... 10 2.3.3 Recommendations from Residential Assessment ................................ ....................... 10 3.0 Introduction ................................ ................................ ................................ ........................ 10 3.1 Chemical Identity ................................ ................................ ................................ ........... 10 3.2 Phy sical/Chemical Characteristics ................................ ................................ ................. 11 3.3 Pesticide Use Pattern ................................ ................................ ................................ ...... 12 3.4 Anticipated Exposure Pathway s ................................ ................................ ..................... 13 3.5 Consideration of Environmental Justice ................................ ................................ ....... 13 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................ 14 4.1 Summary

of Toxicological Effects ................................ ................................ ................ 14 4.2 Safety

Factor for Infants and Children (FQPA Safety Factor) ................................ ....... 16 4.2.1 Completeness of the Toxicology Database ................................ ................................ 16 4.2.2 Evidence of Neurotoxicity ................................ ................................ .......................... 16 4.2.3 Evidence of Sensitivity /Susceptibility

in the Developing or Young Animal ............. 17 4.2.4 Residual Uncertainty in the Exposure Database ................................ ......................... 17 4.3 Toxicity

Endpoint an d Point of Departure Selections ................................ .................... 17 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 21 5.1 Residues of Concern Summary and Rationale ................................ ............................... 21 5.2 Food Residue Profile ................................ ................................ ................................ ...... 22 5.3 Water Residue Profile ................................ ................................ ................................ .... 23 5.4 Dietary

Risk Assessment ................................ ................................ ................................ 24 5.4.1 Description of Residue Data Used in Dietary Assessment ................................ ......... 24 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ .................... 24 5.4.3 Acute Dietary

Risk Assessment ................................ ................................ .................... 25 5.4.4 Chronic Dietary

Risk Assessment ................................ ................................ .............. 25 5.4.5 Summary

Table ................................ ................................ ................................ ........... 25 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ ..... 26 6.1 Residential Handler Exposure ................................ ................................ ........................ 26 6.2 Residential Post - Application Exposure ................................ ................................ .......... 29 6.3 Residential Risk Estimates for Use in Aggregate Assessment ................................ ...... 34 6.4 Residential By stander Post - application Inhalation Exposure ................................ ........ 37 6.5 Spray

Drift ................................ ................................ ................................ ...................... 37 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ....... 38 7.1 Acute Aggregate Risk ................................ ................................ ................................ .... 38 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ............................... 38 7.3 Long - Term (Chronic) Aggregate Risk ................................ ................................ ........... 39Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 3 of 56 7.4 Cancer Aggregate Risk ................................ ................................ ................................ ... 40 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ....... 40 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .... 40 9.1 Short - and Intermediate - Term Handler Risk ................................ ................................ . 42 9.2 Short - and Intermediate - Term Post - Application Risk ................................ ................... 45 9.2.1 Dermal Post - Application Risk ................................ ................................ .................... 46 9.2.2 Inhalation Post - Application Risk ................................ ................................ ................ 46 10.0 References ................................ ................................ ................................ .......................... 47 Appendix A. Toxicology Profile and Executive Summaries ................................ ....................... 48 Appendix B. Phy sical/Chemical Properties ................................ ................................ ................. 55 Appendix C. Review of Human Research ................................ ................................ ................... 56Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 4 of 56 **1.0 Executive Summary**  The Registration Division (RD) requested that the Health Effects Division (HED) conduct a human health risk assessment to support an IR - 4 petition (PP# 2E8029) for the proposed foliar uses of the insecticide indoxacarb on the following agricultural crops: 1) new uses on dry beans and succulent beans and 2) expanded crop group uses on small fruit vine climbing subgroup 13 - 07F (except kiwifruit) and low - growing berry subgroup 13 - 07H (except strawberry). 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, is an oxadiazine class insecticide active ingredient (ai) . It is registered for use in both agricultural and residential sites. Permanent tolerances are established under 40 CFR 180.564(a) for the combined residues of indoxacarb and its R- enantiomer on a number of plant as wel l as livestock commodities (tolerances on poultry commodities also include several indoxacarb metabolites) . The primary residues of toxicological concern for risk assessment are indoxacarb (S - enantiomer) and its R - enantiomer ; various metabolites and degradates are also included as residues of concern in milk, poultry commodities and drinking water. This assessment takes into account the proposed crop uses and previousl y registered uses on other crops and in residential sites. Indoxacarb is formulated as granular; impregnated materials; water dispersible granules; emulsifiable, flowable and soluble concentrates; and solution - ready- to - use products. Indoxacarb products are frequently

formulated as a mixture of the insecticidall y active S - enantiomer and the insecticidally

inactive R - enantiomer. The percent active ingredient and application rates listed on indoxacarb product labels only reflect the S - enantiomer ; labels do not reflect the amount of R - enantiomer in the mixtures . Adjustments are made in this assessment to add in the percent of R - enantiomer in product mixtures so that the total amount of indoxacarb applied (both S - and R enantiomers) is considered. The term ‘indoxacarb’ generally refers to the S - enantiomer (also called DPX - KN128 or KN128) but may also refer to a mixture. Mixtures may appear as 1) isomer enriched DPX - MP062 (also referred to as MP062) which is a mixture containing the S enantiomer and its R - enantiomer at approximately a 75:25 ratio , or 2) racemic mixture DPX JW062 (also referre d to as JW062) which is a mixture of the enantiomers at a 50:50 ratio . The R - enantiomer is also referred to as IN - KN127 or KN127. The database for indoxacarb is complete and is sufficient for characterizing toxicity . Toxicology studies have been performed using either MP062 or JW062 (S - enantiomer and R - enantiomer mixtures ) or the KN128 (S - enantiomer onl y) . The toxicity

profiles for KN128, MP062 and JW062 in rats, mice and dogs with both subchronic and chronic oral exposures were qualitativel y similar. The endpoints that most frequently defined the lowest - observed - adverse - effect - level (LOAEL) were non - specific, and included decreases in body weight, weight gain, food consumption and food efficiency. These compounds also affected the hematopoietic s ys t em by decreasing the red blood cell count, hemoglobin and hematocrit in rats, dogs and mice .Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 5 of 56 There was no evidence of reproductive effects in the 2 - generation reproduction study in rats . There was no evidence of susceptibility from either in utero or neonatal exposure to both rat and rabbit young or in the developmental neurot oxicity study in rats . Neurotoxicity

was seen in animal studies in rats and mice but at doses much higher than those selected for point s of departure (which are based on chan ges in body weight, food consumption and changes in hematology) for the current risk assessment . There is no evidence of t eratogenicity , mutagenicity , or carcinogenicity in the indoxacarb studies. 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 . The only new toxicity

information received since the last indoxacarb risk assessment s (D351087 , 5/18/09, Indoxacarb. Health Effects Division (HED) Human Health Risk Assessment for Bushberry Crop Subgroup 13 - 07B and Beets (Garden **)** and D365306 , 5/26/09 , Indoxacarb. Addendum to the Health Effects Division (HED) Hum an Health Risk Assessment for Bushberry Crop Subgro up 13 - 07B and Beets (Garden) ) is the immunotoxicity study , which did not indicate immunotoxic potential for indoxacarb. The toxicity endpoints have not changed with the exception of the addition of a long - term oral endpoint to cover residential uses of that duration and a revision to the dermal toxicity endpoint. The long - term oral endpoint and point of departure are the same as th ose selected for short - and intermediate

–term durations. A re evaluation of the available dermal toxicity studies, including rat in vivo , and rat and human in vitro studies, has been performed. Based on this evaluation, it has been determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity is therefore not expected in humans . Acute and chronic dietary ( combined food and drinking water) assessments were performed for indoxacarb using partially refined assumptions such as residues from field trail data and, where available, percent crop treated estimates and processing factors. Estimated drinking water concentrations were derived from modeling procedures. The resulting acute and chronic dietary exposures are below HED’s level of concern for the general U.S. population and all population subgroups (aPAD or cPAD <100%). No new residential uses are being requested with this petition; however, there are existing residential uses ( ornamental lawns and turf/golf courses , and spot - on applications for the control of fleas and ticks on domestic animals ) that have been previousl y assessed and are assessed herein t o reflect updates to HED’s 2012 Residential SOPs 1 , policy changes for body

weight assumptions , and a re - evaluation of the dermal toxicity of indoxacarb . In addition, there are existing residential uses (insect control treatments of household premises; Arilon Insecticide 20% ai , EPA Reg. No. 100 - 1501 and A perion Insecticide 14.5 % ai , EPA Reg. No. 352 - 770 ) wh ich do not appear to have been previously assessed and are assessed herein. 1 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 6 of 56 Indoxacarb RTU bait stations and gels products are formulated at very low application rates and are designed to be self

- contained; therefore, handler contact is expected to be negligible and post - application exposures are not expected. Exposure and risk f or these uses were not quantified. Inhalation assessments are not performed for appl yi ng pet spot - on treatments as inhalation exposure is not expected from these uses. D ermal exposures are expected to be negligible when appl yi ng spot - on products ; in addition , indoxacarb does not have a dermal toxicity endpoint for humans. Therefore, a quantitative handler assessment is not performed for the indoxacarb pet spot - on treatments. Residential adult handler scenarios assessed include turf applications and indoor spray applications (inhalation only). Residential post - application scenarios assessed include 1) children ’s exposure (inhalation and non - dietary oral) to treated pet s, treated turf and spraytreated indoor surfaces and 2) adult exposure to spray- treated indoor surfaces (inhalation onl y). Most indoxacarb residential handler (adult) and post - application (adult and children) exposure scenarios result in risk estimates below HED’s level of concern . However, for spot- directed treatments of the indoor directed spray , incidental oral (hand - to - mouth) exposure estimates alone for children exceed HED’s level of concern. For crack and crevice treatment only scenario of the indoor directed spray , the combined inhalation and incidental oral ris k estimates for children are not of concern. Based on the existing and newly proposed uses of indoxacarb, exposures can occur both from dietary sources (food and water) and in residential settings. Acute, short - term, intermediate - term and long - term (chronic) aggregate (combined food, water and residential exposure) assessments were performed for indoxacarb. The scenarios resulting in the highest exposures are selected as protective scenarios for the aggregate assessments. There are no acute, short - term, intermediate term, or long - term (chronic) aggregate risk estimates of concern for adult (handler or post application) or child (post - application) exposure to indoxacarb as a result of current and proposed uses. **Note: the aggregate assessme nt for indoor surface directed spray assumed**  **only crack and crevice**  **treatment. The residential post -**  **application (hand -**  **to -**  **mouth) exposure to the**  **spot**

**- directed**  **sprays resulted in risks of concern for children and was not used in the aggregate assessment. A** **t this time, labels for the indoor surface directed sprays do not limit the use to only crack and crevice.**  A quantitative dermal risk assessment is not required for indoxacarb . All occupational handler scenarios assessed associated with the proposed uses result in inhalation MOEs that do not exceed HED's level of concern ( MOEs ≥ 100) for short - and intermediate - term exposure durations at label specified personal protective equipment ( PPE ) . Further, there were no risks of concern identified for post - appli cation exposure to indoxacarb associated with these new uses. No additional (PPE) is required. The label restricted entry interval (REI) of 12 hours is appropriate and in compliance Worker Protection Standard requirements. Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898 (see Section 3.5 of this document). For information regarding human studies, see Appendix C.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 7 of 56 **2.0 HE**  **D Recommendations**  Assuming spot - directed spray treatments are removed from residential product labels (i.e. use limited to crack and crevice onl y) , HED has no objection to registration and associated tolerances for the use of indoxacarb on dry bean s , s uc culent bean s , small fruit vine climbing subgroup 13 - 07F (except kiwifruit) and low growing berry subgroup 13 - 07H (except strawberry) . Additional requirements are outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Secti on 2.2, and label modifications are discussed in Section 2.3. **2.1 Data Deficiencies**  Residue Chemistry 860.1200 Directions for Use The proposed label directions are adequate for evaluating the residue data for the proposed new uses. However, the labels should be revised to clarify discrepancies or add specificity (see Section 2.3.1 of this document). 860.1550 Proposed Tolerances A revised Section F should be submitted according to Table 2.2.2. 860.1650 Submittal of Analy tical Reference Standards An anal ytical standard for the insecticide indoxacarb is currentl y available in the EPA National Pesticide Standards Repository . However, the indoxacarb standard has an expiration date of 4/2013. A reference standard should be sent to the Anal ytical Chemistry Laboratory

located in Fort Meade to the attention of either Theresa Cole or Thuy Nguyen at the following address: USEPA National Pesticide Standards Repository /Anal ytical Chemistry

Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755 - 5350 Please note that mail will be returned if the entire extended zip code is not used when addressing correspondence to the Repository . Toxicology and Hazard None. Occupational and Residential Exposure None.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 8 of 56 **2.2 Tolerance Considerations**  **2 .2.1**  **Enforcement Analytical Method**  A number of adequate methods are available for enforcing indoxacarb tolerances on plant commodities. These protocols are all common moiety methods which measure both indoxacarb and its R - enantiomer as a single component . The primary p rotocol for the tolerance enforcement of plant commodities is DuPont method AMR 2712 - 93 which is an HPL C/UV procedure. It has been validated by the Agency

and forwarded to the FDA for inclusion in PAM Vol. II (D267339, S. J. Lev y, 10/12/20 00). For the confirmation of residues in plant commodities, DuPont method AMR 3493 - 95 Supplement No. 4 is a GC/MSD procedure is also available. This method has also been v alidated b y the Agency and forwarded to the FDA accordingl y (D282821, S. J. Lev y, 0 5/ 0 9/20 02). Residues are quantified using the m/z 527 ion, and confirmatory anal ys es utilize the 218, 321 and 527 ions. Another HPL C/UV procedure developed by the registrant, DuPont - 11978, is also available for tolerance enforcement analy ses (D313518, S. J. Levy, 02/18/2005). This protocol works b y uniquely combin ing the extraction procedure of method AMR - 3493 - 95 with the cleanup and determination techniques developed in m ethod AMR 2712 - 93. **2.2. 2**  **Recommended Tolerances** HED recommends that 40 CFR 180.564 be amended by establishing or removing tolerances for the plant commodities as listed in the Table 2.2.2. Tolerances for livestock commodities and rotational crops are not needed to support the proposed uses of indoxacarb . The tolerances for indoxacarb in p lant commodities are defined as follows : Tolerances are established for residues of indoxacarb, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only 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(3 H ) - carbox yl ate, and its R - enantiomer, (R) - methyl 7 - chloro - 2,5 - dihydro - 2 - [[(methoxycarbonyl )[4 - (trifluoromethox y)phenyl ]amino]carbonyl]indeno[1,2 - e ][1,3,4][ oxadiazine - 4a(3 H ) - carbox yl ate, in or on the commodity .Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 9 of 56 **Table 2.2.2**  **. Tolerance Summary fo r**  **Indoxacarb .**  **Comm odity**  **Established/Proposed Tolerance (ppm)**  **HED -**  **Recommended Tolerance (ppm)**  **Comments ( correct** 

**commodity definition )**  Bean, dry, seed 0.07 0. 2 Pea, southern, seed 0.1 Remove Bean, succulent 0.64 0.9 Bean, forage 37 50 Cowpea, forage Cow pea, hay -- 100 Small fruit vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F 2.0 2 Lo w growing berry, except straw berry , subgroup 13 - 07H 0.9 1 Cranberry 0.90 Remove Grape 2.0 Remove **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** The registrant - proposed tolerances for indoxacarb are different from those recommended by the HED. The recommended tolerances were derived by using the Organization for the Economical Cooperation and Development (OECD) calculation procedures while the registrant used the North America Free Trade Agreement (NAFTA) calculation procedures. In addition, the tolerance for indoxacarb on dry beans covers the southern pea variety (cowpea) which already has a tolerance established in the CFR. Since the forage and hay of cowpea are the onl y significant feedstuff associated with dry beans, the correct commodity definition would be cowpea, forage instead of bean, forage. HED is recommending a tolerance be established for residues of indoxacarb on cowpea hay ; a tolerance for cowpea hay was not proposed. In order to harmonize with the Codex maximum residue level (MRL) for cowpea (see discussion in 2.2.4 below), the tolerance for dry bean obtained b y the OECD calculation procedures (0.06 ppm) will be increased to 0.2 ppm. The registrant should submit a revised Section F in which the proposed tolerances are the same as those recommended b y the HED. **2.2. 4**  **International Harmonization** U.S. tolerances are recommended for dry beans, succulent beans, small fruit vine climbing subgroup 13 - 07F, and low growing berry subgroup 13 - 07H based on residues of indoxacarb and its R - enantiomer. Maximum residue limits (MRLs) have not been established by Canada or Mexico. However, Codex has established MRL s for grapes (2 ppm), dry grapes (5.0 ppm), cranberries (1ppm), dry

chick - pea (0.2 ppm), dry mung bean (0.2 ppm), and dry cowpea (0.1 ppm) based on measurement of indoxacarb and its R - enantiomer. The U.S. tolerances for raisins (5.0 ppm) and cranberries (1 ppm) are harmonized with the corresponding Codex MRL s. The U.S. tolerance for grapes (subgroup 13 - 07F) obtained with the OECD calculator (3 ppm) is higher than the Codex MRLfor grapes (2 ppm). Th e U.S. crop field trial data for grapes show that the highest residue is 1.74 ppm, and the registrant proposed a tolerance level of 2.0 ppm. HED recommends establishment of a grape tolerance level of 2 ppm in order to harmonize with Codex. The tolerance level for dry bean (0.06 ppm) obtained by the OECD calculationIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 10 of 56 procedures will be increased to 0.2 ppm in order to harmonize with the Codex MRL s for dry chick pea and dry

mung bean. **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews**  The following label recommendations are needed to clarify discrepancies or add specificity:  Under the application instructions (page 3 of Avaunt ® label) in clude dry bean in the sentence “For bushberry , cranberry , **dry bean** , pome and stone fruit the minimum interval between treatments is 7 day s.”

 Under the tabulated instructions (page 6 of Avaunt® label and page 5 of Steward ® EC label) for dry

bean and/or succulent bean edit the sentence “Make a uniform application in approximately

20 - 100 gallons of water per acre” to specify the volume for ground and/or aerial applications. **2.3.2 Recommendations**  **from Occupational Assessment** None. **2.3.3 Recommendations f**  **rom Residential**  **Assessment** The assessment for indoxacarb indoor surface s directed sprays resulted in post - application risk estimates of concern for children for spot- directed treatment scenarios ; however, when the surfaces directed spray

treatments were assumed to be limited to crack and crevice only , risk estimates were not of concern. HED recommends amending the EPA Reg. No. 100 - 1501 label to restrict indoor residential uses to only c rack and crevice treatments limiting applications to areas not accessible to young children ; any spot, perimeter, or baseboard treatments should be restricted on the label. **3.0 In**  **troduction 3.1**  **Chemical Identity**Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 11 of 56 **Table 3.1 Indoxacarb Nomenclature.**  Com pound

Common name Indoxacarb Com pany experimental name DPX - KN128 IUPAC name (S) - me thyl 7 - chloro - 2,5 - dihydro - 2 - [[(methoxycarbonyl)[4 - (trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2 - e][1,3,4]oxadiazine 4a(3 H ) - carboxylate CAS name methyl (4aS) - 7 - chloro - 2,5 - dihydro - 2 - [[(methoxycarbonyl)[4 - (trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2 - e][1,3,4]oxadiazine 4a(3H) - carboxylate CAS registry number 173584 - 44 - 6 End - use product (EP) 30% WDG (DuPont Avaunt® Insecticide; EPA Reg. No. 352 - 597) and 16% Em usifiable Concentrate (Steward ® EC Insecticide; EPA Reg. No. 352 - 638) Com pound

Common name R- enantiomer of indoxacarb Com pany name IN - KN127 (pesticidally inactive ) **3.2 Physical/Chemical Characteristics**  Indoxacarb has a very

low vapor pressure of 1.9x10 - 10 mm Hg at 25 oC; volatilization is not expected to be a significant route of dissipation for this pesticide. The octanol water partition coefficient (Kow = 44000) suggests that it is lipophilic. In doxacarb is sl ightly soluble in water ( 0.8 mg/L at pH 7 ) . Indoxacarb is stable to aqueous photoly sis and hydroly sis. Aerobic aquatic, aerobic soil, and anaerobic aquatic metabolism of indoxacarb results in half - lives of 71 day s, 267 day s, and 577 day s, respectively . See Appendix B for a table of p hy sicochemical p roperties of indoxacarb. O N N

O O CH 3 Cl N O O O

O C F 3 C H 3

O N N

O O C H 3 Cl N O O O C H 3

O C F 3Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 12 of 56 **3.3 Pesticide Use Pattern**  IR - 4 has submitted field trial data in support of a petition p roposing tolerances for the use of Avaunt ® WDG and Steward® EC on dried beans and Avaunt ® WDG on succulent beans. In addition, crop subgroup tolerances and registration of Avaunt® WDG for use on small fruit vine climbing subgroup (except kiwifruit) 13 - 07F, and low growing berry subgroup (except strawberry) 13 - 07H are proposed based on established tolerances for grapes and cranberries . The proposed new uses are summarized below in Table 3. 3. Refer to section 2.3 for recommended modifications to the proposed labels. **Table 3. 3**  **Summary of Directions for Use of Indoxacarb.** Applic. Timing, Type, and Equip. 1 Form ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations 2 **Bean, succulent**  Broadcast foliar applications when insects reach economic thresholds; ground or air equipment 30% WDG [352 - 597] 0.11 NS 0.44 3 A minimum 7 - day RTI is specified. Make a uniform application of approximately 20 - 100 gal/A . **Bean, dry** Broadcast foliar applications when insects reach economic thresholds; ground or air equipment 30% WDG [352 - 597] and 16% EC [352 - 638] 0.11 NS 0.44 7 A minimum 7 - day RTI is specified. Make a uniform application of approximately 20 - 100 gal/A . **Sm all fruit vine climbing, except fuzzy kiwifruit, subgroup 13**  **- 07F**  Broadcast foliar applications when insects reach economic thresholds; ground or air equipment 30% WDG [352 - 597] 0.11 NS 0. 22 7 A minimum 21 - day RTI is specified. Apply in a minimum of 10 gal/A and 50 gal/A for aerial and ground applications, respectively. **Low growing berry, except strawberry, subgroup 13 -**  **07H** Broadcast foliar applications when insects reach economic thresholds; ground or air equipment 30% WDG [352 - 597] 0.11 NS 0.44 30 A minimum 7 - day RTI is specified. Apply in a minimum of 5 gal/A and 10 gal/A for aerial and ground applications, respectively. 1 Do not apply through any type of irrigation system, expect for application to cranberry, mint, potato, and sweet corn, and as allowed on supplemental labels. 2 Applications may include the use of an adjuvant. Rotational crop restrictions: (1) 30%WDG: Crops with labeled uses and alfalfa, cotton, peanuts and soybeans may be planted immediately following harvest of a treated crop. Do not plant any food or feed cro ps not registered for use with indoxacarb for 30 days after last use. (2) 16% EC: Crops that are on this label and all brassica leafy vegetables, cucurbit vegetables, fruiting vegetables, leafy green vegetables, leafy petiole vegetables, pome f ruit and st one fruit, plus sweet corn, cranberry, grape, mint, southern pea and the tuberous and corm vegetables found in crop subgroup 1C (arracacha, arrowroot, Chinese artichoke, edible canna (Queensland arrowroot), bitter and sweet cassava, chayote(root), chufa, d asheen (taro), ginger, leren, potato, sweet potato, tanier (cocoyam), tumeric, yam bean (jicama, manoic pea) and true yam) may be planted immediately following harvest. Do not plant for food or feed any other crops not registered for use with indoxacarb fo r 30 days after last use.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 13 of 56 **3.4 Anticipated Exposure Pathways**  Indoxacarb is registered for use on numerous agricultural crops as well as on pets, turf and inside homes. Exposure to indoxacarb may occur from ingestion of residues in/on foods and in drinkin g water, and via the dermal and inhalation routes for adults using indoxacarb products in occupational and residential settings. In addition, both ad ults and children may

be exposed dermally or via inhalation in post - application scenarios on golf courses , lawns, and in home s; children may

also be exposed orall y in post - application scenarios on pets, lawns and in homes . There is a potential for post - application dermal or inhalation exposure for workers re - entering treated fields. Risk assessments have been previousl y conducted for indoxacarb (2009, D351087 and D365306) . The toxicity

endpoints and points of departure have not changed with the exception of the addition of a long - term oral point of departure to cover residential uses of that duration and a revision to the dermal toxicity endpoint. A re - evaluation of the dermal toxicity studies, including rat in vivo , and rat and human in vitro studies, has been performed. Based on this evaluation, it has been determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day

and dermal toxicity

is therefore not expected in humans. In addition, residential SOPs have since been revised (2012 ) and there are registered residential use products for which assessments have not been previously performed . This risk assessment considers the aforementioned relevant exposure pathway s based on all of the existing and proposed new uses of indoxacarb. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP co nsiders a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and/or the CDC under the Nat ional Health and Nutrition Examination Survey /What We Eat in America (NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized b y subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary

exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietaryIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 14 of 56 patterns among specific subgroups. **4.0 Hazard Characterization and D**  **ose -**  **Response Assessment** The only new toxicity

information received since the last risk assessment (2009; D351087 and D365306) is the immunotoxicity study , which was negative at doses up to 23 mg/kg/day . The toxicity endpoints have not changed with the exc eption of the addition of a long - term oral endpoint to cover residential uses of that duration and a revision to the dermal toxicity endpoint. The long - term oral endpoint and point of departure is the same as that selected for short - and intermediate

–term durations. A re - evaluation of the dermal toxicity studies, including rat in vivo , and rat and human in vitro studies, has been performed. Based on this evaluation, it has be en determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal L OAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity is therefore not expected in humans. **4.1 Summary of Toxicological Effe**  **cts** Indoxacarb products contain the enantiomeric compounds indoxacarb (S - enantiomer; DPX KN128) and its R - enantiomer (IN - KN127). DPX - MP062 (also referred to as MP062) is a mixture containing the S - enantiomer and its R - enantiomer at approximately a 75:25 ratio. DPX JW062 (also referred to as JW062) is the racemic mixture of the enantiomers. Many of the toxicity studies were conducted with JW062 (50:50). HED’s Hazard Identification Assessment Review Committee (HIARC; HED Doc No. 013528) determined that it is appropriate to use data from DPX - JW062 (50:50) to satisfy the requirements for dietary subchronic, chronic, oncogenicity and reproductive studies. Based on previous conclusions b y the HIARC, HED also accepted the same rationale for bridging the data f rom DPX - JW062 and DPX - MP062 to register DPX - KN128 formulations ( S - enantiomer onl y ; no R - enantiomer). The toxicity

profiles for KN128, MP062 and JW062 in rats, mice and dogs with both subchronic and chronic oral exposures were qualitativel y similar. Dermal subchronic exposure in the rat also resulted in a similar profile. The toxic signs occurred at similar doses and with a similar magnitude of response, with females generall y being more sensitive than males. The endpoints that most frequently

defined th e lowest - observed - adverse - effect - level (LOAEL) were non specific, and included decreases in body weight, weight gain, food consumption and food efficiency . These compounds also affected the hematopoietic sy stem by decreasing the red blood cell count, hemo globin and hematocrit in rats, dogs and mice. Itwas frequentl y accompanied b y an increase in reticulocytes in all three species and an increase in Heinz bodies (dogs and mice onl y). None of these signs of toxicity appeared to get worse over time. In on e subchronic rat study, the parameters appeared to return to normal levels following a four- week recovery period. High doses in the rats and mice also sometimes caused mortality . Neurotoxicity

was observed in rats and mice but at higher doses (>100 mg/kg/day) than the hematologic effects (3.3 mg/kg/day) on which the risk assessments are based. Neurotoxicity was characterized by

one or more of the following sy mptoms in both male and female rats and mice: weakness, head tilting, and abnormal gait or mobi lity with inability

to stand, ataxia. ThereIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 15 of 56 was possible evidence of lung damage in the acute inhalation studies with both MP062 and JW062. Subchronic (28 days) inhalation toxicity on indoxacarb in rats was characterized by increased spleen weights, increased pigmentation and hematopoiesis in the spleen, and hematological changes. There was no evidence of carcinogenicity in either the rat or mouse in acceptable studies (JW062). JW062 was not mutagenic in a complete battery of mutagenicity studies. There was also no evidence of mutagenicity with either KN128, or MP062. Therefore, KN128, MP062 were classified as “not likely” to be carcinogenic in humans by all relevant routes of exposure. In rats, both JW062 and MP062 were rapidly absorbed and eliminated following oral administration. The metabolite profile for DPX - JW062 was dose dependent and varied quantitatively

between males and females. Differences in metabolite profiles were also observed for the different label positions. Fat tissue contained the greatest level of radioactivity and, for both compounds, was greater in female rats. Both MP062 and JW062 were extensively metabolized and the metabolites were eliminated in the urine, feces, and bile. All of the biliary metabolites appear to undergo further biotransformation in the gut. A quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day . The rat 28 - day dermal study

had a wide dose spacing at the lowest two doses (i.e. 50 mg/kg/day and 500 mg/kg/day), thus the rat NOAEL value of 50 mg/kg/day may be well below the no - effect dose in both rats and humans. The rat in vivo dermal absorption was 4.91%, with results from an acceptable guideline study . In comparison, the ratio of the LOAELs from the rat developmental study and the rat 28 - day

dermal study of similar durations estimates the rat dermal absorption to be a much lower value of 0.8% (i.e. 100 x 4 mkd/500 mkd), with the rat dermal absorption ty picall y multipl e times higher than humans. Based on the in vitro dermal absorption data for human skin and rat skin, the rat dermal absorption was 17.5X higher than human dermal absorption, thus the calculated indoxacarb internal dose would be much higher in rats than humans. Specificall y for indoxacarb, the rat in vitro absorption was 15.2% and human in vitro absorption was 0.87%. Therefore, the dermal triple pack data was utilized to refine the dermal POD from the rat sub - chronic dermal study. Using the NOAEL value of 50 mg/kg/day from the route - specific 28 - day dermal study

in rats and the 17.5x ratio of human skin to rat skin absorption, the equivalent human dermal NOAEL is 875 mg/kg/day

for indoxacarb (mixed isomers, 50 mkd x 15.2%/0.87%). The corresponding human der

mal LOAEL value is calculated to be 8750 mg/kg/day , thus a dermal assessment is not required for indoxacarb. Additionally , utilizing the 4.91% rat dermal absorption and the rat:human dermal absorption ratio of 17.5X, the human equivalent dermal absorption is estimated to be very

low, at 0.28% , using the parallelogram method. The toxicological database for indoxacarb is complete and adequate for dose response assessment and susceptibility determinations. The immunotoxicity study in mice did not indicate to xicity to the immune system at doses up to 23 mg/kg/day . In the 28 - day inhalation study

(rats) increased spleen weights, pigmentation and hematopoiesis in the spleen, and hematological changes were observed at the highest dose tested (75.6 mg/kg/day). Increased spleen weights were also observed in the 28 - day dermal rat study

(500 mg/kg/day). The increase in spleen weights are not considered immunological in origin but can be considered a result of theIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 16 of 56 hemoly tic effects, which is the mode of action of indoxa carb. Indoxacarb is currentl y regulated based on a NOAEL of 2.0 mg/kg/day for chronic dietary

exposure (protective of hemoly tic effects) and 12 mg/kg/day for acute dietary

exposure. KN128 and MP062 appear to be of similar acute oral toxicity with an acute oral toxicity category II, while JW062 appears less toxic acutely ( acute oral toxicity

category IV) . MP062 and JW062 had low acute inhalation toxicity . MP062 and JW062 had moderate to low ocular irritant properties, while KN128 was practicall y non - irrit ating to the rabbit’s eyes. By the dermal route, KN128, MP062 and JW062 demonstrate low toxicity . By the maximization test, KN128 and MP062 were considered dermal sensitizers, while JW062 was not a sensitizer. **4.2 Safety Factor for Infants and Children**  **(FQPA Safety Factor)** The following factors supporting reduction of the FQPA safety factor (SF) to 1X: 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 postnatal toxicity ; 4) the acute neurotoxicity, subchronic neurotoxicity, and developmental neurotoxicity studies are available and all endpoints used in this risk assessment are protective of neurotoxic effects ; and 5) exposures estimates will not underestimate actual exposures . **4.2.1 Completeness of the Toxicology Database**  The toxicity

database for indoxacarb is complete. There was no evidence of reproductive effects in the 2 - generation reproduction study in rats. Teratogenici ty

was not observed in rats or rabbits. There was no evidence of susceptibility from either in utero or neonatal exposure to both rat and rabbit young or in the developmental neurotoxicity study in rats. HED has confidence that the risk assessment conducted with a reduced FQPA safety factor (1X) will provide a reasonable certainty of no harm to the safety of infants and children. **4.2.2 Evidence of Neurotoxicity**  Neurotoxicity

was observed in rats and mice but at higher doses (>100 mg/kg/day) than the hematologic effects (3.3 mg/kg/day) on which EPA’s risk assessments are based. Neurotoxicity was characterized by

one or more of the following sy mptoms in both male and female rats and mice: weakness, head tilting, and abnormal gait or mobility with inabi lity

to stand, ataxia. Acute and subchronic neurotoxicity screening batteries were performed using MP062 in rats. Neurotoxicity

was characterized by

clinical signs (depression, abnormal gait, head shake, salivation) and functional - observation battery (FO B) (circling behavior, i ncoordination, slow righting reflex, decreased forelimb grip strength, decreased foot splay , decreased motor activity). However, there was no evidence of neurohistopathology in any study. There was no evidence of increased sensiti vity

of offspring in the developmental neurotoxicity study using KN128. Clinical observations, motor activity , acoustic startle habituation, and learning and memory testing were all comparable between the control and treated groups. Mean brain weight, grossIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 17 of 56 and microscopic examinations and morphometric measurements of the brain were also comparable between the controls and treated groups. **4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  There was no evidence of susceptibili ty from either in utero or neonatal exposure to both rat and rabbit young with either MP062 or JW062. There was no evidence of increased susceptibility in the young in the developmental neurotoxicity study in rats with KN128. There was no evidence of rep roductive effects in the 2 - generation reproduction study in rats (JW062). No evidence of teratogenicity was observed in rats and rabbits with MP062 or JW062 nor evidence of teratogenicity in rats treated with KN128. **4.2.4 Residual Uncertainty in the Exp**  **osure Database** The database for indoxacarb is extensive and is sufficient for characterizing toxicity and hazard. There are no outstanding toxicity or exposure data and the FQPA safety factor is reduced to 1X. HED used partially

refined assumptions in th e dietary exposure assessment, including the use of percent crop treated and field trial residue values . Upper- bound estimates of potential exposure through drinking water were used . In addition, the residential exposure assessment was conducted such that residential exposure and risk will not be underestimated. The aggregate exposure and risk estimates presented in this assessment will not underestimate actual exposure and risk expected based on the current and proposed use patterns. **4.3 Toxicity Endpo**  **int and Point of Departure Selections** There have been no changes since the last risk assessment to the prior dose - response assessment, endpoint selection or cancer classification, except for the addition of the long - term incidental oral category

for to re sidential uses of that duration and the re - evaluation of the dermal toxicity endpoint. The long - term incidental oral point of departure is the same as that selected for the short - and intermediate - term incidental oral durations. A re - evaluation of the derm al toxicity studies, including rat in vivo , and rat and human in vitro studies, has been performed. Based on this evaluation, it has been determined that a quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day

and dermal toxicity

is therefore not expected in humans. The endpoint selections for indoxacarb are listed in Table 4.3.1. Acute Dietary Endpoint: An acute reference dose (aRfD) of 0.12 mg/kg was established fo r the general U.S. population (including infants and children). It was based on an acute oral neurotoxicity

study in the rat. A NOAEL of 12 mg/kg was based on decreased body weight, body- weight gain, and food consumption in females observed at the LOAEL of 50 mg/kg. The NOAEL is based on a 7% body weight decrease (in females onl y on day 8, but no significant differences were noted for day s 1, 2 or 15). Currently , a 10% decrease in adult body weight is the threshold for an adverse effect, thus this study N OAEL is considered to be very conservative . The standard 100 UF was applied to account for interspecies extrapolation and intraspeciesIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 18 of 56 variation. A FQPA SF of 1x is applicable for acute dietary risk assessment. Thus, the acute population - adjusted dose (aPAD) is equivalent to the aRfD of 0.12 mg/kg. An endpoint of concern attributable to a single dose for females 13 - 49 was not identified in the database. Chronic Dietary Endpoint: The chronic RfD (cRfD) of 0.0 2 mg/kg/day was based on the: 1) rat 90 - day subchronic toxicity study; 2) rat subchronic neurotoxicity study ; and 3) rat chronic/ carcinogenicity

study . The selected NOAEL was 2.0 mg/kg/day . The LOAEL s for the three co critical studies were: 1) 3.8 mg/kg/day ; 2) 3.3 mg/kg/day ; and; 3) 3.6 mg/kg/day . These were based on decreased body weight, alopecia, body- weight gain, food consumption and food efficiency in females. In addition, study #3 also had decreased hematocrit, hemoglobin and red blood cells only

at 6 months in females. Using a weight - of - evidence approach, the NOAEL for use in establishing the cRfD was 2.0 mg/kg/day). This NOAEL was also supported by the developmental neurotoxicity study in which the sy stemic toxicity NOAEL was 1.5 mg/kg/day . The standard 100 UF was applied to account for interspecies extrapolation and intraspecies variation. A FQPA SF of 1x is applicable for chronic dietary risk assessment. Thus, the chronic population - adjusted dose (cPAD) is equivalent to the cRfD of 0.02 mg/kg. Short-, Intermediate -, and Long- Term Incidental Oral: The short, intermediate and long - term endpoints were selected from the studies mentioned in the chronic dietary endpoint (see above), using the NOAEL of 2 mg/kg. A margin of exposure (MOE) of 100 is considered adequate for incidental oral exposure risk assessment. Short-, Intermediate -, and Long- Term Dermal Endpoints: A quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day . The rat 28 - day dermal study

had a wide dose spacing at the lowest two doses (i.e. 50 mg/kg/day

and 500 mg/kg/day), thus the rat NOAEL value of 50 mg/kg/day may be well below the no - effect dose in both rats and humans. The rat in vivo dermal absorption was 4.91%, with results from an acceptable guideline study . In comparison, the ratio of the LOAELs from the rat developmental study and the rat 28 - day

dermal study

of similar durations estimates the rat dermal absorption to be a much lower value of 0.8% (i.e. 100 x 4 mkd/500 mkd), with the rat dermal absorption typically multiple times higher than humans. Based on the in vitro dermal absorption data for human skin and rat skin, the rat dermal absorption was 17.5X higher than human dermal absorption, thus the calculated indoxacarb internal dose would be much higher in rats than humans. Specifically for indoxacarb, the rat in vitro absorption was 15.2% and human in vitro absorption was 0.87%. Therefore, the dermal triple pack data was utilized to refine the dermal POD from the rat sub - chronic dermal study. Using the NOAEL value of 50 mg/kg/day from the route - specific 28 - day dermal study

in rats and the 17.5x ratio of human skin to rat skin absorption, the equivalent human dermal NOAEL is 875 mg/kg/day for indoxacarb (mixed isomers, 5 0 mkd x 15.2%/0.87%). The corresponding human dermal LOAEL values is calculated to be 8750 mg/kg/day , thus a dermal assessment is not required for indoxacarb. Additionally , utilizing the 4.91% rat dermal absorption and the rat:human dermal absorption rati o of 17.5X, the human equivalent dermal absorption is estimated to be very low, at 0.28%, using the parallelogram method. Short- , Intermediate - and Long- Term Inhalation Endpoints: The short - , intermediate - , and long - term inhalation endpoints were select ed from a 28 - day inhalation toxicity

study in rats withIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 19 of 56 MP062. The NOAEL of 23 μg/L/day (equivalent to 6 mg/kg/day) was based on increased spleen weights, pigmentation and hematopoiesis in the spleen, hematological changes and mortality (females) seen at the LOAELof 290 μg/L/day (equivalent to 75.69 mg/kg/day). The effects do not seem to be progressing as study duration increases from subchronic to chronic since the NOAELs of oral subchronic and chronic studies are similar. Therefore, use of the 28 - day inhalation study

is also appropriate for the long - term exposure scenario. MOEs of 100 are considered adequate for inhalation exposure risk assessment. Carcinogenicity: Indoxacarb is classified as “not likely” to be carcinogenic to humans via relevant ro utes of exposure. Therefore, a quantitative cancer risk assessment is not required. **Table 4.3.1**  **Points of Departure and Toxicological Endpoints Selected for INDOXACARB for**  **Various Exposure Scenarios. Exposure**  **Scenario Dose for Use in Risk** 

**Assessment, UF**  **FQPA SF* and** **Level of Concern for Risk**  **Assessment Study and Toxicological** 

**Effects** Ac ute Dietary females 13 - 49 years of age An endpoint of concern specific to females 13 - 49 and attributable to a single dose was

not identified in the toxicity study data base, thus an acute RfD was not established. Ac ute Dietary general population including infants and children NOAEL= 12 mg/kg

UF = 100 **Acute RfD** = 0.12 mg/kg UF A= 10x UF H=10x FQPA SF = 1x **aPAD** = = 0.12 mg/kg A cute oral rat neurotoxicity

study. LOAEL = 50 mg/kg based on decreased body weight and body - weight gain in females (MP062) . Chronic Dietary all populations NOAEL= 2.0 mg/kg/day

UF = 100 **Chronic RfD** = 0.02 mg/kg/day UF A= 10x UF H=10x FQPA SF = 1x **cPAD** = = 0.0 2 mg/kg/day Weight of evidence approach

wa s used from four studies: 1) Subchronic toxicity study rat (MP062) . 2) Subchronic neurotoxicity study - rat (MP062) . 3) Chronic/carcinogenicity study - rat (JW062) . 4) Two generation rat reproduction study (JW062). LOAEL = 3.3 mg/kg/day based on decreased body weight, body - weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 mo nths. Short - Term Incidental Oral **(1 to 30 days)** Oral NOAEL= 2.0 mg/kg/day UF A= 10x UF H=10x FQPA SF = 1x Residential LOC for MOE = 100 Weight of evidence approach

wa s used from four studies: 1) Subchronic toxicity study rat (MP062) . 2) Subchronic neurotoxicity study - rat (MP062) .Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 20 of 56 Occupational LOC for MOE = 100 3) Chronic/carcinogenicity

study - rat (JW062) . 4) Two generation rat reproduction study (JW062). LOAEL = 3.3 mg/kg/day based on decreased body weight, body - weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 mo nths. Intermediate - Term Incidental Oral (1 - 6 mo nths) Oral NOAEL= 2.0 mg/kg/day UF A= 10x UF H=10x FQPA SF = 1x Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Weight of evidence approach

wa s used from four studies: 1) Sub chronic toxicity study rat (MP062) . 2) Subchronic neurotoxicity study - rat (MP062) . 3) Chronic/carcinogenicity study - rat (JW062) . 4) Two generatio n rat reproduction study (JW062 ). LOAEL = 3.3 mg/kg/day based on decreased body weight, body - weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 mo nths. Long - Term Incidental Oral (1 - 6 mo nths) Oral NOAEL= 2.0 mg/kg/day UF A= 10x UF H=10x FQPA SF = 1x Residential LOC for MOE = 100 Occupational LO C for MOE = 100 Weight of evidence approach

wa s used from four studies: 1) Subchronic toxicity study rat (MP062) . 2) Subchronic neurotoxicity study - rat (MP062) . 3) Chronic/carcinogenicity study - rat (JW062) . 4) Two generation rat reproduction study (JW062). LOAEL = 3.3 mg/kg/day based on decreased body weight, body - weight gain, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6 mo nths. Short - Term

Dermal ( **1 to 30 days** ) Intermediate - Term Dermal (1 - 6 mo nths) A quantitative dermal assessment is not required for indoxacarb, since the calculated human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 21 of 56 Long - Term

Dermal ( **> 6 Months** ) Short - Term Inhalation ( **1 to 30 days**  ) Intermediate - Term Inhalation (1 - 6 mo nths) Long - Term Inhalation ( **> 6 Months**  ) Inhalation NOAEL= 23 μg/L/day (6 mg/kg/day) UF A= 10x UF H=10x FQPA SF = 1x Residential LOC for MOE = 100 Occupational LOC for MOE = 100 28 - day rat inhalation toxicity

study (MP062) . The LOAEL of 290 μg/L/day

(75.69 mg/kg/day). is based on increased spleen weights, pigmentation and hematopoiesis in the spleen, hematological changes and mo rtality (females). Cancer (oral, dermal, inhalation) “Not likely” to be carcinogenic to humans since no evidence of carcinogenicity in either the rat or mouse studies, and no evidence of mutagenicity. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = pot ential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term risk assessment. UF DB = to account for the absence of key data (i.e., lack o f a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concer n. N/A = not applicable. **5.0 Dietary Exposure and Risk Assessment**  **5.1 R** **esidues of Concern Summary and Rationale** The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1. **Table 5.1 Summary of Metabolites and Degradates to be included in th**  **e Risk Assessment and**  **Tolerance Expression**  **1** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Indoxacarb 2 and its R - enantiomer 3 Indoxacarb and its R - enantiomer

Rotational Crop I ndoxacarb and its R - enantiomer I ndoxacarb and its R - enantiomer

Livestock Ruminant I ndoxacarb and its R - enantiomer (for all) M etabolite IN - MP819 (for milk only) I ndoxacarb and its R - enantiomer

Poultry I ndoxacarb, its R- enantiomer, and

the metabolites IN - JT333, IN JU873, IN - KB687, IN - KG433, IN - KT319, 5 - HO - IN - JT333, and Metabolite F I ndoxacarb, its R- enantiomer, and the metabolites IN - JT333, IN JU873, IN - KB687, IN - KG433, and IN - KT31 9Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 22 of 56 **Table 5.1 Summary of Metabolites and Degradates to be included in th**  **e Risk Assessment and**  **Tolerance Expression**  **1** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Drinking Water Indoxacarb, and the degradation products IN - JT333, IN - KG4333, IN - KT413, and IN - ML437 - 0H 1 Adapted from: S. Levy, D325479, 03/09/2007; and D402100, Christopher M. Koper, 11/06/2012. 2 “Indoxacarb” in this table refers to the S - enantiomer (KN - 128) 3 R- enanti o mer of indoxacarb (KN - 127) **5 .2**  **Food Residue**  **Profile** The dry bean and snap bean field trials submitted with this petition are adequate to support the proposed new uses on dry bean and succulent bean . A sufficient number of trials were conducted on each crop at 1x the maximum proposed rate in the appropriate geographic regions with the proper representative raw agricultural commodities ( RACs ) being collected for anal ys is . Samples were anal yz ed using adequate anal ytical methods ; total indoxacarb (both S - and R enantiomer) was measured. S ample storage durations are supported b y the avail able storage stability data. The current plant - back restrictions on the label remain adequate. Processing studies are not required for these RAC s . The tolerance for dry

beans covers the southern pea variety, cowpea. Cowpea is the only dry bean crop c onsidered for livestock feeding (cowpea seed, forage and hay). Residue data have been submitted and a tolerance has been proposed for residues of indoxacarb on dry bean (cowpea) forage. However, residue data for cowpea hay have not been submitted nor has a tolerance been proposed. HED is recommending establishment of a tolerance for indoxacarb on cowpea hay

of 100 ppm. The recommended hay tolerance is derived from the highest forage residue to which a drying factor has been applied. Specificall y, the 32 ppm residue is multiplied by the ratio of maximum percent dry matter for hay

and forage (32 *86/30=92). This results in a very conservative tolerance level for indoxacarb on cowpea hay which was considered in dietary burden calculations. Cowpea (forage and hay) are fed to dairy cattle. For snap beans (with pods), the total combined residues of i ndoxacarb (KN128 and KN127 ) ranged from 0.04 ppm to 0.59 ppm. Residues in whole snap bean plants/foliage were found between 1.3 ppm and 32 ppm. For dry bean seeds, total residues ranged from <0.01 ppm to 0.0 69 ppm . Adequate residue decline data was generated with snap beans and dry beans indicating that residues of indoxacarb decline fairly rapidly after treatment. Residue data for cranberries and grapes was previously evaluated and considered acceptable. The data for cranberries is adequate to support the tolerance for low growing berry subgroup 13 - 07H. The use pattern of the grape field trial correspond to the same single application rate and PHIof the proposed use pattern for small fruit vine climbing subgroup 13 - 07F but a higher maximum seasonal application rate (0.44 lb ai/A instead of 0.22 lb ai/A) and shorter RTI (5 - day s instead of 21 - day s). Since the single appli cation rate and PHI are similar and higher residuesIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 23 of 56 than the proposed tolerance would not be expected , it is recommended to use available residue data without applying a scaling factor to adjust the residue level. The existing cranberry and grape residue data are considered adequate to recommend tolerances for the corresponding crop subgroups. **5.3 Water Res**  **idue Profile** EFED performed a Tier II drinking water assessment (DWA) which utilized modeling to estimate the surface water and groundwater concentrations of indoxacarb in drinking water source water (pre - treatment) resulting from use on vulnerable sites (D402100 , 11/6/13 , Tier II Drinking W

ater Assessment for the New Use Registration of Indoxacarb on Dry Beans, Snap Beans, Small Fruit Vine Climbing Subgroup 13 - 07F and Low - Growing Berry Subgroup 13 - 07H ). No monitoring data were available for indoxacarb at the time of this assessment. Based on the Metabolism Assessment Review Committee (MARC) recommendations, a Total Toxic Residue (TTR) approach was used for the parent indoxacarb and the degradation products with toxicological concern (IN - JT333, I N - KG4333, IN - KT413, IN - ML437 - 0H) for the drinking water assessment. The recommended estimated drinking water concentrations (EDWCs) for the human health risk assessment are based on highest predicted value for surface water and groundwater (Table 5.3), which are based on two applications of 0.11 lbs. a.i./acre/season on cranberry and four applications of 0.11 lbs. a.i./acre on beans and berries respectivel y. For acute and chronic dietary risk assessments , respectively , the 1 - in - 10 year peak ( **59.26 ppb** ) and the 1 - in - 10 year annual average ( **18.48 ppb** ) indoxacarb residues of concern in surface water from the Provisional Cranberry

Model (PCM) were used. **Table 5 .**  **3 Recommended**  **Estimated Drinking Water Concentrations (EDWCs) 1**  **fo r Surface Water**  **and Ground Water –** **Indoxacarb and Degradation Products**  **Drinking Water**  **Source Model** 

**Scenario Me**  **thod 2**  **Maximum Application Rate**  **(interval between applications)**  **1 -**  **in -**  **10**

**year acute**  **( μg/L**  **) 1**  **- in**  **- 10** 

**year chronic**  **( μg/L**  **) 30**  **- year** 

**average (**  **μg/L )**  Surface Water Provisional Cranberry Model

Cranberry PCM 2 app @ 0.11 lb a.i./acre **59.26 18.48**  18.48 Ground Water SCI - GROW

(Beans, Berries) -- 4 app @ 0.11 lb a.i./acre 0.33 0.33 0.33 1 For surface water (PRZM/EXAMS), EDWC values adjusted with a Percent Cropped Area (PCA) factor of 0.87. For ground water (SCI - GROW), no PCA adjustment was utilized. 2 PCM = The Provisional Cranberry Model (PCM) is a provisional refinement to the Tier I Rice Model (v1.0, May 8, 2007). Refinements include the addition of simple degradation processes in dry and flooded conditions and a water depth of twelve inches, rather than the water depth of four inches used in the rice model. These modifications allow estimation of screening - level peak and annual mean EDWC s of residues of concern that may occur in untreated surface water used as drinking water following use on cranberries.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 24 of 56 **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  Refined acute probabilistic and chronic dietary (food plus drinking water) exposure ass essment s were conducted for the existing and proposed food uses of indoxacarb ( I. Negrón - Encarnación, 5/1/ 13, D408983 , Indoxacarb Acute and Chronic Aggregate Dietary (Food and Drinking W ater) Exposure and Risk Assessment for the Section 3 Registration Acti on on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13 - 07F and Low Growing Berry Subgroup (except strawberry) 13 - 07H ) . A cancer dietary

exposure assessment w as not conducted for indoxacarb because indoxacarb has been classified as “not likely to be carcinogenic.” The dietary assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM - FCID) Version 3.16 , which uses food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey , What We E at in America, (NHANES/WWEIA) from 2003 to 2008. Anticipated residues (ARs) for all registered and proposed food commodities were based on fie ld trial data (FTD) , and for some crops tolerance level residues were used . Residue estimates for many current uses were further refined using percent crop treated ( %CT ) data . Available processing data for indoxacarb were used to refine ARs for apples/p ears (juice), potato (dry , chips), cotton (oil), tomato (paste and puree), peanut (oil), so ybean (oil), grapes (raisin and juice), prunes (dried), and mint (oil), and other commodities where translation was applicable. DEEM - FCID  (ver. 7 .81) default proce ssing factors (PFs) were assumed for all other processed commodities. EDWCs were provided by EFED (C. Koper , D402100, 11/06/12 ) and incorporated directly into the DEEM - FCID  analy ses . Both the acute and chronic anal ys es w ere conducted using estimated surface water residues generated using the Provisional Cranberry Model. For acute and chronic assessments, HED is concerned when dietary risk exceeds 100% of the aPAD and cPAD, respectively . The DEEM - FCIDTM anal ys es estimate the dietary exposure of the U.S. population and various population subgroups: all infants (< 1 year old), children 1 - 2, children 3 - 5, children 6 - 12, youth 13 - 19, females 13 - 49, adults 20 - 49, and adults 50+ years. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The following maximum percent crop treated estimates ( BEAD Screening Level Usage Analysis (SLUA) , 10/12/12 ) were used in the acute dietary risk assessment for the following crops that are currentl y registered for indoxacarb : apples: 10 %; broccoli: 70%, cabbage: 35%; cauliflower: 60%; cherries: 2.5 %; lettuce: 40%; peaches: 2.5%; peanuts: 10%; pears: 2.5%; potatoes: 2.5%; soy beans: 2.5%; spinach: 5%; sweet corn: 10 %; tomatoes: 40% . The following average percent crop treated BEAD estimates were used in the chronic dietary risk assessments for the following crops that are currentl y re gistered for indoxacarb : apples: 5 %; broccoli: 50%, cabbage: 25%; cauliflower: 40%; celery : 5%; cherries: 1 %; grapes: 1%; lettuce: 10%; peaches: 2.5%; peanuts: 2.5%; pears: 1%; potatoes: 1%; soy beans: 1%; spinach: 2.5%; sweet corn: 2.5 %; tomatoes: 20%. For all other crop commodities, including the proposed uses (dry bean, succulent bean and smallIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 25 of 56 fruit vine climbing subgroup (except kiwifruit) 13 - 07F and low growing berry subgroup (except strawberry) 13 - 07H) , 100% of the crop treated was assumed. **5.4.3 Acute**  **D ietary Risk Assessment**  Estimated acute dietary

exposure, using fairl y refined assumptions, to indoxacarb from food and drinking water is below HED’s level of concern for all population subgroups. Combined dietary exposure from food and drinking water at the 99.9 th percentile of exposure is estimated to be 0.03 3 mg/kg/day

for the overall U .S. population, equivalent to 27 % of the aPAD. The population subgroup with the highest estimated acute dietary exposure to indoxacarb is all infants, with an estimated exposure at the 99.9 th percentile of 0 .058 mg/kg/day , equivalent to 49 % of the aPAD. Results of the dietary

assessment s can be found in Table 5.4.5 below. **5.4.4 Chronic Dietary Risk Assessment**  Estimated chronic dietary exposure, using fairly r efined assumptions, to indoxacarb from food and drinking water is below HED’s level of concern for all population subgroups. Combined dietary exposure from food and drinking water is estimated to be 0.0011 mg/kg/day for the overall U.S. population, equivalent to 5.7 % of the cPAD. The population subgroup with the highest estimated chronic dietary exposure to indoxacarb is children, 1 to 2 years old, with an estimated exposure of 0.0024 mg/kg/day , equivalent to 1 2 % of the cPAD. Results of the dietary

asses sment s can be found in Table 5.4.5 below. **5 .4.5**  **Summary Table Table**  **5.4.5 . Summary of Dietary**  **(Food and Drinking Water) Exposure and Risk for Indoxacarb**  **Population Subgroup Acute Dietary**  **(99.9 Percentile) Chronic Dietary**  **Cancer Dietary**  **Exposure (m**  **g/kg/day) % aPAD** * **Dietary Exposure**  **(m g/kg/day)**  **% cPAD*** **Dietary Exposure**  **(m g/kg/day)**  **Risk** General U.S. Population 0.032762 27 0.001133 5.7 All Infants (<1 year old)* **0.058294 49**  0.001772 8.9 N/A N/A Children 1 - 2 years old* 0.054158 45 **0.002381 12**  Children 3 - 5 years old 0.046841 39 0.001818 9.1 Children 6 - 12 years old 0.035434 30 0.001105 5.5 Youth 13 - 19 years old 0.025623 21 0.000743 3.7 Adults 20 - 49 years old 0.025109 21 0.001036 5.2 Adults 50+ years old 0.030965 26 0.001165 5.8 Females 13 - 49 years old 0.026456 22 0.001037 5.2 *T he subpopulation(s) with the highest risk estimates are highlight in bold print.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 26 of 56 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  No new residential uses and no occupational uses at residential sites are being requested with this petition; however, there are existing residential uses (turf and spot - on pet applications ) that have been previousl y assessed and are assessed herein t o reflect up dates to HED’s 2012 Residential SOPs 2 , policy

changes for body

weight assumptions , and a re - evalu ation of the dermal toxicity of indoxacarb . In addition, there are existing residential uses (insect control treatments of household premises ; Arilon Insectic ide 20% ai , EPA Reg. No. 100 - 1501 and A perion Insecticide 14.5 % ai , EPA Reg. No. 352 - 770 ) which do not appear to have been previously assessed and are assessed herein. These existing uses may potentially result in handler and post - application inhalation and dermal exposures for adults and post - application dermal, inhalation, and oral exposures to children. The risk estimates from residential exposures will impact the human health aggregate risk assessment for indoxacarb. Note that dermal exposures resulting from residential uses are not quantitatively assessed as a dermal toxicity endpoint is not identified for indoxacarb. Only

the inhalation and incidental oral exposures are assessed for the residential uses of indoxacarb. **6.1 Residential Handler Exposure**  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 each 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. Residential handler exposure i s expected to be short - term in duration. Intermediate - term exposures are not likely because of the intermittent nature of applications by

homeowners. The indoxacarb handler assessment considers short - term inhalation exposures only since a dermal toxicity endpoint is not identified. The anticipated use patterns and current labeling indicate that exposure to pesticide handlers is likely during the residential uses of indoxacarb products . In doxacarb use patterns and current labeling indicate several likel y residential handler exposure scenarios: (1) Placements of ready- to - use (RTU) bait stations . (2) S pot - on applications of gels (crack and crevices) for household insect control (indoor treatments ) . (3) Spot - on treatments for the control of fleas and ticks on dogs and cats . (4) Broadcast, perimeter and ant mound treatment on ornamentals, trees, and lawns/turf utilizing granular and liquid formulations (outdoor treatments) . (5) Indoor s pray applications with granular and liquid formulations for insect control on households/ domestic dwellings ( c rack and c revice and spot directed treatments ) .

2 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 27 of 56 Indoxacarb RTU bait stations and gels products are formulated for very low application rates ( e.g., 6.6 x 10 - 7 lb ai/spot to 5.2 x10 - 5 lb ai/placement) and are designed to be self - contained; therefore, handler contact is expected to be negligible and exposure/risk for these uses were not quantitatively assessed . The spot - on product for the control of fleas and ticks on dogs and cats is designed to be self

- contained as it is app lied directly from the tube to the pet with the tip of the applicator used to part the pet’s hair . Therefore, handler exposure is expected to be minimal for this ty pe of applications . Inhalation assessments are not performed for applyingpet spot - on treatments, as inhalation exposure is not expected from these uses. Therefore, a handler assessment is not performed for the indoxacarb pet spot - on treatments. Indoxacarb liquid and granular formulations ( e.g., Provaunt 1.25 SC and Advion G) , are registered fo r use in residential lawns, recreational areas and golf courses. Additionally , a dry flowable formulation (

Provaunt Insecticide DF) is registered for use in residential lawns and recreational areas. Even though the label s states that these products are “ intended to be applied by professional commercial operators (PCO) onl y”, this label restriction is not considered sufficient to preclude use b y homeowners; therefore , these uses were assessed. Other granular products intended for residential treatments on ornamentals, trees, and lawns such as Chemsico Insect Bait (EPA Reg. No. 9688 - 217), and ant mound treatment product, Tomcat Ant Killer (EPA Reg. No. 12455 - 107), are also formulated at very low application rates (maximum application rate of 8 x 10 - 8 lb ai/ft2 ). MOE estimates for these uses will be well above a million, and; therefore, were not quantified . Two indoxacarb formulations : Arilon Insecticide 20% ai (EPA Reg. No. 100 - 1501 ) and Aperion Insecticide 14.5% ai (EPA Reg. No. 352 - 770) , were identified for use i n households and domestic dwellings. Even though the label s state that both products are “ intended to be applied by PCO s only”, this restriction is not considered sufficient to preclude use by homeowner/residential applicators ; th erefore , these uses were assessed. Although outdoo r treatments are also permitted, onl y the indoor uses were assessed since the outdoor applications are expected to result in lower risk/exposure estimates than the indoor spray applications and the turf us es assessed. The quantitative inhalation exposure/risk assessment developed for residential handlers for existing indoxacarb uses is based on the following scenarios : (1) Mixing/loading/appl yi ng granular formulation for insect control on lawns/turf . (2) Mixing/loading/appl yi ng liquid flowable formulation for insect control on lawns/turf . (3) Mixing/loading/appl yi ng water- soluble packaging formulation for i ndoor s pray applications with manually- pressurized hand wand ( c rack and c revice and spot directed treatments ) for insect control i n households/domestic dwellings . (4) Mixing/loading/appl yi ng liquid flowable formulation for i ndoor s pray applications with manually- pressurized hand wand ( c rack and c revice) for insect control on households/domestic dwellings . Residential Handler Exposure Data and AssumptionsIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 28 of 56 A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. The se assumptions and factors, including application rate, body weights, unit expos ure, etc. are detailed in D411342 (A. Rivera - Lupianez, 5/1/13, Indoxacarb Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on Bean (dry), Bean (snap), Bean (forage), and Small Fruit Vine Climbing Subgroup 13 - 07F a nd Low - Growing Berry Subgroup 13 - 07H ) and the 2012 Residential SOPs 3

. The inhalation e xposure and risk estimates are presented for the residential scenarios that led to the highest exposure ( i.e. , backpack and manually pressurized hand wand applications of liquid spray s on turf, bell y grinder application of granules on turf, and manually pressurized hand wand applications for indoor spray treatments). Residential handler exposure scenarios for the indoxacarb S - enantiomer and its R - enantiomer 75:25 ratio mixture (KN128/KN 127) formulation are summarized as follows: KN128/KN 127 ( 75:25 isomeric mixture): 1. Lawn/Turf: Provaunt 1.25 SC 14.5% ai (EPA Reg. No. 352 - 637); a liquid formulation for use on turf (residential lawns , recreational areas, and golf courses ) . 2. Lawn/Turf: Advion G 0.22% ai (EPA Reg. No. 100 - 1483 ); a granular formulation for use on turf (residential lawns , recreational areas, and golf courses ) . 3. Lawn/Turf: Provaunt Insecticide DF (EPA Reg . No 100 - 1487 ); a dry flowable formulation for use on turf (residential lawns , recreational areas, and golf courses ) . 4. Indoor Spray

( Crack and Crevice and Spot Treatment): Arilon Insecticide 20% ai (EPA Reg. No. 100 - 1501 ); a water- soluble packaging formulation for use on h ouseholds/domestic dwellings. 5. Indoor Spray

(Crack and Crevice): A

perion Insecticide 14.5 % ai (EPA Reg. No. 352 - 770 ); a liquid formulation for use on households/domestic dwellings. Summary of Residential Handler Non - Cancer Exposure and Risk Estimates KN128/KN127 (

75:25 Isomeric Mixture) Exposure Scenarios - Lawn/Turf and Indoor Crack and Crevice/Spot-Directed Treatments : The residential handler exposure assessment for turf (lawn) and indoor (crack and crevice and spot - directed) applications resulted in short - term inhalation MOEs that do not exceed HED's level of concern ( i.e., MOEs ≥ 100). Table 6 .1. 1 presents a summary of the residential handler scenarios assessed . **Table 6**  **.1. 1**  **. Residential Handler Short**  **- Term**  **Exposure and Ris k Estimates for Indoxacarb**  **: KN128/** **KN 127 (**  **75:25 Isomeric Mixture)**  **Exposure Scenario Level of**  **Concern Inhalation Unit** 

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

**Application Rate**  **1 Area** 

**Treated or Am**  **ount Handled**  **Daily 2**  **Inhalation**

**Dose (m** **g/k g/day)**  **3 MOE**  **4**

3 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 29 of 56 **Table 6**  **.1. 1**  **. Residential Handler Short**  **- Term**  **Exposure and Ris k Estimates for Indoxacarb**  **: KN128/** **KN 127 (**  **75:25 Isomeric Mixture)**  **Exposure Scenario Level of**  **Concern Inhalation Unit** 

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

**Application Rate**  **1 Area** 

**Treated or Am**  **ount Handled**  **Daily 2**  **Inhalation**

**Dose (m** **g/k g/day)**  **3 MOE**  **4** Mixer/Loader/Applicator (M/L/A)

Lawns/Turf Provaunt Insecticide DF - Dry Flowable Formulations

– EP A Reg. No. 100 - 1487 (Former: EPA Reg. No. 352 - 716) Mannually Pressurized Hand Wand/ Backpack 100 1.1 0.0065 lb ai/gal 5 gal **0.00045 1**  **3 ,000**  Provaunt 1.25 SC - Liquid Formulations - EP A Reg. No. 352 - 637 Backpack (liquid) 100 0.14 0.0065 lb ai/gal 5 gal 0.00005 7 105 ,000 Manually Pressurized Hand Wand (liquid) 100 0.018 7.3 x 10 - 6 825 ,000

Advion G - Granular Formulations - EP A Reg. No. 100 - 1483 (Former: EP A Reg. No. 352 - 651) Belly grinder (granules) 100 0.039 0.000013 lb ai/ft2 1,200 ft2 7 .6 x 10 - 6 785 ,000 Crack and Crevice and Spot - Directed Treatments (Indoor Environments) Arilon Insecticide 20% ai - EP A Reg. No. 100 - 1501 (Former: EPA Reg. No. 352 - 776 ) Manually Pressurized Hand Wand (water dispersible packets) 100 1.1 0.011 lb ai/gal (0.00004 lb ai/ft2 ) 0.5 gal 0.000 076 8 0 ,000 Aperion Insecticide 14.5% ai - EP A Reg. No. 352 - 770 Manually Pressurized Hand Wand (liquid) 100 1.1 0.010 lb ai/gal (0.00004 lb ai/ft2 ) 0.5 gal 0.00 006 86 ,000 1 . Based on registered label (EPA Reg. No.). Application rates = maximum application rates from labels (EPA Reg. No.: 352 - 637, 100 - 1487, 100 - 1483, 100 - 1501 , 100 - 1498 , and 352 - 770 ). The application rate for all mixture formulations 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. 2 . Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html ). 3. 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 Wei ght (kg). 4. Inhalation MOE = Inhalation NOAEL ( 6 mg/kg/day) ÷ Inhalation **6.2 Residential**  **Post -**  **Application Exposure** There is the potential for post - application exposure for individuals exposed as a result of being in an environment , such as on a lawn or floor or petting an animal, that has been previousl y treated with indoxacarb. Residential post - application exposures ( e.g., exposures from treated lawns and indoor environments ) , are generally considered to be intermittent and short - term in duration . However, because of the preventative nature of pet products and the potential for extended usage in more temperate parts of the country , the residential post - application exposures to treated petsIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 30 of 56 may be short - , intermediate - , or long - te rm in duration . The post - application assessment considers inhalation and oral exposures only since a dermal toxicity

endpoint is not identified for indoxacarb. The toxicological endpoints and points of departure are the same for each route of exposure reg ardless of duration. The quantitative exposure/risk assessment for residential post - application exposures is based on the following scenarios: (1) Treated p ets (dogs and cats): children 1 to < 2 years old (incidental oral); (2) Treated turf: children 1 to < 2 ye ars old (incidental oral); (3) Crack and crevice indoor and spot - directed spray applications: inhalation (adults and yo ung children 1 to <2 years old), and incidental oral (young children 1 to <2 years old) exposures . It should be noted that post - applicati on exposures (incidental oral) from treated golf courses were not quantified since youth old enough to play golf are not expected to exhibit significant hand - to - mouth behavior . Furthermore, the residential lawn assessment provides the highest estimate of p otential exposure from turf applications and is protective of any exposure s to indoxacarb turf treatment scenario s . The lifestages selected for each post - application scenario are based on an analy sis provided as an Appendix in the 2012 Residential SOPs 4

. These lifestages are not the onl y lifestages that could be potentially

exposed for these post - application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed li festages. Two indoxacarb formulations: Arilon Insecticide 20% ai (EPA Reg. No. 100 - 1501) and Aperion Insecticide 14.5% ai (EPA Reg. No. 352 - 770), were identified for insect control i n households and domestic dwellings. Even th ough outdoor treatments are also permitted; outdoor applications are expected to result in lower risk/exposure estimates than indoor spray treatments or turf uses. Therefore , only the indoor uses that would potentially lead to the highest post application exposures were assessed ( i.e., exposure from contact with carpet and hard surfaces resulting from surface directed spray applications). Itshould be noted that even though neither of these labels have been previously assessed, only

the Arilon formulation was assessed for post a pplication exposures. The Aperion Insecticide formulation, a termiticide, was not assessed for post - application exposure since the label use pattern limits indoor uses to “localized spot treatments” such as crawlspaces, basements or attics and post - application exposures are not likely . Furthermore, the assessment of the Arilon formulation, which is applied at a higher application rate than the Aperion formulation, is assumed to provide a conservative surrogate assessment for the Aperion uses. 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. Two chemical specific animal petting studies 4 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 31 of 56 ( MRID s 47834502 and MRID 48010801 ) were used to estimate transferable residues for the incidental oral exposure for children for the treated pet scenario. A chemical specific (indoxacarb) turf transferable re sidue (TTR) study (MRID 4679820) was used to estimate incident al oral exposure for children for the turf (liquid formulations) scenarios. A default TTR was used for the turf granular formulation scenario since the available chemical specific study was only for the liquid formulation. The assumption s and factor s, as well as those regarding application rate and timing, body weights, etc., are detailed in D411342 , 5/1/13, and the 2012 Residential SOPs 5

. Combining Exposure and Risk Estimates Since inhalation and incidental oral exposure routes share a common toxicological endpoint ( i.e., hematological changes), risk estimates have been combined for those routes. Incidental oral ingestion ( i.e., hand - to - mouth , object - to - mouth, and soil ingestion (where appropriate) ) for a given residential scenario should be co nsidered inter- related and it is likely that they occur interspersed amongst each other across time. Combining all of these incidental oral exposure estimate s with the inhalation exposure would be overly- conservative because of the conservative nature of each individual incidental oral assessment. Therefore, the post - application exposure scenarios that were combined for children 1 < 2 ye ars old are the inhalation and hand - to - mouth (the highest incidental oral exposure assessment) for the indoor surfaces directed spray applications. This combination is considered protective of children’s exposure to indoxacarb from residential uses . Summary of Residential Post - application Non - Cancer Exposure and Risk Estimates For the purpose of presentation of post - appli cation exposure and risk estimates, the exposure scenarios for the KN128 (S - enantiomer onl y) formulation and the KN128/KN127 ( 75:25 S - and R - enantiomer mixture ) formulation s have been separated. KN128 (S - enantiomer only) : 1. Treated Pets: Actyvil Liquid RTU Formulation for spot - on treatments on cats (EPA Reg. No. 773 - 93) and dogs (EPA Reg. No 773 - 94). KN128/KN 127 ( 75:25 S - and R - isomeric mixture): 1. Lawn/Turf: Provaunt 1.25 SC 14.5% ai (EPA Reg. No. 352 - 637); a liquid formulation for use on turf (residential lawns , recreational areas, and golf courses ) . 2. Lawn/Turf: Advion G 0.22% ai (EPA Reg. No. 100 - 1483 ); a granular formulation for use on turf (residential lawns , recreational areas, and golf courses ) . 3. Lawn/Turf: Provaunt Insecticide DF (EPA Reg. No 100 - 14 87 ); a dry flowable formulation for use on turf (residential lawns , recreational areas, and golf courses ) . 4. Indoor Spray

(Crack and Crevice and Spot - Directed Treatments): Arilon Insecticide 20% ai (EPA Reg. No. 100 - 1501 ); a water- soluble packaging formulation for use on households/domestic dwellings. **KN128 Exposure Scenarios** Treated Pets Scenarios 5 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 32 of 56 A summary

of the children short - , intermediate - and long - term (ST/IT/LT) exposure and risk estimates from treated pet (cat and dog) scenarios are shown in Table 6.2 .1. Incidental oral (hand to mouth) risk estimates for children for the indoxacarb pet spot - on liquid formulations do not exceed HED’s level of concern (MOEs ≥ 100). **Table 6.2.1 .**  **Residential Post -**  **application ST/IT/LT**  **( Non**  **- Cancer** **) Exposure and**  **Risk Estimates for Indoxacarb: KN128**  **formulation** Lifestage Post - application Exposure Scenario Application Rate a Dose b ,c

(mg/kg/day) MOEs d Combined MOEs Route of Exposure Use Site

Liquid Spot - on Treatments Formulations (Companion Pets) Child 1 to < 2 years old Oral (HTM) Cats 115 (mg ai/pet) 0.0012 1, 6 00 NA Dogs 900 (mg ai/pet) **0.002 4**  **830** a Based on application rates (AR) from labels that led to highest dermal exposure: Actyvil Liquid RTU Formulation for spot - on treatments on cats (EPA Reg. No. 773 - 93) and dogs (EPA Reg. No 773 - 94) b. Fraction Application Rate ( F ar) = Peaked amount of indoxacarb removed as a fraction of dose applied from MRIDs: 48135325 and 48010801; Far = 0.0255 (dogs); 0.0124 (cats). c. Hand - to -Mouth Dose (mg/kg/day) = [(Hand Residue Loading (mg/cm2 ) × Fraction of Hand Mouthed × Surface Area of 1 Hand (150 cm2 ) × Exposure Time (1.5 hrs/day) × # of Replenishment Intervals/hr (4 int/hr) × (1 - ((1 - Saliva Extraction Factor (0.5))^(Number of Hand - to - Mouth Events per Hour (13.9 events/hr) ) ÷ ( # of Replenishment Intervals/hr))] / Body Weight (11 kg child 1 < 2 years ol d)] d. Oral MOE = NOAEL ( 2 mg/kg/day; KN128 )/ Oral Dose (mg/kg/day) **KN128/KN127 ( 75:25**  **Isomeric Mixture) Exposure Scenarios**  Turf Scenarios A summary

of the children short - term post - application exposure and risk estimates from the turf scenarios is shown in Table 6 .2. 2 . C hildren ’s short - term incidental oral risk estimates ( for both liquid and granular formulations ) do not exceed HED’s level of concern (MOEs ≥ 100). Indoor Surfaces Directed Spray Scenarios (Crack and Crevice and Spot-Directed Treatments) A summary

of the adult and children short - term post - application exposure and risk estimates from the indoor spray

uses of indoxacarb is shown in Table 6 .2.2. All adult and children i nhalation risk estimates do not exceed HED’s level of concern (MOEs ≥ 100). For children , the incidental oral risk estimates for crack and crevice treatments do not exceed HED’s level of concern (MOEs ≥ 100). However, for spot - directed treatments, oral (hand - to - mouth) exposure estimates alone for children 1 to < 2 years old exceed HED’s level of concern (MOE = 32). For crack and crevice only scenarios the c ombined inhalation and incidental oral risk estimates for children 1 to < 2 ye ars old are not of concern (MOEs ≥ 100) .Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 33 of 56 **Table 6.2.2. Residential Post**  **- application ST (Non**  **- Cancer) Exposure and Risk Estimates for**  **Indoxacarb: KN128/KN127 ( 75:25**  **Isomeric Mixture).**  Lifestage Post - application Exposure

Scenario Application

Rate a, b (lb ai/A) Dose c, d,

(mg/kg/day) MOEs e, f, g, h, Combined Routes (X indicates included in Combined MOE) Combined

MOEs i Route of Exposure Use Site Lawn/Turf Scenarios Provaunt 1.25 SC - Liquid Formulations and Provaunt Insecticide DF - Dry Flowable Formulations Child 1 < 2 year old Oral Hand - to - Mouth 0.22 lb ai/A (0.29 lb ai total isomer/A) 0.0042 480 NA Object - to - Mouth 0.0001 20 ,000 Soil Ingestion 9.9 x 10 - 6 200 ,000 Advion G - Granular Formulations Child 1 < 2 year old Oral Hand - to - Mouth 0.44 lb ai/A (0.586 lb ai total isomer/A) 0.0009 2 , 3 00 NA Object - to - Mouth 0.00005 4 0 ,000 Soil Ingestion 2 x 10 - 5 100 ,000 Episodic Granular In gestion 0.060 200 Crack and Crevice and Spot Directed Treatments (Indoor Surface Directed Sprays Scenario) Arilon Insecticide 20% ai Adult Inhalation Surface directed sprays

0.00004 lb ai

total isomer /ft2 2.2x 10 - 8 2. 6 x 10 8 NA

Child 1 < 2 years old Oral Hand - to - Mouth

from carpets (crack and crevice treatment) 0.0126 **1 6**  **0 X** 

**1 6**  **0** Hand - to - Mouth from carpets (spot directed Treatment) 0.0632 **32** Object - to - Mouth from carpets (crack and crevice treatment) 0.002 1000 Object - to - Mouth from carpets (spot directed Treatment) 0.008 250 Inhalation Surface directed

sprays 9.6x 10 - 8 **6.2 x 10**  **7 X**  a. Based on application rates (AR) from labels that led to highest dermal exposure: AR = maximum application rates from labels (EPA Reg. No.: 352 - 637, 100 - 1483 , 100 - 1501 and 352 - 770 ). The application rate for all mi xture formulations 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.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 34 of 56 b. Turf Transferable Residue (TTR)

– The highest average value (0.023 μg/cm 2 ) from NY, NC and CA site study (MRID 467 98201) was used for the Provaunt 1.25 SC and Provaunt Insecticide DF formulations assessment. The TTR value was adjusted to 0.031 μg/cm2 to account for 4 parts of to tal (S - and R- ) indoxacarb for every 3 parts of S - indoxacarb. A default predicted Day 0 TTR value (0.013 μg/cm2) was used for Advion G. c. Turf Scenarios Dose Equations Hand - to -Mouth Dose (mg/kg/day) = [(Hand Residue Loading (mg/cm 2 ) × Fraction of Hand Mouthed × Surface Area of 1 Hand (150 cm 2 ) × Exposure Time (1.5 hrs/day) × # of Replenishment Intervals/hr (4 int/hr) × (1 - ((1 - Saliva Extraction Factor (0.5))^(Number of Hand - to - Mouth Events per Hour (13.9 events/hr) ÷ ( # of Replenishment Intervals/hr))] / Body Weight (11 kg child 1 < 2 years old)] Object- to -Mouth Dose (mg/kg/day) = object residue loading (μg/cm2 ) × unit conversion factor (0.001 mg/μg) × object surface area mouthed / event (10 cm2/event) × exposure time (1.5 hrs/day) × # replenishment intervals/hr (4 int/hr) × (1 - ((1 - saliva extraction factor (0.50))^(# Object - to - Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight (11 kg). Soil Ingestion Dose (mg/kg/day) = soil residue (μg/g) × ingestion rate (50 mg/day) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg). Episodic Granular Ingestion Dose (mg/kg/day ) = [(ingestion rate of dry pesticide formulation (g/day) * fraction of ai in dry formulation (unitless) * weight unit conversion factor (1,000 mg/g)] ÷ body weight (11 kg). d. C rack 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 Mouthed (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 (2 0 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 Event s 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 Exchang es per Hour (0.45/hr) x Volume 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 Hour (0.45/hr)

– First Order Decay Rate (2.1 x 10 - 5 ))] ÷ Body Weight (child, 11 kg)] f. Inhalation MOE = Inhalation NOAEL ( 6 mg/kg/day;) ÷ Inhalation Dose (mg/kg/day). g. Oral MOE = NOAEL ( 2 mg/kg/day) / Oral Dose (mg/kg/day) h. Episodic Granular Ingestion MOE = NOAEL ( 1 2 mg/kg/day;) / Episodic Granular Ingestion Dose (mg/kg/day) i. Combined MOE = 1 ÷ [(1/incidental oral MOE) + (1/ Inhalation MOE )], where applicable. **6.3 Residential Risk Estimates for Use in Aggregate**  **Assessment** Table s 6.3. 1 and 6.3.2 show residential risk estimates that can be used in the aggreg ate assessment for indoxacarb . The scenarios and lifestages resulting in the highest residential exposures are selected for use in the aggregate assessment and are considered protective of other scenario exposures (those risk estimates in bold in the tables are included in the aggregate assessments) . For indoxacarb, there are potential residential exposures from indoor a pplications, outdoor/lawn applications and pet applications. Each of these scenarios are assessed using high - end,Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 35 of 56 conservative assumptions (e.g., maximum application rate , high - end area treated or amount han dled, no dissipation of residue over the exposure duration, etc). Because each scenario reflects the use of high - end inputs, the individual residential scenarios are not combined for use in the aggregate; rather, the scenario resulting in the highest exposure is aggregated with food/water to be protective of all possible residential scenarios. Multiple residential scenarios are also not combined in many cases because available survey data indicate that the probability of multiple residential products (e.g., a pet care product and an indoor product) , co ntaining the same active ingredient, being used on the same day is very low. Exposure from the pet spot - on use is assumed to occur over short - , intermediate - , and long - term durations. As is the case for all the residential exposure scenarios, the long - term exposure assessment for the pet uses are conducted using high - end, conservative inputs (e.g., maximum application rates, day- 0 residue values, no dissipation of residues over time) resulting in a very conservative long - term exposure/risk estimate that w ould not be appropriate to include in the short - term aggregate assessment as “background” exposure. Based on the potential residential scenarios for indoxacarb and the considerations noted above, the following is a list of the recommended residential scenarios for the indoxacarb aggregate assessments:

 The short - term residential exposure for use in the adult aggregate assessment reflects residential handler inhalation exposures from mixer/loader/applicator scenarios for dry flowable formulations treatments on turf via m anually p ressurized h and w and or b ackpack .  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 crack and crevice treatments with surface directed spray s. The incidental oral (hand - to - mouth) risk estimate for the indoor spot- directed treatments was of concern by

itself and is not included in the aggregate.  The intermediate - and long - term residential exposure for use in the child (1<2 years old) aggregate assessment reflects post - application incidental oral (hand - to - mouth) exposures from treated pets.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 36 of 56 **Table 6**  **. 3.1**  **. Residential Exposures for the Indoxacarb**  **Aggregate Assessment (KN128**  **; Pet Treatm ent** **) .**  **Lifestage Residential Handler**  **Residential Post**  **- application** 

**Dose (m**  **g/k g/day)**  **MOE Dose**  **(m g/k** **g/day MOE**  **Dermal Inhalation**  **Total Dermal**  **Inhalation Total**  **Dermal Inhalation**  **Oral Total**  **Dermal Inhalation**  **Oral Total**  **Short –**  **Term (Pet Treat me**  **nt)** Adult N/A N/A N/A N/A N/A N/A N/A N/A **N /** **A** Child 1<2 N/A N/A N/A 0.0024 0.0024 N/A N/A 8 30 830 **Intermediate -**  **or Long**  **- Term (Pet Treatment)**  Adult N/A N/A N/A N/A N/A N/A N/A N/A **N /** **A** Child 1<2 N/A N/A 0.0024 0.0024 N/A N/A 8 30 **830** N/A= not applicable **Table 6.3.2. Residential Exposures for the Indoxacarb Aggregate Assessment (KN128/127 ; Turf**  **or Indoor Use)**  **Lifestage Residential Handler**  **(Turf) Residential Post**  **- application**  **(Indoor Use)**

**Dose (mg/kg/day) MOE**  **Dose (mg/kg/day) MOE**  **Dermal Inhalation**  **Total Dermal**  **Inhalation Total**  **Dermal Inhalation**  **Oral Total**  **Dermal Inhalation**  **Oral Total**  **Sho rt**  **- Term Term (Turf**  **or Indoor)**  Adult N/A 0.00045 0.00045 N/A 13,000 **1 3**  **,000** N/A 2.2 x 10 - 8 N/A 2.2 x 10 - 8 N/A 2. 7 x 10 8 N/A 2.0 x 10 8 Child 1<2 N/A N/A 9.6 x 10 - 8 .0126 0.0126 N/A 6.2 x 10 7 160 **160** N/A= not applicable 1 . Turf Use Scenario 2. Indoor Environment ScenarioIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 37 o f 56 **6.4 Residential Bystander**  **Post -**  **application Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for indoxacarb at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV). However , volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearby pesticide applications. The Agency sought exp ert 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, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify th e need for and, subsequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation expos ure assessment for indoxacarb. **6.5 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for indoxacarb. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information 6 ). The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply

the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risk estimates associated with drift. Although a quantitative residential post - application inhalation exposure assessment was not performed as a result of indoxac arb drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers and there were no risk estimates of concern. This exposure scenario is representative of high - end inhalation (drift) exposure and may be co nsidered protective of indoxacarb outdoor agricultural and commercial post - application inhalation exposure scenarios . Furthermore, residential turf uses were quantitatively assessed as part of this risk assessment; risk estimates addressed in the residential turf assessment provide a worst case estimate of potential exposure from spray drift. It is noted that the 0.44 lb ai/acre application rate for turf was modeled to estimate post - application residential exposure of children. As this rate is eq ual

6 Available: http://www.epa.gov/opp0 0001/factsheets/spraydrift.htmIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 3 8 o f 56 to or higher than agricultural application rates for indoxacarb , this scenario is protective of any exposure of children via spray drift from agricultural indoxacarb applications. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with th e FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Based on the existing and newly proposed uses of indoxacarb, exposures can occur both from dietary sources (food and water) and in residential settings. Uses of indoxacarb that may result in residential exposures include indoor treatments , spot - treatment of companion animals, and turf ( lawn uses and gol f courses). The aggregate risk assessments are intended to be representative of exposures that are likel y to co - occur. The scenarios expected to result in the highest exposures are used as representative scenarios for the aggregate assessment and are co nsidered protective of other scenarios . The lifestages selected for the aggregate assessments represent the population subgroups expected to be the most highl y exposed for each scenario. For more information on the exposure scenarios selected for aggregat e assessment, see Section 6.3 above. **7.1 Acute Aggregate Risk**  Ty pically , HED does not consider residential exposures when assessing acute aggregate risk unless such exposures can be characterized as a series of single - day exposures, which is not the case for indoxacarb . Therefore, acute aggregate risk estimates for indoxacarb are equivalent to the acute dietary (food and drinking water) risk estimates (Section 5.4) and are below HED’s level of concern. **7. 2**  **Short -**  **Term Aggregate Risk** The short - term aggregate risk for indoxacarb includes background contribution from dietary (food and drinking water) exposure plus the highest short - term residential exposure s for adults and children ( Table 7.2.1 below) . The short - term aggregate assessment for adults includes residential exposure from mixing, loading and applying indoxacarb to turf. The short - term ag gregate risk estimate for adult s is below HED ’s level of concern. The short - term aggregate assessment for children includes post - application exposure from indoor spray- treated surfaces. The short - term a ggregate risk estimate for children is below HED’s level of concern. Not e that the indoor spray- treated aggregate assessment assumes only crack and crevice treatment since the spot - treated directed spray s exposure estimate was of concern b y itself for children .Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 39 o f 56 **Table 7.2 .1**  **Short -**  **Term Aggregate Risk Calculations**  **Population Short**  **- Term Scenario** 

**LOC for Aggregate**  **Risk 1**  **Dietary**

**MOE 2**  **MOE Oral**

**Residential Exposure**  **3 MOE** 

**Inhalation Residential**  **Exposure 4**  **Aggregate MOE (food,**

**water, and residential)**  **5** Adult 100 1800 NA 13,000 1 6 00 Child (1<2 yrs) 100 840 160 6.2 x 10 7 130 1 LOC =100 (10x inter - and 10x intra - species uncertainty factors ) 2 MOE dietary = [(short - - term oral NOAEL)/(chronic dietary exposure )]. Oral NOAEL= 2 mg/kg/day. Chronic dietary exposure value from Table 5.4.5 3 MOE oral = [(short - - term oral NOAEL)/(hand - to - mo uth residential exposure)]. Oral NOAEL= 2 mg/kg/day. Oral exposure value from Table 6.3. 2 (indoor use) **4** MOE inhalation = [(short - term oral NOAEL)/( inhalation exposure). Oral NOAEL= 2 mg/kg/day .Inhalation exposure value from Table 6.3.2 (turf or indoor use) 5 MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE inhalation)] **7.3 Intermediate**  **- /** **Long -**  **Term ( Chronic** **) Aggregate Risk**  The intermediate - /long - term ( or chronic ) aggregate risk for indoxacarb includes contribution from dietary

(food and drinking water) exposure plus the intermediate - /long - term post application exposure to treated pets. The intermediate - /long - term aggregate risk estimate for children post - application exposure to treated pets is below HED’s level of concern ( Table 7.3) . For adults, since there is no expectation of inhalation or non - dietary oral exposures to treated pets, the intermediate - /long - term aggregate risk assessment for indoxacarb is equivalent to chronic dietary

risk assessment conduct ed in Section 5.4 of this document and is below HED’s level of concern. **Table 7. 3**  **Intermediate -** **/ Long**  **- Term Aggregate Risk Calculations** 

**Post -**  **Application T**

**reated Pets (KN128 ) Population**  **Long -**  **Term Scenario**

**LOC for Aggregate**  **Risk 1**  **Dietary**

**MOE 2**  **MOE Oral**

**Residential Exposure**  **3 MOE** 

**Inhalation Residential**  **Exposure 4**  **Aggregate MOE (food,**

**water, and residential) 5**  Child (1<2 yrs) 100 840 8 30 NA 420 1 LOC=100 (10x inter - and 10x intra - species uncertainty factors) 2 MOE dietary = [( long - term oral NOAEL)/(chronic dietary exposure)]. Oral NOAEL= 2 mg/kg/day. Chronic dietary exposure value from Table 5.4.5 3 MOE oral = [( long - term oral NOAEL)/(hand - to - mouth residential exposure)]. Oral NOAEL= 2 mg/kg/day . Residential exposure value from Table 6.3.1 4 Not applicable. Inhalation exposures not expected. 5 MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE inhalation)]Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 40 o f 56 **7.4 Cancer Aggregate Risk**  Indoxacarb is classified as “Not Likely to be Carcinogenic to Humans;” therefore, cancer risk is not a concern and cancer risks are not quantified . **8.0 Cumulative Exposure/Risk Characterization**  EPA does not have, at this time, available data to deter mine whether indoxacarb , an oxadiazine class insecticide , has a common mechanism of toxicity with other substances. 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 as to indoxacarb and any other substances and indoxacarb does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that indoxacarb has a common mechanism of toxicity with other substanc es. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning comm on mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/ . **9.0 Occupational**  **Exposure/Risk Characterization** The insecticide indoxacarb is formulated as granular, impregnated materials, water dispersible granules, emulsifiable, flowable, soluble concentrates, and solution - ready- to - use. Indoxacarb formulations can be used by homeowners and b y commercial applicators to be used in agricultural and non - agricultural use sites IR - 4 has proposed a Section 3 registration (Petition# 2E8029 ) for proposed foliar uses of the active ingredient indoxacarb on the following agricultural crops: 1) new uses on dry beans and succulent beans and 2) expanded crop group uses on small fruit vine climbing subgroup 13 - 07F and low - growing berry

subgroup 13 - 07H . Occupational assessments are performed for the new uses on dry

beans and succulent beans. Existing grape and cranberry uses were reassessed in this document to reflect updates to the Agricultural Reentry Task Force (ARTF) database regarding transfer coefficients (TC) data since both crops are included in the new subgroups. The end - use product s included in this IR - 4 petition are Avaunt® 30% WDG (EPA Reg. No. 352 - 597) and StewardTM EC (EPA Reg. No. 352 - 638 ). The Avaunt ® formulation contain s an isometric mixture of 75% indoxacarb (insecticidally active S - enantiomer; DPX - KN128) and 25% of the R - enantiomer (insecticidall y i nactive; IN - KN127). The percentage of active ingredient indicated on the Avaunt® label and the labeled use rates for each crop are based only on the amount of S - indoxacarb ( KN128 ) and do not reflect the amount of the toxicologically

significant R - enantiomer (KN127). Therefore, to determine combined exposures to both for risk assessment the maximum proposed label rate of application is adjustedIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 41 o f 56 to account for the 25% isomer not reflected on the label ( i.e., lb total indoxacarb applied = application rate * 4/3). The Steward product contains only the S - enantiomer ( KN128 ) ; therefore, the proposed label rate does not need to be adjusted. Avaunt ® insecticide , a WDG formulation containing 30% of insecticidall y active ingredient (S indoxacarb) is proposed for foliar uses on dry beans, succulent beans , small fruit vine climbing subgroup 13 - 07F , and low - growing berry subgroup 13 - 07H at a maximum single application rate of 0.11 lb ai/acre or 0.147 lb total (S - and R - ) indoxacarb per acre (0.11 *4/3= 0.147). In addition , Steward® EC insecticide , an emulsifiable concentrate containing 15.84% of S - i ndoxacarb (and no R - indoxacarb) is proposed for uses on dry beans at a maximum single application rate of 0.11 lb ai/acre . The proposed maximum seasonal application rate for dry and succulent beans and the low growing berry

subgroup is 0.44 lb ai/acre (4 applications at 0.11 lb ai/acre are permitted). For the small fruit vine climbing subgroup, the proposed maximum seasonal application rate is of 0.22 lb ai./acre (2 applications at 0.11 lb ai/acre are permitted). A erial , airblast, ground foliar spray applications , and chemigation techniques (cranberry only) are the proposed application methods. According to the proposed label, pre - harvest intervals (PHIs) range from 3 to 30 day s. The REI specified on the labels is 12 hours. The proposed labels require applicators and other handlers to wear a long - sleeved shirt and long pants and shoes plus socks, plus chemical resistant gloves. The proposed uses and application rates are further described in Table 9.0. **Table 9.0 Summ**  **ary of Directions for Use of Indoxacarb.** Applic. Timing, Ty pe, and Equip. Form ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) * Max.

No. Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations **Beans, Dried** Broadcast foliar applications Air, Ground (groundboom) DuPont TM

Steward ® EC 15.84% ai EC (EPA Reg. No. 352 - 638) 0.11 NS 0.44 7 Retreatment interval (RTI) is 7 days Broadcast foliar applications Air, Ground (groundboom) DuPont TM

Avaunt® 30% ai WDG (EPA Reg. No. 352 - 597) 0.11

(adjusted to 0.147) NS 0.44

(adjusted to 0.586) 7 Retreatment interval (RTI)

is 7 days **Beans, S ucculent**  Broadcast foliar applications Air, Ground (groundboom) DuPont TM

Avaunt® 30% ai WDG (EPA Reg. No. 352 - 597) 0.11

(adjusted to 0.147) NS 0.44

(adjusted to 0.586) 3 Retreatment interval (RTI)

is 7 days **Sm all Fruit Vine Climbing Subgroup 13**  **- 07F**  Broadcast foliar applications Air, Ground DuPont TM

Avaunt® 30% ai WDG 0.11

(adjusted to 0.147) NS 0.22

(adjusted to 0.293) 7 Retreatment interval (RTI)

is 21 daysIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 42 o f 56 * Based on proposed application rates for DuPont TM Steward ® EC ( EPA Reg. No. 352 - 638 ) and DuPont TM Avaunt ® ( EPA Reg. No. 352 - 597 ) . DuPont TM Avaunt ® contain s an isometric mixture of 75% indoxacarb (insecticidally active S - enantiomer; DPX - KN128) and 25% of the R - enantiomer (insecticidally inactive; IN - KN127). The percentage of active ingredient indicated on the Avaunt® label and the labeled use rates for each crop are based only on the amount of indoxacarb (KN128). Therefore, the maximum proposed label rate of application must be adjusted to account for the 25 % isomer not reflected as “ai” ( i.e., lb total indoxacarb = application rate * 4/3). **9.1 Short** **- and**  **Intermedia te**  **- Term**  **Handler Risk** HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary dep ending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used b y a handler can cause exposure levels to differ in a manner spec ific to each application event. Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially

be used, occupational handler inhalation (short - term and intermediate - term) exposure is expected from the proposed uses of indoxacarb on dry beans, s ucculent beans and the uses on small fruit vine climbing subgroup 13 - 07F and low - growing berry subgroup 13 - 07H . Dermal exposure to handlers is not quantitatively assessed as a toxic endpoint is not identified f or dermal exposure to indoxacarb. The quantitative expo sure/risk assessment developed for occupational handlers is based on the following scenarios: 1) Mixing/loading liquids for aerial and groundboom applications; 2 ) Mixing/loading water dispersible granules for aerial, chemigation, airblast , and groundboom application s, 3) Applying Spray s via aerial equipment , airblast and groundboom equipment; 4 ) Mixing/loading/appl yi ng water dispersible granules via mechanically pressurized handgun;and, 5 ) Flaggin g for aerial spray applications. It is the policy

of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical - specific data, include PHED 1.1, the AHETF database, th e Outdoor Residential Exposure Task Force (ORETF) database, or other registrant - submitted occupational exposure studies. Some of these data are (groundboom, airblast) (EPA Reg. No.

352 - 597) **Low -**  **Growing Berry Subgroup 13 -**  **07H** Broadcast foliar applications Air, Ground (groundboom), Chemigation (cranberry only), Mechanically pressured hand gun DuPont TM

Avaunt® 30% ai WDG (EPA Reg. No. 352 - 597) 0.11

(adjusted to 0.147) NS 0.22 to 0.44

(0.293 to 0.586 depending on pest) 30 Broadcast applications may

need supplemental spot treatment in localized areas of heavy insect pressureIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 43 o f 56 proprietary

( e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values re commended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 7 ”, which, along with additional information on HED pol icy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 8

. Estimates of inhalation exposure were calculated at “baseline ” level of personal protective equipment (PPE). “ Baseline ” is defined as a sin gl e layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator . The proposed labels require applicators and other handlers to wear a long - sleeved shirt and long pants and shoes plus socks, plus chemical - resistant gloves. A series of assumptions and exposure factors served as the basis for completing the occupational risk assessments. See D411342 , 5/1/13, complete details regarding body weight assumptions, absorption, unit exposures, area treated, exposure durations, and the associated calculations. Summary of Occupational Handler Short - Term and Intermediate - Term (Non - Cancer) Exposure and Risk Estimates The Agency

matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate , agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadil y from the mid 1990’s. Over the same time period, the u se of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to onl y 1% in the most recent (2012) NAAA survey . The Agency will continue to monitor all available information sources to best assess and characteri ze the exposure potential for human flaggers in agricultural aerial applications. HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are a ssessed using the engineering control (enclosed cockpits) and baseline attire (long - sleeve shirt, long pants, shoes, and socks); per the Agency ’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective g loves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators. Table 9.1 presents a summary of the short - and intermediate - term occupational handler exposures and risks. All occupational handler scenarios assessed result in inhalation MOEs that do not exceed HED's level of concern (MOEs ≥ 100) for short and intermediate - term exposure durations at label specified PPE ( i.e ., no respirator ).

7 Available: http://www.epa.gov/opp00001/science/handler - exposure - table.pdf 8 Available: http://www.epa.gov/pesticides/science/handler - exposure - data.htmlIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 44 o f 56 **Table 9.1**  **Occupational Handler ST and IT (** **Non -**  **Cancer )**  **Exposure and Risk Estimates for Indoxacarb**  **. Exposure Scenario**  **Crop or Target Inhalation**  **Unit Exposure (μg/lb ai)**  **1 Maximum** 

**Application Rate**  **2 (lb ai/A)**  **Area Treated**

**or Amount Handled Dail** **y (acres)**  **3 Inhalation**  **Mitigation Level**  (Baseline, no respirator) **Dose (m**  **g/k g/day)**  **4 MOE**  **5** Mixer/Loader Mixing/Loading Water Dispersible granules (WDG) for Aerial Applications Fruit, small vine climbing - Sub group 13 - 07F 8.96 0.147 350 0.00576 1000 Bean (snap), Low- Growing Berry Subgroup 13 - 07H Mixing/Loading Water Dispersible granules (WDG) for Aerial Applications Bean (dry) 8.96 0.147 1,200 0. 0 198 300 Mixing/Loading Water Dispersible granules (WDG) for Airblast Applications Fruit, small vine climbing - Sub group 13 - 07F 8.96 0.147 40 0.00065 9,000 Mixing/Loading Water Dispersible granules (WDG) for Chemigation Applications Fruit, small vine climbing - Sub group 13 - 07F (cranberry0 8.96 0.147 350 0.005 7 6 1,000 Mixing/Loading Water Dispersible granules (WDG) for Groundboom Applications Bean (snap), 8.96 0.147 80 0.00131 4,600 Low- Growing Berry Subgroup 13 - 07H Mixing/Loading Water Dispersible granules (WDG) for Groundboom Applications Bean (dry) Bean (dry) 8.96 0.147 200 0.00329 1, 800 Mixing/Loading Liquid Flowables for Aerial Applications 0.219 0.11 1,200 0.0003 1 6 ,000 Mixing/Loading Liquid Flowables for Groundboom Applications 0.219 0.1 1 200 0.00006 98 ,000 Applicator Applying Sprays via Airblast Equipment (Open Cab) Fruit, small vine climbing - Sub group 13 - 07F 4.71 0.147 40 0.00034 17,3 00 Applying Sprays via Gr oundboom Equipment Bean (snap), 0.32 0.147 80 0.00005 120 ,000 Low- Growing Berry Subgroup 13 - 07HIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 45 o f 56 **Table 9.1**  **Occupational Handler ST and IT (** **Non -**  **Cancer )**  **Exposure and Risk Estimates for Indoxacarb**  **. Exposure Scenario**  **Crop or Target Inhalation**  **Unit Exposure (μg/lb ai)**  **1 Maximum** 

**Application Rate**  **2 (lb ai/A)**  **Area Treated**

**or Amount Handled Dail** **y (acres)**  **3 Inhalation**  **Mitigation Level**  (Baseline, no respirator) **Dose (m**  **g/k g/day)**  **4 MOE**  **5** Applying Sprays via Gr oundboom Equipment Bean (dry) 0.34 0.147 200 0.00012 48 ,000 0.1 1 0.00009 64,000 Flagger Flagging f

or Aerial Spray Applications Bean (snap), LowGr owing Berry Subgroup 13 - 07H, and Fruit, small vine climbing - Sub group 13 - 07F, 0.35 0.147 350 0.00022 2 7 , 0 00 Flagging for aerial spray applications Bean (dry) 0.35 0.147 0.000 16 2 7 ,000 0.35 0.1 1 0.0001 36,000 Mixer/Loader/Applicator Applying Water Dispersible Granules Via Mechanically Pressurized Handgun Fruit, small vine climbing - Sub group 13 - 07F 3.9 0.147 1000 gallons 0.00716 840 Bean (snap), Low- Growing Berry Subgroup 13 - 07H 1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” September 2012 **]** ); Level of mitigation: Baseline, PPE, Eng. Controls. 2. Based on registered or proposed label s: DuPont TM Avaunt ® 30% ai WDG (EPA Reg. No. 352 - 597) and DuPont TM Steward ® EC 15.84% ai EC (EPA Reg. No. 352 - 638). The application rate used to calculate MOEs for Avaunt applications has been adjusted by a 4/3 factor t o account for 4 parts of t otal indoxacarb for every 3 parts of S - indoxacarb. 3. Exposure Science Advisory Council Policy #9.1. 4. Inhalation Dose = I

nhalation Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre or gal) × Ar ea Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg). 5. Inhalation MOE = I

nhalation NOAEL ( 6 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Occupational Handler Cancer Exposure and Risk Equations Cancer risk estimates are not provided for indoxacarb since it is classified as not likely carcinogenic to humans . **9.2 Short** **- and Intermediate**  **- Term**  **Post -** **Application Risk**  HED uses the term post - application to describe exposures that occur when individual s are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the ty pe of activity , the nature of the crop or target that was treated, the ty pe of pesticide application, and the chemical ’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for post - application exposure.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 46 o f 56 Dermal and inhalation exposures to indoxacarb may occur for post - application wor kers. A quantitative dermal assessment is not performed since a dermal toxicity endpoint is not identified for indoxacarb. A quantitative occupational post - application inhalation exposure assessment was not performed for indoxacarb; however, an inhalation exposure assessment was performed for occupational/commercial handlers , which is likel y to result in higher exposure than would occur post - application . Therefore, these handler inhalation exposure estimates would be protective of occupational post - application inhalation exposure scenarios. **9.2.1 Dermal Post**  **- A** **pplication Risk** Occupational Post - Application Dermal Exposure Data and Assumptions Short - and intermediate - term dermal post - application risk estimates were not quantified , since the calculated human dermal L OAEL exceeds the limit dose of 1000 mg/kg/day and dermal toxicity to indoxacarb is not expected . Restricted Entry

Interval The REI specified on the proposed label is 12 hours and is based on the acute toxicity of Indoxacarb. Indoxacarb is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential. Itis not a skin sensitizer. Un der 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12 - hour REI . Therefore, the [156 subpart K] Worker Protection Statement interim REIof 12 hours is adequate to protect agricultural workers from post - application exposures to indoxacarb. **9.2.2 Inhalation Post** **- A** **pplication Risk** Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for indoxacarb at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), and low vapor pressure (2.5 x 10 - 8 ). However, there are multiple potential sources of post - application inhalation exposure to individuals performing pos t - application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. 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, and received the SAP’s final report on March 2, 2010 9 . The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational post - application inhalation exposure int o the Agency's risk assessments. If new policies or procedures are put into place, the Agency

may revisit the need for a quantitative occupational post - application inhalation exposure assessment for indoxacarb.

9 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 47 o f 56 Although a quantitative occupational post - a pplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure th an post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. **10.0 References**  A. Rivera - Lupianez, 5/1/13, D411342 , Indoxacarb : 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 . I. Negrón - Encarnación, 5/1/13 , D408983, In doxacarb Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13 - 07F and L ow Growin g Berry

Subgroup (except strawberry) 13 - 07H . I. Negrón - Encarnación, 5/2 /13 , D408982, Indoxacarb. Petition for the Establishment of Permanent Tolerances and Registration for Use on D ry Bean, S nap B ean, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13 - 07F and L ow Growing Berry Subgroup (except strawberry) 13 - 07H . Summary of Anal ytical Chemistry

and Residue Data. C. Koper, 11/06/12, D402100, Tier II Drinking Water Assessment for the New Use Registration of Indoxacarb on Dry

Beans, Snap Beans, Smal l Fruit Vine Climbing Subgroup 13 - 07F and Low - Growing Berry

Subgroup 13 - 07H. D. Drew, 5/26/09, D365306, In doxacarb. Addendum to the Health Effects Division (HED) Human Health Risk Assessment for Bushberry Crop Subgroup 13 - 07B and Beets (Garden). D. Drew, 5/18/09, D351087, Indoxacarb. Health Effects Division (HED) Human Health Risk Assessment for Bushberry Crop Subgroup 13 - 07B and Beets (Garden**).** HIARC Report on Indoxacarb, HED Doc No. 013528 (June 24, 1999)Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 48 o f 56 **A ppendix**  **A . Toxicology Prof**  **ile and Executive Summaries** A.1 Toxicology

Data Requirements The requirements (40 CFR 158.340) for indoxacarb are in Table 1. Use of the new guideline numbers does not im ply that the ne w (1998) guideline protocols were used. **Table A. 1**  **Toxico logy**  **Requirements for Indoxacarb Guideline Number and Toxicity Study**  **Required Satisfied**  870.1100 Ac ute Oral Toxicity ................................ ...................... 870.1200 Ac ute Dermal Toxicity ................................ ................. 870.1300 Ac ute 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 Sub - chronic (Rodent) ................................ ........... 870.3150 Oral Sub - chronic (Non - Rodent) ................................ ... 870.3200 21 - Day

Dermal ................................ ............................. 870.3250 90 - Day

Dermal ................................ ............................. 870.3465 90/28 - Day Inhalation ................................ ................... yes yes yes CR CR yes

yes yes

-- yes 870.3700 Developmental Toxicity (Rodent) ............................... 870.3700 Developmental Toxicity (Non - rodent) ......................... 870.3800 Reproduction ................................ ................................ yes yes yes yes

yes yes 870.4100 Chronic Toxicity (Rodent) ................................ ........... 870.4100 Chronic Toxicity (Non - rodent) ................................ .... 870.4200 Oncogenicity (Rat) ................................ ....................... 870.4200 Oncogenicity (Mouse) ................................ .................. 870.4300 Chronic/Oncogenicity ................................ .................. yes no yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity: Gene Mutation - bacterial ..................... 870.5300 Mutagenicity: Gene Mutation - mammalian ................ 870.5375 Mutagenicity: Structural Chromosomal Aberrations ... 870.539 5 Mutagenicity: Cytogenetics 870.5500 Mutagenicity: Other Genotoxic Effects ....................... yes yes yes yes yes yes

yes yes yes ye s 870.6100 Ac ute Delayed Neurotoxicity (Hen) ............................. 870.6100 90 - Day

Neurotoxicity (Hen) ................................ ........ 870.6200 Ac ute Neurotoxicity Screening Battery (Rat) .............. 870.6200 90 - Day

Neuro toxicity . Screening Battery (Rat) ........... 870.6300 Developmental Neurotoxicity ................................ ...... no no yes yes CR -

- yes yes yes 870.7485 General Metabolism ................................ ..................... 870.7600 Dermal Penetration ................................ ....................... 870.7800 Immunotoxicity....................................................................... yes no yes yes

yes yesIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 49 o f 56 A.2 Toxicity

Profile s **Table A.2.1 Acute Toxicity Data on**  **Indoxacarb (DPX -**  **KN128) Guideline No./Study Type**  **MRID # Results**  **Toxicity Category**  870.1100 Acute oral toxicity 44477115 LD50 = 179 (F) and 843 (M) mg/kg (rat) II 870.1200 Acute dermal toxicity 46240001 LD 50 > 5000 mg/kg (rat) IV 870.1300 Acute inhalation toxicity N/A N/A IV 870.2400 Primary eye irritation 46240002 Not a eye irritant (rabbit) IV 870.2500 Primary dermal irritant 46240003 Not a dermal irritant (rabbit) IV 870.2600 Skin sensitization 46240004 Is a dermal sensitizer (Guinea Pig) NA **Table A.2.2 Acute Toxicity Data on DPX** **- MP062 Technical (94.5%;)**  **80% DPX KN128, 20% IN KN127 Study**  **Type MRID #**  **Results Toxicity**  **Category** 870.1100 Acute oral toxicity 44477113 LD 50 = 1730mg/kg males 268 mg/kg females <1000 mg/kg combined (rat) II

870.1200 Acute dermal toxicity 44477118 LD 50 >5000mg/kg (limit test) (rat) IV 870.1300 Acute inhalation toxicity 70%MUP 44477120 LC 50 > 5.5 mg/L males,

females and combined IV 870.2400 Primary eye irritation 44477122 Moderate eye irritant (rabbit) III 870.2500 Primary dermal irritant 44477125 Not a dermal irritant (rabbit) IV 870.2600 Skin sensitization 44477126 Magnusson - Kligman Maximization test, Is a dermal sensitizer (Guinea Pig) NA **Table A.2.3 Acute Toxicity Data on DPX** **- JW062 (**  **50% DPX KN128,50% IN KN127)**  **Guideline No./ Study Type MRID No.**  **Results Toxicity**  **Category** 870.1100 Acute oral toxicity 44701601 LD 50 > 5000 mg/kg (males, females, combined) (in corn oil) IVIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 50 o f 56 870.1200 Acute dermal toxicity 44477119 LD 50 > 2000 mg/kg (males, females, combined) (rabbit) III 870.1300 Acute inhalation toxicity 44477121 LC 50 > 5.4 mg/L males LC 50 = 4.2 mg/L females (rat) IV 870.2400 Primary eye irritation 44701602 Slight eye irritant (rabbit) IV 870.2500 Primary dermal irritation 44701603 Slight dermal irritation (rabbit) IV 870.2600 Skin sensitization 44701604 Is not a dermal sensitizer Magnusson - Kligman Maximization test, (Guinea Pig) NA

**Table A.2.4 Sub**  **- Chronic, Chronic, and Other Toxicity Data on**  **Indoxacarb (DPX -**  **KN128) Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses** 870.3700a Prenatal developmental in rodents - rat 46240005(2004)

Acceptable/guideline 0, 0.5, 1.0, 2.0, or 3.5 mg/kg/day **Materna** l NOAEL = 2.0 mg/kg/day LOAEL = 3.5 mg/kg/day, based on decrease in maternal overall body - weight gain and adjusted body- weight gain. **Developm ental**  NOAEL = 2.0 mg/kg/day LOAEL = 3.5 mg/kg/day, based on decreased mean fetal weight. Gene Mutation 870.5100 46240006 (2004)

Acceptable/guideline strains TA98, TA100, TA1535 and TA1537 of S. ty phimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9 activation for the concentration range 2.5 - 5000 μg/plate Gene Mutation 870.5300 46240007 (2003)

Acceptable/guideline negative for mutagenic activity for the following concentration range 5 - 50 μg/mL (±S9) Cy togenetics 870.5375 46240008 (2003)

Acceptable/guideline no evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 1.25 - 100 μg/mL ( + S9) 870.6300 Developmental neurotoxicity - rat 46749002 (2006)

46749003 (2006) Acceptable/non - guideline 0, 0.5, 1.0, 1.5, or 3.0 mg/kg/day **Maternal system ic/neurotoxicity**  NOAEL = 1 .5 mg/kg/day LOAEL = 3.0 mg/kg/day, based on the adverse clinical signs observed, decreased body- we ight gain and food consumption and mortality. **Offspring systemic/neurotoxicity** NOAEL= 1.5 mg/kg/day LOAEL = 3.0 mg/kg/day, based on an increased incidence of stillbirths, decreased mean pup body weight at birth and increased pup mortality during PND 1 - 4 in males and females, and increase in number of learning trials to reach criterion and increased latency in males. 870.7800 Immunotoxicity 48478002 (2011)

Acceptable/guideline Immunotoxicity NOAEL=23 mg/kg/day HDT Sy stemic NOAEL=23 mg/kg/day HDT Sy stemic LOAEL was not established (>23 mg/kg/day).Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 51 o f 56 **Table A.2.5 Sub**  **- Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX** **- MP062)**  **80% DPX KN128, 20% IN KN127**  **Guideline No./ Study Type**  **MRID No. (year)/**

**Classification /Doses Results**  870.3100 90 - Day oral toxicity rodents 44477129 (1997)

Acceptable/guideline M: 0, 10, 50, 100, 200 ppm M: 0, 0.6, 3.1, 6.0, 15 mg/kg/day F: 0, 10, 25, 50, 100 ppm, F: 0, 0.76, 2.1, 3.8, 8.9 mg/kg/day NOAEL = 3.1 (M), 2.1 (F) mg/kg/day LOAEL = 6.0 (M), 3.8 (F) mg/kg/day based on decreased body weight, body - weight gain, food consumption and food efficiency.

870.3200 28 - Day dermal toxicity 44477134 (1997)

acceptable (guideline) 0, 50, 500, 1000, 2000 mg/kg/day NOAEL = 2000 mg/kg/day LOAEL = >2000 mg/kg/day in rats. 870.3200 28 - Day dermal toxicity 44983901 (1999)

acceptable/guideline 0, 50, 500, 1000, 2000 mg/kg/day NOAEL = 50 mg/kg/day LOAEL = 500 mg/kg/day based on decreased body weights, body -weight gains, food consumption, and food efficiency in F, and changes in hematology parameters (incr. reticulocytes), the spleen (incr. abs. and rel. weight

–M only, gross discoloration), clinical signs of toxicity in both sexes in rats. [Based on the in vitro dermal absorption data from rat skin and human skin (i.e. 15.2% and 0.87%, respectively), the human equivalent NOAEL is 875 mg/kg/day (i.e. 50 x 15.2%/0.87%). Thus, the calculated human dermal LOAEL of 8750 mg/kg/day exceeds the dermal limit dose of 1000 mg/kg/day. See MRIDs 45911401, 45911402, 45911403] 870.3465 28 - Day inhalation toxicity 45870001 (2003)

Acceptable/non guideline 0, 4.6, 23, 290 μg/L/day NOAEL = 23 μg/L/day LOAEL = 290 μg/L/day (75.69 mg/kg/day), based on increased absolute and relative spleen weights, pigmentation and hematopoiesis in the spleen, and hematological changes. 870.3700a Prenatal developmental in rodents - rat 44477138, 44477142

(1997) Acceptable (guideline) 0.0, 0.5, 1.0, 2.0, or 4.0 mg/kg/day (in PEG) **Maternal** NOAEL = 2.0 mg/kg/day LOAEL = 4.0 mg/kg/day based on decreased mean body weights, body -weight gains, food consumption. **Developmental** NOAEL = 2.0 mg/kg/day LOAEL = 4.0 mg/kg/day based on decreased fetal weights. Gene Mutation 870.5100 44477149 (1997)

acceptable/guideline Negative: strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with andIndoxacarb Human Health Risk Assessment DP No. D4 16367

Page 52 o f 56 **Table A.2.5 Sub**  **- Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX** **- MP062)**  **80% DPX KN128, 20% IN KN127**  **Guideline No./ Study Type**  **MRID No. (year)/**

**Classification /Doses Results**  without S9 activation for the concentration range 10 - 5000 μg/plate Gene Mutation 870.5300 44477147 (1997)

acceptable/guideline Negative: negative for mutagenic activitity for the following concentration ranges: 3.1 - 250 μg/mL ( - S9); 3.1 - 250 μg/mL (+S9) Cytogenetics 870.5375 44477146 (1996)

acceptable/guideline Negative: no evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 15.7 - 1000 μg/mL ( + S9) Cytogenetics 870.5395 44477148 (1997)

acceptable/guideline Negative: no evidence of mutagenicity for the following dose ranges: 3000 - 4000 mg/kg - males; 1000 - 2000 mg/kg - females Other Effects 870.5550 44477151 (1997)

acceptable/guideline Negative: no evidence of mutagenic activity at the following concentration range: 1.56 - 200 μg/mL; cytotoxicity was seen at concentrations of > 100 μg/mL 870.6200a Acute neurotoxicity screening battery 44477127 (1997)

acceptable/guideline M: 0, 25, 100, 200 mg/kg F: 0, 12.5, 50, 100 mg/kg NOAEL = 100 mg/kg (M), 12.5 mg/kg (F) LOAEL = 200 mg/kg (M) based on decreased body weight gain, decreased food consumption, decreased forelimb grip strength, and decreased foot splay. 50 mg/kg (M) based on decreased b ody weight and body weight gain 870.6200b Subchronic neurotoxicity screening battery 44477135 (1997)

acceptable/guideline M: 0, 10, 100, 200 ppm 0.57, 5.6, 12 mg/kg/d, F: 0, 10, 50, 100 ppm 0.68, 3.3, 6.1 mg/kg/d NOAEL =0.57 (M), 0.68 (F) mg/kg/day LOAEL = 5.6 (M), 3.3 (F) mg/kg/day based on decreased body weight and alopecia.

870.7600 Dermal penetration (Triple pack study) 45911401 (2002)

45911402 (2002) 45911403 (2002) Acceptable/guideline 0, 13.3, 2000 μg/cm2 for 6 hours Dermal absorption ranged from 0.41% to 0.94% following 6 hours exposure in rats. Following a 162 hours post dosing, the absorption in rats ranged from 0.88% to 4.91% depending upon the dose/dilution. The in vitro dermal absorption for rat skin was 15.2% and the in vitro dermal absorption in human skin was 0.87%, or 17.5X lower. The equivalent dermal absorption in humans was calculated to be 0.28%. **Table A.2.6 Sub**  **- Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX** **- JW062)**  **( 50% DPX KN128, 50%**  **IN KN127) Guideline No./**  **MRID No. (year)/ Results** Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 53 o f 56 **Study Type Classification/Doses**  870.3700a Prenatal developmental in rodents - rat 44477140, 44477143

(1997) acceptable/guideline 0, 10, 100, 500, 1000 mg/kg/day (in methyl cellulose) **Maternal** NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on mortality, clinical signs, and decreased mean body weights, body - weight gains, and food consumption. **Developm ental**  NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on decreased numbers of live fetuses/li tter. 870.3700a Prenatal developmental in rodents - rat 44477139 (1997)

acceptable/guideline 0, 20, 40, 80, or 120 ppm 1.11, 2.2, 4.1, 5.7 mg/kg/day (rounded to 2 sig. fig.) **Maternal** NOAEL = 1.1 mg/kg/day LOAEL = 2.2 mg/kg/day based on decreased mean body weights, body- weight gains, food consumption, and food efficiency. **Developm ental**  NOAEL = 1.1 mg/kg/day LOAEL = 4.1 mg/kg/day based on decreased fetal body weights. 870.3700b Prenatal developmental in nonrodents - rabbit 44477141 (1995)

acceptable/guideline 0, 250, 500, or 1000 mg/kg/day in methyl cellulose **Materna** l NOAEL = 500 mg/kg/day LOAEL = 1000 mg/kg/day based on slight decreases in maternal body - weight gain and food consumption. **Developm enta**  l NOAEL = 500 mg/kg/day LOAEL = 1000 mg/kg/day based on decreased fetal body weights and reduced ossification of the sternebrae. 870.3800 Reproduction and fertility effects 44477144 (1997)

acceptable/guideline 0, 20, 60, 100 ppm M : 0, 1.3, 3.9, 6.4 mg/kg/d F : 0, 1.5, 4.4, 6.9 mg/kg/d **Parental/System ic**  NOAEL = 1.5 mg/kg/day LOAEL = 4.4 mg/kg/day based on decreased body weights, body- weight gains, and food consumption of F 0 females, and incr. spleen weights in the F 0 and F 1 females. **Reproductive** NOAEL = 6.4 mg/kg/day LOAEL > 6.4 mg/kg/day. **Offspring** NOAEL = 1.5 mg/kg/day LOAEL = 4.4 mg/kg/day based on decrease in the body weights of the F 1 pups during lactation. 870.4100a Chronic toxicity rodents - rat 44477145 (1997)

acceptable/guideline 0, 20, 40, 60, 125, 250 ppm M : 0, 0.80, 1.6, 2.4, 5.0, 10 mg/kg/day F : 0, 10, 20, 40, 60, 125 ppm 0, 0.55, 1.0, 2.1, 3.6, 7.8 mg/kg/day NOAEL = 5 (M), 2.1 (F) mg/kg/day LOAEL = 10 (M), 3.6 (F) mg/kg/day based on decreased body weight, body- weight gain, and food consumption and foo d efficiency; decreased HCT, HGB and RBC at 6 months in F only. **No evidence of carcinogenic potential.**

870.4100b Chronic toxicity dogs 44477136 (1997)

acceptable/guideline 0, 40, 80, 640, 280 ppm M : 0, 1.1, 2.3, 18, 34 mg/kg/day F : 0, 1.3, 2.4, 19, 36 mg/kg/day NOAEL = 2.3 (M), 2.4 (F) mg/kg/day LOAEL = 18 (M), 19 (F) mg/kg/day based on decreased HCT, HGB and RBC; incr. Heinz bodies and reticulocytes and assoc. secondary microscopic changes in the liver, kidneys, spleen, and bo ne marrow ; incr. abs. and rel. liver weights. 870.4200 Carcinogenicity rats see 870.4100a see 870.4100a **No evidence of carcinogenicity.**Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 54 o f 56 870.4300 Carcinogenicity mice 44477137 (1997)

0, 20, 100, 200/150/125 ppm M : 2.6, 14, 22 mg/kg/day F : 4.0, 20, 31 mg/kg/day (rounded to 2 sig. fig.) NOAEL = 2.6 (M), 4.0 (F) mg/kg/day LOAEL = 14 (M), 20 (F) mg/kg/day based on decreased body weight, body- weight gain, and food efficiency and clinical signs indicative of neurotoxicity. **No evidence of car cinogenicity.**  Gene Mutation 870.5100 44701606 (1995)

acceptable/guideline Negative: strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9 activation for the concentration range 10 - 5000 μg/plate. Gene Mutation 870.5300 44701607 (1995)

acceptable/guideline Negative for mutagenic activity for the following concentration ranges: Negative;100 - 1000 μg/mL ( - S9); 100 - 1000 μg/mL (+S9), precipitate > 1000 μg/mL Cy togenetics 870.5375 44701608 (1995)

acceptable/guideline Negative: No evidence of chromosomal aberrations induced by the test article over background for the following concentration ranges: 19 - 300 μg/mL ( - S9), 19 - 150 μg/mL (+S9); partial insoluble & cytotoxicity > 150 μg/mL Cy togenetics 870.5395 44701610 (1995) Negative: No evidence of mutagenicity at 2500 or 5000 mg/kg Other Effects 870.5550 44701609 (1995)

acceptable/guideline Negative: No evidence of mutagenic activity at the following concentration range: 0.1 - 50 μg/mL, cytotoxicity observed at > 50 μg/mL 870.6200a Ac ute neurotoxicity screening battery 44477128 (1996)

acceptable/guideline 0, 500, 1000, 2000 mg/kg NOAEL >= 2000 mg/kg (M) = < 500 mg/kg (F) LOAEL > 2000 mg/kg (M) < 500 mg/kg (F) based on clinical signs, decreased body- weight gains and food consumption, and FOB effects 870.7485 Metabolism and pharmacokinetic 44477152, 44477153

(1997) acceptable/guideline Both **indoxacarb** and **JW062** were extensively metabo lized and the metabolites were eliminated in urine, feces, and bile. The metabolite profile for **JW062** wa s dose dependent and varied quantitative ly

between males and females. Differences in metabolite profiles were also observed for the different label po sitions (indanone and trifluoromethoxyphenyl rings). All biliary metabolites undergo further biotransformation in the gut. The proposed metabolic pathway for both **indoxacarb** and **JW062** has multiple metabolites bearing one of the two ring structures.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 55 o f 56 **Appendix B**  **. Physical/Chemical Properties** 

1 EFED memo D402100, 11/6/12 **T able**  **B.1 Physicochemical Properties of Indoxacarb**  Parameter Value Reference Melting point/range 140 - 141oC DP# D244253, S. Levy, 1/19/2000 pH 5.32 at 25oC Density 1.34 at 20oC Water solubility 15.4 ± 2.3 ppb in pH 5 buffer 800 ppb at pH 7 (20 ◦ C) 1 Solvent solubility 1.72 g/L in n - heptane; 14.5 g/L in 1 - octanol; 103 g/L in methanol; 117 g/L in o - xylene; 139 g/L in acetonitrile; 160 g/L in ethyl acetate; and >250 g/kg in methylene chloride, acetone, and dimethyl - formamide Vapor pressure (25°C) 2.5 x 10 - 8 Pa (1.9x10 - 10 mmHg) Dissociation constant, pKa Does not dissociate at pHs of 2.42 - 11.36 Octanol/water partition coefficient, Log(KOW) 4.65 at pH 5 UV/visible absorption spectrum Molar absorptivities at three maxima were affected by pH, but not over wavelengths of environmental significance.Indoxacarb Human Health Risk Assessment DP No. D4 16367

Page 56 o f 56 **Appendix C**  **. 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 data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database ; the ARTF database; and the Outdoor Residential Exposure Task Force (ORETF) database , are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with a pplicable ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 10

.

10 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/opp0000 1/science/residential - exposure - sop.html