UN IT ED S T A TES ENVIRONM EN TAL PROTECTION A GE NCY

WASHIN G TON, D. C

. 20460

O F F IC E OF
C HE M I CAL S AFETY AND
POLL UT I O N PREVE N TIO N MEMORANDUM



### Date: May 9, 2013

SUB JE CT : 

### lndoxacarb. H uman Health Risk Assessment Scoping D ocu m ent i n Suppo rt of Reg i stration Review.

FROM:

THR U :

T O: PC Code: 067710

Decision No. : 475167

Petition No.: NA

R i sk Assessment Type: Single Chemical Aggregate

TXRNo.: NA

MRlDNo

. : NA



### Da n ette Drew,**Chem** 

### '

, DP Barcode: 409209 Registration No.: NA Regulatory Ac t ion: Registration Review Scoping

CaseNo. : NA

CAS No

. : 173584-44-6

40 CFR: §180.564**~** . .... 

### Ana Rivera

- Lupianez, Chemis t '
.....-**~-** 

## ::>

William Irwin

, Ph.D., T oxicologist

### /)J~ 

# \ \**~~** R i sk Assessmen t Branch V N il 

# oc-l..M>'1/y\.

Health Effects D i vision (7509P) 

# j____

M i chael S. Metzger, Branch Chief t+J_J 

# J V

Risk Assessment B r anch VI V II



### Hea l th Effects Division (7509P)

Office of Pest i c i de Programs

K at i e Wey r auch, Chemica l Review Manager

Risk Management and Implementation B r anch V

Pesticide Re-eva l uation Div i sion (7508P)

Office of Pesticide Programs

Attached is t h e Healt h Effects Div i s i on's (l-IED) human health risk assessment scoping (s t a t us upda t e ) document for indoxacarb to support the registration review process.

Page 1 

### of29

### Page 2 of 29

Executive Summary

HED has considered the available risk assessments for indoxacarb and its toxicity, exposure and usage databases, as well as the most current Agen cy science and assessment policies. HED performed this evaluation in order to determine the scope of work necessary to support the established tolerances and existing registrations during registration review. The primary source

of information for this ev aluation was the recent indoxacarb human health risk assessment ( 5/2/13 , D 402099 ) which was performed to support a petition for the proposed uses of indoxacarb on dry beans and succulent beans and to expand crop group uses on small fruit vine climbing subg roup 13

- 07F and low

- growing berry subgroup 13

- 07H.

Indoxacarb, (S)

- methyl 7

- chloro

- 2,5

- dihydro

- 2

- [[(methoxycarbonyl)[4

- (trifluoromethoxy)phenyl] amino]carbonyl]indeno[1,2

- e][1,3,4]oxadiazine

- 4a(3H)

- carboxylate, is an oxadiazine class insecticide registere d for use in both agricultural and residential sites. Residential uses include spot

- on treatments of cats and dogs, indoor and outdoor directed sprays, and use on turf (lawns and golf courses)

. 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 well as livestock commodities (tolerances on poultry commodity also include several indoxacarb metabolites). The primary residues of toxicological concern for risk asses sment are
indoxacarb and its R

- enantiomer; various metabolites and degradates are also included as residues of concern in milk, poultry commodities and drinking water.

Indoxacarb is formulated as granular; impregnated materials; water dispersible granul es; emulsifiable, flowable and soluble concentrates; and solution

- ready

- to

- use products. Indoxacarb products are frequently formulated as a mixture of the insecticidally 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 the indoxacarb risk assessment s , where

necessary, 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 (al so referred to as JW062)

which is a mixture of t he enantiomers at a 50:50 ratio . The R

- enantiomer is also referred to as

IN

- KN127 or KN127.

The toxicity database for indoxacarb is complete and is sufficient for the characterization of a wide variety of toxic effects, including potential carcinogenic, mutagenic, developmental, reproductive and immunotoxic effects. There are no outstanding toxicity data requirements for

indoxacarb and t he current toxicological endpoints, points of departure ( PODs ) , and FQ PA and

other uncertainty factors reflect current policy.

The indoxacarb residue chemistry database is complete. No new data are needed to assess potential dietary exposure and risk and there are currently no acute or chronic dietary (food and

### Page 3 of 29

water) ris ks of concern for indoxacarb. During registration review, a new dietary risk assessment is not anticipated for indoxacarb registration review

.

There are no residential handler or post

- application risk estimates of concern for the current uses of indoxacarb, except for indoor surface directed sprays when a spot

- directed treatment is

assumed. In that case, non

- dietary oral (hand

- to

- mouth) post

- application exposures for children
exceeded HED’s level of concern. When a crack and crevice only treatment (limiting applications to areas not accessible to young children) is assumed for the spray, there are no risk

estimates of concern. The current label does not specifically restrict the indoor spray use to crack and crevice only

.

T here are no acute, short

- and intermediate

- term, or long

- term (chronic) aggregate (food, water, and residential) risk estimates of concern when it is assumed that indoor surface directed spray treatments are limited to crack and crevice only. A revised aggregate risk assessment is not anticipated for indo xacarb registration review.

The occupational exposure database is complete for indoxacarb. There are no occupational handler or post

- application exposure risk estimates of concern. A revised occupational assessment is not anticipated for indoxacarb regi stration review.

Chemical Use Profile

Indoxacarb, (S)

- methyl 7

- chloro

- 2,5

- dihydro

- 2

- [[(methoxycarbonyl)[4

- (trifluoromethoxy)phenyl] amino]carbonyl]indeno[1,2

- e][1,3,4]oxadiazine

- 4a(3H)

- carboxylate, is an oxadiazine class insecticide active ingredient (a i). 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 racemic mixture of the S

- e nantiomer and R

- enantiomer. The percentage of active ingredient and application rates on the product labels for the mixtures only reflect the S

- enantiomer. Adjustments are made in indoxacarb risk assessment s to account for (add in) the percent of R

enant iomer in product mixtures. Indoxacarb i s registered for use on agricultural crops and in

residential s ettings. Residential uses include spot

- on treatments of cats and dogs, indoor and outdoor directed sprays, and use on turf (lawns and golf courses). P ermanent 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 well as livestock commodities (tolerances on poultry

commodit ies also include several indoxacarb metabolites).

The nomenclature and physiochemical properties of indoxacarb can be found in Appendix A

.

Hazard Identification/Toxicology

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 only).

### Page 4 of 29

The toxicity profiles fo r KN128, MP062 and JW062 in rats, mice and dogs with both subchronic and chronic oral exposures were qualitatively similar. The endpoints that most frequently

defined the lowest

- observed

- adverse

- effect

- level (LOAEL) were non

- specific, and included

decreas es in body weight, weight gain, food consumption and food efficiency. These compounds also affected the hematopoietic system by decreasing the red blood cell count, hemoglobin and hematocrit in rats, dogs and mice.

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 s tudies in rats and mice but at doses much higher than those selected for points of departure (which are based on changes in body weight, food consumption and changes in hematology) for the current risk assessment

. There is no evidence of t eratogenicity

,

m utagenicity, or carcinogenicity in the indoxacarb studies. T he immunotoxicity study did not indicate immunotoxic potential for indoxacarb.

The FQPA safety factor ( SF ) for indoxacarb is reduced to 1 X based on the following : 1) the hazard and exposure dat abases are complete; 2) there are no concerns for pre

- and/or postnatal toxicity; 3) there are no residual uncertainties with regard to pre

- and/or post

- natal toxicity; and 4) the acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) and developmental neurotoxicity (DNT) studies are available and all endpoints used in this risk assessment are protective of any neurotoxic effects

.

See Appendix B , Tables B.1 through B.3.6

, for a summary of the most recent toxicological endpoints and points of departure ( PODs ) for use in indoxacarb risk assessments , available toxicity studies, and the toxicity profile.

Conclusion : T he indoxacarb toxicity database is complete. A ll of the required toxicity data have

been received and reviewed. T he toxicological endpoints

, PODs , and FQPA and other uncertainty factors selected for use in the most recent risk assessment reflect current policy.

Dietary Exposure

Residue Chemistry

T he magnitude of the residue database is complete

. The nature of the residue is understood

based on the available metabolism and residue studies ; the residue of concern for tolerance regulation of plant and livestock commodities is the combined residues of indoxacarb and its R

enantiomer (tolerances on poultry commodity also include several ind oxacarb metabolites). The primary residues of toxicological concern for risk assessment are indoxacarb and its R

enantiomer; various metabolites and degradates are also included as residues of concern in milk, poultry commodities and drinking water. (See Appendix C for a table of residues of concern.) A number of adequate methods are available for enforcing indoxacarb tolerances

.

### Page 5 of 29

Dietary Assessment

The last dietary risk assessment was conducted May 1

, 2013 as part of human health risk assessment to support proposed new uses for indoxacarb ( I

. Negrón

- Encarnación

, 5/1/13,

D408983

, Indoxacarb Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registrati on Action on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13

- 07F and Low Growing Berry Subgroup (except strawberry) 13

- 07H ) and included all registered and proposed food uses.

A cute and chronic dietary (food and water) exposure 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 Nutrit ion Examination Survey, What We Eat in America, (NHANES/WWEIA) . The assumptions included anticipated residues derived from field trail data and, where available, percent crop treated estimates and processing factors. All residues of

concern were included in the dietary assessment.

Estimated drinking water concentrations (EDWCs) for indoxacarb and the degradates of concern were provided by EFED (C. Koper , D402100, 11/06/12) and incorporated directly into the

DEEM

- FCID analyses

. T he acute and chronic EDWCs were generated using the Pesticide Root Zone/Exposure Analysis Modeling System (PRZM/ EXAMS )

. Total Toxic Residue (TTR) approach was used for the parent indoxacarb and the degradation products with toxicological concern (IN

- JT333, IN

- KG4333, IN

- KT41 3, IN

- ML437

- 0H) for the drinking water assessment.

There were no dietary risk estimates of concern. The acute dietary (food and drinking water) risk was estimated at 36% of the aPAD for the general U.S. population and at 65% of the aPAD for infants, t he population subgroup with the highest estimated acute exposure. The chronic dietary (food and water) risk was estimated at 8 % of the c PAD for the general U.S. population and at

16 % of the c PAD for children (1

- 2 years old) , the population subgroup with th e highest

estimated chronic exposure

.

Conclusions: The indoxacarb residue chemistry database is complete

. No new data are needed to assess potential dietary exposure and risk and there are no dietary risks of concern for

indoxacarb

. A new dietary risk a ssessment is not anticipated for the registration review of

indoxacarb.

Residential (Non

- Occupational) Exposure

Indoxacarb residential uses which may result in handler or post

- application exposures include

the use on o rnamental lawns and turf /golf courses , spot

- on applications for domestic animals

, and insect control t reatments of indoor and outdoor household premises.

A residential assessment was performed as part of the indoxacarb 2013 human health risk assessment for use in the aggregate asses sment. E xisting residential uses (turf and spot

- on pet applications ) were revised in that assessment t o reflect updates to HED’s 2012 Residential

### Page 6 of 29

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 ) which did not appear to have been previously assessed. Those

uses were assessed in the 2013 risk assessment using the updated assumptions.

The residential lawn assessment provide d the highest estimate of potential exposure from turf applications and is p rotective of any exposure s for children or adults from indoxacarb turf

treatments , including golfing activities. The indoor spray scenarios are protective of any exposures to indoxacarb outdoor perimeter treatments. Only oral and inhalation routes were

a ssessed as there is no dermal toxicity expected for indoxacarb

.

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 pets, treated turf and spray

treated indoor surfaces and 2) adult exposure to spray

- treated indoor surfaces (inhalation only).

Residential Handler

The residential adult handler exposure assessment for turf ( granular and liquids used on lawn s )

and indoor spray (crack and crevice and spot

- directed) applications resulted in short

- term
inhalation MOEs that do no t exceed HED's level of concern.

Indoxacarb ready

- to

- use ( 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 exposure/risk for these uses were not assessed.

The spot

- on product for the c ontrol of fleas and ticks on dogs and cats is designed to be self

contained as it is applied 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 type o f applications. In addition, there is no human dermal toxicity endpoint for indoxacarb. Inhalation assessments are not performed for applying pet spot

- on treatments, as inhalation exposure is not expected from these uses. Therefore, a quantitative handler assessment is not performed for the indoxacarb pet spot

- on treatments.

Residential Post

-

Application

Two chemical specific animal petting studies ( 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 turf transferable re sidue (TTR) study (MRID 4679820) was used to estimate incidental oral exposure for children f or 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 applic ation rate and timing, body weights, etc., are detailed in Indoxacarb: Occupational and Residential Risk Assessment to Support Request for Section 3 Registrations on

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 7 of 29

Bean (dry), Bean (snap), Bean (forage), and Small Fruit Vine Climbing Subgroup 13

- 07F and

Low

- Growing Berry Subgroup 13

- 07H ( A. Rivera

- Lupianez

, D 411342 , 5/1/13) and the 2012

Residential SOPs 2



### .

The short

- , intermediate

- and long

- term residential post

- application exposure (non

- dietary oral exposure only; inhalation exposure not expected) and ri sk estimates from indoxacarb

- treated pet scenarios for children do not exceed HED’s level of concern

.

The short

- term post

- application exposure (non

- dietary oral exposure only; inhalation exposure not expected) and risk estimates from the indoxacarb

- treated turf scenarios (for both liquid and granular formulations) for c hildren do not exceed HED’s level of concern.

For the indoor surface directed spray scenarios (crack and crevice and spot

- directed treatments )

, the adult and children sho rt

- term inhalation risk estimates do not exceed HED’s level of concern. For children, the incidental oral risk estimates for crack and crevice treatments do not exceed
HED’s level of concern. However, for spot

- directed treatments, oral (hand

- to

- mouth) ex posure estimates alone for children (1 to < 2 years old) exceed HED’s level of concern. For crack and crevice only scenarios the combined inhalation and incidental oral risk estimates for children are

not of concern.

Residential bystander exposures res ulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of indoxacarb . The Agency is in the process of evaluating these types of exposures and may, as appropriate, develop policies and procedures

to identi fy the need for and, subsequently, the way to incorporate post

- application exposure into the Agency's risk assessments. The need for a bystander risk assessment for indoxacarb should be examined during registration review.

Furthermore, residential turf u ses 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 t urf was modeled to estimate post

- application residential exposure of children. As this rate is equal 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.

Conclusions: There are no residential risk estimates of concern for the current uses of indoxacarb, except for indoor surface directed sprays whe n a spot

- directed treatment is assumed. In that case, non

- dietary oral (hand

- to

- mouth) exposures for children (1 to <2 yrs) exceeded
HED’s level of concern. When a crack and crevice only treatment is assumed for the spray

, there are no risk estimates of concern. The c urrent label do es not restrict the indoor spray use to
crack and cr evice only. An updated residential risk assessment is not anticipated for indoxacarb under registration review.

Aggregate Risk Assessment

2 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 8 of 29

For aggregate risk assessment, risk estimates resulting from food, drinking water, and residential

uses are combined. Uses of indoxacarb that may result in residential exposures include indoor
treatments, spot

- treatment of companion animals, and turf use

. Acute, short

- and intermediate

term, an d long

- term (chronic) aggregate assessments were recently performed for indoxacarb in

the May 2, 2013 risk assessment . The scenarios resulting in the highest exposures are selected as protective scenarios for the ag gregate assessments (i.e. lawn applications for handlers; post

application exposure to pets and indoor sprays )

.

There are no acute, short

- term, intermediate

- term, or long

- term (chronic) aggregate risk estimates of concern for adult (handler or post

- appl ication) or child (post

- application) exposure to indoxacarb as a result of current and proposed uses. Note: the aggregate assessment 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 a risk estimate of concern for children and was not used in the aggregate assessment. At this time, labels for the indoor surface directed sprays do not limit the use to only crack and crevi ce.

Conclusions: T here were no a cute, short

- and intermediate

- term, or long

- term (chronic) aggregate (food, water, and residential) risk estimates of concern when it is assumed that indoor surface directed spray treatments are limited to crack and crevice only. A revised aggregate risk assessment is not anticipated for indoxacarb registration review.

Cumulative Risk Assessment

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechani sm of toxicity. EPA does not have, at this time, available data to determine whether indoxacarb has a common mechanism of toxicity with other

substances. Therefore, a cumulative risk assessment has not been performed for indoxacarb.

Occupational Exposure

There are no indoxacarb

- specific data available for assessing occupational exposure and risk associated with registered products containing indoxacarb. In the absence of chemical

- specific data, HED has relied on information in the studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database ; the ARTF database; or the Outdoor Residential Exposure Task Force (ORETF) database and standard assumptions with respect to the area treated and surrogate unit exposure data. A quantitative dermal risk assessment is not required since there is no dermal toxicity expected for

indoxacarb. Dislodgeable foliar residue (DFR) data are not required for indoxacarb.

Occupational Handler

Occupational assessments were recently performed (2013 assessment) for the proposed new uses on dry beans and succulent beans. Existing grape and cranberry uses were also reassessed at that

time since both those crops are included in the new subgroup defi nitions that were being added to existing labels ( small fruit vine climbing subgroup 13

- 07F and low

- growing berry subgroup

13

- 07H )

. Previous assessments have been perfor med for other agricultural crops ( e.g., garden

### Page 9 of 29

beets, Brassica l eafy v egetables, t urnip g reens )

. In addition, t he scenarios in the 2013

assessment , particularly mixing/loading dry flowable in support of aerial applications on beans (a high acreage crop), are representative of occupational handler worse case scenarios; therefore,

risk e stimates are protective of indoxacarb current uses

.

All occupational handler scenarios assessed (existing and proposed uses) result ed 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 ).

Occupational Post

-

Application

Dermal and inhalation exposures to indoxacarb may occur for post

- application workers. A quantitative dermal assessment is not performed since a dermal toxicity endpoint is not identified

for indoxacarb. A quantitative occupational post

- application inhalation exposure assessme nt was not performed for indoxacarb since post

- application inhalation exposures are not expected for

workers ; however, an inhalation exposure assessment was performed ( D411342, 5/1/13) for occupational/commercial handlers

.

There are no risks of concern i dentified for occupational post

- application exposure to

indoxacarb

. The label restricted entry interval (REI) of 12 hours is appropriate and in compliance Worker Protection Standard requirements.

Conclusions: The occupational exposure database is compl ete f or indoxacarb. There are no occupational handler or post

- application exposure risk estimates of concern. A revised occupational assessment is not anticipated for indoxacarb registration review.

Public Health and Pesticide Epidemiology Data

Based on the low frequency and severity of incident cases reported for indoxacarb in both IDS

and NIOSH SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incid ent information and if a concern is triggered, additional analysis will be included in the risk assessment.

The Agricultural Health Study (AHS) is also a potential source of information associated with human health effects associated with certain pesticid es. Indoxacarb is not included in the AHS, and therefore this study does not provide information for this report

. (E. Evans

, 3/13/ 13, D409841, Indoxacarb: Review of Human Incidents .)

Tolerance Assessment and International Harmonization

Permanent toleran ces are established under 40 CFR 180.564(a) for the combined residues of

indoxacarb and its R

- enantiomer on a number of plant as well as livestock commodities (tolerances on poultry commodit ies also include several indoxacarb metabolites). Adequate analyt ical methodology is available for data collection and tolerance enforcement purposes.

### Page 10 of 29

There are Codex maximum residue limits (MRLs) established for indoxacarb; these are also expressed as indoxacarb and its R

- enantiomer. A few of the U.S. tolerance leve ls are harmonized with Codex MRLs, but most are not harmonized. During registration review the Agency will further evaluate the tolerance levels to determine if they can be harmonized with Codex. There are no MRLs established for Canada. A summary of th e U.S. tolerances and Codex MRLs is presented in Appendix D.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the

most recent human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.epa.gov/fedreg/eo/eo12898.htm . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variabilit y of diets within the U.S. (including different ages, regions, and ethnicities), and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further

refines the risk assessments to ensure th at the risk estimates are based on the best available

information.

Human Studies

Recent indoxacarb risk assessment s rel y 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 e thics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 3



### .

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies inclu de acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including ef fects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and

chronic studie s that assess growth, developmental and reproductive effects in different

3 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/opp00001/science/residential

- exposure

- sop.html

### Page 11 of 29

taxonomic groups. As part of its most recent registration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), indoxacarb is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (includ ing pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered appro ach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. T ier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide c hemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Indoxacarb is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays for indoxacarb

. For further information

on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

Data Requirements

No ne

.

References

E. Evans

, 3/13/ 13

, D409841, Indoxacarb : Review of Human Incidents

.

D. Drew, 5/2/13

, D402099, 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.

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

, Indoxacarb Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action

### Page 12 of 29

on Dry Beans, Succulent Beans, Small Fruit Vine Climbing Subgroup (except kiwifruit) 13

- 07F

and Low Growing Berry Subgroup (except strawberry) 13

- 07H

.

C. Koper, 11/6/12, D 402100 , Tier II Drinking Water Assessment for the New Use Registration of Indoxacarb on Dry Beans, Snap Beans, Small Fruit Vine Climbing Subgroup 13

- 07F and

Low

- Growing Berry Subg roup 13

- 07H.

### Page 13 of 29

Appendix A The chemical structure and physiochemical properties of indoxacarb are found in Tables A .1 and

A .2 below.

Table A .1 Indoxacarb Nomenclature.

Compound

Common name Indoxacarb

Company experimental name DPX

- KN128

IUPAC name (S)

- methyl 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

- c hloro

- 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% Emusifiable Concentrate (Steward ® EC Insecticide; EPA Reg. No. 352

- 638)

Compound

Common name R

- enantiomer of indoxacarb

Company name IN

- KN127 ( pesticidally inactive )

T able A.2 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

### Page 14 of 29

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, pK

a Does not dissociate at pHs of 2.42

- 11.36

Octanol/water partition coefficient, Log(K OW ) 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.

### Page 15 of 29

A ppendix B

Toxicology

B.1 Doses and Toxicological Endpoints

Table B.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

Acute 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.

Acute 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 Acute 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 = = 0.02 mg/kg/day Weight of evidence approach

was 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

months.

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

Occupational LOC

for MOE = 100 Weight of evidence approach

was 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,

### Page 16 of 29 food consumption and food efficiency; decreased hematocrit, hemoglobin and

red blood cell s only at 6

months.

Intermediate

- Term Incidental Oral (1

- 6 months) 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

was 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 ga in, food consumption and food efficiency; decreased hematocrit, hemoglobin and red blood cells only at 6

months.
Long

- Term Incidental Oral (1

- 6 months) 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

was 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

months.

Short

- Term Dermal ( 1 to 30 days )

Intermediate

- Term Dermal (1

- 6 months)

Long

- Term Dermal ( > 6 Months ) A quantitative dermal assessment is not required for indoxacarb, since the calculated

human dermal LOAEL exceeds the limit dose of 1000 mg/kg/day.

Short

- Term Inhalation ( 1 to 30 days )

Intermediate

- Term Inhalation NOAEL= 23 μg/L/day (6 mg/kg/day) UF A = 10x

UF H =10x FQPA SF = 1x

Residential LOC for 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,

### Page 17 of 29

Inhalation (1

- 6 months)

Long

- Term Inhalation ( > 6

Months ) MOE = 100

Occupational LOC

for MOE = 100 pigmentation and

hematopoiesis in the spleen, hematological changes and mortality (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 det ermine 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 = potential 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., la ck of 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.



### \

### Page 18 of 29

B.2 Toxicology Data Requirements

The toxicology data requirements (40 CFR 158.340) for the food uses of indoxacarb are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.



### Table B.2 Toxico logy Requirements for Indoxacarb

Guideline Number and Toxicity Study Required Satisfied

870.1100 Acute Oral Toxicity

................................ ...................... 870.1200 Acute Dermal Toxicity

................................ ................. 870.1300 Acute Inhalation Toxicity

................................ ............. 870.2400 Primary Eye Irritation

................................ .................. 870.2500 Primary Dermal Irritation

................................ ............. 870.2600 Dermal Sensitization

................................ .................... yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes

870.3100 Oral 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 Acute Delayed Neurotoxicity (Hen)

............................. 870.6100 90

- Day Neurotoxicity (Hen)

................................ ........ 870.6200 Acute 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

yes
CR= conditionally required

### Page 19 of 29

B.3 Toxicity Profile

Table B.3.1 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 B .3. 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 B

. 3.3 Acute Toxicity Data on DPX

- JW062 ( 50% DPX KN128,50% IN KN127)

Toxicity

### Page 20 of 29

Guideline No./ Study Type MRID No. Results Category

870.1100 Acute oral toxicity 44701601 LD 50 > 5000 mg/kg (males, females, combined) (in corn oil) IV

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 B.3.4 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. Developmental 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. typhimurium 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)

Cytogenetics

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 systemic/neurotoxicity NOAEL = 1.5 mg/kg/day LOAEL = 3.0 mg/kg/day, based on the adverse clinical signs observed, decreased body

- weight 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 incr eased latency in males.

870.7800 48478002 (2011) Immunotoxicity NOAEL=23 mg/kg/day HDT

### Page 21 of 29

Table B.3.4 Sub

- Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX

- KN128)

Guideline No./ Study Type MRID No. (year)/

Classification /Doses

Immunotoxicity Acceptable/guideline Systemic NOAEL=23 mg/kg/day HDT Systemic LOAEL was not established (>23 mg/kg/day).

Table B

. 3. 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 = M 3.1 mg/kg/day F 2.1 mg/kg/day LOAEL = M 6.0 mg/kg/day, F 3.8 mg/kg/day based on decreased body weight, body

- weight gain, food consumption and food effic iency.

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 44477138, 44477142 Maternal NOAEL = 2.0 mg/kg/day

### Page 22 of 29

Table B

. 3. 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

Prenatal developmental in

rodents

- rat (1997)

Acceptable (guideline) 0.0, 0.5, 1.0, 2.0, or 4.0 mg/kg/day (in PEG) LOAEL = 4.0 mg/kg/day based on decreased mean body weights, body

- weight gains, food consumption. Developmental NOAEL = 2.0 mg/kg/d ay 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 and 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 

### study 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 body 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 a bsorption 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

### Page 23 of 29

Table B

. 3. 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

0.87%, or 17.5X lower. The equivalent dermal absorption in humans was calculated to be 0.28%.

Table B.3.6 Sub

- Chronic, Chronic, and Other Toxicity Data on Indoxacarb (DPX

- JW062) ( 50% DPX KN128, 50% IN KN127)

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

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. Developmental NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on decreased numbers of

live fetuses/litter.

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. Developmental 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. Developmenta 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/Systemic NOAEL = 1.5 mg/kg/day LOAEL = 4.4 mg/kg/day based on decreased body weights, body

- weight gains, and food consumptio n 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 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 food efficiency; decreased HCT, HGB and RBC at 6 months in F only.

### Page 24 of 29 F: 0, 10, 20, 40, 60, 125

ppm 0, 0.55, 1.0, 2.1, 3.6, 7.8 mg/kg/day 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 bone marrow; incr. abs. and rel. liver weights.

870.4200 Carcinogenicity rats see 870.4100a see 870.4100a No evidence of carcinogenicity.

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 carcinogenicity.

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

Cytogenetics

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

Cytogenetics

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 Acute 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 meta bo lized and the metabolites were eliminated in urine, feces, and bile. The metabolite profile for JW062 was dose dependent and varied quantita tive ly between males and females. Differences in metabolite profiles were also observed for the

### Page 25 of 29 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.

### Page 26 of 29

Appendix C

Table C.1 Summary of Metabolites and Degradates to be included in the Indoxacarb 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 Indoxacarb and its R

enantiomer Indoxacarb and its R

enantiomer

Livestock Ruminant Indoxacarb and its R

enantiomer (for all)

Metabolite IN

- MP819 (for milk only) Indoxacarb and its R

enantiomer

Poultry Indoxacarb, its R

- enantiomer,

and the metabolites IN

- JT333,

IN

- JU873, IN

- KB687, IN

KG433, IN

- KT319, 5

- HO

- IN

JT333, and Metabolite F Indoxacarb, its R

- enantiomer,

and the metabolites IN

- JT333,

IN

- JU873, IN

- KB687, IN

KG433, and IN

- KT319

Drinking Water Indoxacarb, and the degradation products IN

JT333, IN

- KG4333, IN

KT413, and IN

- ML437

- 0H

### Page 27 of 29

Appendix D

Table D.1 Summary of US and International Tolerances and Maximum Residue Limits for Indoxacarb (PC067710)

US Canada Mexico 1 Codex 2

40 CFR 180.564 (a) (1):

Plants and Livestock: (a) General. (1) indoxacarb, (S)

- methyl 7

- chloro

- 2,5

- dihydro

- 2

- [[(methoxycarbonyl)[4

- (trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2

- e ][1,3,4][oxadiazine

- 4a(3 H )

- carboxylate, and its R

- enantiomer, (R)

- methyl 7

- chloro

- 2,5

- dihydro

- 2

- [[(methoxycarbonyl)[4

- (trifluor omethoxy)phenyl]amino]carbonyl]indeno[1,2

- e ][1,3,4][oxadiazine

- 4a(3 H )

- carboxylate. None Plant/Livestock

commodities: sum of

indoxacarb and its R

enantiomer.

The residue is fat

soluble.

Commodi ty Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2

Apple, wet pomace 3.0 Alfalfa, forage 10 Alfalfa, hay 50 60 alfalfa fodder Beet, garden, roots 0.30 Beet, garden, tops 6.0 Bushberry subgroup 13

- 07B 1.5
Cattle, fat 1.5
Cattle, meat 0.05 2 (fat) meat from

mammals other than marine mammals) Cattle, meat byproducts 0.03 0.05 Edible offal (mammalian) Corn, sweet, forage 10 Corn, sweet, kernel plus cob with husk

removed 0.02 0.02 sweet corn (corn

on

- the

- cob)
Corn, sweet, stover 15 25 maize fodder dry Cotton, gin byproducts 15
Cotton, undelinted seed 2.0 1 cotton seed Cranberry 0.90 1 Fruit, pome, except pear, group 11 1.0 0.5 apple 0.2 pear Fruit, stone, group 12 0.90 1 3 prunes
Goat, fat 1.5
Goat, meat 0.05 2 (fat) meat from

mammals other than marine mammals) Goat, meat byproducts 0.03 0.05 Edible offal (mammalian) Grain, aspirated fractions 45 Grape 2.0 2 Grape, raisin 5.0 5 dried grapes(=currants, raisins and sultanas) Hog, fat 1.5

### Page 28 of 29

Table D.1 Summary of US and International Tolerances and Maximum Residue Limits for Indoxacarb (PC067710)

US Canada Mexico 1 Codex 2

Hog, meat 0.05 2 (fat) meat from

mammals other than marine mammals) Hog, meat byproducts 0.03 0.05 Edible offal (mammalian)
Horse, fat 1.5
Horse, meat 0.05 2 (fat) meat from

mammals other than marine mammals) Horse, meat byproducts 0.03 0.05 Edible offal (mammalian)

Milk 0.15 0.1
Milk, fat 4.0 2

Okra 0.50
Pea, southern, seed 0.10

Peanut 0.01 0.02 (*) Peanut, hay 40 50 peanut fodder

Pear 0.20 0.2
Pear, oriental 0.20 Peppermint, tops 11 Sheep, fat 1.5 Sheep, meat 0.05 2 (fat) meat from

mammals other than marine mammals) Sheep, meat byproducts 0.03 0.05 Edible offal (mammalian) Soybean, hulls 4.0 Soybean, seed 0.80 Spearmint, tops 11 Turnip, greens 12 Vegetable, Brassica , leafy, group 5 12 0.2 broccoli,

cauliflower 3 cabbages, head Vegetable, cucurbit, group 9 0.60 0.5 Fruitng vegetables,

cucurbits Vegetable, fruiting, group 8 0.50 0.5 eggplant 0.3 peppers

0.5 tomato Vegetable, leafy, except Brassica , group 4 14 7 head lettuce

15 leaf lettuce Vegetable, tuberous and corm, subgroup 1

- C 0.01 0.02 potato

Recommended Tolerances Bean, dry, seed 0.1 0.2 chick

- pea (dry), 0.2 mung bean (dry) 0.1 cowpea (dry)
Bean, succulent 0.9 Bean, forage 50 Small fruit vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 3 2 grapes

### Page 29 of 29

Table D.1 Summary of US and International Tolerances and Maximum Residue Limits for Indoxacarb (PC067710)

US Canada Mexico 1 Codex 2

Grape, raisin 5.0 5 Dried grapes (=currants, raisins and sultanas) Low growing berry, except strawberry, subgroup 13

- 07H 1 1 cranberry

MRLs with NO US Equivalent Cotton fodder, dry 20

Mints 15

S oybean (dry) 0.5

US Canada Mexico 2 Codex 3

40 CFR 180.564 (a) (2): Poultry: (2) sum of indoxacarb, (S)

- methyl

- 7

- chloro

- 2,5

- dihydro

- 2

- [[(methoxycarbonyl)[4

- (trifluoromethoxy)

- phenyl]amino]carbonyl]indeno[1,2e] [1,3,4]oxadiazine

- 4a(3 H )

- carboxylate, its R

- enantiomer, (R)

- methyl 7

- chloro

- 2,5

- dihydro

2

- [[(methoxycarbonyl)[4

- (trifluoromethoxy) phenyl]amino]carbonyl]indeno [1,2

- e] [1,3,4] oxadiazine

- 4a(3 H )

- carboxylate, and the metabolites: IN

- JT333, methyl 7

- chloro

2,5

- dihydro

- 2

- [[[4

- (tr ifluoromethoxy)phenyl]

- amino]carbonyl]indeno[1,2

- e][1,3,4]oxadiazine

- 4a(3 H )

- carboxylate; IN

- KT319, (E)

- methyl 5

- chloro

- 2,3,

- dihydro

- 2

- hydroxy

- 1

- [[[(methoxycarbonyl)[4

- (trifluoromethoxy)phenyl]amino]

- carbonyl]hydrazono]

- 1 H

- indene

- 2

- carboxylate; IN

- JU873 , methyl 5

- chloro

- 2,3

- dihydro

- 2

- hydroxy

- 1

- [[[[4

- (triflurormethoxy)

- phenyl]amino]carbonyl]hydrazono]

- 1 H

- indene

- 2

- carboxylate;

IN

- KG433, methyl 5

- chloro

- 2,3,

- dihydro

- 2

- hydroxy

- 1

- [[[(methoxycarbonyl)[4

- (trifluoromethoxy)phenyl]amino]carbonyl]

- hydrazono]

- 1 H

- indene

- 2

- carboxylate; and IN

- KB687, methyl [4

- (trifluoromethoxy)phenyl]carbamate, calculated as the stoichiometric equivalent of indoxacarb None Plant/Livestock

commodities: sum of

indoxacarb and its R

enantiomer.

The residue is fat

soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3

Egg 0.20 0.02 Poultry, fat 0.20 Poultry, meat 0.06 0.01 (*) (fat) Poultry, meat byproducts 0.06 0.01 (*) poultry edible

offal of Completed: M. Negussie; M. Negussie; 02/15/2013

1 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 Note: Indoxacarb is a fat

- soluble compound. Previously, the milk MRL would have been marked with an "F" to indicate a procedure for calculating “MRLs” for processed dairy products. Currently, indoxacarb MRLs for milk and milk fat are available to support “MRLs” for processed dairy products (2005).