UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: May 9, 2013 

SUBJECT: lndoxacarb. Human Health Risk Assessment Scoping Document in Support of 

Registration Review. 

FROM: 

THRU: 

TO: 

PC Code: 067710 

Decision No.: 475167 

Petition No.: NA 

Risk Assessment Type: Single Chemical 

Aggregate 

TXRNo.: NA 

MRlDNo.: NA 

Danette Drew, Chem ' , 

DP Barcode: 409209 

Registration No.: NA 

Regulatory Action: Registration Review 

Scoping 

CaseNo.: NA 

CAS No.: 173584-44-6 

40 CFR: §180.564 

~ ..... 

Ana Rivera-Lupianez, Chemist ' .....- ~- ::> 

William Irwin, Ph.D., Toxicologist /)J~ \ \ ~~ Risk Assessment Branch V N il oc-l..M>'1/y\. 

Health Effects Division (7509P) j____ 

Michael S. Metzger, Branch Chieft+J_J J V 

Risk Assessment Branch VI VII 

Health Effects Division (7509P) 

Office of Pesticide Programs 

Katie Weyrauch, Chemical Review Manager 

Risk Management and Implementation Branch V 

Pesticide Re-evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Health Effects Division's (l-IED) human health risk assessment scoping 

(status update) document for indoxacarb to support the registration review process. 

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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 Agency 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 evaluation was the recent indoxacarb human health risk assessment 

(5/2/13, D402099) 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 subgroup 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 registered 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 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. 

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 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 assessments, 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 (also referred 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 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 the current toxicological endpoints, points of departure (PODs), and FQPA 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) risks 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.

There 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 indoxacarb 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 registration 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 (ai). 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-enantiomer 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 assessments to account for (add in) the percent of Renantiomer in product mixtures. Indoxacarb is registered for use on agricultural crops and in 

residential settings. 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 Renantiomer on a number of plant as well as livestock commodities (tolerances on poultry 

commodities 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 for 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 

decreases 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 neurotoxicity study in rats. Neurotoxicity was seen in 

animal studies 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 teratogenicity, 

mutagenicity, or carcinogenicity in the indoxacarb studies. The immunotoxicity study did not 

indicate immunotoxic potential for indoxacarb.

The FQPA safety factor (SF) for indoxacarb is reduced to 1X based on the following: 1) the 

hazard and exposure databases are complete; 2) there are no concerns for pre- and/or postnatal 

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

4) the acute neurotoxicity (ACN), subchronic neurotoxicity (SCN) and developmental 

neurotoxicity (DNT) studies are available and all endpoints used in this risk assessment are 

protective of any neurotoxic effects.

See 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: The indoxacarb toxicity database is complete. All of the required toxicity data have 

been received and reviewed. The 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

The 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 Renantiomer (tolerances on poultry commodity also include several indoxacarb metabolites). The 

primary residues of toxicological concern for risk assessment are indoxacarb and its Renantiomer; 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 Registration 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. 

Acute 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 Nutrition 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. The 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- KT413, 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, the population subgroup with the highest estimated acute exposure. The chronic dietary 

(food and water) risk was estimated at 8% of the cPAD for the general U.S. population and at 

16% of the cPAD for children (1-2 years old), the population subgroup with the 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 assessment 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 ornamental lawns and turf/golf courses, spot-on applications for domestic animals, 

and insect control treatments 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 assessment. Existing residential uses (turf and spot-on pet 

applications) were revised in that assessment to reflect updates to HED’s 2012 Residential 
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SOPs1, 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 Aperion 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 provided the highest estimate of potential exposure from turf

applications and is protective of any exposures 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 

assessed 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 spraytreated 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 lawns) 

and indoor spray (crack and crevice and spot-directed) applications resulted in short-term 

inhalation MOEs that do not 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 control of fleas and ticks on dogs and cats is designed to be selfcontained 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 of 

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 (MRIDs 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 residue (TTR) study (MRID 4679820) was 

used to estimate incidental 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 assumptions and factors, as well as those 

regarding application 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, D411342, 5/1/13) and the 2012 

Residential SOPs2.

The short-, intermediate- and long-term residential post-application exposure (non-dietary oral 

exposure only; inhalation exposure not expected) and risk 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 children 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 short-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) exposure 

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 resulting 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 identify 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 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 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 when a spot-directed treatment is assumed. 

In that case, non-dietary oral (hand-to- mouth) exposures for children (1to <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 current label does not restrict the indoor spray use to 

crack and crevice 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 intermediateterm, and 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 aggregate assessments (i.e. lawn applications for handlers; postapplication 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-application) 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 postapplication (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 crevice.

Conclusions: There were 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 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 mechanism 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 definitions 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 performed for other agricultural crops (e.g., garden 
Page 9 of 29

beets, Brassica leafy vegetables, turnip greens). In addition, the 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 estimates are protective of indoxacarb current uses.

All occupational handler scenarios assessed (existing and proposed uses) resulted 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 assessment 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 identified 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 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 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 incident 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 pesticides. 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 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 commodities also include several indoxacarb metabolites). Adequate 

analytical 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 levels 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 the 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 variability 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 that the risk estimates are based on the best available 

information.

Human Studies

Recent indoxacarb risk assessments rely 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 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 website3. 

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include 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 effects 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 studies 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 (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to 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 chemicals. 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 callins, 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

None.

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 Bean (dry), Bean (snap), Bean 

(forage), and Small 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, D402100, 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 Subgroup 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]oxadiazine4a(3H)-carboxylate

CAS name methyl (4aS)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-

(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine4a(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)

O

N

N

O O

CH3

Cl N

O

O

O

O

CF3

CH3

O

N

N

O O

CH3

Cl N

O

O

O

CH3

O

CF3

Table 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 10-8Pa (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.
Page 15 of 29

Appendix 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

UFA= 10x

UFH=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

UFA= 10x

UFH=10x

FQPA SF = 1x 

cPAD = 

= 0.02 mg/kg/day

Weight of evidence approach 

was used from four studies: 

1) Subchronic toxicity studyrat (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 UFA= 10x

UFH=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 studyrat (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 cells only at 6 

months.

Intermediate-Term 

Incidental Oral (1- 6 

months)

Oral NOAEL= 2.0 mg/kg/day UFA= 10x

UFH=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 studyrat (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.

Long-Term 

Incidental Oral (1- 6 

months)

Oral NOAEL= 2.0 mg/kg/day UFA= 10x

UFH=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 studyrat (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)

UFA= 10x

UFH=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 determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk 

assessment. UFDB = to account for the absence of key data (i.e., lack 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 concern. 

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 Toxicology 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 ...

870.5395 Mutagenicity: Cytogenetics

870.5500 Mutagenicity: Other Genotoxic Effects .......................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (Hen).............................

870.6100 90-Day Neurotoxicity (Hen) ........................................

870.6200 Acute Neurotoxicity Screening Battery (Rat) ..............

870.6200 90-Day Neurotoxicity. 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 LD50 > 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 LD50 = 

1730mg/kg males

268 mg/kg females

<1000 mg/kg combined (rat)

II

870.1200 Acute dermal 

toxicity 44477118 LD50 >5000mg/kg (limit test) (rat)

IV

870.1300 Acute inhalation 

toxicity

70%MUP

44477120

LC50 > 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 LD50 > 5000 mg/kg (males, 

females, combined) (in corn oil)

IV

870.1200 Acute dermal toxicity 44477119 LD50 > 2000 mg/kg (males, 

females, combined) (rabbit)

III

870.1300 Acute inhalation toxicity 44477121 LC50 > 5.4 mg/L males

LC50 = 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

Maternal 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 increased 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 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/nonguideline

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/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 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 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 
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

Maternal NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day based on slight decreases in 

maternal body-weight gain and food consumption.

Developmental NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day based on decreased fetal bodyweights 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 consumption of F0 females, and 

incr. spleen weights in the F0 and F1 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 F1 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 metabolized 

and the metabolites were eliminated in urine, feces, and bile. 

The metabolite profile for JW062 was dose dependent and 

varied quantitatively between males and females. 

Differences in metabolite profiles were also observed for the 
Page 25 of 29

different label positions (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 Expression1

Matrix Residues included in Risk 

Assessment

Residues included in Tolerance 

Expression

Plants

Primary Crop Indoxacarb2

and its Renantiomer3Indoxacarb and its Renantiomer

Rotational Crop Indoxacarb and its Renantiomer 

Indoxacarb and its Renantiomer 

Livestock

Ruminant

Indoxacarb and its Renantiomer (for all)

Metabolite IN-MP819 (for 

milk only)

Indoxacarb and its Renantiomer 

Poultry

Indoxacarb, its R-enantiomer, 

and the metabolites IN-JT333, 

IN-JU873, IN-KB687, INKG433, IN-KT319, 5-HO-INJT333, and Metabolite F

Indoxacarb, its R-enantiomer, 

and the metabolites IN-JT333, 

IN-JU873, IN-KB687, INKG433, and IN-KT319

Drinking Water

Indoxacarb, and the 

degradation products INJT333, IN-KG4333, INKT413, 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 Mexico1 Codex2

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-

(trifluoromethoxy)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 fatsoluble.

Commodity

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

US Canada Mexico1 Codex2

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 (cornon-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 Mexico1 Codex2

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, exceptBrassica, 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 Mexico1 Codex2

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

Soybean (dry) 0.5

US Canada Mexico2 Codex3

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-dihydro2-[[(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-chloro2,5-dihydro-2-[[[4-(trifluoromethoxy)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 fatsoluble.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

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.

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

3Note: 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).