Studies Requested in DCIs for Registration Review Case:

Indoxacarb

I. Studies to be Called-In:

GuidelineNumber

a

40 C

F

R 158

Citation

b

DataRequirementStudy type

c

Average TestCostTotal PaperworkBurden Cost

d

Total PaperworkBurden Hours

e

835.1230 158.1300 Leaching and adsorption/desorption – sediment leaching and 

soil adsorption/desorption EF $23,750.00 $8,313.00 105

835.1240 158.1300 Leaching and adsorption/desorption – soil column leaching EF $46,780.00 $16,373.00 208

835.2120 158.1300 Hydrolysis EF $25,230.00 $8,831.00 112

835.4100 158.1300 Aerobic soil metabolism EF $94,375.00 $33,031.00 419

835.4200 158.1300 Anaerobic soil metabolism EF $71,300.00 $24,955.00 316

835.4300 158.1300 Aerobic aquatic metabolism EF $44,475.00 $15,566.00 197

835.6100 158.1300 Terrestrial field dissipation- storage stability in soil portion 

only EF $22,000.00 $7,700.00 98

850.61001158.1300 Environmental chemistry - analytical method for soil and 

associated independent laboratory validation EF $22,000.00 $7,700.00 98

850.61001158.1300 Environmental chemistry- analytical method for water and 

associated independent laboratory validation EF $22,000.00 $7,700.00 98

850.1075 158.630 Acute toxicity estuarine and marine organisms –

estuarine/marine fish (DPX-MP062) EE $11,576.00 $4,051.00 51

850.2100 158.630 Avian oral toxicity (DPX-MP062) EE $10,100.00 $3,535.00 45

850.4100 158.660 Terrestrial plant toxicity seedling emergence (TEP with 

DPX-MP062) EE $20,375.00 $7,131.00 90

850.4100 158.660 Terrestrial plant toxicity seedling emergence (TEP with 

DPX-KN128) EE $20,375.00 $7,131.00 90

850.4150 158.660 Terrestrial plant toxicity, vegetative vigor (TEP with DPXMP062) EE $24,500.00 $8,575.00 109

850.4150 158.660 Terrestrial plant toxicity with vegetative vigor (TEP with 

DPX-KN128) EE $24,500.00 $8,575.00 109

Non-GDLN 158.75 Larval honey bee acute oral toxicity (DPX-MP062) SS $36,000.00 $12,000.00 160

Non 

GDLN2,3 158.630 (ORD Study Method EPA 600/R-099-064) Chronic Freshwater Sediment Testing Flowthrough: (Hyallela azteca) EE $110,000.00 $38,500.00 488

Non 

GDLN2,3 158.630

(ORD Study Method: EPA 600/R-099-064) Chronic 

Freshwater Sediment Testing Flowthrough: (Chironomus 

dilutus or C. tentans)

EE $110,000.00 $38,500.00 488

Non 

GDLN2,3 158.630

(ORD Study Method: EPA 600/R-099-020) Chronic 

Estuarine/Marine Sediment Testing Flowthrough: 

(Leptocheirus plumulosus)

EE $110,000.00 $38,500.00 488

Studies required for Indoxacarb degradates

835.2120 158.1300 Hydrolysis (IN-JT333) EF $25,230.00 $8,831.00 112

835.2120 158.1300 Hydrolysis (IN-MP819) EF $25,230.00 $8,831.00 112

835.4100 158.1300 Aerobic soil metabolism (IN-JT333) EF $94,375.00 $33,031.00 419

835.4100 158.1300 Aerobic soil metabolism (IN-MP819) EF $94,375.00 $33,031.00 419

835.4300 158.1300 Aerobic aquatic metabolism (IN-JT333) EF $44,475.00 $15,566.00 197

835.4300 158.1300 Aerobic aquatic metabolism (IN-MP819) EF $44,475.00 $15,566.00 197

835.1230 158.1300 Leaching and adsorption/desorption – sediment leaching and 

soil adsorption/desorption (IN-JT333) EF $23,750.00 $8,313.00 105

835.1230 158.1300 Leaching and adsorption/desorption – sediment leaching and 

soil adsorption/desorption (IN-MP819) EF $23,750.00 $8,313.00 105

835.1240 158.1300 Leaching and adsorption/desorption – soil column leaching

(IN-JT333) EF $46,780.00 $16,373.00 208

835.1240 158.1300 Leaching and adsorption/desorption – soil column leaching EF $46,780.00 $16,373.00 208
Studies Requested in DCIs for Registration Review Case:

Indoxacarb

(IN-MP819)

850.1075 158.630 Freshwater Fish Toxicity (Degradate IN-MP819) EE $11,957.00 $4,185.00 53

850.61001158.1300 Environmental chemistry for soil associated independent 

laboratory validation (IN-JT333) EF $22,000.00 $7,700.00 98

850.61001158.1300 Environmental chemistry for soil associated independent 

laboratory validation (IN-MP819) EF $22,000.00 $7,700.00 98

850.61001158.1300 Environmental chemistry for water associated independent 

laboratory validation (IN-JT333) EF $22,000.00 $7,700.00 98

850.61001158.1300 Environmental chemistry for water associated independent 

laboratory validation (IN-MP819) EF $22,000.00 $7,700.00 98

850.61001158.1300 Environmental chemistry for sediment associated 

independent laboratory validation (IN-JT333) EF $22,000.00 $7,700.00 98

850.61001158.1300 Environmental chemistry for sediment associated 

independent laboratory validation (IN-MP819) EF $22,000.00 $7,700.00 98

Totals: $1,484,513.00 $518,980.00 6,590

Paperwork Burden – Indoxacarb total

1 The environmental chemistry analytical methods have recently been renumbered to GDLN 850.6100. See: 

http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-0008

2 All sediment testing should include quantification of parent indoxacarb, IN-JT333 and IN-MP819 in both pore water and 

sediment and report results (i.e.., endpoints) in terms of parent indoxacarb, IN-JT333 and IN-MP819.

3 A tiered approach using toxicity data from sub-chronic (10-day) sediment toxicity tests with parent indoxacarb and the three 

species may be used to determine which species should undergo chronic toxicity testing.

II. Pesticide Indoxacarb

Indoxacarb is a broad-spectrum oxadiazine insecticide, which is used in agricultural sites and indoor and 

outdoor in non-agricultural sites including residential, commercial, institutional and industrial sites. Indoxacarb 

is registered for use against caterpillars, beetles, leafhoppers, ants, fire ants, cockroaches, mole crickets, fleas 

and ticks. The term “indoxacarb” generally refers to any of several chemical forms of the compound, 

differentiated by S-enantiomer to R-enantiomer ratio. There are two degradates of concern with Indoxacarb, 

including IN-JT333 and IN-MP819. There is currently one technical registrant and three technical 

registrations. Indoxacarb was first registered as a pesticide in the U.S. in 2000. Since it was registered after 

1984, it was not subject to the reregistration requirements of FIFRA. The FWP was signed on 

(Month/Day/Year). All documents relevant to this registration review case can be found in the Indoxacarb

docket (EPA-HQ-OPP-2013-0367) at www.regulations.gov. 

III. Public Comments

During the 60-day public comment period on the Indoxacarb Preliminary Work Plan, which opened on 

June 26, 2013 and closed on August 26, 2013, the Agency received seven public comments, five of 

which required responses. Comments were submitted by the following: The Northwest Horticultural 

Council, the Physicians Committee for Responsible Medicine, the California Stormwater Quality 

Association (CASQA), the Central Valley Water Quality Control Board, and the San Francisco Bay 

Water Quality Control Board. The response to these comments is found in the document, Response to 

Public Comments on the EFED Registration Review Problem Formulation, (Sternberg, Koper, Sankula,

November 2013) and BEAD Response to Comments Received During Indoxacarb Registration Review 

Docket Opening (Kaul, Smearman, Alsadek, November 2013) and are summarized below. The 

comments do not address the timeline described in the PWP, but they do address the planned ecological 
Studies Requested in DCIs for Registration Review Case:

Indoxacarb

and human health risk assessments and data requirements. In the PWP, EPA also solicited comments on 

the specific topics of environmental justice, water quality concerns, and trade irritants, comments and 

supporting information were received on those issues.

This section does not capture every comment made about the PWP nor all of the Agency’s responses. 

Summarized below are public comments that resulted in changes to the anticipated registration review 

data needs, risk assessments, or timeline, or are of a broader regulatory nature. Public comments and 

EPA responses in their entirety are located in the docket, EPA-HQ-OPP- 2013-0367. Summarized 

public comments and Agency responses related to the anticipated ecological risk assessment or data 

needs are in the Response to Public Comment on the EFED Registration Review Problem Formulation 

for Indoxacarb (D415048) while those relevant to the anticipated economic impacts or data needs are in 

the BEAD Response to Comments Received During the Indoxacarb Registration Review Docket Opening 

(Kaul, Smearman, Alsadek, November 18, 2013). 

Comment 1: Northwest Horticultural Council in EPA-HQ-OPP-2013-0367.

Indonesia and Saudi Arabia, who are among the top export markets for U.S. apples, do not have a 

maximum residue limit (MRL) for indoxacarb residues in apples. Saudi Arabia also has no MRL for 

indoxacarb in pears. Brazil, China and Canada have no MRL on cherries. In addition, Canada has 

no tolerance for indoxacarb. These countries are top export markets for Northwest growers; 

therefore, we request that EPA harmonize MRLs for these countries with US tolerances. 

EPA Response 1: During registration review, the Agency will work to minimize trade irritants and 

harmonize US tolerances with MRLs with its trading partners, to the extent feasible (and consistent 

with domestic law). To facilitate this, the Agency works with the USDA Foreign Agricultural Service

and the United States Trade Representative to identify potential trade irritants. EPA is currently

working with some of the countries identified by Northwest Horticultural Council to assist with the 

development of science-based MRLs. 

 Comment 2: We also encourage the use of (Q)SAR data either in place of, or addition to, the fish 

experimental data. When correctly applied, (Q)SARs can feasibly replace in vivo data in some instances; 

the submission of (Q)SAR data in addition to in vivo data would increase Agency and registrant comfort 

and confidence with the use and evaluation of data from such methods, and so we encourage the 

registrant to do so.

EPA Response 2: (Q)SAR-type data may be considered in the absence of experimental data at the time 

of the Registration Review ecological risk assessment.

Comment 3: ASQA, August 26, 2013: Additional study is needed on environmental fate and aquatic 

toxicity to invertebrates in water and sediment, for parent compound and degradates. CASQA strongly

believes that the following additional studies should be included as required studies in both the Work 

Plan and in Tables 9-1 / 9-2 of the Problem Formulation to address data gaps:
Studies Requested in DCIs for Registration Review Case:

Indoxacarb

 Provide environmental fate-related data for the major indoxacarb degradates, IN-JT333 and INMP819.

 Develop chronic toxicity end points for freshwater and marine invertebrates for the major 

degradates, IN-JT333 and IN-MP819.

 Provide both acute and chronic ecological effects studies for aquatic invertebrates in sediment, 

both for parent indoxacarb and the major degradates, IN-JT333 and IN-MP819.

Comment 4: Central Valley Regional Water Quality Control Board: Ecological Risk Assessment 

Requires Sediment Toxicity Data: Life-cycle toxicity testing and/or sublethal/chronic toxicity testing in 

a sediment exposure with a sensitive species (e.g., a chironomid). One data gap that is not proposed to 

be filled is the effects on benthic organisms in sediment exposures...The Office of Pesticide Programs 

required toxicity data from sediment exposures with Hyalella azteca for the registration review of 

pyrethroids, and a sediment exposure toxicity test should also be required for indoxacarb. To date, there 

are very few sublethal or chronic exposure toxicity data for aquatic organisms available for 

indoxacarb...Of the few available aquatic organism toxicity data for this compound, it appears that 

chironomids are more sensitive than amphipods (Ding et al. 2011); thus a life-cycle toxicity test or a test 

reporting sublethal endpoints for chironomid sediment exposures should be required in the data call in.

Comment 5: San Francisco Bay Water Quality Control Board: OPP should require studies to 

address ecological effects data gaps, including (1) data on the environmental fate of indoxacarb 

degradates IN-JT333 and IN-MP819; (2) chronic toxicity end point for freshwater and marine 

invertebrates for these same degradates; and (3) acute and chronic ecological effects studies for aquatic 

invertebrates in sediment for indoxacarb and its degradates.

EPA Response 3, 4, 5: In regards to requiring studies to generate data on the environmental fate of 

indoxacarb degradates IN-JT333 and IN-MP819, EFED recommends requesting the following 

additional environmental fate data for IN-JT333 and IN-MP819 based on toxicity data indicating that 

degradate IN-JT333 is more acutely toxic to freshwater fish and degradate IN-MP819 is more acutely

toxic to freshwater invertebrates than parent indoxacarb:

 Guideline 835.2120 – Hydrolysis (TGAI)

 Guideline 835.4100 – Aerobic Soil Metabolism (TGAI)

 Guideline 835.4300 – Aerobic Aquatic Metabolism (TGAI)

 Guideline 835.1230 – Adsorption/Desorption (Batch Equilibrium) (TGAI)

 Guideline 835.1240 – Leaching (TGAI)

 Guideline 850.6100 – Environmental Chemistry Methods (ECMs) and Associated 

Independent Laboratory Validations (ILVs) for Soil, Water and Sediment (IN-JT333 and INMP819)

In regards to requiring studies to generate chronic toxicity endpoints for freshwater and marine 

invertebrates for indoxacarb degradates IN-JT333 and IN-MP819, the problem formulation indicates 

that, in the absence of these data, chronic toxicity endpoints for freshwater and marine invertebrates will 

be estimated using available toxicity data for parent indoxacarb and acute toxicity relationships between 

the degradates and parent. The Agency considers this to be a conservative approach, and a rationale for 
Studies Requested in DCIs for Registration Review Case:

Indoxacarb

why the Agency’s approach is not reasonable has not been provided. Therefore, the Agency does not 

recommend requesting chronic toxicity data for freshwater and marine invertebrates for IN-JT333 and 

IN-MP819.

The Agency considers the commenter’s concerns regarding the toxicity of indoxacarb and degradates 

IN-JT333 and IN-MP819 to sediment-dwelling invertebrates to be valid. In addition, indoxacarb 

triggers the Part 158 data requirement for (non-guideline) whole sediment, chronic freshwater and 

marine invertebrates testing. Therefore, the Agency recommends requesting non-guideline, whole 

sediment, chronic sediment tests with the midge Chironomus dilutus, freshwater amphipod Hyalella 

azteca, and estuarine/marine amphipod Leptocheirus plumulosus with parent indoxacarb. A tiered 

approach using toxicity data from sub-chronic (10-day) sediment toxicity tests with parent indoxacarb 

and the three species may be used to determine which species should undergo chronic toxicity testing. 

All sediment testing should include quantification of parent indoxacarb, IN-JT333, and IN-MP819 in 

both pore water and sediment and report results (i.e., endpoints) in term of parent indoxacarb, IN-JT333, 

and IN-MP819. Consistent with what was proposed in the problem formulation for the aquatic 

assessment, The Agency will use the toxic equivalency (TEQ) approach to assess the toxicity of both 

parent indoxacarb and degradates IN-JT333 and IN-MP819 to sediment-dwelling invertebrates using the 

results of this testing. 

Comment 6: CASQA: Require registrants to develop practical environmental chemical analysis 

methods... CASQA appreciates OPP’s acknowledgement in the Problem Formulation (Table 9-1) of the 

need for “Analytical Methods – Soil and Water”. However, the Problem Formulation should clearly 

specify that such analytical methods are needed for indoxacarb and its major degradates, IN-JT333 and 

IN-MP819, in both water and sediment.

We further request that EPA develop specifications for this requirement that ensure that the registrant 

will develop practical analytical methods for indoxacarb and its major degradates in both water and 

sediment. Although EPA often requires registrants to submit analytical methods for measurements of 

pesticides in soil and water, these methods are often not sufficiently sensitive for the analysis of 

pesticides at environmentally relevant concentrations for environmentally relevant matrices, such as 

ambient waters and sediments, wastewater effluent, and biosolids... Analytical methods are needed that 

are practicable for use in commercial and government analytical laboratories, and are capable of 

producing analytical results with sufficiently low detection limits to quantify pesticides at 

environmentally relevant levels. Such methods do not exist for many pesticides; we are not aware of 

commercially available analytical services for indoxacarb. This requirement should be explicitly

included in the Work Plan and Table 9-1 of the Registration Review Work Plan.

Furthermore, as a general practice, the pesticide manufacturer, at the time of initial registration of its 

product, should be required by EPA to develop such analytical methods, to allow for meaningful 

environmental monitoring of the impacts of approved pesticides.

Comment 7: Central Valley Regional Water Quality Control Board: Chemical Analysis Method 

Needed: Development of a EPA-approved chemical analysis method for both water and sediment 

matrices. The use of indoxacarb will likely increase in California as it is employed as a replacement 

product for more restricted compounds, and as use increases, it will be necessary to monitor for 
Studies Requested in DCIs for Registration Review Case:

Indoxacarb

indoxacarb in ambient waters and sediments. A standard chemical analysis method for both the parent 

compound and major degradates is necessary for effective environmental monitoring. At this time, there 

are no reported detections of indoxacarb in water in California because no environmental monitoring 

studies have been conducted, and will not likely occur until there is a standard method available from 

the US EPA. Lack of a chemical method and monitoring may delay or hinder recognition of potential 

problems. Because indoxacarb is a hydrophobic pesticide, it is likely to be found in the sediment and 

both sediment and aqueous chemical analysis methods are needed for effective environmental 

monitoring.

Comment 8: San Francisco Bay Water Quality Control Board: OPP should require the registrant to 

develop practical analytical methods for indoxacarb and its major degradates in both water and sediment 

that obtain detection levels at environmentally relevant concentrations.

EPA Response 6, 7, 8: The Agency concurs with the commenters and submission of data on the 

environmental chemistry methods (ECMs) and associated independent laboratory validations (ILVs) is 

anticipated to be required for indoxacarb and its major degradates for water, soil and sediment. If there 

is risk concern for a given taxon, ECMs should be available for the environmental media in which 

organisms of the taxon reside. These ECMs should have limits of quantitation (LOQ) for the residues of 

concern that are lower than the relevant toxicological levels of concern. Based on the toxicity profile of 

indoxacarb, its properties, and results of previous risk assessments, the ECMs for the analysis of soil, 

water and sediment will be required and reviewed by the Agency.

Comment 9: CASQA: Require registrants to produce water quality monitoring data. OPP has requested 

submittal of water quality monitoring data for indoxacarb in the Preliminary Work Plan (p.13). CASQA 

agrees that monitoring data would be invaluable for registration review. We encourage EPA to require 

pesticide registrants to provide environmental monitoring data for products registered for uses in urban 

areas, and especially to require provision of such data from urban creeks (both water and sediment 

matrices).

OPP has requested submittal of water quality monitoring data for indoxacarb in the

Preliminary Work Plan (p.13). CASQA agrees that monitoring data would be invaluable for

registration review. We encourage EPA to require pesticide registrants to provide

environmental monitoring data for products registered for uses in urban areas, and especially

to require provision of such data from urban creeks (both water and sediment matrices).

Comment 10: Central Valley Regional Water Quality Control Board: Little monitoring data is 

available for indoxacarb, but one study did report detections in bed sediments of urban streams in central 

Texas (Hintzen et al. 2009). The detection frequency of indoxacarb of 37.7% was approaching that of 

some pyrethroids (41.2-94.1%). The reported sediment concentrations in this study were a mean of 8.0 

μ/g OC and a maximum of 69 μ/g OC. The 10-d sediment LC50 for Chironomus dilutus is 11.3 μ/g 

OC, indicating that potentially toxic levels of indoxacarb are already occurring (Ding et al. 2011). This 

study of urban streams highlights the similarity between indoxacarb and pyrethroids, and how the 

lessons learned from non-agricultural use of pyrethroids can be applied to indoxacarb during this 

registration review to prevent more widespread problems than potentially already exist. This includes 

modeling urban runoff from outdoor applications to impervious surfaces, and potentially similar 

restrictions on applications to these types of surfaces as were recently adopted for pyrethroids. Limiting 
Studies Requested in DCIs for Registration Review Case:

Indoxacarb

applications to crack and crevice and spot treatment instead of band treatments could prevent the next 

wave of pesticide contamination in urban streams.

EPA Response 9, 10: The Agency will use the best available data for the Registration Review risk 

assessment as indicated in the indoxacarb problem formulation and determine if additional monitoring 

data are needed on a case-by-case basis.

IV. Need for and Uses of the Data Generated 

Study Title: Larval Honey Bee Acute Oral Toxicity (DPX-MP062)

Rationale for Requiring the Data

The available toxicity studies do not address possible affects on brood (larvae and pupae) survival. Indoxacarb may be directly sprayed on pollen 

and/or nectar of treated plants and subsequently brought back to hive where larvae and pupae may be exposed. Because of the potential for pollen 

and nectar to be contaminated with indoxacarb, and subsequently brought back to the hive, it is important to determine the toxicity of this 

compound to brood. Therefore, a non-guideline honeybee larval toxicity study is needed.

The Office of Pesticide Programs has made available interim guidance regarding ecological testing for invertebrates with the honey bee. These 

can be found at: 

http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/terrestrial_biology_tech_team/honeybee_data_interim_guidance.htm

Practical Utility of the Data

How will the data be used?

The data will be used to assess risk to non-target listed and non-listed terrestrial invertebrate species. This study would allow the Agency to refine 

the screening level risk assessment for beneficial terrestrial invertebrates to determine whether indoxacarb use causes unreasonable adverse effects 

to these taxa. The effects data will be used to determine the potential for risk to beneficial terrestrial invertebrates through direct effects on larval 

bees. 

How could the data impact the Agency’s future decision-making?

The data EPA intends to call in will inform the determination required under FIFRA or the ESA as to whether continued registration of a pesticide 

is likely to result in unreasonable adverse effect non-target species or is not likely to jeopardize listed or endangered species or its critical habitat. 

The lack of these data will limit the flexibility that the Agency and registrants have in coming in to compliance with ESA and could result in 

significant use restrictions. In addition, the lack of these data may result in assumed risk and potential mitigation of indoxacarb formulations under 

FIFRA.