2

• Guideline 835.1230 – Adsorption/Desorption (Batch Equilibrium) (IN-JT333 and INMP819; TGAI)

• Guideline 835.1240 – Leaching (IN-JT333 and IN-MP819; TGAI)

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

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

IN-MP819)

• Non-guideline whole sediment, chronic invertebrates freshwater and marine with 

Chironomus dilutus, Hyalella azteca, and Leptocheirus plumulosus (indoxacarb, TGAI): 

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.
3

1. Comment from the Northwest Horticultural Council

Comment: “The insecticide indoxacarb is primarily used as a single application, late season 

treatment for suppression of earwigs in sensitive, high value varieties of apple. This use pattern 

should have minimal effect on bee populations.”

Response: The Agency appreciates this clarification of the use pattern of indoxacarb on apple.

2. Comments from the Physicians Committee for Responsible Medicine

Comment: “We recommend that OECD Test Guideline 223, Avian Acute Oral Toxicity Test, be 

used as the protocol instead of EPA Guideline 850.2100 in the interest of reducing the numbers 

of animals used by up to 61%1

. We also refer the registrant to the “Guidance for Classifying 

Studies Conducted Using the OECD Test Guideline 223 (TG223) (Acute Avian Oral Sequential 

Dose Study)” available on the Agency’s website.”

EPA Response: EFED concurs that the “Guidance for Classifying Studies Conducted Using the 

OECD Test Guideline 223 (TG223) (Acute Avian Oral Sequential Dose Study)”1 should be 

consulted if the registrant intends to submit an avian acute oral study based on OECD Test 

Guideline 223. It should be noted that one of the criteria cited in the guidance for classifying a 

study based on OECD Test Guideline 223 as “acceptable” is that study is conducted using 

bobwhite quail. The guidance further states that “other test species may be acceptable if they 

have low background mortality in the laboratory and do not regurgitate during the study; 

however, if a species other than bobwhite quail is used, the study should be reviewed by the 

Terrestrial Biology Tech Team (TBTT) - see below; please note that the background mortality 

data for the species in question should be available from the submitting laboratory at the time of 

the TBTT review.”

Comment: “With respect to the acute toxicity for estuarine and marine fish, it appears that some 

data is available: “Indoxacarb, its R-enantiomer and degradates are, “moderately to very highly 

toxic” to freshwater and estuarine/marine fish on an acute basis with LC50s ranging from 0.024 

to > 1.3 mg/L.”2

We also found data that may be of use to meet the freshwater fish toxicity requirement using 

coldwater species; according to this study, Indoxacarb has an LC50 of 650ppb in rainbow trout.3

LC50 values are also available for carp and channel catfish.4

If this data is not sufficient then we recommend the registrant conduct an acute threshold or 

“limit test” which can reduce the number of animals used. This approach was first pioneered on 

the observation that fish are rarely more sensitive than algae and daphnia.5,6 The fish median 

 1

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

ian_acute_oral_oecd_tg223.htm
4

lethal concentration (LC50) test is replaced with an acute threshold test in which fish testing

would be performed at one concentration only (the lowest EC50 concentration obtained with 

previous algae and daphnia testing). A version of this approach has been adopted by the OECD 

as a guidance document.7

In this case since the EC50 in invertebrates is already known and so low, conducting a limit test 

for fish at this level could accomplish the Agency’s data needs while using many fewer fish than 

a full acute toxicity study, and providing an effective level of protection to wild fish 

populations.”

Response: The Agency is aware of the cited data for the acute toxicity of indoxacarb to 

freshwater and estuarine/marine fish. This data is among those cited in Table 5-1 of the problem 

formulation. According to OPPTS 850.1075: Fish Acute Toxicity Test, Freshwater and Marine, 

“Definitive testing may be waived if limit testing with at least 30 organisms shows LC50 levels 

to be greater than 1,000 mg/L based on 100 percent active ingredients (AI), or the limits of water 

solubility or dispersibility. For pesticides, a lower level of 100 mg AI/L may be tested when 

estimated environmental concentrations are not expected to exceed 100 mg/L (ppm) as might 

occur with pesticide use. Prior to selection of definitive test concentrations it may be advisable to 

conduct a range-finding test. Results of any range-finding and limit tests should be reported with 

results of the definitive test.”

Comment: “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.”

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

of the Registration Review ecological risk assessment.

3. Comments from CASQA, the Central Valley Regional Water Quality Control 

Board, and the San Francisco Bay Water Quality Control Board

Topic: Assessing risk from urban sources of exposure

CASQA Comment: “Risk Analysis modeling approach must explicityly include urban 

sources/pathways. 

The Work Plan should explicitly address assessment of potential ecological effects from urban 

runoff sources, including the following elements:

• Develop Conceptual Models: CASQA strongly recommends development of conceptual 

models of indoxacarb fate and transport, with flow charts illustrating the principal 

pathways for pesticides to cause effects in the terrestrial and aquatic environments, 

including explicit depiction of urban runoff pathways to receiving waters. These
5

conceptual model diagrams should be used to guide the development of the ecological 

risk assessment. (See additional information in Modeling Attachment to this letter.)

• Specify Mathematical Modeling Approach: neither the Problem Formulation nor the 

Preliminary Work Plan include any reference to modeling of urban runoff; both 

documents should be revised to incorporate mathematical modeling to address urban 

rainfall/runoff exposure pathways.

• Separately include “landscaped (pervious)” areas and “impervious” areas as urban source 

categories in conceptual models and mathematical modeling.

• Account separately for water and sediment matrices in assessments of both exposure and 

effects for aquatic organisms in conceptual models and mathematical modeling.

• Calculate four-day rolling averages and number of exceedances of biological criteria 

(e.g., LC50) every three years in the analysis of the modeling results, and include the 

four-day, three-year exposure estimates when assessing risks to aquatic organisms.”

Central Valley Regional Water Quality Control Board Comment: Urban runoff from 

outdoor applications to impervious surfaces and turf should be modeled.

San Francisco Bay Water Quality Control Board Comment: The risk assessment must 

include modeling that fully accounts for urban fate and transport mechanisms, particularly the 

broad expanses of impervious and highly compacted pervious surfaces; washoff3 following 

impervious surface applications due to precipitation and irrigation spray; and direct flow through 

storm drains to rivers, streams, and bays. OPP has included these elements in its registration 

review for bifenthrin. Please see the Registration Review Problem Formulation for Bifenthrin 

(Docket ID Number EPA–HQ–OPP–2010–0384). 

Response: In the problem formulation section of the preliminary draft of the Registration 

Review ecological risk assessment for indoxacarb, EFED will revise the risk exposure pathways 

of concern to include relevant urban sources of exposure to indoxacarb including droplets, drift, 

and deposition on impervious surfaces. 

EFED acknowledges the need for an improved urban runoff scenario. However, at the present 

time, EFED considers the use of the impervious scenario (a PRZM modeling scenario) as the 

most suitable available modeling approach for impervious runoff. The PRZM impervious 

scenario may be used in the tier 2 coupled aquatic models PRZM/EXAMS along with a 

residential or other suitable scenario such as rights-of-way (ROW) to obtain EECs. The 

conceptual model for the residential scenario integrates simultaneous modeling of the individual 

use scenario with an impervious scenario. This approach assumes that no watershed is 

completely covered by either the 1⁄4 acre lot (the basis for the residential scenario) or 

undeveloped land (the basis for the ROW scenario) for residential and ROW use patterns; 

therefore, differential amounts of runoff will occur within the watershed. The impervious 

scenario was developed to represent the paved areas within a watershed not including roads, 

parking lots, sidewalks, and buildings outside the 1⁄4 acre lot (the 1⁄4 acre lot scenario accounts for 

impervious surfaces such as buildings within the represented area). By modeling a separate 

scenario for impervious surfaces, it is also possible to estimate that amount of exposure that 

could occur when the pesticide is oversprayed onto this surface. Using two scenarios in tandem 

requires post-processing of the modeled output in order to derive a weighted EEC that represents 
6

the contribution of both the pervious (i.e., residential and ROW scenarios) and the impervious 

surfaces. Exposure from both scenarios can also be weighted and aggregated. The daily time 

series from each model run should be copied from the times series file (NAME_TS.out) 

generated from the PRZM graphical user interface (PE5.pl) into the spreadsheet provided. The 

time series data are then weighted based on percentage of impervious surface, the percentage of 

the pervious surface treated, and an adjusted time series is created. Rolling averages for the 

relevant durations of exposure (e.g., 21 day and 60 day averages) are calculated, and the relevant 

one-in-ten year return EEC is generated from these distributions.

The Agency intends to use available non-agricultural use and usage data, such as the Kline 

database, the California Department of Pesticide Regulation’s (CDPR) Pesticide Use Reporting 

Data and Pest Control Operator’s usage survey, and the Residential Joint Venture Task Force 

homeowner survey data, to make certain reasonable assumptions regarding various applications 

and information related to urban/residential use. Due to the limited data available, exposure to 

the environment and uncertainties will be characterized. Detailed information on nonagricultural use and usage of indoxacarb would be useful to reduce those uncertainties for the 

Registration Review ecological risk assessment for indoxacarb.

Topic: Environmental fate and ecological effects data gaps

CASQA Comment: 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:

• Provide environmental fate-related data for the major indoxacarb degradates, IN-JT333 

and IN-MP819.

• 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.

Sediment toxicity testing should be performed with spiked sediments, rather than by adding the

test chemicals to the overlying water. This provides a much more accurate assessment of actual

toxicity to benthic organisms. The sediment studies also should include Chironomus dilutus, as

Ding et al. (2010) found this species to be much more sensitive to indoxacarb than Hyalella

azteca, an amphipod commonly used in sediment toxicity testing.”

Central Valley Regional Water Quality Control Board Comment: 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)
7

“One data gap that is not proposed to be filled is the effects on benthic organisms in sediment 

exposures. lndoxacarb has low water solubility and a high octanol-water partition coefficient 

(log Kow=4.65), and it is likely that it will partition to sediments once it enters a waterway. 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. One study on stream 

macroinvertebrates reported that indoxacarb exposure can induce downstream drift at 

concentrations as low as one-tenth of the LC50 (Beketov and Liess 2008). 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.”

San Francisco Bay Water Quality Control Board Comment: 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. 

Response: 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 

IN-MP819)

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. EFED considers this to be a 

conservative approach, and a rationale for why EFED’s approach is not reasonable has not been 

provided. Therefore, EFED does not recommend requesting chronic toxicity data for freshwater 

and marine invertebrates for IN-JT333 and IN-MP819.

EFED considers the commenters’ 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 
8

and marine invertebrates testing. Therefore, EFED 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, EFED will use the toxic 

equivalency (TEQ) approach to assess the toxicity of both parent indoxacarb and degradates INJT333 and IN-MP819 to sediment-dwelling invertebrates using the results of this testing. 

Topic: Environmental chemical analysis methods

CASQA Comment: 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.”

Central Valley Regional Water Quality Control Board Comment: Chemical Analysis 

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

sediment matrices
9

“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 

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.”

San Francisco Bay Water Quality Control Board Comment: “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.”

Response: 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. 

Topic: Water monitoring data

CASQA Comment: 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).”

Central Valley Regional Water Quality Control Board Comment: “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 
10

outdoor applications to impervious surfaces, and potentially similar restrictions on applications 

to these types of surfaces as were recently adopted for pyrethroids. Limiting applications to 

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

pesticide contamination in urban streams.”

Response: 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.

Topic: Consideration of California-specific data/scenarios

Central Valley Regional Water Quality Control Board Comment: “The Preliminary Work 

Plan (p. 6) reports an average of 39,000 pounds a.i. indoxacarb for 558,000 treated acres from 

2007-2011; based on the PUR data, it appears that use in California makes up the majority of 

agricultural use nationwide. If this is true, then ecological risk assessment should specifically 

assess California conditions, crops, and aquatic life and wildlife, particularly in the intensive 

agricultural areas of California where toxicity in waterways has already been documented by 

current-use pesticides, such as the Central Coast and Central Valley.”

Response: In the case of a nation-wide risk assessment conducted under Registration Review, 

the action area will encompass the entire U.S. and its territories.

Topic: Use of most sensitive species

San Francisco Bay Water Quality Control Board Comment: “The modeling must account for 

aquatic organism exposures in both water and sediment matrices, using the most sensitive 

species. For sediment exposures, Chironomus dilutus is more sensitive to indoxacarb than 

Hyalella azteca.”

Response: As stated above, EFED recommends requesting non-guideline, whole sediment, 

chronic sediment tests with Chironomus dilutus, Hyalella azteca, and 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.