
I. Studies to be Called-In:
 Guideline Number [a]
 40 CFR 158 Citation [b]
 Data Requirement
 Study type [c]
 Average Test Cost
 Total Paperwork Burden Cost [d]
 Total Paperwork Burden 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
850.6100[1]
158.1300
Environmental chemistry - analytical method for soil and associated independent laboratory validation 
                                      EF
                                                                     $22,000.00
                                                                      $7,700.00
                                                                             98



                                       
                                                                               
                                                                               
                                                                               
850.6100[1]
158.1300
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 DPX-MP062)
                                      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 GDLN[2,3]
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 GDLN[2,3]
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 GDLN[2,3]
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 (IN-MP819)
                                      EF
                                                                     $46,780.00
                                                                     $16,373.00
                                                                            208
850.1075
158.630
Freshwater Fish Toxicity (Degradate IN-MP819)
                                      EE
                                                                     $11,957.00
                                                                      $4,185.00
                                                                             53
850.6100[1]
158.1300
Environmental chemistry for soil associated independent laboratory validation (IN-JT333)
                                      EF
                                                                     $22,000.00
                                                                      $7,700.00
                                                                             98
850.6100[1]
158.1300
Environmental chemistry for soil associated independent laboratory validation (IN-MP819)
                                      EF
                                                                     $22,000.00
                                                                      $7,700.00
                                                                             98
850.6100[1]
158.1300
Environmental chemistry for  water associated independent laboratory validation (IN-JT333)
                                      EF
                                                                     $22,000.00
                                                                      $7,700.00
                                                                             98
850.6100[1]
158.1300
Environmental chemistry for water associated independent laboratory validation (IN-MP819)
                                      EF
                                                                     $22,000.00
                                                                      $7,700.00
                                                                             98
850.6100[1]
158.1300
Environmental chemistry for  sediment associated independent laboratory validation (IN-JT333)
                                      EF
                                                                     $22,000.00
                                                                      $7,700.00
                                                                             98
850.6100[1]
158.1300
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 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:
      
   * 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.

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 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.  The Agency considers this to be a conservative approach, and a rationale for 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 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 u/g OC and a maximum of 69 u/g OC.  The 10-d sediment LC50 for Chironomus dilutus is 11.3 u/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 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.


