Docket ID No. EPA-HQ-OPPT-2013-0171

Response to Public Comments on the 
Public Review Draft of the 
Information Collection Request (ICR) entitled: 
"Tier 2 Testing of Certain Chemicals Under the Endocrine Disruptor Screening Program (EDSP)"
                         (78 FR 37803, June 24, 2013)
                                 June 25, 2015
Table of Contents
I.	Introduction	1
II.	Commenters	2
III.	Comments and Responses	3
A.	Evaluate whether the proposed collection of information is necessary for the
proper performance of the functions of the Agency including practical utility.	3
B.	Evaluate the accuracy of the Agency's estimates of the burden	4
C.	Enhance the quality, utility, and clarity of the information to be collected.	5
D.	Minimize the burden of the collection of information	5
E.	Time Alloted for the for the Reproduction and Fertility Effects test 
(OCSPP Guideline 870.3800)..	6
F.	Additional Comments	6

Introduction 

EPA's Endocrine Disruptor Screening Program (EDSP) was established under section 408(p) of the Federal Food, Drug, and Cosmetic Act (FFDCA), which required EPA to develop a chemical screening program using validated test methods and other scientifically relevant information (OSRI) to determine whether certain substances may have estrogenic effects in humans. The EDSP consists of a two-tiered approach to screen chemicals for potential endocrine disrupting effects. The purpose of Tier 1 screening is to identify substances that have potential bioactivity with the estrogen, androgen, or thyroid hormonal systems using a battery of assays. Based on a Weight of Evidence (WoE) analysis, substances that have potential bioactivity with estrogen, androgen or thyroid systems will be considered for Tier 2 testing. Tier 2 tests are designed to establish dose-response relationships for any potential adverse effect to be used in risk assessment. Additional information about the EDSP is available through the Agency's Web site at http://www.epa.gov/endo.

This "Response to Public Comments" document specifically addresses public comments EPA received on a draft information collection request (ICR) (EPA ICR No. 2479.01) under the Paperwork Reduction Act (PRA), 44 USC 3501 et seq., covering the information collection activities associated with Tier 2 testing of chemicals under EPA's EDSP. The ICR addresses the information collection activities for those List 1 chemicals that were screened under Tier 1 and are now proceeding to testing under Tier 2. The ICR covers the full range of information collection activities associated with Tier 2 of the EDSP, including the paperwork activities associated with the issuance of Tier 2 orders, initial responses from order recipients, paperwork activities associated with generating the data requested, and submitting the data to EPA pursuant to the order.

This "Response to Public Comments" document provides a summary of the comments specifically received on, and related to, to the ICR, and the Agency's responses to those comments. 
Commenters

The following table identified the five sets of comments filed. Note that number 5 (EPA-HQ-OPPT-2013-0171-0007) included three signatures representing three separate affiliations.

                                    #[(1)]
                                   DCN[(2)]
                              Commenter Name[(3)]
                                  Affiliation
                                   Code[(4)]
                                       1
EPA-HQ-OPPT-2013-0171-0003
Clare Thorp
Senior Director, Human Health Policy, CLA
Administrator, EPF
Endocrine Policy Forum
                                      EPF
                                       2
EPA-HQ-OPPT-2013-0171-0004
S. Slaughter
The Center for Regulatory Effectiveness
                                      CRE
                                       3
EPA-HQ-OPPT-2013-0171-0005
Emily V. Tipaldo
Manager, Regulatory and Technical Affairs
American Chemistry Council
                                      ACC
                                       4
EPA-HQ-OPPT-2013-0171-0006
Not stated
Council of Producers & Distributors of Agrotechnology
                                     CPDA
                                       5
EPA-HQ-OPPT-2013-0171-0007
Patricia L. Bishop
Research Associate, Regulatory Testing Division
People for the Ethical Treatment of Animals
                                 PETA (et al.)


Kristie Sullivan, MPH
Director, Regulatory Testing Issues
Physicians Committee for Responsible Medicine



Catherine Willett, PhD
Director, Regulatory Toxicology, Risk Assessment and Alternatives
Animal Research Issues
The Humane Society of the United States

Key:
(1) This is the number that is used in this document to refer to this particular commenter/set of comments.
(2) This is the number that is used to identify this comment in the docket at www.regulations.gov
(3) This is the name of the individual that submitted the comments, along with their affiliation, if provided.
(4) This is the code used in this document to identify commenters.



Comments and Responses
This document summarizes the comments received and the Agency's response -- grouping similar topics together.  The first five groups reflect the five specific areas the Agency explicitly requested comment on in its federal register notice, as follows:
A. Evaluate whether the proposed collection of information is necessary for the proper performance of the functions of the Agency, including whether the information will have practical utility.
B. Evaluate the accuracy of the Agency's estimates of the burden of the proposed collection of information, including the validity of the methodology and assumptions used.
C. Enhance the quality, utility, and clarity of the information to be collected.
D. Minimize the burden of the collection of information on those who are to respond, including through the use of appropriate automated electronic, mechanical, or other technological collection techniques or other forms of information technology, e.g., permitting electronic submission of responses.  In particular, EPA is requesting comments from very small businesses (those that employ less than 25) on examples of specific additional efforts that EPA could make to reduce the paperwork burden for very small businesses affected by this collection. 
E. EPA is specifically requesting comments on the duration of the time allotted for the Reproduction and Fertility Effects test (OCSPP Guideline 870.3800).  The Agency is considering a range from 24 to 48 months, but for the purpose of the ICR calculations, it is assumed that all work will be completed within the 3-year duration of the ICR.

Evaluate whether the proposed collection of information is necessary for the proper performance of the functions of the Agency, including whether the information will have practical utility.

Commenter CRE: Asserts that EPA has not demonstrated that the Tier 2 tests have practical utility or that they meet Information Quality Act (IQA) guidelines.

Agency Response: EPA disagrees that the practical utility of the information obtained from the Tier 2 tests has not been demonstrated and that the tests do not meet Information Quality Act (IQA) guidelines.

The purpose of EDSP Tier 1 data are to determine if a chemical has potential endocrine bioactivity.  EDSP Tier 1 data are mechanistic in nature.  Endocrine bioactivity potential is identified for a chemical after the EDSP Tier 1 battery has been conducted and an EDSP Tier 1 WoE determination has been completed.  The EDSP Tier 1 WoE also identifies if any EDSP Tier 2 testing will be required.  The purpose of EDSP Tier 2 testing is to identify whether there is an interaction with the endocrine system and establish a quantitative, dose-response relationship for any adverse effects that might result from that interaction.  EDSP Tier 2 dose-response data will be critical to identifying the hazard associated with the chemical when conducting a risk assessment.  The practical utility of EDSP Tier 2 data are to provide this dose-response information for risk assessment purposes.  EDSP Tier 2 data will provide a hazard endpoint for potential regulation of the chemical.  Again, this is the practical utility of EDSP Tier 2 data and has been outlined in the EDSP Tier 2 ICR supporting statement.

EPA has extensive experience in using data from multiple sources to develop integrated assessments of hazard, modes of action/mechanisms of toxicity, and overall potential for risk. EPA scientists will continue to use such experience, together with data from EDSP Tier 2 tests, to address the potential of chemicals to cause adverse effects as a consequence of interaction with the endocrine system.  In fact, EPA has considered the potential interaction of a chemical with the endocrine system in making certain pesticide registration decisions.  For example, EPA considered endocrine-mediated effects in preparing the risk assessments of procymidone and vinclozolin.

The Agency is confident that it has reasonably projected and minimized paperwork burden and cost, and demonstrated practical utility of the data requested.

Commenters EPF:  Asserts that practical utility cannot be definitively judged until the Agency responds to, and implements the recommendations from two Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panels (SAP):

   1)	June 25-28, 2013, EDSP Tier 2 Ecotoxicity Tests
   2)	July 30-August 2, 2013, Weight-of-Evidence (WoE): Evaluating Results of EDSP Tier 1 Screening

According to EPF, the Tier 2 Ecotox Tests SAP report is expected to:

   "provide the SAP's opinion on the reproducibility of results and factors that may impact interpretation of whether or not the proposed Tier 2 tests are adequate to provide a more comprehensive assessment of the potential of a test chemical to cause endocrine-mediated adverse effects in the subject taxa."

The WoE SAP report:

   "is expected to provide recommendations to EPA that will help them determine how many compounds proceed to Tier 2 and which studies are needed
   
EPF specifically questioned:

   "If the [WoE] SAP recommendations are adopted, how will these costs be captured in a transparent fashion?  Will a specific Policies and Procedures section be added at a later date to a revised WoE document?"

Agency Response: EPA has reviewed the panel reports to which the commenter is refering to.  EPA has implemented the pertinent changes to the Tier 2 test methods suggested by the SAP.

The Agency received the FIFRA SAP's final report on the Tier 2 test methods in September 2013.  The report was generally supportive of EPA's Tier 2 tests and stated "the Panel supports the scientific rationale and purpose, representative species chosen, biological and toxicological relevance of the major endpoints selected and measured, and the validation process used by EPA for all four proposed Tier 2 ecotoxicity tests."  The FIFRA SAP did recommend some improvements to the Tier 2 tests, which the Agency considered and implemented.  However, EPA notes that the particular changes recommended by the FIFRA SAP pertained neither to the overall practical utility of the Tier 2 tests nor to the burdens and costs associated with these tests.

The Agency received the SAP's final report on the WoE methods in October 2013.  The report was generally supportive of EPA's approach to making EDSP Tier 1 WoE decisions.  The particular Tier 2 studies being requested (for chemicals identified as having potential endocrine bioactivity in the Tier 1 program) were not discussed at this FIFRA SAP meeting.  Discussion of these studies was not, therefore, a component of the meeting report.  

Commenters ACC & PETA (et al.):  Assert that practical utility cannot be definitively judged until the Agency responds to, and implements the recommendations from two Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panels (SAP):  

Agency Response: EPA disagrees with that the practical utility of the information obtained from EDSP Tier 2 testing cannot be determined until after the recommendations of the FIFRA SAP are responded to/implemented.  Furthermore, this concern has been "overcome by events," namely, the FIFRA SAP reports for these meetings have been issued and reviewed by EPA.

Commenter CPDA: Asserts that because the Agency has not demonstrated the practical utility of the Tier 1, List 1 screening ICR in accordance with OMB's Terms of Clearance; the Agency cannot demonstrate the practical utility of this Tier 2, List 1 testing ICR.

Agency Response: The Agency asserts: 1) that practical utility of the Tier 1, List 1 screening ICR has been established, 2) that EPA satisfied the Tier 1, List 1 Terms of Clearance, and 3) that the status of the Tier 1, List 1 ICR is a separate issue from the status of this Tier 2, List 1 testing ICR.

The May 21-23, 2013, EDSP Tier 1 Screening Assays and Battery Performance FIFRA SAP external peer review panel reconfirmed the practical utility of the Tier 1 battery to determine whether a chemical has potential endocrine bioactivity.  The performance of each assay and the Tier 1 battery were judged to have performed as anticipated (Tier 1 Assay SAP Final Report). 

With respect to the terms of clearance related to OMB's approval of the Tier1, List 1 ICR, OMB's renewal of the ICR on July 31, 2013 is evidence that EPA satisfied the Terms of Clerance..  The Agency notes that the language the commenter refers to as the OMB Terms of Clearance was significantly revised by OMB for the renewal in 2013. EPA remains engaged in the process of fulfilling the conditions outlined in this revision.

Commenter PETA (et al.): Recommends that the Agency consider OSRI submissions in Tier 2 testing.
Commenter CPDA:  For EDSP List 1 Tier 1, EPA rejected an excessive proportion of EDSP OSRI, and without transparent review.

Agency Response: The Agency agrees with PETA's suggestion that EPA should consider OSRI submissions in Tier 2 testing.  The Agency will continue to consider OSRI submissions, including OSRI submissions in Tier 2 testing.  Furthermore, EPA has now included OSRI submissions in EDSP ICR calculations (which were not included in early ICRs related to the EDSP).

EPA disagrees, however, with CPDA comments related to the acceptance rate for OSRI.  In more than half of all the instances where OSRI was submitted for a chemical (27 of 47 or ~57.4%), EPA determined that the requirement for one or more EDSP Tier 1 study had been met because the OSRI submitted was determined to be sufficient.  All EDSP List 1 Tier 1 OSRI submissions and EPA's review of the submissions can be accessed at http://www.epa.gov/endo/pubs/EDSP_OSRI_Response_Table.pdf.  As for the transparency of OSRI reviews, again the table just cited provides ample support.  For every List 1 chemical that cited OSRI, the table provides a link to chemical specific docket at www.regulations.gov to both the rationale (supplied by the order recipient) and EPA's detailed review of this OSRI.  
Also, an EDSP WOE Guidance document has been revised based on the public comments received and an amended document has been placed in the docket at www.regulations.gov under Docket ID No. EPA HQ OPPT 2010 0877.

Evaluate the accuracy of the Agency's estimates of the burden of the proposed collection of information, including the validity of the methodology and assumptions used.
Commenters EPF and ACC: Assert that the Agency cannot accurately estimate burden and costs until after the exact number of chemicals that will proceed to Tier 2 testing is known; and the Agency implements recommendations from both the Tier 2 Ecotox Tests and the WoE SAPs.  The commenters challenge the Agency's estimates of the number of List 1 chemicals that will proceed to Tier 2 testing (26), the estimated number of respondents (210), and both the industry and agency burdens associated with Tier 2 testing and data evaluation. 

Agency Response:  The Agency agrees that the exact number of chemicals that will proceed to the EDSP Tier 2 are not known.  However, the Agency disagrees that the ICR cannot move forward until the exact number of chemicals that will proceed to Tier 2 testing is known.  EPA had previously estimated 210 respondents as a reasonable upper bound estimates in spite of the uncertainties.  For purposes of the ICR and the requirements of the Paperwork Reduction Act, it is more important that the burden is not underestimated than that it be exact.  The nature of the particular uncertainties surrounding the respondent estimate as described in the ICR supporting statement would tend to indicate that 210 is an overestimate.  The Agency was clear in the Tier 2 ICR supporting statement that 210 respondents is an overestimation.  

As time has passed since the draft ICR went out for public comment, the Agency now believes that the estimate of 210 respondents can be reduced (for the purpose of ICR burdens and costs calculations) to 100 respondents.  100 respondents is still an upper-bound estimate that should not underestimate the number of respondents. When a clearer, more accurate estimation of the number of respondents is available, EPA will submit a revision to OMB.  The Agency continues to support its upper-bound estimate that no more than 26 chemicals from List 1 will proceed to Tier 2 testing.

See Agency Response in section A (above) for the Agency's position on the timing of the Tier 2 ICR as it relates to the FIFRA SAPs.

Commenters ACC and CPDA:  Assert that the Agency underestimates the industry cost associated with complying with the ICR.
Commenter ACC:  Requests that the Agency submit the final Tier 2 test guidelines to a representative number of qualified laboratories and requests detailed cost estimates, including costs for the analytical chemistry requirements to establish a solid basis for the cost calculation in the ICR.

Agency Response:  EPA disagrees with these comments.  The Agency is confident that the projections in the ICR are reasonable upper-bound estimations of the costs associated with the issuance of (and compliance with) EDSP Tier 2 orders.  As above, no factual evidence was submitted by the commenters that the industry costs are likely to be underestimates.  Furthermore, Tier 2 tests are similar to multi-generation studies currently required by EPA's Office of Pesticide Programs (OPP).  These studies are an established basis from which EPA reasonably extrapolated the estimated costs of the EDSP Tier 2 tests.  In particular, one of the four Tier 2 tests (Mammalian 2-Generation Rat) has been required for decades by OPP and those costs are especially well-known.

Enhance the quality, utility, and clarity of the information to be collected.
Commenters EPF, CRE, ACC, CPDA & PETA (et al.):  Assert that the agency cannot maximize the quality, utility and clarity of the information collection until the agency implements recommendations from 1) the Tier 2 Ecotox Tests SAP, 2) the WoE SAP, and 3) the May 21-23, 2013, Tier 1 Assay SAP.  Commenters assert that this ICR should not have been issued for comment until the final test guidelines and protocols were publically available.

Agency Response: See Agency Response in section A (above) for the agency's position on the timing of the Tier 2 ICR as it relates to the FIFRA SAPs.

Minimize the burden of the collection of information on those who are to respond, including through the use of appropriate automated electronic, mechanical, or other technological collection techniques or other forms of information technology, e.g., permitting electronic submission of responses.  In particular, EPA is requesting comments from very small businesses (those that employ less than 25) on examples of specific additional efforts that EPA could make to reduce the paperwork burden for very small businesses affected by this collection. 
Commenter EPF: Supports the agency's use of automated electronic submission processes and recommends that the agency issue Data Entry Spreadsheet Templates (DESTs) and Standard Evaluation Procedures (SEPs) before any tests commence to promote efficiency. Further, the commenter recommends increasing the amount of time alloted between the initial test order response (order date plus 90 days, plus 10 days) and the final submission of data (order date plus 24 to 48 months).  Furthermore EPA asserts that this will allow for discussion and resolution of questions and uncertainties, and minimize industry burden associated with processing extension requests.

Agency Response:  The Agency is planning on having the SEPs and DESTs, available in advance of issuance of Tier 2 orders.  These documents serve several purposes including clarifying some specific expectations of the guideline requirements.  Also, if the respondent knows they intend to generate the data, they are neither obligated to wait the 90 plus days to submit their response, nor to commence the study.  If the order recipients are concerned about the conduct of a study in the timeframe provided, a protocol can be submitted with your response "to generate the data" for agency review to minimize questions and issues.  The Agency established the timeframes for the studies after considering the amount of time one might reasonably expect is needed to complete each test, including the planning activities before commencement of testing, actual performance of the test, analyzing test results, completing the final study report, and submission preparations to the Agency.

EPA is specifically requesting comments on the duration of the time allotted for the Reproduction and Fertility Effects Test (OCSPP Guideline 870.3800). The Agency is considering a range from 24 to 48 months, but for the purpose of the ICR calculations, it is assumed that all work will be completed within the 3-year duration of the ICR.
Commenter EPF: 48 months should be the minimum time allotted for registrants to complete and report the Reproduction and Fertility Effects test when required.

Agency Response:  To ensure consistency and allow ample time for conducting the mammalian reproduction and fertility effects test (OCSPP Guideline 870.3800), the Agency will allow respondents 48 months to complete this test.  While the Agency will allow 4 years to complete the Tier 2 tests, the ICR calculates the total estimated costs rather than annualized cost over 4 years.

Additional Comments
Commenter EPF: Regarding alternative responses to Tier 2 test orders...

   # Request an exemption under FFDCA section 408(p)(4).
      The commenter questions whether exemption under FFDCA section 408(p)(4) is really a viable option for Tier 2, presuming the Agency would only issue a Tier 2 test order for a given chemical if it believed that there was in fact potential for the chemical to interact with endocrine systems based on the results of Tier 1 screening and OSRI.
      
      Agency Response: The Agency agrees.  The basis for an exemption order under FFDCA section 408(p)(4) would be that the substance is not anticipated to produce in humans or any other organism an effect similar to that produced by a naturally occurring estrogen, androgen, or thyroid hormone.  EPA acknowledges that the very same evidence justifying the initial issuance of a Tier 2 test order would also tend to weigh against issuing an exemption order under FFDCA section 408(p)(4).       
      
      As suggested by the commenter, EPA is revising the ICR supporting statement and accompanying Tier 2 order templates to remove the discussion about requesting an exemption order under FFDCA section 408(p)(4) as one of the response options for Tier 2 test order recipients.  The determination to issue an exemption order under FFDCA section 408(p)(4) is one that must be made by the Agency.  In the context of the ICR, there is no paperwork burden associated with the Agency's issuance of such an exemption order, which does not involve any respondent activities.
      
Pre-enforcement challenges to the test order.
      Commenter EPF asserts that the existing guidance on this option is unclear.
      
      Agency Response: The Agency disagrees.  EPA's conclusions about the availability of pre-enforcement review of the validity of test orders are discussed in detail in the 2009 Policies and Procedures document.  With respect to informal administrative review, EPA disagrees that it is unclear what sufficient detail means.  Sufficient detail means "sufficient specificity and detail to allow the Agency to adequately and fairly evaluate the issue(s) presented."  74 FR 17560, 17576 (April 15, 2009).  EPA acknowledges the Commenter EPF's statement that it is currently unclear about "what types of situations" would give a test order recipient cause to challenge the validity of any particular test order.  But EPA disagrees that the identified uncertainty (relating to the potential to litigate the validity of a test order) represents an impediment to estimating the burden of complying with the test orders.  
       
Additional EDSP testing is unnecessary because the chemical is an endocrine disruptor or was used as a "positive control" in the EDSP Tier 2 validation effort.
      The commenter asserts that this option does not make sense in relationship to Tier 2 testing.

      Agency Response: The Agency concurs as long as the EDSP Tier 2 validation is suitable for the regulatory need.  This option will be deleted.  

Commenter CRE:  Asserts that EPA is planning to abandon the EDSP Tier 1 screening and Tier 2 tests in favor of the CompTox.

Agency Response:  The Agency articulated its vision for in vitro replacement of in vivo studies in the EDSP21 Work Plan.  The Agency is considering the use in vitro studies as alternatives or replacement of the EDSP Tier 1 screens over time.  When decisions are made to use computational and high throughput methods in the EDSP, those decisions will be based on sound science with the goals of reducing testing cost, reducing the use of live animals, reducing paperwork burden and increasing efficiency in providing both human health and environmental protection.  EPA does not have an imminent plan to replace the EDSP Tier 2 tests with computational and high throughput alternative tests.
