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

I. 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 

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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. 

II. 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-OPPT2013-0171-0003Clare Thorp

Senior Director, Human Health 

Policy, CLA

Administrator, EPF

Endocrine Policy Forum

EPF

2 EPA-HQ-OPPT2013-0171-0004

S. Slaughter The Center for Regulatory 

Effectiveness CRE

3

EPA-HQ-OPPT2013-0171-0005Emily V. Tipaldo

Manager, Regulatory and 

Technical Affairs

American Chemistry Council

ACC

4 EPA-HQ-OPPT2013-0171-0006

Not stated Council of Producers & 

Distributors of Agrotechnology CPDA

5 EPA-HQ-OPPT2013-0171-0007

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.

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III. 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,

1 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.

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.

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 doseresponse 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.

1 78 FR 37803, June 24, 2013.

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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

procymidone2 and vinclozolin3.

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 Tests4

2) July 30-August 2, 2013, Weight-of-Evidence (WoE): Evaluating Results of EDSP Tier 1 

Screening5

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.

2 To access the documents related to the procymidone decision, go to

http://www.epa.gov/pesticides/reregistration/procymidone/. 3 To access the documents related to the vinclozolin decision, go to

http://www.epa.gov/pesticides/reregistration/vinclozolin/.

4 Hereafter referred to as the Tier 2 Ecotox Tests SAP.

5 Hereafter referred to as the WoE SAP.

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The Agency received the FIFRA SAP's final report on the Tier 2 test methods in September 

20136. 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 20137. 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 SAP8

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 

Report9

). 

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 

6 http://www.epa.gov/scipoly/sap/meetings/2013/june/062513minutes.pdf

7 http://www.epa.gov/scipoly/sap/meetings/2013/july/073013minutes.pdf 

8 Hereafter referred to as the Tier 1 Assay SAP. 9 http://www.epa.gov/scipoly/sap/meetings/2013/may/052113minutes.pdf

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Clerance.10. 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.

11 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.

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.

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.

10 http://www.reginfo.gov/public/do/PRAViewICR?ref_nbr=201210-2070-003

11 In the 2013 version of the Terms of Clearance OMB specifically stuck the sentence, "In addition, in order to 

ensure that EPA has maximized the practical utility of the Tier 1 assays as the program moves forward, EPA 

should ensure sufficient opportunity prior to submission of any revision to this collection for public comment and 

peer review of the EPA tools to be developed to guide agency decisions on whether a chemical must proceed to 

Tier 2, including the Weight of the Evidence Approach and Standard Evaluation Procedures." Replacing it with, 

"OMB acknowledges the EPA's outreach to the public and peer reviewers and encourages continuous efforts for 

stakeholder involvement while developing the protocols on whether a chemical must proceed to Tier 2, including 

the Weight of the Evidence Approach and Standard Evaluation Procedures."

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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.

C. 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.

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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. 

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.

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.

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.

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F. 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. 

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Commenter CRE: Asserts that EPA is planning to abandon the EDSP Tier 1 screening and 

Tier 2 tests in favor of the CompTox.

12

Agency Response: The Agency articulated its vision for in vitro replacement of in vivo studies

in the EDSP21 Work Plan13. 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.

12 Computational Toxicology Research Program. http://www.epa.gov/ncct/

13 U.S. EPA, Endocrine Disruptor Screening Program for the 21st Century: (EDSP21 Work Plan), Summary 

Overview, September 30, 2011. 

http://www.epa.gov/endo/pubs/edsp21_work_plan_summary%20_overview_final.pdf

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