35350 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices 

may claim all or part of a response 

confidential. EPA will disclose 

information that is covered by a claim 

of confidentiality only to the extent 

permitted by, and in accordance with, 

the procedures in TSCA section 14 and 

40 CFR part 2. 

Burden statement: The annual public 

reporting and recordkeeping burden for 

this collection of information is 

estimated to average 31.5 hours per 

response. Burden is defined in 5 CFR 

1320.3(b). 

The ICR, which is available in the 

docket along with other related 

materials, provides a detailed 

explanation of the collection activities 

and the burden estimate that is only 

briefly summarized here: 

Respondents/Affected Entities: 

Entities potentially affected by this ICR 

are companies that manufacture, 

process or import chemical substances, 

mixtures or categories. 

Estimated total number of potential 

respondents: 1. 

Frequency of response: On occasion. 

Estimated total average number of 

responses for each respondent: 1. 

Estimated total annual burden hours: 

31.5 hours. 

Estimated total annual costs: $2,388. 

This includes an estimated burden cost 

of $2,388 and an estimated cost of $0 for 

capital investment or maintenance and 

operational costs. 

III. Are There Changes in the Estimates 

from the Last Approval? 

There is a decrease of 916 hours in the 

total estimated respondent burden 

compared with that identified in the ICR 

currently approved by OMB. This 

decrease reflects additional both 

adjustment changes from a reduction in 

the assumed number of PAIR reports 

filed annually, and program changes 

resulting from mandatory electronic 

submissions of PAIR reports. In recent 

years (FY 2011–FY 2014), EPA has 

received no PAIR submissions and, for 

the purposes of this analysis, EPA 

assumes an annual rate of one 

submission per year. At the time OMB 

last renewed this ICR, EPA estimated an 

average of 33 reports from 14.8 

submitters based on fiscal year 2006– 

2010 data. The ICR supporting 

statement provides a detailed analysis of 

the change in burden estimate. This 

change is both an adjustment and a 

program change. 

IV. What is the Next Step in the Process 

for this ICR? 

EPA will consider the comments 

received and amend the ICR as 

appropriate. The final ICR package will 

then be submitted to OMB for review 

and approval pursuant to 5 CFR 

1320.12. EPA will issue another Federal 

Register document pursuant to 5 CFR 

1320.5(a)(1)(iv) to announce the 

submission of the ICR to OMB and the 

opportunity to submit additional 

comments to OMB. If you have any 

questions about this ICR or the approval 

process, please contact the technical 

person listed under FOR FURTHER

INFORMATION CONTACT. 

Authority: 44 U.S.C. 3501 et seq. 

Dated: June 10, 2015. 

James Jones, 

Assistant Administrator, Office of Chemical 

Safety and Pollution Prevention. 

[FR Doc. 2015–14946 Filed 6–18–15; 8:45 am] 

BILLING CODE 6560–50–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

[EPA–HQ–OPPT–2015–0305; FRL–9928–69] 

Use of High Throughput Assays and 

Computational Tools; Endocrine 

Disruptor Screening Program; Notice 

of Availability and Opportunity for 

Comment 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Notice. 

SUMMARY: This document describes how 

EPA is planning to incorporate an 

alternative scientific approach to screen 

chemicals for their ability to interact 

with the endocrine system. This will 

improve the Agency’s ability to fulfill its 

statutory mandate to screen pesticide 

chemicals and other substances for their 

ability to cause adverse effects by their 

interaction with the endocrine system. 

The approach incorporates validated 

high throughput assays and a 

computational model and, based on 

current research, can serve as an 

alternative for some of the current 

assays in the Endocrine Disruptor 

Screening Program (EDSP) Tier 1 

battery. EPA has partial screening 

results for over 1800 chemicals that 

have been evaluated using high 

throughput assays and a computational 

model for the estrogen receptor 

pathway. In the future, EPA anticipates 

that additional alternative methods will 

be available for EDSP chemical 

screening based on further 

advancements of high throughput assays 

and computational models for other 

endocrine pathways. Use of these 

alternative methods will accelerate the 

pace of screening, decrease costs, and 

reduce animal testing. In addition, this 

approach advances the goal of providing 

sensitive, specific, quantitative, and 

efficient screening using alternative test 

methods to some assays in the Tier 1 

battery to protect human health and the 

environment. 

DATES: Comments must be received on 

or before August 18, 2015. 

ADDRESSES: Submit your comments, 

identified by docket identification (ID) 

number EPA–HQ–OPPT–2015–0305, by 

one of the following methods: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the online 

instructions for submitting comments. 

Do not submit electronically any 

information you consider to be 

Confidential Business Information (CBI) 

or other information whose disclosure is 

restricted by statute. 

• Mail: Document Control Office 

(7407M), Office of Pollution Prevention 

and Toxics (OPPT), Environmental 

Protection Agency, 1200 Pennsylvania 

Ave. NW., Washington, DC 20460–0001. 

• Hand Delivery: To make special 

arrangements for hand delivery or 

delivery of boxed information, please 

follow the instructions at http://

www.epa.gov/dockets/contacts.html. 

Additional instructions on 

commenting or visiting the docket, 

along with more information about 

dockets generally, is available at http:// 

www.epa.gov/dockets. 

FOR FURTHER INFORMATION CONTACT: For 

technical information contact: Jane 

Robbins, Office of Science Coordination 

and Policy (OSCP), Office of Chemical 

Safety and Pollution Prevention, 

Environmental Protection Agency, 1200 

Pennsylvania Ave. NW., Washington, 

DC 20460–0001; telephone number: 

(202) 564–6625; email address: 

robbins.jane@epa.gov. 

For general information contact: The 

TSCA-Hotline, ABVI-Goodwill, 422 

South Clinton Ave., Rochester, NY 

14620; telephone number: (202) 554– 

1404; email address: TSCA-Hotline@

epa.gov. 

SUPPLEMENTARY INFORMATION: 

I. General Information 

A. Does this action apply to me? 

This action is directed to the public 

in general, and may be of interest to a 

wide range of stakeholders including 

those interested in endocrine testing of 

chemicals (including pesticides), and 

the EDSP in general. Since others also 

may be interested, the Agency has not 

attempted to describe all the specific 

entities that may be affected by this 

action. 

B. What is the agency authority for 

taking this action? 

The EDSP is established under section 

408(p) of the Federal Food, Drug and 


asabaliauskas on DSK5VPTVN1PROD with NOTICES
Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices 35351 

Cosmetic Act (FFDCA), 21 U.S.C. 

346a(p). Section 408(p)(1) requires EPA 

‘‘to develop a screening program, using 

appropriate validated test systems and 

other scientifically relevant information 

to determine whether certain substances 

may have an effect in humans that is 

similar to an effect produced by a 

naturally occurring estrogen, or such 

other effects as [EPA] may designate.’’ 

[21 U.S.C. 346a(p)(1)]. Section 408(p)(2) 

requires that the screening program be 

implemented ‘‘after obtaining public 

comment and review . . . by the 

scientific advisory panel established 

under section 25(d) of the Federal 

Insecticide, Fungicide, and Rodenticide 

Act. . .’’ [21 U.S.C. 346a(p)(2)]. 

This document describes the new 

scientific methods that are available as 

alternatives to some of the current EDSP 

Tier 1 screening assays and solicits 

public comment on EPA’s plan to use 

these alternative approaches to screen 

chemicals for their ability to interact 

with the endocrine system. The 

approach described in this document is 

not binding on either EPA or any 

outside parties, and EPA may depart 

from the approach presented in this 

document where circumstances warrant 

and without prior notice. 

C. What action is the agency taking? 

This document describes and solicits 

comments on how EPA is planning to 

incorporate scientific advancements and 

tools into the EDSP. The adoption of 

scientific advancements into the EDSP 

has been underway and part of the 

public dialogue about EDSP for several 

years. As EPA has consistently 

indicated, the Agency intends to 

continue to incorporate in the EDSP 

new methods involving high throughput 

assays and computational toxicology. 

Also, EPA has identified a universe of 

approximately 10,000 chemicals as 

potential candidates for screening and 

testing under the EDSP (Ref. 1). This 

approach is expected to accelerate the 

pace of screening, add efficiencies, 

decrease costs, and reduce animal 

testing. 

EPA is planning to incorporate the 

partial screening results from validated 

high throughput assays and 

computational models as an alternative 

to data from some of the current assays 

in the EDSP Tier 1 screening battery. 

Currently, EPA has partial screening 

results for over 1800 chemicals that 

have been evaluated using the high 

throughput assays and computational 

model for the estrogen receptor 

pathway. 

The use of high-throughput assays 

and computational models for EDSP 

screening is an initial step in EPA’s 

integration of 21st-century integrated 

assessment and testing approaches 

broadly, beyond EDSP, across a wide 

range of chemicals related to regulatory 

and non-regulatory decisions made in 

programs under the Agency’s purview 

(Ref. 2). Much of the knowledge gained 

in using these approaches for EDSP 

screening will be useful in applying 

high throughput assays and 

computational models to thousands of 

chemicals across many toxicological 

endpoints and exposure scenarios. 

D. What should I consider as I prepare 

my Comments for EPA? 

1. Submitting CBI. Do not submit this 

information to EPA through 

regulations.gov or email. Clearly mark 

the part or all of the information that 

you claim to be CBI. For CBI 

information in a disk or CD–ROM that 

you mail to EPA, mark the outside of the 

disk or CD–ROM as CBI and then 

identify electronically within the disk or 

CD–ROM the specific information that 

is claimed as CBI. In addition to one 

complete version of the comment that 

includes information claimed as CBI, a 

copy of the comment that does not 

contain the information claimed as CBI 

must be submitted for inclusion in the 

public docket. Information so marked 

will not be disclosed except in 

accordance with procedures set forth in 

40 CFR part 2. 

2. Tips for preparing your comments. 

When preparing and submitting your 

comments, see the commenting tips at 

http://www.epa.gov/dockets/

comments.html. 

II. Background 

A. What is the Endocrine Disruptor 

Screening Program (EDSP)? 

The Food Quality Protection Act 

(FQPA) of 1996 amended FFDCA to 

require EPA ‘‘to develop a screening 

program, using appropriate validated 

test systems and other scientifically 

relevant information, to determine 

whether certain substances may have an 

effect in humans that is similar to an 

effect produced by a naturally occurring 

estrogen, or such other effects as [EPA] 

may designate’’ (21 U.S.C. 346a(p)(1)). 

Also in 1996, the Agency chartered the 

Endocrine Disruptor Screening and 

Testing Advisory Committee (EDSTAC), 

under the provisions of the Federal 

Advisory Committee Act (FACA) (5 

U.S.C. App. 2, section 9(c)), to provide 

advice on developing an endocrine 

disruptor screening program (Ref. 3). 

The EDSTAC was comprised of 

members representing the commercial 

chemical and pesticides industries, 

Federal and State agencies, worker 

protection and labor organizations, 

environmental and public health 

groups, and research scientists. EDSTAC 

recommended that EPA’s program 

address both potential human and 

wildlife effects; examine effects on 

estrogen, androgen, and thyroid 

hormone-related processes; and include 

non-pesticide chemicals, contaminants, 

and mixtures in addition to pesticide 

chemicals (Ref. 2). 

In 1998, based on the EDSTAC 

recommendations, EPA established the 

EDSP using a two-tiered approach (Ref. 

4). The purpose of Tier 1 (referred to as 

‘‘screening’’) is to identify substances 

that have potential biological activity 

(‘‘bioactivity’’) in the estrogen, 

androgen, or thyroid hormone pathways 

using a battery of assays. The purpose 

of Tier 2 (referred to as ‘‘testing’’) is to 

identify and establish a dose-response 

relationship for any adverse effects that 

might result from the endocrine 

bioactivity identified through the Tier 1 

assays. The ultimate purpose of the 

EDSP is to provide information to the 

Agency that will allow the Agency to 

evaluate any possible endocrine effects 

associated with the use of a chemical 

and take appropriate steps to mitigate 

any related risks to ensure protection of 

public health. 

In 2009, the Agency issued test orders 

requiring Tier 1 screening for 67 

chemicals (‘‘List 1’’) (Ref. 5). Between 

the time needed to review the 

substantial volume of ‘‘other 

scientifically relevant information’’ 

submitted by test order recipients to 

satisfy selected screening assays, the 

time and resources of industry spent 

generating data, the time spent by the 

Agency reviewing the information, and 

the delays resulting from the limited 

laboratory capacity for conducting many 

of the Tier 1 assays and corresponding 

time extension requests, the review of 

the initial List 1 chemicals has taken 

over four years and has imposed 

significant burdens on test order 

recipients and the agency. The Agency 

is still finalizing the data evaluation 

records and determinations concerning 

which of the List 1 chemicals need 

further Tier 2 testing. More information 

on the EDSP history and the status of 

current activities is available at http://

www.epa.gov/endo. 

B. What is meant by ‘‘high throughput 

assays and computational model’’? 

High throughput assays are automated 

methods that allow for a large number 

of chemicals to be rapidly evaluated for 

a specific type of bioactivity at the 

molecular or cellular level. This 

approach, which can help identify 

compounds that may modulate specific 


asabaliauskas on DSK5VPTVN1PROD with NOTICES
35352 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices 

biological pathways, was initially 

developed by pharmaceutical 

companies for drug discovery. The 

results of these methods provide an 

initial understanding of a biochemical 

interaction or possible role of a 

chemical in a given biological process. 

In vitro high throughput assays are 

usually conducted using a microtiter 

plate: a plate containing a grid with a 

large number of small divots called 

‘‘wells.’’ The wells contain chemical 

and/or biological substrate (e.g., living 

cells or proteins). Depending on the 

nature of the experiment, changes can 

be detected (e.g., color, fluorescence, 

etc.) when the chemical is added to 

indicate whether there is bioactivity. 

High throughput microtiter plates 

typically come in multiples of 96 wells 

(96, 384, or 1536), so that through the 

use of robotics, data processing and 

control software, liquid handling 

devices, and sensitive detection 

methods, an extremely large number of 

chemicals can be evaluated very 

efficiently. 

High throughput assays can be run for 

a range of test chemical concentrations 

and produce concentration-response 

information representing the 

relationship between chemical 

concentration and bioactivity. The 

concentration-response data from 

multiple assays can be mathematically 

integrated in a computational model of 

a biological pathway, providing values 

representative of a chemical’s 

bioactivity in that pathway (e.g., 

estrogen receptor pathway). To reduce 

non-specific results, the computational 

model can use results from multiple 

assays and technologies to predict 

whether a chemical is truly bioactive in 

the pathway being evaluated. The most 

prominent cause of non-specific results 

(activity in an assay that is likely not 

due to bioactivity of the chemical in the 

pathways) is cytotoxicity in cell-based 

assays. In other cases, chemicals 

influence the assays through a manner 

dependent on the physics and chemistry 

of the technology platform (i.e., ‘‘assay 

interference’’). 

C. What is ToxCastTM? 

To improve efficiencies in screening 

and testing chemicals, EPA scientists 

are harnessing advances in molecular 

and systems biology, chemistry, 

toxicology, mathematics, and computer 

technology. In doing this, they are 

helping to revolutionize chemical 

screening and safety testing based on 

advances in computational toxicology. 

A major part of this effort is the 

Agency’s Toxicity Forecaster, or 

ToxCastTM, which uses automated, 

robotics-assisted high throughput assays 

to expose living cells or proteins to 

chemicals and measure the results. The 

high throughput assays produce 

concentration-response information 

representing the relationship between 

chemical concentration and bioactivity. 

These innovative methods have the 

potential to quickly and efficiently 

screen large numbers of chemicals and 

other substances. ToxCastTM is part of 

EPA’s contribution to a federal research 

collaboration called ‘‘Toxicity Testing in 

the 21st Century’’, or ‘‘Tox21,’’ pooling 

resources and expertise from EPA, the 

National Institutes of Health and the 

U.S. Food and Drug Administration to 

use robotics for screening thousands of 

chemicals for potential bioactivity (Ref. 

6). 

As part of EPA’s commitment to 

gather and share its chemical data 

openly and clearly, all ToxCastTM

chemical data are publicly available 

through user-friendly web applications 

called the interactive Chemical Safety 

for Sustainability (iCSS) and EDSP21 

dashboards (Refs. 7 and 8). The EDSP21 

and iCSS dashboards provide accessible 

portals for users to search and query the 

ToxCastTM chemical data. Users can 

review chemicals and data of interest, as 

well as export the information. Making 

ToxCastTM data available through the 

dashboards creates an environment that 

encourages external stakeholder 

interactions identifying potential issues, 

concerns, and suggesting improvements. 

D. What is meant by the ToxCastTM ER 

Model for bioactivity? 

The ToxCastTM ER Model for 

bioactivity (‘‘ER Model’’) includes data 

from 18 estrogen receptor (ER) high 

throughput assays from ToxCastTM that 

detect multiple events in the receptor 

pathway. The ER Model also includes a 

computational module that integrates 

the assay data to produce a value for ER 

agonist and antagonist bioactivity for 

each chemical (Ref. 9). An ER agonist 

binds and activates the receptor, and an 

antagonist binds and blocks activation. 

These 18 high throughput assays 

measure bioactivity at different sites 

along the ER pathway including 

receptor binding, receptor dimerization, 

chromatin binding of the mature 

transcription factor, gene transcription 

and changes in estrogen-receptor growth 

kinetics. Bioactivity (i.e., response) is 

measured using various detection 

methods (e.g., fluorescence, etc.) across 

a range of concentrations to examine 

potential concentration-response 

relationships, including no change 

across concentrations indicating no 

bioactivity. Concentration-response 

relationships for each assay are 

mathematically integrated in the ‘‘ER 

Model’’ to quantify bioactivity from 

multiple assays. The computational 

model integrates the results of each of 

the 18 ER assays as an area under the 

curve (AUC) for ER agonist or antagonist 

bioactivity for each chemical. The 

bioactivity values generally range from 

0 to 1 for each chemical, with 0 

indicating no bioactivity and 1 

approximating the positive reference 

chemical (e.g., estradiol for ER 

agonism). 

In order to validate the ER Model, 

ToxCastTM data have been collected and 

reviewed on over 1800 chemicals, 

including ER reference agonists and 

antagonists (Ref. 10). ER agonist and 

antagonist bioactivity scores from the 

‘‘ER Model’’ compare very well with 

reported bioactivity of reference 

chemicals across a range of structures 

and potencies. Of the over 1800 

chemicals tested, over 1700 chemicals 

had very low or no detectable ER 

bioactivity (Ref. 10). The ‘‘ER Model’’ 

bioactivity scores were validated by 

comparing the scores to 45 reference 

chemicals, equivalent to a performancebased approach to validation. EPA also 

compared ‘‘ER Model’’ results to a 

database of curated uterotrophic studies 

published in peer-reviewed literature. 

ER agonist bioactivity scores accurately 

predicted in vivo ER agonist activity for 

a large set (∼150) of chemicals with 

uterotrophic data (Refs. 9 and 11). The 

validation of the ‘‘ER Model’’ as an 

alternative screening method for three 

current Tier 1 assays (ER binding, ER 

transcriptional activation (ERTA), and 

uterotrophic) was peer reviewed by the 

Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) Scientific 

Advisory Panel (SAP) in December 2014 

(Refs. 9 and 11). The FIFRA SAP fully 

endorsed the use of these alternatives 

for the ER binding and ERTA assays; 

however, there was not consensus 

among panel members on the use of the 

‘‘ER Model’’ as an alternative for the 

uterotrophic assay (Ref. 11). In response 

to the concerns raised by the FIFRA 

SAP, EPA has published a paper 

clarifying the relationship between ‘‘ER 

Model’’ bioactivity and uterotrophic 

results, and illustrating that a 

uterotrophic assay would provide no 

added value if ‘‘ER Model’’ data are 

available (Ref. 12). Based on these 

findings, EPA concludes that ‘‘ER 

Model’’ data are sufficient to satisfy the 

Tier 1 ER binding, ERTA and 

uterotrophic assay requirements. The 

Agency intends to build on the 

performance-based validation approach 

presented at the December 2014 FIFRA 

SAP expanding this approach to include 


asabaliauskas on DSK5VPTVN1PROD with NOTICES
Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices 35353 

other key events in the estrogen 

pathway. 

III. Using High Throughput Assays and 

Computational Models for Screening 

A. How Will ToxCastTM data be used for 

screening in the EDSP? 

The ability to screen chemicals 

rapidly for bioactivity in several 

endocrine pathways, and reducing the 

use of animals in testing, have been 

EDSP goals since 1998, when the 

program was first adopted (Ref. 4). As 

previously noted, when the first Tier 1 

orders (for List 1 chemicals) were issued 

in 2009, EPA had not confirmed the 

reliability and relevance of the 

ToxCastTM results so that they could be 

cited as ‘‘other scientifically relevant 

information’’ to satisfy the Tier 1 ER 

binding, ERTA, and uterotrophic assays 

(Ref. 13). However, since that time, EPA 

has reached a critical juncture, 

determining that the science has 

progressed such that reevaluation of 

EPA’s earlier position is warranted. 

Based on scientific advances, EPA 

intends to implement the use of high 

throughput assays and computational 

models to evaluate, and to a significant 

extent, screen chemicals. The in vitro 

high throughput and computational 

model alternatives provide an accurate 

quantitative measure of specific 

endocrine pathway bioactivity and 

mechanisms. The current Tier 1 battery 

includes animal-based assays that do 

not clearly identify or differentiate 

pathways and mechanisms. Specifically, 

the current Tier 1 ER binding, ERTA 

and uterotrophic assays do not provide 

both estrogen agonist and antagonist 

activity and animals are required to 

conduct the ER binding and 

uterotrophic assays. 

EPA is planning to adopt in vitro high 

throughput assays and computational 

models for detecting and measuring ER 

agonist and antagonist bioactivity as an 

alternative for three current Tier 1 

assays: 1) ER binding in vitro assay (Ref. 

14); 2) ER transcriptional activation in 

vitro assay (ERTA) (Ref. 15); and 3) in 

vivo uterotrophic assay (Refs. 16 and 

17). EPA is also planning to accept 

existing results for chemicals that have 

been evaluated using the ToxCastTM

‘‘ER Model’’ for bioactivity. The 

accompanying database contains the ER 

agonist bioactivity and ER antagonist 

bioactivity for over 1800 chemicals and 

identifies those chemicals that are 

pesticide active ingredients, pesticide 

inert ingredients, and on EDSP Lists 1 

or 2 (Ref. 10). This is a ‘‘living’’ database 

that will continue to incorporate 

bioactivity results for chemicals as they 

become available. This database is 

available at http://www.epa.gov/endo 

and in the docket identified for this 

document in a format that can be easily 

reviewed and manipulated 

electronically (Ref. 10). It is important, 

however, not to equate a determination 

of a chemical’s bioactivity from the ‘‘ER 

Model’’ with a determination that a 

chemical causes endocrine disruption. 

The World Health Organization (WHO)/ 

International Programme on Chemical 

Safety (IPCS) defines endocrine 

disruption as being caused by ‘‘an 

exogenous substance or mixture that 

alters function(s) of the endocrine 

system . . . and . . .consequently 

causes adverse health effects in an intact 

organism or its progeny, or 

(sub)populations’’ (Ref. 18). Bioactivity 

is an indicator that a chemical has the 

potential to alter endocrine function, 

but (1) whether the chemical actually 

alters endocrine function and (2) 

whether that altered function produces 

an adverse outcome in an intact animal 

cannot be determined without further 

testing (i.e., Tier 2 testing). 

The EDSP has been developed over 

the past 19 years, and has demonstrated 

that the current screening process may 

take upwards of 5 years before a Tier 1 

decision is available or Tier 2 test orders 

are issued. In light of recent advances in 

high throughput assays and 

computational models, and advances 

likely to come in the next two years, it 

is prudent for the Agency to consider 

new, rapid screening methods. The 

availability of additional alternative 

high throughput assays and 

computational models in the near term 

will allow EPA to screen more 

chemicals in less time, involve fewer 

animals, and cost less for everyone. 

Furthermore, reconsideration of the 

EDSP List 2 chemicals may be 

appropriate since ‘‘ER Model’’ data are 

available for many List 2 and other 

chemicals (Refs. 10 and 19). Ongoing 

use of high throughput assays and 

computational models will address 

thousands of chemicals in the future. 

These advancements in the EDSP 

screening program will not affect the 

overall framework—i.e., the Tier 1 

screening battery and Tier 2 testing 

approach focused on estrogen, androgen 

and thyroid pathways in humans and 

wildlife remains unaffected. Instead, as 

discussed above, EPA is planning to 

adopt sensitive, specific, quantitative, 

and efficient screening methods that 

will rapidly screen many chemicals and 

substantially decrease costs and animal 

use and may be used as an alternative 

to some EDSP Tier 1 screening assays. 

Accordingly, EPA intends a future 

recipient of an EDSP test order to be 

able to satisfy the screening requirement 

for ER, ERTA, and uterotrophic in one 

of three ways: (1) cite existing 

ToxCastTM ‘‘ER Model’’ for bioactivity 

data as ‘‘other scientifically relevant 

information’’ (where available); (2) 

generate new data relying on the 18 ER 

high throughput assays and the 

ToxCastTM ‘‘ER Model’’ for bioactivity; 

or (3) generate their own data using the 

current Tier 1 ER binding, ERTA, and 

uterotrophic assays. 

B. How Does EPA intend to use high 

throughput assays and computational 

models for the EDSP in the future? 

EPA believes that ongoing adoption of 

alternative methods and technologies 

will continue to advance EDSP 

screening of chemicals for bioactivity in 

the estrogen, androgen, and thyroid 

pathways. EPA is continuing research 

on the ‘‘ER Model’’ to determine if 

ToxCastTM assays can provide 

comparable information as that of the 

Female Rat Pubertal and the Fish Short 

Term Reproduction assays. In addition, 

research continues on the ToxCastTM

‘‘AR Model’’ for bioactivity which, if 

fully validated, may be considered as an 

alternative (alone or with the ‘‘ER 

Model’’) for the following current Tier 1 

assays: AR binding, Male Rat Pubertal, 

Hershberger, and Fish Short Term 

Reproduction. Research is also 

underway to develop steroidogenesis 

ToxCastTM (STR) and thyroid (THY) 

bioactivity models. Over time, the 

Agency’s goal is to develop a set of 

‘‘non-animal’’ high throughput assays 

and computational bioactivity models as 

an alternative to all of the assays in the 

current Tier 1 screening battery. The 

following table is intended to illustrate 

the evolution of screening in the EDSP: 

Current EDSP Tier 1 battery of assays Alternative high throughput assays and computational model for EDSP 

Tier 1 battery 

Estrogen Receptor (ER) Binding .............................................................. ER Model (alternative). 

Estrogen Receptor Transactivation (ERTA) ............................................. ER Model (alternative). 

Uterotrophic .............................................................................................. ER Model (alternative). 

Female Rat Pubertal ................................................................................ ER, STR , and thyroid (THY) Models (Future). 


asabaliauskas on DSK5VPTVN1PROD with NOTICES
35354 Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices 

Current EDSP Tier 1 battery of assays Alternative high throughput assays and computational model for EDSP 

Tier 1 battery 

Male Rat Pubertal ..................................................................................... AR, STR, and THY Models (Future). 

Androgen Receptor (AR) Binding ............................................................. AR Model (Future). 

Hershberger .............................................................................................. AR Model (Future). 

Aromatase ................................................................................................ STR Model (Future). 

Steroidogenesis (STR) ............................................................................. STR Model (Future). 

Fish Short Term Reproduction ................................................................. ER, AR, and STR Models (Future). 

Amphibian Metamorphosis ....................................................................... THY Model (Future). 

The table indicates combinations of 

various alternative assays and models 

that might overlap for evaluating 

potential endocrine bioactivity of 

chemicals. The in vitro high throughput 

and computational model alternatives 

provide a focused evaluation of the 

mechanistic aspects of endocrine 

pathways, thereby providing specific 

and quantitative measures of bioactivity. 

Several assays in the Tier 1 battery rely 

on intact animals and identify 

bioactivity in the multiple biological 

pathways present. For this reason, the 

specificity of the in vitro high 

throughput and computational model 

alternatives may be more informative of 

specific endocrine pathway bioactivity. 

The annual EDSP Comprehensive 

Management Plan and future FIFRA 

SAP meetings are opportunities for 

staying informed on EPA’s scientific 

progress on the evolution of Tier 1 

screening in the EDSP. For information, 

visit EPA’s Web site (http://

www.epa.gov/endo) or sign-up to 

receive announcements go to (http://

www.epa.gov/endo/pubs/

assayvalidation/listserv.htm). 

IV. Issues for Comment 

In connection with EPA’s stated 

intention to use the scientific tools 

discussed in this Notice as alternatives 

to some of the current EDSP Tier 1 

screening assays, EPA is specifically 

seeking public comment on the 

following: 

1. The use of the ToxCastTM ‘‘ER 

Model’’ for bioactivity as an alternative 

method for the current ER binding and 

ERTA Tier 1 screening assays. 

2. The use of the ToxCastTM ‘‘ER 

Model’’ for bioactivity as an alternative 

method for the current uterotrophic Tier 

1 screening assay. 

3. The use of results from the 

ToxCastTM ‘‘ER Model’’ for bioactivity 

on over 1800 chemicals as partial 

screening for the estrogen receptor 

pathway. 

V. References 

The following is a listing of the 

documents that are specifically 

referenced in this document. The docket 

includes these documents and other 

information considered by EPA, 

including documents that are referenced 

within the documents that are included 

in the docket, even if the referenced 

document is not physically located in 

the docket. For assistance in locating 

these other documents, please consult 

the technical person listed under FOR

FURTHER INFORMATION CONTACT. 

1. U.S. EPA. Endocrine Disruptor Screening 

Program; Universe of Chemicals and 

General Validation Principles. November 

2012. Available at http://www.epa.gov/

endo/pubs/edsp_chemical_universe_

and_general_validations_white_paper_

11_12.pdf. 

2. U.S. EPA. Endocrine Disruptor Screening 

Program for the 21st Century: (EDSP21 

Work Plan); The Incorporation of In 

Silico Models and In Vitro High 

Throughput Assays in the Endocrine 

Disruptor Screening Program (EDSP) for 

Prioritization and Screening; Summary 

Overview. A Part of the EDSP 

Comprehensive Management Plan. 

September 30, 2011. Available at http:// 

www.epa.gov/endo/pubs/edsp21_work_

plan_summary%20_overview_final.pdf. 

3. U.S. EPA. Endocrine Disruptor Screening 

and Testing Advisory Committee 

(EDSTAC); Final Report. August 1998. 

Available at http://www.epa.gov/endo/

pubs/edspoverview/finalrpt.htm. 

4. U.S. EPA. Endocrine Disruptor Screening 

Program; Proposed Statement of Policy; 

Notice. Federal Register (63 FR 71542, 

December 28, 1998) (FRL–6052–9). 

5. U.S. EPA. Endocrine Disruptor Screening 

Program; Tier 1 Screening Order 

Issuance Announcement; Notice. Federal 

Register (74 FR 54422, October 21, 2009) 

(FRL–8434–8). 

6. U.S. EPA. Office of Research and 

Development (ORD); Description of 

Computational Toxicology Research 

Program. Available at http://epa.gov/

ncct. 

7. U.S. EPA. Interactive Chemical Safety for 

Sustainability (iCSS) Dashboard, Version 

0.5. Available at http://actor.epa.gov/

dashboard. 

8. U.S. EPA. EDSP21 Dashboard. Available at 

http://actor.epa.gov/edsp21. 

9. U.S. EPA. Integrated Bioactivity and 

Exposure Ranking: A Computational 

Approach for the Prioritization and 

Screening of Chemicals in the Endocrine 

Disruptor Screening Program. December 

2014. Docket ID No. EPA–HQ–OPP– 

2014–0614–0003. Available at http://

www.regulations.gov/

#!documentDetail;D=EPA–HQ–OPP– 

2014–0614–0003. 

10. U.S. EPA. Endocrine Disruptor Screening 

Program (EDSP); Estrogen Receptor 

Bioactivity Based on ToxCa TM ‘‘ER 

Model.’’ June 1, 2015. Available at http:// 

www.epa.gov/endo. 

11. U.S. EPA. FIFRA SAP Minutes No. 2015– 

01. FIFRA SAP Meeting on the Integrated 

Bioactivity and Exposure-Based 

Prioritization and Screening, held 

December 2–4, 2014. Docket ID No. 

EPA–HQ–OPP–2014–0614–0029. March 

2, 2015. Available at http://

www.epa.gov/scipoly/sap/meetings/

2014/december/120214minutes.pdf. 

12. Browne, P., Judson, R.S., Casey, W., 

Kleinstreuer, N., Thomas, R.S. Screening 

Chemicals For Estrogen Receptor 

Bioactivity Using A Computational 

Model. Manuscript accepted for 

publication. Environ. Sci. Technol. June 

12, 2015. Available in the docket and 

electronically at http://pubs.acs.org/

journal/esthag. 

13. U.S. EPA. Endocrine Disruptor Screening 

Program; Policies and Procedures for 

Initial Screening; Notice. Federal 

Register (74 FR 17560, April 15, 2009) 

(FRL–8399–9). Note: the status and 

progress of all List 1 Tier 1 orders are 

available at http://www.epa.gov/endo/

pubs/toresources/index.htm. 

14. U.S. EPA. Endocrine Disruptor Screening 

Program Test Guidelines; OPPTS 

890.1250: Estrogen Receptor Binding 

Assay Using Rat Uterine Cytosol (ER– 

RUC). October 2009. EPA 740–C–09–005. 

Available at http://www.epa.gov/ocspp/

pubs/frs/publications/Test_Guidelines/

series890.htm. 

15.U.S.EPA. Endocrine Disruptor Screening 

Program Test Guidelines; OPPTS 

890.1300: Estrogen Receptor 

Transcriptional Activation (Human Cell 

Line (HeLa-9903)). October 2009. EPA 

740–C–09–006. Available at http://

www.epa.gov/ocspp/pubs/frs/

publications/Test_Guidelines/

series890.htm. 

16.U.S.EPA. Endocrine Disruptor Screening 

Program Test Guidelines; OPPTS 

890.1600: Uterotrophic Assay. October 

2009. EPA 740–C–09–0010. Available at 

http://www.epa.gov/ocspp/pubs/frs/

publications/Test_Guidelines/

series890.htm. 

17. Organization of Economic Co-operation 

and Development (OECD). Test 

Guideline No. 440:Uterotrophic Bioassay 

in Rodents: A short-term screening test 

for oestrogenic properties. OECD 

Guidelines for the Testing of Chemicals, 

Section 4, OECD Publishing, Paris. DOI: 

http://dx.doi.org/10.1787/ 


asabaliauskas on DSK5VPTVN1PROD with NOTICES
Federal Register / Vol. 80, No. 118 / Friday, June 19, 2015 / Notices 35355 

9789264067417-en. 

18. World Health Organization (WHO)/

International Programme on Chemical 

Safety (IPCS). Global Assessment of the 

State-of-the-Science of Endocrine 

Disruptors. WHO/IPCS/EDC/02.2. 2002. 

Available at http://www.who.int/ipcs/

publications/new_issues/endocrine_

disruptors/en. 

19. U.S. EPA. Endocrine Disruptor Screening 

Program; Final Second List of Chemicals 

and Substances for Tier 1 Screening; 

Notice. Federal Register (78 FR 35922, 

June 14, 2013) (FRL–9375–8). Available 

at http://www.gpo.gov/fdsys/pkg/FR– 

2013–06–14/pdf/2013–14232.pdf. 

Authority: 21 U.S.C. 346a(p). 

Dated: June 11, 2015. 

James J. Jones, 

Assistant Administrator, Office of Chemical 

Safety and Pollution Prevention. 

[FR Doc. 2015–15182 Filed 6–18–15; 8:45 am] 

BILLING CODE 6560–50–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

[EPA–HQ–SFUND–2006–0361; FRL—9929– 

32–OSWER] 

Proposed Information Collection 

Request; Comment Request; Trade 

Secret Claim Submissions under the 

Emergency Planning and Community 

Right-to-Know Act. 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Notice. 

SUMMARY: The Environmental Protection 

Agency (EPA) is planning to submit an 

information collection request (ICR), 

‘‘Trade Secret Claims Submitted under 

the Emergency Planning and 

Community Right-to-Know Act.’’ (EPA 

ICR No. 1428.10, OMB Control No. 

2050–0078) to the Office of Management 

and Budget (OMB) for review and 

approval in accordance with the 

Paperwork Reduction Act. Before doing 

so, EPA is soliciting public comments 

on specific aspects of the proposed 

information collection as described 

below. This is a proposed extension of 

the ICR, which is currently approved 

through December 31, 2015. An Agency 

may not conduct or sponsor and a 

person is not required to respond to a 

collection of information unless it 

displays a currently valid OMB control 

number. 

DATES: Comments must be submitted on 

or before August 18, 2015. 

ADDRESSES: Submit your comments, 

referencing Docket ID No. EPA–HQ– 

SFUND–2006–0361, online using 

www.regulations.gov (our preferred 

method), by email to 

superfund.docket@epa.gov, or by mail 

to: EPA Docket Center, Environmental 

Protection Agency, Mail Code 28221T, 

1200 Pennsylvania Ave. NW., 

Washington, DC 20460. 

EPA’s policy is that all comments 

received will be included in the public 

docket without change including any 

personal information provided, unless 

the comment includes profanity, threats, 

information claimed to be Confidential 

Business Information (CBI) or other 

information whose disclosure is 

restricted by statute. 

FOR FURTHER INFORMATION CONTACT: Sicy 

Jacob, Office of Emergency 

Management, Mail Code 5104A, 

Environmental Protection Agency, 1200 

Pennsylvania Ave. NW., Washington, 

DC 20460; telephone number: (202) 

564–8019; fax number: (202) 564–2620; 

email address: jacob.sicy@epa.gov. 

SUPPLEMENTARY INFORMATION: 

Supporting documents which explain in 

detail the information that the EPA will 

be collecting are available in the public 

docket for this ICR. The docket can be 

viewed online at www.regulations.gov 

or in person at the EPA Docket Center, 

WJC West, Room 3334, 1301 

Constitution Ave. NW., Washington, 

DC. The telephone number for the 

Docket Center is 202–566–1744. For 

additional information about EPA’s 

public docket, visit http://www.epa.gov/ 

dockets. 

Pursuant to section 3506(c)(2)(A) of 

the PRA, EPA is soliciting comments 

and information to enable it to: (i) 

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; (ii) evaluate the 

accuracy of the Agency’s estimate of the 

burden of the proposed collection of 

information, including the validity of 

the methodology and assumptions used; 

(iii) enhance the quality, utility, and 

clarity of the information to be 

collected; and (iv) 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. EPA will consider the 

comments received and amend the ICR 

as appropriate. The final ICR package 

will then be submitted to OMB for 

review and approval. At that time, EPA 

will issue another Federal Register 

notice to announce the submission of 

the ICR to OMB and the opportunity to 

submit additional comments to OMB. 

Abstract: This information collection 

request pertains to trade secrecy claims 

submitted under Section 322 of the 

Emergency Planning and Community 

Right-to-Know Act of 1986 (EPCRA). 

EPCRA contains provisions requiring 

facilities to report to State and local 

authorities, and EPA, the presence of 

extremely hazardous substances 

(Section 302), inventory of hazardous 

chemicals (Sections 311 and 312) and 

manufacture, process and use of toxic 

chemicals (Section 313). 

Section 322 of EPCRA allows a 

facility to withhold the specific 

chemical identity from these EPCRA 

reports if the facility asserts a claim of 

trade secrecy for that chemical identity. 

The provisions in Section 322 establish 

the requirements and procedures that 

facilities must follow to request trade 

secrecy treatment of chemical identities, 

as well as the procedures for submitting 

public petitions to the Agency for 

review of the ‘‘sufficiency’’ of trade 

secrecy claims. 

Trade secrecy protection is provided 

for specific chemical identities 

contained in reports submitted under 

each of the following: (1) Section 303 

(d)(2)- Facility notification of changes 

that have or are about to occur, (2) 

Section 303 (d)(3)—Local Emergency 

Planning Committee (LEPC) requests for 

facility information to develop or 

implement emergency plans, (3) Section 

311—Material Safety Data Sheets 

(MSDSs) submitted by facilities, or lists 

of those chemicals submitted in place of 

the MSDSs, (4) Section 312—Emergency 

and hazardous chemical inventory 

forms (Tier I and Tier II), and (5) Section 

313 Toxic chemical release inventory 

form. 

Form Number: EPA Form 9510–1. 

Respondents/affected entities: Entities 

potentially affected by this action are 

manufacturers or non-manufacturers 

subject to reporting under Sections 303, 

311/312 or 313 of the Emergency 

Planning and Community Right-toKnow Act (EPCRA). 

Respondent’s obligation to respond: 

Mandatory if the respondents would 

like to claim the chemical identity for 

any of the chemicals as trade secret in 

any of the reports required to be 

submitted under EPCRA. 

Estimated number of respondents: 

332 (total). 

Frequency of response: Annual for 

claims submitted under EPCRA Sections 

312 and 313. 

Total estimated burden: 3,154 hours 

(per year). Burden is defined at 5 CFR 

1320.03(b). 

Total estimated cost: $206,155 (per 

year). No capital and operation and 


asabaliauskas on DSK5VPTVN1PROD with NOTICES