[Federal Register Volume 71, Number 51 (Thursday, March 16, 2006)]
[Notices]
[Pages 13597-13598]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-3763]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


National Toxicology Program (NTP), NTP Interagency Center for the 
Evaluation of Alternative Toxicological Methods (NICEATM); Notice of 
Availability of a Revised List of Recommended Reference Substances for 
Validation of In Vitro Estrogen and Androgen Receptor Binding and 
Transcriptional Activation Assays: Request for Comments and Submission 
of In Vivo and In Vitro Data

AGENCY: National Institute of Environmental Health Sciences (NIEHS), 
National Institutes of Health (NIH).

ACTION: Request for Comments and Submission of Data.

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SUMMARY: The National Toxicology Program (NTP) Interagency Center for 
the Evaluation of Alternative Toxicological Methods (NICEATM) announces 
the availability of an addendum to the report entitled, ``Interagency 
Coordinating Committee on the Validation of Alternative Methods 
(ICCVAM) Evaluation of In Vitro Test Methods for Detecting Potential 
Endocrine Disruptors: Estrogen Receptor and Androgen Receptor Binding 
and Transcriptional Activation Assays'' [NIH Publication 03-4503]. The 
addendum describes the rationale for proposed revisions to the original 
list of recommended reference substances for validation of in vitro 
estrogen receptor (ER) and androgen receptor (AR) binding and 
transcriptional activation (TA) assays. The original list was made 
publicly available in June 2003 (Federal Register, Vol. 68, No. 106, 
pp. 33171-33172, June 3, 2003). NICEATM requests public comments on the 
substances proposed as substitutes for six of the 78 substances in the 
original list. Data are also requested from in vitro and in vivo 
studies evaluating the estrogenic and androgenic activity of the 78 
substances in the revised list of reference substances.

DATES: Comments and data submissions should be received by May 1, 2006.

ADDRESSES: Correspondence should be sent by mail, fax, or e-mail to Dr. 
William S. Stokes, NICEATM Director, NIEHS, P. O. Box 12233, MD EC-17, 
Research Triangle Park, NC, 27709, (phone) 919-541-2384, (fax) 919-541-
0947, (e-mail) [email protected].

SUPPLEMENTARY INFORMATION:

Background

    In April 2000, the Environmental Protection Agency (EPA) asked 
ICCVAM to evaluate the validation status of in vitro ER and AR binding 
and TA assays that were proposed as possible components of the EPA 
Endocrine Disruptor Screening Program Tier 1 screening battery. ICCVAM 
agreed to evaluate these test methods based on their potential 
interagency applicability and public health significance. NICEATM, 
which administers and provides scientific support for ICCVAM, 
subsequently compiled available data and information on in vitro ER and 
AR binding and TA assays in four draft Background Review Documents 
(BRDs) (available at http://iccvam.niehs.nih.gov/methods/endocrine.htm).
    In collaboration with the ICCVAM Endocrine Disruptor Working Group, 
NICEATM organized an independent scientific evaluation of the 
validation status of the four types of in vitro endocrine disruptor 
screening test

[[Page 13598]]

methods on May 20-21, 2002, in Research Triangle Park, NC (Federal 
Register, Vol. 66, No. 57, pp. 16278-16279, March 23, 2001 and Federal 
Register, Vol. 66, No. 67, pp. 16415-16416, April 5, 2002) (available 
at http://iccvam.niehs.nih.gov/methods/endocrine.htm).
    The final BRDs and the ICCVAM Test Method Evaluation Report, which 
includes the expert panel report, public comments, and other relevant 
documents, were published in May 2003 and announced in a Federal 
Register notice (Vol. 68, No. 106, pp. 33171-33172, June 3, 2003) 
(available at http://iccvam.niehs.nih.gov/methods/endocrine.htm).
    NICEATM recently reviewed the commercial availability and cost for 
the 78 substances recommended by ICCVAM for use in in vitro ER and AR 
binding and TA validation studies. A minimum of 44 substances are 
recommended for AR binding and TA assays, while a minimum of 53 
substances are recommended for ER binding and TA assays. This review 
indicated that three substances [anastrazole, CGS 18320B, fadrozole] 
are not commercially available, one substance has restricted commercial 
availability [ICI 182,780] and six others [actinomycin D, 
hydroxyflutamide, 4-hydroxytamoxifen, methyltrienolone, 12-O-
tetradecanoylphorbol-13-acetate, zearalenone] have costs that are 
considered excessive. ICCVAM proposes replacing the four substances 
that are not commercially available or have restricted availability 
with ones having similar ER and AR activity profiles [4-
hydroxyandrostenedione, chrysin, dicofol, raloxifene HCl]. Suitable 
replacements (19-nortestosterone and resveratrol) were identified for 
metyltrienolone and zearalenone, respectively, for two of the expensive 
substances. NICEATM would also prefer to replace four of the highly 
priced substances [actinomycin D, hydroxyflutamide, 4-hydroxytamoxifen, 
12-O-tetradecanoy.lphorbol-13-acetate], but has been unable to identify 
suitable replacements because of their unique activity profiles and/or 
chemical/physical properties. The revised list of 78 substances and a 
discussion about the proposed revisions are included and discussed in 
the ``Addendum to the ICCVAM Evaluation of In Vitro Test Methods for 
Detecting Potential Endocrine Disruptors: Estrogen Receptor and 
Androgen Receptor Binding and Transcriptional Activation Assays,'' 
(available at http://iccvam.niehs.nih.gov see ``Test Method 
Evaluations'') or by contacting NICEATM (see ADDRESSES above.) ICCVAM 
will finalize this list after considering any public comments received 
and forward it to U.S. Federal agencies for their information and 
consideration.

Request for Comments and Request for Data

    NICEATM requests public comments on the four substances (listed 
above) proposed as replacements for substances on the list that are not 
readily commercially available. NICEATM also requests public comments 
on the proposed replacements for the two expensive substances for which 
replacements have been identified, and suggestions for replacements for 
the four expensive substances that remain on the recommended list.
    In order to update the reference substance database, NICEATM 
request data from completed in vitro studies using or evaluating ER and 
AR binding and/or TA assays, and information about ongoing or planned 
studies using or evaluating these test methods. NICEATM also requests 
the submission of data from animal studies that have evaluated the 
endocrine activity of chemicals using, for example, the uterotropic, 
Hershberger, intact male, or male/female pubertal assays. NICEATM is 
especially interested in receiving additional data or information on 
any of the 78 substances included in the reference list. NICEATM 
previously requested data from completed studies using or evaluating ER 
and AR binding and/or TA assays, and information about ongoing or 
planned in vitro or in vivo studies using or evaluating these test 
methods (Federal Register, Vol. 66, No. 57, pp. 16278-16279, March 23, 
2001). Submitted data will be used to update and supplement the 
existing NICEATM database; the current database can be accessed in the 
ICCVAM Test Method Evaluation Report [NIH Publication No. 03-4503] and 
the four final BRDs on ER and AR binding and TA assays [NIH Publication 
No. 03-4504, 03-4505, 03-4506, and 03-4507] (available at http://iccvam.niehs.nih.gov/methods/endocrine.htm).
    When submitting chemical and protocol information/test data, please 
reference this Federal Register notice and provide appropriate contact 
information (name, affiliation, mailing address, phone, fax, e-mail, 
and sponsoring organization, as applicable).
    NICEATM prefers data to be submitted as copies of pages from study 
notebooks and/or study reports, if available. Raw data and analyses 
available in electronic format may also be submitted. If data are 
published in the peer-reviewed literature, citations should be 
provided. Each submission for a chemical should preferably include the 
following information, as appropriate:
     Common and trade name
     Chemical Abstracts Service Registry Number (CASRN)
     Chemical class
     Product class
     Commercial source
     In vitro test protocol used
     In vitro test results
     In vivo test protocol used
     In vivo test results
     The extent to which the study complied with national or 
international Good Laboratory Practice (GLP) guidelines
     Date and testing organization

Background Information on ICCVAM and NICEATM

    ICCVAM is an interagency committee composed of representatives from 
15 Federal regulatory and research agencies that use or generate 
toxicological information. ICCVAM conducts technical evaluations of 
new, revised, and alternative methods with regulatory applicability and 
promotes the scientific validation and regulatory acceptance of 
toxicological test methods that more accurately assess the safety and 
hazards of chemicals and products and that refine, reduce, or replace 
animal use. The ICCVAM Authorization Act of 2000 (Pub. L. 106-545) 
establishes ICCVAM as a permanent interagency committee of the NIEHS 
under the NICEATM. NICEATM administers the ICCVAM and provides 
scientific and operational support for ICCVAM-related activities. 
NICEATM and ICCVAM work collaboratively to evaluate new and improved 
test methods applicable to the needs of Federal agencies. Additional 
information about ICCVAM and NICEATM can be found at the following Web 
site: http://www.iccvam.niehs.nih.gov.

    Dated: March 7, 2006.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences 
and National Toxicology Program.
 [FR Doc. E6-3763 Filed 3-15-06; 8:45 am]
BILLING CODE 4140-01-P