[Federal Register Volume 71, Number 54 (Tuesday, March 21, 2006)]
[Notices]
[Pages 14229-14231]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-4075]


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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); Announcement 
of an Independent Scientific Peer Review Meeting on the Use of In Vitro 
Testing Methods for Estimating Starting Doses for Acute Oral Systemic 
Toxicity Tests and Request for Comments

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

ACTION: Meeting Announcement and Request for Comment.

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SUMMARY: NICEATM in collaboration with the Interagency Coordinating 
Committee on the Validation of Alternative Methods (ICCVAM) announces a 
public, independent, scientific peer review meeting to evaluate the 
validation status of the in vitro 3T3 and normal human keratinocyte 
(NHK) neutral red uptake (NRU) basal cytotoxicity test methods for 
estimating starting doses for in vivo acute oral toxicity tests. These 
two in vitro cytotoxicity test methods are proposed as adjuncts to the 
in vivo acute oral toxicity tests to refine (i.e., to lessen or avoid 
pain and distress) and/or reduce animal use. At this meeting, a 
scientific peer review panel (``Panel'') will peer review the 
background review document (BRD) on the 3T3 and NHK cytotoxicity test 
methods, evaluate the extent that the BRD addresses established 
validation and acceptance criteria, and provide comment on the draft 
ICCVAM recommendations on the proposed use of these test methods, draft 
test method protocols, and draft performance standards. NICEATM 
requests public comments on the BRD, draft ICCVAM test method 
recommendations, draft test method protocols, and draft performance 
standards.

DATES: The meeting will be held on May 23, 2006, from 8:30 a.m. to 5 
p.m. The meeting is open to the public with attendance limited only by 
the space available. In order to facilitate planning for this meeting, 
persons wishing to attend the meeting are asked to register via the 
ICCVAM/NICEATM Web site (http://iccvam.niehs.nih.gov) by May 12, 2006.

ADDRESSES: The meeting will be held at the National Institutes of 
Health (NIH), Natcher Conference Center, 45 Center Drive, Bethesda, MD 
20892.

FOR FURTHER INFORMATION CONTACT: Correspondence should be sent by mail, 
fax, or email 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], Courier 
address: NICEATM, 79 T.W. Alexander Drive, Building 4401, Room 3128, 
Research Triangle Park, NC 27709.

SUPPLEMENTARY INFORMATION:

Background

    In September 2001, ICCVAM recommended that in vitro basal 
cytotoxicity test methods be considered as tools for estimating 
starting doses for in vivo acute systemic toxicity studies (Federal 
Register Vol. 66, No. 189, pp. 49686-7, September 28, 2001). The 
recommendations were based on the Report of the International Workshop 
on In Vitro Methods for Assessing Acute Systemic Toxicity (ICCVAM, 
2001a). The Guidance Document on Using In Vitro Data to Estimate In 
Vivo Starting Doses for Acute Toxicity (ICCVAM, 2001b) was also made 
available at that time. The guidance document provided standard 
procedures for two in vitro basal cytotoxicity test methods and 
instructions for using these test methods to estimate starting doses 
for in vivo testing.

[[Page 14230]]

    U.S. Federal agencies' responses to the ICCVAM recommendations from 
the International Workshop were announced in 2004 (Federal Register 
Vol. 69, No. 47, pp. 11448-9, March 10, 2004). The U.S. Federal 
agencies agreed to encourage, to the extent applicable, the use of in 
vitro tests for determining starting doses for acute oral systemic 
toxicity testing. Furthermore, the U.S. Environmental Protection Agency 
(EPA) specifically encouraged those participating in the High 
Production Volume Challenge Program to consider using the recommended 
in vitro test methods as a supplemental component when conducting any 
new in vivo acute oral toxicity studies for the program (http://www.epa.gov/chemrtk/toxprtow.htm).
    In 2002, NICEATM and the European Committee on the Validation of 
Alternative Methods began a collaborative validation study to 
independently evaluate the usefulness of two in vitro basal 
cytotoxicity test methods proposed for estimating starting doses for in 
vivo rodent acute oral toxicity tests. In vitro NRU cytotoxicity test 
methods using either BALB/c 3T3 fibroblasts, a mouse cell line, or NHK 
cells, primary human epidermal cells, were evaluated in a multi-
laboratory international validation study. During the pre-validation 
phases of the study, the test method protocols were standardized 
further and revised to improve their intra- and inter-laboratory 
reproducibilities. NICEATM recommended using the revised test method 
protocols (Federal Register, Vol. 69, No. 201, pp. 61504-5, October 19, 
2004) rather than the standard procedures outlined in the guidance 
document (ICCVAM, 2001b). During the validation study, 72 reference 
chemicals were tested using the 3T3 and NHK NRU test methods. The in 
vitro NRU cytotoxicity test results were used to estimate acute oral 
LD50 values, which in turn were used to identify the 
starting doses for simulated acute oral toxicity testing using the Up-
and-Down Procedure (UDP; EPA 2002; OECD 2001a) and the Acute Toxic 
Class method (ATC; OECD 2001b). The in vivo test simulations were used 
to compare the number of animals used and the number of deaths expected 
to occur when starting with the default starting doses versus using a 
starting dose based on in vitro cytotoxicity data.
    To assist in an evaluation of the usefulness of these two in vitro 
NRU basal cytotoxicity test methods for estimating starting doses for 
in vivo. acute oral toxicity tests, NICEATM requested the submission of 
existing in vivo and in vitro acute toxicity data (Federal Register, 
Vol. 69, No. 201, pp. 61504-5, October 19, 2004 and Vol. 65, No. 115, 
pp. 37400-3, June 14, 2000). In 2005, NICEATM announced a request for 
nominations of scientists to serve on the Panel and again requested 
existing in vivo and in vitro data (Federal Register Vol. 70, No. 54, 
pp. 14473-4, March 22, 2005).

Expert Panel Meeting

    The purpose of this meeting is the scientific peer review 
evaluation of the validation status of the 3T3 and NHK NRU basal 
cytotoxicity test methods to determine starting doses for the UDP and 
ATC acute oral toxicity test methods in order to refine and reduce the 
use of animals. The Panel will first peer review the BRD on the 3T3 and 
NHK cytotoxicity test methods and then evaluate the extent that the 
BRDs address established validation and acceptance criteria (Validation 
and Regulatory Acceptance of Toxicological Test Methods: A Report of 
the ad hoc Interagency Coordinating Committee on the Validation of 
Alternative Methods, NIH Publication No. 97-3981, http://iccvam.niehs.nih.gov). The Panel will also be asked to provide comment 
on the draft ICCVAM test method recommendations, draft standardized 
test method protocols, and draft performance standards. Information 
about the Panel meeting, including a roster of the members of the Panel 
and the agenda, will be made available two weeks prior to the meeting 
on the ICCVAM/NICETATM Web site (http://iccvam.niehs.nih.gov) or can be 
obtained after that date by contacting NICEATM (see FOR FURTHER 
INFORMATION CONTACT above).

Attendance and Registration

    The public Panel meeting will take place May 23, 2006, at the NIH 
Campus, Natcher Conference Center, Bethesda, MD (a map of the NIH 
Campus and other visitor information are available at http://www.nih.gov/about/visitor/index.htm). The meeting will begin at 8:30 
a.m. and conclude at approximately 5 p.m. Persons needing special 
assistance, such as sign language interpretation or other reasonable 
accommodation in order to attend, should contact 919-541-2475 voice, 
919-541-4644 TTY (text telephone), through the Federal TTY Relay System 
at 800-877-8339, or by e-mail to [email protected]. Requests 
should be made at least seven business days in advance of the event.

Availability of the BRD and Draft ICCVAM Recommendations

    NICEATM prepared a BRD on the 3T3 and NHK NRU basal cytotoxicity 
test methods that contains comprehensive summaries of the data 
generated in the validation study, an analysis of the accuracy and 
reliability of the two test methods, a simulation analysis of the 
refinement and reduction in animal use that would occur if these tests 
were used as adjuncts to the UDP and ATC acute oral systemic toxicity 
test methods, and related information characterizing the validation 
status of these assays. The BRD, draft ICCVAM test method 
recommendations, draft test method protocols, and draft test method 
performance standards will be provided to the Panel and made available 
to the public. Copies of these materials can be obtained from the 
ICCVAM/NICEATM Web site (http://iccvam.niehs.nih.gov) or by contacting 
NICEATM (see FOR FURTHER INFORMATION CONTACT above).

Request for Comments

    NICEATM invites the submission of written comments on the BRD, 
draft ICCVAM test method recommendations, draft test method protocols, 
and draft test method performance standards. When submitting written 
comments, it is important to refer to this Federal Register notice and 
include appropriate contact information (name, affiliation, mailing 
address, phone, fax, email and sponsoring organization, if applicable). 
Written comments should be sent by mail, fax, or email to Dr. William 
Stokes, Director of NICEATM, at the address listed above not later than 
May 5, 2006. All comments received will be placed on the ICCVAM/NICEATM 
website and made available to the Panel, ICCVAM agency representatives, 
and attendees at the meeting.
    This meeting is open to the public and time will be provided for 
the presentation of public oral comments at designated times during the 
peer review. Members of the public who wish to present oral statements 
at the meeting (one speaker per organization) should contact NICEATM 
(see FOR FURTHER INFORMATION CONTACT above) no later than May 12, 2006. 
Speakers will be assigned on a consecutive basis and up to seven 
minutes will be allotted per speaker. Persons registering to make 
comments are asked to provide a written copy of their statement by May 
12, 2006, so that copies can be distributed to the Panel prior to the 
meeting or if this is not possible to bring 40 copies to the meeting. 
Written statements can supplement and expand the oral presentation. 
Each speaker is asked to

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provide contact information (name, affiliation, mailing address, phone, 
fax, email and sponsoring organization, if applicable) when registering 
to make oral comments.
    Summary minutes and a final report of the Panel will be available 
following the meeting at the ICCVAM/NICEATM Web site (http://iccvam.niehs.nih.gov). ICCVAM will consider the conclusions and 
recommendations from the Panel and any public comments received in 
finalizing test method recommendations and performance standards for 
these test methods.

Background Information on ICCVAM and NICEATM

    ICCVAM is an interagency committee composed of representatives from 
15 U.S. 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 while refining (less pain and 
distress), reducing, and replacing animal use. The ICCVAM Authorization 
Act of 2000 (Pub. L. 106-545, available at http://iccvam.niehs.nih.gov/about/PL106545.htm) 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 U.S. Federal 
agencies. Additional information about ICCVAM and NICEATM can be found 
at the ICCVAM/NICEATM Web site: http://iccvam.niehs.nih.gov.

References

EPA. 2002a. Health Effects Test Guidelines OPPTS 870.1100 Acute Oral 
Toxicity. EPA 712-C-02-190. Washington, DC: U.S. Environmental 
Protection Agency.
ICCVAM. 2001a. Report of the international workshop on in vitro 
methods for assessing acute systemic toxicity. NIH Publication 01-
4499. Research Triangle Park, NC: National Institute for 
Environmental Health Sciences. Available at: http://iccvam.niehs.nih.gov/.
ICCVAM. 2001b. Guidance document on using in vitro data to estimate 
in vivo starting doses for acute toxicity. NIH Publication 01-4500. 
Research Triangle Park, NC: National Institute for Environmental 
Health Sciences. Available at: http://iccvam.niehs.nih.gov/. OECD. 
2001a. Guideline for Testing of Chemicals, 425, Acute Oral 
Toxicity--Up-and-Down Procedure. Paris France: OECD. Available at: 
http://www.oecd.org [accessed June 2, 2004]. OECD. 2001b. Guideline 
For Testing of Chemicals, 423, Acute Oral Toxicity--Acute Toxic 
Class Method. Paris France: OECD.

    Dated: March 9, 2006.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences 
and National Toxicology Program.
 [FR Doc. E6-4075 Filed 3-20-06; 8:45 am]
BILLING CODE 4140-01-P