[Federal Register Volume 73, Number 58 (Tuesday, March 25, 2008)]
[Notices]
[Pages 15757-15758]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-5936]


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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); Availability 
of the Interagency Coordinating Committee on the Validation of 
Alternative Methods (ICCVAM) Test Method Evaluation Report: In Vitro 
Cytotoxicity Test Methods for Estimating Starting Doses for Acute Oral 
Systemic Toxicity Tests and the Final Background Review Document for In 
Vitro Cytotoxicity Test Methods for Estimating Acute Oral Systemic 
Toxicity; Notice of Transmittal of ICCVAM Test Method Recommendations 
to Federal Agencies

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

ACTION: Availability of ICCVAM Test Method Evaluation Report and Final 
Background Review Document.

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SUMMARY: NICEATM announces availability of the ICCVAM Test Method 
Evaluation Report: In Vitro Cytotoxicity Test Methods for Estimating 
Starting Doses for Acute Oral Systemic Toxicity Tests (NIH Publication 
07-4519). The report describes two in vitro basal cytotoxicity neutral 
red uptake (NRU) test methods that can be used for estimating starting 
doses for acute oral toxicity tests. The report includes ICCVAM's (a) 
final test method recommendations on the use of these two test methods, 
(b) recommended test method protocols for future use, (c) 
recommendations for future studies to further characterize the 
usefulness and limitations of in vitro methods for assessing acute 
systemic toxicity, and (d) recommended performance standards for tests 
with similar scientific principles and that measure or predict acute 
oral systemic toxicity. The report recommends the use of these methods 
in a weight-of-evidence approach to determine starting doses for acute 
oral systemic toxicity tests with rodents. The report also recommends 
that these in vitro test methods be considered before using animals for 
acute oral systemic toxicity testing and used when determined 
appropriate.
    NICEATM also announces the availability of the final Background 
Review Document: In Vitro Cytotoxicity Test Methods for Estimating 
Acute Oral Systemic Toxicity (BRD) (NIH Publication 07-4518). The BRD 
provides data and analyses from a collaborative international 
validation study organized by NICEATM and the European Centre for the 
Validation of Alternative Methods (ECVAM) to evaluate the usefulness 
and limitations of two in vitro basal cytotoxicity NRU test methods 
using either BALB/c 3T3 mouse fibroblasts (3T3) or primary human 
epidermal keratinocytes (NHK) for estimating acute oral rodent 
toxicity.
    Electronic copies of the ICCVAM Test Method Evaluation Report and 
the BRD are available from the ICCVAM/NICEATM Web site at http://iccvam.niehs.nih.gov or by contacting NICEATM (see FOR FURTHER 
INFORMATION CONTACT). The ICCVAM Test Method Evaluation Report and the 
final BRD have been forwarded to U.S. Federal agencies for regulatory 
and other acceptance considerations where applicable. Responses will be 
posted on the ICCVAM/NICEATM Web site as they are received.

FOR FURTHER INFORMATION CONTACT: Dr. William S. Stokes, Director, 
NICEATM, 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, NIEHS, 79 T.W. 
Alexander Drive, Building 4401, Room 3128, Research Triangle Park, NC 
27709.

SUPPLEMENTARY INFORMATION: 

Background

    In 2002, NICEATM and ECVAM initiated a collaborative, 
international, multi-laboratory validation study to independently 
evaluate the usefulness of the 3T3 and NHK NRU basal cytotoxicity test 
methods for estimating acute oral rodent toxicity and for estimating 
starting doses for in vivo rodent acute oral toxicity tests. The 3T3 
and NHK NRU test methods were evaluated with 72 reference substances. 
Once the study was completed in January 2005, NICEATM prepared a draft 
BRD that contained comprehensive summaries of the data generated in the 
validation study, analyses of the relevance and reliability of the two 
test methods, and simulation analyses of the refinement (i.e., to 
lessen or avoid pain and distress) and reduction in animal use that 
might occur if these tests were used as adjuncts to two acute oral 
toxicity test methods (i.e., the Up-and-Down Procedure and the Acute 
Toxic Class method). The draft BRD was released for public comment on 
March 21, 2006 (Federal Register, Vol. 71, No. 54, pp. 14229-14231).
    On May 23, 2006, NICEATM, on behalf of ICCVAM, convened an 
independent, scientific peer review panel meeting to review the draft 
BRD and evaluate the validation status of the 3T3 and NHK NRU test 
methods for determining starting doses for in vivo acute oral systemic 
toxicity tests. The peer review panel's report was released in July 
2006 (Federal Register, Vol. 71, No. 132, pp. 39122-39123). At a public 
teleconference meeting on August 3, 2006 (Federal Register, Vol. 71, 
No. 132, pp. 39121-39122), the Scientific Advisory Committee on 
Alternative Toxicological Methods (SACATM) reviewed and endorsed the 
conclusions of the peer review panel (minutes from the teleconference 
are available at http://ntp.niehs.nih.gov/files/SACATMAug06MinutesVF081506.pdf).
    ICCVAM considered the peer panel report, public comments, SACATM 
comments, and the draft BRD in finalizing its recommendations on the 
use of these two in vitro basal cytotoxicity test methods for 
estimating starting doses for acute oral systemic toxicity tests. The 
ICCVAM Test Method Evaluation Report includes the ICCVAM

[[Page 15758]]

recommendations on the use of the two in vitro NRU test methods, as 
well as recommended test method protocols, recommendations for future 
studies to further characterize the usefulness and limitations of in 
vitro methods for assessing acute systemic toxicity, recommended 
performance standards for tests with similar scientific principles and 
that measure or predict acute oral systemic toxicity, the peer panel 
report and Federal Register notices. The final BRD, which provides the 
supporting documentation for this report, is available as a separate 
document. The ICCVAM Test Method Evaluation Report and the supporting 
final BRD were forwarded to U.S. Federal agencies for their 
consideration for regulatory acceptance as required by the ICCVAM 
Authorization Act of 2000 (42 U.S.C. 285l-3). Agencies' responses to 
the test method recommendations will be posted on the ICCVAM/NICEATM 
Web site as they are received.

Background Information on ICCVAM, NICEATM, and SACATM

    ICCVAM is an interagency committee composed of representatives from 
15 Federal regulatory and research agencies that use, generate, or 
disseminate 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, and replace animal use. The ICCVAM Authorization Act of 2000 
established ICCVAM as a permanent interagency committee of the NIEHS 
under NICEATM. NICEATM administers 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 on their Web site 
(http://iccvam.niehs.nih.gov).
    SACATM was established January 9, 2002, and is composed of 
scientists from the public and private sectors (Federal Register, Vol. 
67, No. 49, page 11358). SACATM provides advice to the Director of the 
NIEHS, to ICCVAM, and to NICEATM regarding the statutorily mandated 
duties of ICCVAM and activities of NICEATM. Additional information 
about SACATM, including the charter, roster, and records of past 
meetings, can be found at http://ntp.niehs.nih.gov/ see ``Advisory 
Board & Committees'' (or directly at http://ntp.niehs.nih.gov/go/167).

    Dated: March 14, 2008.
Samuel H. Wilson,
Acting Director, National Institute of Environmental Health Sciences 
and National Toxicology Program.
 [FR Doc. E8-5936 Filed 3-24-08; 8:45 am]
BILLING CODE 4140-01-P