[Federal Register Volume 74, Number 188 (Wednesday, September 30, 2009)]
[Notices]
[Pages 50212-50213]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-23534]


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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: The Reduced 
Murine Local Lymph Node Assay, an Alternative Test Method Using Fewer 
Animals To Assess the Allergic Contact Dermatitis Potential of 
Chemicals and Products; Availability of ICCVAM Recommended Murine Local 
Lymph Node Assay Performance Standards; Notice of Transmittal to 
Federal Agencies of ICCVAM Test Method Recommendations for the Reduced 
Murine Local Lymph Node Assay, Updated Murine Local Lymph Node Assay 
Test Method Protocol, and Murine Local Lymph Node Assay Test Method 
Performance Standards

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

ACTION: Availability of ICCVAM Test Method Evaluation Report (TMER) and 
Recommended Test Method Performance Standards; Notice of Transmittal.

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SUMMARY: NICEATM announces availability of the ICCVAM Test Method 
Evaluation Report: The Reduced Murine Local Lymph Node Assay: An 
Alternative Test Method Using Fewer Animals to Assess the Allergic 
Contact Dermatitis Potential of Chemicals and Products (NIH Publication 
09-6439). The TMER provides ICCVAM's evaluation and recommendations for 
the reduced Murine Local Lymph Node Assay (rLLNA) test method as a 
reduction alternative that uses fewer animals compared to the 
traditional Murine Local Lymph Node Assay (LLNA) for assessing the 
potential of test substances to cause allergic contact dermatitis 
(ACD). The report includes ICCVAM's recommendations on (a) the 
usefulness and limitations of the rLLNA, (b) an updated ICCVAM LLNA 
test method protocol, which includes the procedures for conducting the 
rLLNA, (c) future studies to further characterize the usefulness and 
limitations of the rLLNA, and (d) rLLNA test method performance 
standards. The TMER includes the report of an international independent 
scientific peer review panel (hereafter, Panel) and the final rLLNA 
background review document (BRD). The BRD provides the data and 
analyses used to evaluate the current validation status of the rLLNA 
test method for assessing the ACD potential of chemicals and products. 
ICCVAM concluded that the scientific validity of the rLLNA has been 
adequately evaluated and that the performance of the rLLNA, when 
conducted in accordance with the ICCVAM-recommended LLNA test method 
protocol, is sufficient to distinguish between skin sensitizers and 
non-sensitizers. ICCVAM also concluded that the rLLNA would reduce 
animal use by 40% for each test compared to the traditional, multi-dose 
LLNA. Accordingly, ICCVAM recommends that the rLLNA test method should 
be routinely considered before conducting the traditional, multi-dose 
LLNA, and used where appropriate as the initial test to determine the 
potential of chemicals and products to produce ACD. For testing 
situations that require dose-response information, rLLNA-positive 
substances will need to be tested with the traditional multi-dose LLNA. 
This testing should be done using the updated ICCVAM-recommended test 
method protocol, which reduces animal use by 20% compared to the 
original ICCVAM-recommended test method protocol by decreasing the 
minimum number of animals per dose group from five to four.
    NICEATM also announces availability of the ICCVAM Recommended 
Performance Standards: Murine Local Lymph Node Assay (NIH Publication 
09-7357). The ICCVAM recommends that LLNA test method performance 
standards can be used to efficiently evaluate the validity of modified 
versions of the LLNA that are mechanistically and functionally similar 
to the traditional LLNA. The traditional LLNA test method is the 
reference test method used as the basis for establishing the LLNA 
performance standards. The performance standards specify the essential 
test method components that must be included in a modified LLNA in 
order to use the performance standards to evaluate the validity of the 
modified test method. The performance standards also specify a minimum 
list of reference substances to evaluate the accuracy and reliability 
of the modified test method, and the accuracy and reliability values 
that must be achieved in order for the modified test method to be 
considered equal to or better than the traditional LLNA.
    Electronic copies of the ICCVAM rLLNA TMER and the report on 
ICCVAM-recommended LLNA performance standards are available from the 
NICEATM-ICCVAM Web site at http://iccvam.niehs.nih.gov or by contacting 
NICEATM (see FOR FURTHER INFORMATION CONTACT). The two reports have 
been forwarded to U.S. Federal agencies for regulatory and other 
acceptance considerations, where applicable. Responses will be posted 
on the NICEATM-ICCVAM website as they are received.

FOR FURTHER INFORMATION CONTACT: Dr. William S. Stokes, Director, 
NICEATM, NIEHS, P.O. Box 12233, Mail Stop: K2-16, Research Triangle 
Park, NC 27709, (telephone) 919-541-2384, (fax) 919-541-0947, (e-mail) 
[email protected]. Courier address: NICEATM, NIEHS, Room 2034, 530 
Davis Drive, Morrisville, NC 27560.

SUPPLEMENTARY INFORMATION: 

Background

    The U.S. Consumer Product Safety Commission (CPSC) nominated 
several new versions and applications of the LLNA to ICCVAM in 2007 for 
evaluation of their scientific validity (http://iccvam.niehs.nih.gov/methods/immunotox/llnadocs/CPSC_LLNA_nom.pdf). The nomination 
requested that ICCVAM assess the validation status of: (1) the LLNA 
limit dose procedure (i.e., the rLLNA); (2) three modified LLNA test 
method protocols that do not require the use of radioactive materials; 
(3) the use of the LLNA to test mixtures, aqueous solutions, and metals 
(applicability domain for the LLNA); and (4) the use of the LLNA to 
determine ACD potency categories for hazard classification. NICEATM 
published a Federal Register notice (72 FR 27815) requesting public 
comments on the appropriateness and relative priority of the CPSC-
nominated LLNA activities, the development of test method performance 
standards for the LLNA, the nomination of scientists to serve on the 
Panel, and the submission of data from LLNA testing that related to the 
CPSC-nominated LLNA activities, as well as corresponding data from 
human and other animal studies. After considering public comments and 
comments from the Scientific Advisory Committee on Alternative 
Toxicological

[[Page 50213]]

Methods (SACATM), ICCVAM unanimously endorsed the nomination with a 
high priority. ICCVAM and NICEATM began evaluation activities and also 
initiated development of proposed test method performance standards for 
the LLNA since these had not previously been developed (http://iccvam.niehs.nih.gov/methods/immunotox/immunotox.htm). NICEATM and 
ICCVAM compiled a comprehensive draft BRD on the rLLNA test method and 
a draft test method performance standards document for the LLNA and 
released them for public comment in January 2008 (73 FR 1360).
    NICEATM and ICCVAM convened the Panel at a meeting on March 4-6, 
2008, to review the draft BRDs and evaluate the validation status of 
the proposed test methods and applications. The Panel also reviewed the 
extent that the information contained in the draft BRDs supported draft 
ICCVAM test method recommendations for test method uses and 
limitations, updated standardized test method protocols, and proposed 
future studies. The Panel reviewed the draft ICCVAM LLNA test method 
performance standards for their adequacy for assessing the accuracy and 
reliability of test method protocols that are based on similar 
scientific principles and that measure the same biological effect as 
the traditional LLNA. The Panel considered public comments made at the 
meeting as well as public comments submitted in advance of the meeting, 
before concluding their deliberations. The Panel's report was made 
available in May 2008 (73 FR 29136) for public comment. The draft 
ICCVAM BRDs, draft ICCVAM test method recommendations, draft ICCVAM 
LLNA test method performance standards, the Panel's report, and all 
public comments were made available to the SACATM for comment on June 
18-19, 2008 (73 FR 25754).
    ICCVAM considered the Panel's report, all public comments, and 
SACATM comments in finalizing its recommendations for the rLLNA, the 
updated LLNA test method protocol, and LLNA test method performance 
standards. ICCVAM has forwarded its test method recommendations to U.S. 
Federal agencies for consideration, in accordance with the ICCVAM 
Authorization Act of 2000 (42 U.S.C. 285l-3(e)(4)). Agency responses to 
the ICCVAM test method recommendations will be made available on the 
NICEATM-ICCVAM 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://www.iccvam.niehs.nih.gov).
    SACATM was established January 9, 2002, and is composed of 
scientists from the public and private sectors (67 FR 11358). SACATM 
provides advice to the Director of the NIEHS, ICCVAM, and 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/go/167.

    Dated: September 22, 2009.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. E9-23534 Filed 9-29-09; 8:45 am]
BILLING CODE 4140-01-P