[Federal Register Volume 76, Number 145 (Thursday, July 28, 2011)]
[Notices]
[Pages 45254-45256]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-18639]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Report and Recommendations on the Usefulness and Limitations of 
the Murine Local Lymph Node Assay for Potency Categorization of 
Chemicals Causing Allergic Contact Dermatitis in Humans

AGENCY: Division of the National Toxicology Program (DNTP), National 
Institute of Environmental Health Sciences (NIEHS), National Institutes 
of Health (NIH), HHS.

ACTION: Availability of Report and Recommendations; Notice of 
Transmittal.

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SUMMARY: The NTP Interagency Center for the Evaluation of Alternative 
Test Methods (NICEATM) announces availability of an Interagency 
Coordinating Committee on the Validation of Alternative Methods 
(ICCVAM) test method evaluation report (TMER) that includes 
recommendations on the usefulness and limitations of the local lymph 
node assay (LLNA) for categorizing the potency of substances with the 
potential to cause allergic contact dermatitis (ACD) as strong skin 
sensitizers. Strong skin sensitizers are substances considered to have 
a significant potential for causing ACD.
    ICCVAM recommends that a specific potency criterion for positive 
results from ACD safety testing using the LLNA can be used to further 
categorize some chemicals and products as strong skin sensitizers. 
However, since this criterion only identified approximately half of 
strong human skin sensitizers, ICCVAM concluded that failure to meet 
this criterion cannot be used as the basis for determining that a 
substance is not a strong skin sensitizer. Therefore, the potency 
criterion should only be used in a screening approach where chemicals 
that meet the criterion could be categorized as strong skin 
sensitizers, but chemicals that do not meet the criterion would require 
additional testing or information to determine that they are not strong 
skin sensitizers.
    The report and recommendations have been transmitted to Federal 
agencies for their review and response to ICCVAM in accordance with the 
provisions of the ICCVAM

[[Page 45255]]

Authorization Act of 2000 (42 U.S.C. 285l-2).

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

    In 1999, ICCVAM evaluated the validation status of the LLNA as a 
stand-alone alternative test method to the guinea pig maximization test 
(GPMT) and the Buehler test (BT) for assessing the ACD hazard potential 
of products and chemicals (NIH Publication No. 99-4494; http://iccvam.niehs.nih.gov/methods/immunotox/llna_PeerPanel98.htm). Based on 
this evaluation, ICCVAM recommended the LLNA as a valid substitute for 
traditional guinea pig test methods for most testing situations. The 
U.S. Environmental Protection Agency, the U.S. Food and Drug 
Administration, and the U.S. Consumer Product Safety Commission (CPSC) 
subsequently accepted the method as a valid substitute for the GPMT and 
BT. The Organisation for Economic Co-operation and Development (OECD) 
also adopted the LLNA as OECD Test Guideline 429 in 2002. Using the 
LLNA instead of guinea pig tests reduces and refines (decreases or 
eliminates pain and distress) animal use for ACD safety testing.
    In 2007, the CPSC nominated several new versions and applications 
of the LLNA to ICCVAM for evaluation of their scientific validity for 
regulatory testing purposes (http://iccvam.niehs.nih.gov/methods/immunotox/llnadocs/CPSC_LLNA_nom.pdf). The nomination requested that 
ICCVAM assess (1) the validation status of the LLNA limit dose 
procedure (i.e., the reduced LLNA); (2) the 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; and 
(4) the use of the LLNA as a stand-alone assay to determine ACD potency 
categories for hazard classification and labeling. NICEATM published a 
Federal Register notice (72 FR 27815) requesting public comments on (1) 
The appropriateness and relative priority of the CPSC-nominated LLNA 
activities, (2) the nomination of scientists to serve on an 
international independent scientific peer review panel, and (3) 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. ICCVAM assigned these activities a high priority after 
considering comments from the public and endorsement from the 
Scientific Advisory Committee on Alternative Toxicological Methods 
(SACATM). NICEATM and ICCVAM compiled comprehensive draft background 
review documents (BRDs), released them for public comment in January 
2008 (73 FR 1360), and convened a public meeting of the panel on March 
4-6, 2008, to peer review the draft documents. The panel evaluated the 
information in the draft BRDs as to whether it supported draft ICCVAM 
recommendations for (1) Test method usefulness and limitations, (2) 
updated standardized test method protocols, and (3) proposed future 
studies. 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, the panel's report, and all 
public comments were made available to SACATM for comment at its 
meeting on June 18-19, 2008 (73 FR 25754).
    After considering the conclusions and recommendations of the panel, 
comments from SACATM, and public comments, ICCVAM forwarded final 
recommendations for the reduced LLNA (NIH Publication No. 09-6439; 
http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-LD/TMER.htm), LLNA 
performance standards, and the updated LLNA test method protocol (NIH 
Publication No. 09-7357; http://iccvam.niehs.nih.gov/methods/immunotox/llna_PerfStds.htm) to Federal agencies in September 2009 (74 FR 
50212). Agency responses are available on the NICEATM-ICCVAM Web site.
    NICEATM subsequently obtained additional data and/or information 
and revised the draft BRDs for both the traditional and nonradioactive 
LLNA methods. ICCVAM released the revised draft BRDs and the revised 
draft ICCVAM test method recommendations to the public for comment and 
announced a second meeting of the panel (74 FR 8974). The panel 
reconvened in public session on April 28-29, 2009, to review the 
ICCVAM-revised draft documents and to finalize its conclusions and 
recommendations on the current validation status of the nonradioactive 
test methods and the expanded uses of the LLNA for pesticide 
formulations and other products. The panel's report was made available 
for public comment in June 2009 (74 FR 26242). The revised draft ICCVAM 
BRDs, revised draft ICCVAM test method recommendations, the panel's 
report, and all public comments were made available to SACATM for 
comment on June 25-26, 2009 (74 FR 19562).
    After considering the conclusions and recommendations of the panel, 
comments from SACATM, and public comments, along with the 
recommendations of an OECD Expert Consultation on the LLNA convened in 
October and December 2009, ICCVAM finalized and forwarded test method 
recommendations on two nonradioactive versions of the LLNA, LLNA: 5-
Bromo-2'-deoxyuridine-Enzyme-Linked Immunosorbent Assay (BrdU-ELISA) 
(NIH Publication No. 10-7552; http://iccvam.niehs.nih.gov/methods/immunotox/llna-ELISA/TMER.htm) and LLNA: Daicel Adenosine Triphosphate 
(DA) (NIH Publication No. 10-7551; http://iccvam.niehs.nih.gov/methods/immunotox/llna-DA/TMER.htm), and expanded uses of the LLNA for 
pesticide formulations and other products (NIH Publication No. 10-7512; 
http://iccvam.niehs.nih.gov/methods/immunotox/llna-app.htm) to Federal 
agencies in June 2010 (75 FR 37443). Agency responses to these ICCVAM 
test method recommendations are available on the NICEATM-ICCVAM Web 
site.
    The ICCVAM TMER, Usefulness and Limitations of the Murine Local 
Lymph Node Assay for Potency Categorization of Chemicals Causing 
Allergic Contact Dermatitis in Humans (NIH Publication No. 11-7709), 
describes ICCVAM's recommendations for using LLNA test results to 
categorize the potency of some substances identified as having the 
potential to cause ACD in humans as strong skin sensitizers. Strong 
sensitizers are those substances considered to have a significant 
potential for causing hypersensitivity. ICCVAM recommends that a 
specific potency criterion for positive results from ACD safety testing 
using the LLNA can be used to further categorize some chemicals and 
products as strong skin sensitizers. However, since this criterion only 
identified approximately half of the strong human skin sensitizers 
tested, failure to meet this criterion cannot be used as the basis for 
determining that a substance is not a strong skin sensitizer. 
Therefore, the potency criterion should only be used in a screening 
approach where chemicals that meet the criterion

[[Page 45256]]

could be categorized as strong skin sensitizers, but chemicals that do 
not meet the criterion would require additional testing or information 
to determine that they are not strong skin sensitizers.
    The ICCVAM evaluation found that only 52% of the strong human skin 
sensitizers in the validation database would be identified as strong 
skin sensitizers using the LLNA potency criterion in the 2009 United 
Nations Globally Harmonized System of Classification and Labelling of 
Chemicals (GHS). Accordingly, chemicals that do not meet the criterion 
would require additional testing or information to determine that a 
substance is not a strong human skin sensitizer.

Background Information on ICCVAM, NICEATM, and SACATM

    ICCVAM is an interagency committee composed of representatives from 
15 Federal regulatory and research agencies that require, use, 
generate, or disseminate toxicological and safety testing information. 
ICCVAM conducts technical evaluations of new, revised, and alternative 
safety testing methods with regulatory applicability and promotes the 
scientific validation and regulatory acceptance of toxicological and 
safety testing methods that more accurately assess the safety and 
hazards of chemicals and products and that reduce, refine (decrease or 
eliminate pain and distress), or replace animal use. The ICCVAM 
Authorization Act of 2000 (42 U.S.C. 285l-3) established ICCVAM as a 
permanent interagency committee of the NIEHS under NICEATM. NICEATM 
administers ICCVAM, provides scientific and operational support for 
ICCVAM-related activities, and conducts independent validation studies 
to assess the usefulness and limitations of new, revised, and 
alternative test methods and strategies. NICEATM and ICCVAM welcome the 
public nomination of new, revised, and alternative test methods and 
strategies applicable to the needs of U.S. Federal agencies. Additional 
information about NICEATM and ICCVAM can be found on the NICEATM-ICCVAM 
Web site (http://iccvam.niehs.nih.gov).
    SACATM was established in response to the ICCVAM Authorization Act 
[Section 285l-3(d)] and is composed of scientists from the public and 
private sectors (67 FR 11358). SACATM advises ICCVAM, NICEATM, and the 
Director of the NIEHS and NTP regarding statutorily mandated duties of 
ICCVAM and activities of NICEATM. SACATM provides advice on priorities 
and activities related to the development, validation, scientific 
review, regulatory acceptance, implementation, and national and 
international harmonization of new, revised, and alternative 
toxicological test methods. Additional information about SACATM, 
including the charter, roster, and records of past meetings, can be 
found at http://ntp.niehs.nih.gov/go/167.

References

    ICCVAM. 2011. ICCVAM Test Method Evaluation Report: Usefulness and 
Limitations of the Murine Local Lymph Node Assay for Potency 
Categorization of Chemicals Causing Allergic Contact Dermatitis in 
Humans. NIH Publication No. 11-7709. Research Triangle Park, NC: 
National Institute of Environmental Health Sciences. Available at: 
http://iccvam.niehs.nih.gov/methods/immunotox/llna-ELISA/LLNA-pot/TMER.htm.
    ICCVAM. 2010. ICCVAM Test Method Evaluation Report on the Murine 
Local Lymph Node Assay: BrdU-ELISA, a Nonradioactive Alternative Test 
Method to Assess the Allergic Contact Dermatitis Potential of Chemicals 
and Products. NIH Publication No. 10-7552. Research Triangle Park, NC: 
National Institute of Environmental Health Sciences. Available at: 
http://iccvam.niehs.nih.gov/methods/immunotox/llna-ELISA/TMER.htm.
    ICCVAM. 2010. ICCVAM Test Method Evaluation Report on the Murine 
Local Lymph Node Assay: DA, a Nonradioactive Alternative Test Method to 
Assess the Allergic Contact Dermatitis Potential of Chemicals and 
Products. NIH Publication No. 10-7551. Research Triangle Park, NC: 
National Institute of Environmental Health Sciences. Available at: 
http://iccvam.niehs.nih.gov/methods/immunotox/llna-DA/TMER.htm.
    ICCVAM. 2010. ICCVAM Test Method Evaluation Report on Using the 
Murine Local Lymph Node Assay for Testing Pesticide Formulations, 
Metals, Substances in Aqueous Solutions, and Other Products. NIH 
Publication No. 10-7512. Research Triangle Park, NC: National Institute 
of Environmental Health Sciences. Available at: http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-app/TMER.htm.
    ICCVAM. 2009. Recommended Performance Standards: Murine Local Lymph 
Node Assay. NIH Publication No. 09-7357. Research Triangle Park, NC: 
National Institute of Environmental Health Sciences. Available at: 
http://iccvam.niehs.nih.gov/methods/immunotox/llna_PerfStds.htm.
    ICCVAM. 2009. 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 No. 09-6439. Research Triangle 
Park, NC: National Institute of Environmental Health Sciences. 
Available at: http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-LD/TMER.htm.
    ICCVAM. 1999. The Murine Local Lymph Node Assay: A Test Method for 
Assessing the Allergic Contact Dermatitis Potential of Chemicals/
Compounds. The Results of an Independent Peer Review Evaluation 
Coordinated by ICCVAM and NICEATM. NIH Publication No. 99-4494. 
Research Triangle Park, NC: National Institute of Environmental Health 
Sciences. Available at: http://iccvam.niehs.nih.gov/methods/immunotox/llna_PeerPanel98.htm.

    Dated: July 14, 2011.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. 2011-18639 Filed 7-27-11; 8:45 am]
BILLING CODE 4140-01-P