Use of the LLNA for Potency Categorization of Chemicals Causing ACD in Humans

ICCVAM evaluated the use of the murine local lymph node assay (LLNA) for potency categorization of chemicals causing allergic contact dermatitis (ACD) in humans. ICCVAM concluded that the LLNA can be used to categorize substances as strong sensitizers (Globally Harmonized System of Classification and Labelling of Chemicals Subcategory 1A). However, substances that are not identified as strong sensitizers using the LLNA require additional information to categorize them as other than strong sensitizers (Globally Harmonized System of Classification and Labelling of Chemicals Subcategory 1B). Strong sensitizers are those substances considered to have a significant potential for causing hypersensitivity.

Test Method Evaluation Report (June 2011) containing ICCVAM recommendations

Background

For over 10 years, the LLNA has been accepted worldwide as a valid alternative to traditionally accepted guinea pig test methods for assessing ACD hazard potential for most testing situations. However, the use of the LLNA has been limited to a “yes/no” determination of whether or not a substance has the potential to cause ACD in humans.

In January 2007, the U.S. Consumer Product Safety Commission (CPSC) requested that NICEATM and ICCVAM assess the validation status of the LLNA as a stand-alone test method to classify skin-sensitizing chemicals according to potency. The CPSC, under the Federal Hazardous Substances Act, currently only requires products that are considered to be strong skin sensitizers to carry hazard labels warning of ACD hazard potential. Results from tests that could be used to identify potential strong human skin sensitizers would be helpful for the purposes of hazard identification for CPSC and other agencies with an interest in identifying strong skin sensitizers.

Accordingly, NICEATM and ICCVAM evaluated the extent that LLNA results could be used to correctly predict “strong” versus “other than strong” human skin sensitizers. The ICCVAM interagency Immunotoxicity Workgroup (IWG), working with NICEATM, prepared a draft background review document (BRD) and draft recommendations for use of the LLNA for potency categorization of chemicals that cause ACD in humans.

The draft BRD and draft ICCVAM recommendations were reviewed in a public meeting of an international independent scientific peer review panel in March 2008. The peer review panel agreed with ICCVAM that the LLNA can be used as part of a weight-of-evidence evaluation for categorizing skin sensitizers based on potency, although it should not be used as a stand-alone test method for this purpose. The peer review panel also recommended that NICEATM perform additional analyses using alternative approaches that might provide more appropriate thresholds for the human reference data for evaluating the use of the LLNA for potency categorization of human skin sensitizers.

Read peer review panel report (May 2008)

View peer review panel meeting agenda

The final ICCVAM recommendations stating that the LLNA can be used to categorize substances as strong sensitizers are included in the 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. The test method evaluation report also includes an updated ICCVAM-recommended protocol for the LLNA and recommendations for future studies to further evaluate the usefulness and limitations of the LLNA for potency determinations. The final BRD, including the data and analyses on which the recommendations are based, is included as an appendix to the test method evaluation report.

Transmittal of Recommendations to Federal Agencies