Potency Values from the Local Lymph Node Assay: Application to Classification, Labelling and Risk Assessment

Building on previous ECETOC work, a new task force was started in mid 2007 with the remit to: determine whether an EC31 potency value derived from the LLNA2 can be used to provide a cut-off criterion for the classification and labelling of both substances and preparations as a skin sensitiser according to the Globally Harmonised System (GHS) and the Dangerous Substances and Dangerous Preparations Directives, and, if confirmed, develop sub-categories based on EC3 values; evaluate the current use of LLNA data in risk assessment approaches for skin sensitisation and propose a rationale for using concentration responses and corresponding no-effect concentrations by taking into account potency considerations.

Building on previous ECETOC work, a new task force was started in mid 2007 with the remit to:determine whether an EC31 potency value derived from the LLNA2 can be used to provide a cut-off criterion for the classification and labelling of both substances and preparations as a skin sensitiser according to the Globally Harmonised System (GHS) and the Dangerous Substances and Dangerous Preparations Directives, and, if confirmed, develop sub-categories based on EC3 values; evaluate the current use of LLNA data in risk assessment approaches for skin sensitisation and propose a rationale for using concentration responses and corresponding no-effect concentrations by taking into account potency considerations.

The report of this task force has been published in December 2008 as Document No. 46.

The conclusion on the first remit is that although skin sensitising chemicals having high EC3 values may represent only relatively low risks for human health, it is currently not possible to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling of substances as R43.

The task force also reviewed classification of contact allergens according to relative potency based on LLNA data. Specifically, the task force considered whether, in the light of developments since the original recommendations were made, there is reason now to revise those recommendations. Following these deliberations the task force concluded that the recommendation made previously for four sub-categories of skin sensitisation potency, i.e. “extreme', “strong', “moderate' and “weak' to reflect differing skin sensitisation potency based on derived EC3 values, is still the most appropriate classification scheme. The corresponding EC3 values are as given in the following table. The recommendations of an expert group of the (former) ECB (European Chemicals Bureau) are also given, although they have, as yet, not been accepted by any regulatory authority. For perspective, also under GHS the binary categorisation of skin sensitisation in the existing legislation remains, with a requirement to only indicate whether a substance is a sensitiser (Category 1) or not.

Concerning classification and labelling of preparations, the task force made recommendations based on the potency of their individual substances, based on their direct testing and based on comparisons with similar preparations. For the first of these, which is likely the most common case, a proposal was made for potency-based cut-off values; the values are given in the next table. Applying those would provide improved classification and labelling compared with what is currently required by the Dangerous Preparations Directive and its amendment. According to the latter, a level of >1% of a skin sensitiser ingredient requires a hazard categorisation of the preparation as a skin sensitiser, irrespective of potency. For a quantity of >0.1% but <1%, the skin sensitising substance has to be declared on the label, even though the preparation is not classified as sensitising.

To address the second remit, the task force reviewed recently published approaches for quantitative risk assessment of skin sensitising chemicals based on the relationship between the calculated exposure to a sensitising chemical and the acceptable exposure level. The first step in the quantitative risk assessment process is to establish a NESIL3. The task force concluded that EC3 values derived from the LLNA are well suited for the determination of a NESIL because the proliferation of cells in draining lymph nodes is related causally and quantitatively to the extent to which skin sensitisation will be acquired (potency).

With these recommendations regarding the use of potency considerations based on EC3 values, the LLNA is not only a component of hazard identification but can also be considered a key component of risk assessment.

1. effective concentration for a stimulation index of 3 in proliferation of lymph node cells; 2. local lymph node assay; 3. no expected sensitisation induction level