Hazard identification of strong dermal sensitizers

Abstract

Dermal reactions are the most frequently reported chemical health-related occupational hazard. Identifying dermal sensitizers is important for improving workplace safety. This paper takes a close look at the physico-chemical properties and results from the Local Lymph Node Assay (LLNA) to better understand and predict potent dermal sensitizers. The LLNA was used to identify 28 pharmaceutical agents or chemical intermediates as potent dermal sensitizers, EC3 < 1%. Certain parameters were examined to determine if there was any predictability to identify potent dermal sensitizers. These included a computer structure activity analysis using Derek^® for Windows, molecular weight (Mw), calculated log P, and the log-linear extrapolation approach for estimating the potency. With Derek^® for Windows, 13 compounds were identified as negative and 15 as positive for structural alerts, the most common being haloalkanes, and hydrazines. Additional mechanisms of reactivity were postulated for the remaining compounds. The examination of the Mw showed that all molecules had Mw < 550 Da. For 21 compounds, the interpolated vs extrapolated methods for determining the EC3 value were compared. For eight of the 21 compounds, the extrapolated EC3 was in the correct order of magnitude, eight were incorrect (five were too high and three were too low) and five could not be calculated. The use of a tiered approach including examination of the structural and physico-chemical properties and the LLNA to identify potent dermal sensitizers is integral in the selection of effective safe handling guidance to protect from sensitization hazards.

Keywords::

• Local lymph node assay
• structure activity relationship
• dermal sensitization
• haloalkane
• hydrazine

Acknowledgements

We thank David Brandwene, Dr Robert Feldman, and Dr Caren Villano for their in-depth review and comments on the manuscript. We also thank Dr Wendy Luo and Nicholas Roden for their comments.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.