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It is widely accepted that substances must have a molecular weight (MW)<500 to penetrate effectively through the skin to induce sensitization. Roberts et al. (2012. Contact Dermatitis 68: 32-41) evaluated a data set of 699 substances taken from the TIMES-SS expert system and identified that of the 13 substances with a MW>500, five were sensitizers. This provided good evidence to refute such a MW 500 threshold. While Roberts et al. (2012) made a convincing case that the MW>500 cut-off was not a true requirement for sensitization, the number of counter examples identified were too few to draw any statistical conclusions. This updated analysis systematically interrogated a large repository of sensitization information collected under the EU REACH regulation. A data set of 2904 substances that had been tested for skin sensitization, using guinea pigs and/or mice were collected. The data set contained 197 substances with a MW>500; 33 of these were skin sensitizers. Metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitizers substantiated the original findings. The study also assessed whether the same reaction chemistry principles established for low MW sensitizers applied to chemicals with a MW>500. The existing reaction chemistry considerations were found appropriate to rationalize the sensitization behaviour of the 14 sensitizers with a MW>500. The existence of the MW 500 threshold, based on the widespread misconception that the ability to penetrate efficiently the stratum corneum is a key determinant of skin sensitization potential and potency, was refuted. Copyright (c) 2016 John Wiley & Sons, Ltd.