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Within the position paper, genotoxic compounds were split into two categories:

1 1) Genotoxic compounds, for which sufficient evidence existed to support a thresholded mechanism.(A thresholded mechanism is one for which a clearly discernible limit exists below which no significant toxicological effect is observed. Several examples were given within the paper of mechanisms of genotoxicity for which a thresholded mechanism may exist, including, for example, topoisomerase inhibition, inhibition of DNA synthesis, and overload of defense mechanisms.)

2 2) Genotoxic compounds without sufficient evidence for a thresholded mechanism.The position paper stated that such thresholds either were unlikely to exist or would be difficult to prove for DNA‐reactive chemicals.

This categorization of impurities, on the basis of a mechanistic understanding of toxicological action, has remained in place in the finalized ICH M7 guideline, and the belief that DNA‐reactive compounds have no threshold remains widely held. However, as will be explored in a later chapter, there is significant evidence now challenging this for even the most potent of mutagenic carcinogens (Chapter 8).