The ICH M7 Guideline discusses the derivation of Acceptable Intakes (AIs) for mutagenic impurities with positive carcinogenicity data, (Section 7.2.1) and states: “Compound-specific risk assessments to derive acceptable intakes should be applied instead of the TTC-based (Threshold of Toxicological Concern-based) acceptable intakes where sufficient carcinogenicity data exist. For a known mutagenic carcinogen, a compound-specific acceptable intake can be calculated based on carcinogenic potency and linear extrapolation as a default approach. Alternatively, other established risk assessment practices such as those used by international regulatory bodies may be applied either to calculate acceptable intakes or to use already existing values published by regulatory authorities.


In this Addendum to ICH M7, acceptable intakes have been derived for a set of chemicals that are considered to be mutagens and carcinogens and were selected because they are common in pharmaceutical manufacturing, or are useful to illustrate the principles for deriving compound-specific intakes described in ICH M71. Compounds are included in which the primary method used to derive acceptable intakes for carcinogens with a likely mutagenic mode of action is the “default approach” from ICH M7 of linear extrapolation from the calculated cancer potency estimate, the TD50. Compounds are also included which highlight alternative principles to deriving compound-specific intakes.



Posted on the FDA website on 25 September 2015