The ICH guideline on the assessment of mutagenic impurities in pharmaceuticals was recently updated, with the addition of an addendum. In this addendum, included as Appendix 3 in the final version adopted in May, acceptable intakes (AIs) or permissible daily exposures (PDEs) have been derived for a set of carcinogens (including both mutagens and non-genotoxic carcinogens) that are common in pharmaceutical manufacturing. AIs or PDEs have been derived for the following genotoxic carcinogens by linear extrapolation of the TD50 (the dose causing tumours in 50% of experimental animals exposed for their lifetime):

  • acrylonitrile
  • benzyl chloride
  • bis(chloromethyl) ether
  • 1-chloro-4-nitrobenzene
  • p-cresidine
  • dimethylcarbamoyl chloride
  • ethyl chloride
  • glycidol
  • hydrazine
  • methyl chloride

AIs/PDEs have also been derived for the following carcinogens:

  • aniline and aniline HCl, based on a threshold mode of action (haemosiderosis)
  • p-chloroaniline and p-chloroaniline HCl, based on liver tumours for which a mutagenic mode of action cannot be ruled out
  • dimethyl sulfate, for which carcinogenicity data are available but insufficient to derive an AI, and for which the threshold of toxicological concern (TTC) default value has been used
  • hydrogen peroxide, based on 1% of estimated endogenous production

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2017). Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. M7(R1). Current Step 4 version. 31 March 2017.


The above items were taken from the August 2017 issue of Toxicology and Regulatory News which is sent automatically to members of bibra.

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