A draft guidance document issued by the European Medicines Agency outlines a stepwise approach to the genotoxicity testing of herbal products, highly complex mixtures of natural substances whose composition will vary depending on extraction technique, harvesting time etc. Where possible, the main constituents should be isolated and identified before undertaking any risk assessment. Step 1 of the testing strategy is the Ames test, with no further testing needed if this is clean. Step 2 is the mouse lymphoma (or other mammalian cell) assay, and is required if mutagenicity has been demonstrated in step 1, and the Ames mutagen is not known. If step 2 is also positive, step 3 is an in vivo test (mouse micronucleus test or other). Risk assessment considerations then come into play. If the herbal preparation contains an identifiable genotoxic compound, the Threshold of Toxicological Concern (TTC) approach may be justified. Under the TTC approach, intake of a genotoxic impurity at 1.5 μg/day is considered to represent an acceptable risk (excess cancer risk of less than 1 in 100,000 over a lifetime) for most pharmaceuticals, and from this threshold value a permitted level in the active substance can be calculated based on the expected daily dose. “The same approach might be considered for genotoxic constituents in herbal substances/preparations, if sufficiently justified by the applicant.”

[European Medicines Agency. Committee on Herbal Medicinal Products (HMPC). Draft guideline on the assessment of genotoxic constituents in herbal substances/preparations. London, 31 October 2007. EMEA/HMPC/107079/2007. Available at on the internet. Comments on this draft should be submitted by 3 March 2008.] {173987}

The above item is taken from the February 2008 issue of Toxicology and Regulatory News which is sent automatically to members of bibra (click here for more details).

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