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2.4.7.2 Question 7.2
ОглавлениеWith regard to mutagenic impurities with positive carcinogenicity data (Class 1 impurities), the guideline states that: “Compound‐specific risk assessments to derive acceptable intakes should be applied instead of the TTC‐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 (Note 4).”
| Question | Answer |
|---|---|
| If an Ames positive impurity is subsequently tested in an appropriate in vivo assay and the results are positive, does that support setting compound‐specific impurity limits? | No. in vivo gene mutation assays are currently not validated to directly assess cancer risk because the end point is mutation and not carcinogenicity (i.e. they are used for hazard identification). Results from these tests could identify mode of action and/or direct further testing strategy to complement the available data for a weight of evidence approach. |
The Q&A here clarifies that in vivo mutagenicity data cannot be used to set compound‐specific impurity limits and that the proper methods to determine AIs for mutagenic carcinogens is the linear extrapolation from the TD50 or from the BMDL10 (Benchmark Dose Lower Confidence Limit 10%), as described in Note 4 of the guideline.
