Toxicological safety assessment of essential oils used as food supplements to establish safe oral recommended doses.

Essential oils (EOs) are increasingly consumed as food supplements. The few published recommended doses available generally lack details both on the methodology used and concentration limits for substances of concern, including genotoxic carcinogens. We propose a tiered approach based on the toxicological evaluation of maximized concentrations of each constituent present in the EO investigated. The genotoxic potential of each constituent is assessed using literature data or QSAR analyses. Genotoxic constituents are evaluated according to the methodology provided in the ICHM7 guideline. A Toxicological Reference Value (TRV) is associated to each non-genotoxic constituent, using one of the following methodologies (decision-tree successive steps): extraction from recognized databases or clinical studies, application of adequate safety factors to NOAELs established in animal studies, read-across analyses and when none was possible, TTC of Cramer classes. An EO recommended dose is considered safe when the safety margin (ratio between TRV and systemic exposure) for all constituents is all at least equal to 1. In conclusion, this methodology has proven to be robust to establish safe recommended doses for EOs used as food supplements, consistent with those publicly available, and avoiding unnecessary dedicated new animal testing.