Safrole has been demonstrated to be carcinogenic in rodent bioassays at high doses of the pure compound. The use of pure safrole in foods has already been prohibited. Therefore, the main exposure to safrole occurs mainly from consumption of safrole-containing spices especially mace or nutmeg and from foods to which these spices are added.
Translation of cancer risk from the animal data to humans at relevant dietary intake levels needs a better understanding of species-, dose-, interindividual- and matrix dependent in bioactivation and detoxification of safrole. Physiologically based biokinetic model can facilitate this translation. To integrate the food matrix dependent modulation of safrole bioactivation in the risk assessment of safrole, the Margin of Exposure (MOE) approach can be used. When safrole would be tested in rodents in the presence of a matrix containing sulfotransferase inhibitors the MOE values would be higher and the need for risk management actions would be lower.