The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene
elemicin (3,4,5-trimethoxyallylbenzene) in rat and human, based on the PBK models previously developed for the structurally related alkenylbenzenes
estragole,
methyleugenol, and
safrole. Using the newly developed models, the level of metabolic activation of
elemicin in rat and human was predicted to obtain insight in species differences in the bioactivation of
elemicin and read across to the other methoxy
allylbenzenes,
estragole and
methyleugenol. Results reveal that the differences between rat and human in the formation of the proximate carcinogenic metabolite 1'-hydroxyelemicin and the ultimate carcinogenic metabolite 1'-sulfoxyelemicin are limited (<3.8-fold). In addition, a comparison was made between the relative importance of bioactivation for
elemicin and that of
estragole and
methyleugenol. Model predictions indicate that compound differences in the formation of the 1'-sulfoxymetabolites are limited (<11-fold) in rat and human liver. The insights thus obtained were used to perform a risk assessment for
elemicin using the margin of exposure (MOE) approach and read across to the other methoxy
allylbenzene derivatives for which in vivo animal
tumor data are available. This reveals that
elemicin poses a lower priority for risk management as compared to its structurally related analogues
estragole and
methyleugenol. Altogether, the results obtained indicate that PBK modeling provides an important insight in the occurrence of species differences in the metabolic activation of
elemicin. Moreover, they provide an example of how PBK modeling can facilitate a read across in risk assessment from compounds for which in vivo toxicity studies are available to a compound for which only limited toxicity data have been described, thus contributing to the development of alternatives for animal testing.