A 13-week comprehensive toxicity study with adductome analysis demonstrates the toxicity, genotoxicity, and carcinogenicity of the natural flavoring agent elemicin

Elemicin, an alkenylbenzene flavoring, exists naturally in foods, herbs, and spices. Some alkenylbenzenes are hepatotoxic and hepatocarcinogenic in rodents. However, few studies have examined the toxicology of elemicin. In the current study, we comprehensively evaluated the general toxicity, genotoxicity, and carcinogenicity of elemicin using gpt delta rats and DNA adductome analysis. Groups of 10 male F344 gpt delta rats were treated with elemicin by gavage at a dose of 0, 25, 100, or 400 mg/kg bw/day for 13 weeks. Liver weights were significantly increased with histopathological changes in groups receiving 100 mg/kg bw/day or more. Significant increases in serum hepatotoxic parameters were observed in the 400 mg/kg bw/day group. Based on the observed changes in liver weights, 18.6 mg/kg bw was identified as the low benchmark dose. Significant increases in the number and area of glutathione S-transferase placental form-positive foci and gpt mutant frequencies were apparent only in the 400 mg/kg/day group, although elemicin-specific DNA adducts were detected from the lowest dose, suggesting that elemicin exhibited hepatocarcinogenicity in rats only at higher doses. Because elemicin showed no mutagenicity at lower doses, there was an adequate safety margin between the acceptable daily intake and the estimated daily intake of elemicin.