Hepatocarcinogenicity of Estragole (1-Allyl-4-methoxybenzene) and 1′-Hydroxyestragole in the Mouse and Mutagenicity of 1′-Acetoxyestragole in Bacteria 2

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Abstract
Approximately 20% of a dose of estragole, a naturally occurring flavoring agent, was excreted in the urine of outbred male CD®-1 mice as a conjugate (presumably the glucuronide) of 1′-hydroxyestragole. Estragole and its 1′-hydroxy metabolite caused significant increases in the incidences of hepatocellular carcinomas in male CD®-1 mice that received the compounds by sc injection at 1–22 days of age. Estragole induced hepatocellular carcinomas by 15 months in 23 and 39% of the mice that received total doses of 4.4 and 5.2 µmoles, respectively, and lived to an age of 12 months or more. Of the 12-month survivors given a total dose of 4.4 µmoles of 1′-hydroxyestragole, 70% developed hepatocellular carcinomas; the incidence in mice that received only the vehicle (trioctanoin) was 12%. Multiple tumors ocurred in 5, 28, 64, and 0%, respectively, of the mice in each of these 4 groups. Of the mice given a total dose of 4.4 µmoles of 1′-hydroxysafrole, 59% developed hepatocellular carcinomas; 39% of the mice bore multiple liver tumors. As previously demonstrated for 1′-acetoxysafrole, 1′-acetoxyestragole and 1′-acetoxy-1-allyl-4-methoxynaphthalene reacted nonenzymatically with guanosine and inosine to form adducts. These electrophilic esters were strongly mutagenic for the Salmonella typhimurium missense mutant TA100. 1′-Acetoxyallylbenzene had little or no activity in either of these tests. Attempts to demonstrate liver-mediated mutagenicity for 1′-hydroxysafrole and 1′-hydroxyestragole in the bacterial test system were unsuccessful.