Subchronic oral toxicity and genotoxicity of Aurantii Fructus Immaturus water extract

Aurantii Fructus Immaturus (AFI) water extract has been utilized in traditional medicine; however, its toxicity data are still lacking. In this study, we evaluated the general and genetic toxicity of the AFI water extract as a project of the Korea National Toxicology Program (KNTP). Naringin and neohesperidin, marker compounds of AFI, contained in the AFI water extract were 7.63 % and 4.51 %, respectively. These levels were higher than AFI powders, which contain about 4 % naringin and 3 % neohesperidin. The acute oral toxicity study in rats, conducted at doses of 2500-10000 mg/kg, demonstrated that the median lethal dose (LD₅₀) of AFI water extract exceeds 10000 mg/kg. Subacute oral toxicity tests at doses up to 5000 mg/kg/day and subchronic toxicity studies conducted over 13 weeks at similar dose ranges showed no treatment-related adverse effects. Thus, the no-observed-adverse-effect level (NOAEL) of AFI water extract in rats was 5000 mg/kg bw/day. Additionally, three genotoxicity assays (bacterial reverse mutation, in vitro chromosomal aberration, and in vivo micronucleus tests) confirmed that the AFI water extract is not genotoxic. These results will provide the toxicity data for the risk assessment of AFI water extract for human consumption.