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Background: Citrus sunki Hort. ex Tanaka peel has been traditionally used as an ingredient in folk medicine due to its therapeutic effects on promotion of splenic health and diuresis as well as relief of gastrointestinal symptoms. Although a growing interest in health-promoting natural products and the development of highly concentrated products have facilitated consumption of C. sunki peel, its safety assessment has not been explored, posing a potential health risk. In this study, we carried out a series of systemic and genetic toxicity tests on fermented C. sunki peel extract (FCPE) to provide the essential information required for safe use in human., Methods: We conducted acute and 90-day repeated oral toxicity studies in Sprague-Dawley rats to evaluate systemic toxicity, and three genotoxicity assays to measure bacterial mutation reversion, cellular chromosome aberration and in vivo micronucleus formation., Results: Single oral administration of FCPE did not cause any clinical signs and lethality in all animals, establishing LD50 to be over 2000 mg/kg BW. Repeated administration of up to 2000 mg/kg BW FCPE for 90 days revealed no test substance-related toxicity as demonstrated in analysis of body weight gain, food/water intake, blood, serum biochemistry, organ weight and histopathology, collectively determining that the no-observable-adverse-effect-level of FCPE is over 2000 mg/kg BW. In addition, we detected no mutagenicity and clastogenicity in FCPE at 5000 μg/plate for the in vitro assays and 2000 mg/kg BW for the in vivo micronucleus test., Conclusion: FCPE did not cause systemic and genetic toxicity in our model systems at the tested dose levels. These results suggest a guideline for safe consumption of C. sunki peel in human.

Paecilomyces tenuipes is entomogenous fungus that is called snow-flake Dongchunghacho in Korea. Although it is widely used in traditional medicines, its safety has not yet been comprehensively investigated. Therefore, the aim of this study was to evaluate the genotoxicity, acute and subchronic toxicity of P. tenuipes. The acute oral LD50 of P. tenuipes extract in rats was estimated to be greater than 2000mg/kg of body weight. In the subchronic study, the oral treatment of rats with 500, 1000 or 2000mg/kg P. tenuipes extract daily for 13weeks did not induce any dose-related changes (body weight, food consumption, clinical observation, urinalysis, hematology, clinical chemistry and organ weight). In contrast, histopathological observation revealed that P. tenuipes extract induced karyomegaly in outer medulla of kidney in all treated rats. Importantly, P. tenuipes extract exerted the mutagenic potential in Ames assay. Since karyomegalic alterations have been known to be associated with carcinogenicity, our finding on the mutagenicity of P. tenuipes extract supports the possibility on the potential involvement of P. tenuipes in carcinogenicity at least partially. In conclusion, the subchronic oral exposure of P. tenuipes may induce kidney abnormality at the concentration higher than 500mg/kg body weight, although further studies using other animal models are needed to identify the toxicity of P. tenuipes., (Copyright © 2014 Elsevier Inc. All rights reserved.)