Comprehensive Toxicological Evaluation and Safety Assessment of Perilla frutescens Leaf Extract: Repeated-Dose Oral Toxicity and Genotoxicity Studies

Perilla frutescens var. frutescens leaf extract (PFE) has previously demonstrated clinical efficacy in relieving knee joint discomfort. To establish its safety profile, good laboratory practice (GLP)-compliant nonclinical evaluations were conducted in accordance with the Organization for Economic Cooperation and Development (OECD) test guidelines. In the acute oral toxicity test, the acute oral LD50 cutoff was estimated to be above 2000 mg/kg. In 28-day and 90-day repeated-dose oral toxicity studies of up to 5000 mg/kg/day, no mortalities, toxic signs, or adverse changes in body weight were observed. Minor hematological/biochemical shifts and organ weight increases at 5000 mg/kg/day lacked histopathological correlates and were largely reversible following a 28-day recovery period, establishing the no observed adverse effect level (NOAEL) at 5000 mg/kg/day. Furthermore, PFE showed no mutagenic, clastogenic, or aneugenic potential across the bacterial reverse mutation, in vitro chromosomal aberration, or in vivo bone marrow micronucleus assays. These results demonstrate a broad safety margin, supporting the safe application of PFE as a functional food ingredient and nutraceutical agent.