Repeated dose (90 days) oral toxicity study of ursolic acid in Han-Wistar rats

Lotte Geerlofs; Zhiyong He; Sa Xiao; Zhi-Cheng Xiao

doi:10.1016/j.toxrep.2020.04.005

Repeated dose (90 days) oral toxicity study of ursolic acid in Han-Wistar rats

Toxicol Rep. 2020 May 8:7:610-623. doi: 10.1016/j.toxrep.2020.04.005. eCollection 2020.

Authors

Lotte Geerlofs^{1

2}, Zhiyong He^{1

2}, Sa Xiao^{1

2}, Zhi-Cheng Xiao^{1

2}

Affiliations

¹ Department of Anatomy and Developmental Biology, Monash University, Melbourne, 3168, Australia.
² iRiccorgpharm Health Pty Ltd, Melbourne, 3168, Australia.

Abstract

Background: Ursolic acid (UA) has been used in alternative medicine for decades, and there has been a great interest in its medicinal properties. Despite this increased interest, a detailed long-term toxicity study has not been performed. The objective of this study was to determine the long-term toxic effect of UA on clinical chemistry, haematology, coagulation, pathology/morphology, behaviour and motor skills in rats.

Methods: A solution was made by dissolving UA in a mixture of 0.1% Tween 80 and 0.5% hydroxypropyl methylcellulose in Milli-Q Water. The control group received the vehicle, and the test groups received a dose up to 1000 mg/kg/day via oral gavage. The solution was administered to both male and female (Han-Wistar) rats for 90 consecutive days.

Results: UA did not cause any deaths, abnormal body weights or abnormal pathology at all test doses. In addition to that, no toxicological changes were observed in behaviour, neurotoxicity, coagulation, haematology or clinical chemistry that are related to the administration of UA.

Conclusion: This study indicates that oral dosing of UA for 90 consecutive days does not lead to toxic effects at any of the doses. Therefore, the NOAEL for UA is likely to be higher than 1000 mg/kg/day.

Keywords: 90 days; A/G, Albumin/globulin ratio; ALB, Albumin; ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; APTT, Activated partial thromboplastin time; AST, Aspartate aminotransferase; BASO, Basophils; CA, Calcium; CHOL, Cholesterol; CK, Creatine kinase; CL, Chloride; CREAT, Creatine; EOS, Eosinophils; FIB, Fibrogen; GGT, Gamma-glutamyl transferase; GLOB, Globulin; GLUC, Glucose; HGB, Haemoglobin; HPLC, High Performance Liquid Chromatography; HPMC, Hydroxypropyl methylcellulose; K, Potassium; LUC, Large unstained cells percent; LYMPH, Lymphocytes; MCH, Mean corpuscular haemoglobin; MCHC, Mean corpuscular haemoglobin concentration; MCV, Mean corpuscular volume; MONO, Monocytes percent; N.V.L, No visible lesions; NA, Sodium; NEUT, Neutrophils percent; NOEL, No observed effect level; No observed adverse effect level; OA, Oleanonic acid; OECD; OECD, Organisation for Economic Co-operation and Development; PHOS, Inorganic phosphate; PLT, Platelet count; PT, Prothrombin time; RBC, Red blood cell count; RDWG, Red blood cell distribution width gated; RETIC, Reticulocytes; Repeated dose toxicity; TBIL, Total bilirubin; TPROT, Total protein; TRIG, Triglycerides; UA, Ursolic acid; Ursolic acid; WBC, White blood cell count.