Safety evaluation of genipin in Beagle dogs: acute and 28-day repeated oral toxicity studies

Introduction Genipin, a typical iridoid constituent derived from the fruits of Gardenia jasminoides Ellis, is an essential in vivo metabolite of geniposide. It exhibits diverse potent biofunctions, including hepatoprotection, anti-inflammation, neuroprotection, antioxidation, and glycolipid metabolism modulation. Nevertheless, the systemic toxicological profile of genipin remains insufficiently characterized, with particularly limited safety evidence from non-rodent models. This study aimed to evaluate the acute and subacute oral toxicity of genipin in Beagle dogs as a preclinical safety assessment. Methods Acute toxicity was assessed using single oral doses of genipin at 29, 41, 59, 84, 120, and 140 mg/kg. For subacute toxicity, repeated-dose groups were administered 3, 9, and 27 mg/kg/day for 28 days. Clinical signs, body weight, food intake, hematology, clinical chemistry, urinalysis, electrocardiography, fecal occult blood, and histopathology were evaluated. Results The results showed that the oral approximate lethal dose of genipin was 120.0–140.0 mg/kg, with doses ≥41 mg/kg inducing thymic, hepatorenal, and gallbladder toxicity. Repeated 27 mg/kg/day genipin caused gastrointestinal irritation, anemia, prolonged coagulation parameters, and toxicity to the hepatobiliary system, thymus, bone marrow, and gonads; 3 and 9 mg/kg/day genipin induced mild male gonad toxicity. Bone marrow toxicity and gastric mucosal irritation were fully reversible after recovery, while hepatic, thymic, and gonadal toxicity showed partial recovery. Conclusion This study clarified the dose-toxicity relationship, major target organs, and toxic reversibility of genipin following oral exposure in non-rodent species. These findings provide robust preclinical toxicological evidence to support rational dosage optimization, risk assessment, and the safe use of genipin.