Toxicity of minoxidil – Comprehensive in silico prediction of main toxicity endpoints: Acute toxicity, irritation of skin and eye, genetic toxicity, health effect, cardiotoxicity and endocrine system disruption

This article focusses on elucidating the toxicological profile of minoxidil, a widely used pharmacological agent for alopecia, through the application of in silico methods (Percepta ACD/Labs software). This research is driven by the need to understand key toxicological endpoints: acute toxicity, skin and eye irritation, genetic toxicity, cardiotoxicity, disruption of the endocrine system, and estimation of various health effects due to the lack of experimental data for this drug. These parameters are critically evaluated to meet the stringent requirements of the pharmaceutical industry's safety assessments. The results obtained for acute toxicity (LD50 for rats and mouse) indicate that minoxidil exhibits a species-dependent acute toxicity profile e.g. 51 mg/kg bw for intravenous administration in mice. The predicted health effects indicate a 93% risk to the gastrointestinal system, 54% for the kidneys, 52% for the liver, 42% for the blood and lungs, and 39% for the cardiovascular system. The prediction of genotoxicity suggests a moderate probability (48%) of inducing a positive Ames test result. Furthermore, moderate inhibition of the hERG channel indicates potential cardiac risks of Minoxidil. Based on the information obtained, we propose subjecting minoxidil to additional toxicological assessments. The successful adoption of these in silico methodologies aligns with the 3 R s principle (replacement, reduction, and refinement) in the field of modern toxicological studies of minoxidil, all without the use of laboratory animals for the novelty of our toxicity assessment.