Preclinical Toxicology of a Succinic Acid Salt of a Polyhexamethylene Guanidine Derivative: Acute and Repeated-Dose Studies

The growing interest in ocular antiseptics is driven by their broad-spectrum antimicrobial activity and potential to mitigate antimicrobial resistance. In a previous study, systemic effects of ophthalmic drops based on succinic acid derivative of polyhexamethylene guanidine (ss-PHMGd) following ocular instillation were investigated in a preclinical model. The present study aimed to assess the acute toxicity of ss-PHMGd in mice and outbred rats of both sexes after intragastric and ocular administration, its cumulative properties in rats using the Lim method, and its toxicity under repeated dosing conditions, including intraperitoneal administration in rats for 7 days and topical ocular application in Chinchilla rabbits for 30 days. Acute toxicity evaluation showed LD50 values of 672.3 mg/kg in male mice and 693.4 mg/kg in female mice following intragastric administration. No mortality was observed after ocular administration in mice and rats, precluding the determination of toxic or lethal dose levels for this route. The cumulation coefficient (K = 1.76) indicated no cumulative properties. Repeated-dose studies revealed no significant effects on general condition or behavior in rats and rabbits at the tested doses. However, histopathological examination identified pathological changes in the lungs and thyroid gland in some rats after intraperitoneal administration at a dose equivalent to 10 therapeutical doses (TD) (0.3 mg/kg). These findings contribute to the understanding of polyguanidines and are relevant for toxicological evaluation and risk assessment of ss-PHMGd.