“Melaniavet” (ear drops). Study of acute and chronic dermal toxicity in laboratory rats

The acute (subacute) and chronic dermal toxicity of a multi-component agent (gentamicin sulfate, nystatin, ivermectin, dioxidine, dimexide, dexamethasone, lidocaine) with predicted pharmacological activity for external otitis in dogs was investigated. Preliminary studies on the physicochemical and pharmacological properties established that the “Melaniavet” (ear drops) preparation is a stable, miscible formulation for external use. It appears as a clear solution with a yellowish tint and does not separate with sediment formation over 12 months. High-performance liquid chromatography (HPLC) confirmed component compatibility within the preparation and the absence of interactions among individual ingredients when combined in solution. The acute toxicity of “Melaniavet” was evaluated via a single oral administration and dermal application in laboratory rats. The tested agent at a dose of 5000 mg/kg body weight (oral) and 2000 mg/kg (dermal) did not result in mortality or signs of clinical intoxication. The preparation's LD50 is >5000 (2000) mg/kg body weight, classifying it as Class IV in toxicity (low-toxicity substances), category 5 (GHS). A 28-day study on dermal toxicity of the multi-component preparation showed no mortality or signs of intoxication in rats. Experimental animals remained active regardless of the dose administered, and their reflex response and excitability were comparable to those of the control group, which received water on the prepared skin area. Appetite in groups E2 and E3 (5x and 10x the optimal dose) was slightly suppressed, leading to a lower body weight than the control by 12.1 % (P < 0.05) and 13.3% (P < 0.05) at the end of the experiment. Prolonged dermal application of “Melaniavet” at the therapeutic dose (0.6 ml/kg body weight) did not produce significant changes in the weight coefficients of internal organs or indicators reflecting their morphological and biochemical status. However, administration at 5x and 10x the therapeutic dose (3 and 6 ml/kg body weight) increased the weight coefficients of the liver, spleen, heart, and kidneys. In the blood serum of group E3 animals, there was a significant increase in ALT, AST, and AP activity, as well as urea and creatinine levels; the red and white blood cell counts and hemoglobin content showed a tendency to decrease. By the 42nd day, or two weeks after discontinuation of dermal application, experimental groups observed a gradual recovery of functional status.