General toxicity study of gadobenate dimeglumine formulation (E7155) (1)--single dose intravenous and intracisternal toxicity study in rats

Gadobenate dimeglumine formulation (E7155) was evaluated for its general toxicity potential following a single intravenous and intracisternal administration to rats. Dosage levels tested were 3.3, 4.5, 6.0 and 8.0 mmol/kg at the injection rate of 6 ml/min and 7.50, 8.89, 10.54 and 12.50 mmol/kg at 1 ml/min for the intravenous administration route, and 0.15, 0.21, 0.29 and 0.40 mmol/kg for the intracisternal administration route. Parameters measured during the 14-day observation period were mortality, clinical signs and macroscopic examination. After intravenous administration at the injection rate of 6 ml/min, twitches, respiratory blocking and prostration were observed at 6.0 mmol/kg, and dyspnoea and sedation at 3.3 and 4.5 mmol/kg. Deaths occurred within 1 min after administration at 6.0 mmol/kg and above. LD50 values were 7.97 mmol/kg in males and 6.22 mmol/kg in females. After intravenous administration at the injection rate of 1 ml/min, shallow breathing, twitches and sedation were observed at 7.50 mmol/kg and above and respiratory arrest at 8.89 mmol/kg. Deaths occurred within 1 min after administration at 8.89 mmol/kg and above. LD50 values were 9.0 mmol/kg in males and 9.7 mmol/kg in females. After intracisternal administration, symptoms consisted of sedation, staggering gait, dyspnoea, twitches and ataxia at 0.15 mmol/kg and above, prostration, paralysis of forelimbs, and/or hind limbs and chromodacryorrhea at 0.21 mmol/kg, and convulsions at 0.29 mmol/kg and above. Deaths occurred within 7 days after administration at 0.21 mmol/kg and within 5 min at 0.29 mmol/kg and above. LD50 values were 0.42 mmol/kg in males and 0.25 mmol/kg in females.