REPRODUCTIVE AND DEVELOPMENTAL TOXICITY STUDY OF GADOBENATE DIMEGLUMINE FORMULATION (E7155) (3) : STUDY OF EMBRYO-FETAL TOXICITY IN RABBITS BY INTRAVENOUS ADMINISTRATION

Gadobenate dimeglumine formulation (E7155) was daily administered by intravenous injection at 0.3, 0.9 or 2.0 mmol/kg/day to mated NZW female rabbits (20/group) to assess the effect on embryo-fetal development. Treatment with 2.0 mmol/kg/day caused initial, notable loss of body weight and reduction in food consumption. Slightly reduced body weight gain and food intake were recorded at 0.9 mmol/kg/day. There were no obvious adverse effects in dams given E7155 at 0.3 mmol/kg/day. There was a slightly higher incidence of early intrauterine deaths at 0.9 and 2.0 mmol/kg/day. Morphological examination of fetuses at 2.0 mmol/kg/day revealed small eye/microphthalmia and/or retinal irregularities in three fetuses from three separate litters. There was also an increase in the incidence of additional and/or fused sternebral centres and 20-thoracolumbar vertebrae at this dosage. From these results, the No Observed Adverse Effect Level (NOAEL) for general toxicity of dams and embryo-fetal development was 0.3 mmol/kg/day.