Developmental Toxicity Study of Mangafodipir Trisodium Injection (MnDPDP) in New Zealand White Rabbits

Mangafodipir trisodium injection (MnDPDP) is an intravenouslyadministered manganese chelate undergoing clinical evaluationfor magnetic resonance imaging contrast enhancement of the hepatobiliarysystem. The anticipated single clinical dose for adults is 5µmol/kg body wt. MnDPDP, as well as the inorganic salt,MnCl₂ was previously shown to induce a specific syndrome ofskeletal abnormalities in rats. The syndrome malformations includedangulated or irregularly shaped clavicle, femur, fibula, humerus,ilium, radius, scapula, tibia, and/or ulna. The objective ofthe present study was to assess the developmental toxicity ofMnDPDP in a second mammalian species, the New Zealand Whiterabbit. MnDPDP was intravenously administered daily to groupsof rabbits (22 per group) on Days 6 through 18 of pregnancyat doses of 0 (saline), 5, 20, 40, and 60 µmol/kg MnDPDP.Fetuses were examined on Day 29 of pregnancy for external, visceral,and skeletal abnormalities. Treatment with MnDPDP did not resultin overt symptoms of maternal toxicity, and there were no significanteffects on maternal body weight gains or feed consumption. Thematernal no-observed-adverse-effect level (NOAEL), therefore,was 60 µmol/kg MnDPDP. Treatment with MnDPDP resultedin a significant increase in postimplantation loss at 60 µmol/kg,but there was no significant increase in external, visceral,or skeletal abnormalities at any dose. The developmental NOAELfor MnDPDP, therefore, was 40 µmol/kg. These results indicatethat the developmental toxicity profile of MnDPDP differs considerablyin the rat and rabbit. In the rat, this compound induces specificskeletal abnormalities, whereas in the rabbit, embryo/fetaltoxicity is the most sensitive developmental endpoint with noevidence for the induction of specific skeletal abnormalities.