Toxicity of Intravenous Administration of Cremaphor® ELP Formulations in Rats

Abstract

Cremaphor® ELP (CrELP) has been used to emulsify and solubilize water-insoluble substances in pharmaceutical industry for oral, topical and parenteral preparations, but its safety profile via intravenous route is yet to be established. In the current report, a wide range of CrELP concentrations associated with different viscosities was formulated and given intravenously in rats in order to evaluate acute toxicity and tolerability.  Doses of  CrELP were administered once in a fixed volume (5 ml/kg) and concentrations tested in mg/kg included 7.5, 75, 150, 375, 750, 1000, 1250, and 1500, with corresponding viscosity of 1,1, 1.08, 1.6, 3.6, 6, 18, 65 centiPoise (cP), respectively.  Mortality was observed within minutes of intravenous dosing with 1250 and 1500 mg/kg.  Clinical signs of dyspnea, decreased activity, flat body posture, and rough hair coat were observed in rats given 750 or 1000 mg/kg.  Plasma potassium (K⁺) levels were increased at 24 hr post dose compared to pre-dose values at all doses tested.  Histopathologic evaluations of the heart, kidney and lungs revealed myocardial necrosis and inflammation, kidneys tubular necrosis, and lung histiocytosis with hemorrhage.  Collectively, the clinical signs, serum potassium levels and histopathogical findings in rats given 750 and 1000 mg/kg were consistent with compromised tissue perfusion.  No adverse findings were observed in rats given 7.5, 75, 150 or 375 mg/kg CrELP and 375 mg/kg was considered the no adverse effect level (NOAEL) in this study.