Single dose blood toxicokinetics of methacrylonitrile in the F344 rat

Methacrylonitrile (MAN) is a widely used industrial chemical. Minimal information is available on its effects or toxicokinetics; therefore, current investigations were undertaken as part of an overall effort to characterize MAN toxicity in laboratory animals. Groups of male F344 rats were administered MAN intravenously (29, 58, or 116 mg/kg) or perorally (58 mg/kg). Blood samples were collected at various time points after dosing and serum MAN concentrations were measured. Concentration versus time profiles were characterized by two phases and a two-compartment model was selected to fit the data. Toxicokinetic parameters were determined using Simusolv. The 39-min terminal half-life shows that 99% of an i.v. dose is eliminated in less than 5 hr, suggesting that the potential for MAN bioaccumulation is minimal. The volume of distribution at steady-state (747 ml/kg) indicates little distribution of MAN into tissues. Clearance is higher at 29 mg/kg than at the two other doses, suggesting that MAN elimination is saturable at doses above 29 mg/kg. MAN disposition is route-dependent. Approximately 36% of the i.v. dose was exhaled as unchanged MAN, while only 18% was eliminated via this route following po administration. MAN disposition data also suggest that a significant first-pass metabolism may occur because a higher percentage of metabolites was produced following oral vs i.v. administration. Perorally, 39% of the dose was exhaled as CO2 and 22% was excreted into the urine as metabolites over the 24-hr dosing interval. In comparison, following i.v. delivery, 26% of the dose was exhaled as CO2 and 16% was excreted into the urine as metabolites. About equal amounts of acetone were excreted following administration by either route. This information may prove useful in designing long-term toxicity studies for MAN by the National Toxicology Program and in interpreting the results of such studies.