alpha-cyclodextrin and 4-chloro-alpha-alpha-alpha-trifluorotoluene

The application of alpha-cyclodextrin (alpha-CD) as an alternative vehicle for water insoluble and volatile chemicals was investigated in toxicity studies of p-chloro-alpha, alpha, alpha-trifluorotoluene (CTFT). Groups of F344 rats and B6C3F1 mice of each sex were administered CTFT (97% pure) by gavage in either corn oil or alpha-CD aqueous formulations daily for 14 consecutive days. The dose levels used were 10 (mice only), 50, 400, and 1000 mg/kg for corn oil vehicle and 10, 50, and 400 mg/kg (maximum achievable dose at gavage volume of 5 ml/kg) for alpha-CD vehicle. With both vehicles CTFT and alpha 2u-globulin were found to accumulate in the male rat kidney after 14 days of exposure and a dose-related toxic nephropathy was observed at dose of 50 mg/kg or higher. The hepatocellular hypertrophy and cytoplasmic vacuolation of the adrenal cortex which appeared in dosed male and female rats were also found to be independent of vehicle. Clinical pathology findings suggested a mild anemia and cholestasis in rats. With both vehicles no tissue bioaccumulation of CTFT was found in male or female mice. Vehicle-independent hepatocellular hypertrophy and cholestasis were also observed in mice at doses of 400 and 1000 mg/kg. In conclusion, the alpha-CD vehicle does not affect the toxic responses of CTFT in both sexes of both species. The results of the studies suggest that alpha-CD may be an appropriate alternative vehicle for toxicity studies.

Topics: alpha-Cyclodextrins; Alpha-Globulins; Animals; Blood Cell Count; Body Weight; Capsules; Corn Oil; Cyclodextrins; Female; Humans; Infant, Newborn; Kidney; Liver; Male; Mice; Mice, Inbred Strains; Organ Size; Pharmaceutical Vehicles; Proteins; Rats; Rats, Inbred F344; Species Specificity; Toluene

Toxicokinetics of p-chloro-alpha,alpha,alpha-trifluorotoluene (CTFT) after administration as an aqueous alpha-cyclodextrin (alpha-CD) molecular encapsulation suspension (alpha-CD vehicle) or as a corn oil solution (corn oil vehicle) were compared. Male F344 rats were administered intragastrically CTFT in alpha-CD vehicle or corn oil vehicle at dose levels of 10, 50, or 400 mg/kg. Other male F344 rats were administered CTFT intravenously in a 10% Tween 80 aqueous solution. Serial blood samples were taken from a cannulated jugular vein for up to 52 hr after dosing and the CTFT concentrations in whole blood were determined by gas chromatography. The biological elimination half-life of CTFT from the center compartment was not affected by the vehicle used; however, absorption of CTFT from the alpha-CD vehicle was much faster than from the corn oil vehicle. The average absorption half-lives from the alpha-CD vehicle and corn oil vehicle were 17 and 98 min, respectively. Despite the differences in absorption, no statistical difference was observed in the calculated areas under the blood concentration versus time curves (AUC) obtained from rats dosed with either vehicle. Dose proportionality for CTFT was established up to 400 mg/kg and bioavailability was shown to be complete for both vehicles.

Topics: Administration, Oral; alpha-Cyclodextrins; Animals; Biological Availability; Corn Oil; Cyclodextrins; Drug Compounding; Injections, Intravenous; Male; Polysorbates; Rats; Rats, Inbred F344; Toluene