p-Chloro-α,α,α-trifluorotoluene (CTFT) is a volatile, aromatic liquid used as a chemical intermediate in the manufacture of dinitroaniline herbicides. To evaluate the toxicity of CTFT, groups of F344/N rats and B6C3F1 mice of each sex were administered CTFT by gavage once a day for 14 consecutive days in either corn oil or in an experimental molecular complex vehicle, α-cyclodextrin (α-CD). Dose levels selected for CTFT with the α-CD vehicle were 10, 50, and 400 mg/kg; dose levels used with the corn oil vehicle were 10, 50, 400, and 1000 mg/kg. The toxicokinetics of CTFT also were compared by gavage with the different vehicles and by i.v. administration. In genetic toxicity studies, CTFT was not mutagenic in Salmonella typhimurium.
The elimination of an intravenous dose of CTFT from blood is best described by a triexponential equation. The data best fit a 3-compartment kinetic model with a very rapid distribution phase. A biexponential equation was found to best fit the elimination of CTFT from blood following a gavage dose in either corn oil or an aqueous molecular complex suspension, α-CD. However, the biological half-life (t1/2) was the same in both routes, approximately 20 hours. Absorption of CTFT from the α-CD vehicle was found to be much faster than from corn oil. The average t1/2 of the absorption phase for a 10 mg/kg dose of CTFT in the α-CD and corn oil vehicles was 7 and 150 minutes, respectively. Despite the differences in absorption, no statistical difference was observed in the calculated area under blood concentration versus time curves (AUC) obtained from rats dosed with CTFT in either vehicle. Blood concentrations of CTFT were proportional to dose, at levels as high as 400 mg/kg in both vehicles. The bioavailability of CTFT was shown to be complete in both vehicles, through comparing the AUC following oral and i.v. dosing.
In 14-day toxicity studies, 1 of 10 female rats given the top dose of 1000 mg/kg CTFT in corn oil died on day 8; no deaths of male rats or of mice of either sex were attributable to the administration of CTFT. Body weight gains in all groups of rats and mice were similar with the exception of the top dose (1000 mg/kg) groups of male and female rats, which lost weight during the first week and resumed weight gain during the second.
CTFT was found to accumulate in the kidneys of male rats, and there was a linear relationship between the kidney CTFT concentrations and the kidney levels of α2u-globulin, as determined by an ELISA assay. Microscopic changes in male rats included a dose-related toxic nephropathy consistent with that previously described as "hyaline droplet nephropathy." Dosed male and female rats also had hepatocyte hypertrophy and cytoplasmic vacuolization of the adrenal cortex. Clinical pathology findings suggested a mild anemia and cholestasis in rats. In contrast to rats, mice did not show appreciable CTFT concentrations in any tissue evaluated, suggesting a more rapid elimination of the chemical. However, hepatocellular hypertrophy, and clinical pathology findings consistent with cholestasis and mild liver injury, were noted in mice in the 400 and 1000 mg/kg dose groups.
These studies demonstrated that oral doses of CTFT of 400 mg/kg or higher caused liver hypertrophy in rats and mice and adrenal changes in rats. Doses of 50 mg/kg or higher caused "hyaline droplet nephropathy" in male rats. The results were similar with CTFT administered either in corn oil or in α-CD (although absorption of CTFT was somewhat more rapid with α-CD), suggesting that α-CD may be an appropriate vehicle for toxicity studies with other chemicals.