Biochemical toxicology and disposition of therminol 66 heat transfer fluid after inhalation or after dietary administration to male sprague‐dawley rats

Abstract

The objectives of this study were to determine the disposition of Therminol 66 in rats and to determine the effects of this heat‐transfer fluid on liver and kidney microsomal drug‐metabolizing enzymes. Therminol 66 was administered to male Sprague‐Dawley rats at various doses as either a single oral administration at 0, 100, or 300 mg/kg, or as a single 6‐h inhalation exposure at 0 or 350 mg/m³. Animals were killed 48 h after gavage or after termination of inhalation exposure. Additional groups of animals were exposed to Therminol 66 via the diet at 0, 100, 500, or 5000 ppm for 14 d, or via repeated inhalation exposure at 0, 25, 250, or 1200 mg/m³ for 6 h/d for 14 d. These exposure scenarios represent approximately equivalent doses of Therminol 66 by the different routes of administration. No change in body weight was observed after acute oral or inhalation exposure, and little change in body weight was observed in animals administered Therminol 66 via the diet except at the highest dose. There was no change in kidney weight, and liver weights were increased only at the higher doses of Therminol 66. The body weight gain of animals exposed to Therminol 66 via inhalation decreased in a dose‐dependent manner over the 2‐wk exposure period. Results from the disposition study indicated that Therminol 66 did not appear to accumulate in the tissues examined and did not appear to be extensively absorbed after a single oral dose of 300 mg/kg. The whole‐body elimination half‐life was approximately 14 h and occurred primarily via the feces. There was no significant induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity after single oral or inhalation exposures to Therminol 66. Ethoxycoumarin O‐deethylase (ECOD) was significantly induced only in animals exposed to 350 mg/m³ via inhalation. Repeated dietary and inhalation exposures resulted in AHH and ECOD induction only at the highest doses, and the kidney appeared to be less sensitive than the liver. Animals exposed via inhalation demonstrated a greater hepatic inductive effect than did animals exposed via the diet, which may be due to absorption differences. In summary, approximately 30% of an oral dose of Therminol 66 was absorbed from the gastrointestinal tract, there was little accumulation in tissues, and the whole‐body half‐life was approximately 14 h. Induction of drug‐metabolizing enzymes was evident only at the two highest doses, and the liver was more sensitive to the enzyme inducing effects than was the kidney. ECOD activity was affected to a greater extent than was AHH activity, and inhalation produced a greater effect than did dietary exposure.