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A key study was performed with hydrogenated terphenyl to determine the disposition and localization in rats as a function of dose and time, and to determine the effects on liver and kidney microsomal drug-metabolizing enzymes following oral and inhalation administration (Hotz & Brewster, 1990). In this study, hydrogenated terphenyl was administered to male Sprague Dawley rats as either a single oral dose at 0,100, or 300 mg/kg body weight, or as a single 6 hour inhalation exposure of 0 or 350 mg/m3, or in the diet at concentrations of 0, 100, 500 or 5000 ppm, or as a repeated inhalation exposure for 6 hours/day for 14 days at 0, 25, 250, at 1200 mg/m3. Ethoxycoumarin-o-deethylase (ECOD) and aryl hydrocarbon hydroxylase (AHH) activities were determined in liver and kidney S-9 preparations.

Little change in body weight was observed in animals administered hydrogenated terphenyl via the diet except at 5000 ppm. The body weight gain of animals exposed to hydrogenated terphenyl via inhalation decreased in a dose dependent manner over the 2 week exposure period and was significantly different from control at both 250 and 1200 mg/m3. Absolute liver weights from animals administered 5000 ppm in the diet or 250 mg/m3 or 1200 mg/m3 via inhalation were 30 to 70% higher than control liver weights.

Single oral and inhalation exposures to hydrogenated terphenyl produced little or no induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity. However, hepatic AHH activity in animals administered 5000 ppm in the diet, and in animals repeatedly exposed to 250 mg/m3 or 1200 mg/m3 via inhalation, was significantly increased above that of control animals. Ethoxycoumarin-o-deethylase (ECOD) activity in the inhalation and diet groups was increased only in animals receiving the highest doses of hydrogenated terphenyl. In general, renal AHH activity was statistically decreased at high exposure levels, whereas renal ECOD activity appeared to be slightly but not significantly increased compared to controls, regardless of route or length of exposure. Hydrogenated terphenyl produced less induction of microsomal enzymes in the kidney than in the liver for both AHH and ECOD.

Dietary and inhalation exposures produced similar induction patterns in both ECOD and AHH activity However, animals exposed to hydrogenated terphenyl via inhalation demonstrated a greater hepatic inductive effect than did animals exposed to hydrogenated terphenyl via the diet. This effect may be due to greater absorption of hydrogenated terphenyl after inhalation exposure compared to that after dietary exposure.

Results from the disposition study indicated that hydrogenated terphenyl did not appear to accumulate in the body tissues and did not appear to be extensively absorbed after a single oral dose of 300 mg/kg. Whole body elimination was approximately 47 hours and occurred primarily via the feces. Absorption was estimated to be approximately 30% of the administered dose. Of this, 1/3 was eliminated in the urine over the 168 hour observation period. The major route of elimination for hydrogenated terphenyl appeared to be the feces.

In summary, approximately 30% of an oral dose of hydrogenated terphenyl was absorbed from the gastrointestinal tract, there was little accumulation in tissues, and the whole body half-life was less than 1 day. Induction of drug metabolizing enzymes was evident only at the 2 highest doses and the liver was more sensitive to the enzyme inducing effects of hydrogenated terphenyl 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.

In addition, supporting literature data were available on mice that were exposed by inhalation for 4 or 7 hours to radioactive (partial) hydrogenated terphenyl at 10µCi/mL . Clearance of the radiolabel from the respiratory tract was complete within 24 hours. Radioactivity in the gut, which was significantly increased immediately after inhalation, was reportedly equivalent to control values within 24 hours of compound administration. No accumulation was noted in the gut, kidney, and liver since radioactivity levels 24 hours after the final exposure were similar for mice exposed once compared with mice exposed for five consecutive days.Mice were also exposed by oral administration to radioactive (partial) hydrogenated terphenyl at 100µCi/mL and demonstrated radioactivity in the gut, liver, and kidney. The radioactivity was maximal at 4 to 5 hours after administration and steadily disappeared to background levels within 7 days.