Disposition and Metabolism of Cumene in F344 Rats and B6C3F1 Mice

Abstract

ABSTRACT:Cumene is a high-production volume chemical that has been shown to be a central nervous system depressant and has been implicated as a long-term exposure carcinogen in experimental animals. The absorption, distribution, metabolism, and excretion of [ 14 C]cumene (isopropylbenzene) was studied in male rats and mice of both sexes after oral or intravenous administration. In both species and sexes, urine accounted for the majority of the excretion (typically >70%) by oral and intravenous administration. Enterohepatic circulation of cumene and/or its metabolites was indicated because 37% of the total dose was excreted in bile in bile duct-cannulated rats with little excreted in normal rats. The highest tissue 14 C levels in rats were observed in adipose tissue, liver, and kidney with no accumulation observed after repeat dosing up to 7 days. In contrast, mice contained the highest concentrations of 14 C at 24 h after dosing in the liver, kidney, and lung, with repeat dosing accumulation of 14 C observed in these tissues as well as in the blood, brain, heart, muscle, and spleen. The metabolites in the expired air, urine, bile, and microsomes were characterized with 16 metabolites identified. The volatile organics in the expired air comprised mainly cumene and up to 4% ␣-methylstyrene. The major urinary and biliary metabolite was 2-phenyl-2-propanol glucuronide, which corresponded with the main microsomal metabolite being 2-phenyl-2-propanol.

Isopropyl benzene (cumene) [MAK Value Documentations, 2013]

“…Higher 14 C concentrations were determined in the liver and kidneys than in the blood. Compared with after single doses of 14 C-labelled isopropyl benzene, significantly increased 14 C concentrations were found after 3-day oral administration of 18 mgisopropyl benzene/kg body weight only in blood, muscles, skin and the spleen, and after oral administration for 7 days only in the skin (Chen et al 2011).…”

“…In the bile duct-cannulated rats, about 37% of the single intravenous dose was found in the bile within 24 hours. As in the remaining groups only a very small amount of 14 C was eliminated with the faeces, enterohepatic circulation of isopropyl benzene and its metabolites can be concluded (Chen et al 2011).…”

“…It would therefore be possible that in humans, like in the rat, the formation of lung tumours does not take place as a result of the lower concentration of Clara cells and CYP2F. However, in the metabolism of aromatic molecules such as isopropyl benzene or styrene, there is great variation between the species (Chen et al 2011;Sato and Nakajima 1987). The metabolism of isopropyl benzene in the human lungs is not known, so that carcinogenic effects in humans cannot be ruled out.…”

“…α-Methylstyrene α-Methylstyrene is a metabolite of isopropyl benzene that has been found in the exhaled air of mice after oral administration, but was practically absent in that of rats (see Section 3.2). As α-methylstyrene can be converted to α-methylstyrene oxide, which is genotoxic in Salmonella mutagenicity tests, it is suspected that αmethylstyrene plays a role in the induction of isopropyl benzene-induced lung tumours in mice (Chen et al 2011;Rosman et al 1986). After inhalation exposure of mice and rats to α-methylstyrene, effects similar to those that occur after inhalation of isopropyl benzene are observed, for example hyperplasia of the olfactory epithelium.…”

Biodegradation and Metabolism of Tetrabromobisphenol A (TBBPA) in the Bioaugmented Activated Sludge Batch Bioreactor System by Heterotrophic and Nitrifying Bacteria

“…The compound (7), substituted amethyl styrene (AMS) might undergo further biotransformation for stable end products. AMS and its derivatives have been identified as the metabolic products of cumene (Chen et al, 2011). The naturally occurring cumene type compound (8) is a common component in crude oil.…”