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Basic toxicokinetics

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basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Secondary source

Data source

Reference Type:
review article or handbook
No information
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Materials and methods

Test material


Results and discussion

Metabolite characterisation studies

Metabolites identified:

Applicant's summary and conclusion

Executive summary:

Metabolism of cumene by cytochrome P-450 is extensive and takes place within hepatic and extrahepatic tissues, including lung (Sato & Nakajima, 1987), with the secondary alcohol 2-phenyl-2-propanol being a principal metabolite. Metabolites excreted in urine of rats and rabbits include 2-phenyl-2-propanol and its glucuronide or sulfate conjugates, conjugates of 2-phenyl-1,2-propanediol, and an unknown metabolite, possibly the dicarboxylic acid that would result from complete oxidation of the 1- and 3-alkyl carbons of phenylmalonic acid (Research Triangle Institute, 1989; Ishida & Matsumoto, 1992; MAK, 1996). Seczuk & Litewka (1976) also conducted excretion studies with human volunteers exposed to cumene vapours (240, 480, or 720 mg/m3 [49, 98, or 147 ppm]) for 8 h every 10 days. These authors reported excretion of the metabolite 2-phenyl-2-propanol in the urine as biphasic, with a rapid early phase (t1/2 2 h) and a slower later phase (t1/2 10 h); excretion of this metabolite in the urine (about 35% of the calculated absorbed dose) was maximal after 6–8 h of exposure and approached zero at 40 h postexposure. With rats, the extent of elimination across routes of administration (inhalation, oral, or intraperitoneal) and exposure concentrations was very similar, with urine being the major route of elimination, about 70% in all cases (Research Triangle Institute, 1989). Total body clearance in the rats was rapid and complete, with less than 1% of the absorbed fraction being present in the body 72 h after the highest exposure regime examined (5880 mg/m3 [1200 ppm] for 6 h). Following oral administration of cumene in rabbits, 90% was recovered as metabolites in the urine within 24 h (Robinson et al., 1955). Xenobiotica. 1992 Nov;22(11):1291-8. Enantioselective metabolism of cumene. Ishida T, Matsumoto T. Hiroshima Institute of Technology, Japan. Abstract 1. The enantioselective metabolism of cumene (isopropylbenzene) was studied in intact rabbits. 2. Of the total 2-phenyl-1-propanol formed metabolically, 90.3% was shown by h.p.l.c. to be (R)- (+)-2-phenyl-1-propanol. The corresponding values for (S)-(+)-2-phenylpropanoic acid and (R)-(- )-2-hydroxy-2-phenylpropanoic acid were 99.0 and 81.0%, respectively. 3. These results imply that firstly, preferential omega-hydroxylation occurs at the pro-S methyl group and secondly, the oxidation is followed by stereochemical inversion of (R)-(-)-2-phenylpropanol to the corresponding (S)-(+)-acid.