Abstract
Exposure to n-hexane, a component of many industrial solvent mixtures, is known to cause polyneuropathy in man. The concentration of metabolites in urine following exposure may be useful in biological monitoring. In a comparative study experimental animals (rat, rabbit and monkey) were subjected to single inhalatory treatments of 6, 12 and 24 h with 5,000 ppm of pure n-hexane. At the end of the treatments and at intervals thereafter, urine, and in rats also blood, were collected and analyzed for n-hexane and its metabolites. While the urine of rats contained 2-hexanol, 3-hexanol, methyl n-butyl ketone, 2,5-dimethylfuran, γ-valerolactone and 2,5-hexanedione, rabbit and monkey urine were found to contain only 2-hexanol, 3-hexanol, methyl n-butyl ketone and 2,5-hexanedione. Within 72 h of the end of exposure, the principal metabolite was 2,5-dimethylfuran in rats and 2-hexanol in rabbits and monkeys. In all three species the excretion rates of methyl n-butyl ketone, 3-hexanol and 2-hexanol peaked several hours earlier than 2,5-hexanedione (and γ-valerolactone and 2,5-dimethylfuran in rats). In all species 2,5-hexanedione was still detectable in urine 60 h following exposure. n-Hexane metabolites in rat blood were 2-hexanol, methyl-n-butyl ketone, 2,5-dimethylfuran and 2,5-hexanedione. The first two, as well as n-hexane itself, were found in maximum concentration immediately after termination of exposure, while 2,5-dimethylfuran and 2,5-hexanedione, with the longer exposure times, peaked some hours later. The data from urine collected at the end of exposure were compared with those obtained in a parallel study in humans occupationally exposed to a mixture of hexane isomers. Humans chronically exposed to 10–140 ppm n-hexane had 2,5-hexanedione concentrations in urine ranging from 0.4 to 21.7 mg/l, i.e., in the same proportion as rats exposed once for 6 or 12 h to 5,000 ppm.
Similar content being viewed by others
References
Abdel-Rahman MS, Hetland LB, Couri D (1976) Toxicity and metabolism of methyl n-butyl ketone. Am Ind Hyg Assoc J 37: 95–102
Altenkirch H, Stoltenburg G, Wagner HM (1978) Experimental studies on hydrocarbon neuropathies induced by methyl ethyl ketone (MEK). J Neurol 219: 159–170
Baker TS, Rickert DE (1981) Dose-dependent uptake, distribution and elimination of inhaled n-hexane in the Fischer-344 rat. Toxicol Appl Pharmacol 61: 414–422
Brugnone F, Perbellini L (1980) Inquinamento da solventi e mansioni lavorative nei calzaturifici e tomaifici. Med Lav 4: 343–352
Bus JS, While EL, Tyl RW, Barrow CS (1979) Perinatal toxicity and metabolism of n-hexane in Fischer-344 rats after inhalation exposure during gestation. Toxicol Appl Pharmacol 51: 295–302
Couri D, Abdel-Rahman MS, Hetland LB (1978) Biotransformation of n-hexane and methyl n-butyl ketone in guinea pigs and mice. Am Ind Hyg Assoc J 39: 295–300
Di Vincenzo GD, Kaplan CJ, Dedinas J (1976) Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone and methyl ethyl ketone in guinea pig serum and their clearance. Toxicol Appl Pharmacol 36: 511–522
Frontali N, Amantini MC, Spagnolo A, Guarcini AM, Saltari MC, Brugnone F, Perbellini L (1981) Experimental neurotoxicity and urinary metabolites of the C5–C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture. Clin Toxicol 18: 1357–1367
Frontali N, Guarcini AM, Spagnolo A, Amantini MC (1979) Sostanze capaci di provocare polineuropatia, impiegate nell'industria calzaturiera. (triarilfosfati, idrocarburi alifatici C5–C7) Ann Ist Super Sanita 15: 273–324
Herskowitz A, Ishii N, Schaumburg H (1971) A syndrome occurring as a result of industrial exposure. N Engl J Med 285: 82–85
Krasavage WJ, O'Donoghue JL, Di Vincenzo GD, Terhaar CJ (1980) The relative neurotoxicity of methyl n-butyl ketone, n-hexane and their metabolites. Toxicol Appl Pharmacol 52: 433–441
Notten WRF, Henderson PT (1975) The influence of n-hexane treatment on the glucuronic acid pathway and activity of some drug-metabolizing enzymes in guinea pig. Biochem Pharmacol 24: 127–131
Paulson GW, Waylonis GW (1976) Polyneuropathy due to n-hexane. Arch Intern Med 136: 880–882
Perbellini L, Brugnone F, Pastorello G, Grigolini L (1979) Urinary excretion of n-hexane metabolites in rats and humans. Int Arch Occup Environ Health 42: 349–354
Perbellini L, Brugnone F, Silvestri R, Gaffuri E (1981a) Measurement of the urinary metabolites of n-hexane, cyclohexane and their isomers by gas chromatography. Int Arch Occup Environ Health 48: 99–106.
Perbellini L, Brugnone F, Faggionato G (1981b) Urinary excretion of the metabolites of n-hexane and its isomers during occupational exposure. Br J Ind Med 38: 20–26
Perbellini L, Leone R, Fracasso ME, Brugnone F, Venturini S (1981)c Metabolic interference among n-hexane, methylethyl ketone and toluene in rats. 22nd Congr. Eur Soc Toxicol 17–19 August, Dublin (Abstract)
Saida K, Mendell JR, Weiss HS (1976) Peripheral nerve change induced by methyl n-butyl ketone and potentiation by methyl ethyl ketone. J Neuropathol Exp Neurol 35: 207–225
Sanagi S, Seki Y, Sugimoto K, Hirata M (1980) Peripheral nervous system functions of workers exposed to n-hexane at low level. Int Arch Occup Environ Health 47: 69–79
Schaumburg HH, Spencer PS (1976) Degeneration in central and peripheral nervous systems produced by pure n-hexane: an experimental study. Brain 99: 183–192
Spencer PS, Schaumburg HH (1975) Experimental neuropathy produced by 2,5-hexanedione — a major metabolite of the neurotoxic industrial solvent methyl n-butyl ketone. J Neurol Neurosurg Psychiatry 38: 771–775
Spencer PS, Schaumburg HH (1977) Ultrastructural studies of the dying-back process. III The evolution of experimental peripheral giant axonal degeneration. J Neuropathol Exp Neurol 36: 276–299
Spencer PS, Schaumburg HH, Sabri MI, Veronesi B (1980) The enlarging view of hexacarbon neurotoxicity. CRC Crit Rev Toxicol 7: 279–356
Takeuchi Y, Mabuchi C, Takagi S (1975) Polyneuropathy caused by petroleum benzine. Int Arch Arbeitsmed 34: 185–197
Takeuchi Y, Ono Y, Hisanaga N (1981) An experimental study on the combined effects of n-hexane and toluene on the peripheral nerve of the rat. Br J Ind Med 38: 14–19
Takeuchi Y, Ono Y, Hisanaga N, Kitoh J, Sugiura Y (1980) A comparative study on the neurotoxicity of n-pentane n-hexane and n-heptane in the rat. Br J Ind Med 37: 241–247
Vainio H (1974) Activation and inactivation of membrane-bound UDP-glucuronosyltransferase by organic solvents in vitro. Acta Pharmacol Toxicol 34: 152–156
Yamada S (1967) Intoxication polyneuritis in the workers exposed to n-hexane. Jpn J Ind Health 9: 651–652
Yamamura Y (1969) n-Hexane polyneuropathy. Folia Psychiatr Neurol Jpn 23: 45–57
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Perbellini, L., Amantini, M.C., Brugnone, F. et al. Urinary excretion of n-hexane metabolites. Arch Toxicol 50, 203–215 (1982). https://doi.org/10.1007/BF00310852
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00310852