Hexane (all isomers except n-hexane) Classification/MAK value: MAK value dates from: 1991 Synonyms: isohexane 200 ml/m 3 (ppm) 700 mg/m 3 2,3-dimethylbutane dimethylpropylmethane diethylmethylmethane ethyl-trimethylmethane neohexane Chemical names (CAS): 2-methylpentane 3-methylpentane 2,2-dimethylbutane CAS number: 107-83-5 96-14-0 75-83-2 79-29-8 Structural formula: CH 2 CH 2 CH 2 CH 2 HC H 3 C C HC CH 2 Molecular formula: C 6 H 14 C 6 H 14 C 6 H 14 C 6 H 14 Molecular weight: 86.2 86.2 86.2 86.2 Melting point in C: 153.7 118 99.8 128.5 Boiling point in C: 60.3 63.3 49.7 89.9 Vapour pressure in hpa at ( C): n.s. 533 (10.5) 533 (31.0) 533 (39.0) 1 ml/m 3 (ppm) = 3.58 mg/m 3 1 mg/m 3 = 0.28 ml/m 3 (ppm) HC HC 1 Toxic Effects and Modes of Action Isomers of hexane are present in organic solvents, adhesives, protective coatings and paints. They are also components of gasoline (motor spirit, petrol) and can occur as intermediates in the refining of petroleum. Hexane isomers have narcotic effects after brief exposures at high concentrations and are said to be cardiac sensitizers. Neurotoxic effects are not known.
270 Hexane (all isomers except n-hexane) Volume 4 Applied locally, the hexane isomers cause defatting of the skin; on mucous membranes and in the eye they are only moderately irritating. Orally administered hexane isomers are of low toxicity. The effects of chronic exposure on man are not known. The only available long-term animal studies with the hexane isomers are a 40-week feeding study and a 15 week inhalation study with male rats. These produced no evidence of neurotoxic effects like those observed in studies with n-hexane. All the other available animal studies have involved solvent mixtures or gasoline whose components include hexane isomers. The published reports make it clear that almost all of the studied mixtures also contained n-hexane so that the determination of the specific toxicological properties of the hexane isomers is difficult. There are no studies of reproductive toxicity, teratogenicity, mutagenicity or carcinogenicity of mixtures containing only the hexane isomers. 1.1 Pharmacokinetics Hexane isomers are taken in through the lungs and probably also through the skin. Pulmonary retention in shoe factory workers was found to be about 16 % for both 2- methylpentane and 3-methylpentane. The measured values remained fairly constant during the whole shift (4 to 8 hours) and were independent of the concentration of the substances in the workplace air. There was a good correlation between the concentration in the alveolar air and that in blood [1,2]. After a rapid increase during the first 15 minutes and a slower increase during the next hour, the retention coefficient remained constant for the rest of the shift. The amount absorbed is, however, determined by the respiratory minute volume which is higher for heavier work. Thus differences in the systemic dose are to be expected. The substances do not seem to be readily absorbed through the skin. In in vitro studies with excised abdominal rat skin, relatively low values were obtained with 2- methylpentane. A skin area of 2.55 cm 2 absorbed only 0.940 ± 0.058 µg in 4 hours [3]. The relatively low penetration rate (about 0.11 µg/hour/cm 2 ) measured for 2- methylpentane correlates with low solubility in water. Little is known of the metabolism of these substances in the human organism. Studies have shown that 2,2-dimethylbutane, 2-methylpentane and 3-methylpentane are found at high concentrations in adipose tissue, at lower levels in liver and kidney and only in small amounts in muscle and brain tissue. The lowest retention values were found for blood [4]. The metabolites 2-methyl-2-pentanol and 3-methyl-2-pentanol were detected in metabolic studies with 41 workers from 5 shoe factories where 11 250 mg 2-methylpentane/m 3 and 10 204 mg 3-methylpentane/m 3 were found in the workplace air [5, 6]. The metabolite concentrations were highly correlated with the levels of the corresponding hexane isomer. These metabolites could not be detected in an unexposed control group. Therefore the authors recommended that determination of these metabolites could be used for biomonitoring occupational exposure to the hexane isomers. 1,4-Diketones were not produced in the intermediary metabolism. These results correspond to those obtained in studies with rats exposed to 2- methylpentane or 3-methylpentane concentrations of 1500 ml/m 3. Mass spectrometric
Volume 4 Hexane (all isomers except n-hexane) 271 analysis of the 24 hour rat urine revealed only one metabolite of 2-methylpentane, 2- methyl-2-pentanol, and two metabolites of 3-methylpentane, 3-methyl-2-pentanol and 3- methyl-3-pentanol [7]. It is assumed that the hexane isomers are hydroxylated in man by the cytochrome P- 450 system; the mechanism could be like that known for 2-methylbutane which is oxidized on C-2 to the alcohol by rat liver microsomes [8]. Metabolic studies with the C 6 -isomers, however, have not yet been carried out. 2 Effects in Man There are only very few descriptions of the acute toxicity of the hexane isomers on their own. It is assumed that, like 2-methylpentane, the other isomers also cause defatting, drying and sometimes irritation when the liquids come into contact with the skin. Similar effects are also ascribed to the vapour of 3-methylpentane and 2-methylpentane [9]. In the vapour form, 2-methylpentane and 3-methylpentane cause only moderate eye irritation [10]. It is not known to what extent the substances are absorbed through the skin but, in analogy to other alkanes, skin absorption must be assumed to occur. Animal studies indicate that the hexane isomers are not very readily absorbed through the skin. Depending on concentration and exposure time, hexane isomers inhaled in vapour form can cause headache, vertigo and nausea as signs of central nervous system depression. The overall narcotic effects of the hexane isomers are relatively weak, like those of mixtures of branched alkanes (isoparaffins) of which they are the most frequent components [9]. No cases of poisoning with hexane isomers, and particularly no neurotoxic effects, are known from the literature. According to one early study [11], 2-methylpentane has sensitizing effects on the heart but this report has not yet been confirmed. Aspiration of liquid hexane isomers into the lungs results in severe inflammation of the pulmonary tissue (chemical pneumonitis) with subsequent pulmonary bleeding or oedema and in respiratory paralysis and cardiac arrest which are also caused by mixtures of branched alkanes [12, 13]. The effects on man of chronic exposure to hexane isomers without other substances have not been reported in the literature. 3 Effects on Animals 3.1 Acute toxicity A value for the LD 50 of hexane isomers is not known nor are there any other data available for the acute toxicity of these substances.
272 Hexane (all isomers except n-hexane) Volume 4 3.2 Subchronic and chronic toxicity In a study of the effects of inhalation of a number of substances, male Sprague-Daw-ley rats were exposed to purified 2-methylpentane (98 %) or 3-methylpentane (99 %) at a concentration of 1500 ml/m 3, 9 hours daily, 5 days per week for 15 weeks. Apart from body weight reduction in the rats exposed to 2-methylpentane, no effects were seen. Histological examination of the animals after 7 and 14 weeks revealed no pathological changes in the peripheral nervous tissue and especially none of the pronounced axonal changes in the tibial nerve tract which are typical of n-hexane intoxication. Two metabolites, 3-methyl-2-pentanol and 3-methyl-3-pentanol, were found in the urine of rats exposed to 3-methylpentane and only one metabolite, 2-methyl-2-pentanol, in the urine of rats exposed to 2-methylpentane [7]. Groups of 10 male Fischer 344 rats were given doses of 0.5 g/kg or 2.0 g/kg 2- methylpentane or 2,3-dimethylbutane, 5 days per week for 4 weeks (a total of 20 doses) by gavage [14]. The controls received 2.0 g/kg/day of isotonic saline. After 4 weeks, the body weights of the animals in both high dose groups (2-methylpentane and 2,3- dimethylbutane) were reduced markedly relative to those of the controls. The kidney weights were significantly increased above the control values in both groups receiving 2,3-dimethylbutane but not in the 2-methylpentane groups. However, histological examination revealed in all groups an increase in the incidence of regenerative epithelial changes, intratubular protein cylinders and aggregations of hyaline droplets typical of the toxic damage known to be caused by branched alkanes in the renal tubules [15]. A doseresponse relationship could not be recognized in the effects of the low and high doses. The authors make the assumption that branched alkanes such as 2,3-dimethylbutane and 2-methylpentane are primarily responsible for this nephropathy in male rats. However, they ascribe the effects induced in the kidneys to the sex and species specific metabolism of the male rat (increased production of α 2µ -globulin which results in overloading of the lysosomes). These results can, therefore, not be extrapolated to man [14]. 3.3 Neurotoxicity In a 2 phase inhalation study, male Sprague-Dawley rats were exposed to mixtures of hexane isomers with and without n-hexane, 22 hours/day, 7 days/week for 6 months. The effects of this exposure on the central and peripheral nervous systems of the animals were compared with the known effects of n-hexane. Unlike n-hexane and mixtures containing n-hexane, C 6 -mixtures without n-hexane produced neither signs of neurotoxic functional disorders nor histologically detectable differences from the controls in the tissues of the brain, spinal cord, sciatic or tibial nerves. On the other hand, in animals exposed to n-hexane or 1:1 mixtures of n-hexane-free C 6 -compounds with n-hexane, the typical pathological changes of the nerve fibres such as axonal swelling and giant cells in the tibial and sciatic nerves and in the medulla oblongata were seen after as little as 2 months exposure and became more severe with increasing exposure time. These results led to the conclusion that only pure n-hexane and mixtures containing n-hexane have neurotoxic effects; the n-hexane-free C 6 -isomers do not [16].
Volume 4 Hexane (all isomers except n-hexane) 273 4 Manifesto (MAK value, classification) Unlike n-hexane, the n-hexane-free C 6 -isomers cannot be shown to have neurotoxic effects in animal studies. This is ascribed to the fact that neurotoxic 1,4-diketones are not produced in the metabolism of these hexane isomers. Many years of occupational medical experience seem to confirm these findings. In the light of all available results, the nephrotoxic changes observed in male rats treated with the C 6 -isomers are considered to be species and sex specific. On the basis of data obtained with mixtures of branched alkanes, a MAK value of 200 ml/m 3 is established for the n-hexane-free C 6 -isomers. This value must be considered to be provisional. More field studies, particularly of chronic effects, and animal studies to test for teratogenicity and genotoxicity are necessary. The hexane isomers are substances with systemic effects and are classified in category II,1 for the limitation of exposure peaks. 5 References 1. Brugnone, F., L. Perbellini, L. Grigolini, P. Apostoli: Int. Arch. occup. environm. Hlth 42, 355 (1979) 2. Brugnone, F., L. Perbellini, E. Gaffuri, P. Apostoli: Int. Arch. occup. environm. Hlth 47, 245 (1980) 3. Tsuruta, H.: Industr. Hlth 20, 335 (1982) 4. Perbellini, L., F. Brugnone, D. Caretta, G. Maranelli: Brit. J. industr. Med. 42, 162 (1985) 5. Perbellini, L., F. Brugnone, I. Pavan: Toxicol. appl. Pharmacol. 53, 220 (1980) 6. Perbellini, L., F. Brugnone, G. Faggionato: Brit. J. industr. Med. 38, 20 (1981) 7. Frontali, N., M. C. Amantini, A. Spagnolo, A. M. Guarcini, M. C. Saltari: Clin. Toxicol. 18, 1357 (1981) 8. Frommer, U., V. Ullrich, H. Staudinger: Hoppe-Seylers Z. physiol. Chem. 351, 903 (1970) 9. Sandmeyer, E. E.: in Clayton, G. D., F. E. Clayton (Eds.): Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2B, pp 3178, 3186, J. Wiley & Sons, New York, Chichester, Brisbane, Toronto, 1981 10. Wayne, L. G., J. A. Orcutt: J. occup. Med. 2, 383 (1960) 11. Krantz, J. C. jr, C. J. Carr, J. P. Vitcha: J. Pharmacol. exp. Ther. 94, 315 (1948); cited in [9] 12. Gerarde, H. W: Arch. environm. Hlth 6, 329 (1963) 13. Ehrenreich, T: Ann. clin. Lab. Sci. 7, 6 (1977) 14. Haider, C. A., C. E. Holdsworth, B. Y. Cockrell, V. J. Piccirillo: Toxicol. industr. Hlth 1, 67 (1985) 15. Phillips, R. D., B. Y. Cockrell: "Effects of certain light hydrocarbons on kidney function and structure in male rats", in Advances in modern environmental toxicology, Vol. VII Renal effects of petroleum hydrocarbons, p 89, Princeton Scientific Publishers, Inc., Princeton, N. J., USA, 1984 16. Spencer, P.: Neuropathic potential of n-hexane in the presence of other hexane isomers, API Med. Res. Publ. 30-30226 (1982) completed 26. 10. 1990