Toxicological Review of n-Hexane (CAS No. 110-54-3) (PDF)

Data are means ± standard error of the mean (SEM) (n = 3).
Source: Baker and Rickert, 1981.
3.3. METABOLISM
n-Hexane is principally metabolized in the liver. As shown in Figure 3-1, n-hexane is
initially hydroxylated by the action of mixed function oxidases to form either 1- or 3-hexanol in
a detoxification pathway or 2-hexanol in a bioactivation pathway. Through the bioactivation
pathway, 2-hexanol is converted to 2-hexanone and 2,5-hexanediol. Both of these metabolites
are then further metabolized to 5-hydroxy-2-hexanone, 2,5-hexanedione, and 4,5-dihydroxy­
2-hexanone. 2,5-Hexanedione is believed to be the major toxic metabolite produced in humans
following acid hydrolysis of urine samples prior to analysis by gas chromatography (Perbellini et
al., 1981).
Evidence that the liver is the primary location for the initial hydroxylation step for
bioactivation of n-hexane comes from the measurement of hydroxylating activity in isolated
microsomes from liver, lung, brain, and the extensor digitorum longus and soleus skeletal
muscles (Crosbie et al., 1994). Microsomes were incubated with n-hexane in the presence of
reduced nicotinamide adenine dinucleotide phosphate (NADPH) and the rates of production of
the primary alcohols, 1-, 2-, and 3-hexanol, were compared. Liver microsomes produced
significantly more 2-hexanol (1104 ± 205 pmol/minute-mg protein) than microsomes from lung,
brain, and soleus and extensor digitorum longus skeletal muscles (132 ± 25, 3 ± 2, 4 ± 1, 28 ± 5
pmol/minute-mg protein, respectively). Similarly, in liver microsomes, 2-hexanol production
occurred at a much faster rate than that of 1- or 3-hexanol. In contrast, the production of
1-hexanol appeared to occur at a much faster rate in microsomal preparations from the lung.
Metabolism of n-hexane in humans primarily forms 2,5-hexanedione. Perbellini et al.
(1981) identified this metabolite along with 2,5-dimethylfuran, (-valerolactone, and 2-hexanol in
the urine of 41 shoe workers exposed to 11–250 mg/m 3 commercial hexane (a mixture
containing n-hexane). The mean concentrations, determined following acid extraction of the
urine, were 5.4 ± 4.9, 3.7 ± 4.1, 3.3 ± 2.7, and 0.19 ± 0.26 mg/L, respectively. n-Hexane
exposure correlated well both with total metabolites (r = 0.7858) and with 2-hexanol (r = 0.6851)
and 2,5-hexanedione (r = 0.6725) individually.
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