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EC number: 203-777-6
CAS number: 110-54-3
Occupational epidemiology data describing neurotoxicity effects in humans are avaible for n-hexane and have been extensively reviewed by WHO, ATSDR, and U. S. EPA. One key neurotoxicity animal study was identified for n-hexane (Takeuchi, 1980; Klimisch score =2).
Occupational epidemiology data describing
neurotoxicity effects in humans are available for n-hexane and have been
extensively reviewed by WHO, the Agency for Toxic Substances and Disease
Registry (ATSDR), and the U.S. Environmental Protection Agency (U.S.
EPA). One key neurotoxicity animal study was identified for n-hexane
(Takeuchi, 1980; Klimisch score=2).
n-Hexane, neurological effects in humans
Among hydrocarbon solvents, a unique
toxicological effect of n-hexane in humans is its association with
pathological changes in the peripheral nervous system, more specifically
an axonal neuropathy of the lower extremities. Development
of the axonal neuropathy is the consequence of exposure to a neurotoxic
metabolite of n-hexane; 2,4-hexanedione. Although
questions have been raised regarding the potential for other hexane
solvents, including other C6 isomers, to produce similar effects, it has
been shown, primarily through animal models, that hydrocarbons other
than n-hexane do not form the 2,5-hexanedione metabolite and,
accordingly, do not produce similar neurological effects (see for
example WHO, 1991; ATSDR, 1999, U.S. EPA, 2005).
The association of n-hexane exposure with
the development of peripheral neuropathy was first described in studies
of Japanese sandal workers. Based on assessment reviews of
epidemiology studies of n-hexane (e.g., WHO, 1991, ATSDR, 1999, U.S.
EPA, 2005) exposure estimates ranged from 1625 -8125 mg/m3 (500 –
2500 ppm), although these measurements were typically done after the
fact. As additional complications, these workers
typically worked very long hours and often lived in the same location.
The cases were divided into 3 categories based on severity of the
1 Sensory neuropathy
neuropathy with amyotrophy
Studies of 95 employees at an Italian shoe
factory population (Mutti et al., 1982) identified subclinical
neuropathy, particularly significant reductions in nerve conduction
velocity. The approximate average exposure to
n-hexane in the work place was 317 mg/m3 (90 ppm) over a 2 year period.
Additionally, other solvents were used. When
these workers were subdivided into “low” (approximately 243 mg/m3) and
“high” (approximately 475 mg/m3) exposure groups based on n-hexane
levels, there appeared to be a dose-related trend.
A study of Taiwanese press proofers was
reported by Wang et al. (1986). Fifteen cases of
overt peripheral neuropathy were diagnosed among 59 workers distributed
among 16 factories. The average levels of n-hexane
exposure at the two factories, accounting for 8 of the 15 cases, were
669 mg/m3 and 74 mg/m3 respectively. It
was also reported that workers typically worked more than 8 hours/day,
and 12 of the 15 cases slept in the factories overnight. Exposure
to n-hexane air concentrations less than 352 mg/m3 (100 ppm)
was not associated with clinical peripheral neuropathy.
Due in part to concerns about the quality of
the exposure measurements and differences in exposure periods, it has
been difficult to establish thresholds for human effects. One
recommendation is to use data on urinary levels of 2,5-hexanedione as a
biomarker of exposure (SCOEL, 1995). Governa et al.
(1987) reported that subclinical neurological effects were associated
with urinary 2,5 hexanedione concentrations of > 7.5 mg/L
whereas there were few effects among individuals with urinary levels 7.5
mg/L. Based data from Perbellini et al. (1981)
relating urinary excretion of n-hexane metabolites with external
n-hexane exposure, 7.5 mg/L corresponds to approximately 250 mg/m3
Assessment Review References:
ATSDR (Agency for Toxic Substances and
Disease Registry) (1999). Toxicological Profile for
n-Hexane. ATSDR, Atlanta, Georgia.
SCOEL (Scientific Committee on Occupational
Exposure Limits) (1995). Recommendations from
Scientific Expert Group on Occupational Exposure Limits for n-hexane. SEG/SUM/52C.
U.S. EPA (U.S. Environmental Protection
Agency) (2005). Toxicological Review of n-Hexane (CAS No. 110 -54-3) In
Support of Summary Information on the Integrated Risk Information System
(IRIS). November 2005, U.S. Environmental Protection Agency Washington,
WHO, International Program on Chemical
Safety (1991). Environmental Health Criteria (EHC)
122, n-Hexane. World Health Organization, Geneva,
n-Hexane, neurological effects in animals
a key neurotoxicity study, seven rats were exposed to 3000 ppm of
n-hexane vapors for 12 hrs a day for 16 weeks (Takeuchi, 1980;
Klimisch score =2). Body weights and conduction velocity of the
peripheral nerve of the tail was measured at 0, 4, 8, 12 and 16 weeks.
At the end of the exposure period, two animals were sacrificed and the
nerve tissue examined. Two animals died before the end of the exposure
period. All animals showed reduced weight gain after 4 weeks of
exposure. Neurological effects were seen beginning at 10 weeks
exposure. Motor nerve conduction velocity and distal latency were
significantly affected after 4 weeks exposure. Examination of neural
tissue showed damage to the tibial nerve and dorsal trunk of the tail
nerve. The LOAEC for sub-chronic exposure was 3000 ppm (10560 mg/m3).
No NOAEC was found.
on the information presented in the study on anaesthetic activity of n-hexane,
classified as R67, Vapours may cause drowsiness and dizziness in
accordance with Dangerous Substances Directive 67/584/EEC and as STOT
Single Exp. 3 (H336: May cause drowsiness or dizziness) in accordance
with CLP EU Regulation 1272/2008.
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