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EC number: 203-806-2
CAS number: 110-82-7
An NOAEL of 2,000 ppm (6,880 mg/m3) can be assumed for changes in SCOB after acute exposure of rats to cyclohexane.Acute neurotoxicity by inhalation was assessed in human volunteers, with the NOAEC being at the highest dose tested: 250 ppm (860 mg/m3) for 4-hour exposure period (860 mg/m3).
Statistically significant differences from
control in FOB values were seen at 8,000 ppm (28,000 mg/m3) however,
there was a lack of consistency between assessments. Effects observed at
2,000 ppm were considered to be the beginning of behavioural toxic
effects. The authors concluded that "exposure at 400 ppm or 2,000 ppm of
cyclohexane on a group basis did not induce neurobehavioural effects".
neurotoxicity of acute exposure to cyclohexane was studied in a
schedule-controlled operant behaviour (SCOB) study (Christoph et al,
rats (trained in operant performance) received an acute inhalation
exposure to cyclohexane vapour (0 ppm, 500 ppm. 2000 ppm, or 7000 ppm)
for 6 hr. During the operant session (30 min after termination of
exposure), fixed ratio (FR) running rate for the 7000 ppm group
decreased; FR post-reinforcement pause duration and the rate and pattern
of Fl performance were unaffected. Cyclohexane exposures of 500 or 2000
ppm had no detectable effects. No enduring effects of cyclohexane
occurred up to 2 weeks after exposure. Positive control animals dosed
with CPZ or AMPH confirmed the validity of the test method. The NOAEC
was concluded to be 2,000 ppm (6,880 mg/m3).
As part of
a wider programme, a study (conducted with 2 experiments) attempted to
evaluate the behavioural effects of exposure to cyclohexane in animals
and to determine internal levels of exposure at which effects occur
(Lammers et al, 2009). Functional observation battery data revealed
minimal CNS effects (small, non-statistically significant effects of
gait and tremor and statistically significant effect on approach).
were limited effects on the CNS at exposure levels up to 8,000 ppm
(28,000 mg/m3) and there was a lack of consistency between assessments
(notably between the first and third exposure days), this indicates that
the relationship of these small changes to treatment was uncertain. it
is concluded that "exposure at
400 ppm or 2,000 ppm of cyclohexane on a group basis did not induce
neurobehavioral effects" .
animal data (Christoph et al, 2000; Malley et al, 2000) are available
together with a human volunteer study also conducted at TNO (Lammers et
al, 2009), the results from this study are not taken forward for
consideration in the hazard and risk assessment.
performed by TNO (Lammers et al, 2009) was conducted in order to
establish the neurobehavioral effects in human volunteers exposed to 250
ppm (860 mg/m3) of cyclohexane for 4 hours or to placebo and
to 25 ppm (86 mg/m3) only. Twelve human male
volunteers (ages ranging from 20 to 39 years old) were exposed to the
experimental conditions using a double blind, two-way cross-over design.
The two tests were spaced 7 days apart. Subjects were tested using
automated neurobehavioral tests and questionnaires prior to exposure, 45
and 165 minutes after the beginning and about 60 minutes after the
effects observed were a significant improvement in performance under
both treatment conditions the Hand-Eye Coordination Test: sinus
condition; the Colour Word Vigilance Test and the Digit Memory Span Test
during the first test day. There was no compelling evidence for
treatment related effects at 860 mg/m3and the reports of
headache, throat and eye irritation were 'self reported' and subjective.
Evidence of only minimal effects in rats exposed to 28,000 mg/m3suggests
that effects in humans exposed to much lower levels would be unlikely.
The subjective, 'self-reported', effects reported in the human volunteer
study are therefore not taken into account for the determination of a
NOAEC and an NOAEC of 250 ppm (860 mg/m3) is assumed for
the TNO studies (Lammers et al, 2009; Hissink et al, 2009), it was
concluded that with the validated
human PBPK model it was possible to calculate an exposure level which would lead to
neurobehavioral effects in human. This dose would be 3,900 ppm (13,400
mg/m3) leading to a NOAEC of 1,200 ppm (4,125 mg/m3).
Since these values are derived from a model (not actual tested values),
it seems difficult to take them into account for the risk
characterisation instead of the animal data.
assessing these and other human and animal data, SCOEL (1991) concluded
that these results supported a human NOAEC of about 250 ppm which, when
compared with animal data indicating a NOAEC of 500 ppm and a LOAEC of
2000 ppm for narcotic effects in rats and mice, resulted in an IOELV of
200 ppm (8-hr TWA).
These effects are
considered to warrant labelling under CLP: Specific
Target Organ Toxicity - Single exposure, Category 3 following the
criteria for narcotic effects and assign with H336.
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