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Neurotoxicity

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Description of key information

Key value for chemical safety assessment

Effect on neurotoxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: acute inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Assessment taken from EU-RAR, acceptable for assessment.
Principles of method if other than guideline:
An acute neurotoxicity study with rats
GLP compliance:
not specified
Limit test:
no
Species:
rat
Sex:
male/female
Route of administration:
inhalation
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 hours
Frequency of treatment:
once
Remarks:
Doses / Concentrations:
800, 4000 and 8000 ppm
Basis:
other: target concentrations
No. of animals per sex per dose:
22 male and 22 female rats
Control animals:
yes
Neurobehavioural examinations performed and frequency:
Motor activity was evaluated on 14 rats before and immediately following the exposure in a 5-hour session. The remaining eight rats/group were evaluated for their neurobehavioral function using Functional Observation Battery (FOB) prior to and 1, 6 and 24 hours after exposure.
Dose descriptor:
NOAEC
Effect level:
800
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other:
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
2 856 mg/m³
Species:
rat

Additional information

An acute neurotoxicity study was conducted on 22 male and 22 female rats per group that were exposed to 0, 800, 4000 and 8000 ppm (2856, 14280 and 28560 mg/m3) MTBE vapour for 6 hours (Bushy Run Research Center, 1989e). Motor activity was evaluated in 14 rats before and immediately following the exposure. The remaining eight rats/group were evaluated for their neurobehavioral function using Functional Observation Battery (FOB) prior to and 1, 6 and 24 hours after exposure. The FOB observations that were considered biologically relevant were ataxia / duck-walk gait seen in the intermediate and high exposure groups 1 hour post exposure. In addition to these clinical observations, females also exhibited increased lacrimation and piloerection at the two highest doses. Mean motor activity followed a pattern of initial decrease in activity followed by an increase, which then turned to a decline after the first three hours of the experiment. This was seen most clearly in high-dose males. In the low and intermediate groups, activity increased by about one quarter. The effects were mostly reversible within 6 hours.

In the acute inhalation toxicity studies, CNS effects were reported at concentrations from 44 mg/l (4 hours) (lower concentrations were not tested).

A neurotoxicity evaluation was performed in a 13-week inhalation study with rats (Bushy Run Research Center, 1989a). The evaluation was performed with 10 animals/group and included functional observation battery (FOB), measures of motor activity 20 hours after last exposure at an examination of neuropathological signs. Nervous system was also evaluated microscopically, with various sections of the brain, spinal cord and ganglia were included in the examination. Males and females had a depressed absolute brain weight and length in the 8000 ppm (28560 mg/m3) group, although not statistically significantly. FOB parameters showed a few differences relative to control, such as decreased hind-limb grip in mid concentration males and decrease in latency to rotate, which in their inconsistency were not considered indicative of nervous system dysfunction. Although some variation from control was seen in the motor activity of high dose males (-) and mid-dose females (+) on day 55, neither consistency nor dose relation could be found to give these symptoms a biological significance.

Human male volunteers reported mild symptoms, mainly feelings in the head and feeling less cheerful (FIOH, 1997). The frequency of symptoms was related to the exposure level (0, 25, 75 ppm) and reached statistical significance at 75 ppm after 3 hours of exposure to MTBE. These effects were rated as slight. There was no indication found of an objective sign of CNS function impairment in terms of psychomotor performance, sustained attention, or standing steadiness. It should be noted that although sensory symptoms may show greater sensitivity than objective indices, it is possible that symptoms are mediated by mechanisms other than CNS depression, especially as MTBE has an unpleasant odour.

Another human volunteer investigated whether CNS effects occurred after exposure up to 50 ppm MTBE for two hours while the persons were exercising at 50W on a bicycle ergometer (Nihlen, 1998). Effects were measured by a questionnaire. No indications for the occurrence of CNS effects were reported.

Justification for classification or non-classification

In the acute neurotoxicity study, positive FOB observations were observed at concentrations from 4000 ppm (14.28 mg/l) (6 hours exposure). An exposure of 4000 ppm for 6 hours might be more or less equivalent to 4 hours exposure to 6000 ppm (21.4 mg/l) in case of narcotic gases. This is just above the criterion of 20 mg/l over 4 hours set for Specific Target Organ Toxicity (STOT) – Single exposure (Category 2) classification in the CLP Regulation. In the acute inhalation toxicity studies CNS effects occurred at concentrations of 44 mg/l (4 hours) (lower concentrations were not tested). Regarding the 90 days neurotoxicity study, no major transient CNS effects occurred. The available human data do not indicate an objective sign of CNS function impairment. Based on all available data, it is concluded that MTBE does not warrant classification for Specific Target Organ Toxicity (STOT) – Single exposure under CLP Regulation criteria.