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Exposure related observations in humans: other data

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exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline study, published in peer-reviewed literature, used as key study by the SCOEL, acceptable for assessment

Data source

Reference Type:
Experimental exposure to methyl tertiary-butyl ether. II. Acute effects in humans.
Nihlén A, Wålinder R, Löf A & Johanson G
Bibliographic source:
Toxicology and Applied Pharmacology, 148, 281-7

Materials and methods

Type of study / information:
Acute effects after controlled MTBE exposure of male volunteers.
Endpoint addressed:
acute toxicity: inhalation
Principles of method if other than guideline:
Assessing acute health effects after exposure to 5, 25, or 50 ppm MTBE while the persons were exercising at 50W on a bicycle ergometer, both with objective methods and a questionnaire.
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
tert-butyl methyl ether
EC Number:
EC Name:
tert-butyl methyl ether
Cas Number:
Molecular formula:
tert-butyl methyl ether
Details on test material:
purity: 99.8% (Sigma-Aldrich, Germany)


Ethical approval:
other: The study was performed after written consent from the participants, approval from the Regional Ethical Committee at the Karolinska Institute, Solna, Sweden, and according to the Declaration of Helsinki.
Details on study design:
Ten healthy, nonsmoking male volunteers of 23 to 51 years of age were exposed (two at a time) to 5, 25, or 50 ppm MTBE in an exposure chamber during two hours while the persons were exercising at 50W on a bicycle ergometer. All subjects were first exposed to the high level, whereas the order of exposures to the intermediate and low levels was randomised; there was at least a two-week interval between the exposures. The subjects were unaware of the exposure sequence. The low level of 5 ppm was chosen such that the volunteers could smell MTBE in all exposures.
The subjects rated the degree of nasal irritation, ocular irritation, throat irritation, the smell, discomfort, and central nervous system effects before, during, and after all three exposure occasions using a questionnaire. Answers were given on a 100-mm visual analog scale, graded from "not at all" to "almost unbearable".
Ocular blinking frequency, eye redness, tear-film break-up time, self-reported tear-film break-up time and conjunctival epithelial damage were measured repeatedly at 50 ppm MTBE. Similarly, nasal lavage samples were analysed for albumin, eosinophilic cationic protein, myeloperoxidase, lysozyme and for total cells. Nasal peak flow measurements were performed at all exposure levels, and acoustic rhinometry at the two lower levels.
Exposure assessment:
Details on exposure:
The average chamber air concentrations were 4.8, 24 and 49 ppm.
Exposure was to MTBE in an exposure chamber (20 m3) with controlled climate (average temperature 20°C, 40% relative humidity, 18–20 air exchanges/hr).

Results and discussion

The mean concentrations of MTBE in blood levelled off towards the end of exposure reaching 1.4, 6.5, or 13 μmol/l at the 5, 25, or 50 ppm levels of exposure.
The ratings of solvent smell increased dramatically (ratings up to 50% of the scale) as the volunteers entered the chamber and declined slowly with time (p < 0.05, repeated-measures ANOVA). All other questions were rated from "not at all" to "hardly at all" (0-10% of the scale) with no significant relation to exposure. The eye measurements showed no effects of MTBE exposure. Blockage index, a measure of nasal airway resistance calculated from the peak expiratory flows, increased significantly after exposure; however, the effect was not related to exposure level. In addition, a non-significant tendency of decreased nasal volume was seen in the acoustic rhinometry measurements, but with no clear dose-effect relationship. This study suggests no or minimal acute effects of MTBE vapor upon short-term exposure to 50 ppm MTBE.

Applicant's summary and conclusion