TR 072 : Methyl tert-Butyl Ether (MTBE) Health Risk Characterisation | June 1997
Methyl tert-butyl ether (MTBE) is a colourless flammable liquid with a distinctive ethereal odour. It is used almost exclusively as a gasoline additive. It is added to unleaded gasoline in quantities between 2 and 5% (w/w), to raise the octane level, or up to 15% (w/w) to improve combustion efficiency as a measure to reduce air pollution from automotive exhaust emissions.
Minor applications include its use in clinical practice as a solvent for the dissolution of gallstones.
Although the data on occupational exposure available to the Task Force were limited, they provided an indication of the magnitude of the potential exposure for workers. Occupational exposure may occur during MTBE production and loading, when handling gasoline containing MTBE or when working as a service station attendant or garage worker. The relevant route of such exposure is inhalation. Whereas MTBE production is associated with relatively low exposures (< 10 mg/m3), loading operations may result in higher exposures (mean values of 20 mg/m3, peak values of about 200 mg/m3). Mean short-term exposure measurements for loading and delivery of gasoline containing 10-15% MTBE were between 13 and 91 mg/m3 with a maximum of 226 mg/m3. Since most fuels in Europe currently contain only 2 to 5% MTBE as an octane enhancer, these findings were considered by the Task Force to be a ‘worst case’ situation. For service station attendants and garage workers in the US, the mean exposures were < 3.5 mg/m3 and 7.56 mg/m3, respectively. The most likely source of consumer exposure to MTBE arises from gasoline evaporation during car refuelling and its duration us very short. A study of consumer exposure in Finland measured concentrations of 6.0-7.5 mg/m3 at service stations delivering gasoline containing 11% of MTBE.
Biotransformation of MTBE leads to the formation of tert-butanol (TBA) and formaldehyde, which in turn are further metabolised. TBA excretion proceeds relatively slowly (half-life of 8 h in humans). For formaldehyde the detoxification rate is much faster than its rate of formation from MTBE and therefore this route of metabolism is judged not to contribute to the toxic effects of MTBE discussed in this report. Toxicokinetic data do not indicate reasons for concern with regard to bioaccumulation of MTBE of any of its metabolites.
Skin and respiratory irritation are regarded as effects of prime concern following acute exposure, MTBE possesses a low order of acute toxicity in experimental animals exposed via oral, dermal and inhalation routes. LD50 values exceed 2,000 mg/kg for oral and dermal exposure, and the inhalation LC50 value is 85,000 mg/m3 for 4 hours. Sub-lethal acute exposure evokes local irritation at the site of contact and transient clinical signs characteristic of central nervous system (CNS) depression. Skin contact with MTBE causes reversible moderate to severe irritation in rabbits whereas MTBE was found to be only slightly irritant to the rabbit eye. MTBE vapour at concentrations above 300 mg/m3 evokes slight transient irritation to the respiratory system of laboratory animals. For sensory and respiratory irritation an RD50 value (50% reduction of breathing rate) of 16,600 mg/m3 was determined for MTBE in the mouse. The Task Force recommended that MTBE be labelled as irritant (Xi) with the corresponding R-phrase 38 (irritating to skin).
There have been no cases of reported sensitisation to MTBE in humans exposed by skin contact to the neat material or to gasoline containing MTBE. Studies in animals also failed to demonstrate skin sensitising potential on the part of MTBE, adding weight to the conclusion that MTBE is not a skin sensitiser.
MTBE caused anaesthesia in experimental animals when inhaled at concentrations of 28,800 mg/m3. Reversible CNS effects were detected in a rat study at 14,400 mg/m3 (LOAL) using a functional observation battery and 6 hours of exposure. The NOAEL in this study was 2,880 mg/m3. Observations suggesting transient CNS depression were consistently made also in animal studies using repeated inhalation and oral exposure. However, all effects were consistently made also in animal studies using repeated inhalation and oral exposure. However, all effects were reversed when exposure ended and repeated exposure did not lead to NOAELs that were lower than for single exposure.
Principle effects observed following repeat oral and inhalation exposure of rats and mice to MTBE are local irritation, transient anaesthetic effects (as observed with many other low molecular weight ethers), chronic nephropathy and hepatocellular hypertrophy. The NOAEL for sub-chronic oral exposure is 300 mg/kg and for chronic inhalation exposure 1,400 mg/m3. The latter value corresponds to daily retained doses (for calculation see page 29) of 102 and 113 mg/kg for male and female rates, respectively and 182 and 184 mg/kg for male and female mice, respectively.
MTBE has been tested extensively in vitro and in vivo for its genotoxic potential. The weight of evidence shows MTBE is not genotoxic. The conclusion is supported by the information for TBA, which is not genotoxic in several in vitro and in vivotests, and formaldehyde, which though genotoxic in a number of tests, is rapidly detoxified by the body thereby removing the potential to damage the cell.
Tumours in rodents result from exposure to MTBE at doses exceeding the Maximum Tolerated Dose (MTD). An inhalation study in rats demonstrated a tumourigenic response in the male kidney at 10,800 and 28,800 mg/m3(corresponding to daily retained doses of 384 and 1023 mg/kg, respectively), but a non-genotoxic mechanism unique to the male rate is probably involved. An apparent increase in the incidence of Leydig cell tumours in male rats treated via inhalation was not considered to be relevant to humans. An inhalation studies with mice showed an increase in the incidence of liver adenomas in female animals at 28,800 mg/m3 (corresponding to a daily retained dose of 1824 mg/kg). A non-genotoxic mechanism is likely to be involved.
Further mechanistic studies are currently underway to clarify the mechanisms for the induction of these tumours.
Effects reported in an oral gavage study include an increase in rat Leydig cell tumour incidence and elevated combined lympohoma/leukaemia incidence in female rats. The Task Force considered the rat Leydig cell tumour findings as not predictive of hazard to humans. Furthermore, the importance of the combined lymphomas/leukaemia incidence from this oral gavage study was unclear due to deficiencies in the study report.
Overall, the Task Force concluded that the doses necessary to evoke neoplastic effects are equal to or greater than the doses that induce non-neoplastic effects in female mouse liver and male rat carcinogenic effect. The Task Force concluded that MTBE is not carcinogenic according to the criteria in EU Directive on Dangerous Substances 67/548/EEC (EEC, 1993B).
Effects of MTBE vapour on reproduction and development have been evaluated in well-conducted inhalation studies with rats, mice and rabbits. Foetal toxicity and developmental toxicity were observed only at concentrations clearly toxic to the mother. MTBE was not embyotoxic or teratogenic at exposure levels not causing maternal toxicity and did not adversely affect reproduction.
A large body of data is available from human experience with MTBE, including case reports of clinical use of MTBE for gallstone dissolution, studies reporting subjective complaints by garage workers and service station attendants, large population studies with sophisticated study design and controlled exposure concentration and health complaints, this has not been confirmed in subsequent studies. This absence of an association is in line with short-term experimental studies that showed no specific studies. Human experimental data do not indicate irritation of the respiratory tract at concentrations of 180 mg/m3 for two hours. Exposure to 270 mg/m3 for three hours caused mild mucous membrane irritation in some volunteers. Objective symptoms on the CNS have not been observed in volunteer studies up to 270 mg/m3. Subjective symptoms at this concentration were reported by volunteers (mainly feeling of heaviness in the head). At 180 mg/m3 no symptoms were reported.
Table 1 on page 5 summarises the conclusions with regard to MTBE-related health effects. Irritation observed after short-term exposure in humans as well as liver and kidney toxicity observed after long-term exposure in experimental animals are considered to be the critical effects for the health risk characterisation of MTBE. Mild respiratory irritation occurred at a concentration of 270 mg/m3 for three hours in human volunteers, whereas 180 mg/m3 for two hours did not evoke such effects. The lowest NOAEL for liver and kidney effects after chronic inhalation exposure was 102 mg/kg/day (retained dose in male rats). The basis for the risk characterisation is a comparison of these three different doses/concentrations with occupational and consumer exposure data.
The available data on short-term peak exposure levels (about 200 mg/m3) did not indicate concerns with regard to respiratory irritation. Comparison of the NOAEL for long-term liver and kidney effects revealed margins of safety between 180 to 300 fold for service station attendants and garage workers. A 17,000 fold margin of safety was calculated for consumer exposure during car refuelling.
Compliance with an occupational exposure limit of 90 mg/m3 or 25 ppm MTBE (8-h TWA) is considered by the Task Force to protect workers from any potential health hazards. This concentration corresponds to a daily retained MTBE dose of about 5.1 mg/kg for a 70kg adult (on the basis of a ventilation volume of 10m3/8-h shift and a relative respiratory uptake of 40%) and provides a margin of safety of 20 when compared with the lowest NOAEL determined in chronic animal inhalation experiments. Respiratory irritation is regarded as the critical effect for higher short-term exposures. In humans, no effects were observed at a concentration of 180 mg/m3 for 2 hours, while at 270 mg/m3 for three hours only weak irritating effects on the mucous membranes were reported in some volunteers. Therefore a limit of three times the TWA (270 mg/m3 or 75 ppm) is considered to be an appropriate short-term, peak exposure limit (15-min STEL).
The risk characterisation for MTBE does not indicate concern for human health with regard to current occupational and consumer exposures.