Toxicological evaluation and limit values for Methyl-tertiary-butyl ether (MTBE), Formaldehyde, Glutaraldehyde, Furfural

6. Summary

Description

MTBE is a colourless liquid with characteristic terpene-like odour.

Use

MTBE is used as an octane enhancing additive in gasoline with a content of 7-11 vol%.

Environment

Due to the high vapour pressure of MTBE (245 mmHg at 25 ^oC) release to the environment mainly occur through evaporation.

In soil and water MTBE is very persistent towards biodegradation. In soil MTBE may evaporate from surface soil, while wash-out into the ground water may occur from deeper soil layer because of the relatively high water solubility of the substance (48 g MTBE/ l water).

In air MTBE undergo photochemical degradation.

Human exposure

Inhalation is considered the most important exposure route for human MTBE exposure. Short term exposure levels of 6-7.5 mg/m³ MTBE have been measured during refuelling cars at tank stations. In Fairbanks in Alaska where 15% MTBE gasoline is used during winter time an average outdoor and indoor level of 0.020 mg/m³ was measured. Based on such data a level for the ambient air in urban areas in Denmark could preliminary be estimated to 0.005-0.010 mg/m³.

Toxicokinetics

MTBE is rapidly taken up by inhalation exposure in humans with a retention of 30-40%. From animal studies it has been shown that MTBE is easily absorbed after oral and dermal exposure.

MTBE is rapidly eliminated from the body, mainly through expired air as the unchanged compound. MTBE is to some extent metabolised to tert-butyl alcohol (TBA) and formaldehyde. In the organism TBA has a longer half-life than MTBE. In humans elimination of MTBE from blood occurred in three phases with half-lives of 10 minutes, 1.5 hour and 19 hours.

Human toxicity

For humans an average odour detection limit of 0.19 mg/m³ has been detected in air and 0.18 mg/l in water. From the occupational environment and from areas where MTBE content in gasoline was increased up to 15 vol% there have been several reportings of irritation of eyes and respiratory tract, headache, nausea, dizziness and other unspecific symptoms. However, no causal relationship to MTBE exposure could be derived from these data, as the persons have been exposed to gasoline vapours and exhaust emission as well. In order to elucidate the effect of MTBE two controlled laboratory experiments with humans have been conducted. In these studies a one hour exposure to 5 and 6 mg/m³ MTBE, respectively, did not result in any subjective symptoms other that sensation of odour.

A third chamber study with exposure up to 180 mg/m³ MTBE for 2 hours was also negative with respect to the induction of any irritation symptoms, while a study using an exposure level of 270 mg/m³ resulted in mucous membrane irritation and feeling of heaviness in the head.

Animal toxicity acute effects

In animals the oral LD₅₀-value for rats is about 3800 mg/kg. The LC₅₀-value for rats after 4 hours exposure is about 85 000 mg/m³.

In mice an RD₅₀-value (the concentration that produce a 50% decrease in respiratory rate) of 16 600 mg/m³ was registered indicating respiratory tract irritation of the substance. Exposure to 10 800 mg/m³ has resulted in swollen periocular tissue and spasm of the eyelids.

CNS effects have been observed in connection with inhalation exposure: hypoactivity, sedation, ataxia, weakness, loss of righting reflex, lack of startle reflex, tremors and unconsciousness. Changes in motor activity occurred in rats down to an exposure level of 2880 mg/m³. Oral administration of 1200 mg/kg to rats produced anaesthesia that lasted for up to 2 hours.

The kidney and the liver has been demonstrated to be the target organ in short term studies with repeated exposure. From inhalation studies a LOAEL of 2880 mg/m³ could be set based on increased relative liver and kidney weights in rats. From studies with oral administration a NOAEL of 100 mg/kg/d and a LOAEL of 300 mg/kg/d in rats could be set due to these effects. (A LOAEL of 90 mg/kg/d was found in a 28-day oral study with rats due to increased value in mean corpuscular haemoglobin, however this effect could not be verified from other studies).

chronic effects / carcinogenicity

From long term/ carcinogenicity studies a NOAEL of 1440 mg/m³ could be set for female rats based on effects on liver and kidneys at the higher exposure levels (10800 and 28800 mg/m³). A LOAEL of 1440 mg/m³ could be set for males due to slight increase in nephropathy (maybe related to a2m-globulin accumulation). In mice a NOAEL of 1440 mg/m³ could be set.

Carcinogenicity studies using inhalation exposure to 0, 1440, 10800, and 28800 mg/m³ were conducted with rats and mice. In male rats, exposure to 10800 mg/m³ and 28800 mg/m³ produced increased incidences of renal tubular cell adenomas and carcinomas and dose related increase in interstitial cell (Leydig cell) adenomas of the testes. In mice, 28800 mg/m³ produced an increased incidence of hepatocellular adenomas in the female animals.

It has been suggested that the occurrence of renal tubular cell tumours in male rats could be the follow of a2m-globulin nephropathy as accumulation of a2mglobulin has been demonstrated after MTBE exposure to male rats. However, MTBE has only been shown to be a very mild inducer of a2m globulin nephropathy, and therefore the mechanism behind the tumourigenic effects in the male rat kidney seems not to be fully elucidated.

In a study with gavage administration of 0, 250, and 1000 mg/kg/day to rats a statistically increased incidence of testicular Leydig cell tumours occurred at the highest dose level. However, longer life-time of high dose male rats may to some extent explain this finding as the occurrence of Leydig cell tumours is age related. In female a significantly and dose-related increased in the sum of lymphoma and leukaemia was observed at both dose levels.

Reproductive and developmental effects

MTBE has not produced any reproductive effects in one single - and one two-generation test with rats. From developmental studies with rats mice and rabbits no indication of developmental or teratogenic effects were found below maternal toxic dose levels. NOAEL for maternal toxicity was found in the range of 3600 to 10800 mg/m³ and LOAEL for maternal toxicity and foetal toxicity (reduced foetal body weight) was found to 14 400 mg/m³.

Mutagenic and genotoxic effects

MTBE has been found negative in in vivo mutagenicity tests for DNA repair and micronuclei formation in mice after inhalation exposure. In vitro bacterial assays and an assay with rat hepatocytes were negative. One in vitro test with a mouse lymphoma cell line with metabolic activation resulted in positive result which was shown to be due to the formation of formaldehyde.

Carcinogenicity

See above.