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

7. Evaluation

Inhalation exposure

For inhalation exposure sensory irritation of eyes and respiratory tract should be considered as critical effects from short term exposure. Based on the recent evaluation by WHO (1998) significant irritation in the general population occurs above levels of 0.1 mg/m³, and thus this level may be considered as a NOAEL for the general population. Thus this value will be used as the basis for the limit value in air.

With respect to long term exposure the development of nasal cancer should be considered as critical effect. From experimental animal data there seems to be a threshold at about 5-6 mg/m³ for the development of tumours in the nasal cavities, as none of these tumours were found below this level at which clear cytotoxic effects occur. Several data indicate that cytotoxicity is a prerequisite for the development of cancer.

Some important aspects with respect to cytotoxic effects of formaldehyde should be mentioned. Cytotoxicity in the nasal cavities after long term exposure has been observed down to 2 ppm (2.5 mg/m³) but not at 0.7 ppm (0.86 mg/m³). At dose levels in the 0.1-1 ppm range primates are expected to be about a factor 10 (see table 5.1) less susceptible compared to rats because rats are subjected to more concentrated exposure than primates due to a more narrow and complex anatomy of the nasal cavity resulting in enhanced retention of formaldehyde in certain area of the nasal cavity. Cytotoxicity has been found more related to formaldehyde concentration than the total exposure expressed as the product of concentration and duration (c x t).

The well documented genotoxic potential of formaldehyde argues against a threshold for the carcinogenic effects, as the genotoxic effects are thought to be linked to the carcinogenic effect of the substance. Opponents for a threshold of formaldehyde argue, that the substance due to high reactivity at low levels will react with proteins and macromolecules in the mucous and at the outer cell surface or be metabolised by nasal mucosal formaldehydedehydrogenase which protects against the genotoxic potential of the substance. Thus formaldehyde exposure has to exceed these saturable defence mechanisms before the substance can exert genotoxic activity on a cellular level. Therefore the genotoxic potential may first (or especially) be expressed at higher levels where also cytotoxicity occur, and where increased cell turnover make expression of the genotoxic effects more probable. Such a threshold phenomenon would explain the very steep dose-response relationship for the development of nasal tumours and therefore it seems most relevant to use a threshold approach when making a risk assessment for formaldehyde.

oral exposure

For oral exposure the induction of lesions in the gastrointestinal mucosa, the development of gastrointestinal tumours, the development of histopathological changes in the kidneys, and leukaemia should all be considered as critical effects.

With respect to development of lesions of the gastric mucosa and histopathological changes in the kidneys a NOAEL of 15 mg/kg/day was obtained in a long term study with oral administration of drinking water containing formaldehyde.

One oral study with rats resulted in dose related increase in incidences of leukaemia when formaldehyde was administered in drinking water (from 50 to 1500 ppm). When tumour type and occurrence on sex was considered level of significance was reached at the two highest dose levels of 1000 and 1500 ppm (corresponding to 100 and 150 mg/kg b.w./day) i.e. NOAEL at 500 ppm (corresponding to 50 mg/kg b.w./day). Further increased incidences of different types of gastro-intestinal tumours occurred, most clearly at 1500 ppm (and at 2500 ppm in a subsequent study with only one dose group included).

Thus, effects in the gastro-intestinal tract seem to be the most consistent effects observed in these three oral long term studies. As for effects in the respiratory tract, it can not be excluded that the irritant effects of formaldehyde could give rise to some of the tumour types observed in the gastro-intestinal tract. Thus, the NOAEL value of 15 mg/kg b.w./day will be used as basis for the calculation of a TDI value.

dermal exposure

The induction of dermal sensitisation and the development of allergic response are considered as critical effects from dermal formaldehyde exposure. The LOAEL/NOAEL values for induction of dermal sensitisation has been found at formaldehyde concentrations of 0.37% / 0.037% formaldehyde after ten times 48-72 hours of occlusive exposure to formaldehyde. The LOAEL for provocation of allergic responses in formaldehyde sensitised persons was found to exposure of a 30 ppm formaldehyde preparation in the axilla (occlusive dressing for 48 hours). Exposure by occlusive dressing placed on the back resulted in LOAEL at 250 ppm formaldehyde and NOAEL of 50 ppm for the development of allergic response in sensitised persons.