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

5. Regulations, limit values

Ambient air
Denmark (C-value): 0.02 mg/m³ (MST 1996).

Drinking water
Denmark: -
WHO (1996): 900 mg/l, based on a 20% allocation of a TDI value of 150 mg/kg per day. The TDI value is based on a NOAEL of 15 mg/kg per day from the chronic oral study by Til (1989) using a uncertainty factor of 100.

Soil
-

OELs
Denmark: 0.4 mg/m³ (At 1996).

Classification
Formaldehyde is classified for acute toxic effects (T;R23/24/25 - toxic by inhalation, in contact with skin and if swallowed), for corrosive properties (C;R34 - causes burns), for carcinogenic effects (Carc3;R40 - possible risks of irreversible effects) and for sensitisation (R43 - may cause sensitisation by skin contact) (MM 1996).

IARC/WHO
Group 2A, based on limited evidence for carcinogenicity in humans and sufficient evidence from inhalational animal experiments (IARC 1995).

US-EPA

U.S. EPA (1986): 0.08 mg/m³ as 10^-6 lifetime risk (calculated from the data by Kerns et al. (1983) using the linearised multistage model) (U.S. EPA 1986 - quoted from IRIS 1992).

U.S. EPA (1991): 3 mg/m³ as 10^-6 lifetime risk (using DNA-protein cross-link dosimetry in the nasal cavity as indicator for dose at the target tissue, and considering differences in anatomy of the nasal cavities between rats and primates (resulting in greater retention of formaldehyde in the nasal cavities of rats compared to monkeys)) (U.S. EPA 1991, Hernandez et al. 1994).

5.1 Comments concerning risk assessment

The findings of nasal tumours in rats in specific parts of the nasal mucosa has led to extensive research for determining the underlying causes for the development of these tumours.

Several specific points have been observed (Heck et al. 1990):

tumour dose-response

Studies in rats indicate that the development of squamous cell carcinomas in the nasal cavities follows a very steep dose response relationship, where the development of the tumours starts at 5-6 ppm (with an incidence of about 1%) and rapidly increases in the exposure range up to 14-15 ppm (to an incidence of 44%).

cytotoxicity

No tumours have been seen at exposure levels below cytotoxic levels. A critical concentration (> 2ppm) rather than the total dose determines whether cytotoxicity and lesions in the mucosa occur.

cell proliferation

Cell damage and increased cell proliferation seems to be a prerequisite for the development of tumours in the nasal cavities of the rat.

distribution of dose

In monkeys formaldehyde-induced lesions in the respiratory tract were found to be very similar in nature to those observed in rats. However, the lesions in the respiratory tract in monkeys were more widespread. After single exposure to formaldehyde the concentration of DNA-protein cross-links in the target tissue of the turbinates and anterior nose is significantly lower in monkeys compared to rats (see tissue dosimetry below).

defence mechanisms

Two saturable defence mechanisms have till now been identified in rats: covalent binding of formaldehyde to protein molecules present in the nasal mucus and metabolism by nasal mucosal formaldehydedehydrogenase. Other defence mechanisms such as repair of DNA-protein cross-links, may also be saturable as concentration increases.

tissue dosimetry, DNA-protein cross links

Inhalation of formaldehyde leads to the formation of DNA-protein cross links in the nasal respiratory mucosa. Species differences in the formation of DNA-protein cross links is illustrated in figure 5.1 which shows the relation between 6 hours formaldehyde exposure level in the range of 0.9-7.3 mg/m³ and cross-link formation in rats and rhesus monkeys. In rats the formation of DNA-protein cross-links was non-linear related to the formaldehyde concentration with a more steep dose-response relationship above 3-4 mg/m³ formaldehyde (IARC 1995).

(from IARC 1995).

These findings illustrate a more intense exposure of specific part of the nasal mucosa in rats compared to monkeys at identical exposure level.

A pharmacokinetic model to predict the degree of DNA-protein cross-links in humans showed lower formation of DNA-protein cross-links in humans compared to rats and rhesus monkeys. Furthermore, the studies showed that repeated daily exposure did not lead to higher levels of DNA-protein cross-links than single exposure, indicating that no accumulation takes place and that the cross-links in the nasal mucosa is rapidly repaired (IARC 1995).

revision of risk assessment

Due to the large differences of the anatomy of the nasal cavities between rats and primates and due to the shown differences in the formation of DNA-protein cross-links in the nasal target tissue, U.S. EPA re-evaluated their prior risk assessment from 1986. Calculating the cancer risk for monkeys, using DNA-protein cross links as indicator for the target tissue exposure, a risk estimate of 3 x 10^-5 was calculated for monkeys at an average exposure level of 0.1 mg/m³ formaldehyde (this corresponds to 3.3 mg/m³ as a 10^-6 life-time risk), see Table. 5.1.

Table 5.1 Comparison of upper bound estimates (the upper 95% confidence limits) of human lifetime carcinogenic risk for lifetime exposure to formaldehyde. The estimates are calculated by the use of the linearised multistage model.

a: estimated using 1987 unit risk 1.6 x 10^-2/ ppm.

b: incorporated rat and monkey dosimetry data.

Comparing the 0.1 mg/m³ risk level a 66 times reduced risk estimate

was obtained by the new approach, where a factor 2.5 could be ascribed to a new linearised multistage model and a factor 25 to DNA-protein cross link dosimetry and the differences between rat and monkey. (U.S.EPA 1991, Casanova et al. 1991, Hernandez et al. 1994, Conolly et al. 1995).