Toxicological evaluation and limit values for Methyl-tertiary-butyl ether (MTBE), Formaldehyde, Glutaraldehyde, Furfural 6. SummaryDescription Formaldehyde is a colourless, flammable gas, highly soluble in water. The most common commercially available form is a 30-50% aqueous solution. Industrial use The main use of formaldehyde is in the production of resins for various industries e.g. the wood industry. Formaldehyde itself is used for preservation, disinfection and embalming of biological specimens. It is used as a preservative in many consumer products e.g. cosmetics. In biological organisms Formaldehyde is an essential metabolic intermediate in the biosynthesis of purines, thymidine and certain amino acids, and is thus expected to occur in most life-forms. Naturally occurring concentration of free and reversible bound formaldehyde in the blood of humans has been determined to 2.6 mg/kg. In food items formaldehyde occurs at a concentration of 3-60 mg/kg in fruits and vegetables and at levels of about 6-20 mg/kg in fish and meat. Environment The background level for formaldehyde in air is <1mg/m3, but in urban areas where formaldehyde is a part of vehicle exhaust and also generated from photochemical oxidation of volatile hydrocarbons levels of 1-20 mg/m3 have been reported. Rainwater is reported to contain 0.1-0.2 mg formaldehyde/ kg. Drinking water in general contains less than 0.1 mg/l. Human exposure Indoor air levels of 10 to 1000 mg/m3 are reported due to vaporising from furniture and building materials. Tobacco smoke may significantly contribute to the formaldehyde air level. Thus the indoor climate may result in a daily exposure of several mg of formaldehyde. The daily intake from food is estimated to 1.5-14 mg/day. The dermal use of formaldehyde containing cosmetics is not considered to contribute to systemic exposure of formaldehyde as absorption is regarded to be negligible. Toxicokinetics When inhaled the highly hydrophilic formaldehyde is retained by the mucosa of the upper respiratory tract. The reactive formaldehyde is thought to react with proteins in the mucous layer or with macromolecules of the epithelial cells. Thus, no increase in formaldehyde blood levels could be determined in rats and monkeys exposed to either 17.6 or 7.3 mg/m3. After oral exposure formaldehyde is rapidly absorbed and may be either metabolised and eliminated as CO2 or be incorporated into purines and amino acids via the one-carbon pool biosynthesis. No data indicate increased levels of formaldehyde in blood following formaldehyde exposure by the inhalational, oral or dermal route. However, exposure to radiolabelled formaldehyde show distribution and metabolic incorporation in tissue and elimination of radioactivity through expired air and urine. These data indicate that formaldehyde almost instantaneously undergoes metabolic conversion to formate (or reacts with macromolecules) before entering the systemic blood stream. Human toxicity vapour exposure Odour, upper respiratory tract irritation and eye irritation are typical effects observed in humans exposed to low levels of formaldehyde. Although a great amount of human data exist with respect to the induction of these effects by formaldehyde exposure, big differences in quality of data and big variability of individual sensitivity makes it difficult to identify a no effect level for sensory irritation. Different expert groups have recently evaluated the data on sensory irritation and the following irritation thresholds were stated:
At higher exposure levels of formaldehyde biting sensation (2.5-3.7 mg/m3) and lachrymation (5-6.2 mg/m3) occur, while pulmonary oedema and danger to life may be the consequence of even higher concentrations (37-60 mg/m3). Vapour exposure to formaldehyde is generally not considered to produce respiratory tract sensitisation. From occupational data reduced lung function has been reported in relation to occupational exposure above 2 mg/m3. Workers exposed to formaldehyde more frequently developed inflammation and histological changes in the nasal cavities, and increased incidences of nasal cancer have been found in workers exposed to formaldehyde. oral exposure Oral ingestion of few millilitres of concentrated formaldehyde solution (about 40%) may be fatal, resulting in pronounced injury in the oesophagus and the gastrointestinal tract. skin/ eye contact Contact with skin with concentrated formaldehyde may cause corrosive burns. Contact with eyes may result in severe injury and loss of vision. Formaldehyde is a strong skin sensitiser. The lowest concentration resulting in skin sensitisation in human experiments is 0.37% formaldehyde. The lowest concentration for provocation of an allergic response in sensitised persons is 30 ppm (30 mg/kg) for occlusion exposure in the axilla. Animal toxicity inhalation exposure Long term inhalational exposure to rats and mice has resulted in the development of squamous cell carcinomas of the nasal cavities. Especially rats are sensitive showing a steep dose-response relationship for the development of tumours in the range of 7-17 mg/m3. The development of tumours has been found to be related to delivered target site dose (measured as formaldehyde induced DNA-protein cross links) and tumours were always found to occur at cytotoxic exposure levels, i.e. at levels resulting in cell damage and increased cell proliferation. Compared to other primates (monkeys) the target tissue in the nasal mucosa of the rats were found to be more heavily exposed. This was found to be related to the structure of the nasal cavities of the rodent, where the more complex anatomy and narrow airflow increases the absorption/ retention of formaldehyde from the inhaled air. oral exposure In two long term studies in which rats were dosed with formaldehyde through the drinking water treatment related hyperplastic lesions, ulceration and atrophy developed in the forestomach and glandular stomach at dose levels of 50 and 82 mg/kg/day (drinking water contents of 0.1% and 0.19%), respectively. The corresponding NOAEL were 10 and 15 mg/kg/day (formaldehyde drinking water contents of 0.02 and 0.026%), respectively. No increases in the incidences of tumours were found in these two studies. In one of the studies, however, the mortality was greatly increased at the highest dose level of 0.5% formaldehyde in drinking water, and no animals survived the hole exposure period of 2 years. In another study using formaldehyde contents of 10, 50, 100, 500, 1000, 1500 ppm in drinking water, a dose related increase in leukaemia was observed among the rats. When cases of leukaemia were separated on sexes and grouping of different types of leukaemia was considered significant increased incidences occurred at the two highest levels. Further, increased incidences of different types of tumours in the gastrointestinal tract were found. No clear dose response was found a the lower levels, however, at 1500 ppm (and in a subsequent study at 2500 ppm) clearly increased incidences occurred. Some of these tumours were noticed to occur spontaneously very rarely. Reproductive and developmental effects Formaldehyde did in various experimental studies not show any adverse effect with respect to reproductive parameters and foetal developmental, at dose levels not resulting maternal toxicity. Genotoxicity Formaldehyde is considered as a genotoxic substance. In vivo studies have resulted in DNA-protein cross link in the nasal mucosa of rodents and monkeys, in chromosomal anomalies in lung cells of rats and in micronuclei formation in the gastrointestinal tract mucosa. Positive results were obtained in in vitro studies with respect to DNA damage and mutation in bacteria, and DNA-single strand breaks, chromosomal aberrations, sister chromatid exchange and gene mutation in human cells.
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