Formaldehyde. Health-based recommended occupational exposure limit Authors:Dutch expert committee on occupational standards (DECOS)

Source: Health Council of the Netherlands (Gezondheidsraad) Vol:02 OSH (2003) 124 p
ABSTRACT:

"Current limit values. The current occupational exposure limit for formaldehyde in the Netherlands is 1.5 mg/m3 (1 ppm), TWA-8 h and 3.0 mg/m3 (1,5 ppm), TWA-15 min. This limit is still not legally binding. The American Conference of Governmental Industrial Hygienists (ACGIH) has set a Threshold Limit Value of 0.37 mg/m3 (0.3 ppm), as a ceiling and classified formaldehyde as a suspected human carcinogen, Group A2. The Deutsche Forschungsgemeinschaft endorsed a MAK value of 0.37 mg/m3 (0.3 ppm) as an 8 hour time-weighted-average (TWA-8 h), with a notation as a sensitizing agent, and classified formaldehyde into carcinogen category 4 (genotoxicity playing no or at most a minor part). The United Kingdom adheres to an MEL of 2.5 mg/m3 (2 ppm), TWA-8 h. The European Union has classified the carcinogenic effects of formaldehyde in category 3. Toxicokinetics. Under normal conditions, inhaled formaldehyde is absorbed in the upper respiratory tract. After absorption of' 14C-formaldehyde, radio-activity is distributed to various organs and tissues with the highest concentrations found in the oesophagus, followed by the kidneys, liver, intestine and lungs. Retention in the nasal passages of the rat was estimated at 93% of the inhaled amount, regardless of airborne concentrations. It was estimated that absorption of concentrated solutions of formalin through the skin amounted to 319 mg/cm3 per hour. Formaldehyde is a normal metabolite in mammalian systems and it is rapidly metabolized to formate, which is partially incorporated via normal metabolic pathways into the one-carbon pool of the body or further oxidized to carbon dioxide. There are two pathways of final elimination: via exhalation and via the kidneys. Effects. The target organs of formaldehyde vapour are the eyes, nose and throat. The predominant effect of short-term formaldehyde exposure in humans is sensory irritation, first experienced in the eyes, followed by perception of the odour and then irritation of the nose and throat accompanied by discomfort, lachrymation, sneezing, coughing, nausea and dyspnoea. For most individuals sensory irritation does only slightly occur until an (short-term) exposure concentration of 1.2 mg/m3 (1 ppm). However, at lower exposure levels (0.26-0.29 mg/m3 (0.22-0.24 ppm) for a longer time period sensory irritation may still occur in a substantial percentage of exposed persons. In one, not well documented, study, 19% of the exposed subjects still reported eye irritation at an exposure concentration of 0.29 mg/m3 (0.24 ppm). No changes in pulmonary function have been found in humans exposed to formaldehyde concentrations up to 3.6 mg/m3 (3 ppm). In experimental animals, irritation of eyes, nose, throat and lungs was observed at exposure concentrations higher dm 2.4 mg/m3 (2.0 ppm). In mice a 10-min RD50 (the concentration associated with a 50% decrease in respiratory rate) for formaldehyde of 3.6 = 0.34 mg/m3 (3.0 ppm = 0.28 ppm) has been reported. There is no convincing evidence of formaldehyde being able to sensitize the respiratory tract. Skin sensitization is induced by direct skin contact with formaldehyde solutions in concentrations higher than 2%. Formaldehyde-induced allergic contact dermatitis has been estimated to occur in 3 to 6% of the population. There is overwhelming evidence that high concentrations of formaldehyde vapour.(12 mg/m3 (10 ppm) or higher) can induce nasal cancer in rats but these is no convincing evidence for respiratory tract cancer risk in humans. Three different meta-analyses of epidemiological studies have shown inconsistent results. In two of them, a relationship between exposure to formaldehyde and the occurrence of nasopharyngeal cancer was observed, while an association with nasal cancer was ambiguous. In these two meta-analyses, the authors did not correct for the unreported studies in which no cases of nasal cancers were found. This must have led to an overestimation of the overall relative risk for nasopharyngeal cancer. In a third, more recently published meta-analysis, this correction for the underreporting was made. In addition, the exposure potential for the jobs included in the analysis was evaluated. The authors concluded that the epidemiological studies do not support a causal relationship between formaldehyde exposure and nasopharyngeal cancer. The committees endorse this conclusion and further conclude that the currently available epidemiological database does not provide support for a nasal cancer risk at exposure levels lower than 0.3 mg/m3 (LOAEL for sensory irritation). Also from the epidemiological studies it seems unlikely that exposure to formaldehyde affects lung cancer risk. The effects of short-term exposure to airborne formaldehyde in experimental animals are cytotoxic damage to and regenerative proliferation of the nasal respiratory epithelium. The histopathological changes range from slight hyperplasia and squamous-cell metaplasia of the ciliated and non-ciliated respiratory epithelium in specific areas (found at low effective exposure concentrations, ie. 2.4 to 3.6 mg/m3 (2 to 3 ppm)) to severe rhinitis, necrosis and extensive hyperplasia and metaplasia of major portions of the nasal respiratory epithelium (found at exposure concentrations of about 7.2 mg/m3 (6 ppm) and higher. Substantial increases in nasal epithelial cell turnover rates occur in rats after exposure to concentrations of 7.2 mg/m3 (6 ppm). Most NOAELs in these short-term studies were found between 1.2 and 2.4 mg/m3 (1 or 2 ppm). In all studies with a NOAEL of 1.2 mg/m3 (1 ppm) the LOA-EL was higher than 2.4 mg/m3 (2 ppm). This might indicate that also in these studies 2.4 mg/m3 might have been a NOAEL if indeed this exposure level would have been included in these experiments. However, (slightly and transiently) increased cell turnover rates have occasionally been found at levels between 0.6 to 2.4 mg/m3 (0.5 to 2 ppm). Effects after long-term inhalation exposure to formaldehyde in experimental animals include inflammatory, degenerative and regenerative changes of the nasal mucosa and squamous-cell carcinomas of the nasal respiratory epithelium. The non-neoplastic nasal changes range from a minimal degree of hyperplasia and squamous-cell metaplasia of the nasal respiratory epithelium (occasionally seen at concentrations of approximately 2.4 mg/m3 (2 ppm) or lower) to rhinitis, necrosis and extensive restorative hyperplasia and metaplasia bf the nasal respiratory epithelium invariably seen at concentrations of about 7.2 mg/m3 (6 ppm) and higher. High incidences of squamous-cell carcinomas have been found in rats at exposure levels of 12 mg/m3 (10 ppm) or higher. In most long-term studies, a NOAEL of 1.2 or 2.4 mg/m3 has been reported. However, in one long-term study in rats 2.4 mg/m3 (2 ppm) appeared to be a LOAEL and in another long-term rat study a LOAEL as low as 0.36 Mg/M3 (0.3 ppm) was reported. No adequate data were available on genetic effects of formaldehyde in humans. Formaldehyde is comprehensively genotoxic in a variety of experimental systems, ranging from bacteria to rodents in vivo. Formaldehyde given by inhalation or gavage to rats induced chromosomal aberrations in lung cells, micronuclei in gastro-intestinal tract cells and sperm-head anomalies. Inhalation of formaldehyde leads to formation of DNA-protein cross-links in the nasal respiratory epithelium of rats and monkeys. The formation of DNA-protein cross-links is a sublinear function of the formaldehyde concentration in inhaled air from 0.86 to 18.4 mg/m3 (0.7-15 ppm). There is no detectable accumulation of DNA-protein cross-links during repeated exposures. In V79 Chinese hamster cells, formaldehyde induced DNA-protein crosslinks, sister-chromatid exchanges and micronuclei, but no gene mutations, in concentrations similar to those inducing cytotoxicity, suggesting that formaldehyde-induced DNA-protein crosslinks are related to cytotoxicity and clastogenicity. It has been suggested that the nasal inflammation and proliferation induced by formaldehyde exposure may contribute to the induction of genetic alterations through a variety of mechanisms including generation of reactive oxygen species, alterations in nucleotide pools, free radical formation, and clonal expansion with further mutation of genetically altered cells. With respect to the mechanism underlying the nasal carcinogenicity of formaldehyde in rats, there is a large body of data suggesting an association between the cytotoxic, genotoxic and carcinogenic effects of formaldehyde. The steep non-linear dose-response curve for nasal tumours - indicating a more than proportionate decrease in carcinoma incidence at low concentrations - is most probably due to the fact that defence mechanisms of the nose (mucociliary clearance, detoxification by dehydrogenase, DNA repair) are very effective at low concentrations, but can be overwhelmed and inactivated at high concentrations; consequently, cell and tissue damage and finally tumours occur at high concentrations only. This also means that formaldehyde in concentrations not leading to tissue damage most probably cannot act as a complete carcinogen (causing initiation, promotion and progression). In several animal studies, inhalation of formaldehyde was not found to affect reproduction. Hazard assessment. From the toxicological data base, it was evident that the effects of concern of formaldehyde are sensory irritation and cytotoxicity-induced regenerative hyperplasia and metaplasia of the nasal respiratory epithelium accompanied by nasal carcinomas in rats after long-term exposure to high cytotoxic concentrations. Controlled studies in volunteers revealed a wide variation in individual susceptibility to sensory irritation from formaldehyde. For most persons sensory irritation (eye, nose and/or throat) did not occur until an exposure concentration of at least 1.2 mg/m3 (1.0 ppm). However, at lower exposure levels sensory irritation may still occur in a substantial percentage of exposed individuals, and in one, not well documented study 19% of the exposed subjects reported eye irritation at an exposure concentration of 0.29 mg/m; (0.24 ppm). In experimental animals, irritation of eyes, nose, throat and lungs was observed at exposure concentrations greater than 2.4 mg/m3 (2.0 ppm). Overall, weighing the total body of data, both committees estimated that 0.3 mg/m3 (0.25 ppm) formaldehyde is the lowest obeserved adverse effect level (LOAEL) at which sensory irritation may occur in a low but significant percentage of exposed workers. Therefore, based on sensory irritation only, DECOS would recommend a HBR-OEL for formaldehyde of 0.15 mg/m3 (0.12 ppm), providing a margin of safety (of 2) which DECOS considers large enough to prevent significant sensory irritation in workers, taking into account that (I) the critical effect (sensory irritation) is a local effect, (II) the incidence of the effect at 0.3 mg/m3 is low (19%) and may not be different from the background incidence in controls and (III) minimal sensory irritation may rapidly subside due to accommodation. Then, the DECOS discussed whether an exposure limit of 0.15 mg/m3 (0.12 ppm), is low enough to protect workers against cytotoxic-induced hyperproliferation of the nasal respiratory epithelium, and consequently also against the potential risk of nasal cancer. Nasal carcinomas in rats have only been found after exposure to high, cytotoxic concentrations causing rhinitis, necrosis and regenerative hyperplasia and squamous metaplasia of the nasal respiratory epithelium. The crucial role of tissue damage followed by hyperplasia and metaplasia of the nasal respiratory epithelium in formaldehyde carcinogenesis has been demonstrated in a convincing way, has , meanwhile been widely recognized, and has been included in human cancer risk assessment of formaldehyde. The committees found it reasonable to conclude that the response of the respiratory tract to formaldehyde will be qualitatively similar in rats and humans. If in humans exposure of formaldehyde is accompanied by recurrent tissue damage at the site of contact, formaldehyde may be assumed to have carcinogenic potential in man via mechanisms of cytotoxicity. Correspondingly, if the respiratory tract tissue is not recurrently injured, exposure of humans to relatively low, non-cytotoxic levels of formaldehyde can be assumed to be associated with a negligible cancer risk. Both committees (DECOS and NEG) observed that the majority of short- and long-term inhalation studies with formaldehyde in experimental animals reveals a NOAEL of 1.2 or 2.4 mg/m3 (1 or 2 ppm). However, in a few studies slight histopathological changes of the nasal respiratory epithelium were observed at levels ranging from 0.36 to 2.4 mg/m3 (0.3 to 2 ppm) formaldehyde. Three meta-analysis of human epidemiological studies have shown inconsistent results. In two of them a significant relation between exposure to formaldehyde and nasopharyngeal cancer risk was observed. The association between formaldehyde exposure and nasal cancer was ambiguous. However, according to the committees, in these meta-analyses the authors did not correct for the unreported studies in which no cases of nasal cancers were found. This must have led to an overestimation of the overall relative risk of nasopharyngeal cancer. In the third, more recent, published meta-analysis, a correction was made for underreporting, and the authors concluded that there was no support for a causal relation between formaldehyde exposure and nasopharyngeal cancer. The committees endorsed this conclusion and concluded that the currently available epidemiological database on formaldehyde does not provide evidence for a respiratory tract cancer risk at exposure levels lower than 0.3 mg/m3 (LOAEL for sensory irritation). In conclusion, DECOS is of the opinion that an health based occupational exposure limit (HBR-OEL) of 0.15 mg/m3 (0.12 ppm) formaldehyde is low enough to protect workers against nasal tissue damage, and as a consequence, also against the potential risk of nasal cancer. To avoid peak exposures possibly entailing cytotoxicity-induced hyperproliferation and metaplasia of the nasal respiratory epithelium, the DECOS recommends a Short Term Exposure Limit (STEL). Data from human studies indicate that short term exposure to formaldehyde at concentrations up to approximately 1.0-1.2 mg/m3 leads to slight irritation of the eyes only. Therefore, the DECOS recommends a STEL of 0.5 mg/m3 (twa 15 minutes) which is considered low enough to avoid any significant sensory irritation, and thus nasal toxicity as well. Recommended occupational exposure limit. DECOS recommends a health-based occupational exposure limit of 0.15 mg/m3 (0.12 ppm) formaldehyde in air, TWA-8 h, and a short term exposure limit, 15 min TWA, of 0.5 mg/m3 (0.42 ppm). "

 

Health effects of selected chemicals 3. Urea Formaldehyde Resin

Authors:

Graa Thomsen K
 

 

S"derlund E

Source: Nord Vol:28 (1995) pp 211-37
ABSTRACT:

"Urea formaldehyde (UF) resins are oligomers or polymers based on urea and formaldehyde. UF resins are thermosetting plastics used in adhesives, moulding, laminating, coating, flexible foams, electric insulators, textile and paper treatment. They have the form of an amorphous powder or liquid depending on the degree of polymerization, and can be cured by heat and catalysts. The low molecular weight resins are soluble in water and release free formaldehyde with time. High molecular resins are stable and seem only to release free formaldehyde upon heating. Limited information on the toxicity of the UF resins has been found. In general, high molecular weight resins are considered to be practically nontoxic, whereas low molecular weight resins relatively easily release free formaldehyde causing toxic effects in experimental animals. If no toxicity data are available for a given UF resin, an assessment of the risk of possible adverse effects in humans has to be based on information regarding the physico-chemical properties of the resin, especially the degree of curing and content of free formaldehyde. In addition, thermal decomposition leads to the formation of toxic products such as hydrogen cyanide and carbon monoxide. No information on toxicokinetic parameters of UF resins was located in the available literature. A low acute oral toxicity was found in rat (LD50 > 5 800 - 10 000 mg/kg), mouse (LD50 > 10 000 mg/kg) and guinea pigs (LD50 > 2 320 mg/kg). Similarly, a low acute dermal toxicity was found in rat (LD50 >2 100 mg/kg) and rabbit (LD50 > 2 200 - 5 000 mg/kg). From the available toxicity data, a low acute inhalation toxicity in rat (LC50 > 200 mg/l) was evident. Irritation of the skin, resulting from dermal contact with low molecular weight UF resins containing 1.2 to 29% free formaldehyde, has been reported in guinea pigs. However, cured UF resin applied on the skin of rabbits did not cause measurable skin irritation. In other studies with commercial UF resins, only minimum skin irritation was noted in rabbits. In humans, skin irritation has been related to occupational and general exposure to UF resins. Eye irritation related to exposure to UF resins has not been sufficiently tested. Powdered resin has caused lacrimation, but no inflammation. Other studies with commercial UF resins indicate that they are only weak eye irritants. Lacrimation has also been reported in humans using textiles with UF resin finish. In humans, cases of irritation of mucous membranes has been reported. The irritative effects of UF resins are most likely due to their content of free formaldehyde or their ability to slowly liberate formaldehyde with time. In two studies where UF resins were orally administered to animals daily for periods up to 9 weeks, no adverse toxic effect was found. However, inhalation of 0.1 mg/l of the UF resin CT-244-85A (66 - 71% urea formaldehyde polymer with a cellulose filler) over a 28-day period resulted in lung injury in exposed rats. UF resins have not, however, been sufficiently tested in order to evaluate possible toxic effects from repeated exposure. In humans exposed to UF resin products (UF insulation foam or particle boards) diffuse symptoms such as chest oppression, headache, abnormal tiredness, menstrual irregularities and irritation have been reported. In experimental animals, no studies regarding possible allergic effects of UF resins were located. In humans, several studies have described allergic contact dermatitis and incidences of dermatitis up to approximately 10% have been reported. Allergy to UF resins can be caused by formaldehyde or intermediates from the production. The most frequent sensitizer is dimethylolurea (urea-formaldehyde). Hypersensitivity to urea-formaldehyde and formaldehyde are often connected. No information with respect to possible carcinogenic or reproductive/teratogenic effects were located. When two different UF resins were tested for bacterial mutagenicity in several strains of S typhimurium, no genotoxic effects were noted. Formaldehyde, on the other hand is known to display a wide range of toxic effects including carcinomas of the nasal cavity in rats, mutations in bacteria and primary DNA damage in mammalian cells, but no reproduction toxicity or teratogenicity. Thus, resins containing relatively high concentrations of free formaldehyde may have toxic effects similar to those of formaldehyde. In conclusion, the critical effects for urea-formaldehyde resins appear to be their skin sensitization potential and ability to cause weak irritation of the skin, eye and mucous membranes. The UF resins have not, however, been sufficiently tested for toxic effects following repeated exposure. "
 

Health effects of selected chemicals 3. Phenol Formaldehyde Resin

Authors: Graa Thomsen K     Soderlund E Source: Nord Vol:28 (1995) pp 153-73 ABSTRACT: "Phenol-formaldehyde resins are polymers of a phenol, or a mixture of phenols, and formaldehyde. They are particularly heat resistant, good electrical insulators and have adhesive properties. Para-tertiary-butylphenol-formaldehyde resin is the most frequently used resin, especially as adhesives. Other areas of use include thermosettings, laminates and impregnations, binders, surface coatings, and abrasive paper. Phenol-formaldehyde resins occur as resoles, resins and resites depending of the degree of cross-linking. The resins contain several impurities (i.e. reaction intermediates, raw materials and degradation products). In general they are insoluble in water and their solubility in organic solvents varies. Degradation occurs gradually from 150 degrees C. No information on the toxicokinetics of phenol-formaldehyde resins were available. The resins appear to have a low acute oral or dermal toxicity in experimental animals. The oral LD50 in rats has been reported to be 2 900 mg/kg or higher and the dermal LD50 in rabbits is > 16 ml/kg. No LC50 -value following inhalation exposure was found. However, deaths have been noted in rats inhaling vapours of a phenol-formaldehyde resin. Studies in experimental animals and observations in humans have clearly shown that phenol-formaldehyde resins are irritating to eyes, skin and mucosal membranes. No studies were available regarding repeated or prolonged exposure to phenolformaldehyde resins. In humans, cases claiming neurotoxic effects have been reported. However, detailed neuropsychologic testing failed to reveal any definite evidence of organic brain damage. Genotoxic effects are equivocal, since in two studies to detect bacterial mutagenicity both negative and positive results were found. Interestingly, persons occupationally exposed to a phenol-formaldehyde resin revealed an increase in chromosomal aberrations. No carcinogenicity studies were located in the literature. Concerning reproductive effects and teratogenicity, limited data are available. Damage to rat spermatocytes following inhalation exposure to a phenolformaldehyde resin has been reported. Furthermore, teratogenic effects due to inhalation exposure of mice and humans to a phenol-formaldehyde resin containing relatively large amounts of ethanol have been suggested. Several sensitizing agents have been detected in phenol-formaldehyde resins using the Guinea Pig Maximization Test. Both epidemiological studies and case reports clearly have shown that phenol-formaldehyde resins cause contact dermatitis in humans. Up to 1 - 3 % of a population of people with skin diseases has been shown to give positive reactions to phenol-formaldehyde resins. From the available toxicological data the critical effects related to phenolformaldehyde exposure are its allergic effects and its ability to cause irritation of the skin, eye and mucosal membranes. "