Acetaldehyde

Carcinogenicity

Justification for classification or non-classification

Acetaldehyde is currently classified for carcinogenicity in category 1B (harmonized classification - Annex VI of regulation (EC) 1272/2008).

This classification is regarded as appropriate based on the argumentation outlined in the Discussion.

Additional information

Acetaldehyde is currently classified for carcinogenicity in Cat. 1B (harmonized classification - Annex VI of regulation (EC) 1272/2008).

This classification is regarded as appropriate based on the argumentation outlined in the Discussion.

Considerations Regarding the Evaluation of Carcinogenicity Classification for Acetaldehyde

Acetaldehyde is currently classified for carcinogenic potential as Carc. 1b (H350); as presented in Annex VI of regulation (EC) 1272/2008, as amended 5.10.2018. As proposed in the 2015 CLH Report - Proposal for Harmonised Classification and Labelling and adopted by the RAC Committee for Risk Assessment on 16 September 2016.

Genotoxicity

Acetaldehyde is classified Muta. 2, as summarized in Section x.x of this dossier and the 2015 CLH report.

Carcinogenic Potential in Humans: Epidemiology

As stated by the RAC (2016), there is little or no epidemiological data to support statements concerning an association between exposure to acetaldehyde and cancer. Therefore, it is considered that human data are insufficient to make a final conclusion on the carcinogenic potential of acetaldehyde in humans.

Some indirect evidence for acetaldehyde carcinogenic potential is provided by studies of ethyl alcohol (ethyl alcohol metabolized to acetaldehyde) consumption, but those studies are not directly related to assessing the carcinogenic hazards and risk of acetaldehyde and are excluded from this summary.

Carcinogenic Potential in Animal Bioassays

As discussed below, in laboratory animal studies there is sufficient evidence that inhaled acetaldehyde induces carcinogenic effects in nasal passages (portal of entry effects only).

Oral Exposure

In a carcinogenicity study (Soffritti et al., 2002) with male and female Sprague-Dawley rats, there were no clear increases in the number of tumour-bearing animals in any of the exposed groups compared to the control group. A significantly increased total number of tumours (per 100 animals) in groups exposed to 50 mg/L (females only), and 2,500 mg/L (males; females). There was a lack of statistical analysis, and a limited examination of non-neoplastic end-points, and the findings are confounded by possible intercurrent respiratory infection in the rat colony (Netherlands HCot 2014). For these reasons, the findings of the study are considered of questionable relevance.

In another study (Homann et al., 1997), male Wistar rats were exposed to acetaldehyde via drinking water for eight months. No tumours were observed in tongue, epiglottis and forestomach. Cell proliferation was significantly increased in these three organs, and the epithelia were significantly more hyperplastic than in control animals. Due to numerous deficiencies, including only one dose group and limited tissue pathology, no meaningful conclusions about the carcinogenicity of acetaldehyde can be made from this study.

Additionally, no tumours were found in Syrian golden hamsters given acetaldehyde by intratracheal installation weekly or biweekly for 52 weeks, followed by a recovery period of 52 weeks (Feron, 1979).

Inhalation Exposure

Feron et al. (1982) exposed hamsters to a single exposure concentration of 1,500 ppm (2,700 mg/m³), which exceeded the MTD, as the dose had to be reduced during the study due to severe toxicity. for seven hours a day, five days per week for 52 weeks. Acetaldehyde induced rhinitis, hyperplasia and metaplasia of the nasal, laryngeal and tracheal epithelium. Since this was the only dose group used, this lessens the reliability of the study, the results of which should be interpreted with caution. No individual tumour reached statistical significance.

In a carcinogenicity by Woutersen et al. (1986), Wistar rats inhaled acetaldehyde at different concentrations for six hours a day, five days per week for a maximum of 28 months. Exposed animals showed lower survival rates and body weights compared to controls. This was most pronounced in males exposed to the highest concentration (3,000 ppm). Gross examination at autopsy did not reveal acetaldehyde-related lesions, except for decolourisation of the fur and nasal swellings in all exposed groups the authors reported nasal swellings and hyper- and metaplasia in the respiratory and olfactory as well as laryngeal epithelium in exposed animals. Animals of all exposed groups showed increased mortality and growth retardation compared to control-group. The high and mid doses exceeded the MTD and the exposure concentrations in the high dose group had to be reduced. After 102 weeks, all top-concentration rats had died. When the study was terminated after 121 weeks, in the mid-concentration group only about 20% of the animals were still alive compared to 40% males and 50% females in the control group. Squamous cell carcinoma was seen in males in all dose-groups as well as in the control-group. These lesions were mainly noted in the mid and/or high exposure groups and were statistically significantly increased in some groups when compared to controls. No lesions were found in the lungs. Major exposure-related nasal lesions were found at the end of the exposure period, which comprised thinning of the olfactory epithelium with loss of sensory and sustentacular cells at all concentrations. Exposure-related neoplastic lesions were observed in the nose. The relative lower tumour incidences in the high exposure groups were explained by early mortality due to other causes than cancer, although any interpretation in the presence of lethal doses is confounded. Doses in the top dose group where reduced over time but the differences in body weights, between control group, top dose group and partly the mid dose group exceeded the value of approximately 10% reduction in body weight gain. In a follow-up publication, the same authors reported on the interim results obtained in the first 15 months of the study. Nasal lesions were reported in exposed animals, indicating chronic and permanent inflammation. There were no treatment-related neoplasms found in organs outside the respiratory tract in this study.

Dermal Exposure

No reliable carcinogenicity studies via the dermal route were identified.

Mechanistic Considerations for Carcinogenicity

Homeostasis Represents a Practical Threshold for Mutagenicity and Carcinogenicity of Inhaled Acetaldehyde

Acetaldehyde is a product of normal metabolism in all living organisms, including humans. To avoid adverse effects, homeostatic mechanisms have evolved to keep intra-cellular concentrations within a normal physiological range. To avoid adverse effects, homeostatic mechanisms have evolved to be highly efficient and, by definition, there is no added risk when in a homeostatic state.

Intra-cellular AA concentrations are kept at physiological concentrations by ALDH2 activity. However, when exogenous exposures to acetaldehyde are high, the physiological concentrations may be exceeded and adverse effects produced. The concentration where exogenous formaldehyde saturates normal metabolism varies, based on the route of exposure and exposure duration, and understanding when exposures exceed the capacity of the body to effectively manage acetaldehyde is a critical component of any risk evaluation.

Toxicokinetic and Toxicodynamic Considerations for Identifying a Practical Threshold for Mutagenicity

As stated by the RAC in their 2016 opinion “In general, data indicate a highly effective metabolism. In laboratory studies, half-time values in the blood for acetaldehyde were found to be three minutes in rats (after repeated exposure by inhalation) and mice (following a single intraperitoneal injection)” And “In general, it appears that systemic levels of acetaldehyde following exposure will be low and will decrease quickly after the end of exposure.”

At high concentrations of intracellular acetaldehyde, ALDH activity will not be sufficient to oxidise all acetaldehyde to acetic acid and acetaldehyde may accumulate. Saturation of metabolism of acetaldehyde by ALDH indicating limited enzyme capacity is suggested to occur at acetaldehyde concentrations of 300 ppm (Stanek and Morris, 1999).

In agreement with the literature, the RAC in their 2016 opinion also stated “The key event after acetaldehyde exposure involves Schiff's base formation with DNA and proteins to elicit genotoxicity and/or cytotoxicity. DNA repair, apoptosis and other stress-related adaptive responses, and replacement of proteins or redundancy in protein function all act in conjunction to reduce the impact of the formation of these adducts. This is followed by metabolic deactivation of acetaldehyde via ALDH2. If the action of ALDH2 is sufficient, and when it is combined with DNA repair, apoptosis, and other stress-related responses, no increase in genotoxic outcomes will occur. [Bold added for emphasis]

As also stated by the RAC (2016) – “In vivo, tissue acidification occurs, caused by the production of acetic acid, which adds to the cytotoxicity of DNA and protein adducts. Because of the constant presence of (endogenous) acetaldehyde in cells, the dose-response for mutagenicity will depend on the capacity of cells to maintain the intracellular acetaldehyde concentration at sufficiently low levels.”

Biomarkers of Exposure/Molecular Dosimetry Considerations for Identifying a Practical Threshold for Mutagenicity

Acetaldehyde is a reactive electrophile which reacts with nucleophilic groups of cellular macromolecules, such as proteins and DNA, to form adducts. It has been shown that acetaldehyde that is incubated with ribonucleosides and deoxyribonucleosides forms adducts with cytosine or purine nucleosides, and one of acetaldehyde guanosine adducts is N2-ethylguanosine.

A recent study by Moeller et al. (2013) has demonstrated that exposure to acetaldehyde does not produce N2-ethylidine-dG adducts above background level until an exposure concentration of 50 μM is exceeded. (This study had limits of detection for the adducts in the amol range.) 

Cancer Mode of Action

Acetaldehyde is a skin, eye and respiratory tract irritant. The nature of acetaldehyde’s nasal injury following chronic inhalation exposure at high concentrations (sufficient to cause marked reductions in body weights and survival ) and degenerative changes (cytotoxicity) followed by hyperplastic and metaplastic transformation, along with cell proliferation at higher exposure concentrations. These changes precede tumor development and are generally believed to play a significant role in the carcinogenic process at the point of contact, for both acetaldehyde and the structurally related one carbon aldehyde - formaldehyde. Concentrations of acetaldehyde in the rat inhalation studies induced chronic tissue damage in the respiratory tract (Feron et al., 1982; Woutersen et al., 1986; Woutersen and Feron, 1987).

The nature of acetaldehyde’s nasal injury following chronic inhalation exposure at high concentrations suggests degenerative changes initially followed by hyperplastic and metaplastic transformation, along with cell proliferation at higher exposure concentrations; these changes precede tumour development. Indeed, all concentrations of acetaldehyde in the rat inhalation studies induced chronic tissue damage in the respiratory tract. Woutersen et al. (1986) originally concluded that “These observations strongly support the hypothesis that the nasal tumours arise from epithelium which is damaged by acetaldehyde, via the olfactory epithelium in the low concentration group and both the olfactory and the respiratory epithelium in the mid- and top-concentration groups.”

A cytotoxicity with regenerative hyperplasia mode-of-action for acetaldehyde was recognized by the RAC (2016), although they felt the alternative hypothesis of a mutagenic MOA strictly involving genotoxicity could not be ruled out without further research that better characterizes the potential for low-dose mutagenic effects, when stating:  The mechanistic basis for the increased incidence of tumours only at the initial site of contact with acetaldehyde in exposed animals has not been established. It is possible that both the irritant nature of acetaldehyde and its genotoxicity were key factors.

In both carcinogenicity studies by the inhalation route, tumours were found at acetaldehyde concentrations which were clearly irritating to the nasal and laryngeal tissue (≥ 750 ppm). Lower concentrations were not tested. Erosion and degeneration of the nasal and laryngeal epithelium was seen in mice after exposure to markedly lower concentrations (125 ppm) of acetaldehyde. In rats same is true for inflammation and histological changes in the nasal epithelium (243 ppm). However, some studies also indicate genotoxic effects at these low concentrations. In combination with the findings on the mutagenic properties of acetaldehyde, a genotoxic mechanism of tumour formation cannot be ruled out.

References

Feron VJ, Kruysse A, and Woutersen RA. Respiratory tract tumours in hamsters exposed to acetaldehyde vapour alone or simultaneously to benzo(a)pyrene or diethylnitrosamine. Eur J Cancer Clin Oncol, 1982; 18(1): 13-31.

Netherlands HCot -  Health Council of the Netherlands, Acetaldehyde: Reevaluation of the Carcinogenicity and Genotoxicity, Nov 2014, pg 43.

RAC (Committee for Risk Assessment) - Opinion proposing harmonised classification and labelling at Community level of vinyl acetate (ECHA/RAC/DOC No CLH-O-0000001742-77-01/F; Adopted 10 June 2011; http://echa.europa.eu/documents/10162/0314bc3c-eb3c-442d-be4d-91a2c8d79311

Soffritti M, Belpoggi F, Lambertin L, Lauriola M, Padovani M, and Maltoni C. Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats. Ann N Y Acad Sci 2002; 982: 87-105.

Stanek JJ and Morris JB (1999). The effect of inhibition of aldehyde dehydrogenase on nasal uptake of inspired acetaldehyde. Toxicol. Sci. 49(29):225-231.

Woutersen RA, Appelman LM, Van Garderen-Hoetmer A, and Feron VJ. Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology, 1986; 41(2): 213-31.

Woutersen, RA and Feron, VJ. (1987) Inhalation toxicity of actaldehyde in rats. IV. Progression and regression of nasal lesions after discontinuation of exposure. Toxicology, 1987;47, 295–305.

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From both the efficient but thresholded detoxification and the natural endogenous levels of acetaldehyde a thresholded mode of action can be assumed. Above threshold concentrations, cytotoxicity (only at the olfactory mucosa), mitogenic actions and genotoxic actions were observed. Cytotoxicity mainly contributed by acetic acid is the earliest lesion in the olfactory mucosa. Next stages in the continuum to tumor development include the regenerative cell proliferation and simultaneously occurring genotoxic effects of acetaldehyde.

The DFG Commission for the evaluation of MAK values classified Acetaldehyde as carcinogenic working material within the category 5. That means that if the MAK value of 50 ppm is not exceeded Acetaldehyde is not likely to play a relevant risk for human carcinogenesis. The commission justifies this threshold with the facts that no systemic tumors were reported at concentrations that lead to local tumors and that the standard deviation of endogenous acetaldehyde levels covers the range of occupational exposure.