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Description of key information

Contradictory results are available on the enhancing effects of formaldehyde on the immune response to allergens in clinical inhalation studies in volunteers. But more weight has to be given to the study with the more rigorous exposures indicating that formaldehyde does not increase pulmonary dysfunction in asthmatics.

Key value for chemical safety assessment

Additional information

There is limited indication for modulation of sensitization to allergens in mice after inhalation exposure to 0.2 ppm (Fujii et al. 2005). However, these data are not sufficient for final evaluation.

In a double-blind, randomized cross-over study (wash-out interval 16 days) 19 mite-sensitized volunteers were exposed for 30 min to a mean formaldehyde concentration of 0.092 mg/m³ (0.077 ppm) in an exposure chamber at rest. Clinical symptoms (subjective) were documented via questionnaire immediately after exposure. Thereafter mite allergen inhalation challenge was performed (nebulizer) with increasing concentrations of house dust mite (HDM) extract. Lung function parameters were measured before HDM challenge and hourly after challenge for 6 h. Sputum induced by bronchial challenge with metacholine were collected 24 h before and after mite challenge and eosinophil cationic protein levels in fluid phase-induced sputum were measured. No clinical signs were noted due to formaldehyde exposure and volunteers did not differ in lung function parameters or metacholine challenge prior to formaldehyde (or air) exposure or after formaldehyde exposure. However, the inhaled dose of the allergen HDM inducing an immediate response was significantly reduced after formaldehyde exposure compared with sham exposure and the maximum percentage FEV reduction (late response to HDM challenge) observed during the 6 h follow up was significantly higher in the formaldehyde exposure group. Pulmonary function or other parameters were not altered. In conclusion, the exposure to low levels of formaldehyde significantly enhanced bronchial responsiveness to mite allergen in mite-sensitized subjects with asthma (Casset et al., 2006; see IUCLID Section 7.10.3).

These results are in contrast to the recently published study of Ezratty et al. (2007; Section Human information) in which a similar study design was used. In this study with double-blind, randomized cross-over design, 12 volunteers with asthma (all volunteers with confirmed allergy to grass pollen) were exposed at rest to filtered air or 0.5 mg/m³ (0.4 ppm) formaldehyde for 1 h (2 exposures, wash-out interval 2 weeks). Immediately after exposure an allergen inhalation challenge followed (grass pollen). Lung function was measured immediately before, during and 8 h after allergen challenge. Response to methacholine 8 h after the allergen challenge was also tested. Sputum induction for measurement of inflammatory markers at baseline and immediately after metacholine challenge was performed. A questionnaire 0, 15, 30, 45, and 60 min after start of formaldehyde exposure (or air) should clarify subjective symptoms. No relevant treatment related clinical adverse reactions were found in volunteers; all 12 volunteers completed examinations. Lung function parameters did not show direct effects during or after formaldehyde exposure in comparison to sham exposure. Allergen (grass pollen) bronchial challenge revealed slight but not significant difference between the first exposure to formaldehyde or air-only (no wash-out) and the second exposure (after a wash-out); there was a tendency for a protective effect after formaldehyde exposure (lower immediate bronchial allergen response). Methacholine bronchial challenge (8 h after the end of the allergen challenge) showed that formaldehyde exposure did not affect the allergen-induced increase in responsiveness to methacholine. Formaldehyde exposure did not alter sputum parameters. Conclusion: In 12 patients with intermittent asthma and sensitized to grass pollen no effects were found on the respiratory allergen responsiveness to grass pollen after 1 h inhalation exposure to 0.5 mg/m³ (0.4 ppm) formaldehyde.

When comparing the investigations of Casset et al. (2006) and Ezratty et al. (2007) it should be noted that the negative study of Ezratty was carried out at a higher formaldehyde concentration (0.5 mg/m³ vs 0.092 mg/m³) with a longer exposure duration (1 h vs 30 min). This more rigorous exposure situation should have led to a more pronounced reaction while instead no formaldehyde related effect was observed. On the other hand, different allergens (grass pollen vs mite dust) were used which might have influenced the outcome of the studies. Also, Nielsen et al. (2010, 2013) assessed the contradictory results of Casset and Ezratty in detail and concluded that the total database does not indicate that formaldehyde exposure leads to an exacerbation of lung function in asthmatics.

For comparison, in controlled clinical studies formaldehyde-related increase in pulmonary dysfunction was not evident in asthmatics at concentrations of up to 3 ppm and an exposure period up to 3 hours (see BfR 2006)). Epidemiological data are not sufficient for evaluation (see IUCLID Section 7.10.2) since confounding by other air pollutants can hardly be controlled.

Data on respiratory sensitization are presented in the Summary and discussion of Section Sensitization.

In the literature update up to May 2022, the following studies were identified.

Apart from studying genotoxicity as mentioned above, Costa et al. (2013, supporting) also determined the cell percentage (but not the absolute counts) of lymphocyte subpopulations (total T, T-helper, T- cytotoxic, and B-lymphocytes) in 35 anatomy/pathology workers compared to 35 unexposed control subjects. Exposure levels to formaldehyde were 0.36 ppm (range 0.23-0.69). The cell percentage of total T lymphocytes was significantly decreased in exposed workers.

Jia et al. (2014, supporting) studied 118 formaldehyde exposed workers in comparison to 79 controls. The exposed subjects were divided into a high (0.36-1.53 ppm) and a low (0.07-0.23 ppm) exposure group. It isreported that the urinary excretion of formic acid was significantly increased in both subgroups compared to controls.This finding is highly improbable, especially for the low exposure group, taking into account the low exposure levels and the report of Gottschling et al. (1984) who did not detectsignificant changes in formate excretion over a 3-week period of exposure to FA at a concentration in air of less than 0.4 ppm. There was a significant increase in the percentage of CD19+ lymphocytes and CD56+ lymphocytes were only increased in the low exposure group. Moreover, there were significant changes in cytokine levels: in both subgroups IL-10 was increased and IL-8 was decreased, and in the high exposure group only there was an increase of IL4 and a decrease of IFN-gamma.

Justification for classification or non-classification

Based on all available data, classification as an immunotoxic substance is not triggered according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.