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EC number: 200-001-8
CAS number: 50-00-0
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.
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 April 20, 2015, 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
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
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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