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EC number: 200-001-8
CAS number: 50-00-0
LD50(oral, rat) = 640 mg/kg bw (similar to OECD TG 401, non-GLP)
LC50(inhalation, rat, 4h) < 463 ppm (OECD TG 403, GLP), local effects
LD50(dermal) no data available, but not required as formaldehyde has corrosive properties.
Mortality rates in male Wistar rats after oral application of formaldehyde
Dose in mg/kg bw
In a reliable study comparable to OECD TG 401, 6 - 16 male Wistar rats were gavaged with formalin or paraformaldehyde solution in water at concentrations of 2 or 4 %.
The range of LD50 values was between 460 and 830 mg/kg bw. There is no significant difference between the paraformaldehyde and the formalin solution, nor any significant difference concerning the concentration (2 or 4 % solutions).
The mean oral LD50 value of five independent experiments in male Wistar rats is 640 mg/kg bw.
In a reliable GLP-conform study according to OECD TG 403, male and female Wistar rats were exposed to 463 ppm (analytical concentration) of formaldehyde as a vapor to determine the acute inhalation toxicity (single 4-hour exposure, whole body).
At 463 ppm all of five male and five female animals died. Lethality was observed on study day 1 or 2. Clinical signs of toxicity in animals comprised gasping, respiration sounds, breathing in stretched position, closed eyelid, red discharge and red encrusted nose, poor general condition, salivation, piloerection and yellow discolored fur. Findings were observed from hour 1 of exposure until the death of the animals. The mean body weights of the animals´surviving the exposure period decreased until death. During necropsy all animals showed dilated stomach, which were filled with gaseous content. Four males and four females additionally showed similar findings in the intestine. Moreover, two males showed effusion (clear fluid) in the thoracic cavity.
Under the current study condition, the LC50 was < 463 ppm (analytical concentration) in Wistar rats after 4 hour inhalation exposure to a vapor of formaldehyde.
In acute toxicity studies local irritation is the main effect.
In the study of Tsuchiya et al. (1975; comparable to OECD 401 with acceptable restrictions (i.e., symptoms not described; no necropsy; purity of test substance not given) male Wistar rats (n = 6 - 16) were gavaged with formalin or paraformaldehyde solution in water at concentrations of 2 or 4 %. The range of LD50 values was between 460 and 832 mg/kg bw. There is no significant difference in acute toxicity between the paraformaldehyde and the formalin solution, nor any significant difference concerning the concentration (2 or 4% solutions). The mean oral LD50 value of five independent experiments is 640 mg/kg bw.
In a study comparable to OECD Guideline No. 401 (with acceptable restrictions: clinical symptoms not described; no data on necropsy given; purity of test substance not given) male Wistar rats (n= 10 per dose) were gavaged with formaldehyde solution in water at a concentration of 2%. The post exposure period was 14 days. Rats died within the first 2 days after application. The authors calculated an LD50 of 800 mg/kg bw (Smyth et al., 1941).
Further data on acute oral toxicity in humans:
In a case report (Kochhar et al., 1986) severe oesophageal burns and superficial ulceration of the stomach has been observed in a subject after ingestion of ca. 45 mL of 37% aqueous solution of formaldehyde. Similar results were reported after a gulp of 40% formaldehyde solution (OECD 2002).
A review on toxicity of ingested formalin in accidental, homicidal or suicidal attempts is available (Pandey et al., 2000). Ingestion of formaldehyde may cause burning in the mouth and oesophagus, nausea and vomiting of tissue and blood, coffee ground emesis, abdominal pain, and diarrhoea. Further it can cause liver and kidney damage, leading to jaundice, albuminuria, haematuria and anuria, acidosis and convulsions or central nervous system depression and lead to unconsciousness and death resulting from cardiovascular failure. The fatal dose in humans is about 60-90 mL formalin (no further details given).
In the study of Skog (1950; comparable to OECD 403 with acceptable restrictions) 8 rats per dose were exposed for 30 minutes to 600-1700 mg/m³ (9 dose groups; 3-week post exposure observation period). Rats became listless and showed lachrymation, secretion from the nose; whining and rattling sound of respiration; rats gasped (similar signs observed after s,c, injection); respiration troubles lasted for several days (oedema); last death as late as the 15th day after exposure (bronchitis in this rat). Histopathology (limited documentation on dose-relationship) revealed local effects (lung oedema) as well as effects in liver (hyperaemia, perivascular oedema, necrosis) and kidney (perivascular oedema) which might be regarded as secondary effects due to the severe lesions in respiratory tract.
Conclusion: LC50 (30 min) rat = 1000 mg/m³ corresponding to 830 ppm.
In a study comparable to OECD Guideline 403 (OECD, 2002; secondary literature and not assignable but reliability 2 given in OECD SIDS Formaldehyde) 6 -10 male rats per dose were exposed for 4 hours to concentrations between 230 and > 900 mg/m³ formaldehyde gas (21 dose groups); the post exposure observation period was not given. The symptoms (restlessness, excitation, laboured breathing, gasping and lateral position) suggested local effects in the respiratory tract. No mortality occurred at 280 - 430 mg/m³.
Conclusion: LC50 (4 h) = 588 mg/m³ = 490 ppm in rats.
In inhalation hazard tests (BASF AG, 1980 a,b, & 1981) atmospheres enriched with formaldehyde by passing air through 1% solution in water resulted in no mortality after an exposure period of 7 h but clinical signs suggesting local effects on the respiratory tract and the eyes; using the same experimental design but 2.5% formaldehyde solution in water lethal effects occurred after 7 h exposure but not after 3 h exposure. Using 5% aqueous solution all rats survived an exposure period of 1 h but 2/6 died after 3 h exposure and all rats died after an exposure period of 7 h.
Morphological changes of the nasal epithelium in rats have been shown even at low concentrations (Bhalla et al., 1991). The exposure of rats to 10 ppm formaldehyde (12 mg/m³; n= 6) for 4 h resulted in morphological alteration of the epithelium in the nasal cavity. Light and electron microscopy showed ciliary destruction and cell separation in naso- and maxilloturbinates, cellular swelling (more prominent 24 h after exposure period compared to 1 h post exposure) throughout the turbinates, pores on the cell surfaces and between adjacent cells in the middle meatus, and mucous release of goblet cells in nasoturbinates.
Swenberg et al. (1983a, see Section Repeated dose toxicity) exposed rats to 15 ppm for 1-9 days (6h/d). After 1 day of exposure, acute degeneration of the respiratory epithelium with edema and congestion was evident. Initial lesions were most severe on the tips of the maxilloturbinates and nasoturbinates.
Time dependency of early histopathological lesions can be seen from a study primarily designed to investigate the time and concentration dependency of formaldehyde-induced effects on mucociliary function in rats (Morgan et al., 1986, details presented in Section Repeated dose toxicity). A single 6 h exposure to 15 ppm produced only minimal histopathological lesions (separation of epithelial cells, intravascular margination, local tissue infiltration) in the anterior nasal passages, the maxilloturbinates, the nasoturbinates and the lateral wall. The mucous flow rate was reduced but the effect was not significant.
The histopathological alterations after short term exposure to formaldehyde are reflected by data for cell proliferation. Early experiments demonstrated that the different sensitivity of rats and mice for tumor induction is also reflected by cell proliferation as measured by pulse labeling with [3H]-thymidine. A single 6-h exposure to 15 ppm caused a 13-fold increase in cell proliferation in rats and an 8-fold increase in mice (Chang et al., 1983; see details in Section Repeated dose toxicity). The proliferative response was most pronounced in the basal cell layer. Rats showed early degeneration and sloughing of respiratory epithelial cells with evidence of early hyperplasia. Mice had only mild serous rhinitis and focal degeneration of the respiratory epithelium. With an optimization of the labeling procedure (pulse labeling 18 h post exposure) a transient increase in cell proliferation was seen in rats exposed to 0.5 or 2 ppm for just one day (Swenberg et al., 1986, see Section Repeated dose toxicity).
In a series of experiments the time, concentration and location-dependency of formaldehyde exposure on mucociliary function in rats was studied (Morgan et al., 1986). After exposure the animals were sacrificed, the nasal mucosa was dissected and placed in a glass observation chamber mounted with a microscope and fiber optics illumination. In an acute exposure experiment male rats were exposed to 15 ppm over 10, 20, 45, 90 min and 6 h or to 2 ppm over 90 min or 6 h and the nasal mucociliary apparatus was evaluated directly after exposure. In addition, after exposure to 15 ppm over 90 min and 6 h a recovery period of 1 h was allowed for before observation of the mucociliary function. No effects were observed at 2 ppm. At 15 ppm the extent of formaldehyde-induced inhibition of mucociliary function was time-dependent, with increasing areas of mucostasis and ciliastasis being induced during the 6 h exposure period. The areas of inhibition of mucus flow exhibited the same site specificity as ciliastasis while being generally more extensive. The recovery period of 1 h led to recovery of mucociliary function especially in the more posterior areas of the affected regions. However, in areas of recovery mucus flow rate was still reduced indicating incomplete recovery of function. The regions of inhibition of mucociliary function generally correlated well with the distribution of formaldehyde-induced nasal squamous cell carcinomas.
The concentration of formaldehyde producing a 50% decrease in respiratory rate (RD50) of rats after 10 min of exposure was 32 ppm (38 mg/m³). In mice, however, the same experimental designs resulted in a RD50 (10 min) of 4.9 ppm (5.9 mg/m³). These species differences might influence repeated dose toxicity (Chang et al., 1981).
To determine the acute inhalation toxicity (single 4-hour exposure, whole body) of Formaldehyde as a vapor, a study was performed in male and female Wistar rats according to OECD-Guideline method 403, as well as EC and EPA guidelines under GLP (BASF 2015, key). The actual measured concentration was 463 ppm (analytical concentration). At 463 ppm all of five male and five female animals died. Lethality was observed on study day 1 or 2. Clinical signs of toxicity in animals comprised gasping, respiration sounds, breathing in stretched position, closed eyelid, red discharge and red encrusted nose, poor general condition, salivation, piloerection and yellow discoloured fur. Findings were observed from hour 1 of exposure until the death of the animals. The mean body weights of the animals surviving the exposure period decreased until death. During necropsy all animals showed dilated stomach, which were filled with gaseous content. The LC50 was < 463 ppm (analytical concentration).
Further data on acute inhalation toxicity in humans:
No effects on lung function parameters were found in controlled clinical studies in volunteers exposed for 5 h to up to 2 ppm (Andersen & Molhave, 1983) or exposed for 3 h to up to 3 ppm (3.6 mg/m³; Kulle et al., 1987). In a recent study Lang et al. (2008) exposed healthy volunteers over 4 h up to 0.5 ppm formaldehyde with 4 peaks of 1 ppm (15 min each) including cycle ergometry (80 Watt, 3 times, 15 min each). No effects were noted on nasal resistance and flow (active anterior rhinomanometry), pulmonary function by body plethysmography (airway resistance, peak expiratory flow, forced expiratory volume by 1 sec, maximum mid expiratory flow) or reaction time. Nasal resistance and flow rates measured by anterior active rhinometry as well as self-reported tear film break-up time were not affected in volunteers at 0.7 ppm or 0.4 ppm with peaks of 0.8 ppm (Mueller et al., 2013).
Pulmonary effects in asthmatic people were examined with controlled exposure to formaldehyde in three independent studies (BfR, 2006). In these controlled clinical studies, formaldehyde-related increases in pulmonary dysfunction were not evident in asthmatics at concentrations of up to 3 ppm and an exposure period up to 3 hours.
Lung function was reported to be affected at workplaces at formaldehyde concentrations higher than 1 ppm and exposure duration of 2 -3 h. But as summarized by Greim (2000) the validity of these studies is limited (no controlled exposure concentration, peak exposure, co-exposure not excluded) and they do not allow to draw any firm conclusion.
Data on chemosensory irritation of eyes, nose and throat in humans are reported in the summary and discussion of Section Irritation and Corrosivity.
IARC (2006) presented a summary on toxic effects in animals (see IUCLID Section 7.12) as well as a summary on toxic effects in humans (see IUCLID Section 7.10.3) including data on acute toxicity.
Mueller et al. (2013, key) further refined the results obtained by Lang et al. (2008). 41 male volunteers (non-smokers, age ±9.9 years) were exposed in a randomised schedule to 0, 0.5, 0.7 ppm and to 0.3 ppm with 4 15 min peaks of 0.6 ppm and to 0.4 ppm with peaks of 0.8 ppm. During exposure 4 cycle ergometer units at 80 W were performed for 15 min. Subjective pain perception induced by nasal application of carbon dioxide served as indicator for sensitivity to sensory nasal irritation to define subjects hyper- and hyposensitive for irritation. The following parameters were examined before and after exposure: subjective rating of symptoms and complaints (Swedish Performance Evaluation System), conjunctival redness, eye-blinking frequency, self-reported tear film break-up time and nasal flow rates. In addition, the influence of personality factors on the volunteer’s subjective scoring was examined (Positive And Negative Affect Schedule; PANAS). No indications for subjective or objective indications of sensory irritation were obtained under these exposure conditions. There was a statistically significant differences for olfactory symptoms, especially for the ‘perception of impure air’ when comparing the subjective symptoms under formaldehyde exposure with zero exposure. These subjective complaints were more pronounced in hypersensitive subjects. When comparing the studies of Lang and Mueller, Lang et al. (2008) observed subjective symptoms of eye irritation already at 0.3 ppm while these effects were not found by Mueller et al. (2013, key) even at higher exposures. This is explained by Mueller et al. (2013) by the fact, that negative affectivity was significantly higher in the subjects exposed in the Lang study as compared to those of Mueller. The increased ‘perception of impure air’ was attributed by the authors impairment of well-being caused by situational and climatical conditions in the exposure chamber, because a statistically significant difference in symptom scores between FA exposures and control condition was missing, and hypersensitive subjects reported statistically significantly higher complaints even after exposure to 0 ppm. The NOAEC for sensory irritation was 0.7 ppm over 4 h and 0.4 ppm with peaks of 0.8 ppm.
In the context of a restriction of formaldehyde and formaldehyde releasers, the sensory irritation studies of Lang et al. (2008) and Müller et al. (2014) were reevaluated (RAC & SEAC, Opinion on an Annex XV dossier proposing restrictions on formaldehyde and formaldehyde releasers, compiled version, adopted 13 March 2020 by RAC and 17 September 2020 by SEAC). In the view of RAC, such small numbers of volunteers and such a high variability of EBF in both studies do not allow a dose-related effect to be detected (unless the effect is sufficiently strong). Under these conditions (small size of samples, males only, very high variability of the test parameter, lack of data on continuous EBF monitoring during exposure) the lack of observed effects cannot be considered as evidence for the absence of dose-related effects. In addition to the uncertainties reported above, the variability of the results obtained might not reflect the variability of the general population, particularly of children, as indicated in a review by the JRC (2005). It is also noted that the respective exposure treatments in the studies by Lang et al. and Müller et al. were rather short (4 h) single exposure events (Lang et al., 2008). It is not known whether the threshold value for EBF would be different (i.e. lower) for formaldehyde, if exposure duration and/or frequency were expanded. Further weaknesses were identified in the Lang study: Data from male and female volunteers were pooled, although increased eye redness in females indicated a gender-specific difference.
In conclusion on the study of Lang et al. (2008) and Mueller et al. (2013), RAC considers that the absence of a sensory irritation effect at formaldehyde concentrations below 1.24 mg/m³ (1 ppm) is uncertain. Due to high variability of the measured effect (large ranges, high standard deviations), the low numbers of volunteers (yielding low statistical power) and the additional uncertainties identified, false negative results at 0.62 mg/m³ (0.5 ppm) or lower cannot be excluded. The studies of Lang et al. (2008) and Mueller et al. (2013), thus, cannot be used to derive a DNEL, because the uncertainties are too high and the lack of observed effects cannot be considered as evidence for the absence of dose-related effects.
In addition to the uncertainties reported above, the variability of the results obtained might not reflect the variability of the general population, particularly of children.
As a consequence, two new sensory irritation studies were initiated with specifically addressing the shortcomings and deficiencies of the studies of Lang et al. and Müller et al..
The importance to clearly differentiate between sensory irritation and olfaction was demonstrated by Berglund et al. (2012, key). 31 subjects (18–35 years old) were exposed to formaldehyde at concentrations varying between 6.36 and 1000 ppm corresponding to the Swedish TLV. Exposure was carried out in a hood exposure system and the volunteers took one sniff of the atmosphere over 3 sec (3 sniffs/min).P50absolute thresholds were for formaldehyde odor 110 ppb (range 23–505). For sensory irritation the P50 could not be calculated because too few subjects were studied and the exposure was limited to 1000 ppb. But all thresholds for irritation were higher than for odor.In a comprehensive review about factors that may influence olfaction Greenberg et al. (2013, key) concluded that perception of odor cannot be used as a surrogate marker for chemical exposure. Odor perception is affected by the psychological state and bias because odor is often negatives biased by association with health-related symptom.
Some further studies in humans on self-reported symptoms during prolonged work with formaldehyde are mentioned here, although not related to single exposures. As far as subjective symptoms were recorded these studies are less reliable than those in volunteers under controlled exposure conditions. The major problems stem from factors like exposure to mixtures of unknown composition, peak exposures that were not controlled for, or recall bias to former exposures. Basically the main subjective symptoms were reported by students of a gross anatomy dissection course using a more detailed questionnaire (Mori et al., 2013, supporting). The symptoms were reversible 6 months after the course. Pre-existing allergies did not change during the course. Apart from subjective reportings, again the problem is exposure assessment. Exposure was reported to be about 0.2 ppm, but this was measured by area and not by personal sampling for 20 min after start of the course. Thereby personal peak exposures could not be accounted for.
Some studies reported objective parameters associated with formaldehyde exposure. Neghab et al. (2011, supporting) carried out a cross sectional study with 70 workers of a melamine-formaldehyde producing factory including 24 non-exposed referents. In total 7 air samples were taken over 40 min. The frequency of some of the self-reported respiratory symptoms (e.g. cough, chest tightness, episodes of chest illness associated with cold) was significantly higher in the exposed population and pre- and post-shift parameters of pulmonary function showed significant decrements. A recovery of lung function capacity was observed following temporary cessation of exposure. Airborne formaldehyde exposures clearly exceeded current exposure limit values with 0.78 ppm (SD=0.4). Hisamitsu et al. (2011, supporting) investigated serum IgE levels, olfactory tests and nasal sensitivity to histamine in 41 medical students before, during and after an anatomy dissection course. Olfactory abnormalities and increased histamine sensitivity were observed during and immediately after the course, but the effects were reversible and disappeared after completion of the course. Formaldehyde concentrations ranged from 0.51-0.97 ppm (mean 0.67) in the center of the laboratory.
According to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the substance has to be classified as Acute Tox Cat 3 (oral and dermal) H311, and H301 and for inhalation Cat 2, H330.
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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