Formaldehyde

Endpoint summary

Description of key information

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.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

partly limited documentation

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

no symptoms described, no necrospy

GLP compliance:

no

Remarks:

pre-GLP study

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

TEST MATERIAL
- 2 and 4 % formaldehyde solution prepared from the special-grade paraformaldehyde and the commercial special-grade formalin (inludes methyl alcohol of more than 10 %)

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 100 - 200 g
- Housing: 5 rats per cage
- Diet: solid feed

ENVIRONMENTAL CONDITIONS
- Temperature: 18 - 20°C

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED
- At a dose of 675 mg/kg bw 33 mL/kg
- At a dose of 1140 mg/kg bw 28.5 mL/kg

Doses:

230, 300, 400, 520, 675, 875 mg/kg (2 % solution)
400, 520, 675, 875, 1140 mg/kg (4 % solution)

No. of animals per sex per dose:

6 - 16

Control animals:

no

Details on study design:

Duration of observation period following administration: at least one week

Statistics:

Litchfield method to determine LD50

Sex:

male

Dose descriptor:

LD50

Effect level:

460 mg/kg bw

95% CL:

330 - 650

Remarks on result:

other: 2 % test substance

Sex:

male

Dose descriptor:

LD50

Effect level:

832 mg/kg bw

95% CL:

617 - 965

Remarks on result:

other: 4 % test substance

Sex:

male

Dose descriptor:

LD50

Effect level:

550 mg/kg bw

95% CL:

420 - 715

Remarks on result:

other: 2 % test substance

Sex:

male

Dose descriptor:

LD50

Effect level:

710 mg/kg bw

95% CL:

550 - 910

Remarks on result:

other: 2 % test substance

Sex:

male

Dose descriptor:

LD50

Effect level:

640 mg/kg bw

95% CL:

551 - 742

Remarks on result:

other: 4 % test substance

Mortality:

Rats died in most cases within 24 h after application.

Clinical signs:

other: no data

Gross pathology:

no data

 

Mortality rates in male Wistar rats after oral application of formaldehyde
2% formaldehyde
Formalin solutions		Paraformaldehyde solutions
Dose in mg/kg bw	Mortality	Dose in mg/kg bw	Mortality
675	7/7	675	5/8
520	3/7	520	4/8
400	1/6	400	2/8
300	1/7	300	1/8
230	0/7	230	1/8
		875	9/9
		675	4/9
		520	2/9
		400	0/9
		300	0/9
4% formaldehyde
Formalin solutions		Paraformaldehyde solutions
Dose in mg/kg bw	Mortality	Dose in mg/kg bw	Mortality
1140	13/16
875	11/16	875	13/16
675	8/16	675	9/16
520	0/16	520	2/16
400	0/16	400	3/16

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

LD50 = 640 mg/kg bw

Executive summary:

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

640 mg/kg bw

Quality of whole database:

similar to OECD TG 401, non-GLP, K2

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Mar 06, 2015 to Aug 12, 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

Sep 07, 2009

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

May 30, 2008

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

Aug, 1998

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

TEST MATERIAL
- Purity: formaldehyde 10.1 g/100 g (Titration)
- Lot/batch No.: CMPKQ0901
- Expiration date of the lot/batch: 09 Apr 2015
- Physical state / appearance: liquid / colorless, clear

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability: expiry date: 09 Apr 2015, under storage conditions over the test period was guaranteed by the sponsor, and the sponsor holds this responsibility
- Homogeneity: homogeneous by visual inspection

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories B.V. Kreuzelweg 53, 5961 NM Horst, Netherlands
- Females nulliparous and non-pregnant: yes
- Age at study initiation: male animals approx. 9 weeks, female animals approx. 11 weeks
- Weight at study initiation: animals of comparable weight (± 20 % of the mean weight). Mean weight males 261.5 g, mean weight females 214.3 g
- Housing: single housing in Type III (polycarbonate cages) (floor area about 800 cm²) with wooden gnawing blocks and play tunnel
- Diet: Kliba laboratory diet, mouse/rat maintenance “GLP”, 10 mm pellets, Provimi Kliba SA, Kaiseraugst, Basel Switzerland, ad libitum
- Water: Tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24°C
- Humidity: 30 - 70 %
- Air changes (per hr): 15
- Photoperiod: 12 hours / 12 hours

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remark on MMAD/GSD:

not specified

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Test-substance preparation: unchanged
- Equipment: continuous infusion pumps PHD Ultra, Atomization vaporizer (glass) with thermostat
- Generation technique: a vapor was generated, was produced by continuously pumping amounts of the test substance into the thermostated vaporizer and using compressed air, was mixed with streams of conditioned air and passed into the inhalation systems
- Generator temperature: 40°C
- Whole-body inhalation system: IKA 02 (glass-steel construction, volume V 200 L), animals were kept in compartmentalized wire cages (DKIII) and were exposed inside the chamber, homogenous distribution of test substance atmosphere has been verified with model vapors
- Conditioned air: the central air conditioning system provides cold air of about 15°C, cold air passes through an activated charcoal filter, is adjusted to room temperature of 20 to 24°C and passes through a second particle filter, so generated conditioned air was used to generate inhalation atmospheres
- Compressed air: compressed air was produced by an oil-free compressor, air was filtered by an inlet air strainer and introduced into the compressor, after passing through a second ultra-filter, the compressed air (15 bar) was stored in a storage of 1500 or 5000 L, compressed air was conducted to the laboratories via pipes, where the pressure is reduced to 6 bar
- Exhaust air: was filtered and conducted into the exhaust air of the building, exposure system was located inside an exhaust cabin in an air-conditioned laboratory, during exposure, the following scheduled parameters were recorded four times at about 1- hour intervals: supply air flow (compressed air): 1.0 m³/h, plus a dilution air (condition air): 2.0 m³/h (from a central air-conditioning system)
- Exhaust air flow: 2.9 m³/h, flow was adjusted and continuously measured with a flowmeter, lower amount of exhaust air, which was adjusted by means of a separate exhaust air system, achieved a positive pressure inside the exposure system ensuring that the mixture of test substance and air was not diluted with laboratory air in the breathing zones of the animals

ANALYTICAL INVESTIGATIONS
- The concentration in the inhalation atmospheres was determined by gas samples (sampled in evacuated gas container)
- The nominal concentration was calculated from the amount of test substance dosed and the supply air flow
- Sampling position: immediately adjacent to the animals' noses at a separate spare port
- Sampling: Gas sample into evacuated gas sampling tubes (glass)
- Mean and standard deviation were calculated for the concentration from the results of the 8 individual measurements

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Remarks on duration:

plus equilibration time of the inhalation systems (t99 about 18 min)

Concentrations:

463 ppm

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: at least 14 days
- Body weight determination: once during the acclimatization period, shortly before exposure (day 0) and at least on days 1, 3 and 7, and before the sacrifice of the animals at the end of the observation period, body weight was measured in animals that died from study day 1 onwards
- Signs: clinical observations were recorded for each animal separately several times during exposure and at least once daily on the pre-exposure day and during the observation period
- Mortality: a check for any dead or moribund animal was made twice each workday and once on Saturdays, Sundays and on public holidays
- Pathology: at the end of the observation period the surviving animals were sacrificed with CO2-inhalation in a chamber with increasing concentration over time, and were subjected to gross-pathological examination as well as the animal which died

Statistics:

For results of the type ”LC50 greater than”, ”LC50 approx.”, or ”LC50 smaller than”, the binomial test was used for statistical evaluation.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

< 463 ppm

Based on:

test mat.

Exp. duration:

4 h

Mortality:

All of the five male and the five female animals died. Lethality was observed on study day 1 or 2.

Clinical signs:

other: gasping, respiration sounds, breathing in stretched position, closed eyelid, red discharge, red encrusted nose, poor general condition, salivation, piloerection, yellow discolored fur

Body weight:

The mean body weights of the animals surviving the exposure period decreased until death.

Gross pathology:

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.

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

LC50 (inhalation, rat, 4h) < 463 ppm

Executive summary:

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

< 463 ppm air

Physical form:

inhalation: vapour

Quality of whole database:

OECD TG 403, GLP, K1

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In acute toxicity studies local irritation is the main effect.

 

Oral exposure

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).

Inhalation exposure

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.

Justification for classification or non-classification

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.