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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
study report
Reference Type:
Exposure study to examine chemosensory effects of formaldehyde on hyposensitive and hypersensitive males
Mueller J.U., Bruckner T., Triebig G.
Bibliographic source:
Int Arch Occup Environ Health, Jan;86(1):107-117

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
basic toxicokinetics
acute toxicity: inhalation
eye irritation
respiratory irritation
Principles of method if other than guideline:
Forty-one healthy male volunteers (aged 32 years ± 9.6) were exposed for five days (four hours per day) during one week in a randomised schedule to formaldehyde concentrations of 0.3 ppm with a peak exposure of 0.6 ppm (four times for 15 minutes), 0.4 ppm with a peak exposure of 0.8 ppm (four times for 15 minutes), 0.5 ppm and 0.7 ppm. The following parameters were examined before and immediately after exposure: conjunctival redness, tearfilm break-up time, nasal resistance, nasal flow and olfactory function (n-butanol threshold, odour discrimination and identification). Eye blinking frequency together with the volunteers´ subjective rating of their symptoms and complaints (SPES) were determined within the last 15 min of exposure. In addition, the influence of personality factors on the volunteer’s subjective scoring was examined (PANAS).
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): formaldehyde
Specific details on test material used for the study:
- Formaldehyde (pure)
- Test material form: gas


Type of population:
- Number of subjects exposed: 41
- Sex: male
- Age: 32 ± 9.6 years

- Exclusion criteria: active smokers (status was verified by cotinine test), allergy, acute infection, alcohol consumption of more than 50 grams per day, illegal drug intake, insufficient visus without visual aid (*), eye blinking frequency > 20/min, exposure to formaldehyde at the workplace or at home, acute or chronic diseases of the respiratory tract, metabolism, heart or skin

* Visual aids (spectacles) had to be removed by the participants during exposure and examinations. Contact lens bearers were asked to remove their lenses and use spectacles instead at least one week prior to the beginning of exposure.
Ethical approval:
not specified
Route of exposure:
Reason of exposure:
Exposure assessment:
Details on exposure:
All individuals were exposed for 5 days (4 hours per day) during one week in a randomised schedule to formaldehyde.

Generation and measurement of formaldehyde were done by a chemist. Paraformaldehyde was weighed using a precision scale and vaporised at 200°C in a flask over a magnetic hot plate stirrer. The vapour was then introduced into the exposure chamber via a metallic duct. Adjustment of formaldehyde concentrations was realised by means of an exhauster. Three fans ensured homogeneous distribution of the gas throughout the exposure chamber. In the process,
placement, direction and speed of the fans were chosen adequately so as to avoid a possible irritation, e.g. of the subject’s eyes, by the resultant draft of air.
Real-time monitoring of formaldehyde concentrations was carried out using an ASYNCO formaldehyde monitor (Interscan®, HCHO). In order to verify the results of real-time monitoring, two air samples by means of air sampler cartridges (WATERS “XPoSure®) were taken daily from the exposure chamber and then analysed through HPLC/UV detection.

The exposure chamber has a total volume of approximately 30 m3 (length: 4.3 m, width: 2.9 m, height: 2.4 m). The temperature and the humidity inside the chamber were measured and documented on an hourly basis.

Exposure took place on five consecutive days (Monday to Friday). Exposure time was set at four hours per day with predefined concentrations of formaldehyde throughout five days. Volunteers were examined approximately within one hour before start and one hour after the end of exposure each day. Apart from recording of the eye blinking frequency and completion of the SPES questionnaire, which were performed during the last 15 minutes of exposure inside the exposure chamber, no examinations took place in the course of the daily exposure phase. A maximum of four subjects were exposed per exposure week, separated into two groups with staggered start of exposure by one hour. Due to additional examinations undertaken on Mondays and Fridays, exposure on those days had to be time-staggered by two hours. During the 4-hour duration of exposure per day, volunteers had to undergo a total of four
cycle ergometer units at 80 watts for 15 minutes at predefined times. On days with exposure peaks, two of those ergometric units were carried out at the time of an exposure peak. Subjects were asked not to eat shortly before an examination and during exposure.

For further details on exposure see table below.
The following examinations were done before exposure:
• medical history and physical examination
• testing for cotinine in the urine to ensure participants were non-smokers
• PANAS questionnaire to determine positive and negative affectivity
• determination of basal eye blinking frequency (20/min)
• active anterior rhinomanometry
• CO2 threshold (= basis for breakdown of the volunteers into different sensitivity groups)
• sniffing sticks (discrimination and identification of odours)

The following examinations were performed daily before and one hour after exposure:
• CO2 threshold
• olfactory function (n-butanol threshold, odour discrimination and identification)
• photo documentation of conjunctival redness
• measurement of tearfilm break-up time
• active anterior rhinomanometry
• conjunctival redness
• tearfilm break-up time
• nasal resistance and flow

The following examinations were done daily before and within the last 15 minutes of exposure:
• video recording of eye blinking frequency
• SPES questionnaire (Swedish Performance Evaluation System)

The following tests were performed three times at weekly intervals after exposure was finished:
• sniffing sticks (including n-butanol odour threshold, odour discrimination and odour
identification) within one hour after the last exposure and during the three follow-up
• CO2 threshold

Measurement of Conjunctival Redness
Digital photographs were taken to document any dilatation of the conjunctival blood vessels as an indication of possible irritant effects of formaldehyde on the mucous membrane of the external eye. A standardised ophthalmologic grading scale of the CCLRU (Cornea and Contact Lens
Research Unit) was used to categorise the conjunctivities.

Determination of Eye Blinking Frequency Using Digital Video Recording
By means of a digital camcorder the eye blinking frequency of a subject was documented. For a period of some five minutes the subject’s right eye was recorded. Afterwards, a special video editing software (“Cut-assistant” V.0.9..12.2) allowed coherent video sequences of exactly one minute length to be generated from these video data files. All sequences obtained were counted manually on a 19-inch computer screen and in
randomized sequence, i.e. the person counting did neither know the volunteer nor the concentration of formaldehyde that was set in the specific recording. Similarly as for conjunctival redness, counting was performed by two independent investigators.

Measurement of Tearfilm Break-up Time
To measure the “tear film break-up time“, participants were directed to sit in an upright and relaxed position, to give a start command after a number of random winks of the eyes (3-4) and to keep their eyes fixed on a mark located at eye level on the opposite wall. When the command had been issued, a stop watch was started to measure and note down the time elapsed until the first closure of the subject’s eyelid. The participants were instructed to held their eyes open as long as possible and to keep them fixed on the wall mark.

Active anterior rhinomanometry (AAT) was used to determine the resistance in nasal respiration based on the JAEGER Rhinoscreen®.

Examination of the Olfactory Function
To identify possible effects of formaldehyde on the olfactory system, so-called “sniffin’ sticks®“ (BURGHART Medizintechnik, Germany) were used in this study. This is a commercial screening test to determine an individual’s smelling capability and the olfactory function.
The test was used to identify the n-butanol concentration that a subject can just (threshold) recognise.

Determination of Unspecific Sensitivity
A major aim of this study was to investigate a possible influence of differences in susceptibility to unspecific irritation (CO2-sensitivity) on the magnitude of irritation induced by formaldehyde. In this respect the volunteers first had to be subdivided into hypersensitive und hyposensitive ones. Determination of the CO2 threshold: The participants where exposed to CO2 (40, 60 and 80% CO2) by a gas delivery system („Trigeminometer“ built by Benno Schuster, Dresden, Germany). The participant indicated sensation of pain on a VAS. For this purpose, a 100 mm long horizontal line without further subdivisions was drawn on the subject’s questionnaire. The two ends of the scale were designated as „none at all“ and „unbearable“.

Data input was done using the database Microsoft Access 2000. All statistical calculation was performed using SAS version WIN 9.1. Categorical data were summarised by means of absolute and relative frequencies (counts and percentage). Quantitative data were summarised by means of the following summary statistics: the number of observations, the arithmetic mean, standard deviation (SD), minimum, median and maximum.

Results and discussion

Clinical signs:
No clinical findings.
Results of examinations:
In summary, the described results showed that the maximum concentrations used, i.e., 0.7 ppm formaldehyde over four hours and four times 15 minutes peak concentration of 0.8 ppm superimposed to 0.4 ppm, did not lead to irritant effect on the eye and nose parameters investigated (the NOAEL was 0.7 ppm without peak exposure and 0.4 ppm with 0.8 ppm peaks).

Applicant's summary and conclusion

In summary, the test substance exposure did not lead to objective signs of ocular or nasal irritation.
Executive summary:

The results obtained from the respective eye tests did not reveal any FA-induced irritant effects, up to the maximum concentrations which were 0.4 ppm with 0.8 ppm peak (4 times; 15 minutes each) and 0.7 ppm (over 4 hours), respectively. Conjunctival irritation: For conjunctival irritation, the authors observed numerically decreasing or constant post-exposure conjunctival redness levels rather than increased ones. This finding was not only restricted to the total collective of subjects, but also applied to the individual sensitivity groups, which exhibited a predominant decrease of conjunctival redness as well. Eye blinking frequency tended to decrease after FA exposure both in the total and the different sensitivity groups. It was only noticed a slight, albeit statistically not significant increase of eye blinking frequency in extremely hypersensitive volunteers after exposure to 0.5 ppm FA but not at 0.7 ppm FA. Tearfilm break-up time: Sensitivity-dependent effects on tearfilm break-up time by FA could not be identified. Nasal irritation: Nasal flow investigations revealed no uniform trend but an existence of a dose-effect relationship could not be derived. Therefore, it was concluded that any significant changes were not caused at all (or merely to a minor degree) by irritant effects FA has on the mucous membranes of the nose. The n-butanol threshold examinations conducted daily before and immediately after exposure did not indicate any significant concentration-dependent olfactory threshold changes. A dose-effect relationship was not apparent. There are no significant differences in the results of target parameters between hypo- and hypersensitive subjects