Registration Dossier

Administrative data

respiratory sensitisation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable, well-documented publication, which meets basic scientific principles

Data source

Reference Type:
Nasal Irritation and Pulmonary Toxicity of Aliphatic Amines in Mice
Gagnaire, F., S. Azim, P. Bonnet, P. Simon, J. P. Guenier and J. de Ceaurriz
Bibliographic source:
Journal of Applied Toxicology, Vol. 9(5), 301-304

Materials and methods

Principles of method if other than guideline:
no guideline required
GLP compliance:
not specified

Test material

Details on test material:
- Name of test material (as cited in study report): methylamine
- Substance type:liquid or as a solution of the gaseous amine in water
- Analytical purity: high purity

Test animals

Details on test animals and environmental conditions:
- Source:IFFA CREDO, Domaine des Oncins, Saint Germain sur l'Arbresle
- Weight at study initiation: 20-25 g
- Diet (e.g. ad libitum): UAR-Alimentation, Villemoisson ad libitum
- Water (e.g. ad libitum): tab water ad libitum
- Acclimation period: 1 day
- Inhalationchamber: 200 l stainless-steel with adjustable airflow (10-30 m3/h), negative pressure to prevent leakage of test atmosphere
(additional airflow bubbled through the liquid amines and the vaporized compounds were diluted with air to the required concentration before entering the exposure chamber)

Test system

Route of induction exposure:
Route of challenge exposure:
other: exposed via tracheal cannulation
not specified
4 to 6 different exposure concentrations, range 85 - 192 ppm
No. of animals per dose:

Results and discussion

RD 50 = 141 ppm, 95 % confidence interval (ppm), tentative standard on the basis of 0.1 RD 50 < 15

Any other information on results incl. tables

For all amines, except for allylamine and diallylamine, the onset of action was very rapid, ca. 30 s to 1 min. For both of the amines previously mentioned, the effect became maximal after 10-15 min of exposure. At the end of a 15-min exposure period, the recovery of respiratory frequencies to the pre-exposure values was also rapid, ca. 1 min.

The effects were slower to develop than in non-cannulated mice, the maximal effects being obtained after 120 min of exposure. After the end of exposure there was incomplete, if any, recovery, especially for the highest concentrations.

Applicant's summary and conclusion

Interpretation of results:
other: irritation: 141 ppm provoke an RD 50
Methylamine is irritating the respriatory tract. In concentrations of 141ppm a 50 % decrease of the respiratory rate in rats was found.
Executive summary:

Previous studies with several chemicals have shown that the RD50 values can be used successfully to predict safe industrial exposure. At 0.1 RD50, humans would experience some slight discomfort and this should be the highest level permitted in industry. At 0.01 RD50 no sensory irritation is observed and a convenient threshold limit value (TLV) would be 0.3 RD50 the midpoint on a logarithmic scale between the. 0.1 and 0.01 RD50. The present data show that, for seven amines out of ten compounds for which TLVs exist (Table 2), the current TLVs are always < 0.1 RD50 but higher than 0.01 RD50. For dimethylamine, trimethylamine and cyclohexylamine, a TLV of 10 pprn seems too high and should be divided by a factor of two.

In nasal irritation and pulmonary toxicity study of 20 aliphatic amines in mice, Gagnaire et al. exposed mice to airborne MMA to determine RD50 value (Gagnaire et al., 1989). This value indicates 50% decrease in the respiratory rate and considered to be successfully used to predict safe industrial exposure. The onset of action of MMA was very rapid, ca. 30 sec. to 1 min. 141 ppm of MMA was determined as RD50 in mice. At the end of a 15 -min exposure period, the recovery of respiratory frequencies to the pre-exposure values was also rapid, ca.1 min. Due to the rapid recovery of respiratory frequency in mice, monomethylamine is considered to be moderately irritating to the upper respiratory airways.

The differences between RD50 and RD50TC indicate that amines are essentially irritants for upper airways. While the respiratory rate responses of oronasally exposed mice indicative of nasal irritation set in rapidly and were reversible when exposure to the irritants ceased, the respiratory rate responses of cannulated mice were slower to develop than in oronasally exposed mice, and no, or incomplete, recovery was observed after the end of exposure, when mice were allowed to breathe fresh air.