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Administrative data

Description of key information

Buckley et al., 1985, Fundamental applied toxicology.V. 5, 341-352 (1985), exposure of rats or mice by inhalation to 0, 10, 50, or 175 ppm dimethylamine (DMA) for 6 hr/day, 5 days/week for 12 months.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
18.7 mg/m³
Study duration:
chronic
Species:
rat

Additional information

Repeated dose toxicity: oral

Darad et al. performed in 1983 a chronic repeated dose toxicity test. 30 rats (Wistar) each were exposed to a daily oral administration of dimethylamine through drinking water. Nitrite, as well as DMA, caused higher in vitro lipoperoxidation, free lysosomal enzyme activities and cytosolic superoxide dismutase activity in liver. Many of the parameters examined (microsomal lipoperoxidation, enzyme activities of acid phosphatase and cathepsin as lysosomal enzymes, enzyme activity of superoxide dismutase) are indicative of a free radical-mediated damage to the cellular and subcellular membrane in rats administered nitrite and/or DMA. The administration of nitrite or DMA appears to decrease the total activity of both the lysosomal enzymes. DMA alone did not have any effect on SOD activity. The increased levels of the cytosolic SOD due to the administration of nitrite or DMA may indicate a higher generation of the superoxide radicals. The increase in lipoperoxidation may result in membrane damage and is further indicated by the labialization of lysosomal enzymes. The results are indicating a free radical-mediated damage to the cellular and subcellular membranes. In conclusion DMA is able to disturb the barrier function of the skin by altering the protective characteristics.

Repeated dose toxicity: inhalation

Gross et al. performed in 1987 a chronic test on Fisher 344 rats with dimethylamine by the route of inhalation. The test duration was 2 years; the substance was administered 6 hours per day at concentrations of 175 ppm. The animals showed a treatment-induced destruction of nasal tissues including loss of the anterior third of the nasoturbinate and the anterodormucus flow patterns with mucus bypassing affected regions. Mucus flow rates were generally increased over those of chronic control animals. In four out of six animals in the chronic study mucociliary activity resembling that in areas lined by respiratory epithelium was observed as a posterior extension of ciliated epithelium into regions normally lined by olfactory epithelium. This was seen during the visual examination and was presumed to represent respiratory metaplasia. Additionally focal degeneration of the squamous epithelium in the nasal vestibule and extensive vacuolation of both the respiratory and olfactory epithelia in the anterior nasal passages was found. These findings are indicating that a considerable repair occurs in the regions lined by squamous epithelium and resolution of the vacuolation following chronic exposure. In histopathological examinations the tissues showed varying degrees of chronic inflammation in the nose. It is interesting that metaplasia to a respiratory-type epithelium occurs at both extremities of the respiratory tract. However, it remains to be determined whether these responses are protective in nature or whether similar mechanisms are responsible for these changes in the nose and lung. It is of interest that despite severe tissue destruction in the anterior nose following a single 6 hr exposure, the nasal lesions exhibited very little evidence of progression, even after 2 years of exposure. These findings indicate a possible regional susceptibility to DMA toxicity or a degree of adaptation by the rat to continued DMA exposure. The acute epithelial degeneration led to squamous metaplasia in chronically exposed animals in both the present study and the study reported by Buckley et al. (1985) presumably as a protective or adaptive response.

In the respiratory epithelial-lined regions of the anterior nasal cavity, acute epithelial degeneration led to squamous metaplasia in chronically exposed animals in both the present study and the study reported by Buckley et al. (1985) presumably as a protective or adaptive response. The lesions in rats exposed to DMA for 2 years (reported by Gross et al., 1987) were very similar to those reported previously for rats exposed for 6 or 12 months (Buckley et al.,1985). Lesions were most severe in the anterior regions of the nose and comprised focal or regional squamous metaplasia, with the normal respiratory epithelium being replaced by a stratified squamous epithelium. This response was associated with chronic active inflammation and occurred in regions with complete loss of mucociliary function. The only consistent response to exposure was moderate to severe goblet cell hyperplasia. At the highest concentration (175 ppm) Buckley et al. reported a depressed mean body weight gain of rats and mice to approximately 90% of control after 3 weeks of exposure. They found severe alterations in the nasal passages. The middle concentration of 50 ppm did cause significantly lower alterations and the lowest dose of 10 ppm only caused slight alterations in a few animals. Two distinct locations in the nose were affected: the respiratory epithelium in the anterior nasal passages, and the olfactory epithelium, especially that lining the anterior dorsal meatus. There was focal destruction of the anterior nasoturbinate and nasal septum, local inflammation, and focal squamous metaplasia of the respiratory epithelium in rats and mice. Mild goblet cell hyperplasia was observed only in rats. The olfactory epithelium exhibited extensive loss of sensory cells with less damage to sustentacular cells. There was also loss of olfactory nerves, hypertrophy of Bowman’s glands, and distension of the ducts of these glands by serocellular debris in regions underlying degenerating olfactory epithelium. At the 175-ppm exposure level, rats had more extensive olfactory lesions than mice, with hyperplasia of small basophilic cells adjacent to the basement membrane being present in rats but not mice. After 12 months of exposure to 10 ppm DMA, minimal loss of olfactory sensory cells and their axons in olfactory nerve bundles was observed in the nasal passages of a few rats and mice. These results indicate that the olfactory sensory cell is highly sensitive to the toxic effects of DMA, with minor lesions being produced in rodents even at the current threshold limit value of 10 ppm. A LOAEC can be set at 10 ppm (18.7 mg/m³), since only a few animals were affected with slight alterations. This value was taken further for the DNEL derivation.

A study performed in 1969 by Coon et al. investigated the reaction of various animals to inhalation of DMA at a concentration of 9 mg/m³. The duration of exposure was 90 days continuously. No death or signs of toxicity were found. Additionally all hematologic values were normal. On histopathologic examination only interstitial inflammatory changes were noted in the lungs of all species. Since only one experiment each was made for formaldehyde, dimethylamine, and ethanol, there are insufficient data to apply to a CSG. The continuous exposure to dimethylamine at 9 mg/m³ produced mild inflammatory changes in the lungs of all species and dilated bronchi in 3 of 3 rabbits and 2 of 3 monkeys.

Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008.