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Description of key information

The most critical effects of the substance after repeated inhalation exposure were effects on the lungs. Based on the available studies the overall NOAEC for local effects is 1.21 mg/m3. The overall systemic NOAEC is >3.08 mg/m3.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
1.21 mg/m³

Additional information

The inhalation toxicity of aerosols of aluminium potassium fluoride was studied in a subacute (28-day) study in rats (performed according to OECD guideline 412 and under GLP). Exposure was to concentrations of 0 (control), 106, 300 or 603 mg/m3 (TNO, 1999a).

Local effects were considered critical. A concentration-related statistically significant increase in relative lung weight was observed in male and female rats of all test groups. Absolute lung weights were statistically significantly increased in males of the mid and high concentration group and in females of all test groups.

Histopathological changes were induced in the nasal passages, larynx, bifurcation and lungs. These changes, listed below, were slightly more prominent in males than in females.

- Degenerative and proliferative changes in the olfactory and respiratory epithelium were induced in the posterior part of the nasal passages of animals from all test groups.

- Degenerative and proliferative lesions of epithelium covering the arythenoid projections and epiglottis were found in the larynx of high concentration group animals and of one low concentration group animal.

- Proliferative changes at the tip of the carina at the bifurcation were induced in high concentration group animals.

- In the lungs, alveolar macrophage accumulation was observed in animals of all test groups, with signs of macrophage disintegration in animals of the high concentration only.Inflammation as occasionally observed in controls was enhanced in animals of the test groups and shifted from predominantly lymphocytic in controls to a granulomatous reaction in animals of the mid and high concentration group. Bronchial and bronchiolar epithelial hypertrophy was observed mainly in high concentration group animals, although a few low and mid concentration group animals were affected as well.

From the results of this study, it was concluded that even at the lowest concentration tested (100 mg/m3) histopathological changes were induced in the nose, and in a few animals, in the lungs as well. The NOAEC is therefore below 100 mg/m3.

Subsequently, the inhalation toxicity of aerosols of aluminium potassium fluoride was studied in a subacute (28-day) study in male rats. Groups of 6 male rats were exposed to target concentrations of 0 (control), 1.00, 3.10, 10.3, or 103.8 mg/m3 (TNO, 2003). The study was performed under GLP and according to a protocol equivalent or similar to OECD guideline 412. In line with the other subacute study, local effects were considered critical.

Concentration-related statistically significant increases in absolute and relative lung weight were observed in rats exposed to 3, 10 or 100 mg/m3. Macroscopic examination at necropsy did not reveal treatment-related changes.

Observed histopathological changes in the nasal passages, larynx, and lungs were:

- Focal olfactory epithelial necrosis was observed in all animals exposed to 100 mg/m3, in one animal exposed to 10 mg/m3, and in one animal exposed to 3 mg/m3. Focal vacuolation of the olfactory epithelium, possibly a precursor of necrosis was observed in a few animals exposed to 10 mg/m3, and in one animal exposed to 3 mg/m3. Respiratory epithelial metaplasia was observed in all animals exposed to 100 mg/m3, goblet cell hyperplasia of the respiratory epithelium was observed in a few animals exposed to 10 mg/m3. No treatment-related lesions were observed in the anterior part of the nose.

- Sqaumous metaplasia of the larynx with an underlying granulomatous inflammation was seen in animals exposed to 100 mg/m3.

- In the lungs, treatment-associated lesions consisted of typical alveolar macrophage accumulations, accompanied by cellular debris/material lying freely in the alveolar lumen (all test groups), inflammation (3, 10 and 100 mg/m3 test groups) and bronchial/bronchiolar epithelium alterations (3, 10 and 100 mg/m3 test groups). In addition, the incidence of BALT germinal centre development increased with the concentration.

It was concluded that exposure to 3 mg/m3 and higher induced increased absolute and relative lung weights, and histopathological changes in the nose and in the lungs, including typical alveolar macrophage accumulations. Typical alveolar macrophages, however, were also observed in animals exposed to 1 mg/m3. The additional presence of cellular debris/material in the alveolar lumina of a few of these animals suggests impaired or insufficient clearance capacity of the alveolar macrophages, which is considered to be an adverse reaction to the exposure with the test compound. A No-Observed-Effect-Level (NOEL) could, therefore, not be established. However, as the number of accumulated macrophages was small and there was only a tiny amount of deposited material/cellular debris, the concentration of 1 mg/m3 was considered to be a Minimal-Observed-Adverse-Effect Concentration (MOAEC).

 

In the sub-chronic (90-day) study with rats performed according to OECD guideline 413 and under GLP, aluminium potassium fluoride concentrations of 0 (control), 0.32, 1.21, or 3.08 mg/m3 were investigated (TNO, 2004b, 2009).

Increases in both absolute and relative numbers of neutrophils were observed in females of the high concentration group at the end of the exposure period, but a statistical significant degree was reached in absolute number only. At the end of the recovery period, absolute and relative neutrophil counts were still higher in females. The increase in the percentage of neutrophils in these females was accompanied by a decrease in the percentage of lymphocytes at that time.

Absolute and relative lung weights were higher in females of the high concentration at the end of the exposure period; a statistical significant degree was observed in absolute weight only. In males no such changes were seen. At the end of the recovery period, no changes in lung weights were observed. 

Macroscopic examination at necropsy did not reveal treatment-related changes. Microscopic examination of the respiratory tract at the end of the 90-day exposure period revealed a concentration-related change in the lungs consisting of typical alveolar macrophage accumulations in animals of the mid and high concentration group. A tissue reaction appeared absent. The macrophage accumulations persisted after a recovery period of 60 days. The macrophages were somewhat smaller in size when compared to those in animals of the high concentration group at the end of the exposure period, but more conspicuous because their cytoplasm was darkly stained. Despite the persistent presence of the macrophages, a tissue reaction was still absent. The presence of the macrophages are considered a physiological response to the exposure and therefore not considered adverse as such. Therefore, 1.21 mg/m3 is considered a NOAEC.

 

Based on the available studies the overall NOAEC for local effects is 1.21 mg/m3. The overall systemic NOAEC is >3.08 mg/m3.

Justification for classification or non-classification

Respiratory tract effects were observed in rats after subchronic inhalation of aluminium potassium fluoride from 3.08 mg/m3(0.00308 mg/L) (90-day inhalation study, 6 hours/day, 5 days/week (TNO, 2004b)). The NOAEC for these effects was 1.21 mg/m3(0.00121 mg/L). Under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification with H372 (STOT, Cat. 1) is applicable for the inhalation route.