Registration Dossier

Administrative data

Description of key information

In a guideline-compliant rat inhalation study, a LC50 of 4470 mg/m3 was derived. No mortality and no clinical sings were observed at 1330 mg/m3.
After oral administration to rats, an LD50 exceeding 5000 mg/kg bw was derived in several studies.
The acute dermal LD50 was greater than 2100 mg/kg bw.

Key value for chemical safety assessment

Additional information

An inhalation LC50 of 4470 μg/L (SD 850 μg/L) was obtained for Sprague-Dawley rats after a 4-hour continuous whole-body exposure to synthetic cryolite ( Huntingdon Research Centre Ltd., 1993). This study was conducted in compliance to OECD TG 403.

After a 4-hour exposure to 4.34 mg/L 5/5 male and 1/5 female rats died within 10 days; after a 4-hour exposure to 2.83 mg/L 1/5 male (on day 4) and 0/5 female rats died; after an exposure to 1.33 mg/L no mortality was observed. Clinical signs during the exposure to cryolite dust were partial closing of the eyes in the highest dose, exaggerated respiratory movements in the medium group and no signs in the lower group. The majority of rats dying as a result of exposure to 4.34 mg/L cryolite showed signs of lethargy for 1-5 days prior to death. Other signs observed prior to death were hypothermia, piloerection and the adoption of a hunched posture; surviving animals recovered within 15 days of the observation period. At necropsy, a high lung weight to bodyweight ratio was found for all deceased rats and survivors. Macroscopic pathology demonstrated swollen and severe congestion of the lungs in decedents. Abnormalities seen in rats that survived the exposure were subpleural foci in the lungs and congested lungs. Histological examination was confined to the lungs, liver and kidneys (kidneys demonstrating unspecific findings): in the lungs, increased alveolar macrophages with/without alveolar septal fibrosis adjacent to alveolar ducts, sometimes with focal alveolar epithelialisation was observed in all cryolite exposed rats. There was some evidence of a dose-related effect on the severity of the observed lesions. Alveolar congestion/haemorrhage was recorded in all decedents treated with cryolite at the high and intermediate dose levels, and in 4/9 rats in the intermediate and 2/10 in the low dose groups killed at termination. A dose-related effect on severity was noted. Alveolitis was reported in 4/6 decedent rats and 1/4 terminal rats in the high dose group, 1/1 decedent and 1/9 terminal rats in the intermediate group. This change was not seen in any rat in the lower dose group. Prominent goblet cells in the bronchiolar epithelium were recorded in 2/6 decedent and 3/4 terminal rats in the high dose and in 1/9 terminal rats in the intermediate dose group. Changes seen only in decedent rats include hyaline membranes with/without alveolar edema in all high and intermediate dose rats, bronchiolar epithelium basophilia and hyperplasia in 4/6 decedents and early thrombus in pulmonary artery in 2/6 decedents in the high dose group.

This study triggers classification of cryolite with R20, 'harmful by inhalation'. Therefore, a DNEL has to be derived for acute inhalation exposure. As starting point for this derivation the concentration of 1.33 mg/L (1330 mg/m3) is taken. At this concentration alveolar congestion/haemorrhage was observed (LOAEC).

Regarding the oral route, no mortality was observed within an observation period of 14 days in a limit test according to OECD guideline 401 using 5 female and 5 male Sprague Dawley rats. The animals were treated with 5000 mg/kg bw of synthetic cryolite suspended in water. Some of the treated animals showed piloerection starting 6 hours after administration. This effect lasted up to day 5. At necropsy, no treatment related macroscopic findings were observed (RBM, 1990).

In a study compliant to OECD TG 401 using Wistar rats, an oral LD50 > 5000 mg/kg bw was derived. Cryolite was suspended in peanut oil and administered in a single dose intragastrically to 5 male and 5 female rats, using a rigid metal stomach tube. None of the animals died within an observation period of 14 days. The clinical signs observed were piloerection and increased salivation. No pathological findings were obtained after necropsy (Bayer AG, 1987).

In a screening study on acute toxicity (no details on method were provided) no mortality was observed in rats after oral administration of synthetic cryolite (purity not given) up to 2500 mg/kg bw. Five groups of 15 male rats each (strain not given) were dosed with 100, 250, 500, 1000 and 2500 mg/kg bw cryolite using cremophor as vehicle; the observation period was 14 days. Reduction of overall appearance and laboured breathing was observed in all rats dosed with 250 mg/kg bw and higher within 5 days after administration. No pathological findings were presented (Bayer AG, 1972).

For the dermal route also an acute toxicity study is available (Elars Bioresearch Laboratories, Inc., 1981). One dosage group of 2.1 g/kg bw and an untreated control group were tested concurrently. Each group contained ten rabbits (five males and five females). The test material remained in contact with the skin for 24 hours under occlusive conditions. At the end of 24 hours, the bandaging was removed and the skin wiped with gauze sponges to remove excess test material. Subsequently, the animals were observed for 14 days. No signs of systemic toxicity were observed in rabbits at a dosage of 2.1 g/kg bw. Based on histopathological results, the test material did produce evidence of mild dermal irritation and inflammation at the test site in New Zealand White rabbits. The acute dermal LD50 for cryolite was greater than 2.1 g/kg bw under the specified conditions.

Justification for classification or non-classification

In accordance to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for acute oral and dermal toxicity based on the available data.

After inhalation of cryolite an acute LC50 of 4.47 mg/L was estimated in rats (4 hours exposure). Therefore, classification as harmful (Xn); R20 is appropriate in accordance to Directive 67/548/EEC. Under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification with H332 (Cat. 4) is applicable.