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A NOAEC of 0.21 mg/m3 based on local effects in the lungs observed in the semi-chronic inhalation study is taken as starting point for the risk assessment. No systemic effects were observed up to the highest concentration tested (4.6 mg/m3).
In an epidemiological study, no definite indications of skeletal effects were seen in aluminium smelter workers with long-term occupational exposure to 0.48 mg fluoride/m3.
The critical effect following repeated dietary exposure to cryolite in experimental animals was fluoride accumulation and its effect on non-neoplastic bone disease - skeletal fluorosis. Dental fluorosis (hypoplasia/hypomineralisation of dental enamel and dentine) represents a most sensitive adverse effect related to cryolite treatment. Changes in dental enamel described as striations in tooth enamel were observed after giving cryolite in diet and drinking water to rats at 0.58 mg/kg bw/day for 14 weeks.

Key value for chemical safety assessment

Additional information

There are two 2-week range finding inhalation toxicity studies (in conformance with requirements of the standard repeated dose toxicity testing protocols) in rats available. The data were used to establish exposure concentrations for use in a 90-day investigation. Cryolite was administered to Sprague-Dawley CD rats for 6 hours a day, 5 days a week for 2 weeks by inhalation of particulates of the test substance using a whole body exposure system. In the first study, groups of rats (5/sex/group) were exposed to cryolite concentrations of 60 mg/m³ (low dose), 130 mg/m³ (mid dose), or 470 mg/m³ (high dose). In the second study with identical group arrangement the mean exposure levels were 5.1 mg/m3(low dose) or 13.6 mg/m3(high dose). A further group of rats (5/sex) acting as a control was exposed to air only.

In both range finding studies, no treatment-related mortalities were reported. In addition, no other relevant treatment related systemic effects were found in both studies.

A NOAEC for local effects (effects on the lungs) could not be established for both studies. So, the lowest concentration tested in both 2-week range finding inhalation toxicity studies, 5.1 mg/m3, was set as LOAEC (Huntingdon Research Centre Ltd., 1994a, 1994b).

In the 90-day inhalation study according to OECD TG 413 (the recovery period was extended to 13 weeks) groups of Sprague-Dawley CD rats (10/sex/group) were snout-only exposed to cryolite concentrations of 0, 0.21, 1.04, and 4.6 mg/m3 for 6 hours a day, 6 days a week for a period of 13 consecutive weeks (Huntingdon Life Sciences Ltd., 1997a).

At termination, increased lung weights were present in rats of both sexes of the high dose cryolite group. A similar but less obvious effect was present following 13 weeks of recovery. Pulmonary inflammatory lesions were observed in a majority of animals receiving cryolite at the high dose, and to a lesser degree, in some animals from the mid dose group. In the majority of animals from the high dose cryolite group, treatment-related findings in the lungs have comprised varying degrees of macrophage aggregation which contained brown pigmented material around alveolar ducts and alveolitis with thickening of alveolar duct walls. In addition, perivascular inflammatory infiltration with increased collagen in the alveolar duct walls and extension of bronchiolar epithelium into alveolar ducts were observed. Macrophages containing brown pigmented material were also present in the tracheobronchial and mediastinal lymph nodes of the high dose cryolite rats. The observed lung changes in cryolite exposed rats were typical of a non-specific reaction over time to a particulate with irritant properties, and attempts at clearance of deposited material via the lung macrophage/lymph node routs. No treatment-related laryngeal changes were seen in cryolite exposed animals. The treatment-related changes had, with the exception of the increased lung weights and the presence of small foci of brown pigmented alveolar macrophages, resolved after the recovery period.

No effects of treatment were evident in clinical signs, bodyweight gain, food or water consumption. Haematological, biochemical and urinalysis parameters did not indicate findings considered of toxicological significance.

In conclusion, the NOAEC for systemic effects in male and female rats was 4.6 mg/m3 and the NOAEC for local toxic effects on the respiratory tract in rats was 0.21 mg/m3.

In the key epidemiological study, no definite cases of skeletal fluorosis occurred among the 570 pot room workers at an aluminium smelter who were exposed to about 0.48 mg fluoride/m3 for at least 50% of their time at work for more than 10 years. There were no observed differences among the groups with regard to occurrence of back and joint problems (Chan-Yeung et al., 1983). Based on this study, a systemic NOAEC of 0.48 mg/m3 is established.

Data on oral animal toxicity studies in conformance with requirements of the standard repeated dose toxicity testing protocols are reported. Fluoride accumulation was the critical adverse effect in several feeding studies in rats and dogs. Fluoride was accumulated at all dose levels of cryolite tested in rats and dogs for different duration of exposure. It was not possible to identify the NOAEL for this effect in any of the repeated oral dose studies. After a repeated administration of cryolite for 90 days fluoride accumulation was observed in rats from the lowest dose tested of 50 ppm (3.8 mg/kg bw/day in males, 4.5 mg/kg bw/day in females) upwards (Weltman, 1996), and in dogs from 500 ppm (17 mg/kg bw/day) upwards (Hagen and Strouse, 1996), respectively.

In repeated dose toxicity studies data on clinical and histopathological examinations of teeth were not routinely reported. Indicators of dental fluorosis as enamel striations, changes in colouration and physical properties of the teeth (hypoplasia/hypomineralisation of dental enamel and dentine) have been noted in albino rats receiving cryolite at 0.58 mg/kg bw/day for 14 weeks (University of Illinois).

For local effects of cryolite on the digestive tract a local NOAEL of 50 ppm (corresponding to about 3.8 mg/kg bw/day in males, and 4.5 mg/kg bw/d in females) could be derived from the 90-day feeding study in rats (Weltman, 1996). Lesions in the stomach, including epidermal hyperplasia and hyperkeratosis/acanthosis in the nonglandular portion of the stomach, and submucosal inflammation in the glandular portion, were observed in Crl:CD(SD)BR rats at ≥5000 ppm (corresponding to about ≥399.2 mg/kg bw/day in males and ≥455.9 mg/kg bw/day in females) after a 90 day administration in the diet. The gastrointestinal lesions were probably caused by hydrofluoric acid (hydrogen fluoride), which can be released from ingested cryolite in the stomach.

For the dermal route, no reliable data are available.

Justification for classification or non-classification

Local effect in rats after subchronic inhalation of predominantly respirable cryolite dust was lung toxicity seen as interstitial pneumonia at a low concentration of 1.04 mg/m3(0.001 mg/L) cryolite (90-day inhalation study, 6 hours/day, 5 days/week (Huntington Life Sciences Ltd., 1997a)). This concentration is far below the cut-off value of 0.25 mg/L established by EU Directive 67/548/EEC for attributing R48/20 (Harmful: danger of serious damage to health by prolonged exposure by inhalation) in a 90-day inhalation study. According to EU Directive 67/548/EEC, classification with R48/23 (Toxic: danger of serious damage to health by prolonged exposure by inhalation) should be applied if the effects are observed at levels of one order of magnitude lower (i.e. 10-fold) than the cut-off value for classification with R48/20. Therefore, classification with R48/23 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 H372 (STOT, Cat. 1) is applicable for the inhalation route.

 

The critical effect following repeated dietary exposure to cryolite in experimental animals was fluoride accumulation and its effect on non-neoplastic bone disease - skeletal fluorosis - observed in rats (males/females) from the lowest dose tested of 3.8/4.5 mg/kg bw/day upward and in dogs from 17 mg/kg bw/day, respectively (90-day studies). Dental fluorosis (hypoplasia/hypomineralisation of dental enamel and dentine) represents a most sensitive adverse effect related to cryolite treatment. Changes in dental enamel described as striations in tooth enamel were observed after giving cryolite in diet and drinking water to rats at 0.58 mg/kg bw/day for 14 weeks. Toxic effects on the bones and teeth in rats were also reported in early repeated dose toxicity studies. These identified dose levels are far below the cut-off value for attributing R48/22 (50 mg/kg bw/day) in a 90-day study in rats according to EU Directive 67/548/EEC. Similarly, as the dose level at which these effects are observed are over 10 times lower than the cut-off level for classification with R48/22, classification and labelling with T, R48/25 (Toxic: danger of serious damage to health by prolonged exposure if swallowed) should be applied. 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 oral route.