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Description of key information

The results of studies of repeated dose oral toxicity indicate that calcium fluoride exhibits typical fluoride toxicity, however the low water solubility of the substance indicates that the oral bioavailability of fluoride from the substance is less than other salts such as sodium fluoride, thereby limiting its toxicity. The results of a 28-day inhalation study with the insoluble salt aluminium fluoride did not show any evidence of fluoride toxicity at the highest exposure concentration of 50 mg/m3. The results of this study therefore indicate the low bioavailability of fluoride following inhalation exposure.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
50 mg/m³
Study duration:
subacute
Species:
rat

Additional information

Oral studies

In a study using 12 paired groups of albino rats, Lawrenz et al (1939) administered fluoride in the form of calcium fluoride or cryolite in the drinking water for 14 weeks. Total fluoride intake (from the basal diet and drinking water) amounted to a dose level of approximately 0.75 mg/kg bw/d. Bodyweight gain and food consumption were retarded in both dose groups. Clinical signs were limited to transient haematuria in both groups, and the appearance of dental striations in all animals from Week 8 -10. Analytical derminations at necropsy revealed fluoride retention of approximately 59%, and that the large majority of the fluoride in the body was present in the skeleton (~96%). No differences were apparent between the treated groups. The authors conclude that the effects of fluoride from these two insoluble salts are comparable.

Smith & Leverton (1934) investigated the comparative toxicity of various forms of inorganic fluoride in a 6 -week feeding study in male rats. They noted that overt effects of calcium difluoride toxicity (bodyweight reduction, mortality) were seen only at very high concentrations compared to other, water-soluble fluorides. In contrast, mild dental effects were seen at comparable fluoride levels for all of the compounds investigated, however the more severe effects were only seen at much comparatively much higher concentrations of calcium difluoride. The results of the study therefore indicate that the toxicity of calcium difluoride is markedly influenced by its low water solubility.

Sodium fluoride studies

The much greater water solubility of sodium fluoride (41300 mg/L) compared to calcium fluoride (15 mg/L) means that the bioavailability of fluoride from NaF is likely to be much greater than that of fluoride from CaF2 and therefore represents a worst case.

In a 14-day range-finding study in the mouse, mortality was seen at the highest dose level of 800 ppm; signs of toxicity (reduced weight gain, abnormal gait and posture, reduced water consumption) were also apparent at this dose level. A NOAEL of 400 ppm is determined for this study. In a 6 -month rat study, the effects of exposure to NaF were limited to reduced weight gain, dental fluorosis, thickening and ulceration of the gastric mucosa at the highest dose level of 300 ppm; gastric effects were also seen at 100 ppm. The fluoride content of plasma, bone and teeth increased with dose levels. The NOEL for this study was 30 ppm, however these local effects are not considered to be relevant for the risk assessment therefore a NOAEL of 100 ppm can be determined. In a 6 -month nouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm. Skeletal effects were seen in males at the lowest dose level of 50 ppm.

Dermal studies

A waiver is proposed: fluoride toxicity has been adequately charcterised by other routes of exposure and dermal absorption is likely to be negligible.

Inhalation study

No data are available for calcium difluoride, however a study is available for the insoluble salt aluminium fluoride. Read-across is proposed as the substances are similarly of low water solubility, The bioavailability of fluoride followoing inhalation is therefore likely to be comparable.

The inhalation toxicity of an aerosol of aluminium trifluoride was investigated in a sub-acute 28 day study in Wistar rats. Groups of 5 rats/sex were exposed to target concentrations of 0 (control), 1, 7 or 50 mg/m³, for 6 hours/day, 5 days/week for 28 days (a total of 20 exposures). No treatment-related abnormalities were noted during exposure. There were no treatment-related effects on food consumption, food conversion efficiency and body weight gain. In the high-dose males there was a relative and absolute increase in the concentration of neutrophils, an increase of the globulin concentration, and an increase in both absolute and relative liver and lung weights. The increase in absolute and relative lung weights was also seen in high-dose females. There were treatment-related histopathological changes in the lungs of all exposed animals and in the tracheobronchial lymph nodes of high-dose males and females. In the lungs of animals from the high-dose group, multifocal alveolar 'pigment' macrophages with particulate material in their cytoplasm were accompanied by inflammatory changes. In the tracheobronchial lymph nodes of all rats in the high-dose group, the pigment was seen as deposits of (phagocytised) particulate material in the cortex and medulla. In the lungs of the low and mid-dose group, only very slight focal (low-dose) or very slight multifocal (mid-dose) macrophages containing a single or a few pigments were seen. Since phagocytosis and processing of foreign material is a normal function of alveolar macrophages, the presence of pigment macrophages in the lungs of the animals of the low and mid-dose groups was not considered to be an adverse toxicological effect.

The 28 day inhalation NOAEL for aluminium trifluoride was 7 mg/m³.

The effects of the substance on the liver are not consistent with fluoride toxicity, but are consistent with the effects of aluminium. It can therefore be concluded that there is no evidence of systemic fluoride toxicity in this study.

Justification for classification or non-classification

The available data do not indicate that the substance is classified for repeated dose toxicity according to the CLP Regulation (1272/2008/EC).