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Toxicological information

Carcinogenicity

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Description of key information

No data for carcinogenicity are available with the substance identified as reaction mass of calcium fluoride (47.5% w/w), calcium sulfate (ca 22.3%) and calcium carbonate (ca 12.09%). However, carcinogenicity studies are available on calcium fluoride and carcinogenicity study with calcium sulfate or calcium carbonate is not deemed necessary as described below. Therefore, the carcinogenicity potential of the registered substance is based on its constituents using a weight of evidence approach.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
29.3 mg/kg bw/day
Study duration:
chronic
Species:
other: rats and mice
Quality of whole database:
The NOAEL of the registered substance is based on the NOAEL of Calcium fluoride extrapolated from the NOAEL of sodium fluoride determined in the 2-year carcinogenicity studies conducted in rat and mouse exposed by oral route

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Harmonised classification

Reaction mass of calcium fluoride and calcium sulfate and calcium carbonate has no harmonised classification according to the Regulation (EC) No. 1272/2008 (CLP).

 

Self classification

Based on the information available on its three main constituents, no self-classification is proposed regarding carcinogenicity of the reaction mass of calcium fluoride and calcium sulfate and calcium carbonate according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).

Additional information

Regarding calcium fluoride, no carcinogenicity studies available. However studies are available for the water soluble salt sodium fluoride. 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.

Studies from NTP were performed both in the rat and in the mouse :

The NTP rat study showed evidence of an effect of sodium fluoride administration on the bones and teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological and clinical chemistry parameters and organ weights were unaffected by treatment. Serum, urine and bone fluoride concentrations were increased in all treated groups; the urine calcium concentration was also marginally higher in females at the highest dose level. Osteosclerosis was seen in females at the highest dose level. The incidence of osteosarcoma was increased in males at the intermediate dose level (2%) and the high dose level (4%) but was within the historical range (0 -6%; mean 0.5%). The NTP concluded that the study provides 'equivocal evidence' for carcinogenicity in male rats.

The NTP mouse study showed evidence of an effect of sodium fluoride administration on the teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological parameters and organ weights were unaffected by treatment. Clinical chemistry revealed elevated ALP activity in females at the highest dose level. Microscopic findings were limited to dentine dysplasia in male mice at 175 ppm, equivalent to 29.3 mg CaF2/kg bw/day (bsed on the equivalence of 15.75 mg NaF/kg bw /day and the molecular weight of NaF= 41.988 g/mol and CaF2= 78.074 g/mol).There was no evidence of carcinogencity in either sex.

An additional carcinogenicity study with NaF performed both in the rat is available (Maurer et al, 1990). No evidence of carcinogenicity was seen in this rat study, at dose levels sufficient to cause toxicity.

The European Risk Assessment Report for Hydrogen Fluoride (2001) concludes that the data are sufficient to suggest that fluoride is not carcinogenic in animals.

 

For calcium sulfate or calcium carbonate, there are no lifetime animal studies available in order to directly investigate for possible carcinogenic activity. However, calcium sulfate and calcium carbonate gave negative results in the in vitro and in vivo genotoxicity studies for calcium sulfate. Moreover, in the repeated dose studies with calcium sulfate or calcium carbonate, there is no evidence that these constituents are able to induce hyperplasia or pre-neoplastic lesions. Furthermore, the long term human data does not provide any indications of carcinogenicity.

 

Based on a weight of evidence approach using the information on the constituents, no carcinogenicity classification is warranted for the registered substance according to the criteria of CLP based on evidence from genotoxicity, repeated dose toxicity studies and long term human studies.