reaction mass of potassium tetrafluoride and tripotassium hexafluoroaluminate

Carcinogenicity

Description of key information

The substance is not considered carcinogenic.

Justification for classification or non-classification

Based on the available data and in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for carcinogenicity.

Additional information

Systemic carcinogenicity

Carcinogenicity studies with the target substance or with any of its analogues are not available. As fluoride has been identified as the moiety of toxicological concern, studies with fluorides other than with target/ananlogue substances are considered. Four carcinogenicity studies with sodium fluoride (two diet studies and two drinking water studies) are available (NTP, 1990; Maurer, 1990; Maurer, 1993).

 

Mice

 

Mice were exposed to NaF in their drinking water daily for two years in concentrations of 0, 25, 100 or 175 mg/L (NTP, 1990). These concentrations were equal to average dose levels of 0, 1.27, 5.11 and 8.50 mg F^-/kg bw/day for the females and to 0, 1.08, 4.34 and 7.55 mg F^-/kg bw/day for the males. The diet contained 8.66 mg F^-/kg (equivalent to 1.23 mg/kg bw/day). Observations included clinical status, body and organ weights (liver, kidneys and brain at interim sacrifices), urinalysis, haematology, clinical chemistry (limited), and complete histopathology. Teeth showed dose-related discolouration and mottling in all groups including the controls, but at higher incidences and earlier in time in the exposed groups. Dental attrition was enhanced in the 175 mg/L dose groups; in the males slightly more pronounced than in the females. Dentine dysplasia was significantly increased in the 175 mg/L males group. Other non-neoplastic lesions were not found. Some neoplastic lesions (lymphomas, hepatocellular neoplasms, harderian gland adenomas, pituitary adenomas) were seen, but these lesions were either not treatment-related or of no biological significance (NTP, 1990).

 

In a combined toxicity/carcinogenicity diet study, Maurer et al. (1993) exposed mice for two years to nominally 0, 4.0, 10, and 25 mg NaF/kg bw/day (equal to 0, 1.79, 4.43 and 11.17 mg F^-/kg bw/day, respectively). Through the (low-fluoride) diet the animals received 0.45 mg F^-/kg bw/day. Observations included clinical status, body and organ weights (extensive) and histopathology (extensive). Dose related changes in teeth were found at 4 mg/kg bw/day and above comprising, amongst others, fractures, attrition and discolouration, which were accompanied by ameloblast dysplasia, cystic hyperplasia, degeneration and vacuolation. Various skeleton malformations (enostosis, osteosclerosis, hyperostosis) were observed at 10 mg/kg bw/day and above. Ossification or mineralisation of stifle joints, occasionally together with arthritis were seen in males and females at 10 and 25 mg/kg bw/day. Soft tissue lesions, though looked for were not reported. The dental and bone lesions were considered to be related to exposure to fluoride. Other changes in relative organ weights or tissues (including testes) were not found, but quantitative data were not provided. Especially in the high dose group an enhanced number of benign osteomas were observed in which a high density of retroviral particles were seen. The authors concluded that with respect to the occurrence of the osteomas the study is inconclusive because the presence of the retroviral infection might have enhanced the genesis of these tumours (Maurer et al, 1993).

 

Rats

 

Rats were exposed to NaF in their drinking water daily for two years in concentrations of 0, 25, 100 or 175 mg/L (NTP, 1990). These concentrations were equal to average dose levels of 0, 0.59, 2.48, 4.29 mg F^-/kg bw/day for the females and to 0, 0.50, 2.35 and 3.89 mg F^-/kg bw/day for the males. The diet contained 8.66 mg F^-/kg (equivalent to 0.43 mg/kg bw/day). Observations included clinical status, body and organ weights (liver, kidneys and brain at interim sacrifices), urinanalysis, haematology, clinical chemistry (limited), and complete histopathology. Teeth showed whitish discolouration and mottling with increasing incidences from 25 mg/L. At 100 mg/L and higher these colour changes were accompanied by dental attrition, deformities and malocclusion. In males at 25 mg/L and higher and in females at 100 mg/L and above increases in dentine dysplasia and ameloblast and odontoblast degeneration were found. The effects were more pronounced in male animals. In the females of the 175 mg/L group an increased incidence in osteosclerosis was observed. In male animals osteosarcomas were observed with incidences of 0/80, 0/51, 1/50 and 3/80 in the 0, 25, 100 and 175 mg/L groups, respectively. Osteosarcomas were not reported for the females. The authors considered the results equivocal with respect to the carcinogenic potential of NaF. No other indications for the formation of neoplastic lesions were obtained; neither were other treatment-related lesions found (NTP, 1990).

 

In a combined toxicity/carcinogenicity study, Maurer et al (1990) exposed rats for two years to 0, 4.0, 10, and 25 mg NaF/kg bw/day (equal to 0, 1.81, 4.52 and 11.24 mg F^-/kg bw/day, respectively). Through the (low-fluoride) diet the animals received 0.16 mg F^-/kg bw/day. Observations included clinical status, body and organ weights (extensive) and histopathology (extensive), clinical chemistry (not specified), and urinalysis (not specified). Dental aberrations (ameloblast dysplasia and enamel hypoplasia) were increased (dose-related) in all groups. Dental fractures and malocclusions were enhanced at 10 and 25 mg/kg bw/day. The females were no less sensitive than the males. Subperiosteal hyperostosis was observed in particular in the bones of the skulls of males at 10 mg/kg bw/day and above. In the females this effect was less pronounced.Relative and absolute stomach weight were significantly increased at 10 mg/kg bw/day and above. Mononuclear cell infiltration of the glandular epithelium was increased (dose-related) from 4mg/kg bw/day in the male and from 10 mg/kg bw/day in the females. Chronic inflammation and regeneration of the glandular mucosa occurred in the males at 10 mg/kg bw/day and above. In the females these effects were seen at 4 mg/kg bw/day and above and at 25 mg/kg bw/day respectively. In 24 other tissues (including testes) no lesions were reported, but quantitative data were not provided. In some animals neoplastic bone lesions were seen (sarcoma, osteosarcoma, chordoma, chondroma) but these lesions were incidental and randomly distributed among the groups. In the stomach of one control male a papilloma was found. Other soft tissue neoplasms were not reported in detail but it was stated that "there was no evidence that fluoride altered the incidence of preneoplastic and neoplastic lesions at sites of fluoride toxicity or at any other site in rats of either sex" (Maurer et al. 1990).

 

Discussion of the studies with NaF (taken from the European Union Risk Assessment Report on Hydrogen Fluoride. 2001)

 

In the rat drinking water study, equivocal indications for osteosarcomas in males were obtained, but the rat diet study was negative, despite clear indications of fluoride intoxication. The mouse drinking water study was also negative. The mouse diet study was confounded by the presence of a retrovirus which may have (co)-induced the growth of benign osteomas thus thwarting the interpretation of the study. In the diet studies (Maureret al, 1990; Maureret al, 1993) bone fluoride levels were higher than in the drinking water studies (NTP, 1990), while in the diet studies no indications for osteosarcomas were obtained. Furthermore, the osteomas were considered to be reminiscent of hyperplasias rather than true bone neoplasms. It was concluded that the available data is sufficient to suggest that fluoride is not a carcinogenic substance in animals.

 

Since the results with the oral studies with NaF give no indications that fluoride has a carcinogenic potential in animals and taking into account that reaction mass of potassium aluminium tetrafluoride and tripotassium hexafluoroaluminate is not mutagenic in vivo there is no reason for concern with regard to carcinogenicity of reaction mass of potassium aluminium tetrafluoride and tripotassium hexafluoroaluminate.

 

References

- European Chemicals Bureau (2001). European Union Risk Assessment Report. Hydrogen Fluoride.

- NTP (1990)Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No. 7681-49-4) in F344/n Rats and B6C3F1 Mice (Drinking Water Studies). NTP Technical Report Series, No. 393, NIH Publ. No. 91-2848, National Toxicology Program.

- Maurer JK, Cheng MC, Boysen BG, Anderson RL (1990). Two-year carcinogenicity study of sodium fluoride in rats. J. Nat. Cancer Inst. 82; 13: 1118-1126.

- Maurer JK, Cheng MC, Boysen BG,Strandberg JD, Weisbrode SE, Seymour JL, Anderson RL (1993). Confouded carcinogenicity study of sodium fluoride in CD-1 mice. Reg. Toxicol. Pharmacol. ;18: 154-168.

Local carcinogenicity

Regarding local carcinogenicity, the local effects after semi-chronic exposure in the 90 days inhalation key study were considered. 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. From these results, it was concluded that exposure to aluminium potassium fluoride at levels of 3.08 mg/m3 induced increased lung weights (females), increased numbers of neutrophils in blood (females) and typical alveolar macrophage accumulations in the lungs (both sexes). Exposure to 1.21 mg/m3 resulted only in the presence of macrophages in the lungs. The presence of these macrophages are considered a physiological response to the exposure and therefore not considered adverse as such. No changes were observed in animals exposed to 0.32 mg/m3. Therefore, in case of chronic of exposure, there is no concern if exposure will be below the concentration at which the local effects occur (as these will be the trigger for the occurrence of possible preneoplastic lesions). Therefore, the DNEL for local effects based on the NOAEC of 1.21 mg/m3 regarding repeated dose toxicity will also cover possible local carcinogenic effects.