Aluminium fluoride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

42 mg/kg bw/day

Additional information

Information regarding the speciation of both the registered substance, aluminium fluoride (AlF3), and a read-across substance, cryolite, was sourced from a literature article reporting computer-aided QSAR estimates of the speciation of the substances in aqueous media utilizing SOLGASWATER (version Win SGW) model. The author tabulated the expected Al(III) speciation at pH 7.2 and an ionic strength of 0.15, intended to represent a physiological medium, for additions of AlF3 and of cryolite of 0.001 mM, 0.1 mM and 10 mM. At 0.001 mM, both substances gave identical distributions of only hydroxy-Al species, at 0.1 mM both substances gave very similar distributions of predominantly hydroxy- and hydrox-fluoro-Al species, and at 10 mM both substances gave very similar distributions of predominantly hydroxy-fluoro- and fluoro-Al species. On the basis that exposure to the registered substance, AlF3, or to the read-across substance, cryolite, is expected to generate very similar proportions of essentially the same aluminium complexes within the solubility range of AlF3, cryolite is considered to be an appropriate surrogate for AlF3.

Information on the reproductive toxicity of aluminum fluoride was obtained from a study conducted with the read-across substance trisodium hexafluoroaluminate (cryolite). The effects of cryolite were evaluated in a dietary two-generation reproduction toxicity study, equivalent to OECD test guideline 416. Sprague-Dawley rats were administered cryolite concentrations of 0, 200, 600, or 1800 ppm in the diet (Schroeder, 1994). Based on intake, these concentrations corresponded to pre-mating dose levels of 0, 14, 42, or 128 mg/kg bw/day for males and 0, 16, 49, or 149 mg/kg bw/day for females). Noteworthy effects included significantly decreased pup body weights on lactation days 7, 14, and 21 in the F1 offspring and on lactation days 4, 7, 14, and 21 in the F2 offspring at the highest dose level (1800 ppm). Gross findings of pale kidneys, pale livers, and enlarged hearts were noted in the weanlings of the 1800 ppm dose level.  Parental findings included dental fluorosis, characterized by whitening of the incisors, in most treated animals of both generations. Bevelled anterior lower incisors were reported in³67% of high dose animals in both generations. No study information was available.

On the basis of this data, the NOAEL for reproductive toxicity was considered to be 42 mg/kg bw/day. This dose corresponds to the calculated paternal cryolite intake level at 600 ppm in the diet. A NOAEL for parental effects could not be established due to findings of dental fluorosis.

Short description of key information:
Information on the effects of aluminum fluoride on reproduction can be obtained from a two-generation reproductive toxicity study in rats conducted with the read-across substance trisodium hexafluoroaluminate (cryolite). The reproductive effects of cryolite was assessed in a two-generation dietary study in rats, equivalent in design to OECD test guideline 416 (GLP-compliance not reported). A NOAEL of 42 mg/kg bw/day (600 ppm) was identified for reproductive toxicity due to decreased pup body weights at higher dose levels. A NOAEL for parental toxicity could not be established due to findings of dental fluorosis in treated animals.

Effects on developmental toxicity

Description of key information

Information on the effects of aluminum fluoride on developmental toxicity can be obtained from an oral prenatal toxicity study conducted with the read-across substance trisodium hexafluoroaluminate (cryolite).  A prenatal development study in mice, equivalent to OECD Test Guideline 414 (GLP status unknown), identified an oral NOAEL of 100 mg/kg bw/day for developmental toxicity and a NOAEL of 30 mg/kg bw/day for maternal toxicity.  Effects on the skeletal structure of the fetuses were only noted at doses resulting in maternal mortality and are not supportive of developmental toxicity.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

100 mg/kg bw/day

Additional information

Information on the effects of aluminum fluoride on developmental toxicity can be obtained from a prenatal toxicity study conducted with the read-across substance trisodium hexafluoroaluminate (cryolite). The effects of cryolite on development were evaluated in an oral gavage prenatal development study in mice, equivalent to OECD Test Guideline 414 (GLP status unknown) (Nemec, 1991).  Pregnant dams were administered 0 (aqueous methylcellulose suspension vehicle), 30, 100, or 300 mg/kg bw/day of cryolite from gestation days 6 through 15 (n=25/group). Noteworthy findings included increased maternal mortality at 300 mg/kg bw/day, the presence of dark red stomach contents in the 300 mg/kg bw/day dams, and a red glandular portion of the stomach starting at 100 mg/kg bw/day or more. An increase in bent ribs and bent limbs were noted in fetuses at the 300 mg/kg bw/day dose level. On the basis of these findings, the derived NOEL for maternal toxicity was considered to be 30 mg/kg bw/day and the derived NOEL for developmental toxicity was 100 mg/kg bw/day. Since effects on the fetuses were noted at severely maternal toxic doses, there is no support that the read-across substance (cryolite) was teratogenic in mice. 

 

The RAC has reviewed the data from this study and others and has noted the following:

 ¿RAC is of the view that the maternal mortality in the two ¿positive¿ mouse studies is too high to allow any meaningful conclusions on developmental toxicity to be drawn from these studies (CLP Regulation, Annex I §3.7.2.4.4 ¿Maternal mortality greater than 10% is considered excessive and the data for that dose level shall not normally be considered for further evaluation¿). Overall, there is no support for classification from the developmental toxicity studies.¿

Justification for classification or non-classification

According to the ECHA (2010), it is believed that the decreased pup weights in both generations of the 2-generation study in rats fed cryolite (acceptable surrogate for AlF3) via the diet is the only sign of developmental toxicity in animal studies that can be assessed in relation to the classification criteria. In relation to Category 2 (CLP), it is a borderline case with regard to whether the 11-26% decrease in pup growth is sufficient for classification. Arguments against classification are that no reporting of maternal toxicity in such a short summary does not necessarily mean that aside from dental fluorosis there was indeed no other maternal toxicity, and that the decreased pup weight was not adverse enough to affect the reproduction in F1. Although being a borderline case, RAC does not support classification for reproductive toxicity, Cat 2 (CLP) (or Repro Cat. 3 (R63)), because the evidence for developmental toxicity is too limited and the quality of the reporting too poor to warrant classification. As such, the notifiable substance is not classified for reproductive toxicity as data are conclusive but not sufficient for classification.

 

ECHA (2010). Opinion Proposing Harmonised Classification and Labelling at Community Level of Trisodium Hexafluoroaluminate (Cryolite), Natural and Synthetic. (ECHA/RAC/CLH-O-0000001052-90-02/F & ECHA/RAC/CLH-O-0000001051-92-03/F).,: European Chemical Agency (ECHA), Committee for Risk Assessment (RAC). Available at: http://echa.europa.eu/doc/about/organisation/rac/final_clh_opinion_cryolites_cas15096-52-3_cas13775-53-6.pdf.