Aluminium fluoride

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
In accordance with Regulation (EC) No 1907/2006 Annex VIII section 8.8.1, a toxicokinetics study is not required as assessment of the toxicokinetic behaviour of the substance has been derived from the relevant available information. This assessment is located within the endpoint summary for toxicokinetics, metabolism and distribution.

Additional information

The physicochemical properties of aluminum fluoride (i.e. the low molecular weight (83.976 g/mol), pKa (5.5 to 7.0) [3], and slight solubility of AlF3 in aqueous solutions) favour its absorption (oral and via inhalation), especially in the slightly basic pH of the small intestine (where AlF3 would dissociate to a lesser extent than in an environment with a low pH). Aluminum fluoride dissociates to release fluoride ions and/or exchange fluoride for hydroxide, depending on both the pH and the fluoride concentration [3].

 

Due to the lack of information on the dermal route of exposure, the default dermal absorption for AlF3, a compound with a log P outside the range of -1 and 4, was estimated to be 10% [4].

 

No clinical signs of systemic toxicity were observed following acute oral exposure of rats or guinea pigs to AlF3 at doses of up to 2000 and 600 mg/kg body weight, respectively or in rats following acute inhalation exposure to up to 0.530 mg AlF3/L air [5,6]. As tissue/blood levels of AlF3 were not measured in any of these studies, they cannot suggest that AlF3 was not absorbed; although they do suggest that the doses of AlF3 administered were not sufficiently high to cause systemic toxicity.

 

Aluminum fluoride was not a skin or eye irritant in rabbits or a skin sensitizer in guinea pigs.

 

Animal studies were available regarding inhalation exposure to AlF3 dust. In a 28-day study, Wistar rats were exposed to 0, 1, 7, or 50 mg/m3 for 6 hours/day and 5 days/week. At the highest dose, increases in absolute and relative lung weights and changes in the tracheobronchial lymph nodes were observed [7]. High-dose animals also demonstrated increased absolute and relative liver weights, which may be indicative of systemic absorption of the test substance. In another inhalation toxicity study, rats were exposed to aluminum fluoride at a concentration equivalent to 0.41 mg Al/m3 for 6 hours/day, 5 days/week, for 5 months. Results suggested alveolar macrophage damage and increases in lysozyme levels, but no evidence of systemic absorption was presented [8].

 

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.

 

In a 12-month toxicity study in Beagle dogs, the read-across surrogate kryocide (trisodium hexafluoroaluminate) was administered daily to animals in the diet at doses of 0, 3000, 10000 or 30000 ppm [9]. Clinical signs such as emesis were noted at the lowest dose. Body weight gain was noted in males at the highest dose. Hemotological changes noted included nucleated red cells in males at the highest dose; decreased red cell count, haemoglobin, hematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and platelets; and increased incidence of specific alterations in red blood cell morphology were noted in males and females of the 10000 ppm dose group. Increased leukocytes were noted only in females. Clinical chemistry parameter changes noted included decrease total serum protein and calcium in male and in serum albumin in females at the mid-dose. Increased lactate dehydrogenase and decreased blood sodium in males or females were noted at the high-dose. A decrease in the specific gravity of urine was noted at the low-dose in females. Renal lesions (such as regeneration of the tubular epithelium, interstitial fibrosis, tubular dilation, interstitial infiltration with lymphocytes, dilatation of Bowman¿s space) were observed. These observations suggest absorption of kryocide by the oral route and possible renal excretion.

 

Aluminum fluoride was administered to Long-Evans rats in the drinking water at 0.5 ppm for 52 weeks [10]. Mortality was increased compared to the control group, and rats experienced a progressive general decline in appearance during the experiment. Aluminum levels were measured in brain and kidney tissues and the animals administered aluminum fluoride had elevated levels of aluminum compared to the control group. There was no difference between groups in the aluminum levels in the liver. Aluminum fluorescence used to measure aluminum levels demonstrated that aluminum was exclusively associated with brain vasculature as it occurred in deposits within the lumen, within endothelial cells, and the adventitia. Greater amounts of fluorescence were observed in the deeper layers of the neurocortex and in the hippocampus of the left hemisphere than in the right. Aluminum fluorescence was detected within the glomeruli and tubules of the kidney; however more fluorescence was associated with vasculature. Aluminum fluorescence was detected in the sinuses and blood vessels in the livers of all animals. Glomerular hypercellularity and mesangial proliferation was apparent in animals administered AlF3. A deposition of protein also was noted in the tubules. There was a significant increase in the extent of monocyte infiltration in the kidneys of animals treated with AlF3 compared to controls. Following dissociation of the aluminum fluoride complex, it appears that aluminum distributes into the brain and possibly the blood-brain barrier. Aluminum fluoride also distributes to the kidneys, further providing evidence for renal excretion.

 

Two reproductive toxicity studies were conducted with the read-across surrogate kryocide. An oral developmental toxicity study was conducted in CD-1 mice [11]. Animals were administered kryocide daily by oral gavage at doses of 0, 30, 100, or 300 mg/kg bw/day on Days 6 to 15 of gestation. Increased maternal mortality and dark red contents in the stomach was observed at the high-dose and red glandular stomachs were noted at the mid-dose. Embryotoxicity, bent ribs and bent limb bones were noted in fetuses at the high-dose. Thus, as embryotoxicity was not observed in the absence of maternal toxicity, no deduction can be made regarding possible transfer of the test substance across the placenta. In a two-generation dietary reproduction study in rats, kryocide was administered to Sprague-Dawley rats in the diet at doses of 0, 200, 600 or 1800 ppm [12]. Decreased pup body weights, pale organs (liver and kidney), and enlarged hearts were noted in pups of the high-dose group. Dental fluorosis was noted in most treated animals of both generations and bevelled anterior edge of the lower incisor was observed in at least two-thirds of the high-dose animals from both generations. These results suggest that kryocide may be absorbed by the oral route and may cause irritation in the stomach, but do not provide evidence that the test substance can pass the placental barrier.

 

In conclusion, the physicochemical properties of AlF3 favour its ready absorption by the oral and inhalation routes, and experimental data from toxicology studies provide evidence to support this likelihood. Dermal absorption is considered to be minimal and likely on the order of 10%. Aluminum fluoride dissociates to release fluoride ions and/or exchange fluoride for hydroxide, depending on both the pH and the fluoride concentration. Experimental evidence suggests that the substance may cross the blood-brain barrier but no convincing evidence exists to indicate that it may cross the placental barrier. Based on evidence of the presence of aluminum in the kidney following oral exposure, renal excretion may be probable, although specific information on excretion is not available.

 

References

[1] Alufluor AB, 2003, Material Safety Data Sheet,,- 251 09,.

 

[2] Behrens A & Andersen KJ, 2002. Solubility of AlF3, DHI Water & Environment, Agern Allé 11, DK-2970 Hørsholm,, Report number 190001-01-01.

 

[3] Sjöberg S, 2002. Chemical Speciation in Aqueous Al3+ -F- -OH- systems of Relevance to Natural Waters and body Fluids: the dissolution of AlF3 and Na3AlF6 (cryolite), Department of Inorganic chemistry, Umeå University, Sweden

 

[4] European Chemicals Agency, 2008. Guidance on information requirements and chemical safety assessment. Chapter R.7C Endpoint Specific Guidance.

 

[5] Bollen LS, 2001, Acute Oral Toxicity Study in the Rat, SCANTOX, DK-4623 Lille ,, Report number 41864.

 

[6] European Commission - European Chemicals Bureau, 2000, IUCLID Dataset for CAS No. 7784-18-1

 

[7] Muijser H & Junker K, 2006, Sub-acute (28-day) inhalation toxicity study with aluminium trifluoride in rats, TNO Quality of Life Utrechtseweg 48, PO Box 360, 3700 AJ Zeist Zeist The Netherlands, Report number V6049

 

[8] Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, 2008, Toxicological Profile for Aluminum.

 

[9] Tompkins E, 1992. One Year Dietary Toxicity Study in Dogs with Kryocide: Final Report. WIL Research Labs Inc, Report number WIL-75033. Unpublished Study Cited in European Union Risk Assessment Report (CAS No: 13775-53-6; 15096-52-3): Trisodium hexafluoroaluminate. European Commission, Joint Research Centre, Institute for Health and Consumer Protection, European Chemicals Bureau.

 

[10] Varner, JA, Jensen KF, Horvath W, Isaacson RK. Chronic Administration of Aluminum-Fluoride or Sodium-Fluoride to Rats in Drinking Water: Alterations in Neuronal and Cerebrovascular Integrity.

 

[11] Nemec MD, 1991. A developmental toxicity study of Kryocide in Mice. WIL Research Laboratories, Inc. Unpublished Study Cited in the European Union Risk Assessment Report (CAS No: 13775-53-6; 15096-52-3): Trisodium hexafluoroaluminate. European Commission, Joint Research Centre, Institute for Health and Consumer Protection, European Chemicals Bureau.

 

[12] Schroeder R, 1994. A Two-Generation Dietary Reproduction Study in Rats with Kryocide (Cryolite). Pharmaco LSR, Inc. Toxicology Services(address not reported), Report number 90-3633.Unpublished Study Cited in European Union Risk Assessment Report CAS No: 13775-53-6; 15096-52-3): Trisodium hexafluoroaluminate. European Commission, Joint Research Centre, Institute for Health and Consumer Protection, European Chemicals Bureau.