Aluminum sodium oxide

Endpoint summary

Additional information

There are no data available on the genotoxic potential of sodium aluminate.

Sodium aluminate is a strong base (pH > 11.5). Therefore, in vitro testing of sodium aluminate using standard protocols is difficult as the outcome may be influenced by pH effects. In aqueous medium at physiological pH, sodium aluminate precipitates as insoluble aluminium hydroxide while sodium and hydroxide ions remain in solution.

There are no indications of genotoxic properties for sodium and hydroxide ions (EU RAR NaOH, 2007). Therefore, information available on the genotoxic potential of aluminium compounds was taken into account for hazard assessment, since the pathways leading to toxic outcomes are considered to be dominated by the chemistry and biochemistry of the aluminium ion (Al³⁺) (Krewski et al., 2007; ATSDR, 2008).

In vitro

Bacterial test systems

In bacteria, aluminium compounds have been considered, in general, to be non mutagenic (Krewski et al., 2007). No mutagenic activity was observed with aluminium as measured by the Rec-assay using Bacillus subtilis (Nishioka, 1975). Aluminium oxide, chloride and sulphate were also negative in the Rec-assay with the Bacillus subtilis H17 rec+ and M45 rec- strains at concentrations of 1 to 10 mM (Kada et al., 1980; Kanematsu et al., 1980). Aluminium chloride hexahydrate was neither mutagenic nor cytotoxic in Salmonella typhimurium TA102 at concentrations up to 1000 nM/plate (Marzin & Phi, 1985). Ahn and Jeffrey (1994) reported no positive findings with aluminium chloride (0.3 and 3.0 ppm) in the absence of S9 metabolic activation in the TA98 strain. No induction of his mutations were seen by Gava et al. (1989) in the TA104, TA92, TA98, TA1000 strains exposed to aluminium acetylacetonate (1.9-48 µmol/plate), aluminium lactate (1.8 - 5.5 µmol/plate), or aluminium maltolate (0.5-3.7 µmol/plate). In the Salmonella typhimurium strain TA104, a his gene mutation to aluminium acetylacetonate (1.8 - 48 µmol/plate) was observed; however, negative responses were reported when comparisons were made between the absence and presence of metabolic activation.

Mammalian cell gene mutation

Aluminium hydroxide and aluminium chloride were tested in a mammalian cell gene mutation study according to OECD guideline 476 and in compliance with GLP (Covance, 2010b). Mouse lymphoma L5178Y cells were exposed in two experiments to aluminium hydroxide at eight concentrations from 6.094 to 780 µg/mL (ca. 2 to 270 µg Al/mL) for 3 h, both with and without metabolic activation (S9 mix). Cells were treated with aluminium chloride at five concentrations from 3.125 to 50 µg/mL (ca. 0.6 to 10 µg Al/mL) for 3 h in the presence and absence of metabolic activation. In an additional experiment, cells were exposed to aluminium chloride for 24 h at eight concentrations from 5 to 120 µg/mL (ca. 1 to 24 µg Al/mL) without metabolic activation, and for 3 h at eight concentrations from 5 to 50 µg/mL (ca. 1 to 10 µg Al/mL) with metabolic activation. Negative (vehicle) and positive (5-20 µg/mL methyl methanesulfonate with S9 activation; 0.5-3 µg/mL benzo-[a]-pyrene without S9 activation) controls were included in each experiment.

In the experiments with aluminium hydroxide, the mutation frequencies at all the tested concentrations were less than the sum of the mean control mutant frequency plus global evaluation factor (GEF = 126 mutants per 10^-6viable cells). Although a significant positive linear trend in mutation frequencies was observed in the presence of S9 in one of the experiments, no corresponding increase in mutant frequencies approaching the GEF was observed, and the effect was not observed in the other experiment. Therefore, this observation was not considered biologically relevant. For aluminium chloride, the mutant frequencies at all the tested concentrations were less than the sum of the mean control mutant frequency plus the (GEF). A negative linear trend was also observed. The positive control substances showed the expected results.

In another study similar to OECD guideline 476, no forward mutations at the thymidine kinase (tk) locus were induced in the L5178Y mouse lymphoma assay with cells exposed to aluminium chloride at concentrations from 570 to 625 µg/mL (ca. 115 to 125 µg Al/mL) for 4 h (Oberly et al., 1982).

Micronucleus

The capability of aluminium sulphate for inducing micronuclei (MN) in human lymphocytes was studied after a 72-h exposure to 500, 1000, 2000, 4000 µM (corresponding to 1000, 2000, 4000, 8000 µM Al) (Migliore et al., 1999). Blood samples were obtained from two young, healthy donors. The cell cultures were exposed to the test solutions 24 h after PHA stimulation followed by a 48 h incubation period. The percentage of binucleated cells was used as a parameter for proliferation. No obvious toxicity was observed. Aluminium sulphate induced significant increases of MN in binucleated cells at most of the tested doses. Aluminium sulphate produced a significant 1.9- and 2.5-fold increase over controls at 1000 and 2000 µM (2000 and 4000 µM Al), respectively, in cells from donor A. In cells from donor B, a 2.3- to 3.5-fold increase over controls was induced, with the maximum induction observed at 1000 µM (2000 µM Al). The positive controls (Mytomicin C and griseofulvin) gave the expected results. The levels of MN in the negative controls were less than 1%. Production of both centromere negative and centromere positive MN was observed consistent with both clastogenic and aneuploidogenic potential, respectively.

The induction of micronuclei and apoptosis was analysed in human peripheral blood lymphocytes treated for up to 72 h with 1, 2, 5, 10 and 25µg/mL of aluminium chloride (corresponding to ca. 0.2, 0.4, 1.01, 2.02, 5.06 µg Al/mL ) (Banasik et al. 2005). Exposure to aluminium chloride resulted in a dose-dependent induction of micronuclei with a maximum frequency of micronuclei per 1000 cells at 10 µg aluminium chloride/mL (2.02 µg Al/mL). A dose-dependent induction of apoptosis was also observed, especially in cells treated during the G1-phase of the cell cycle. The interpretation of the results from this study is limited by the uncertainty in the actual phase of the cell cycle targeted by the different treatment durations and the significant levels of apoptosis observed at relatively low concentrations of Al.

In another study, lymphocytes from non-smoking, non-alcoholic males and females in three age groups, 0 to 10 years, 21 to 30 years and 41 to 50 years were examined for the formation MN (Roy et al., 1990). Cells were treated with aluminium sulphate at an aluminium concentration of 60 µM-Al for 72 h. MN frequencies were significantly higher than corresponding controls for cultures of human lymphocytes obtained from women aged 41-50 years and men aged 21-30 years. Results from other age/gender groups did not differ from their corresponding controls. When combined, the treated groups exhibited a significantly higher frequency of MN per cell than the combined control groups (1.46 ± 0.52 versus 0.94 ± 0.52 per cell in the combined treated and control groups, respectively). The study is limited by the application of only one concentration of aluminium sulphate and the lack of a positive control.

Chromosome aberration

The frequency of structural chromosome aberrations was examined in human peripheral lymphocytes obtained from 4 young (aged 21 to 26 years), healthy, non-smoking donors after exposure to 5, 10, 15 and 25 µM aluminium chloride at different phases of the cell cycle (Lima et al. 2007). For the G1 phase, lymphocytes were treated with a combination of 0.2 mL PHA and aluminium chloride and then incubated for 52 h at 37 ºC until fixation. For the transition G1-S phase, cultures were treated with aluminium chloride 24 h after stimulation with PHA and then incubated for 52 h at 37 ºC until fixation. For the S phase, pulse treatments of aluminium chloride were administered for 1 h and 6 h at 24 h after PHA stimulation. After each pulse treatment, cells were washed once in serum-free medium, re-incubated in the complete medium for 52 h prior to fixation. For the G2 phase, 69 h cultures were treated with aluminium chloride for 3 h and then fixed immediately, giving a total incubation time of 72 h. It is unclear how many cultures were used per dose and time point. The CA results are presented as single values, although results ought to have been available from 4 cultures, i.e. one from each of the 4 donors. No measure of the variability was provided. There is also uncertainty concerning the types of structural aberrations included in the "total" damage index. Both gaps and breaks were included in the index and whether the breaks were chromatid and/or chromosome was not specified. Methanol was used as the vehicle although this does not appear to have compromised the chromosome aberration results from the study. Total aberrations (gaps plus breaks) were significantly higher than the control in all treated cultures in the G1 and G1/S phases, the S phase and the G2 phase. During the G1 phase, the treated cultures also exhibited significantly increased polyploidy and endoreduplication compared with the negative control. Although not reaching statistical significance, breaks alone showed a dose-related increase. The results are positive but require qualification due to reduction of the mitotic index below 50% of the negative control at most of the aluminium chloride concentrations tested. Therefore, the result for chromosome aberrations is positive, but of unclear biological relevance. The authors suggested that aluminium chloride-related adverse effects result from interference with the mitotic apparatus. 

Incubation of human peripheral blood lymphocytes with 20 µg aluminium sulphate/mL (3.15 µg Al/mL) for 72 h induced chromosomal aberrations (Roy et al., 1990). The CA reported were limited to an increase in gaps and breaks.

Sister chromatid exchange

Increased sister chromatid exchange (SCE) was observed in human lymphocytes from female donors of different age groups exposed to an aluminium concentration of 60 µM-Al (as aluminium sulphate) (Roy et al., 1990). The increased SCE was not consistently observed in cells from donors in all age groups and was in all cases < 2-fold of the corresponding control. It is therefore questionable whether these increases are of biological significance. The study used only one concentration.

Comet assay

DNA damage was analysed in human peripheral blood lymphocytes treated for 72 h with 1, 2, 5, 10 and 25µg/mL of aluminium chloride (corresponding to ca. 0.2, 0.4, 1.01, 2.02, 5.06 µg Al/mL ) (Lankoff et al., 2006). Significant DNA damage was induced at 5 and 10 µg aluminium chloride/mL (1.01 and 2.02 µg Al/mL) as observed in the alkaline comet assay. Apoptosis observed at these test concentration levels was 10-20%. At 2 µg aluminium chloride/mL (0.4 µg Al/mL) and above, oxidised purines and pyrimidines were induced as indicated by the modified comet assay. The results of the alkaline comet assay from this study were positive but, due to the increase in apoptosis as DNA damaged increased, it is not possible to separate cytotoxic effects from oxidative genotoxic effects based on these results.

The alkaline comet assay was used to measure DNA damage in cells treated with aluminium chloride (at 0, 5, 10, 15, 25 µM Al) and fixed after different durations of culture (Lima et al., 2007). Damage was assessed visually on the basis of tail size (score 0, 1, 2, 3 or 4) of 100 comets summing the scores to give a total damage score. Methanol was used as a negative control and ethyl methanesulphonate as a positive control. These results were presented as a graph only. All tested concentrations showed significantly more DNA damage than the methanol negative control culture. However, the damage levels were not significantly different from the positive control. The lack of an index of apoptosis did not allow discrimination of effects due to cytotoxicity from any due to genotoxicity. It was also not reported whether the levels of damage in the methanol control was consistent with levels typically found in the test laboratory.

DNA damage was examined in human (Jurkat) T-cells after treatment with 50, 100, 500, 1000 and 5000 µM-Al (as aluminium chloride) using the neutral Comet Assay, which detects predominantly double strand breaks (Caicedo et al. 2008). Cell viability was measured using propidium iodide staining, cell proliferation using 3 H-thymidine uptake and apoptosis using caspase-9 immunostaining and flow cytometry. Aluminium did not result in significant inhibition of proliferation, significant increases in DNA double strand breaks, or a significant effect on viability at any concentration applied. Apoptosis was significant only at 5000 µM-Al. The cells used in this study have not been extensively used with this assay. The responses observed are thus of unclear biological significance. The pH used for lysing and unwinding was also not clear from the report in the article.

Mammalian cell transformation

Aluminium chloride was not transforming in the Syrian hamster embryo cell transformation assay after exposure to up to 20 µg/mL for 7 to 8 days (DiPaolo and Casto, 1979). At this concentration, aluminium chloride induced a reduction in cloning efficiency.

 

In vivo

Micronucleus

Aluminium hydroxide was tested in a mammalian erythrocyte micronucleus assay conducted according to OECD guideline 474 and compliant with GLP (Covance, 2010a). Three groups of Sprague Dawley rats (6 per group) were exposed by oral gavage to doses of 500, 1000, and 2000 mg/kg bw/day (corresponding to 175, 350 and 700 mg Al/kg bw/day), one group (negative control) received the vehicle (1% carboxymethylcellulose in deionised water), and one group (positive control) received Cyclophosphamide, a known mutagen. The test substance was administered in two doses 24 h apart. The maximum dose tested was selected based on data from a range-finder experiment. The frequency of micronucleated PCE (% MN PCE) was analysed in the bone marrow, sampled 24 h after the final administration. The % MN-PCE values in all three dose groups were not significantly different from those in the vehicle control group; individual %MN PCE for all treated animals were also within the range of historical vehicle control distribution data. No signs of general toxicity or bone marrow toxicity (based on the proportions of immature erythrocytes) were observed in this study. The authors concluded that aluminium hydroxide did not induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats treated at up to 2000 mg/kg/day.

In another study following OECD guideline 474, suspensions of aluminium oxide were administered to female albino Wistar rats (5 animals per group) by oral gavage (Balasubramanyam et al., 2009a). Concentrations of 500, 1000 and 2000 mg aluminium oxide/kg bw in 1% Tween 80/doubly-distilled water were used. These concentrations correspond to 265, 529 and 1058 mg Al/kg bw. Three types of aluminium oxide particles were examined: bulk material (50 to 200 µm in diameter), 30 and 40 nm aluminium oxide particles, respectively. A negative control group was treated with the vehicle only. A positive control group received a single intraperitoneal dose of 40 mg/kg bw of cyclophosphamide.

The percentage of PCEs was not significantly different from the vehicle control in any treated group indicating that cell death was not occurring as a result of treatment. At both 30 and 48 h after administration of the last dose, both the nanoparticles-treated groups showed evidence of a positive dose response for the number of MN-PCEs. At 48 h, the number of MN-PCEs per 2000 PCEs scored was 1.8 ± 0.75 in the negative control group, 5.0 ± 1.1 in the 265 mg Al/kg bw/day group, 10.6 ± 1.7 in the 529 mg Al/kg bw/day group and 16.6 ± 2.7 in the 1058 mg Al/kg bw/day group for 30 nm aluminium oxide. The value for the cyclophosphamide positive control was 30.2 ± 4.2. The results of this study were positive for the nanosized material but negative for the 50-200 µm sized aluminium oxide bulk particles.

Balasubramanyam et al. also reported results from a MN assay using peripheral blood cells (Balasubramanyam et al., 2009b). The same experimental design (5 rats per group) and dose levels were used. A dose-response relationship was evident for the number of MN-PCEs for both groups treated with nanomaterials (30 and 40 nm aluminium oxide particles). No statistically significant effect was evident for the larger particles, aluminium oxide bulk material.

An earlier study used high dose levels of aluminium sulphate (250 and 500 mg/kg bw (20 and 40 mg Al/kg bw)) as a known inducer of micronucleated polychromatic peripheral erythrocyte (mnPCE) formation (Roy et al., 1992) in murine bone marrow cells. A significant increase in mnPCEs was induced 24 hrs after a second aluminium intraperitoneal dose of 500mg/kg bw in Swiss albino mice. No changes were seen at the 250 mg/kg bw dose level.

Chromosome aberration

In the study by Balasubramanyam et al. (2009a) described above, the assessment of chromosome aberrations in bone marrow cells was conducted in accordance with OECD guideline 475 with the analysis of 500 well-spread metaphases (100 per animal) for each treatment 18 and 24 h post-administration. Aneuploidy, polyploidy, gaps, breaks, minutes, acentric fragments and reciprocal translocations were counted. The mitotic index was determined on 1000 cells at both sampling times; slides were selected randomly and coded by analysts blind to treatment group. There was no indication of an effect of treatment on the mitotic index. Eighteen hours after the final dosing, total chromosome aberrations (including and excluding gaps) were significantly higher than in the control for both the 529 mg Al/kg bw and 1058 mg Al/kg bw dose groups in cells from animals treated with 30 nm aluminium oxide particles. For the group treated with 40 nm particles, total chromosome aberrations were significantly higher than the control only in cells from the 1058 mg Al/kg bw dose group. For the individual types of chromosome aberrations, significant differences for pairwise comparisons between treatment groups and control were observed only for aneuploidy. Gaps, breaks, minutes and acentric fragments showed some evidence of increases with dose in the groups treated with nanomaterials (30 and 40 nm). Statistical testing reported in the study indicated no significant differences for any treatment level of aluminium oxide bulk material when compared with the control group. The mean ± sd total aberrations for the control, 265, 529 and 1058 mg Al/kg bw were 0.6 ± 0.3, 0.6 ± 0.3, 2.2 ± 0.8, and 4.3 ± 1.0, respectively.

In a repeated-dose study by Roy et al. (1991), aluminium sulphate was administered to groups of male rats by oral gavage at 17, 21, 29, 43, 86 and 172 mg Al/kg bw /day for 7, 14 and 21 days. Five animals were sacrificed at each concentration-time point and the chromosome aberrations and mitotic index were determined in bone marrow cells. Chromatid breaks were counted as a single break and dicentrics and translocations as two breaks aberrations. Dicentrics and translocations occurred in the controls at levels higher than expected. A significant dose-response relationship was observed for chromosome aberrations at all three time points. Results were not consistently associated with duration of exposure and only limited information on experimental methods was provided.

In an earlier study, measurements of chromosomal aberrations in mice injected with aluminium chloride were reported (Manna and Das, 1972). Mice (4 per dose level) were given intraperitoneally 1 mL/30 g bw of 0.1 M, 0.05 M and 0.01 M aluminium chloride. For the highest dose level, bone marrow cells were fixed at 1, 2, 4, 8, 12, 16, 20, 24, 48 and 72 h post-injection. The 0.05 M and 0.01 M doses had a fixation interval of 20 hours. Animals injected with distilled water served as control. No positive control was included. The number of metaphases examined for the treated animals varied. A dose response relationship was not evident and no measure of toxicity was given. The effect in the control series was reported to be negligible as determined from 2000 metaphase complements. In the treated series, qualitatively the effect was more or less the same at different intervals as well as at different concentrations, in the form of erosion, stickiness, etc. as general and sub-chromatid, chromatid and chromosome breaks, translocations, gaps and constrictions in the individual chromosomes. The frequency of aberration per cell was 0.11 at 1 h, 0.24 at 4 h and 0.25 at 72 h. The frequency did not vary significantly between 4 and 72 h. Further, the frequency of aberration per cell at 20 h was 0.12 in 0.01 M, 0.20 in 0.05 M and 0.26 in 0.1 M solution. The frequency of chromatid type break was 4.5%, 8.4% and 13.5% respectively for the three concentrations used. Higher concentration induced higher frequency but the increase was not proportional.

A single-dose experiment in male Swiss albino mice was conducted to determine the effect of priming with ascorbic acid and a fruit extract on clastogenic effects due to exposure to lead and aluminium (Dhir et al., 1990). Groups of mice (6 per dose) were administered aluminium sulphate by intraperitoneal injection at 250, 500 and 1000 mg/kg bw (corresponding to 0, 20.2, 40.5, 81.0 mg Al/kg bw). The non-primed exposed groups from this study are potentially informative for the current hazard identification. Chromosome aberrations (CAs) were assessed 24 hours after the administration of the test compound. Chromosome and chromatid breaks were counted as single breaks and rearrangements as two breaks. Gaps were not included. 50 metaphase plates were scanned per animal. The mitotic index (MI) was determined as the number of metaphases in 1000 cells per animal. Both positive and negative controls were employed. A dose-dependent increase in chromosome breaks per bone marrow cell was reported. The number of CA per cell was 0.02 ± 0.01 in the negative control (mean ± SEM), 0.10 ± 0.01 in the 250 mg/kg dose group, 0.14 ± 0.02 in the 500 mg/kg dose group and 0.18 ± 0.01 in the 1000 mg/kg dose group. A significant decrease in mean mitotic index relative to the negative saline control was observed at 500mg/kg and 1000 mg/kg. In the 250 mg/kg dose group, the MI was 96% of the level in the negative saline control. In the 500 mg/kg group the MI was 80% of the negative control and in the 1000 mg/kg group it was 43%. Given the concurrent reduction in mitotic index, the increase in CA could be an indirect result of cytotoxicity.

Comet assay

In the Balasubramanyam et al. (2009b) study described above, the percentage of tail DNA (% Tail DNA) migration in rat peripheral blood cells was assessed using the alkaline comet assay. Genotoxic effects were evaluated in groups of 5 female Wistar rats 4, 24, 48 and 72 h after single doses of 500, 1000 and 2000 mg/kg bw of nanosized aluminium oxide (30 and 40 nm, respectively) and aluminium oxide bulk material (50-200 µm). The corresponding aluminium doses were 264.6, 529.2 and 1058.4 mg Al/kg bw. The % Tail DNA was estimated from 150 cells per rat. Both aluminium oxide nanoparticles showed statistically significant dose related increases in % Tail DNA at the two higher concentrations. The results showed the highest levels of damage 24 hours after dosing, with a subsequent decrease at 48 and 72 hours suggesting either cell death or DNA repair. Aluminium oxide bulk material did not induce statistically significant changes over control values.

Conclusion

The available information does not provide indications for a mutagenic potential of aluminium compounds in bacteria (Krewski et al, 2007). No or not significant mutations were found at the thymidine kinase (tk) locus of mouse lymphoma L5187Y cells treated with aluminium hydroxide and aluminium chloride at any of the doses tested (Covance, 2010b; Oberly et al., 1982).

In vitro studies with human blood lymphocytes showed positive responses to aluminium sulphate for micronuclei formation (Migliore et al., 1999) and to aluminium chloride for the induction of chromosome aberrations (Lima et al., 2007). Aluminium chloride has also been shown to induce oxidative DNA damage in human lymphocytes (Lankoff et al., 2006). However, double DNA strand breaks were not observed at concentrations up to 5000 µM-Al (as aluminium chloride) in human jurkat T-cells (Caicedo et al., 2008). This supports an oxidative mechanism of action leading to single strand effects only. Thus, there is some evidence that soluble aluminium salts may induce DNA damage, probably by an oxidative mechanism.

The most relevant and methodologically strongest in vivo studies are those conducted by Covance (2010a) and by Balasubramnyam et al. (2009a, b).

In the Covance (2010a) study, the induction of micronuclei in the bone marrow was investigated in rats given aluminium hydroxide by oral gavage. No induction of micronuclei was observed up to the highest dose administered (2000 mg aluminium hydroxide/kg bw/day, corresponding to 700 mg Al/kg bw/day).

In the studies by Balasubramanyam et al. (2009a, b), the genotoxic effects of aluminium oxide particles were investigated in vivo. Single doses of aluminium oxide particulate suspensions were administered to rats by oral gavage. The study results were positive for the nano-sized materials with evidence of a dose-response relationship, while the genotoxicity levels for aluminium oxide bulk material (50 to 200 μm diameter particles) were not statistically significantly different from those for the control. The relevance of the results with nanomaterials for hazard assessment is unclear as the observed effects may have been related to the presence of nanoparticles as foreign bodies in the cells rather than to the chemical properties of the test material itself. Low toxicity, poorly soluble substances, such as aluminium oxide, have produced inflammatory effects in vitro, when present as nanoparticles. The proposed mechanism of action is the production of reactive oxygen species (ROS) (Donaldson and Stone, 2003; Nel et al., 2006; Oberdörster et al., 2005, 2007; Duffin et al., 2007; Dey et al., 2008). Current scientific knowledge does not allow differentiation of genotoxic effects due to the physical (nanoparticle) nature from genotoxic effects due to the chemical characteristics of the test substance (Landsiedel et al., 2009; Singh et al., 2009; Gonzalez et al., 2008). However, in the current scientific debate regarding the genotoxic effects of nanoparticles of many different substances, the possibility that nanoparticles stimulate an inflammatory response leading to oxidative stress in the cells and consequently to DNA damage is the most accepted hypothesis. Balasubramanyam et al. (2009a, b) reported tissue aluminium oxide levels elevated in a dose-response manner for the groups treated with nano-sized materials, consistent with transfer of the nano-sized particles across the gastrointestinal mucosa (Florence, 1997; Hagens et al., 2007). A particle size dependence of gastrointestinal absorption was apparent. Aluminium oxide levels in the tissues of animals dosed with the larger 50 to 200 μm diameter particles were not elevated to a statistically significant level, consistent with the notion of a low bioavailability of aluminium compounds (see Toxicokinetics).

The positive results observed in studies of aluminium sulphate reported by Dhir et al. (1990) and Roy et al. (1992) occurred with non-physiologically-relevant intraperitoneal administration of the test substances and were methodologically weaker. Thus, on a weight of evidence approach, aluminium compounds in non-nanoparticle size ranges do not induce genotoxic effects in somatic cells in vivo when administered by a physiologically relevant route.

Taken together, the weight of evidence does not support a systemic mutagenic hazard for soluble and insoluble aluminium compounds. Therefore, independently of possible unspecific pH effects, there are no indications for a genotoxic potential of sodium aluminate specifically related to its chemical identity.

 

References not in IUCLID

Ahn, H.W., and Jeffery, E.H. (1994). Effect of aluminum on fluoride uptake by Salmonella typhimurium TA98; implications for themutagenicity assay. J. Toxicol. Environ. Health 4:357-368.

Dey S, Bakthavatchalu V,et al.(2008). Interactions between SIRT1 and AP-1 reveal a mechanistic insight into the growth promoting properties of alumina (Al2O3) nanoparticles in mouse skin epithelial cells. Carcinogenesis 29(10): 1920-1929.

Donaldson K, Stone V (2003), Current hypotheses on the mechanisms of toxicity of ultrafine particles, Ann.Ist.Super.Sanita 39: 405-410

Duffin R, Tran L, Brown D et al. (2007). Proinflammogenic effects of low-toxicity and metal nanoparticles In Vivo and In Vitro: Highlighting the role of particle surface area and surface reactivity. Inhalation Toxicology 19: 849-856.

EU RAR NaOH (2007). European Union Risk Assessment Report sodium hydroxide. Office for Official Publications of the European Union.. Available via: http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/sodiumhydroxidereport416.pdf

FlorenceAT. (1997). The oral absoprtion of micro- and nanoparticulates: Neither exceptional or unusual. Pharmaceut Res 14(3): 259-266.

Gava, C., Perazzolo, M., Zentilin, L.,, A.G., Corain, B., Bombi, G.G., Palumbo, M., and Zatta, P. (1989). Genotoxic potentiality and DNA binding properties of acetylacetone, maltol, and their aluminum (III) and chromium (III) neutral complexes. Toxicol. Environ. Chem. 22:149-157.

Gonzalez L, Lison D, Kirsch-Volders M. (2008).Genotoxicity of engineered nanomaterials: A critical review. Nanotoxicology 2(4): 252-273.

Hagens WI, Oomen AG, de Jong WH et al. (2007). What do we (need to) know about the kinetic properties of nanoparticles in the body? Reg Toxicol Pharmacol 49: 217 229.

Kada, T., Hirano, K., and Shirasu, Y. (1980). Screening of environmental chemical mutagens by the rec(-) assay system with Bacillus subtilis. In Chemical Mutagens: Principles and Methods for their Detection. eds. A. Hollaender and F.J. Serres, pp. 149-173.: Plenum Press.

Landsiedel R, Kapp MD, Schulz M, et al.(2009). Genotoxicity investigations on nanomaterials: Methods, preparation and characterization of test material, potential artifacts and limitations - Many questions, some answers. Mutat Res 681: 241-258.

Nel A, Xia T, Madler L, Li N (2006). Toxic potential of materials at the nanolevel, Science 311: 622-627

Nishioka, H. (1975). Mutagenic activities of metal compounds in bacteria.Mutat. Res. 31:185-189.

Oberdorster G, Oberdorster E, Oberdorster J (2005).Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles, Environmental Health Perspectives 113: 823-839

Oberdorster G, Stone V, Donaldson K (2007).Toxicology of nanoparticles: A historical perspective, Nanotoxicology 1: 2-25

Singh N, Manshian B, Jenkins GJS et al. (2009). Nanogenotoxicology: The DNA damaging potential of engineered nanomaterials. Biomaterials 3891-3914.

Short description of key information:
Based on read-across from aluminium compounds within a weight of evidence approach:
In vitro:
Negative results in bacterial systems (rec assay with with Bacillus subtilis; Ames tests with Salmonella typhimurium)
Negative results in mammalian cell gene mutation assays (mouse lymphoma L5178Y cells - tk forward mutation assay)
In vivo:
Negative results in mammalian erythrocyte micronucleus tests
Negative results in a mammalian bone marrow chromosome aberration test

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on read-across from aluminium compounds within a weight of evidence approach, the available information on the genotoxic potential of sodium aluminate is conclusive but not sufficient for classification according to DSD (67/548/EEC) and CLP (1272/2008/EC).