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Description of key information

Based on read-across
Oral: NOAEL (chronic, rat) 30 mg Al/kg bw/day as aluminium citrate.
Inhalation: LOAEC (subchronic, rat) 70 mg Al/m³ as aluminium oxide.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
70 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

There are no studies available on the repeated dose toxicity of aluminium oxide by the oral and dermal route.

Oral

In terms of hazard assessment of toxic effects, available data on the repeated dose toxicity of other aluminium compounds was taken into account by read-across following a structural analogue approach, since the pathways leading to toxic outcomes are likely to be dominated by the chemistry and biochemistry of the aluminium ion (Al3+) (Krewski et al., 2007).

A GLP study was performed in accordance with OECD Test Guideline (TG) 422 (Beekhuijzen 2007). No mortality or clinical signs of intoxication were observed in male and female Wistar rats due to treatment with Al chloride basic at dose levels of 40, 200, and 1000 mg/kg bw/day.

Treatment with Al chloride basic by oral gavage revealed paternal toxicity (irritation effect on glandular stomach mucosa, local effect) at 1000 mg/kg bw/day in both the male and female Wistar rats. Based on findings observed macroscopically (red foci or thickening of the grandular mucosa of the stomach) and supported by microscopic examination, the maternal/parental NOAELfor local toxic effects on stomach was established at 200 mg/kg bw/day and LOAEL – at level 1000 mg/kg bw/day, for both males and females.

Several statistically significant changes in clinical biochemistry parameters were observed at 1000 mg/kg bw/day suggesting a possible impact on the blood system (decreased Hb level in males, MCHC in both Al treated males and females), on the liver (decreased alkaline phosphatase activity, decreased total protein and albumin levels in blood serum) and possibly the kidney functions (increase potassium level) at this dose. Decreased Hb levels were observed in two other doses in males but no dose response relationship was observed. Lack of relevant baseline values for the observed clinical data limit the interpretation of the results. The authors consider clinical biochemistry and haematology changes observed at 1000 mg/kg bw/day to be of slight nature and generally within the range expected for rats of this age and strain. Because any morphological correlates were absent, these changes were considered not indicative of organ dysfunction and not of toxicological significance.

No reproduction, breeding and early post-natal developmental toxicity was observed in rats at 1000 mg/kg bw/day for males and females. Based on the reported results, a NOAEL for reproduction, breeding and early post-natal developmental toxicity was suggested at a level of 1000 mg/kg bw/day.

In another study (Hicks et al., 1987) Male Sprague-Dawley rats were exposed to aluminium-compounds with diet. The animals were randomly assigned to five groups, 25 animals in each. The groups received 1) basal diet (control), 2) Aluminium hydroxide (302 mg Al/kg bw/day), 3) KASAL -the basic form of sodium aluminium phosphate containing ≈6% of Al (141 mg Al/kg bw/day), 4) KASAL II - the basic form of sodium aluminium phosphate containing ≈13% of Al (67 mg Al/kg bw/day) and 5) KASAL II (288 mg Al/kg bw/day). Treatment continued for 28 days, during which the animals were observed twice daily for their behaviour, signs of toxicity, and mortality. General physical examinations, body weight and food consumption measurements were performed weekly. After 28 days of treatment, 15 animals from each group were killed. Blood was collected from 5 rats of each group for blood cell counts, haemoglobin concentration, haematocrit and serum chemistry measurements. These rats were subjected to gross necropsy and histopathological examination. Femurs from 10 rats were taken for possible aluminium analysis; femurs from 5 rats were analyzed for Al concentrations. Five rats were allowed to recover for 2 months and five rats for 5 months after termination of the treatment. During these recovery periods, the rats received the basal diet and were observed daily; body weight and food consumption were measured monthly. Femurs were collected at autopsy from these rats for aluminium analysis. During the entire experimental period, no mortality was reported and no treatment-related clinical signs were observed. All clinical observations were characteristic of male Sprague-Dawley rats of relevant age. There were no significant group differences in body weight, food and water consumption and haematological parameters. A mild (2-4%) but significant increase in serum sodium level was observed in all treated. However, all increased sodium levels were within the range of historical control for rats of the same age in the laboratory. A significant 16% increase in absolute kidney weight was reported in the group of rats receiving KASAL II at 67 mg Al/kg bw/day. This increase appeared not to be treatment-related because no such increase was seen in the group of animals treated with this substance at 288 mg Al/kg bw/day. There were no other significant group differences in organ weights. All lesions seen at microscopic examination were “those normally expected for young adult male Sprague-Dawley rats. No lesions suggestive of a treatment-related effect were seen. Aluminium concentrations in all femur samples from all groups were <1 ppm and most were below the limit of detection or quantification. The distribution of samples in which Al was not detectable, was detectable but not quantifiable or was quantifiable, was similar in all the groups. It should be noted that this comparison was based on small numbers of samples from each group (5). Al was quantifiable in all 5 samples from animals treated with Al(OH)3, in 2 samples from the control animals and in none of the samples from animals treated with KASAL or KASAL II. The results of this study provide no evidence for significant deposition of Al in the bone and for toxicity of Al hydroxide or basic food grade sodium aluminium phosphate (KASAL and KASAL II) during 28-day dietary administration at daily doses up to ≈300 mg Al/kg bw/day. 

Sodium aluminium phosphate was administered to beagle dogs with diet at concentrations 0% (control), 0.3%, 1.0% and 3.0% for 6 months (Katz et al., 1984). There were no significant group differences in body weight throughout the experiment. Reductions in mean body weight occurred in all groups during week 27, which the authors attributed to “pretermination tests and increased handling by technicians”. No treatment-related clinical signs and no ocular changes in any of the animals were observed. In most weeks, treated male and female dogs consumed less food than control dogs. In male animals, none of the differences in mean food consumption values was statistically significant. In females, significant reductions occurred “sporadically”. The authors did not consider these differences in food consumption as “toxicologically significant”, the conclusion that was supported by the absence of corresponding reduction in body weights. The treatment did not have any effect on haematological and blood biochemistry parameters, urinalysis results and results of analysis for occult blood in faeces. There were no significant differences in mean organ weights between the treated groups and the control group. Gross pathology and histopathology findings were in the “normal range of variations for dogs of this strain and age”; no treatment-related lesions were observed. The results of this study provide no evidence for toxicity of acidic form of sodium aluminium phosphate during 6-month administration at concentrations up to 3% in the diet.

Aluminium citrate was administered to ten female Sprague Dawley rats with drinking water at a concentration of 80 mmol/L for 8 months (Vittori et al. 1999). Plasma iron concentration and total iron-binding capacity were not different in the control and the Al treated rats, indicating that the Al treated animals were not depleted of iron. There were no significant group differences in blood urea concentration, which suggests that kidney function was not altered by Al administration. Significantly lower haematocrit and blood Hb concentration were observed in the Al treated rats than in the control rats. Significantly higher reticulocyte count, abnormal erythrocyte morphology, a significant inhibition of (late colony-forming unit-rethroid, CFU-E) growth and a significant reduction of59Fe uptake in the bone marrow were reported in the Al treated rats. Plasma haptoglobin concentration was significantly lower in the Al treated animals than in the control animals. This and the presence of abnormal erythrocytes in the Al treated rats are indicative of intravascular haemolysis. Scanning electron microscopy combined with EDAX detected Al inside circulating erythrocytes with abnormal shape from animals in the Al treated group. Al concentrations in the bone, spleen, liver, kidney and plasma were significantly higher in the Al treated group than in the control group. No significant group difference in brain Al concentrations was seen. There was no correlation between plasma Al concentrations and Al levels in the organs or any other biochemical data. The results of this study suggest that Al affects erythropoiesis in rats with normal renal function.

A GLP study (ToxTest TEH-113, 2010, GLP, OECD TG 426),was designed “to develop data on the potential functional and morphological hazards to the nervous system that may arise from pre-and post-natal exposure to Aluminium citrate”. Pregnant Sprague-Dawley dams (n=20 per group) were administered aqueous solutions of Aluminium citrate 3225 mg/Al-citrate/ kg bw/day (300 mg Al/kg bw/day); 1075 mg/Al-citrate/kg bw/day (100 mg Al/kg bw/day); 322.5 mg/Al citrate/kg bw/day (30 mg Al/kg bw/day).

Two control groups received either a sodium citrate solution (citrate control with 27.2 g/L) or plain water (control group). The Al citrate and Na-citrate were administered to damsad libitumvia drinking water from gestation day 6 until weaning of offspring. Litter sizes were normalized (4 males and 4 females) at postnatal day (PND) 4. Weaned offspring were dosed at the same levels as their dams. Male and female rats sacrificed at PND 23. Endpoints and observations in the dams included water consumption, body weight, a Functional Observational Battery (FOB), morbidity and mortality. Endpoints were assessed in both female and male pups that targeted behavioural ontogeny (motor activity, T-maze, auditory startle, the Functional Observational Battery (FOB) with domains targeting autonomic function, activity, neuromuscular function, sensimotor function, and physiological function), cognitive function (Morris swim maze), brain weight, clinical chemistry, haematology, tissue/blood levels of aluminium and neuropathology at the different dose levels.

There were no significant Al-citrate treatment-related effects on mean body weights observed in the dams during the gestation and postnatal periods. The Na-citrate group, however, was significantly lighter than the control group on PND 15 (7.3%; p=0.0316). Eight dams in the high dose aluminium group were found to have diarrhoea compared with none in the other treatment groups. The low and mid-dose Al-citrate groups consumed more water than the control group but the high dose group did not, suggesting that the effect was not simply due to treatment. There were no significant treatment-related differences in gestational length. There were no consistent treatment-related effects observed for the Functional Observational Battery (FOB) tests in the dams. 

In the female pups, Na-citrate and high dose groups had significantly lower pre-weaning body weights than the control (control versus Na-citrate, p<0.0001; control versus high dose, p=0.0072). In the male pups, the control group mean body weights were significantly greater than the Na-citrate group (p<0.0001) and also significantly greater than the high dose group (p=0.0051). The mid-dose group mean body weight was significantly greater than the Na-citrate group (p=0.0405). In the female pups, the mean number of days to reach vaginal opening was 31.3 (±2.1, sd) in the control group and 39.7 (±5.6, sd) in the high dose Al-citrate group, a significant difference (p<0.0001). In males, the mean number of days to reach preputial separation was 39.6 (±2.1, sd) in the control group and 42.5 (±3.2, sd) in the high dose group, also a significant difference in the pair-wise comparisons (p<0.0001). FOB observations showed no clear treatment-related effect among the neonatal pups that were assessed at PND 5 and 11 or in the juvenile pups assessedca.PND 22. No consistent treatment-related effects were observed in ambulatory counts (motor activity) and no significant effects were observed for the auditory startle response, T-maze tests (pre-weaning Day 23 cohort). Haematology parameters showed no significant treatment-related effects in the Day 23 cohort. Serum biochemistry changes associated with aluminium toxicity such as elevated alkaline phosphatase were observed at PND 23. The authors state the levels remained within the normal range. Whole body Al levels in neonatal pups from high dose females and males were greater than those in the control groups. There were no significant sex differences. Concentrations of Al in bone showed the strongest association with Al dose and some evidence of accumulation over time in all of the Al-treated groups. Of the central nervous system tissues, Al levels were highest in the brainstem. Although levels of Al were relatively low in the cortex (< 1µg/g), they were positively associated with Al levels in the liver and femur.  

The study used adequate numbers of animals and randomization to reduce bias, assessed endpoints in both female and male offspring, and studied a wide range of neurotoxicity endpoints. Haematology, clinical chemistry, pathology and general toxicity endpoints were also assessed. Three dose levels were used although the highest was close to the MTD. The results from this study are informative for developmental and neurotoxic effects due to prenatal and early postnatal exposure of rats to high doses of aluminium (30 mg Al/kg bw/day, 100 mg Al/kg bw/day and 300 mg Al/kg bw/day). The study showed no treatment related effects of Al-citrate on maternal body weight, neurobehavior and gestational length. No dose and treatment-relevant effects of Al-citrate on neuromotor maturation and neurobehavioral activity, learning and memory, haematological and clinical biochemistry parameters, post-mortem structure of the internal organs followingin-uteroand lactation exposure were observed. Delayed development of both male and female pups was observed in the high dose Al-citrate group and also in the Na-citrate group. The effect is considered treatment-related but whether the effect is secondary to decreases in body weight is not clear. In addition, as an effect was observed in the Na-citrate group, the role of aluminium in causing this effect can not be concluded (nor excluded). Reported results suggest the possible transfer of Al from dams to pupsin-utero, although a contribution from breast milk PND 0 to 4 is also possible.

Inhalation

Human Studies

Impaired lung function has been observed in some but not all studies among workers in potrooms (Soyseth and Kongerud, 1992; Kongerud et al., 1994; Radon et al., 1999; Chan-Yeung et al., 1983; Fritschi et al., 2001). Based on an assessment of the available data, the weight of evidence does not support an important role for alumina in the development of potroom asthma. The weight of evidence supports an irritative effect of the fluoride component of pot emissions (Taiwo et al., 2006; Søyseth et al., 1992, 1994, 1997; Sorgdrager et al., 1998; Kongerud and Samuelsen, 1991). Eklund et al. (1989) observed elevated fibronectin in BALF of exposed potroom workers. Tornling et al. (1993) compared BAL biochemistry in Sprague-Dawley rats on single intratracheal instillation of primary or secondary alumina. The fluoride-containing secondary alumina exhibited a reversible, short-term inflammatory response.

Fibronectin was elevated in both the primary and secondary alumina-treated groups suggesting an influence of the alumina component on the extracellular matrix and possibly the development of chronic effects. No fibrosis was observed despite the mode of administration, however. 

Results from cross-sectional studies among bauxite-exposed workers in alumina refineries are inconclusive concerning a chronic respiratory irritative effect associated with the cumulative exposure levels encountered (Beach et al., 2001; Fritschi et al. 2001/2003; Townsend et al., 1985, 1988). Limitations with respect to possible selection biases and the lack of measurements of the respirable fraction limit interpretation of the results from these studies. Al-Masalkhi and Walton (1994) reported aluminium pneumoconiosis in a 62 year-old aluminium production worker. Lung fibrosis has been observed in workers in the alumina abrasive industry exposed to high levels (Jederlinic et al., 1990; Riddell, 1948; Shaver and Riddell, 1947; Wyatt and Riddell, 1949). Separating the effect of a high dose to particulate matter or possible co-exposures and any chemical-specific effect of aluminium oxide is not possible.

Some studies among aluminium welders have shown decrements in lung function (Fishwick et al., 2004; Abbate et al., 2003; Nielsen et al., 1993) and others have not (Sjogren and Ulfvarson, 1985; Kilburn et al., 1989). Sjogren and Ulfvarson (1985) observed an association between respiratory symptoms and exposures to ozone. The small sample sizes, questionable comparability of referent groups (e. g. Kilburn et al., 1989) and possible (residual) confounding by smoking and irritative co-exposures such as ozone and other fume constituents are limitations of the available studies. 

Cases of fibrosis have been reported in welders (Hull and Abraham, 2002; Vallyathan et al., 1982). Herbert et al. (1982) observed desquamative interstitial pneumonia in an aluminium welder whose lung biopsy showed high concentrations of aluminium-containing particulates that were found predominantly in alveolar macrophages. Vandenplas et al. (1998) reported asthma associated with aluminium welding in a 32-year old atopic male. An increase in bronchial responsiveness (histamine provocation test) was observed after challenge exposure to aluminium fume without fluoride-containing flux. 

Animal studies

Gross et al. (1973) did not observe development of alveolar proteinosis or thickening of alveolar walls in rats, hamsters or guinea pigs exposed to Al2O3dust (66% <1μm). Pigott et al. (1981) reported no evidence of fibrosis in a repeated dose inhalation study that administered alumina fibres (Saffil) at levels between 2 and 3 mg/m³. The only pulmonary response observed was the occurrence of pigmented alveolar macrophages. 

Ess et al. (1993) investigated the subacute and chronic effects of short-term ITI administration (50 mg total dose, five 0.1 mL injections of suspension in sterile saline over a period of 2 weeks) of five smelter-grade and two laboratory-grade aluminas to Sprague-Dawley rats. These doses were sufficient to overload clearance mechanisms. All the dusts led to an inflammatory reaction in the alveoli evidenced through significantly elevated BALF total protein, LDH and sustained increases in PMN compared with the saline control. Only the laboratory grade aluminas showed signs of fibrosis (collagen) one year post-instillation, however.    

 

Mechanism of Action

Overall, the results of the availablein-vitrostudies described earlier support the low cytotoxicity of poorly soluble aluminium oxide. Aluminium hydroxide and the closely related oxyhydroxide are similarly poorly soluble. These substances can be considered PSPs i.e. poorly soluble particulates of low cytotoxicity.

Summary

The current weight of evidence does not support a chemical-specific hazard on inhalation exposure to alumina (aluminium oxide, aluminium hydroxide) as experienced by the worker population. Gross et al. (1973) and Pauluhn (2009a) are considered the most adequate studies from which to obtain a dose descriptor to form the basis for a DNEL for repeated dose toxicity (inhalation, local effect) for these substances. The NOAEC from Gross et al. (1973), a subchronic study, for aluminium oxide (mean diameter 0.8 µm) is 70 mg/m³. The NOAEC from Pauluhn (2009a; sub-acute study; MMAD=1.7μm; agglomerated nanomaterials) for aluminium oxyhydroxide is 3 mg/m³ for a range of sensitive endpoints.

Considering aluminium oxide fume, the available information supports a low fibrogenicity (Stern and Pigott, 1983) and low cytotoxicity. 

 

Dermal

No animal studies are available in which the repeated exposure toxicity of aluminium has been investigated


Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

According to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria for repeated dose toxicity, no classification is required.

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