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Diss Factsheets

Administrative data

Description of key information

Based on read-across
Oral: NOAEL (chronic, rat) 322.5 mg/kg bw/day of aluminium citrate (equivalent to 30 mg Al/kg bw/day)

Key value for chemical safety assessment

Additional information

There are no studies available on the repeated dose toxicity of sodium aluminate by the oral, dermal or inhalation route.

Sodium aluminate is a strong base (pH > 11.5) and thus corrosive to the skin and mucous membranes. The introductory sections to Annexes VII-X of the REACH regulation (EC No. 1907/2006) point out that in vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided. Furthermore, due to the corrosive properties of sodium aluminate, repeated human exposure by any route is considered not significant as the corresponding operational conditions and necessary risk management measures (use of PPE) to avoid contact are in place under normal handling and use conditions. Additionally, before new tests are carried out data from structurally related substances (read-across approach) shall be assessed first.

In terms of hazard assessment of toxic effects at potentially non-irritant concentrations, 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; ATSDR, 2008).

 

Oral

Several studies on the repeated dose toxicity of aluminium compounds are published in the literature and have been extensively reviewed (Krewski et al., 2007; ATSDR, 2008). For this report only the most relevant and reliable key studies were summarized (Beekhuijzen, 2007; ToxTest. Alberta Research Council Inc., 2009).

Both key studies are combined repeated dose reproductive or developmental studies. Therefore, the results of these investigations are presented in more detail in the respective section (Toxicity to reproduction).

In summary, in the combined repeated dose and reproduction/developmental screening study by Beekhuijzen (2007), treatment with aluminium chloride basic (Al(OH)1.3Cl1.7) by oral gavage in male and female Wistar rats at dose levels of 3.6, 18 and 90 mg Al/kg bw/day revealed local toxic effects at the highest dose, comprising inflammation of the glandular stomach mucosa. Based on these findings, the LOAEL for local effects was 90 mg Al/kg bw/day, and the local NOAEL was 18 mg Al/kg bw/day. No systemic effects were observed up to the highest dose. Thus, the systemic NOAEL was higher or equal to 90 mg Al/kg bw/day.

In the developmental neurotoxicity and chronic toxicity study by ToxTest. Alberta Research Council Inc. (2009), groups of Sprague-Dawley rats were exposed to 322.5, 1075 and 3225 mg/kg bw/day of aluminium citrate (equivalent to 30, 100 and 300 mg Al/kg bw/day) via drinking water. Pregnant animals were exposed during gestation (starting on gestational day 6) through weaning, and the offspring was exposed during post-weaning and continuing up to post-natal day 364.

No relevant signs of systemic toxicity (mortality, clinical signs, body weight, water consumption, Functional Observational Battery (FOB)) were observed in the dams exposed up to the highest dose. Therefore, 3225 mg/kg bw/day of aluminium citrate (equivalent to 300 mg Al/kg bw/day) was considered the systemic NOAEL for dams in this study. However, no necropsy and histopathological examinations were performed in these animals.

In offspring animals exposed up to post-natal day 364, a significant decrease in post-weaning body weight was observed in the high dose aluminium citrate group in both males and females. Urinary tract pathology was observed in high and to a certain extent also in mid dose rats, more frequently in the males. The results showed no evidence of an effect on memory, motor activity, learning, or any other neurobehavioural effects, with one exception, that the study investigated in detail. Also extended neuropathological examination did not show any treatment related effects. The only effect related to neuromuscular function that was observed in this study was a reduced fore- and hindlimb grip strength in both sexes of the mid and high dose group and a reduction in foot splay in females of the mid and high dose group in adult offspring (but not in neonatal and juvenile animals). However, according to the authors, the latter findings may also be related to body weight differences and cannot unequivocally be attributed to neurotoxicity. The most prominent findings in this studies were urinary tract lesions at necropsy (4 males, 1 female in the mid dose group, 8 females and 23 males in the high dose group). Other findings in the high dose group included decrease in body weight in animals exposed up to post-natal day 120; defecation (more boluses produced by females compared to the controls); urination (males produced more urine pools that controls); tail pinch (females displayed more exaggerated responses); the albumin/globulin ratio (males exposed up to post-natal day 64 had a greater mean ratio than the controls). A LOAEL of 1075 mg/kg bw/day of aluminium citrate (equivalent to 100 mg Al/kg bw/day) was assigned based on this study. Accordingly, the NOAEL based on kidney and possible neuromuscular effects was 322.5 mg/kg bw/day of aluminium citrate (equivalent to 30 mg Al/kg bw/day).

In another study, the oral toxicity of aluminium nitrate nonahydrate was examined in a subchronic 100-days study in Sprague-Dawley female rats. Aluminium nitrate nonahydrate was given orally via drinking water at 0, 360, 720 and 3600 mg/kg bw/d, which corresponds to 0, 26, 52 and 260 mg/kg bw/d when expressed as aluminium dose. Nutritional and toxicological parameters were monitored throughout the study. At the end of the study, animals were sacrificed and assessed for gross pathology and histopathological changes. At 260 mg Al/kg bw/d a statistically significant decrease in body weight gain and food and water consumption was observed. All other toxicological parameters measured were not or not significantly changed in relation to the exposure. At 26 and 52 mg Al/kg bw/d no significant toxic effects were reported, therefore the NOAEL was 52 mg Al/kg bw/d via drinking water (Domingo et al., 1987).

 

Inhalation

Sodium aluminate (CAS No. 1302-42-7) is a strong base (pH > 11.5) and thus fulfils the criteria for classification as corrosive to the skin (category 1A) according to CLP regulation (1272/2008/EC). In addition, the substance also fulfils the requirements to be labelled as EUH071 corrosive to the respiratory tract.

Due to the corrosive properties of sodium aluminate, human exposure by the inhalation route is unlikely to occur under normal working conditions as it should be avoided by implementation of the corresponding operational conditions and necessary risk management measures (use of PPE).

Furthermore, data for particle size distribution provided a MMAD of 115.6 µm for sodium aluminate; only 10 % of the particles are respirable, as the diameter is below 5.132 µm (Chilworth 2010, RL1). Therefore the substance has in general a low exposure potential to the alveolar region of the lung. Conducting inhalation toxicity tests with a low-respirable atmosphere would not produce scientifically meaningful results for systemic toxicity. Instead, most of the inhaled material would presumably intercept in the naso-pharyngeal region and cause adverse local effects there due to the corrosive properties of the substance.

This expected adverse local effect however is already covered by the EUH071 labelling, and specific systemic effects after administration by inhalation are not expected, as the respirable fraction of the substance is too low.

Therefore, testing on the toxicity of sodium aluminate after repeated dose administration by the inhalation route in experimental animals is considered scientifically unjustified and should be avoided for reasons of animal welfare.

 

Dermal

Sodium aluminate is a strong base (pH > 11.5) and thus fulfils the criteria for classification as corrosive to the skin (category 1A) according to CLP regulation (1272/2008/EC).

Due to the corrosive properties of sodium aluminate, human exposure by the dermal route is unlikely to occur under normal working conditions as it should be avoided by implementation of the corresponding operational conditions and necessary risk management measures (use of PPE). Furthermore, bioavailability via the dermal route is expected to be very low.

Therefore, testing on the toxicity of sodium aluminate after repeated dose administration by the dermal route in experimental animals is considered scientifically unjustified and should be avoided for reasons of animal welfare.

Moreover, no animal studies are available in which the repeated exposure toxicity of aluminium has been investigated (ATSDR, 2008).

 

Human data

Oral

The subacute effects of aluminium on cognitive function were examined in patients with Alzheimer’s disease (AD) and related dementias and in age-matched and younger volunteers with normal cognitive function (Molloy et al. 2007). The subjects received a single oral dose of aluminium hydroxide (Wyeth Amphojel antacid) and citrate for 3 days followed by a 3-week washout period, and then 3 days of matched placebo administration, or vice versa. Levels of aluminium in serum were measured and the daily dose of aluminium hydroxide was adjusted to a target aluminium level of 50-150 µg/L. The administered doses ranged from 960 to 2880 mg aluminium hydroxide per person per day, corresponding to ca. 330-1000 mg aluminium per person per day. Neuropsychological tests were conducted at baseline and 90 min after the third dose of aluminium hydroxide or placebo.

A large interindividual variation in aluminium serum levels was observed in all study groups after the same initial dose of aluminium hydroxide plus citrate. No significant differences in neuropsychological scores were observed after aluminium ingestion both in normal volunteers and in patients with cognitive impairment.

 

Dermal

Aluminium compounds are widely used in antiperspirants without harmful effects to the skin or other organs (Sorenson et al. 1974). Some people, however, are unusually sensitive to topically applied aluminium compounds. Skin irritation was reported in subjects following the application of aluminium chloride hexahydrate in ethanol used for the treatment of axillary or palmar hyperhidriosis (excessive sweating) (Ellis and Scurr 1979; Goh 1990) or the use of a crystal deodorant containing alum (Gallego et al. 1999).

As mentioned above, due to the corrosive properties of sodium aluminate, human exposure by the dermal route is unlikely to occur under normal working conditions as it should be avoided by implementation of the corresponding operational conditions and necessary risk management measures (use of PPE). Furthermore, bioavailability via the dermal route is expected to be very low.

References not in IUCLID:

Sorenson, JRJ, Campbell, IR, Tepper, LB, et al. (1974). Aluminum in the environment and human health. Environ Health Perspect 8:3-95.

Ellis, H and Scurr JH. (1979). Axillary hyperhidrosis -topical treatment with aluminium chloride hexahydrate. Postgrad Med J 55:868-869.

Gallego, H, Lewis, EJ, Crutchfield, CE (1999). Crystal deodorant dermatitis: Irritant dermatitis to alum-containing deodorant. Cutis 64(1):65-66.

Justification for classification or non-classification

Based on read-across from aluminium and other aluminium compounds as structural analogues, the available data on the repeated dose toxicity sodium aluminate is conclusive but not sufficient for classification according to DSD (67/548/EEC) and CLP (1272/2008/EC).