Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Due to the available data, it is considered that the absorption and associated bioavailability of Aluminium sulphate and of other soluble Aluminium salts are similar. Following absorption by any route of exposure, Aluminium is present in the body as the ionic species (Al3+) which is consequently the determining driver regarding the systemic effects of Aluminium salts, even including acute toxicity. 
Hence, it can be assumed that Al3+ is the substance of biological interest and that the toxicological effects of Aluminium sulphate can be attributed exclusively to Al3+.
Oral absorption is lower to 1% as confirmed in the key studies (0.21%). Dermal and inhaled aborption are assumed to be lower to 1% for aluminium sulphate

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
0.21
Absorption rate - dermal (%):
1
Absorption rate - inhalation (%):
1

Additional information

In general, the toxicokinetic behaviour of substances is based on physico-chemical characteristics and the bioavailability.Due to the available data it is considered that the absorption and associated bioavailability of Aluminium sulphate and of other soluble Aluminium salts are similar. Following absorption by any route of exposure, Aluminium is present in the body as the ionic species (Al3+) which is consequently the determining driver regarding the systemic effects of Aluminium salts, even including acute toxicity. Hence, it can be assumed that Al3+ is the substance of biological interest and that the toxicological effects of Aluminium sulphate can be attributed exclusively to Al3+.

 

In addition, few data are available for Sulphate ions (SO42-). However, sulphur is naturally present and abundant in foodstuffs. Absorption of sulphate depends on the amount ingested. Near-complete absorption of dietary sulphates may occur at low concentrations, depending on the counter-ion, but absorption capacity can be saturated at higher artificial dosages resulting in cathartic effects. No studies were located regarding distribution after exposure to Sulphate. Sulphate levels are regulated by the kidney through a reabsorption mechanism (OECD SIDS, 2005). No studies were located regarding the metabolism in humans and animals after exposure to sulphate. However, sulphate is a normal constituent of human blood and does not accumulate in tissues (OECD SIDS, 2005). Sulphates are found in all body cells, with highest concentration in connective tissues, bone and cartilage. At high sulphate doses that exceed intestinal absorption, sulphate is excreted in faeces. Sulphate is usually eliminated by renal excretion. It has also an important role in the detoxification of various endogenous and exogenous compounds, as it may combine with these to form soluble sulphate esters that are excreted in the urine (OECD SIDS, 2005). Finally, no more information is available about absorption, distribution, metabolism and excretion of sulphate ions as it has little toxicological interest.

 

ABSORPTION:

 

Oral absorption

 

Absorption is a function of the potential for a substance to diffuse across biological membranes. In addition to molecular weight the most useful parameters providing information on this potential are the octanol/water partition coefficient (log Pow) value and the water solubility. Indeed, the main identified factors influencing absorption of Aluminium are solubility, pH and the chemical species (ATSDR, 2008; PHG, 2001; WHO, 1997; JECFA, 2001, 1989).

 

Following ingestion, the Aluminium sulphate is quickly and completely dissociated into the Aluminium (Al3+) and sulfate ions (SO42-) ions in the acidic aqueous conditions of the stomach (pH≈2) and gut. Therefore, the toxicological properties of this salt after oral uptake can be assessed by the effects of its dissociation products and thus mainly by the Aluminium ion, as explained above.

 

Human studies indicate that only a small percentage of Aluminium that is normally ingested via the diet and drinking water is absorbed. Most estimates of average gastrointestinal absorption of Aluminium under normal dietary conditions are in the range of 0.1 - 0.6 %, although some human studies indicate that absorption of the more bioavailable forms. These forms are particularly complexes of Aluminium with particular carboxylic acids, (e.g. Aluminium citrate) which may be absorbed in the order of 0.5 - 5 % (ATSDR, 2008; PHG, 2001).

 

Animal studies showed that Aluminium absorption via the gastrointestinal tract is usually less than 1%.

The recent study of Priest (2010) investigated the bioavailability of several Aluminium salts (Aluminium sulphate, Aluminium citrate, Aluminium hydroxide) as well as Aluminium chloride, which is the closest analogue to Aluminium chloride basic. The results performed showed that the measured mean bioavailability in rat for some of soluble Aluminium salts of interest in this dossier decreased in the order: Aluminium sulphate (0.21%), Aluminium citrate (0.079%), Aluminium chloride (0.054%), Aluminium hydroxide (0.025%).Although the result for Aluminium sulphate was unexpectedly higher than for other mineral acid salts tested, it corresponds closely with the uptake levels measured in two human volunteers that swallowed drinking water that contained26Al introduced as Aluminium sulphate (0.20%).Due to the use of the same experimental methods for the different substances, the results from the human study can be quantitatively compared to the data from the animal study as both test substances were administered without co-exposures to ligands that may influence the bioavailability. The human result for Aluminium hydroxide (0.01%) was similar to that obtained using the rat model. Additionally, the measured bioavailability of the Aluminium citrate in the rat was well within the range of measured/estimated values of 0.047% to 1% in man for citrate (and orange juice).

 

The results of the study of Wenker (2007) determined that the average oral absorption for Aluminium sulphate was 0.037% for males and 0.001% for females. This study also indicates that absorption is very low and concurs with the results of Priest for Aluminium sulphate (0.054%). Therefore, the results of both studies contribute to the overall evidence that Aluminium and its salts show low bioavailability after oral uptake.

 

Dermal absorption

 

While Aluminium compounds such as Aluminium chloride basic are a common additive for some cosmetics, there are only limited human data on the dermal absorption of Aluminium available. Indeed, aluminium salts are used in underarm antiperspirants where the Aluminium is soluble at low pH in the formulation, before being rendered insoluble as it is neutralised by the sweat on the skin’s surface and within sweat ducts (SCCS, 2014). This behaviour limits the bioaccessibility of Aluminium on living skin.In the form of an ionic Aluminium complex, the Aluminium salts will exhibit only shallow penetration of the skin, due to binding in the upper layers of the stratum corneum. The results of a non GCP guideline preliminary study of the dermal absorption of antiperspirants using labelled Aluminium estimated that the proportion of Aluminium that is absorbed averaged 0.012% using only two volunteers (Flarenget al.,2001). However, SCCS (2014) considers that Aluminium absorption after dermal exposure to cosmetics is still poorly understood based on the poor quality available studies, which have not been carried out according to the current requirements.

Finally, following the results of the acute dermal studies from this dossier, neither systemic effect nor local effects are observed during the acute dermal testing and skin irritation studies. Moreover, no sensitisation potential of Aluminium sulphate was observed in a relevant study which only would become apparent when some absorption via the skin is anticipated. Therefore, local toxicity is not expected after Aluminium sulphate exposure by dermal contact. Moreover, considering the absence of systemic effects during testing by the dermal route, the high water solubility of Aluminium sulphate that induces rapid dissociation of the substance into the Al3+ and the sulfate ion at the surface of skin, very low absorption (<1%) is expected to occur during dermal exposure to Aluminium sulphate.

 

Inhalation absorption

 

The amount and location of deposition in the respiratory tract depends on the respiratory tract architecture, breathing pattern, hygroscopic of Aluminium sulphate and the particle size distribution. In the same way, lung clearance and retention depends on the particle size and shape, animal species, the in vivo dissolution rate and any biochemical interaction between the dissolved substance and lung proteins.

Only one study was available concerning the deposition and transfer of Aluminium sulphate to the systemic circulation via serum and urinary Aluminium concentrations of five Aluminium sulphate manufacturers (Riihimaki et al., 2008). They studied the suitability of determining Aluminium in serum or urine as a form of biological monitoring by airborne and internal Aluminium exposure assessment in five manufacturers of Aluminium sulphate and showed that the mean 8-hour time-weighted average concentration of Aluminium was 0.13 mg/m3for the Aluminium sulphate plant with particles ranging from 1 to 10 µm in diameter, i.e. which can reach the alveoli. The mean post-shift serum and urinary concentrations of Aluminium were 0.13 and 0.58 µmol/L respectively, without any temporal changes between two shifts. Based on the assumption of a 10% deposition on the basis of particle size, the calculation suggests that 6.7% of the Aluminium deposited in the alveoli was taken up for Aluminium workers without evidence of a lung burden. However, the conclusions about the absorbed fractions were hampered by: the turn-over of Aluminium in the bone, by the uncertainty of the magnitude of alveolar deposition (which has an inverse relationship to the absorbed fraction) and by the actual Aluminium species, i.e. bauxite and Aluminium sulphate as dust in the plant. Although Aluminium sulphate is water soluble, it is likely to precipitate in the airway mucosa and become cleared, like bauxite particles, by the mucocilliary escalator. Dissolved Aluminium particles deposited on the respiratory epithelium in close proximity to interstitial fluid may complex with organic molecules and thus retain the ability to pass cross the respiratory epithelium. Therefore, it could be assumed that, following exposure by inhalation, the Aluminium sulphate particles deposited in the lung (<10µm diameter) might be absorbed at the same magnitude as by the oral route, i.e. <1%. For larger particles of Aluminium sulphate(i.e. particles <100 µm but >10 µm), they may be captured in the nasopharyngeal and upper respiratory areas and then transferred in the gastrointestinal tract by mucosal movement and mucocilliary action. Consequently, the toxicity of Aluminium sulphate via inhalation exposure is primarily determined by its potential for toxicity via the oral route.

This is corroborated by the results of the acute inhalation studies from this dossier as neither systemic effect nor local effects are observed in during the two acute inhalation studies with Aluminium chloride hydroxide sulfate solution or Catapal Alumina Fines (powder of Aluminium oxide and Aluminium hydroxide).

 

METABOLISM & DISTRIBUTION

 

Aluminium is not metabolised in the liver. Once in the blood Aluminium is believed to be present almost exclusively in the plasma where it is bound mainly to transferrin and to a lesser extent to albumin. It was observed that 89% of the Aluminium in serum is bound to citrate and transferrin which may play a significant role in the distribution of Aluminium (ATSDR, 2008; PHG, 2001; WHO, 1997). Normal physiological levels of Aluminium in serum are approximately 1 – 3 μg/L (ATSDR, 2008).

 

There are limited data on distribution of Aluminium in humans, but the distribution of Aluminium in animals after oral exposure has been evaluated in a number of studies (ATSDR, 2008). These studies are particularly informative because they provide information on distribution of Aluminium in various tissues and demonstrate that Aluminium concentration in different tissue can increase substantially following oral exposure despite the low bioavailability of Aluminium.

Evidence from animal studies suggests that Aluminium might accumulate in the brain (grey matter) where it distributed preferentially to the hippocampus. As it can be also anticipated for metals, Aluminium can interact with ions in the matrix of bone where it displaces the normal constituents of the bone, leading to retention of the metal, which determines to a large extent the total Aluminium body burden. In addition to the distribution of Aluminium to the brain, bone, muscle and kidneys of orally exposed animals, there is limited animal evidence indicating that Aluminium has the potential to cross the placenta (which may serve as a partial barrier during in utero development) and to accumulate in the foetus and be distributed to some extent to the milk of lactating mothers (ATSDR, 2008; PHG, 2001). This is corroborated by the results observed in in the developmental and one-year chronic neurotoxicity study of Aluminium citrate in rats exposed to the test substance via drinking water (ToxTest. Alberta Research Council Inc., 2010). Whole body Aluminium levels in neonatal pups from high dose females and males were greater than those in the control groups, without significant sex differences. These results suggest transfer of Aluminium from dams to pups in utero, although a contribution from breast milk PND 0 to 4 is also possible. Aluminium levels were assayed in several tissues in the pup cohorts. Levels of Aluminium in whole blood were highest in the Day 23 cohort animals and declined with time, possibly due to the lower amounts of test substance containing water consumed once the pups matured. Although during the lactation period pups may have consumed some water/test solution, the results suggest that transfer of Aluminium from dams to pups can occur through breast milk. Concentrations of Aluminium in bone showed the strongest association with Aluminium dose and some evidence of accumulation over time in all of the Aluminium-treated groups. Of the central nervous system tissues, Aluminium levels were highest in the brainstem.  Although levels of Aluminium were relatively low in the cortex (< 1µg/g), they were positively associated with Aluminium levels in the liver and femur. In females, Aluminium levels in the high dose group remained elevated relative to the other groups at all time-points suggesting that accumulation might have occurred (ToxTest. Alberta Research Council Inc., 2010).

 

EXCRETION

 

Excretion data collected in animal studies are consistent with the results from human studies where the difference in the excretion rates most likely reflects differences in gastrointestinal absorption following oral exposure. There is insufficient information to comment on biliary excretion of Aluminium in humans (WHO, 1997).

From human dietary balance studies, it is clear that most of the ingested Aluminium is unabsorbed: Aluminium levels determined in faeces ranged from 76 to 98 % of the oral dose (ATSDR, 2008; PHG, 2001). Following ingestion in humans, absorbed Aluminium from the blood is eliminated in the kidney and excreted in the urine (ATSDR, 2008; PHG, 2001; WHO, 1997).

 

READ-ACROSS approach:

 

Based on the similar behaviour as described above, data from the different soluble Aluminium salts are used in read-across approach to assess the toxicological properties of Aluminium sulphate. Hence, the data from the other soluble Aluminium salts are considered as a starting point in the hazard assessment of Aluminium sulphate taking into account the differences in bioavailability using available toxicokinetic information.

 

In conclusion, the soluble aluminium salts considered for the hazard assessment of Aluminium sulphate are:

Aluminium citrate: CAS# 31142-56-0

Aluminium chloride basic: CAS# 1327-41-9

Aluminium chloride hydrate: CAS# 10124-27-3

Aluminium chloride hexahydrate: CAS# 7784-13-6

Aluminium chloride hydroxide sulphate: CAS# 39290-78-3

Aluminium potassium sulphate: CAS# 10043-67-1 (dodecahydrate: CAS# 7784 -24 -9)

Aluminium ammonium bis-sulphate: CAS# 7784-25-0

Aluminium hydroxide: CAS# 21645-51-2

Vista Alumina Catapal Fines: 75 % aluminium oxide (CAS# 1344-28-1), 25 % aluminium hydroxide (CAS# 21645-51-2)

 

REVIEW REFERENCES

- Agency for Toxic Substances and Disease Registry / ATSDR (2008) Toxicological profile for Aluminium, U. S. Department of Health and Human services, Public Health Service, September 2008, 357 p.

- Joint FAO/WHO Expert Commitee on Food Additives / JECFA (2001) JECFA / IPCS, INCHEM. Aluminium, 1 p.

- JECFA (1989) JECFA / IPCS, INCHEM. Aluminium, 28 p.

- OECD SIDS Initial Assessment Profile (2005) Ammonium sulphate; CAS N°: 7783 -20 -2. UNEP publication.

- Public Health Goal / PHG (2001) Aluminium in Drinking Water, April 2001, 74 p.

- SCCS (2014) Opinion on the safety of Aluminium in cosmetic products. SCCS/1525/14.

- World Health Organisation / WHO (1997), Environmental Health Criteria n°194 - Aluminium. International Programme on Chemical Safety.