Aluminum chloride, basic

Endpoint summary

Description of key information

Due to the available data, it is considered that the absorption and associated bioavailability of Aluminium chloride basic 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 chloride basic can be attributed exclusively to Al3+.

Oral absorption is lower to 1% as confirmed in the key studies (0.054%). Dermal and inhaled aborption are assumed to be lower to 1%  for aluminium chloride basic.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

0.054

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 chloride basic and of other soluble Aluminium salts (e.g.Aluminium sulphate, Aluminium citrate and Aluminium hydroxide) 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 chloride basic can be attributed exclusively to Al³⁺.

 

Based on this similar behaviour, data from the different soluble Aluminium salts (e.g., Aluminium citrate, Aluminium chloride, Aluminium sulphate, Aluminium hydroxide, etc.), are used for read-across to assess the toxicokinetic properties. Moreover, it is reasonable to consider data obtained from the other soluble Aluminium salts, as a starting point in the hazard identification of Aluminium chloride basic and taking into account differences in bioavailability using available toxicokinetic information.

 

Regarding chloride ions (Cl^-), only few data are available (WHO, 2003). The toxicity of chloride itself is largely unknown, as the behaviour of the salts depends in general on the associated cation. However, 88% of chloride in humans is extracellular and contributes to the osmotic activity of body fluids. The electrolyte balance in the body is maintained by adjusting total dietary/drinking water intake and by excretion via the kidneys and gastrointestinal tract. Chloride is almost completely absorbed from drinking water in normal individuals, mostly from the proximal half of the small intestine. Normal fluid loss amounts to about 1.5 - 2 L/day, together with about 4g of chloride/d. Most (90-95%) is excreted in the urine, with minor amounts in faeces (4-8%) and sweat (2%). Finally, no more information is available about absorption, distribution, metabolism and excretion of chloride ions as it has only 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 (logPow) 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 chloride basic is quickly and completely dissociated into the Aluminium (Al3+) and chloride (Cl-) 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 study of Wenker (2007) determined that the average oral absorption for Aluminium chloride basic as 0.028% for males and 0.026% for females, respectively. This also indicating, that oral absorption is very low which concurs with the results of Priest for Aluminium chloride (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 chloride basic 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 chloride basic exposure by dermal contact. Moreover, considering the absence of systemic effects during testing by the dermal route, the high water solubility of Aluminium chloride basic that induces rapid dissociation of the substance into the Al3+ and the chloride ion at the surface of skin, very low absorption (<1%) is expected to occur during dermal exposure to Aluminium chloride basic.

 

Inhalation absorption

 

The amount and location of deposition in the respiratory tract depend on respiratory tract architecture, breathing pattern and the droplet size distribution when the substance occurs as a solution for Aluminium chloride basic.

The acute toxicity study included in this dossier (NOTOX 2010) performed with polyaluminum chloride hydroxide sulphate delivered as fine droplet aerosol, did not show any clinical and macroscopic effects. This result suggests that also absorption of Aluminium chloride basic by inhalation is not significant following acute exposure due to the similar properties of the substances.

No chronic toxicity by inhalation data is available for the solution of Aluminium chloride basic. However, following chronic exposure, Aluminium chloride basic could reach the alveolar system if it occurred as a fine droplet aerosol (< 10 µm diameter) and then might pass cross the respiratory epithelium into the blood. Therefore, it could be assumed that following exposure by inhalation, Aluminium contained in the fine droplets (<10 µm diameter) might be absorbed across at the same magnitude as by the oral route, i.e. <1%. For larger droplets of Aluminium chloride basic (i.e. droplets < 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. This is demonstrated in the repeated dose toxicity by inhalation of Aluminium chlorohydrate (Stone, 1979). Consequently, the toxicity of Aluminium chloride basic via inhalation exposure is primarily determined by its potential for toxicity via the oral route by which absorption is below 1% as determined in Priest's study.

 

METABOLISM AND 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 chloride, basic. Hence, the data from the other soluble Aluminium salts are considered as a starting point in the hazard assessment of Aluminium chloride basic taking into account the differences in bioavailability using available toxicokinetic information.

 

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

Aluminium citrate: CAS# 31142-56-0

Aluminium chloride hydrate: CAS# 10124-27-3

Aluminium chloride hexahydrate: CAS# 7784-13-6

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

Aluminium potassium sulphate: CAS# 10043 -67 -1

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

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 Committee on Food Additives / JECFA (2001) JECFA / IPCS, INCHEM. Aluminium, 1 p.

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

- 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.

- World Health Organisation / WHO (2003), Chloride in drinking water. WHO/SDE/WSH03.04/03