Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Bioavailability of aluminium compounds including aluminium sulphate studied in rats; study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Objective of study:
absorption
Qualifier:
no guideline followed
Principles of method if other than guideline:
A bioavailability study is performed to measure the fraction of aluminium that leaves the gastrointestinal tract and enters the bloodstream following the ingestion of aluminium compounds.
GLP compliance:
yes
Radiolabelling:
yes
Remarks:
Al 26 - 26Al is as a carrier free solution was sourced from the PRIME Laboratory, Purdue University, Indiana, USA.
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (Canada).
- Age at receipt: 6 weeks
- Weight at receipt: Approximately 120 g
- Fasting period before study: Animals were fasted for 24 hours prior to test item administration.
- Housing: Animals were housed two per cage
- Individual metabolism cages: Yes
- Acclimation period:4-6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 24 °C
- Humidity: 60%
- Photoperiod: 12 h dark / 12 h light
Route of administration:
other: oral: by gastric tube/in honey or intravenous
Vehicle:
other: insoluble powders - either as particulates suspended in water with added 1% carboxymethylcellulose or mixed with honey
Details on exposure:
Administration by gastric tube or honey: All test solutions were administered to the rats via a gastric feeding tube. Insoluble powders were administered either as particulates suspended in water with added 1% carboxymethylcellulose (to maintain a suspension) or added to the back of the rat tongue in honey – which experience has shown ensured that the particles were swallowed.
Administration by intravenous injection: 0.5 mL of aluminium citrate solution containing 0.19ng of 26Al was injected into the saphenous vein of rats under anaesthesia.

VEHICLE:
- Aluminium citrate injection: 1% citrate solution buffered at pH 6.5
- Solution for Ingestion: Aluminium citrate, Aluminium chloride, Aluminium nitrate and Aluminium sulphate
- Test Suspension: Aluminium hydroxide (1% carboxymethylcellulose in water); Aluminium oxide (2% carboxymethylcellulose in water); Aluminium Metal, Powdered pot electrolyte (honey); FD&C Red 40 aluminium lake (with added propylene glycol and 1% carboxymethylcellulose); SALP, KASAL and Sodium aluminium silicate
Duration and frequency of treatment / exposure:
Single administration
Remarks:
Doses / Concentrations:
Administered doses are as follows: 27Al dose per rat (mg); 26Al dose per Rat (ng)
Aluminium citrate injection: 0 mg, 0.19 ng
Aluminium chloride: 50 mg, 1.24 ng
Aluminium nitrate: 50 mg, 1.77 ng
Aluminium sulphate: 50 mg, 2.44 ng
Aluminium citrate: 50 mg, 1.47 ng
Aluminium hydroxide: 17 mg, 12.2 ng
Aluminium oxide: 23 mg, 17.9 ng
Aluminium metal: 6.9 mg, 1.2 ng
Powdered pot electrolyte: 26 mg, 2.40 ng
SALP: 10 mg, 0.46 ng
KASAL: 10 mg, 0.31 ng
Sodium aluminium silicate: 27 mg, 0.60 ng
FD&C Red 40 aluminium lake*: 414 mg, 0.96 ng
*: total mass of product
No. of animals per sex per dose / concentration:
12 females for aluminium citrate injection
6 females each for aluminium chloride, aluminium nitrate, aluminium sulphate, aluminium citrate, aluminium hydroxide, aluminium oxide, aluminium metal, powdered pot electrolyte, SALP, KASAL, sodium aluminium silicate and FD&C Red 40 aluminium lake
6 females for control group
Control animals:
other: received water without added 26Al
Positive control reference chemical:
Not applicable
Details on study design:
Intravenous injection: An initial experiment used 12 rats. This experiment was conducted in order to measure the fraction of bloodstream aluminium (i.e. uptake) that is retained by rats at 7 days post-injection. All rats were injected with an ultra-filtered aluminium citrate solution pH 6.5 prepared from 26Al in 0.02M nitric acid mixed with an equal volume of 2% trisodium citrate. After 7 days the animals were sacrificed and the fraction of the injected aluminium retained in the animal carcasses (less pelts) was determined. The fraction of 26Al intake was then determined by comparing the results for six rats where the short carcass was employed with the results for six carefully prepared entire rats.

Oral ingestion: Seventy-eight rats were then used for the subsequent ingestion study. Each test compound was administered to 6 rats. Test solutions / suspensions were prepared with the aim of administering ~ 1.4 ng of 26Al as citrate, nitrate, chloride and sulphate and >10 ng of 26Al as insoluble particulates and metal. (Note: these levels could not be achieved for the SALP, Kasal, sodium aluminium silicate, and FD&C red 40 aluminium lake and aluminium metal because the production method for these could not be scaled down sufficiently to produce small batch sizes. This resulted in the production of larger batches of test materials that contained much less 26Al/g than planned). These administered amounts were confirmed / adjusted by the analysis of triplicate doses. In addition, six control animals received water without added 26Al. After 7 days the rats were sacrificed and their pelts wetted to minimise dusting. The short carcass samples were ashed in a muffle furnace and white ash was produced. A known amount (typically 10 mg) of stable 27Al was added to each sample. The samples were then dissolved in acid and aluminium extracted by precipitation. Ion sources were prepared and the sample 26Al(ng): 27Al(g) ratio determined using AMS. The amount of 26Al present in each sample was then calculated from this ratio and then corrected to account for the radionuclide discarded with the unanalysed body parts. The fraction of aluminium absorbed was calculated by reference to the amount of 26Al administered and the fractional retention of injected aluminium at 7 days post-intake.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption)
- Tissues and body fluids sampled: Full rat carcass (excluding the pelt and gastro-intestinal tract (GIT)) and short-carcass samples (which excluded the pelt, GIT, paws, tail and head – all of which were potentially contaminated by 26Al residues present in the bedding from urine and faeces)
- Time and frequency of sampling: Seven days after 26Al administration the control and experimental rats were euthanized (using carbon dioxide gas and cervical dislocation) and samples were collected.
Other:
- Carcass samples were kept in muffle furnace to 500 °C. After 12 hours at this temperature the ash was cooled, dissolved in 8 M nitric acid, dried and then re-ashed at 500 °C to produce a white ash for analysis.
- Measurement of 26A1 Content of Samples: The 26Al content of samples was analysed by using accelerator mass spectrometry (AMS).
- Determination of fractional GIT absorption: The amount of 26Al remaining in test rats at 7 days post-administration (after short-term clearance is completed) of the isotope by injection directly into the bloodstream and by gastric tube into the stomach were compared. The fractional bioavailability of each administered test compound was determined:
Bioavailability =Fraction administered dose in carcass at 7 days (by ingestion) / Fraction administered dose in carcass at 7 days (by injection)

In each case the carcass sample content was determined from the short-carcass sample content by multiplying the latter by a correction factor of 1.7 – derived from the comparison of the full carcass and short carcass results for the rats injected with 26Al-labelled citrate. For each material the mean bioavailability was calculated, ± the standard deviation of the mean (n = 5 or 6).
Statistics:
None
Preliminary studies:
Not applicable
Bioaccessibility (or Bioavailability) testing results:
- The results of the analysis of the six rats that received 26Al are shown in Table 7.1.1/1. It can be seen that the mean 26Al: 27Al ratio was 5.0 x 10^-13. This is ratio is about 500 times lower than that measured in the carcasses of rats that received aluminium citrate injections and about 7 times lower than the ratios measured following the administration of 26Al-labelled compounds. This background level is acceptable and was subtracted from all subsequent 26Al results prior to the calculation of 26Al sample content and absorbed fraction.
- At 7 days after injection 14.6% of the injected 26Al remained in the full rat carcass. In contrast only 8.6% of the injected 26Al remained in the short carcass samples that were used for the remainder of the study. It follows that a correction factor of 1.7 was used to estimate retention at 1 week for all experimental samples that employed the short carcass sample.
- AMS results of the analysis of administered doses showed that the mean amounts of 26Al administered were 1.6 ng for aluminium citrate, 1.1 ng for aluminium chloride, 1.9 ng for aluminium nitrate, 2.4 ng for aluminium sulphate, 12.2 ng for aluminium hydroxide, 17.9 ng for aluminium oxide, 1.3 - 1.5 ng for the aluminium metal, 2.4 ng for the powdered pot electrolyte, 0.46 ng for the SALP, 0.31 ng for the Kasal, 0.51 ng for the sodium aluminium silicate and 0.96 ng for the FD&C red 40 aluminium lake.
- Estimates of GI tract bioavailability were possible for all of the test materials except the aluminium metal, SALP and Kasal. In these cases the amount of 26Al present in the samples was insufficient to determine the 26Al: 27Al ratio. A reanalysis is expected. The calculated fractional uptake of 26Al for all the aluminium solutions was similar and ranged from a high uptake of 0.002 for aluminium sulphate to a low uptake of 0.0006 for aluminium chloride. The fractional uptake of 26Al administered as insoluble particulates was lower: 0.0003 for aluminium hydroxide; 0.0002 for aluminium oxide and 0.0003 for the 26Al administered as powdered pot electrolyte; 0.001 for the sodium aluminium silicate; 0.0009 for the FD&C red 40 aluminium lake. The results for aluminium metal, SALP and Kasal were <0.0003, <0.001 and <0.001, respectively.

Table 7.1.1/2: Mean measured fractional uptake of aluminium following gastric administration of 26Al – labelled compounds

 

Compound

Mean Fraction

SD

Upper 95% CI

Lower 95% CI

Aluminium Citrate

7.9 x 10-4

5.7 x 10-5

9.0 x 10-4

6.7 x 10-4

Aluminium Chloride

5.4 x 10-4

1.5 x 10-4

8.3 x 10-4

2.5 x 10 -4

Aluminium Nitrate*

4.5 x 10-4

1.3 x 10-4

7.0 x 10-4

2.0 x 10-4

Aluminium Sulphate

2.1x 10-3

7.9 x 10-4

3.7 x 10-3

5.6 x 10-4

Aluminium Hydroxide

2.5 x 10-4

4.1 x 10-4

1.1 x 10-3

-5.7 x 10-4

Aluminium Oxide

1.8 x 10-4

3.8 x 10-4

9.4 x 10-4

-5.9 x 10-4

Aluminium Metal

<6.0 x 10-4

 

 

 

Powdered Pot Electrolyte*

4.2 x 10-4

3.6 x 10-5

1.2 x 10-3

-3.1 x 10-4

SALP

<5.8 x 10-4

 

 

 

Kasal**

<7.7 x 10-4

 

 

 

Sodium Aluminium Silicate

1.2 x 10-3

1.1 x 10-4

1.5 x 10-3

1.0 x 10-3

FD&C Red 40 aluminium lake

9.3 x 10-4

2.0 x 10-4

1.3 x 10-3

5.4 x 10-4

*One outlier result censored **5 rats only The results of the present study in the rat confirm this expectation with the measured bioavailability decreasing in the order: aluminium sulphate (2.1 x 10-3); sodium aluminium silicate (1.2 x 10-3); FD&C red 40 aluminium lake (9.3 x 10-4); aluminium citrate (7.9 x 10-4); aluminium chloride (5.4 x 10-4); aluminium nitrate (4.5 x 10-4); aluminium in powdered pot electrolyte (4.2 x 10-4); aluminium hydroxide (2.5 x 10-4); aluminium oxide (1.8 x 10-4). The results for aluminium metal, SALP and Kasal were below the detection limit under the AMS conditions employed (<1.0 x 10-4, <5.8 x 10-4, and < 7.7 x 10-4, respectively), but are being reanalysed using different AMS conditions. Given the level of uncertainty in the mean (average SD ~13% of mean) bioavailability the ranked values given above should be treated with caution. However, it can be safely concluded that under the experimental conditions employed: the most bioavailable species was aluminium administered as aluminium sulphate: other soluble species, sodium aluminium silicate and FD&C red 40 aluminium lake have a similar bioavailability – within the range 5 x 10 -4 to 1 x 10-3; insoluble species were less bioavailable than soluble species with a bioavailability of about 2 x 10-4.

Conclusions:
Bioaccumulation potential cannot be judged based on study results.
Under the experimental conditions, the most bioavailable aluminium compound was aluminium sulphate with an oral absorption rate of 0.21%.
Executive summary:

A study was performed to determine the bioavailability of Aluminium compounds in Sprague-Dawley rats. Initially 12 rats intravenously injected with aluminium citrate (0.19 ng 26Al) and after 7 days the animals were sacrificed and the fraction of the injected aluminium retained in the animal carcasses was determined. Subsequent to intravenous injection study, the following substances (as 27Al dose per rat (mg) and 26Al dose per Rat (ng), respectively) were administered to 6 rats of each by oral administration:

Aluminium chloride: 50 mg, 1.24 ng; Aluminium nitrate: 50 mg, 1.77 ng; Aluminium sulphate: 50 mg, 2.44 ng; Aluminium citrate: 50 mg, 1.47 ng; Aluminium hydroxide: 17 mg, 12.2 ng; Aluminium oxide: 23 mg, 17.9 ng; Aluminium metal: 6.9 mg, 1.2 ng; Powdered pot electrolyte: 26 mg, 2.40 ng; SALP: 10 mg, 0.46 ng; KASAL: 10 mg, 0.31 ng; Sodium aluminium silicate: 27 mg, 0.60 ng; FD&C Red 40 aluminium lake*: 414 mg, 0.96 ng

Control rats received water without added 26Al. After 7 days the animals were sacrificed and the fraction of the injected aluminium retained in the animal carcasses was determined. The 26Al content of samples was analysed by using accelerator mass spectrometry (AMS). The fraction of aluminium absorbed was calculated by reference to the amount of 26Al administered and the fractional retention of injected aluminium at 7 days post-intake.

At 7 days after injection 14.6% of the injected 26Al remained in the full rat carcass. In contrast only 8.6% of the injected 26Al remained in the short carcass samples that were used for the remainder of the study.  AMS results of the analysis of administered doses showed that the mean amounts of 26Al administered were 1.6 ng for aluminium citrate, 1.1 ng for aluminium chloride, 1.9 ng for aluminium nitrate, 2.4 ng for aluminium sulphate, 12.2 ng for aluminium hydroxide, 17.9 ng for aluminium oxide, 1.3 - 1.5 ng for the aluminium metal, 2.4 ng for the powdered pot electrolyte, 0.46 ng for the SALP, 0.31 ng for the Kasal, 0.51 ng for the sodium aluminium silicate and 0.96 ng for the FD&C red 40 aluminium lake.

 

Estimates of GI tract bioavailability were possible for all of the test materials except the aluminium metal, SALP and Kasal. The calculated fractional uptake of 26Al for all the aluminium solutions was similar and ranged from a high uptake of 0.002 for aluminium sulphate to a low uptake of 0.0006 for aluminium chloride. The fractional uptake of 26Al administered as insoluble particulates was lower: 0.0003 for aluminium hydroxide; 0.0002 for aluminium oxide and 0.0003 for the 26Al administered as powdered pot electrolyte; 0.001 for the sodium aluminium silicate; 0.0009 for the FD&C red 40 aluminium lake. The results for aluminium metal, SALP and Kasal were <0.0003, <0.001 and <0.001, respectively. It can be seen that highest fractional uptake 2.1 x 10 -3 (0.21%) was found following the ingestion of 26Al-labelled aluminium sulphate and the lowest uptake followed the administration of the aluminium oxide – 1.8 x 10-4 (0.02%). The results show that the compounds administered as suspensions (hydroxide, oxide, metal and powdered pot electrolyte) were less bioavailable than the soluble compounds (citrate, chloride, nitrate and sulphate).

 

Under the experimental conditions, the most bioavailable aluminium compound was aluminium sulphate with an oral absorption rate of 0.21%.

Description of key information

Due to the available data, it is considered that the absorption and associated bioavailability of several 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 hydroxide sulphate (ACHS) can be attributed exclusively to Al3+.

Oral absorption is lower to 1% as confirmed in the key study Priest, 2010 (0.054% for aluminium chloride basic, 0.21% for aluminium sulphate and 0.018% for aluminium hydroxide). Therefore, dermal and inhaled aborption are assumed to be lower to 1%  for aluminium chloride hydroxide sulphate. Consequently, as soluble aluminium salt, it is likely that ACHS exhibits similar bioavailability regarding absorption by oral and dermal route, by inhalation.

None aluminium salts (sulfate, nitrate, chloride and hydroxide) accumulate in significant amount in any organs as demonstrated in the bioavailability study.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
1
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 hydroxide sulphate (ACHS) and of other soluble Aluminium salts (e.g. Aluminium sulphate, Aluminium chloride basic, Dialuminium chloride pentahydroxide, Aluminium citrate and Aluminium hydroxide, etc) 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 hydroxide sulphate can be attributed exclusively to Al3+.

 

Based on this similar behaviour, data from the different soluble Aluminium salts (e.g., Aluminium citrate, Aluminium chloride basic, 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 hydroxide sulphate and taking into account differences in bioavailability using available toxicokinetic information. Target ACHS contains several counter ions: chloride, hydroxide and sulphate; the inorganic analogues were selected having at least one common anion, possibly with varying ratio, but no additional different anion.

 

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.

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 Kow) value (not relevant for inorganic substance) 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 hydroxide sulphate is quickly and completely hydrolysed into the Aluminium (Al3+), chloride (Cl-), sulphate (SO4)- and hydroxide (OH)- ions in the acidic aqueous conditions of the stomach (pH≈2) and gut. In aqueous solution Al3+ does not occur as the free ion but is surrounded by six molecules of water to form (Al(H2O)6)3 +. As the pH increases, protons are removed from the co-ordinated waters to give various hydolysis products. progressive hydrolysis leads to the formation of Aluminium hydroxide. 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. 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 contained 26Al 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 (2010) for Aluminium salts (<<1%).

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 hydroxide sulphate 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 (Flareng et 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 hydroxide 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 chloride hydroxide sulphate exposure by dermal contact. Moreover, considering the absence of systemic effects during testing by the dermal route, the high water solubility of Aluminium chloride hydroxide sulphate that induces rapid hydrolysis of the substance into the Al3 +, sulphate and chloride ion at the surface of skin, very low absorption (<1%) is expected to occur during dermal exposure to Aluminium chloride hydroxide sulphate.

 

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 hydroxide sulphate.

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.

No chronic toxicity by inhalation data is available for the solution of Aluminium chloride hydroxide sulphate. However, following chronic exposure, Aluminium chloride hydroxide sulphate 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 hydroxide sulphate (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 hydroxide sulphate 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 performed in rats exposed to Aluminium citrate 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).

However, at lower dose of Al3+ (30 mg/kg bw/d), none aluminium salts (sulfate, nitrate, chloride and hydroxide) accumulate in significant amount in any organs as demonstrated in the bioavailability study of Semple (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 ACHS. Hence, the data from the other soluble Aluminium salts are considered as a starting point in the hazard assessment of ACHS taking into account the differences in bioavailability using available toxicokinetic information.

 

In conclusion, the soluble aluminium salts considered for the hazard assessment of ACSare:

Aluminium citrate: CAS# 31142-56-0

Aluminium chloride (anhydrous): CAS# 7446 -70 -0

Aluminium chloride (6H2O): CAS# 7784-13-6

Aluminium chloride basic: 1327 -41 -9

Dialuminium chloride pentahydroxide: CAS# 120 -91 -0

Aluminium sulphate: CAS# 10043 -01 -3

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

 

Categories Display