Bis(acetato-O)hydroxyaluminium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Aluminum hydroxide diacetate monohydrate

Cas Number:

80164-67-6

Molecular formula:

C4H7AlO5 H2O

IUPAC Name:

Aluminum hydroxide diacetate monohydrate

Test material form:

solid

Administration / exposure

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgement of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of aluminium hydroxide diacetate is 162.1 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is likely (ECHA, 2008). The compound has a moderate log Pow of -0.63 and absorption is therefore favourable. However the low solubility in lipids together with the moderate to low water solubility of 13 mg/L limits the absorption.
The limited gastrointestinal absorption is strengthened by the results achieved in the oral toxicity studies with rats. No effects were seen in the acute oral toxicity study. However, the repeated dose test showed some toxic effects after oral administration of the substance.

Krewski et al. (2007) described an oral bioavailability of aluminium from water between 0.1 to 0.4 % further supporting the suggested low oral adsorption based on the substance properties.

Considering the low vapour pressure of the test substance and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. Based on the particle size distribution, it is likely that dust particles are inhaled or reach the lower lung region in order to become systemically available. Absorption is again limited by the moderate to low water solubility that would prevent that particles dissolve into the mucus lining of the respiratory tract.

Aluminium bioavailability from occupational inhalation exposure has been reported to be around 2 % according to Krewski et al. 2007.

In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 162.1 g/mol a dermal uptake can be expected. Due to a high lipophilicity of the test item, it will not easily pass the skin layers and therefore shows a rather limited skin penetration. As the chemical consists of a particulate at room temperature, it has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when placed in contact to the skin.
The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing. The test substance was regarded as non irritating in an acute dermal irritation study in vitro. No evidence of tissue damage was observed which in turn could have favoured direct absorption into the systemic circulation. Considering the negative immunological response obtained in the GMPT assay, a systemic availability can be regarded as low.
Based on the physical-chemical properties and the results of the testing with dermal application, the degree of systemic availability by absorption or penetration through skin can be regarded as neglible.

Details on distribution in tissues:

Based on the physicochemical properties and the results achieved from the comprehensive toxicity testing, small amounts of aluminium hydroxide diacetate can become systemically available. Once adsorbed, the substance will most likely be transported within the body via the blood stream and gain access to the body tissues potentially bound to macromolecules due to its low water solubility. Approximately 90 % of the absorbed aluminium in plasma is carried by the iron binding protein transferrin. Around 11 % is associated with citrate. Cellular uptake in organs and tissues is considered to be slow and most likely occurs via transferrin –receptor mediated endocytosis (EFSA, 2008). Around 60, 25, 10, 3 and 1% of the aluminium body burden can be found in the bone, lungs, muscle, liver and brain, respectively (Krewski et al. 2007). Aluminium concentration in tissue can increase with age in a number of tissues and organs of experimental animals (EFSA, 2008).

Details on excretion:

After oral intake, unabsorbed aluminium will be excreted via the feces. Due to the neutral pH in the duodenum aluminium ion is converted to insoluble aluminium hydroxide with the majority being precipitated in the intestine with subsequent excretion via feces. However, only 2 % of the aluminium body burden is excreted via bile. The majority of above 95 % is excreted via urine (Krewski et al., 2007). This is also applicable for aluminium hydroxide diacetate as its molecular weight is well below 500 Da. According to the calculated BCF value and the available log Pow, bioaccumulation can be excluded for aluminium hydroxide diacetate.

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Executive summary:

Based on its physicochemical properties systemic availability of aluminium hydroxide diacetate will be limited. When taken up by the oral route, uptake is considered to be low. Based on the physicochemical properties transdermal absorption can be regarded as neglible. Considering the low vapour pressure and the particle size distribution some amounts of aluminium hydroxide diacetate are expected to be inhalable under normal use conditions. The substance is expected to be distributed and metabolised within the body if becoming systemically available. Referring to the EFSA opinion of 2008 above 90 % of plasma aluminium is associated with transferrin. After uptake the substance is likely to be excreted via urine. Excretion via feces is a secondary but minor route. Based on the physicochemical properties and the calculated BCF value, bioaccumulation can be excluded for aluminium hydroxide diacetate.