Bis(acetato-O)hydroxyaluminium

Endpoint summary

Link to relevant study record(s)

Reference

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

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

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

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.

Metabolites identified:

no

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.

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

0.4

Absorption rate - inhalation (%):

2

Additional information

General

The following sections provide an overview of the toxicological profile and toxicokinetic behaviour of the compound aluminium hydroxide diacetate. This white organometallic substance is an aluminium salt. It is used as intermediate in pharmaceutical production.

Certain endpoints (repeated dose and reproductive toxicity) were addressed using the source substance aluminium citrate. Both source and target substance dissociate in aqueous media to aluminium and the respective counter ions (acetate or citrate). Acetate and citrate are ubiquitous in nature. Both are metabolic intermediates in the tricarboxylic acid cycle (TCA) respiration pathway found in all animal and plant cells. There is little evidence that citrate or acetate have adverse effects when taken up repeatedly even in large doses. Thus, available kinetic publications used for this kinetic statement concentrate on the aluminium moiety being the toxicological relevant ion.

 

Toxicological profile of aluminium hydroxide diacetate

The substance aluminium hydroxide diacetate was tested for acute oral toxicity in rats revealing a LD50 value above 2000 mg/kg bw. Following an administration of 2000 mg/kg bw (limit dose), no mortalities occurred and no signs of systemic toxicity were observed. Further no macroscopic alterations were seen at necropsy. All treated animals showed the expected gains in body weight throughout the study period.

 

According to Annex VIII of Regulation (EC) No 1907/2006 acute dermal toxicity testing does not need to be conducted because the substance does not meet the criteria for classification as acutely toxic or STOT SE by the oral route (see above). Furthermore, no systemic effects were observed in an in vivo study with dermal exposure (skin sensitisation). Thus, the acute systemic toxicity of the test substance following dermal exposure is expected to be low.

 

In an acute dermal irritation study performed in vitro the test substance did not cause any signs of skin irritation and the substance was not considered to be a skin irritant.

 

Based on the results of an acute eye irritation study in vitro the test substance did show an eye hazard potential. Thus, the test substance is inducing serious eye damage.

 

The test substance was analysed for skin sensitisation properties in a guinea pig maximisation test (GPMT) and was considered non-sensitising as no immunological responses were determined. No signs of systemic toxicity were observed in this study.

 

Aluminium hydroxide diacetate was tested negative in a bacterial reverse mutation assay (Ames test) with and without metabolic activation (S9 mix) and was considered to be non-mutagenic in this test system.

No mutagenic potential was observed in Chinese hamster ovary cells in an in vitro cell gene mutation test (HPRT). Similarly, the results of an in vitro chromosome aberration test gave no indication that the test substance induces chromosomal aberration in Chinese hamster V79 cells with and without metabolic activation. Therefore, the substance was considered to be non-genotoxic under in vitro conditions.

 

No repeated dose toxicity data was available for the test substance. Thus read across was performed with the source substance aluminium citrate. It was tested for its oral toxicity in a chronic developmental neurotoxicity test in pregnant female rats and their respective offspring according to OECD guideline 426. Treatment started on gestational day (GD) 6. The concentrations administered were aimed to deliver aluminium doses of 30, 100 and 300 mg/kg bw/d based on an expected daily water intake of 120 mL/kg bw/d. The test substance was administered in drinking water. 20 litters per dose group were kept after delivery. The litters were standardized to 4 pups/sex. One pup of each sex was assigned to one of four groups that were designed for the neurobehavioural testing on post natal days (PND) 23, 64, 120 and 364. Dams were exposed from gestational day 6 through lactation and then the offspring was exposed post-weaning until postnatal day 364. A NOAEL of 30 mg Al/kg bw/d was determined.

No mortality or severe clinical signs were observed for the dams. The majority of observations throughout the dosing groups consisted of mild dermatological lesions like alopecia or porphyrin staining. Furthermore diarrhea was observed in 8 animals of the high dose group. Thus, most observations were mild stress-related symptoms. Body weight of the treated dams was comparable to the control animals for the gestational and post-natal period. Water consumption was significantly higher in the low- and mid-dose groups; however no dose response was observed. No higher water consumption was observed in the high dose dams. Aluminium-induced renal toxicity (hydronephrosis, urethral dilatation, obstruction and/or presence of calculi) was seen in pups of the high-dose group (300 mg Al/kg bw/d) and to a lesser extent in the mid-dose group (100 mg Al/kg bw/d) especially in males.

Alterations of hind-limb and fore-limb grip strength (neuromuscular parameters) were observed in both males and females from 100 mg/kg bw. Those effects were partly considered secondary to body weight changes. No other major neurological pathology or neurobehavioural effects were observed. The effect on grip strength was stronger in younger animals. Thus, effects of exposure in utero and/or during lactation seem to be more important than exposure during the later stage. In fact these are the most sensitive time points relating to the developmental effects used as the critical end-point for the NOAEL derivation. Dams were treated with the target dose or higher during gestation and lactation period. Therefore, the lowering in the treatment dose noted in adult pups was not considered to have an impact on the study results.

A delayed sexual maturation was observed in male and female offspring of the high dose group compared to lower doses. This effect was also observed in the sodium citrate group clearly suggesting a general ionic effect due to changes in water and or food consumption.

Findings in the brain tissue observed during histopathological examination at study termination (364-day group) were seen both in treated and in control group animals. Thus this effect was not considered as treatment related and was likely considered to be due to aging. The levels of aluminium in tissue were generally regarded as dose related. The strongest association was observed regarding aluminium levels in bone.

 

Toxicokinetic analysis of aluminium hydroxide diacetate 

Aluminium hydroxide diacetate consists as a fine white powder at room temperature with a molecular weight of 162.1 g/mol. The substance has a water solubility of 13 mg/L at 20 °C. The log Pow was calculated to -0.63 and a BCF value of 3.162 L/kg was calculated. The substance revealed a very low vapour pressure of below 9.0E-6 Pa at 20 °C.

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.

 

Distribution / Metabolism:

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).

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.