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EC number: 205-518-2 | CAS number: 142-03-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- 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.
Reference
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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