Aluminum magnesium oxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

theoretical assessment

Type of information:

other: theoretical assessment based on physchem properties and all data available

Adequacy of study:

key study

Study period:

February 2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Theoretical assessment taking all currently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

GLP compliance:

no

Type:

absorption

Results:

Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 10% (inhalation) and 10% (dermal) for risk assessment purposes.

A chemical substance can enter the body via the gastrointestinal tract, the lungs and the skin. In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration. [1]

Aluminium magnesium oxide is an inorganic substance with a very low water solubility (approximately 0.013 mg/L at 20°C). As the substance is an inorganic substance, there is no information on the partition coefficient. The very low water solubility is indicative for low systemic uptake as Aluminium magnesium oxide will only dissolve to a limited extent into the gastrointestinal fluid. The moderate molecular weight (≥275.3 g/mol, ≤287.4) is not considered to have a significant influence on systemic uptake of Aluminium magnesium oxide.

No data are available on the dissociation constant of Aluminium magnesium oxide, therefore it is unclear in which state (ionized or not ionized) the substance will be present under physiological circumstances in the stomach or intestinal tracts. Since it is generally thought that ionized substances do not readily diffuse across biological membranes, the state of the substance might hamper uptake. Although Aluminium magnesium oxide is expected to dissociate in the low pH environment of the stomach into Mg²⁺and Al³⁺, the presence of these ions in the intestine, where further systemic uptake occurs, is considered to be low, as the intestinal pH is significantly higher than in the stomach.

Considering all this data, there are indications that oral absorption of Aluminium magnesium oxide is largely hampered: being an inorganic substance with moderate molecular size, and the very limited ability to dissolve in water do not favour systemic uptake. Therefore, for risk assessment purposes oral absorption of Aluminium magnesium oxide of 10% can be considered as worst case assumption. [2] The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

As the substance is a solid which melts above 300 C, determination of the vapour pressure of the substance is not feasible as it is considered to be very low. Therefore that the amount of Aluminium magnesium oxide that will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapour is considered to be negligible.

Aluminium magnesium oxide is a powder, with a mean particle size of around 25.61 µm; 88.6% of the particles have a particle size below 100 μm, 84.7% below 50 μm and about 50% of the particles are smaller than 15 μm. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm can reach the alveolar region of the respiratory tract. Based on the size of the particles, 84.7% below 50 μm is therefore expected to be able to reach all parts of the lung upon inhalation. If the substance reaches these regions, Aluminium magnesium oxide is not likely to dissolve in the mucus lining the respiratory tract due to the very limited water solubility, and therefore absorption is considered to be limited. Also uptake through respiratory epithelium will be limited for Aluminium magnesium oxide due to the very limited water solubility.Aluminium magnesium oxide deposited in the tracheobronchial region is expected to be cleared from the lungs by the mucocilliary mechanism and might be swallowed. However, a small amount (particles around 1μm) may be taken up by phagocytosis and transported to the blood via the lymphatic system.Therefore, for risk assessment purposes the inhalation absorption of Aluminium magnesium oxide is set at 10%. [2]

Aluminium magnesium oxide is a powder and its water solubility is very limited. Therefore the ability to dissolve into the surface moisture of the skin to allow uptake and partitioning from the stratum corneum into the epidermis is considered restricted. According to the guidance on dermal absorption [2], a default value of 100% skin absorption is generally used unless molecular weight is above 500 and log Pow is outside the range [-1, 4]. Since the substance is inorganic with a very low water solubility and no log Pow value, it does not meet either criteria. However, it is generally accepted that dermal absorption is not higher than oral absorption. Therefore, the dermal absorption of Aluminium magnesium oxide is considered to be 10% for risk assessment purposes, equal to oral absorption. [2]

Once absorbed, distribution of the test substance throughout the body is not expected based on its very low water solubility. After uptake, it is not expected that Aluminium magnesium oxide is metabolized, as it is an inorganic substance. Excretion will take place via urine and faeces. [3] Bioaccumulation is expected to be limited.

References:

Ref. 1 Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

Ref. 2 Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 6.0 November 2016.

Ref. 3 Parkinson A. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001.

Conclusions:

A toxicokinetic assessment was performed based on the available data of the substance Aluminium magnesium oxide. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 10% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Description of key information

A toxicokinetic assessment was performed based on the available data of the substance Aluminium magnesium oxide. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 10% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

A chemical substance can enter the body via the gastrointestinal tract, the lungs and the skin. In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration. [1]

Aluminium magnesium oxide is an inorganic substance with a very low water solubility (approximately 0.013 mg/L at 20°C). As the substance is an inorganic substance, there is no information on the partition coefficient. The very low water solubility is indicative for low systemic uptake as Aluminium magnesium oxide will only dissolve to a limited extent into the gastrointestinal fluid. The moderate molecular weight (≥275.3 g/mol, ≤287.4) is not considered to have a significant influence on systemic uptake of Aluminium magnesium oxide.

No data are available on the dissociation constant of Aluminium magnesium oxide, therefore it is unclear in which state (ionized or not ionized) the substance will be present under physiological circumstances in the stomach or intestinal tracts. Since it is generally thought that ionized substances do not readily diffuse across biological membranes, the state of the substance might hamper uptake. Although Aluminium magnesium oxide is expected to dissociate in the low pH environment of the stomach into Mg²⁺and Al³⁺, the presence of these ions in the intestine, where further systemic uptake occurs, is considered to be low, as the intestinal pH is significantly higher than in the stomach.

Considering all this data, there are indications that oral absorption of Aluminium magnesium oxide is largely hampered: being an inorganic substance with moderate molecular size, and the very limited ability to dissolve in water do not favour systemic uptake. Therefore, for risk assessment purposes oral absorption of Aluminium magnesium oxide of 10% can be considered as worst case assumption. [2] The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

As the substance is a solid which melts above 300 C, determination of the vapour pressure of the substance is not feasible as it is considered to be very low. Therefore that the amount of Aluminium magnesium oxide that will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapour is considered to be negligible.

Aluminium magnesium oxide is a powder, with a mean particle size of around 25.61 µm; 88.6% of the particles have a particle size below 100 μm, 84.7% below 50 μm and about 50% of the particles are smaller than 15 μm. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm can reach the alveolar region of the respiratory tract. Based on the size of the particles, 84.7% below 50 μm is therefore expected to be able to reach all parts of the lung upon inhalation. If the substance reaches these regions, Aluminium magnesium oxide is not likely to dissolve in the mucus lining the respiratory tract due to the very limited water solubility, and therefore absorption is considered to be limited. Also uptake through respiratory epithelium will be limited for Aluminium magnesium oxide due to the very limited water solubility.Aluminium magnesium oxide deposited in the tracheobronchial region is expected to be cleared from the lungs by the mucocilliary mechanism and might be swallowed. However, a small amount (particles around 1μm) may be taken up by phagocytosis and transported to the blood via the lymphatic system.Therefore, for risk assessment purposes the inhalation absorption of Aluminium magnesium oxide is set at 10%. [2]

Aluminium magnesium oxide is a powder and its water solubility is very limited. Therefore the ability to dissolve into the surface moisture of the skin to allow uptake and partitioning from the stratum corneum into the epidermis is considered restricted. According to the guidance on dermal absorption [2], a default value of 100% skin absorption is generally used unless molecular weight is above 500 and log Pow is outside the range [-1, 4]. Since the substance is inorganic with a very low water solubility and no log Pow value, it does not meet either criteria. However, it is generally accepted that dermal absorption is not higher than oral absorption. Therefore, the dermal absorption of Aluminium magnesium oxide is considered to be 10% for risk assessment purposes, equal to oral absorption. [2]

Once absorbed, distribution of the test substance throughout the body is not expected based on its very low water solubility. After uptake, it is not expected that Aluminium magnesium oxide is metabolized, as it is an inorganic substance. Excretion will take place via urine and faeces. [3] Bioaccumulation is expected to be limited.

References:

Ref. 1 Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

Ref. 2 Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, Version 6.0 November 2016.

Ref. 3 Parkinson A. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001.