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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
theoretical assessment
Type of information:
other: theorectical assessment based on physchem properties and all data available
Adequacy of study:
key study
Study period:
March 2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Remarks:
Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
422-150-1
EC Name:
-
Molecular formula:
Hill formula: Mg4.3 Al2(OH)12.6 (CO3)0-0.75 (ClO4)0.5-2.0 . (0-5)H2O CAS formula: Mg4.3 Al2(OH)12.6 (CO3)0-0.75 (ClO4)0.5-2.0 . (0-5)H2O
IUPAC Name:
Aluminium-magnesium-carbonate-hydroxide-perchlorate-hydrate
Test material form:
solid: particulate/powder
Details on test material:
- Appearance: white powder
- Storage condition of test material: at room temperature

Results and discussion

Main ADME results
Type:
absorption
Results:
Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 50% (inhalation) and 10% (dermal) for risk assessment purposes.

Any other information on results incl. tables

A substance can enter the body via the gastrointestinal tract, the lungs, or the skin, depending on the route of exposure.

After oral administration, in general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract. Alcamizer 5 is poorly soluble in water, therefore passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage of such molecules across membranes with the bulk passage of water) is expected to be low.

Due to its poor solubility in water and its limited ability to penetrate biomembranes related to its size, oral absorption is considered to be limited. For risk assessment purposes oral absorption of Alcamizer 5 is set at 10% (1). The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

For inhaled substances the processes of deposition of the substance on the surface of the respiratory tract and the actual absorption have to be differentiated. The vapour pressure of Alcamizer 5 is low indicating a low volatility and Alcamizer 5 is not expected to reach the nasopharyngeal region via inhalation of vapour.Alcamizer 5 particles are relatively small with 90% of the particles smaller than 3.54μm. In general, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm can enter the alveolar region of the respiratory tract in humans (2). This indicates that during exposure by inhalation to Alcamizer 5, the substance can reach the nasopharyncheal region and subsequently the tracheo/bronchial/pulmonary region. Once Alcamizer 5 reaches the lung tissue, it will not dissolve within the mucus lining of the respiratory tract due to its poor solubility in water. Alcamizer 5 deposited in the tracheobronchial region is expected to be cleared from the lungs by the mucocilliary mechanism and swallowed. However, a small amount (particles around 1μm) may be taken up by phagocytosis and transported to the blood via the lymphatic system. In case of uptake, macrophages will then either translocate particles to the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues. Based on the above data, for risk assessment purposes the inhalation absorption of Alcamizer 5 is set at 50% (2).

Alcamizer 5 is a powdery solid. Given the fact that Alcamizer 5 is poorly soluble in water, it is not expected to be dissolved in the moisture of the skin and uptake will therefore be limited, and consequently dermal absorption is likely to be low. Furthermore, its inorganic nature is not indicative for fast uptake.

According to the criteria given in the REACH Guidance (2), 10% dermal absorption will be considered in case MW >500 and log Pow <-1 or >4, otherwise 100% dermal absorption should be used. As no partition coefficient and no molecular weight is available, Alcamizer 5 cannot be tested against the criteria for limited dermal absorption. It is, however, generally accepted that dermal absorption is equal or lower compared to oral absorption for non-irritating substances, and therefore a dermal absorption of 10% is considered to be more appropriate. Therefore, for risk assessment purposes dermal absorption is set at 10%.

Once absorbed, wide distribution of Alcamizer 5 throughout the body is not expected based on its poor solubility in water and absorbed Alcamizer 5 is not expected to bio-accumulate significantly in the body upon exposure (3). The part of Alcamizer 5 that is taken up will be excreted via urine in its separate ions; for oral uptake most of Alcamizer 5 will be excreted via feces.

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.

Applicant's summary and conclusion

Conclusions:
A theoretical toxicokinetic assessment was performed based on the available data of Alcamizer 5. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 50% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.