Fatty acids, C16-18 (even numbered), aluminum salts

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Additional information

Assessment of the Toxicokinetic Behaviour of Fatty acids, C16-18 (even numbered), aluminum salt

 

Fatty acids, C16-18 (even numbered), aluminum salt is produced in an indirect/precipitation process based on a two-step procedure: first, a sodium soap is produced based on NaOH (aq) and Fatty acids (C16-18) followed by precipitation of the aluminium soap by adding aluminium sulphate (Al₂(SO₄)₃, aq). Due to the variation in the ratio of aluminium sulphate and fatty acids, different grades of aluminium salts are obtained which differ in the content of “Aluminum mono-/di/tri-stearate”. In general, the higher the ash content, the higher the mono-content. Fatty acids, C16-18 (even numbered), aluminum salts contain approx. 2 – 8.5% aluminium, 6 – 15% ash content, (Al₂O₃with water soluble salts) and up to 20% free fatty acids including C16 and C18 saturated fatty acids.

Bonds between metal salts and carboxylic acids are known to readily dissociate into the corresponding metal and carboxylic acid in the ambient environment (at neutral pH) and in the digestive tract (at low pH), as determined for Aluminium di- and tristearate in the US HPV Chemical Challenge Program (2007). Thus, Fatty acids, C16-18 (even numbered), aluminum salt is considered to dissociate into aluminium, stearic (C18) and palmitic (C16) acid. Therefore, it is feasible to discuss the toxicokinetik behaviour of aluminium, stearic and palmitic acid as occurring dissociation products in accordance to Article 13 (1) of Regulation (EC) No 1907/2006.

 

Basic toxicokinetics

 

In accordance with Regulation (EC) 1907/2006, Annex VIII, Column 1, Item 8.8 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substance Fatty acids, C16-18 (even numbered), aluminum salts was conducted to the extent that can be derived from the relevant available information including physico-chemical and toxicological characteristics in addition to data obtained from breakdown products including C16 and C18 fatty acids and aluminium salts.

 

Fatty acids, C16-18 (even numbered), aluminum salt is a solid white powder which is poorly water soluble (< 1 mg/L, Peter Greven, 2012a) with a molecular weight of 316.41 – 877.39 g/mol and a vapour pressure of 0.15 Pa at 20 °C (Peter Greven, 2012b).The octanol/water partition coefficient (log Pow) of Fatty acids, C16-18 (even numbered), aluminum salt cannot be determined because the substance does not dissolve in water.

 

 

Absorption

 

Absorption of a substance depends on the potential to diffuse across biological membranes, a process determined by the molecular weight, the log Pow and water solubility (ECHA, 2012).

 

 

Oral:

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favorable for oral absorption (ECHA, 2012). With a molecular weight range of 316.41 – 877.39 g/mol oral absorption of fatty acids, C16-18 (even numbered), aluminum salts in the gastrointestinal tract is likely for monostearates but impeded for di- or tristearates due to their size. However, absorption by micelullar solubilisation cannot be excluded after oral ingestion as this route of absorption is likely for highly lipohilic and poorly water soluble (< 1 mg/L) substances.

 

After oral ingestion, nearly complete dissociation of aluminum fatty acid salts is expected to occur in the digestive tract at its low pH which was proven for different metal carboxylates (HPV Chemical Challenge Program, 2007). As the physico-chemical characteristics of the dissociation products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) differ from those of the parent substance prior to absorption into the blood, the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). Fatty acids with a chain length > C12 are mainly absorbed into the walls of the intestine villi where they are assembled into triglycerides prior to absorption in the blood stream. For C18 fatty acids, an absorption rate of 64.4 % was established which increases with decreasing chain length (Jensen et al., 1986). Uptake of aluminium after oral ingestion was proven in a subacute toxicity study by Ondreicka et al. (1966a) in which analysis of aluminium content in faeces and urine determined a significantly higher aluminium intake and faecal excretion in exposed animals. Steinhausen et al. (2004) determined that aluminium is only poorly absorbed in human volunteers after oral ingestion with an uptake of only 0.1% and an intestinal absorption rate of 0.1%, reaching maximum absorption of aluminium in the serum within 1.5 – 6 hours after administration. Further, bioavailability of aluminium is strongly influenced by the presence of dietary constituents which enhance (i.e. carboxylic acid) or inhibit (i.e. phosphate or dissolved silicate) its absorption (ATDSR, 2008).

 

Overall, systemic bioavailability of the parent substance is unexpected. After dissociation in the corresponding carboxylic acids and the aluminium component, high absorption of fatty acids is expected in humans whereas absorption of aluminium is rather low.

 

 

Dermal:

Dermal absorption correlates with molecular size: small molecules may be taken up more easily than bigger molecules. In general, a molecular weight < 100 favors dermal absorption, whereas molecules of molecular weights > 500 may be too large (ECHA, 2012). As the molecular weight of fatty acids, C16-18 (even numbered), aluminum salt ranges between 316.41– 877.39 g/mol, dermal absorption of smaller molecules may be possible. However, as a substance must be sufficiently soluble in water to diffuse from the stratum corneum into the epidermis (ECHA, 2012), dermal uptake of fatty acids, C16-18 (even numbered), aluminum salt is likely to be very low. As no log Pow can be determined for fatty acids, C16-18 (even numbered), aluminum salt due to the low water solubility, QSAR analyses are technically not possible to calculate dermal absorption values. Furthermore, aluminum fatty acid salts do not exhibit irritating properties to skin, hence, enhanced penetration due to local skin damage can be excluded. 

 

Overall, the low water solubility, the high molecular weight (>100) and the fact that the substance is not irritating to skin implies that dermal absorption ofFatty acids, C16-18 (even numbered), aluminum saltsis rather unlikely.

 

 

Inhalation:

Fatty acids, C16-18 (even numbered), aluminum salts have a low vapor pressure of 0.15 Pa at 20 °C thus being of low volatility. However, due to the physical state of the test substance, respiratory absorption in the lung after inhalation of dust cannot be excluded. In general, particles with aerodynamic diameters < 100 μm have the potential to be inhaled by humans. Particles with aerodynamic diameters < 50μm may reach the thoracic region and those < 15μm the alveolar region of the respiratory tract (ECHA, 2012). With a mean median diameter of 25.4 µm, fatty acid aluminum salts may reach the thoracic region (Peter Greven, 2012c, d). After resorption, uptake by micellular solubilisation might be possible due to the lipophilic character and the low water solubility.

 

Overall, a systemic bioavailability ofFatty acids, C16-18 (even numbered), aluminum salt after inhalation of dust cannot be excluded.

 

 

Accumulation:

 

In general, lipophilic substances tend to concentrate in adipose tissue (ECHA, 2012). Therefore,Fatty acids, C16-18 (even numbered), aluminum salthave the potential to accumulate in adipose tissue.

However, as further described in the section metabolism below, Fatty acids, C16-18 (even numbered), aluminum salt is expected to nearly completely dissociate into the fatty acid and aluminium components after oral ingestion.

The log Pow of the respective fatty acids are 7.94 for stearic (C18) and 6.96 for palmitic (C16) acid. Consequently,accumulation in adipose tissue is possible when their intake exceeds their physiological turn over as component for cell membranes or as energy source.  

The largest long-term deposition of aluminium occurs in the bones (Steinhausen et al., 2004), where aluminium concentrates at the mineralization front (Yokel and McNamara 2001).

 

Overall, the available information indicates that bioaccumulation of the parent substance and the dissociation products may be possible.

 

 

Distribution:

 

Distribution within the body depends on physico-chemical characteristics of a substance including molecular weight, lipophilicity and water solubility. In general, the smaller the molecule, the wider is the distribution. Further, lipophilic molecules are likely to diffuse into cells leading to an increased intracellular concentration compared to the extracellular concentration particularly in adipose tissues (ECHA, 2012).

Fatty acids, C16-18 (even numbered), aluminum salt will dissociate nearly completely into its components, namely stearic and palmitic acid and aluminium. Fatty acids are distributed in the organism to different tissues where they are incorporated into cell membranes, used as energy source or stord as triglycerides in adipose tissue depots (Masoro, 1977).

For aluminium compounds, the highest tissue concentrations were found in the liver, spleen, bone, kidney (Myers and Mull 1928) and the brain, which contains lower aluminium concentrations than the other tissues. Within the blood, an equal distribution of aluminium between plasma and cells is present. About 50% of absorbed aluminium is rapidly (< 2 hours) and permanently accumulated in the skeleton of young rats (Johanneau et al. 1997). Furthermore, it was shown that Al administered to pregnant and/or lactating rats is transferred to their offspring through transplacental passage and/or maternal milk (Yumoto et al., 2000).

Overall, the available information indicates that the dissociation products,aluminium and fatty acids will be distributed in the organism. 

 

Metabolism

 

After oral ingestion, nearly complete dissociation of aluminum fatty acid salts is expected to occur in the digestive tract due to its low pH which was proven for different metal carboxylates (HPV Chemical Challenge Program, 2007). The first dissociation products, Fatty acids, C16 and 18, are stepwise degraded within the mitochondria matrix by ß-Oxidation. The released C₂ units are cleaved as acyl-CoA which subsequently entersthecitric acid cycle(CIR, 1987).

 

Aluminium is expected to exist in four different forms in the living organisms, including free ions, low-molecular-weight complexes, physically bound macromolecular complexes, and covalently bound macromolecular complexes (Ganrot 1986). As the Al³⁺ ion easily binds to many macromolecules, its metabolism is determined by its binding affinity to potential ligands and finally to their metabolism. Aluminium forms low-molecular-weight complexes with carbohydrates, organic acids, amino acids, phosphates and nucleotides. Such low-molecular-weight complexes are often chelates which may be very stable. Covalently bound complexes are built between aluminium and proteins, polynucleotides, and glycosaminoglycans. These macromolecular complexes would be expected to be metabolically much less active than the smaller, low-molecular-weight complexes.

 

 

Excretion

 

As Fatty acids, C16-18 (even numbered), aluminum salt will nearly completely dissociate in stearic and palmitic acid and aluminium after ingestion, excretion of the parent compound is expected to be negligible. Fatty acids are used as energy source, stored as lipids in adipose tissue or are incorporated into cell membranes after absorption so that excretion of fatty acids occurs only after excessive intake via the faeces. In contrast, excretion of aluminium via the faeces has been shown in a subacute toxicity study: analysis of aluminium content in faeces and urine after repeated ingestion of aluminium chloride determined a significantly higher faecal excretion in exposed mice whereas urinary excretion and retention of aluminium seemed to be unaffected. In general, unabsorbed aluminium is excreted via the faeces whereas absorbed aluminium is mainly excreted in the urine after years (Steinhausen et al., 2004).

In conclusion, excretion of the parent substance is considered as negligible. Excretion of the dissociation product aluminium is expected to occur mainly in the faeces due to its low absorption rate whereas fatty acid are expected to be eliminated only after excessive intake via the faeces. 

 

References not included in the IUCLID:

ATSDR (Agency for Toxic Substances and Disease Registry) (2008).Toxicological Profile for Aluminum.Atlanta,:Department of Health and Human Services, Public Health Service.

CIR (1987). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, stearic acid. J. of the Am. Coll. of Toxicol.6 (3): 321-401

ECHA. 2012. Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance. European Chemicals Agency, Helsinki

Ganrot, P.O. (1986). Metabolism and possible health effects of aluminum. Environ Health Perspect 65:363-441. 

  

Jensen, C. et al., 1986. Absorption of individual fatty acids from long chain or medium chain triglycerides in very small infants. The American Journal of Clinical Nutrition 43: May 1986, pp 745-751.

Jouhanneau, P. et al. (1997). Gastrointestinal absorption, tissue retention, and urinary excretion of dietary aluminum in rats determined by using 26Al. Clinical Chemistry 43(6): 1023-1028.

Masoro (1977). Lipids and lipid metabolism. Ann. Rev. Physiol.39: 301-321.

Steinhausen et al. (2004). Investigation of the aluminium biokinetics in humans: a 26Al tracer study.Food Chem Toxicol.42(3):363-71.

U.S. High Production Volume (HPV) Chemical Challenge Program (2007).

Yokel RA,McNamara PJ. (2001). Aluminium Toxicokinetics: An Updated MiniReview. Pharmacology & Toxicology 88: 159-167.

Yumoto, S. et al. (2000). Transplacental passage of 26Al from pregnant rats to fetuses and 26Al transfer through maternal milk to suckling rats.Nuclear Instruments and Methods in Physics Research B 172(1-4): 925-929.