Sorbitan, tridocosanoate

Endpoint summary

Description of key information

The physico-chemical properties and the molecular weight of sorbitan tridocosanoate (CAS 93980-59-7)suggest limited absorption via the oral, dermal and inhalation route. In case of oral absorption, the substance is expected to be absorbed by micellar solubilisation. The substance may undergo hydrolysis in the gastrointestinal (GI) tract and may be metabolised in the liver as well as by microbial metabolism. Dermal absorption is expected to be very low. Based on the particle size distribution,systemic bioavailability is considered unlikely after inhalation.

In case of absorption, the substance is likely to distribute into cells. Based on the high log Pow, accumulation in the body fat is favourable for the substance, however, based on the low rate of absorption the distribution and accumulation of sorbitan tridocosanoate is expected to be very low.

A number of skin metabolites, hepatic metabolites and metabolites after microbial metabolism in the GI tract were predicted. While sorbitan tridocosanoate is expected to be excreted mainly via the faeces, hydrolysis products may be more likely excreted via the urine, or, in case of fatty acid β-oxidation, excreted via exhaled air as CO2.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Basic toxicokinetics:

There are no studies available in which the toxicokinetic behaviour of sorbitan tridocosanoate (CAS 93980-59-7) has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of REACH (Regulation (EC) No. 1907/2006) and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), an assessment of the toxicokinetic behaviour of sorbitan tridocosanoate was conducted to the extent that can be derived from relevant available information on physico-chemical and toxicological properties of the test substance.

 

Physico-chemical properties

Sorbitan tridocosanoate (CAS 93980-59-7) is a UVCB substance that appears as yellowish-brown beads-like powder. The molecular weight ranges from 697.08 – 1131.86 g/mol and the partition coefficient log Pow has been estimated to be 5.04 to 8.31 for representative monoester constituents and > 10 for representative diester and triester constituents (QSAR calculation, VEGA v1.1.3 - two models: Meylan/Kowwin v1.1.4, ALogP v1.0.0; SPARC v4.6). The substance has a low water solubility of < 0.525 mg/L at 20 °C and pH 5.9 and a particle size distribution of D50 = 551 ± 23.4 µm (Riken Vitamin, 2017).

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

 

Oral:

The smaller the molecule, the more easily it will be taken up. In general, substances with a molecular weight < 500 g/mol and with a log Pow between -1 and 4 are favourable for oral absorption. Lipophilic compounds can be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (ECHA, 2017).

The physical state of sorbitan tridocosanoate, the high molecular weight of 697.08 – 1131.86 g/mol, the log Pow of 5.04 to 8.31 for representative monoester constituents and > 10 for representative diester and triester constituents as well as the low water solubility < 0.525 mg/L at 20 °C suggest a low potential for oral absorption.

If absorption occurs, the high log Powof the registered substance indicates that micellar solubilisation is the most likely mechanism for oral absorption. However, the high molecular weight of the test substance may complicate its absorption.

There is one acute oral toxicity study (Riken Vitamin, 2017) and an oral repeated dose toxicity study with an reproductive and developmental toxicity screening test (Riken Vitamin, 2021) available. None of the studies revealed evidence for systemic toxicity, as no mortality, clinical signs of toxicity, body weight impairment, food consumption or macroscopical or microscopical changes were noted up to the highest dose levels tested. The acute oral LD50 was determined to be > 2000 mg/kg bw (Riken Vitamin, 2017) and the NOAEL for oral repeated dose toxicity was > 1000 mg/kg bw/day (Riken Vitamin, 2021).

Upon oral ingestion, the potential of a substance to be absorbed in the GI tract can be affected during the passage through the GI tract. Substances can undergo chemical changes in the GI fluids as a result of metabolism by GI flora, by enzymes released into the GI tract or by hydrolysis. These changes will alter the physicochemical characteristics of the substance, which means that predictions made using the physicochemical characteristics of the parent substance may no longer be accurate (ECHA, 2017). The ester groups of sorbitan tridocosanoate may be hydrolysed in the GI tract to form the corresponding alcohol and acid moieties by esterases. The rate of hydrolysis is not known. The smaller molecules of the alcohol and acid moieties may be absorbed faster than the parent molecule.

In conclusion, sorbitan tridocosanoate is expected to have a low absorption rate following oral exposure.

 

Dermal:

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1 - 100 mg/L; and moderate to high if it is between 100 - 10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption. Highly lipophilic substances (log Pow between 4 and 6) that come into contact with the skin can readily penetrate the lipid-rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off (ECHA, 2017).

The physicochemical properties (log Pow 5.04 to 8.31 for representative monoester constituents and > 10 for representative diester and triester constituents) of the substance and the molecular weight (697.08 – 1131.86 g/mol) are in a range suggestive of low absorption through the skin. In addition, based on the low water solubility (< 0.525 mg/L) dermal absorption is expected to be low. By default, if the molecular mass is above 500 g/mol and the log Pow is outside the range [-1, 4], a value of 10% skin absorption is defined (ECHA, 2017; de Heer et at., 1999).

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer, some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017).

The available data on skin irritation (Riken Vitamin, 2017a) and skin sensitisation (Riken Vitamin, 2018) did not show any irritating effects on human non-transformed keratinocytes and in a local lymph node assay in mice. Therefore, no enhanced penetration of the substance due to skin damage is expected.

Overall, taking all available information into account, the dermal absorption potential is considered to be low.

 

Inhalation:

Sorbitan tridocosanoate is a solid of low volatility (< 0.0001 Pa at 20 °C). 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 the alveolar region of the respiratory tract (ECHA, 2017).

Sorbitan tridocosanoate exhibits a D50 of 551 ± 23.4 µm, suggesting that the extent of particles in a respirable size is negligible. However, it cannot be excluded that a small portion of particles inhaled may reach the thoracic region. Substances may be absorbed directly from the respiratory tract or, through the action of clearance mechanisms, may be transported out of the respiratory tract and swallowed. This means that absorption from the GI tract will contribute to the total systemic burden of substances that are inhaled (ECHA, 2017).

As no systemic toxicity was evident after acute oral exposure of the test substance (Riken Vitamin, 2017), the absorption of the test substance by the oral route is expected to be low. Therefore, a low absorption is also considered likely if the test substance is inhaled.

Overall, systemic availability is considered unlikely after inhalation of the test substance. Based on the physicochemical properties of the test item, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapour, gases or mists is not significant.

 

Distribution and accumulation

Distribution of a compound within the body depends on the physicochemical properties of the substance, especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2017).

Based on the physicochemical properties of sorbitan tridocosanoate (log Pow of 5.04 to 8.31 for representative monoester constituents and > 10 for representative diester and triester constituents and a low water solubility of < 0.525 mg/L) and its molecular weight (697.08 – 1131.86 g/mol), the substance is taken up by micellar solubilisation and likely to distribute into cells. For substances with a log Pow > 0, the intracellular concentration may be higher than extracellular concentration, particularly in fat tissue (ECHA, 2017).

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate within the body. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally accepted that substances with high log Pow values have long biological half-lives. The high log Pow value indicates that sorbitan tridocosanoate, in case of absorption, may have the potential to accumulate in adipose tissue (ECHA, 2017). However, the oral, inhalation and dermal absorption is expected to be low and, based on the large size of the molecule it can be assumed that the distribution and accumulation of the test substance in the body is rather low. In addition, experimental results of acute and repeated oral exposure (Riken Vitamin, 2017 and 2021) revealed no macroscopic and/or microscopic changes in tissues and organs. Systemic bioavailability is therefore expected to be low.

 

Metabolism

Biotransformation is one of the main factors, which influence the fate of a substance in the body, its toxicity, and its rate and route of elimination.

The potential metabolites following enzymatic metabolism of the main constituents of the test substance were predicted using the OECD QSAR Toolbox v4.4 (OECD, 2017). This QSAR tool predicts which metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the GI tract. Simplified, 6 dermal metabolites and 63 hepatic metabolites were predicted for the test substance. In addition, up to 111 metabolites were predicted to result from microbiological metabolism. The predicted metabolites contain for example hydroxyl groups or carboxyl groups at various positions, which increase the test items water solubility for excretion.

As a result of hydrolysis of the ester group, the main expected metabolites are sorbitol, anhydrides of sorbitol and docosanoic acid (also behenic acid). Docosanoic acid is metabolised stepwise byβ-oxidation, following the same pattern as other even-numbered, straight-chain aliphatic acids (Bingham et al 2001; HSDB, 2013). It will, therefore, mainly be excreted by expired air as CO₂, or stored as lipids in adipose tissue or used for further physiological processes, e.g., incorporation into cell membranes (Stryer, 1996).

The results of a local lymph node assay (LLNA) in CBA mice give no indication that sorbitan tridocosanoate is activated to a reactive molecule (Riken Vitamin, 2018). In addition, the test item is not activated to mutagenic intermediates under the relevant test conditions. All three experimental studies performed on genotoxicity (Ames test, chromosome aberration test andhypoxanthin-guanin-phosphoribosyl-transferase (HGPRT)test) were negative, with and without metabolic activation (Riken Vitamin, 2018, 2020 and 2021).

 

Excretion

Sorbitan tridocosanoateis a highly lipophilic substance. Upon ingestion, the main route for excretion of hydrophobic substances with a high molecular weight is via the bile and subsequently the faeces. In addition, highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells (ECHA, 2017).

After absorption, possible metabolites from phase I and/or phase II metabolism in the liver or from microbial metabolic processes in the intestine may be conjugated with e.g. glutathione to form more water-soluble compounds which can be excreted via the urine. The fraction of the test substance that is not absorbed in the GI tract and not accumulating in adipose tissue, is expected to be excreted via the faeces.Fatty acid moieties that reach the circulation system will be metabolised for energy generation (Lehninger, 1993). Therefore, the fatty acids will be excreted mainly via exhaled air as CO₂.

 

References:

Bingham, E.; Cohrssen, B.; Powell, C. H.; Patty's Toxicology. Volumes 1-9 5th ed. John Wiley &amp; Sons. New York, N. Y. (2001), p. 725

De Heer C, Wilschut A, Stevenson H and Hakkert BC (1999) Guidance document on the estimation of dermal absorption according to a tiered approach: an update. V98.1237. 1999. Zeist, NL, TNO

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0.

Lehninger AL et al. (1993). Principles of biochemistry, 2^nd edition. Worth Publishers, New York. ISBN No. 0-87901-500-4.

 OECD (2014). (Q)SAR Toolbox v3.3. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Prediction performed 21 June 2016.http://toolbox.oasis-lmc.org/?section=overview

 Stryer, L. (1994): Biochemie.2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad.Verlag.