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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) has been assessed.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2014) and taking into account available information on the analogue substances from which data was used for read-across to cover data gaps.

Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is a polysorbate ester derived from C16 (44%) and C18 (54%) fatty acids linked to polyethoxylated sorbitan containing 1 – 6.5 moles ethylenoxid units (average approximately 4.15 ethylenoxid units). Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is a multi-constituent substance specified by the presence of mono-, di- and triesters which meets the definition of an UVCB substance. The molecular weight ranges from 578.76 – 1492.17 g/mol. Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is a solid, which has a moderate water solubility of 148 mg/L at 20 °C. The log Pow ranges from of 4.02 to 20.76, respectively. A vapour pressure <0.0001 Pa at 20°C was determined for the most representative molecules (for further details, please refer to chapter 4.6 of the technical dossier).

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, 2014).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently soluble in water (> 1 mg/L). Lipophilic compounds may 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 (Aungst and Shen, 1986; ECHA, 2014).

As the molecular weight of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) ranges from 578.76 – 1492.17 g/mol, absorption in the gastrointestinal tract is in general improbable. However, in regard to the molecular weight range, absorption of at least the smaller ingredients cannot be excluded. Absorption of ingredients with higher molecular weights and log Pow values > 4 is considered rather unlikely. However, the moderate water solubility indicates at least a partial solution into GI fluids (ECHA, 2012). Micellular solubilisation by bile salts may enhance absorption, as this mechanism is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986).

The potential of a substance to be absorbed in the (GI) tract may be influenced by chemical changes taking place in 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 and hence predictions based upon the physicochemical characteristics of the parent substance may no longer apply (ECHA, 2014).

After oral ingestion, polysorbates undergo rapid hydrolysis by pancreatic lipase in the gastrointestinal (GI) tract resulting in the free fatty acid and the polyethoxylated sorbitan moiety (EPA 2005; CIR, 1984). In rats, nearly complete hydrolysis was reported for radioactive labelled Polysorbate 80 in a feeding study. Moreover, absorption of the labelled free fatty acid component was determined whereas the polyethoxylated sorbitan moiety was proven to be poorly absorbed in the GI tract, as shown by a high recovery rate of 91% in the faeces of rats (CIR, 1984).

The available acute oral toxicity study on Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) identified a LD50 value > 39800 mg/kg bw (Quigley, 1966). Moreover, no toxicologically relevant effects were noted in acute or repeated dose toxicity studies performed with structural analogue substances (Krantz, 1948, 1949, MHLW Japan, 2007, Potokar, 1984). The lack of acute - and repeated systemic toxicity cannot exclusively be explained by a lack of absorption but rather with a low toxic potential of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated).

In conclusion, based on the available data and physicochemical properties, poor absorption of the parent compound and the first breakdown product, the polyethoxylated sorbitan moiety, is considered after oral ingestion. In contrast, a high absorption rate of the free fatty acid moieties is considered.

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 favour dermal uptake, while for those above 500 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 (ECHA, 2014).

Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) has a moderate water solubility which correlates to moderate dermal absorption potential (ECHA, 2014). The molecular weight exceeds the limit size defined for favourable dermal absorption (500 g/mol), which indicates that at least the components of higher molecular size of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) might be too large to penetrate the skin. Furthermore, the log Pow > 4 points to slow uptake into the stratum corneum and a slow transfer between the stratum corneum and the epidermis (ECHA, 2014). Taken all these aspects into consideration, dermal uptake of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is considered to be impeded due to the physicochemical properties of the substance. This assumption is further supported by QSAR predictions, which estimated a low dermal absorption rate for representative structures of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated)resulting in low dermal absorption potential with a flux ranging from 9.8E-7 – 3.4E-18 mg/cm2/h (please refer to Table 1).

 

Table 1: Dermal absorption values for representative components of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) (covering the different alcohol moieties (dianhydroglucitol, sorbitan and sorbitol) and the lowest to highest molecular weights) (calculated with Dermwin v 2.02, Epiweb 4.1)

Component, SMILES Code

Structural formula

Flux (mg/cm2/h)

C16 Sorbitan monoester OC(COCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCC)C1OCC(O)C1O

C30H58O10

9.8E-7

C18 Sorbitan triester CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOC(COCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCCCC)C1OCC(OCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCCCC)C1O

C84H162O20

3.38E-18

C18 Dianhydroglucitol diester CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOC2COC1C2OCC1OCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCCCC

C58H110O14

1.17E-12

C18 Sorbitol diester CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCC(O)C(O)C(O)C(O)COCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCCCC

C58H114O16

8.76E-13

 

Moreover, it has to be considered that damage to the skin surface may enhance penetration if the substance is a skin irritant or corrosive, (ECHA, 2014). The experimental animal and human data on Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) shows that no significant skin irritation occurred, which excludes enhanced penetration of the substance due to local skin damage (CIR, 1984).

Overall, based on the available information, the dermal absorption potential of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is predicted to be low.

Inhalation

In general, the particle size indicates the presence of inhalable/respirable particles. 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, 2014).

Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is a waxy solid not present in pulverized or granular form. Thus, based on the physicochemical appearance, the potential for exposure and subsequent absorption via inhalation during normal use and handling is considered to be negligible.

As for oral absorption, the molecular weight, log Pow and water solubility are suggestive for absorption of at least the smaller ingredients (for further details, please refer to “Absorption, Oral”).

Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting sorbitan moiety and the free fatty acid available for inhalative absorption.

An acute inhalation toxicity study was performed with the read-across substance Sorbitan monolaurate, ethoxylated (CAS 9005-64-5), in which rats were exposed nose-only to > 5.1 mg/L of an aerosol for 4 hours (Van Huygevoort, 2012). Moreover, Sorbitan laurate (CAS 1338-39-2) was tested for acute inhalation toxicity according to OECD Guideline 436 (Van Huygevoort, 2010). No mortality occurred and no toxicologically relevant effects were observed. Thus, the test substances were not acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption.

Due to the limited information available, absorption via inhalation is assumed to be as high as via the oral route in a worst case approach.

 

Distribution

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, 2014).

Sorbitan fatty acid esters undergo hydrolysis resulting in the fatty acid moiety and the polyoxyethylene moiety, which was shown for Poylsorbate 20 (EPA, 2005). As the ethoxylated sorbitan moiety is expected to be poorly absorbed in the GI tract (EPA, 2005), distribution within the body is expected to be negligible. In contrast, excretion of the ethoxylated residue via bile is expected (HERA, 2009).The fatty acids are distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy and undergo beta-oxidisation. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

 

Metabolism

After oral ingestion, the ester link of the polysorbate molecule undergoes hydrolysis by pancreatic lipase resulting in the fatty acid moiety and the polyethoxylated sorbitan moiety (EPA, 2005). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, Sorbitan fatty acid esters will undergo chemical changes already in the gastrointestinal fluids as a result of enzymatic hydrolysis. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

The first cleavage product, the fatty acid, is stepwise degraded by beta-oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The alpha- and omega-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

Experimental investigations with Sorbitan stearate revealed hydrolysis in vitro (Krantz, 1951) as well as in vivo (Wick, 1953). Incubation with pancreatic lipase for 24 h at 37 °C resulted in a release of fatty acids from the test substance reaching 5.4%.In the same study 21.4% fatty acids were liberated from corn oil, which was used as positive control. After oral administration of 0.5 – 6.5 g radiolabeled test substance /kg bw dissolved in corn oil to rats, 90% of the test substance was hydrolyzed to stearic acid and anhydrides of D-glucitol (Wick, 1953).The resulting anhydrides were poorly absorbed. In contrast, administration as water solution revealed hydrolyses of only 50% Sorbitan stearate.

The second cleavage product, the polyethoxylated sorbitan moiety, is expected to be excreted in the feces and urine without further metabolism (CIR, 1984; EPA, 2005)

Excretion

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. In the rat, molecules that are excreted in the bile are amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have a high molecular weight. In general, in rats for organic cations with a molecular weight below 300 it is unlikely that more than 5-10% will be excreted in the bile, for organic anions this cut off may be lower. Substances excreted in bile may potentially undergo enterohepatic circulation. Little is known about the determinants of biliary excretion in humans. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells (ECHA, 2014).

After oral ingestion, non-absorbed Sorbitan fatty acid esters are suspected to be excreted via the urine and the feces as determined in general for polyethoxylated sorbitans (CIR, 1984; EPA, 2005).

However, as Sorbitan fatty acid esters will be hydrolysed in the gastrointestinal fluids, the cleavage products might be more important for consideration. The highly lipophilic fatty acids will be readily absorbed by micelullar solubilisation und undergo beta-oxidation or will be stored in fat tissue (Ramirez et al., 2001). The remaining polyethoxylated sorbitan moiety is expected to be excreted mainly in the feces and to a smaller extent in the urine (CIR, 1984, EPA, 2005)

References

Aungst B. and Shen D. D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K. K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

CIR (1984). Final Report on the Ssafety assessment of Polysorbat 20, 21, 40, 60, 61, 65, 80, 81 and 85. Journal of the American College of Toxicology, 3(5): 1- 82.

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 (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Office of prevention, pesticides and toxic substances.

EPA (2005). ACTION MEMORANDUM. Reassessment of six inert ingredient exemptions from the requirement of a tolerance. United States Environmental Protetctio Agency, Washington, D.C. 20460

HERA (2009). Human & Evironmental Health Risk Assessment on ingredients of European household cleaning products. Alcohol Ethoxylates. September 2009 (http://www.heraproject.com/RiskAssessment.cfm?SUBID=34)