Dehydrated sorbitol, C18 (unsaturated) fatty acid esters, ethoxylated

Endpoint summary

Additional information

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated; CAS 9005-65-6) 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, 2012), 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 physico-chemical and toxicological properties according to the relevant Guidance (ECHA, 2012) and taking into account available information on the analogue substances from which data was used for read-across to cover data gaps.

Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) is a polysorbate monoester (UVCB) derived from oleic acid and polyethoxylated sorbitan containing either 3 or 5 ethylenoxid units (3EO and 5EO) which are bound to sorbitan.

Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) is a liquid, which has a low to moderate water solubility ranging from 30 – 100 mg/L at 20 °C, pH=6.3 - 7.9 as determined by CMC (Humphrey, 2014). A log Pow of 4.51 and 5.06 is calculated for 5 and 3 ethoxy units, respectively. A vapour pressure <0.0001 Pa at 20°C was determined, irrespective of ethoxylation degree.

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, 2012).

Oral

The molecular weight of Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) is slightly above 500 g/mol, indicating that absorption of the substance is likely but hindered after oral ingestion (ECHA, 2012). The high log Pow in combination with the low water solubility suggests that absorption will mostly occur via micellar solubilisation. The high log Pow and the low water solubility indicate at least partial solution into GI fluids (ECHA, 2012).

The available acute oral toxicity data on Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) consistently showed LD50 values > 20000 mg/kg bw (Krantz, 1945; CIR, 1984). Moreover, no toxicologically relevant effects were noted up to the highest dose level of 8000 mg/kg bw/day in a repeated dose toxicity study (Krantz, 1945).The lack of acute - and short-term systemic toxicity cannot exclusively be explained by a lack of absorption but rather with a low toxic potential of Sorbitan monooleate, ethoxylated.

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 physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2012).

After oral ingestion, polysorbates undergo rapid hydrolysis by pancreatic lipase in the gastrointestinal (GI) tractresulting in the free fatty acid and the polyethoxylated sorbitan moiety (EPA 2005; Fruijtier-Pölloth, 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).

In conclusion, based on the available data and physico-chemical 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 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, 2012).

Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) has a low water solubilty of 30 – 100 mg/L which correlates to a low to moderate dermal absorption potential (ECHA, 2012). The molecular weight exceeds the limit size defined for favourable dermal absorption (500 g/mol), which indicates that Sorbitan monooleate, 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, 2012). Taken all these aspects into consideration, dermal uptake of Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) is considered to be impeded due to the physico-chemical properties of the substance. This assumption is further supported by QSAR predictions, which estimated a low to moderate dermal absorption rate for Sorbitan monooleate containing 3 EO resulting in a medium low dermal absorption potential of not more than 20% (please refer to 7.1.2). For Sorbitan monooleate comprising 5 ethoxy units, low dermal absorption of not more than 10% was predicted considering different QSAR methods and the different water solubilties (30 – 100 mg/L) (please refer to 7.1.2).

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, 2012). The experimental animal and human data show that no significant skin irritation occurred, which excludes enhanced penetration of the substance due to local skin damage (Mezei et al., 1966; Treon, 1963).

Overall, based on the available information, the dermal absorption potential of Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) is predicted to be low for Sorbitan monooleate comprising 5 ethoxy units. Depending on the water solubilty, a low to moderate dermal absorption potential was predicted for Sorbitan monooleate containing 3 ethoxy units.

Inhalation

As the vapour pressure of Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) is very low (< 0.0001 Pa at 20 °C), the volatility is low and hence, the potential for exposure and subsequent absorption via inhalation during normal use and handling is considered to be negligible.

If the substance is available as an aerosol, the potential for absorption via the inhalation route is increased. While droplets with an aerodynamic diameter < 100μm can be inhaled, in principle, only droplets with an aerodynamic diameter < 50μm can reach the bronchi and droplets < 15μm may enter the alveolar region of the respiratory tract (ECHA, 2012).

As for oral absorption, the molecular weight, log Pow and water solubility are suggestive of absorption across the respiratory tract epithelium rather by micellar solubilisation.

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). No mortality occurred and no toxicologically relevant effects were observed. Thus, the test substance is 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 physico-chemical 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, 2012).

 

Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) undergoes rapid hydrolysis leading to release of thepolyethoxylated sorbitan moietyand the free fatty acid (CIR, 1984; EPA, 2005; Fruijitier-Pöllöth, 2005). As the polyethoxylated sorbitan moiety is poorly absorbed in the GI tract (EPA, 2005), distribution within the body is expected to be negligible. 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 (Masoro 1977). 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. An ethoxylated residue might also occur which most likely remains intact and might be excreted via bile into the small intestine as such (HERA 2009).

Experimental data obtained in the repeated dose toxicity studies showed abnormalities in kidney, spleen, testes and ovaries at gross pathology as well as microscopic observations of alterations in kidney, testes, lymphoid tissue, liver, and coronary tissues. Assumably, the test substance and/or their metabolites may at least reach the intestinal organs but probably not cross the placental barrier, since there were no effects on litters observed in the available prenatal study.

 

Metabolism

After oral ingestion, the ester link of the polysorbate molecule undergoes hydrolysis by pancreatic lipase resulting in the fatty acid moiety and thepolyethoxylated sorbitan moiety(CIR, 1984; EPA, 2005; Fruijitier-Pölloth, 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 gastro-intestinal 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).

The second cleavage product, the polyethoxylated sorbitanmoiety, is expected to be excreted mostly in the feces and to a small amount in the urine without further metabolism (CIR, 1984; EPA, 2005; Fruijitier-Pölloth, 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, 2012).

After oral ingestion, non-absorbed Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) is suspected to be excreted non-metabolised mainly in the feces: for polysorbate 20, an excretion rate for the ethxyloated sorbitan moiety of 90% was shown in the feces and 8% in the urine. Similarly, 91% of the ethoxylated sorbitan moiety were determined in the feces and 2.1% in the urine for polysorbate 80 (CIR, 1984; EPA, 2005). 

 

However, as Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) will rapidly be hydrolysed in the gastro-intestinal 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 moietyis excreted mainly in the feces and to a smaller extent in the urine (CIR, 1984; EPA, 2005).

 

References

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