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Description of key information

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Additional information

Justification for grouping of substances and read-across

The Sorbitan fatty acid esters category covers fatty series of analogous esters comprised of D-glucitol and natural fatty acids. The category contains UVCB substances, which exhibit differences in chain length (C8-C18), degree of esterification (mono-, di-, tri- and higher esters) and extent of unsaturation (saturated and mono unsaturated).

The category members are listed in the table below and their composition is defined in IUCLID Section 1.2. The naming of the substances is in accordance with the European Pharmacopeia (2011).

Sorbitan esters are produced generally in two stages. First, a D-glucitol solution is concentrated by heating to remove water, which results in the open chain D-glucitol cyclising with the loss of water to form a mixture of anhydrosorbitols and isosorbide. The mixture is reacted with fatty acid to give the respective mono-, di-, tri- and n-esters as the final products of esterification (JECFA 1973, Gennaro 1990; Canterbery 1997).

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, where by substances may be considered as a category provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substances listed below are allocated to the category of Sorbitan fatty acid esters.

Sorbitan fatty acid esters include:

CAS

EC name

Molecular weight

Fatty acid chain length

Molecular formula

Degree of esterification

CAS 91844-53-0 (*)

Sorbitan octanoate (2:3)

MW 290.35 - 422.66

C8

C10

C14H26O6

C16H30O6

C22H40O7

C26H48O7

Mono-

Mono-

Di-

Di-

CAS 1338-39-2 (*)

Sorbitan laurate

MW 346.46 – 528.79

C12

C18

C18:1

C18H34O6

C24H46O6

C24H44O6

C30H56O7

Mono-

Mono-

Mono-

Di-

CAS 26266-57-9 (*)

Sorbitan palmitate

MW 402.57 – 879.38

C16

C22H42O6

C54H102O8

Mono-

Tri-

CAS 1338-41-6 (*)

Sorbitan stearate

MW 402.57 – 981.56

C16

C18

C22H42O6

C24H46O6

C54H102O8

C60H116O9

Mono-

Mono-

Tri-

Tri-

CAS 1338-43-8 (#)

Sorbitan oleate

MW 428.6

C18:1

C24H44O6

Mono-

CAS 71902-01-7 (*)

Sorbitan isooctadecanoate

MW 430.62 – 963.54

C18 iso

C24H46O6

C42H80O7

C60H114O8

Mono-

Di-

Tri-

CAS 8007-43-0 (*)

Sorbitan, (Z)-9-octadecenoate (2:3)

MW 670.04 – 957.49

C18

C18:1

C41H74O7

C60H108O8

Di-

Tri-

CAS 26658-19-5 (*)

Sorbitan tristearate

MW 879.38 – 981.56

C16

C18

C54H102O8

C60H116O9

Tri-

Tri-

CAS 26266-58-0 (*)

Anhydro-D-glucitol trioleate

MW 957.49

C18:1

C60H108O8

Tri-

CAS 50-70-4 (+)

D-glucitol

MW 182.17

--

--

--

CAS 124-07-2 (+)

Octanoic acid

MW 144.21

--

--

--

CAS 112-85-6 (+)

Docosanoic acid

MW 340.59

--

--

--

MW: molecular weight

(*) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(#) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

(+) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

Grouping of substances into this category is based on:

(1) common functional groups: all members of the category are esters of an alcohol with one or more carboxylic (fatty) acid(s) chain(s). The alcohol moiety D-glucitol is common to all category members. The fatty acid moiety comprises carbon chain lengths from C8-C18 (even-numbered) and includes saturated and mono-unsaturated chains bound to the alcohol resulting in mono-, di-, tri-, n-esters; and

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: Sorbitan fatty acid esters have common metabolic fate that involves stepwise hydrolysis to the respective fatty acid and D-glucitol (Stryer 1996). Fatty acids feed into physiological pathways like the β-oxidation (Stryer 1996) and D-glucitol is metabolized to D-glucose or D-fructose (Touster 1975). In general, hydrolysis of Sorbitan fatty acid esters in vitro and by lipolytic enzymes in the gastrointestinal tract occurs within a maximum of 48h for mono-, di- and triester but decreases with the number of esterified fatty acid so that no hydrolysis of hexa-ester occurs (Krantz 1951, Mattson and Nolen 1972, Treon 1967, Wick 1953). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of D-glucitol and fatty acids will undergo chemical changes already in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In contrast, substances that 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). For the second cleavage product D-glucitol it was found, that it is relatively slowly absorbed from the gastro-intestinal tract compared with glucose and that it can be metabolized by the intestinal microflora (Senti 1986). Once absorbed, D-glucitol is primarily metabolized in the liver. The first step involves oxidation by L-iditol dehydrogenase to fructose which is metabolized by the fructose metabolic pathway (Touster 1975). D-glucitol does not enter tissues other than the liver and does not directly influence the metabolism of endogenous D-glucitol in other tissues (Allison 1979): and

(3) constant pattern in the changing of the potency of the properties across the category: the available data show similarities and trends within the category in regard to physicochemical, environmental fate, ecotoxicological and toxicological properties. For those individual endpoints showing a trend, the pattern in the changing of potency is clearly and expectedly related to the length of the fatty acid chains and the degree of substitution of the alcohol (mono-, di-, tri-, n-ester).

a) Physicochemical properties:

The molecular weight of the category members ranges from 290.35 to 981.56 g/mol. The physical appearance is related to the chain length of the fatty acid moiety, the degree of saturation and the number of ester bonds. Thus, monoesters of short-chain and unsaturated fatty acids (C8-C14 and C18:1) are liquid, while di- and triesters of short- and long-chain fatty acids are solids. All category members a non-volatile (vapour pressure: < 0.0001 kPa). The octanol/water partition coefficient increases with increasing fatty acid chain length and number of ester bonds, ranging from 0.97 (C8-monoester) to >10 (C16-18-triester). The water solubility decreases accordingly (750 mg/L for C8-mono ester to < 0.05 mg/L for C18-triester).

b) Environmental fate and ecotoxicological properties:

All substances in the Sorbitan esters category are readily biodegradable and are thus not expected to persist in the environment. Abiotic degradation via hydrolysis or phototransformation is not considered to be relevant for these substances. The water solubility is generally low, with the exception of the smallest substance sorbitan octanoate, which is highly soluble. The adsorption potential to organic soil and sediment particles increases with the size of the molecule, i.e. chain length and degree of esterification, following a clear trend. Generally, all sorbitan triesters, diesters from fatty acid chain length C12 and monoesters with C18 fatty acids show high adsorption potential (log Koc 3.3 - >10) and are expected to partition mainly in the compartments soil and sediment. Smaller sorbitan mono- and diesters (fatty acid chain length <C18 and <C12, respectively) have lower adsorption potential (log Koc 1.0 - 2.8) and may also be found in the water compartment. Due to the structure consisting of the polar sorbitan and the hydrophobic fatty acid carbon chain, the substances also have surface active properties. Nevertheless, since all category members are readily biodegradable, they are expected to be eliminated in sewage treatment plants to a high extent. Release to surface waters, and thereby exposure of aquatic and sediment organisms, is therefore very unlikely. In soil, the substances are expected to be rapidly degraded. Accumulation into organisms is not expected for members of the Sorbitan esters category, since they can be digested by common metabolic pathways. Evaporation into air and the transport through the atmospheric compartment is not expected since the category members are not volatile based on the low vapour pressure. Based on experimental data, all category members show very low toxicity to aquatic, sediment and terrestrial organisms in both acute and chronic tests.

c) Toxicological properties:

All available experimental data indicate that the members of the Sorbitan fatty acid esters category are not acutely toxic, are not irritating to the skin or to the eyes and do not have sensitizing properties. In addition, no hazard was identified for any category member regarding repeated dose, genetic and reproductive/developmental toxicity.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

 

Basic toxicokinetics

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behavior of the substance Sorbitan tristearate (CAS No. 26658-19-5) was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.

The substance Sorbitan tristearate (molecular weight of 879.38 to 981.56 g/mol) is a solid with waxy-like particles, which is insoluble in water (<0.05 mg/L at 20 °C). The log Po/w is > 10 and the vapour pressure < 0.0001 Pa at 20 °C.

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, 2008).

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, 2008). As the molecular weight of Sorbitan tristearate ranges between 879.38 and 981.56 g/mol, an absorption of the molecule in the gastrointestinal tract is in general improbable.

Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al. (1999)) is applied to the substance Sorbitan tristearate.

The log Pow of > 10 and the water insolubility suggest that Sorbitan tristearate is favourable for absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), which are poorly soluble in water (1 mg/L or less).

After oral ingestion, Sorbitan fatty acid esters will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis.The hydrolysis of Sorbitan fatty acid esters occurs within a maximum of 48h for mono-, di- and tri-ester but decreases with the number of esterified fatty acid so that no hydrolysis of hexa-ester occurs (Krantz 1951, Mattson and Nolen 1972, Treon 1967, Wick and Joseph 1953). The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2008). However, also for both cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract.The highly lipophilic fatty acid will be absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the D-glucitol, being a highly water-soluble substance, will dissolve into the gastrointestinal fluids and slowly be absorbed with a subsequent metabolization in the liver (Senti 1986, Touster 1975).

Overall, a systemic bioavailability of Sorbitan tristearate is considered unlikely whereas absorption of the respective cleavage products is considered likely after in humans.

Dermal

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2008). As the molecular weight of Sorbitan tristearate ranges between 879.38 and 981.56 g/mol, a dermal absorption of the molecule is unlikely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2008). As Sorbitan tristearate is not considered as skin irritating in humans, an enhanced penetration of the substance due to local skin damage can be excluded.

Based on QSAR prediction, a dermal absorption value of 1.06E-011 mg/cm²/event was calculated (molecular weight of 982 g/mol, Dermwin 2012), which indicates a very low potential for dermal absorption.

For substances with a log Pow above 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2008). As Sorbitan tristearate is insoluble in water and the log Pow is > 10, dermal uptake is likely to be very low.

Overall, the calculated very low dermal absorption potential, the low water solubility, the high molecular weight (>100), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of Sorbitan tristearate in humans is considered as very limited.

Inhalation

Sorbitan tristearate has a low vapour pressure of < 0.0001 Pa at 20 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not expected to be significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is melted and sprayed. 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, 2008). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Sorbitan tristearate can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of Sorbitan tristearate in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15 µm.

Accumulation

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow of > 5 implies that Sorbitan tristearate may have the potential to accumulate in adipose tissue (ECHA, 2008).

However, as further described in the section metabolism below, Sorbitan fatty acid esters will undergo esterase-catalysed hydrolysis, leading to the cleavage products D-glucitol and fatty acids.

The log Pow of the first cleavage product D-glucitol is -2.2, indicating a high solubility in water. Consequently, there is no potential for D-glucitol to accumulate in adipose tissue.The second cleavage product, the fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. 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.

Overall, the available information indicates that no significant bioaccumulation of the parent substance in adipose tissue is expected.

Distribution

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. 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, 2008).

Sorbitan fatty acid esters will undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products D-glucitol and fatty acids.

D-glucitol, a small (MW 182.2 g/mol), polar water-soluble substance (log Pow -2.2), will be distributed in aqueous fluids by diffusion through aqueous channels and pores and oxidized by L-iditol dehydrogenase to fructose which is subsequently metabolized by the fructose metabolic pathway (Touster 1975).

The fatty acids are also 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).

Overall, the available information indicates that the cleavage products, D-glucitol and fatty acids distribute in the organism.

Metabolism

Sorbitan tristearate is a Sorbitan fatty acid ester. Esters are known to hydrolyse into carboxylic acids and alcohols by esterases (Fukami and Yokoi, 2012).Therefore it is expected that the test substance hydrolyses to D-glucitol and the respective fatty acids under physiological conditions. 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 that 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).

For the second cleavage product D-glucitol it was found, that it is relatively slowly absorbed from the gastro-intestinal tract compared with glucose and that it can be metabolized by the intestinal microflora (Senti 1986). Once absorbed, D-glucitol is primarily metabolized in the liver.The first step involves oxidation by L-iditol dehydrogenase to fructose which is metabolized by the fructose metabolic pathway (Touster 1975). D-glucitol does not enter tissues other than the liver and does not directly influence the metabolism of endogenous D-glucitol in other tissues (Allison 1979).

However, using the OECD toolbox Vs. 2.3, the liver metabolism simulator provided 39 potential metabolites.

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, 2008).

Due to the high molecular weight and the insolubility in water, excretion of Sorbitan tristearate via urine or bile is unlikely after oral administration.

After oral ingestion, Sorbitan fatty acid esters will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis.As the physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will be different from those of the parent substance the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2008).. However, also for both cleavage products, it is anticipated that they will be absorbed in the gastro-intestinal tract. 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 D-glucitol, being a highly water-soluble substance, will dissolve into the gastrointestinal fluids and slowly be absorbed with a subsequent metabolism to fructose in the liver by L-iditol dehydrogenase (Senti 1986, Touster 1975).Non-metabolized D-glucitol will most probably mainly be excreted via urine, due to the low molecular weight and the high water solubilty of the substance whereas non-absorbed cleavage products including fatty acids will be excreted via faeces. High amounts of D-glucitol in the intestine trigger diarrhea (Peters 1958) and de facto, diarrhea was observed in nearly all acute oral toxicity and repeated dose toxicity studies with Sorbitan fatty acid esters.

Overall, the available information indicates that metabolites of Sorbitan tristearateare excreted by the bile via the faeces (fatty acids) and via the urine (D-glucitol).

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.