Reaction products resulting from the esterification of Sorbitol with C8 – 18 (even) and C18 unsaturated fatty acids in the ratio of 1:1

Endpoint summary

Additional information

Justification for grouping of substances and read-across

The Sorbitan esters category is a series of analogous esters consisting 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).  For the category member Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 (EC 931-434-7), which has already been subject to registration in Phase I, the UVCB name has been used as proposed by the respective lead registrant.

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.

 

Table: Members of the sorbitan esters category

CAS	EC name	Molecular weight (g/mol)	Fatty acid chain length	Molecular formula	Degree of esterification
CAS 91844-53-0 (a)	Sorbitan octanoate (2:3)	290.35 - 422.66	C8 - C10	C14H26O6 C16H30O6 C22H40O7 C26H48O7	Mono- Mono- Di- Di-
CAS 1338-39-2 (a)	Sorbitan laurate*	346.46 – 528.76	C12 - 18 C18:1	C18H34O6 C24H46O6 C24H44O6 C30H56O7	Mono- Mono- Mono- Di-
no CAS (b)	Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1*	346.46 – 528.76	C12 - 18 C18:1	C18H34O6 C24H46O6 C24H44O6 C30H56O7	Mono- Mono- Mono- Di-
CAS 26266-57-9 (a)	Sorbitan palmitate	402.57 – 879.38	C16	C22H42O6 C54H102O8	Mono- Tri-
CAS 1338-41-6 (a)	Sorbitan stearate	402.57 – 981.56	C16 - C18	C22H42O6 C24H46O6 C54H102O8 C60H116O9	Mono- Mono- Tri- Tri-
CAS 1338-43-8 (b)	Sorbitan oleate	428.60	C18:1	C24H44O6	Mono-
CAS 71902-01-7 (a)	Sorbitan isooctadecanoate	430.62 – 963.54	C18 iso	C24H46O6 C42H80O7 C60H114O8	Mono- Di- Tri-
CAS 8007-43-0 (a)	Sorbitan, (Z)-9-octadecanoate (2:3)	679.04 - 957.49	C18:1	C41H74O7 C60H108O8	Di- Tri-
CAS 26658-19-5 (a)	Sorbitan tristearate	879.38 – 981.56	C16 - 18	C54H102O8 C60H116O9	Tri- Tri-
CAS 26266-58-0 (a)	Anhydro-D-glucitol trioleate	957.49	C18:1	C60H108O8	Tri-
CAS 50-70-4 (c)	D-glucitol	182.17	--	--
CAS 124-07-2 (c)	Octanoic acid	144.21	--	--
CAS 112-85-6 (c)	Docosanoic acid	340.59	--	--

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

(b) 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.

(c) 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.

* Sorbitan laurate (CAS 1338-39-2) and Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 (EC 931-434-7) are identical substances, only differing in the naming as decided by their respective lead registrants. Therefore, all study reports and publications on Sorbitan laurate were equally used for hazard assessment of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1. However, for reasons of simplification, the naming of Sorbitan laurate has not been changed in the respective parts of the dossier and is used synonymously for Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1.

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 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 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 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 tri-esters of short- and long-chain fatty acids are solids. All category members are non-volatile (vapour pressure: < 0.0001 Pa). 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.

a)  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 and 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).

Table: Environmental fate parameters of the Sorbitan Esters category

CAS	Phototransformation in air [DT50, 24 h day]	Hydrolysis [DT50, pH 7]	Biodegradation: screening tests	BCF/BAF [L/kg] (Arnot-Gobas)	Adsorption [log Koc] (MCI)
CAS 91844-53-0 (a)	6.9 - 8.5 h	> 1 yr	Readily biodegradable	1.1 - 12.5 / 1.1 - 12.5	1.0 - 2.8
CAS 1338-39-2 (a) *	2.1 - 7.1 h	> 1 yr	RA: CAS 1338-41-6 RA: CAS 1338-43-8	1.3 - 36.5 / 1.3 - 36.5	1.8 - 3.9
No CAS EC 931-434-7 (b)*	2.1 - 7.1 h	> 1 yr	RA: CAS 1338-41-6 RA: CAS 1338-43-8	1.3 - 36.5 / 1.3 - 36.5	1.8 - 3.9
CAS 26266-57-9 (a)	4.4 - 6.4 h	> 1 yr	RA: CAS 1338-41-6	0.9 - 18 / 0.9 - 18	2.9 - > 10
CAS 1338-41-6 (a)	3.7 - 6.4 h	> 1 yr	Readily biodegradable	0.9 - 27 / 0.9 - 27	2.9 - > 10
CAS 1338-43-8 (b)	--	--	Readily biodegradable	--	--
CAS 71902-01-7 (a)	4.0 - 6.1 h	> 1 yr	Readily biodegradable	0.9 - 25.4 / 0.9 - 25.4	3.3 - > 10
CAS 8007-43-0 (a)	1.4 - 2.1	> 1 yr	RA: CAS 26266-58-0	0.9 / 0.9	6.8 - > 10
CAS 26658-19-5 (a)	3.7 - 4.4	> 1 yr	RA: CAS 1338-41-6 RA: CAS 26266-58-0	0.9 / 0.9	> 10
CAS 26266-58-0 (a)	1.4 - 1.5	> 1 yr	Readily biodegradable	0.9 / 0.9	> 10

(a) Category members subject to registration are indicated in bold font.

(b) Substances not subject to registration are indicated in normal font.

* Sorbitan laurate (CAS 1338-39-2) and Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 (EC 931-434-7) are identical substances, only differing in the naming as decided by their respective lead registrants. Therefore, all study reports and publications on Sorbitan laurate were equally used for hazard assessment of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1. However, for reasons of simplification, the naming of Sorbitan laurate has not been changed in the respective parts of the dossier and is used synonymously for Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1.

Lack of data for a given endpoint is indicated by “--“.

Environmental fate and pathways

Experimental studies confirmed that all members of the Sorbitan esters category are readily biodegradable according to the OECD criteria (71 - 91% biodegradation after 28 d). Therefore, the category members will not be persistent in the environment. The degradation via abiotic hydrolysis is not considered to be a relevant degradation pathway in the environment since QSAR calculations using HYDROWIN v2.00 resulted in DT50 > 1 yr at pH 7. Evaporation into air and the transport through the atmospheric compartment is not expected, since all category members are not volatile based on the low vapour pressure.

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. 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.

Bioaccumulation is not expected for members of the Sorbitan esters category, due to low exposure (low solubility and ready biodegradation) and their digestion by common metabolic pathways (Berg et al., 2002; Wick, 1953; Tocher, 2003). Enzymatic breakdown will initially lead to the free fatty acid and anhydrides of sorbitan. From literature it is well known, that these hydrolysis products will be metabolised and excreted in fish effectively (Heymann, 1980; Lech & Bend, 1980; Lech & Melancon, 1980; Murphy & Lutenske, 1990). This is supported by low calculated BCF values of 0.9 - 36.5 L/kg ww (BCFBAF v3.01, Arnot-Gobas, including biotransformation, upper trophic). Please refer to IUCLID Section 5.3 for a detailed overview on bioaccumulation of the Sorbitan esters category members.

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