Registration Dossier

Ecotoxicological information

Endpoint summary

Administrative data

Description of key information

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).

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.

 

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 (*)

Sorbitan octanoate (2:3)

290.35 - 422.66

C8 - C10

C14H26O6

C16H30O6

C22H40O7

C26H48O7

Mono-

Mono-

Di-

Di-

CAS 1338-39-2 (*)

Sorbitan laurate

346.46 – 528.76

C12 - 18

C18:1

C18H34O6

C24H46O6

C24H44O6

C30H56O7

Mono-

Mono-

Mono-

Di-

CAS 26266-57-9 (*)

Sorbitan palmitate

402.57 – 879.38

C16

C22H42O6

C54H102O8

Mono-

Tri-

CAS 1338-41-6 (*)

Sorbitan stearate

402.57 – 981.56

C16 - C18

C22H42O6

C24H46O6

C54H102O8

C60H116O9

Mono-

Mono-

Tri-

Tri-

CAS 1338-43-8 (#)

Sorbitan oleate

428.60

C18:1

C24H44O6

Mono-

CAS 71902-01-7 (*)

Sorbitan isooctadecanoate

430.62 – 963.54

C18 iso

C24H46O6

C42H80O7

C60H114O8

Mono-

Di-

Tri-

CAS 8007-43-0 (*)

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

679.04 - 957.49

C18:1

C41H74O7

C60H108O8

Di-

Tri-

CAS 26658-19-5 (*)

Sorbitan tristearate

879.38 – 981.56

C16 - 18

C54H102O8

C60H116O9

Tri-

Tri-

CAS 26266-58-0 (*)

Anhydro-D-glucitol trioleate

957.49

C18:1

C60H108O8

Tri-

CAS 50-70-4 (+)

D-glucitol

182.17

--

--

 

CAS 124-07-2 (+)

Octanoic acid

144.21

--

--

 

CAS 112-85-6 (+)

Docosanoic acid

340.59

--

--

 

(*) 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 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 estersin vitroand 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 a 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

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 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).

The ecotoxicological parametersfor the aquatic toxicity of the Sorbitan esters category are presented in the following table:

CAS No.

Short-term toxicity to fish

Long-term toxicity to fish

Short-term toxicity to aquatic invertebrates

Long-term toxicity to aquatic invertebrates

Toxicity to aquatic algae

Toxicity to microorganisms

91844-53-0 (*)

LC50 (96 h) > 100 mg/L

 

Waiving

EC50 (2d) = 39 mg/L

NOELR (21d) = 10 mg/L

ErC50 (72h)= 46.5 mg/L

NOEC(72h) = 3.2 mg/L

NOEC = 100 mg/L (biodegradation tox control)

1338-39-2 (*)

 

LC50 (96h) > 100 mg/L

 

Waiving

LL50 (96h) = 452.84 mg/L

 

RA: CAS 91844-53-0

RA:CAS 1338-41-6

RA: CAS 8007-43-0

EL50 (72h) = 17.89 mg/L

 

EC50 (3h) > 100 mg/L

 

26266-57-9 (*)

RA: CAS 1338-41-6

Waiving

RA: CAS 1338-41-6

 

RA: CAS 1338-41-6

RA: CAS 1338-41-6

RA: CAS 1338-39-2

RA: CAS 71902-01-7

RA: CAS 91844-53-0

1338-41-6 (*)

 

LL50 (96 h) > 1000 mg/L

Waiving

EL50(48h) > 1000 mg/L

NOELR (21d) = 16 mg/L

EL50(72h) > 1000 mg/L

NOELR(72h) = 560 mg/L

RA: CAS 1338-39-2

RA: CAS 71902-01-7

RA: CAS 91844-53-0

1338-43-8 (*)

 

--

--

LL50 (48 h) > 10000 mg/L

--

--

--

71902-01-7 (*)

RA: CAS 1338-41-6

Waiving

EC50 (48h) > 0.43 mg/L (highest attainable conc.)

RA: CAS 1338-41-6

RA: CAS 1338-41-6

NOEC = 14.1 mg/L (biodegradation tox control)

8007-43-0 (*)

LL50(96h) > 3200 mg/L

Waiving

LL50(48h) = 7756 mg/L

NOEC = 0.11 mg/L (highest attainable conc.)

EL50(72h) = 1916 mg/L

RA: CAS 1338-41-6

RA: CAS 1338-39-2

RA: CAS 71902-01-7

RA: CAS 91844-53-0

26658-19-5 (*)

RA: CAS 1338-41-6

Waiving

RA: CAS 1338-41-6

RA: CAS 1338-41-6

RA: CAS 8007-43-0

RA: CAS 1338-41-6

RA: CAS 1338-39-2

RA: CAS 71902-01-7

RA: CAS 91844-53-0

26266-58-0 (*)

RA: CAS 1338-41-6

RA: CAS 8007-43-0

Waiving

RA: CAS 8007-43-0

RA: CAS 1338-43-8

RA: CAS 8007-43-0

RA: CAS 8007-43-0 and 1338-41-6

RA: CAS 1338-39-2

RA: CAS 71902-01-7

RA: CAS 91844-53-0

(*) 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

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

Short-term aquatic toxicity data is available for all trophic levels within the Sorbitan esters category. Long-term data is available for aquatic invertebrates and algae. Based on the experimental data, the toxicity of the Sorbitan esters category members to aquatic organisms is low. Additionally, the exposure concentrations of aquatic organisms are expected to be very low, due to the efficient removal of Sorbitan esters in sewage treatment plants by ready biodegradation. Most of the substances are also poorly water soluble and sorptive, which further contributes to their removal from waste water. The toxicity of Sorbitan esters to aquatic organisms was shown to be low in both short and long term studies.

Short term toxicity to fish

The assessment of short-term toxicity to fish for the category members is based on four reliable standard studies conducted with Sorbitan laurate (CAS No. 1338-39-2), Sorbitan, octanoate (2:3) (CAS No. 91844-53-0), Sorbitan stearate (CAS No. 1338-41-6) and Sorbitan, (Z)-9-octadecenoate (2:3) (CAS No. 8007-43-0). The first three studies were conducted with freshwater organisms and the last one with marine fish. No effects were observed in any of the four studies. Since the available studies cover the variability of the category with different fatty acids and water solubilities, all data gaps can be filled by interpolation, and it can be concluded that the toxicity potential of Sorbitan esters to fish is very low.

Long term toxicity to fish

There are no long-term fish studies available for the Sorbitan esters category. However, short-term studies available for fish, daphnia and algae, all indicate a low potential for aquatic toxicity. Moreover NOECs obtained from algal growth studies and daphnia reproduction studies are clearly above 1 mg/L or above the limit of water solubility in the entire category. 

Additionally, the aquatic concentrations of these substances are expected to be very low. All substances are regarded as readily biodegradable and are thus assumed to be eliminated in sewage treatment plants to a high extent. For the larger substances, high adsorption potential further promotes rapid removal from waste water. If fractions of these chemicals were to be released in the aquatic environment, the concentration in the water phase will be reduced by rapid biodegradation and potential of adsorption to solid particles and to sediment. If exposure would occur, food ingestion is likely to be the main uptake route of the Sorbitan esters category members in fish, since the substances will be adsorbed to solid particles potentially ingested by fish. In the case of ingestion, category members are predicted to undergo metabolism. Esters are known to hydrolyse into carboxylic acids and alcohols by esterases (Fukami and Yokoi, 2012). Carboxylesterase activity has been noted in a wide variety of tissues in invertebrates as well as in fish (Leinweber, 1987; Soldano et al, 1992; Barron et al., 1999, Wheelock et al., 2008). Therefore, it is expected that under physiological conditions, members of the Sorbitan esters category will hydrolyse to D-glucitol and the respective fatty acids. The hydrolysis of Sorbitan fatty acid esters occurs within a maximum of 48h for mono-, di- and triesters (Croda 1951, Mattson and Nolen 1972, Treon 1967, Wick and Joseph 1953). The resulting fatty acids are either metabolised via the β-oxidation pathway in order to generate energy for the cell or reconstituted into glyceride esters and stored in the fat depots in the body (Berg, 2002). Larger Sorbitan fatty acid esters that will not be hydrolysed, such as hexaesters, are unlikely to cross biological membranes due to their high molecular weight. Metabolic pathways in fish are generally similar to those in mammals. Lipids and their constituents, fatty acids, are in particularly a major organic constituent of fish and play a major role as source of metabolic energy in fish for growth, reproduction and mobility, including migration (Tocher, 2003). D-glucitol is primarily metabolised in the liver. The first step of its metabolism involves oxidation by L-iditol dehydrogenase to fructose, which is metabolised by the fructose metabolic pathway (Senti, 1986). D-glucitol is naturally found inapples, pears, peaches and prunesand several berries as well as in seaweed and algae (FDA, 1972;Griffin and Lynch 1968, Informatics Inc. 1972).

In conclusion, Sorbitan esters category members will be mainly taken up by ingestion and are digested through common metabolic pathways, providing a valuable energy source for the organism, as dietary fats and sugars. Long-term toxic effects on fish are therefore not to be expected.

Short term toxicity to aquatic invertebrates

The assessment of short-term toxicity of the Sorbitan esters to aquatic invertebrates is based on six reliable standard freshwater and marine studies. No effects were observed for the poorly soluble substances Sorbitan strearate (CAS No. 1338-41-6), Sorbitan isooctadecanoate (CAS No. 71902-01-7) and Sorbitanoleate (CAS No. 1338-43-8). The test substances Sorbitan laurate (CAS No. 1338-39-2) and Sorbitan, (Z)-9-octadecenoate (2:3) (CAS No. 8007-43-0) are poorly soluble as well, but immobilisation was observed at loading rates of LL50 453 mg/L and LL50 7756 mg/L, respectively. As the immobilisation is far above the solubility limit of both substances, undissolved material may still have been present at such high loading rates, even though these tests were performed with water accommodated fractions. The immobilisation could thus be caused by physical effects. For Sorbitan, (Z)-9-octadecenoate (2:3) a sudden increase in mortality from 0% at concentrations up to 1000 - 5600 mg/L to 100% at 10,000 mg/L was reported, and therefore no dose response curve was given. Such an effect is more likely to be caused by the amount of undissolved test material in the test solution, leading to immobilisation of the daphnia, rather than a systemic toxic effect. For the soluble substance (WS 750 mg/L), Sorbitan, octanoate (2:3) (CAS No. 91844-53-0), a low acute toxicity was obtained ( EC50 of 39 mg/L).

 Since this substance is readily biodegradable, it will be quickly removed from the environment, and potential effects will be localised and of short duration (Guidance on the application of CLP criteria v3.0, 2012). The substance is thus not classified as dangerous for the environment.

It can be concluded that for the poorly soluble category members no effects on aquatic invertebrates are expected. The toxicity of the soluble Sorbitan, octanoate (2:3) to aquatic invertebrates is low, and due to ready biodegradation, the substance is not classified as dangerous for the environment. Studies available for the short-term toxicity of Sorbitan esters to aquatic invertebrates cover the different fatty acid chain lengths, as well as the range of water solubility and log Kow of the category members. Data gaps within the category can thus be filled by interpolation.

Long term toxicity to aquatic invertebrates

The assessment of long-term toxicity to aquatic invertebrates is based on three reliable standard studies conducted with Daphnia magna. No effect on reproduction of the test organisms was observed in any of the studies. The test substances Sorbitan, octanoate (2:3) (CAS No. 91844-53-0), Sorbitan stearate (CAS No. 1338-41-6) and Sorbitan, (Z)-9-octadecenoate (2:3) (CAS No. 8007-43-0) cover the variability of the category in terms of fatty acid length, water solubility and Kow. Thus, no effects for other category members are expected.

Toxicity to algae

The assessment of toxicity of Sorbitan esters to algae is based on four reliable standard freshwater and marine studies. No effects were observed in the study carried out with Sorbitan stearate (CAS No. 1338-41-6). With Sorbitan, (Z)-9-octadecenoate (2:3) (CAS No. 8007-43-0) effects were observed, and an EC50 of 1916 mg/L is reported. However, the test concentrations were far above the solubility limit of the substance. Although the test was performed as water accommodated fractions (WAF), the presence of undissolved material cannot be excluded. With Sorbitan laurate (CAS No. 1338-39-2) an EC50 of 18 mg/L was obtained, although the results indicate rather a physical than a systemic toxic effect. Algal growth was namely stimulated compared to the control at concentrations 3.2 mg/L and 10 mg/L, but from 32 mg/L growth inhibition was 100%, i.e. no typical dose response relation could be observed. It can be concluded that for the poorly soluble category members no effects on aquatic algae are expected. For the soluble substance, Sorbitan, octanoate (2:3) (CAS No. 91844-53-0), an EC50 of 47 mg/L was obtained. Thus, the toxicity of the soluble Sorbitan, octanoate (2:3) to aquatic invertebrates is low, and due to ready biodegradation, the substance is not classified as dangerous to the environment.

The studies available for the short-term toxicity to algae of Sorbitan esters cover the different chain lengths and water solubilities and log Kow of the category members. Data gaps within the category can thus be filled by interpolation.

Toxicity to microorganisms                                                              

The assessment of toxicity of Sorbitan esters to microorganisms is based on one standard microorganism study (OECD Guideline 209) and two toxicity controls of standard ready biodegradation studies. In the OECD 209 test conducted with Sorbitan laurate (CAS No. 1338-39-2) no effect on the respiration rate of activated sludge was observed. The toxicity controls available for biodegradation studies for Sorbitan, octanoate (2:3) (CAS No. 91844-53-0) and Sorbitan isooctadecanoate (CAS No. 71902-01-7) showed no toxicity to microorganisms either. It can be concluded that no effects on the STP microorganism community and the subsequent degradation process in sewage treatment plants is expected.

The available studies cover the different chain lengths and the range of water solubility and log Kow of the category members. Data gaps within the category can thus be filled by interpolation.

General conclusion

Finally, the data available on aquatic toxicity for the Sorbitan esters category show a clear, consistent pattern of low toxicity to aquatic organisms for smaller soluble category members and no effects up to the limit of water solubility for the larger substances. The available studies cover the variability of the category in terms of chain length, structure and physico-chemical properties. Data gaps were covered by read-across, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 Grouping of substances and read-across. Read-across substances were chosen based on the similarity of the molecular structure and of physico-chemical properties. Smaller molecular size and higher water solubility were considered worst case, due to higher bioavailability. The category includes one substance with branched fatty acids, Sorbitan, isooctadecanoate. However, the branching only consists of a methyl group at the penultimate carbon atom (iso-structure) and is thereby not relevant for steric hindrance of biochemical processes (Matsumoto et al., 1976; Mao et al., 1995), and does not lead to differences in the relevant physico-chemical properties. This substance is also readily biodegradable as all other Sorbitan esters category members. The iso-structure is thus not considered relevant for read-across for aquatic toxicity. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

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