Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion: not irritating
Eye irritation: not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

The Sorbitan fatty acid esters category covers fatty series of analogous esters comprised of Sorbitan 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 Table 1 and their composition is defined in IUCLID Section 1.2. The naming of the substances is in accordance with the European Pharmacopeia (2011), except 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), for which the UVCB name has been used.

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 Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

 

Overview of Irritation / corrosion

CAS

EC number

EC name

Skin corrosion/irritation

Eye corrosion/irritation

91844-53-0 (a)

215-665-4

Sorbitan octanoate (2:3)

Experimental result:
not irritating

Experimental result:
not irritating

1338-39-2

215-633-3

Sorbitan laurate*

WoE:
Experimental result:
not irritating (human)
RA: CAS 1338-41-6

WoE:
Experimental result:
not irritating

no CAS (b)

931-434-7

Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1*

WoE:
Experimental result:
not irritating (human)
RA: CAS 1338-41-6

WoE:
Experimental result:
not irritating

26266-57-9

247-568-8

Sorbitan palmitate

Experimental result:
not irritating

WoE:
RA: CAS 91844-53-0
RA: CAS 26266-58-0

1338-41-6

215-664-9

Sorbitan stearate

Experimental result:
not irritating

WoE:
Experimental result:
not irritating

71902-01-7

276-171-2

Sorbitan isooctadecanoate

Experimental result:
not irritating

Experimental result:
not irritating

8007-43-0

232-360-1

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

Experimental result:
not irritating

Experimental result:
not irritating

26658-19-5

247-891-4

Sorbitan tristearate

WoE:
Experimental result:
not irritating
RA: CAS 26266-58-0
RA: CAS 1338-41-6

WoE:
RA: CAS 26266-58-0
RA: CAS 1338-41-6

26266-58-0

247-569-3

Sorbitan trioleate (Anhydro-D-glucitol trioleate)

Experimental result:
not irritating

Experimental result:
not irritating

(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.

* Sorbitan laurate and Reaction products resulting from the esterification of Sorbitol with C8-18 (even) and C18unsaturated fatty acids in the ratio 1:1 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.

Skin irritation

Sorbitan octanoate (2:3) was investigated in a GLP-compliant skin corrosion/irritation study performed according to OECD 404 (Hey 2008). 0.5 mL of the unchanged test substance was applied to approximately 6 cm² shaved skin of New Zealand rabbits (2 females and 1 male) with a gauze patch under semi-occlusive conditions for 4 h. After removal of the gauze patch and subsequent washing, the reaction of the treated skin site was evaluated at 1, 24, 48, and 72 h after patch removal. No signs of skin corrosion or irritation were observed. The mean score for edema and erythema over 24, 48, and 72 h was determined as 0 for each test animal. Therefore, the test substance was considered as not irritating under the test conditions chosen.

For Sorbitan laurate, a weight of evidence approach comprising animal and human data was chosen for the hazard assessment of skin irritation properties as the available animal studies are considered as unreliable due to incomplete documentation. In detail, irritating effects of Sorbitan laurate were observed after repeated application of 1-100% test substance over 30 days (Mezei 1966) whereas 10 or 50% Sorbitan laurate did not induce skin irritation after repeated application over a shorter time period of 10 days (Potokar 1983). Moreover, human volunteers revealed no signs of skin irritation after application of Sorbitan laurate undiluted or as a 30% aqueous solution (Croda 1959, 1946). Taken all these data into consideration, Sorbitan laurate is not regarded as skin irritant. Further, Sorbitan stearate, which may be considered as source substance for Sorbitan laurate as it comprises Sorbitan esterified with stearic (C18) instead of lauric acid (C12), did not reveal irritating properties in an in vivo study (see further down). This result supports the conclusion that Sorbitan laurate does not exhibit skin irritating properties.

Sorbitan palmitate was investigated in a skin irritation/corrosion study, which was performed equivalent to OECD 404 (Stearinerie 1987). 0.5 g of the unchanged test substance was applied to the intact and abraded skin of 6 New Zealand male rabbits under occlusive conditions for an exposure period of 24 h. Observation of the treated skin sites was done after 24 and 72 h. A mean edema score of 0 and a mean erythema score of 0.45, the latter reversed within 72 h, was calculated for the intact skin sites. Furthermore, an in vivo study performed with 50% test substance concentration (Treon 1963) and tests in humans with either 30 or 50% Sobitan plamitate (Durfee 1946, Schwartz 1959a/b) or cosmetic products containing 4% test substance (Elder 1985) indicated no irritating effects of the test substance.

The irritation/corrosion potential of Sorbitan stearate was investigated in a study performed equivalent to OECD 404 (Baker 1976). 0.5 g of the unchanged test substance was applied to the intact and abraded skin of 6 albino rabbits under semi-occlusive conditions for an exposure period of 4 h. The skin sites were observed at 4, 24, and 72 h. A mean edema score of 0 and a mean erythema score of 0.3, the latter reversed within 72 h, was calculated for the intact skin sites. Two further in vivo studies (Baker 1977, Wanderer 1963) were conducted with 30% test substance. Both revealed no irritating potential in rabbits. Furthermore, three study reports and publications with a reliability of 4 are available in which test substance concentrations varying between 25 and 60% were applied to the skin of rabbits or mice. None of these studies indicated irritating properties of Sorbitan stearate (Potokar 1984, Mezei 1966, Treon, 1963). These findings are supported by investigations in humans, where 10 and 30% test substance did not induce skin reactions in the volunteers (Cutest 1992, Pasche-Koo 1994, Schwartz 1959, Durfee, 1946).

Sorbitan isooctadecanoate was investigated in an in vitro skin corrosion study similar to OECD 431. The evaluation of cell viability in a human skin model (Skin Topical Testing Model ZK1300) by MTT after exposure to the undiluted test material revealed a reduction in cell viability to 58% after 2 h, thereby indicating no corrosive properties of the test substance (Nitka 1993). Further, the substance was investigated in vivo in a study similarly performed to OECD 404 (Kynoch and Liggett 1977). The test substance (0.5 mL) was applied unchanged to the intact and abraded skin of six albino rabbits under occlusive conditions for an exposure period of 24 h. Examinations of the treated skin sites were made immediately after removal of the patch and 72 h post-exposure. Mean edema and erythema score were 0.94 and 1.78, respectively, calculated over 24, 48, and 72 h. Under the test conditions chosen, the test substance was considered as not irritating. Two further reports revealed moderate or no irritating properties of the test substance in rabbits (CIR 2002a/b). Due to the very poor documentation, these reports were not further taken into consideration for hazard assessment.

For Sorbitan, (Z)-9-octadecenoate (2:3) a study performed similar as to guideline OECD 404 is available, but without details on individual irritation parameters (Rzucidlo 1972). 0.5 mL of the unchanged test substance were applied to the intact and abraded skin of 6 New Zealand rabbits under semi-occlusive conditions for an exposure period of 24 h. Treated skin sites were immediately examined after removal of the patch and 72 h post-exposure. Mean edema and erythema score were 0.78 and 1.89, respectively, calculated over 24, and 72 h, so that the test substance was considered as not irritating under the test conditions chosen. Further in vivo studies performed in mice and rabbits with 5, 10 and 50% test substance concentration, respectively, also showed no irritating properties after repeated application (10 to 20 days) of the test substance (Potokar 1984, Uniqema 2002). Neither human patch tests with 10, 30 and 100% test substance concentration, respectively, revealed any irritating properties (Pasche-Koo 1994, Schwartz 1959, Uniqema 2002).

For Sorbitan tristearate, two in vivo studies with a reliability of 3 and 4 were taken into consideration for hazard assessment in a weight of evidence approach together with human data. No corrosive or irritating effects of the test substance were determined after single application of 30 and 40% test substance to rabbit skin (Treon 1963, Rzucidlo 1967). A similar observation is reported, when the test substance was tested in humans at 40% test substance concentrations (Elder 1985, Osbourn 1967). Furthermore, skin irritating properties of Sorbitan tristearate were predicted by interpolation of data from other category members taken as source substances. In particular, Anhydro-D-glucitol trioleate, being the most complex substance of the category, and Sorbitan stearate, the smallest substance of the category, were chosen. For both source substances, no irritating properties were found in the respective in vivo skin irritation tests (see above and further down).

A GLP compliant OECD 404 guideline study (Harlan, 2012) was performed with Anhydro-D-glucitol trioleate (Sorbitan trioleate). 0.5 mL of the unchanged substance was applied to the clipped skin of two New Zealand white rabbits with a 2.5 x 2.5 cm gauze patch under semi-occlusive conditions for an exposure period of 4 hours. At the end of the exposure period, the gauze patch was removed, the skin site was washed and immediately examined. The evaluation of irritant effects was performed at 1, 24, 48 and 72 h after patch removal. No signs of skin corrosion or irritation were observed. Mean edema and erythema scores over 24, 48, and 72 h were 0, so that the test substance was considered as not irritating under the test conditions chosen. Further data revealed mildly irritating properties of the test substance (Treon 1963, Mezei 1966). However, due to limited documentation, these reports were considered as unreliable with a reliability of 4 and were therefore nor further taken into account for hazard assessment.

Eye irritation

The eye irritation potential of Sorbitan octanoate (2:3) was investigated in vitro in an HET-CAM assay(Weimans 2008). 200 µL of the unchanged test substance were applied to the chorioallantoic membrane (CAM) of fertilised 9 days old chicken eggs. The blood vessels of the CAM were examined 0.5, 2 and 5 minutes after application and every observed reaction (haemorrhage, lysis, coagulation) was noted. Of the total possible scores of 21 a value of 3.83 was evaluated on the CAM, indicating a slightly irritating potential of the test substance. Further,an in vivo eye corrosion/irritation study performed according to OECD 405 under GLP conditions was performed (Hey 2008). 0.1 mL of the unchanged test substance was applied in the conjunctival sac of one eye each of three New Zealand rabbits. The untreated eye served as control. 1, 24, 48, and 72 h after test substance instillation, the grades for conjunctivae, cornea and iris were recorded. The following mean values for all animals were evaluated for the 24, 48, 72 h time window: cornea/iris score 0, chemosis score 0.33 (fully reversible within 48 h), conjunctivae score 0.67 (fully reversible within 7 days). Under the conditions chosen for the test, the test substance was considered to be not irritating to eyes.

Sorbitan laurate was investigated in an eye irritation study performed similar to OECD 405 in which a test substance concentration of merely 10% was applied into the eyes of 6 rabbits each (Potokar 1983). The untreated eye served as control and observations were made 1, 24, 48, and 72 h post-exposure. Overall irritation results for all animals over the 24, 48, and 72h reading time points were calculated as 0 for cornea, iris and chemosis score. The conjunctivae score revealed a value of 0.17. As the effects on conjunctivae were reversible within 36 h, no irritating potential of the test substance was evaluated. In combination with four further poorly documented in vivo studies in which no details on individual irritation parameters after instillation of 30 to 100% test substance concentration were reported, Sorbitan laurate was considered as not irritating to eyes (Hazleton 1952, Iacono 1965 a/b, Draize 1952).

Eye irritating properties of Sorbitan palmitate were predicted by interpolation of data from other category members taken as source substances as no reliable data on eye irritation for Sorbitan palmitate is available. The target substance predominantly contains a C16 fatty acid. Therefore, Sorbitan octanoate (2:3) containing a shorter chain (C8) and the most complex substance of the category (Anhydro-D-glucitol trioleate, C18:1) were chosen. For both source substances, no eye irritating properties were found in the respective in vivo tests (see above and further down). For Sorbitan palmitate itself, two in vivo studies conducted with a test substance concentration of only 30% revealed no signs of eye irritation (cornea, iris, conjuctivae and chemosis scores of 0). Since both reports were of poor quality due to limited documentation, they were not further taken into consideration of hazard assessment.

The eye irritating potential of Sorbitan stearate was evaluated in a study similarly performed to OECD 405 (Munfus 1977 a). 0.1 mL of the unchanged test substance was applied to the rabbit eyes of six animals. 1, 24, 48, 72, 96 h and 7 days later, the animals eyes were examined for ocular effects. The mean irritation scores over all animals calculated with the 24, 48 and 72 h reading time points were as follows: cornea score 0.2, iris score 0, conjunctivae score 0.2 and chemosis score 0.2. The effects were fully reversible within 7 days. Therefore the substance was considered as not eye irritating. This finding is supported by the results of several studies performed with 30 to 100% test substance concentration in the rabbit (Croda 1965, Aigast 1977c/1975 a/b, Baker 1977 b/d, Potokar 1984, Treon 1963).

Sorbitan isooctadecanoate was investigated in an in vivo eye corrosion/irritation study performed according to guideline CFR 16, 1500.42 (Kynoch and Liggett 1977). 0.1 mL of the unchanged test substance was applied in one eye each of six New Zealand rabbits. The untreated eye served as control. 1, 2, 3, 4, and 7 days after test substance instillation, the grades of ocular reaction (including effects on conjunctivae, cornea and iris) were recorded. The following mean values for all six animals were evaluated as mean over 24, 48, and 72 h: cornea/iris score 0, chemosis score 0.056 (fully reversible within 4 days), conjunctivae score 0.72 (fully reversible within 4 days). Under the conditions chosen for the test, the test substance was considered to be not irritating to the eyes.

An eye irritation guideline-study was conducted with Sorbitan, (Z)-9-octadecenoate (2:3) equivalent to the Appraisal of the AFDO, USA (1959). 0.1 mL of the unchanged test substance was applied into one eye of nine rabbits (Wanderer 1963). The untreated eye served as control. Reading points for ocular reactions were 1h post treatment and 1, 2, 4 and 7 days thereafter. No effects on cornea, iris, and conjunctivae were observed (mean scores for all 6 animals over 24, 48, 72 h: 0). In the report, no data on chemosis were given. These findings were supported by results of Mellman (1973) and by reports of minor quality from Potokar (1984) and Iacono (1965), in which 10 or 30% test substance did not exhibit eye irritating potency. Thus, all these data lead to the conclusion that the compound is not irritation to the eye.

Eye irritating properties of Sorbitan tristearate were predicted by interpolation of data from other category members taken as source substances. The target substance predominantly contains C18 stearic acid (tristearate). Therefore, Sorbitan stearate, as C18 monoester, and the most complex substance of the category (Anhydro-D-glucitol trioleate, C18:1) were chosen. For both source substances, no eye irritating properties were found in the respective in vivo tests (see above and further down). No reliable data on eye irritation is available for the target substance. Sorbitan tristearate itself induced overall irritation scores of 0 for cornea, iris and conjuctivae when tested at concentrations of 30 and 40% (Treon 1963, Wanderer 1963, Rzucidlo 1967). Since these reports were of poor quality due to limited documentation, they were not further taken into consideration of hazard assessment.

For Anhydro-D-glucitol trioleate (Sorbitan trioleate) an OECD 405 guideline study was performed under GLP conditions (Harlan, 2012). 0.1 mL of the unchanged test substance was applied to the eyes of two New Zealand white rabbits. 1, 24, 48 and 72 h later, the animal's eyes were examined for ocular effects. The mean irritation scores over all animals calculated for the 24, 48 and 72 h reading time points were as follows: cornea score 0, iris score 0, conjunctivae score 0.15 and chemosis score 0. Conjunctival redness was fully reversible within 48 hours. Therefore the substance was considered as not eye irritating. In addition, eye irritation tests with 30% test substance showed no irritating potential of the test substance (Iacono 1965 a/b), thereby supporting that the test substance does not exhibit eye irritation properties.

Overall conclusion for skin and eye irritation

Based on the available and reliable in vitro and in vivo skin irritation studies performed with Sorbitan fatty acid esters, the category members were not considered to be skin irritating.

The available and reliable in vitro and in vivo studies on eye irritation of Sorbitan fatty acid esters, the category members were not considered as eye irritating.

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

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the Sorbitan fatty acid esters category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, all available data on skin and eye irritation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.