Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
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 naming of the substances is in accordance with the European Pharmacopeia (2011).

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.

Sensitisation data of the Sorbitan fatty acid esters category:

CAS

EC name

Skin sensitisation

91844-53-0

Sorbitan octanoate (2:3)

not sensitising

1338-39-2

Sorbitan laurate

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

26266-57-9

Sorbitan palmitate

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

1338-41-6

Sorbitan stearate

 RA: CAS 26266 -58 -0

71902-01-7

Sorbitan isooctadecanoate

RA: CAS 26266 -58 -0

8007-43-0

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

not sensitising

26658-19-5

Sorbitan tristearate

 RA: CAS 26266 -58 -0

26266-58-0

Anhydro-D-glucitol trioleate

not sensitising

 

Sensitising properties of Sorbitan octanoate (2:3) were investigated in a GLP-compliant GPMT performed according to OECD 406. Therefore, 10 guinea pigs were treated with the following concentrations of the test substance diluted in peanut oil: 5% for intradermal induction, 100% for epidermal induction and challenge. At challenge, no signs of sensitisation were determined in the test and negative control group. The positive control (50% 4-aminobenzoic acid in Vaseline) induced the expected result thereby validating the study. Therefore, sorbitan octanoate (2:3) was not considered as sensitising (Marburger 2006).

Skin sensitising properties of Sorbitan laurate were predicted by interpolation of data from other category members taken as source substances. The target substance predominantly contains a C12 fatty acid (lauric acid). Therefore, Sorbitan octanoate (2:3) with a shorter chain (C8) and the most complex substance of the category (Anhydro-D-glucitol trioleate, C18:1) were chosen as read-across substances. For both source substances, no sensitising properties were found in the respective in vivo tests (see above and further down). No reliable data on sensitisation for Sorbitan laurate itself is available. Particularly, one study of minor quality (RL3) is available in which no sensitising potential was determined in two guinea pigs after repeated intracutaneous injections for ten times at a concentration of 0.1%. In addition, QSAR analysis (Danish EPA, 2010) predicted no sensitising effects for Sorbitan laurate. Further, poorly documented reports on human patch tests with 30 and 100% test substance concentration(Durfee 1946, Schwartz), as well as a retrospective European survey of allergic contact reactions to cosmetics revealed no sensitising effects (Goossens 1999). Hence, based on the data of the target and the source substances, Sorbitan laurate is considered to not be skin sensitising.

 

Sorbitan palmitate mainly contains C16 palmitic acid. Assessment of the skin sensitising properties of this target substance was mainly performed by interpolation of data from Sorbitan octanoate (2:3) containing a shorter chain (C8) and the most complex substance of the category (Anhydro-D-glucitol trioleate, C18:1). For both source substances, no sensitising properties were found in the respective in vivo tests (see above and further down). For the target substance, two human patch tests are available performed with a test substance concentration of 50%. In detail, 50 volunteers were initially treated for 3 days and challenged for 3 days, 7 days after removal of the initial patch. No sensitising effects were observed (Schwartz 1959a/b). Likewise, a patch test with 30% test substance applied to 10 volunteers induced no sensitising potential (Durfee 1946). Hence, based the data of the target and the source substances, Sorbitan palmitate is considered to not be skin sensitising.

Skin sensitising properties of Sorbitan stearate were predicted by read-across to Anhydro-D-glucitol trioleate, the most complex substance of the category (C18:1). No sensitising properties were found for the source substance in the respective in vivo test (see further down). Within a study of poor quality and limited documentation (RL3), the target substance Sorbitan sterate itself was intracutaneously applied to two guinea pigs for ten times at a concentration of 0.1%, revealing no sensitising potential (Atlas Powder Company 1951). In two tests performed with a 30% aqueous solution of Sorbitan stearate, with an initial and a challenge application in 50 and 10 volunteers, respectively, no sensitising effects were observed (Schwartz 1959, Durfee 1946). In a human patch test performed on 1200 eczema patients with common emulsifiers including 5% Sorbitan stearate, no sensitising effects were observed (Hannuksela 1976). Hence, based the data of the target and the source substance, Sorbitan stearate is considered to not be skin sensitising.

Sorbitan isooctadecanoate was investigated for sensitising properties in two studies considered as unreliable due to poor quality and very limited documentation (RL4). In the first study, four GPMTs were conducted with intradermal induction of concentrations of 1-2% were performed revealing “a very low sensitisation potential” (Lanigan 2002). The effect was not further defined and no individual parameters were given. In the second test, a Landsteiner guinea pig test, an intradermal induction of 0.2% test substance resulted in no sensitisation reactions (Lanigan 2002). In a human repeated insult patch test performed with a test substance concentration of 2.5%, no sensitisation was observed in 201 volunteers (Lanigan 2002). Due to the limited data for Sorbitan isooctadecanoate, a read-across to Anhydro-D-glucitol trioleate, the most complex substance of the category, was performed for the prediction of skin sensitising properties induced by Sorbitan isooctadecanoate. No skin sensitising effects of the source substance were observed (Hazleton 2012). Hence, based the data of the target and the source substance, Sorbitan isooctadecanoate is considered as not skin sensitising.

For Sorbitan, (Z)-9-octadecenoate (2:3) human data on sensitisation is available. A human patch test was performed with 50 volunteers under occlusive conditions. The undiluted test substance was initially applied for 3 days and a challenging application for 3 days was done 7 days after removal of the initial patch. None of the volunteers showed a sensitisation reaction to Sorbitan, (Z)-9-octadecenoate (2:3) (Schwartz 1959). In 2002, Uniqema performed a study, investigating a 30% aqueous dispersion in 10 volunteers under occlusive conditions for an initial application of 5 days and a challenge of 2 days after a 10-day induction period. No reaction occured among the 10 participants following either the first or second application of the test substance. This indicates that the substance is not a skin sensitiser (Uniqema 2002). Furthermore, several publications and studies poorly documented are available. One publication included over 1200 eczema patients who were patch-tested with emulsifiers. Among these was the test substance at 20% in petrolatum, which induced an allergic reaction in 6 volunteers (0.5%) (Hannuksela 1976). In 1988, a second cohort of eczema patients was also tested with 20% test substance according to the Finn chamber method. 25 of them (0.56%) showed a positive reaction. In another study with dermatitis patients, emulsifiers were tested for their sensitising potential. The test substance at 20% in petrolatum induced a positive reaction in 7 of the 739 persons tested (Totsi 1990). Asarch and Scheinman (2008) conducted a retrospective data analysis on 112 dermatitis patients that were patch-tested with a 5 and 1% concentration of Sorbitan, (Z)-9-octadecenoate (2:3) in a fragrance mix. 12 volunteers showed a positive reaction (10.7%). All of the patients had previously used cosmetic products containing Sorbitan derivatives orD-glucitol. A further retrospective survey of allergic contact reactions showed that 3 of 475 (0.6%) subjects evaluated had a positive reaction to Sorbitan, (Z)-9-octadecenoate (2:3) (Goossens 1999). The test substance at 20% in petrolatum was also tested in children. All of them showed a positive reaction and had currently used cosmetic products containing the test substance as emulsifier (Castanedo-Tardan and Jacob 2008). Furthermore, three cases of sensitisation after contact to the test substance were described. One boy with allergic contact dermatitis to adaptic wound dressing on the basis of sensitisation to the emulsifiying test substance and another boy and a girl were described, with allergic contact dermatitis caused by the test substance, present as emulsifier in their used emollient (de Ward-van der Spek 2008). A further case report with a positive reaction to the test substance, was described for a woman with a known dermatitis, who was patch-tested with 20% test substance in petrolatum. In another study with 350 volunteers having leg ulcers, 5 (1.4%) showed a strong positive reaction of sensitisation (according to ICDRG criteria) when patch-tested with 2% of the test substance in petrolatum (Mallon and Powell 1994). In a study performed with dermatitis patients and a group of healthy volunteers, the subjects were patch-tested with a battery of emulsifiers. The test substance, applied at 10% in petrolatum, induced positive reactions in the patients, but no positive reaction was seen in the control group of 10 healthy subjects (Pasche-Koo 1994). Taken all this data into consideration, most of the positive reactions described above were observed in patients with skin diseases. Therefore, these results cannot be considered as reliable, since these subjects were probably sensitised previously by the use of cosmetic products during their course of disease. Moreover, methodological descriptions are missing, no definition what is meant by “positive reaction” was given and often the subjects were tested simultaneously with several substances or fragrances with the test substance included as emulsifier. Hence, it could be concluded that the test substance is not a sensitiser when tested in humans. This conclusion is supported by the study conducted by Schwartz 1959 (see above), were none of the 50 healthy volunteers reacted to the undiluted test substance.

Animal in vivo data on sensitisation is not available for Sorbitan tristearate. Therefore, a read-across to Anhydro-D-glucitol trioleate, the most complex substance of the category, was performed for prediction of skin sensitising properties. No skin sensitising effect of the source substance was observed (Hazleton 2012, see below). Two poorly documented reports in humans are available for Sorbitan tristearate itself. In a Schwartz prophetic patch test, 211 volunteers were tested with 40 and 100% of the test substance. Only one person treated with 40% showed a positive reaction (Croda 2002), which was not further described or graded. In the second study, 201 subjects were patch-tested with a 40% aqueous solution with an initial application for 3 days and a challenging application for 2 days (9 - 14 days after removal of initial patch) (Osbourn 1967). Only one subject showed a positive reaction to the initial closed patch, again no further description of the reaction was given. Therefore, based on the data of the target and the source substance, Sorbitan isooctadecanoate is considered to not be skin sensitising.

A guinea pig maximisation test was performed with Anhydro-D-glucitol trioleate according to OECD guideline 406 under GLP conditions (Phycher Bio Developpment 2012). The test substance was applied in olive oil for intradermal induction at a concentration of 2%, at 100% for epidermal induction and at 25, 50 and 100% for challenge and rechallenge, respectively. At challenge, irritation was observed in almost all animals of the negative control group. Therefore, only reactions in the test group animals that exceeded the most severe reactions seen in the control group animals were attributed to skin sensitisation. Hence, no sensitisation reaction was noted in animals from the treated group with the test item at 50 and 100%. In view to clarify these results, a rechallenge phase was performed with the test item diluted at 25 and 50%. No effects were then observed in the negative control group. In the test group challenged with 25 and 50% test substance, 10 and 20% of the animals, respectively, showed a positive reaction 24 h after rechallenge. After 48 h, 10% of the animals treated with 50% test substance during the rechallenge phase showed a positive reaction. The positive control (6.25 and 12.5% alpha-hexylcinnamaldehyde) induced the expected result. Therefore, Anhydro-D-glucitol trioleate was considered not to be sensitising.

Conclusion for skin sensitisation

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

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


Migrated from Short description of key information:
Skin sensitisation: not sensitising

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

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 labeled on this basis.

Therefore, based on the group concept, all available data on skin sensitisation 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.