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:

Sensitisation

Justification for read-across

There is only one human patch test available regarding sensitisation for Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated). In accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 read-across from an appropriate substance is conducted to fulfill the standard information requirements set out in Regulation (EC) No 1907/2006, Annex VII, 8.3.

Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) represents an UVCB substance composed of polyethoxylated sorbitan esterified mainly with C16 (44%) and C18 saturated fatty acids (54%). The analogue substance substance Sorbitan monolaurate, ethoxylated (1-6.5 moles ethoxylated, CAS 9005- 64-5) is also a polyethoxylated sorbitan esterified with lauric acid (C12 saturated fatty acid). Due to structural similarities, the presence of common functional groups and the likelihood of common breakdown products, Sorbitan monolaurate, ethoxylated (1 - 6.5 moles ethoxylated, CAS 9005- 64-5) is considered as structural analogue substance.

Target and source substances are sorbitan esters, which are known to be hydrolysed after oral ingestion at the ester link by pancreatic lipase resulting in the fatty acid moiety and either the polyethoxylated sorbitan or D-glucitol moiety (CIR, 1984; EPA, 2005; Stryer, 1996). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, polysorbates will undergo chemical changes already in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In contrast, substances which 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. The alpha- and omega-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987). The polyethoxylated sorbitan moiety, is expected to be excreted mostly in the feces and to a minor amount in the urine without further metabolism (CIR, 1984; EPA, 2005). Based on the described structural similarities and metabolic fate of target and source substance, the read-across approach is based on the presence of common functional groups, common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals and hence in an overall similar toxicokinetic behaviour. For further details on the read-across approach, please refer to the analogue justification in section 13 of the technical dossier.

For the evaluation of skin sensitizing properties of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated), a weight-of-evidence approach is considered covering read-across to the analogue substance Sorbitan monolaurate, ethoxylated (1-6.5 moles ethoxylated, CAS 9005- 64-5), human patch test data derived from Tween 61 (Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is also referred to as Tween 61) and QSAR analysis on potential protein binding capacities of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) relevant for skin sensitisation.

 

CAS 9005-64-5

A skin sensitization study was performed according to OECD 429 (Notox, 2012) with Sorbitan monolaurate, ethoxylated (<2.5 EO, Polysorbate 21, CAS 9005-64-5). 25, 50 and 100% of the test substance dissolved in acetone/olive oil (4:1, v/v) were applied in a total dose of 25 µl to each ear of 5 female CBA mice each on three consecutive days. On day 6 of the experiment, 3H-methyl thymidine (3H-TdR) was injected into the tail vein of each experimental mouse to assess the proliferative response. Approximately five hours later, all animals were killed and the draining auricular lymph node of each ear was excised into PBS and a single cell suspension was prepared which was precipitated with trichloroacetic acid in preparation for scintillation. The mean DPM/animal value determined for the vehicle control group was 537 DPM. For the experimental groups treated with test substance concentrations of 25, 50 and 100%, values of 1040, 3210 and 2700 DPM, respectively, were found revealing SI values of 1.9, 6.0 and 5.0. The data showed a dose-response, except the 100% dose group did not follow the expected dose-response relationship which is often seen in this kind of studies. The response might be less due to differences in skin penetration (no vehicle present) or viscosity or due to underlying systemic toxicity. An EC3 value of 34% was calculated. A reliability test with an appropriate positive control was performed and revealed the expected results. Under the conditions of this test, the test substance was considered to be a skin sensitizer. Although the LLNA is the recommended test system for skin sensitisation under REACh, it is known that the LLNA can lead to an overpredicted sensitisation potential for surfactants (Ball et al. 2011). Therefore, as the test substance represents a surfactant, a guinea pig maximisation test according to Magnusson and Kligman was conducted additionally (Notox, 2012). The study was performed similar to OECD 406 under GLP conditions with the following concentrations of the test substance dissolved in corn oil: 2% for intradermal induction, 100% for epidermal induction and challenge. At challenge, the test substance at 100% induced no effects in test and control group animals. The positive control (20% alpha hexyl cinnamic acid) induced the expected results. Thus, under the conditions of this test, the test substance was not a skin sensitiser. Taken all these data into consideration, it seems reasonable to interpret the positive result of the LLNA as a false positive result.

Tween 61(Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is also referred to as Tween 61)

In addition to the animal data, Tween 61 was tested in a human patch test (Schwartz 1959). 50 subjects were exposed to the test substance at 60% under occlusive conditions initially for 3 days and in a challenge 7 days after removal of the initial patch. At the end of the 72 h exposure period in the challenging application, no reactions on the skin of any of the subjects were observed. Taking all data into consideration, it is concluded that the test substance is not a skin sensitizer.

QSAR

QSAR predictions based on the OECD QSAR Toolbox v3.3 were performed with four representative components ofSorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) covering the different alcohol moieties (dianhydroglucitol, sorbitan and sorbitol) and the lowest to highest molecular weights (C16 Sorbitan monoester,C18 Sorbitan triester,C18 Dianhydroglucitol diester andC18 Sorbitol diester). The predicted skin sensitisation potential based on protein binding potential was modelled in the OECD QSAR Toolbox v3.3. No alerts for protein binding were found according to OASIS v1.3 (general mechanistic), and no protein binding alerts for skin sensitisation were found according to OASIS v1.3 (endpoint specific). Stuctural alerts were identified forC16 Sorbitan monoester,C18 Sorbitan trimester andC18 Dianhydroglucitol diesterregarding the OECD scheme. Based on these results, especially considering the results of the skin sensitizing relevant profiler, OASIS v1.3 (endpoint specific), Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is not expected to exhibit skin sensitising properties.

Conclusion on skin sensitising properties

The available experimental data, including animal and human observations, point to non-sensitising properties of the read-across analogue. This assumption is further supported by QSAR predictions performed with representative components ofSorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated), which revealed no alerts for protein binding according toOASIS v1.3 (endpoint specific).Thus, Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated)is not considered as skin sensitiser.

References:

Ball N, Cagen S, Carrillo JC, Certa H, Eigler D, Emter R, Faulhammer F, Garcia C, Graham C, Haux C, Kolle SN, Kreiling R, Natsch A, Mehling A (2011): Evaluating the sensitization potential of surfactants: integrating data from the local lymph node assay, guinea pig maximisation test, and in vitro methods in a weight-of-evidence approach.

CIR (1984). Final report on the safety assessment of polysorbat 20, 21, 40, 60, 61, 65, 80, 81 and 85. Journal of the American College of Toxicology, 3(5): 1- 82

CIR (1987). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, stearic acid. J. of the Am. Coll. of Toxicol.6 (3): 321-401

EPA (2005). ACTION MEMORANDUM. Reassessment of six inert ingredient exemptions from the requirement of a tolerance. United States Environmental Protection Agency, Washington, D.C. 20460, USA

Senti, F.R. (1986). Health aspects of sugar alcohols and lactose. Contract No. 223-83-2020, Center for food safety and applied nutrition, Food and Drug Administration, Dept. of Health and Human Services, Washington, D.C. 20204, USA

Stryer, L. (1996). Biochemie. Spektrum Akademischer Verlag; Auflage: 4th edition


Migrated from Short description of key information:
skin sensitisation: no skin sensitising effects
skin sensitisation (observations in humans): no skin sensitising effects

Justification for selection of skin sensitisation endpoint:
Hazard assessment is conducted by means of read-across from structural analogues and human data available for the target substance. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:
Justification for selection of respiratory sensitisation endpoint:
Study not required according to Annex VII-X of Regulation (EC) No 1907/2006.

Justification for classification or non-classification

Based on read-across, the 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.