Registration Dossier

Administrative data

Description of key information

skin irritation: not irritating 
skin irritation (observations in humans): no skin irritating effects
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)

Additional information

Irritation

Justification for read-across

There is only one human patch test available 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 and VIII, 8.1 and 8.2.

According to 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 for human toxicity, 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) “to avoid the need to test every substance for every endpoint”.

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 structurally related substance Sorbitan stearate (CAS 1338-41-6) is a sorbitan also esterified mainly with C16 and C18 (sum of C16 and C18 min. 90%) and is therefore considered as structural analogue substance due to structural similarities, the presence of common functional groups and the likelihood of common breakdown products.

Target and source substance 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). D-glucitol is metabolized to D-glucose or D-fructose (Touster, 1975). D-glucitol will be metabolized by the intestinal microflora (Senti, 1986) or absorbed through the gastrointestinal tract, but slower and less complete than glucose (Allison, 1979). 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). 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. 

As only reliable human data are available on irritation, a weight-of-evidence approach is considered covering read-across to the analogue substance Sorbitan stearate (CAS 1338-41-6) was conducted. In addition, data on skin and eye irritation of Polysorbat 60 were included in the dossier (CIR, 1984). Polysorbate 60 (generic CAS 9005-67-8) is a mixture of stearate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, condensed with approximately 20 moles of ethylene oxide (CIR, 2015). Based on the specification, Polysorbat 60 is regarded as read-across.

Skin irritation

CAS 1338-41-6

The irritation/corrosion potential of Sorbitan stearate (CAS 1338-41-6) 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. Based on these results, Sorbitan stearate (CAS 1338-41-6) is not irritating to the skin.

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. This shows that the chemical is not a primary skin irritant.

Furthermore, Polysorbate 60 (generic CAS 9005-67-8) induced no or only mild irritation to skin (CIR, 1984).

Eye irritation

CAS 1338-41-6

The eye irritating potential of Sorbitan stearate (CAS 1338-41-6) was evaluated in a study similarly performed to OECD 405 (Munfus, 1977). 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.

Furthermore Polysorbate 60 (generic CAS 9005-67-8) produced, at most, only minimal eye irritation that cleared by day 3 (CIR, 1984).

Conclusion on skin and eye irritation properties

Skin and eye irritation properties of the read-across analogue substance Sorbitan stearate (CAS 1338-41-6) and on Polysorbate 60 (generic CAS 9005-67-8) have been investigated in vivo indicating no irritating properties towards the skin or eyes. In addition, human patch test data derived from Tween 61 did not show a skin irritating potential. Therefore, based on these data and the structural similarities, Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is not considered as skin or eye irritant.

 

References:

Allison, R.G. (1979). Dietary sugars in health and disease III. D-glucitol. Contract No. 223-75-2090, Bureau of foods, Food and Drug Administration, Dept. of Health and Human Services, Washington, D.C. 20204, USA

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

CIR (2015). Safety assessment of polysorbates as used in cosmetics. Final amended report, released: July 10, 2015

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

Touster, O. (1975). Metabolism and physiological effects of polyols (alditols). In: Physiological effects of food carbohydrates. 229-239. American Chemical Society, Washington, D.C., USA


Justification for selection of skin irritation / corrosion 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).

Justification for selection of eye irritation endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. 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).

Justification for classification or non-classification

Based on read-across, the 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.