Dehydrated sorbitol, C18 (unsaturated) fatty acid esters, ethoxylated

Endpoint summary

Description of key information

skin irritation: not irritating (based on a weight of evidence approach)
eye irritation (OECD 405): not irritating (based on a weight of evidence approach)

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

Skin Irritation/corrosion

Justification for grouping of substances and read-across

There are no data available on skin irritation of Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated; CAS 9005-65-6). In order to fulfil the standard information requirements set out in Annex VIII, 8.1., in accordance with Annex XI, 1.5., of Regulation (EC) No 1907/2006, read-across to the structurally related substance Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) was conducted.

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 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).

The test substance Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) represents an UVCB substance composed of polyethoxylated sorbitan esterified mainly with C18 unsaturated fatty acids (>60 - 100%). The structurally related substance Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) is considered as structural analogue substance due to structural similarities, the presence of common functional groups and the likelihood of common breakdown products: Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) and Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) are polyethoxylated sorbitan esters linked to oleate with ethoxylation degrees of 3 – 5 or 20 EO, respectively.

Target and source substance are polyethoxylated sorbitan esters, also called polysorbates, which are known to be hydrolysed after oral ingestion at the ester link by pancreatic lipase resulting in the fatty acid moiety and the polyethoxylated sorbitan moiety (CIR, 1984; EPA, 2005; Fruijitier-Pölloth, 2005). 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. 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). The second cleavage product, 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; Fruijitier-Pölloth, 2005). Based on the common metabolic fate of polyethoxylated sorbitan fatty acid esters, 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 exhibit similar toxicokinetic behaviour. For further details on the read-across approach, please refer to the analogue justification in section 13 of the technical dossier.

Discussion

Skin irritation incl. human data

CAS 9005-65-6 (Tween 80 (polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) 

A skin irritation study is available for Tween 80, which did not follow a specific guideline relevant for the assessment of the skin irritating potential (Mezei, 1966). In this study, the test substance was applied daily, either undiluted or in dilutions of 5% and 10% dilution in water or hydrophilic ointment (H.O.) to the clipped trunks of New Zealand White rabbits for a total of 81 days. The untreated sites and sites treated with ointment base of the same animal served as control. Assessment of skin reactions was performed after 3 and 10 days as well as 1 month after the initial treatment. After 3 days, slight erythema and edema were observed in all treatment groups, except for treatment with 5% of the test substance in water which resulted in no visible change on the skin. After 10 days, moderate erythema and edema were observed after treatment with the undiluted test substance and the test substance diluted at 10% in H.O., whereas only slight erythema and edema were found after application of the test substance at 10% in water and 5% in H.O., respectively. Consistent with the 3-day reading time point, no visible change on the skin was observed after treatment with 5% of the test substance in water. As no scoring of the skin reaction was reported and original report was not available, the results of this study was not taken into account for hazard assessment of the test substance.

Furthermore, a primary skin irritation study is available according to the Draize method, in which the undiluted test substance was applied for 24 h to the abraded and intact skin of 6 Albino rabbits under occlusive conditions (Treon, 1963). Skin reactions were observed 24 and 72 h after removal of the test patch and erythema and edema were scored. Based on the observed effects, a primary irritation index of 0.75 was determined. Thus, the substance was considered to be mildly irritating to the rabbit’s skin. However, no individual scoring of the skin reaction was reported, and there was no differentiation whether the effects were observed on abraded or intact skin. Therefore, the results of this study were not taken into account for hazard assessment of the test substance.

Nevertheless, reliable data are available from several human patch tests, in which volunteers were dermally treated with the structurally related substance Tween 80 for the investigation of skin irritation potential in humans.

A single application closed patch epicutaneous test in humans is available, which was performed similar to the COLIPA Guidelines for the Assessment of Skin Tolerance of Potentially Irritant Cosmetic Ingredients (Basketter et al., 2004). The undiluted test substance (0.2 mL) was applied to a Hill Top Chamber containing a Webril pad and placed on skin of the upper outer arm of each 29 volunteers for up to 4 h. To avoid the production of unacceptably strong reactions, the test substance was applied progressively from 15 and 30 min through 1, 2, 3 and 4 h. Skin reactions were scored 24, 48 and 72 h after exposure to the test substance and classified according to a 4 point scale ranging from “0” for “no reaction” to “+++” for strongly positive reactions (strong, often spreading erythema with edema). Only in 1/29 (ca. 3%) individuals a positive irritant reaction to the test material was observed. In contrast, 24/29 (ca. 83%) individuals from the same panel showed a positive irritant reaction to the 20% sodium dodecyl sulphate control. As the reactions to the test substance were substantially and significantly lower than the response to SDS, the substance was not considered to be a human skin irritant.

A further study according to the single application closed patch test method was performed in humans under similar conditions as described under the study above (Robinson, 2001). The patch test method involved application of 0.2 mL of liquid materials onto a Hill Top Chamber (containing a webril pad. The patch was placed against the upper outer arm of 24 human test subjects for periods of exposure of 15 or 30 min through 1, 2, 3, and 4 h. After exposure, patches were removed and the skin sites were very gently wiped with wet gauze to remove excess test material. Each test site was scored for irritation responses 24, 48, and 72 h after patch removal using a simple scale (0, +, ++, +++) of increasing severity. Only in 1/24 (ca. 4%) individuals a positive irritant reaction to the test material was observed. In contrast, 8/27 (ca. 30%) individuals from the same panel showed a positive irritant reaction to the 20% sodium dodecyl sulphate, which served as positive control substance. As the test substance showed a statistically lower incidence of positive responders compared to the positive control, the substance was not considered to be a human skin irritant.

CAS 9005-65-6 (Sorbitan monooleate, ethoxylated (1 -6.5 moles ethoxylated, Tween 81[5EO])

An additional human patch test is available, in which 10 volunteers were treated with the a 12% dilution of Tween 81 for an initial exposure period of 5 days, followed by a 48-h challenging application 10 days after removal of initial patch (Durfee, 1943). The test material was applied generously to an area of one square inch to the inner upper arm of the test subjects, except for one volunteer which received the test material on the deltoid area. The test area was covered with a sterile gauze patch, which was held in place with adhesive tape. In none (0/10) of the volunteers, any evidence for primary irritation was observed after the 5-days exposure to the test substance. At the end of the 48-h exposure period in the challenging application there were no reactions on the skin of any of the subjects. No erythema and vesiculation were observed at the end of the test. Based on the results of this human patch test, the test substance was not considered to be skin irritating in humans.

A further human patch test is available, in which 50 human volunteers were exposed to the undiluted test substance under occlusive conditions initially for 3 days and in a challenge 7 days after removal of the initial patch. At the end of the initial 3-day exposure period as well as at the end of the 72-h exposure period in the challenging application, no reactions on the skin in any of the subjects were observed. Therefore, the substance was not considered to be a skin irritating.

Based on the weight of evidence from both studies, it is concluded that the test substance is not irritating to human skin.

Eye irritation

The eye irritation potential of Sorbitan monooleate, ethoxylated (Tween 81[5EO]) was investigated in 9 (4 male and 5 female) New Zealand albino rabbits according to the FDA guideline “Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics”, which is similar to the currently applied OECD guideline 405 (Iacono, 1963). The undiluted test material (0.1 mL) was placed into the conjunctival sac of one eye, whereas the other eye remained untreated and served as control. In 3 of 9 animals, the test substance was rinsed 2 sec after treatment. In the other 6 animals, the test substance remained in the eye without washing. The eyes were examined and scored 1, 24, 48, 72 and 96 h as well as 7 days after instillation. Chemosis scoring was not performed. Animals exposed to a single application without washing did not show any signs of eye irritation up to the end of the 7-day observation period. No further local or systemic toxic effects were reported. The mean cornea, iris and conjunctivae scores after 24, 48, and 72 h were 0 for all 9 animals, respectively. Thus, under the applied test conditions, the test substance was not considered as eye irritant.

A further eye irritation study was performed with Sorbitan monooleate, ethoxylated (Tween 81 [5EO]) according to the FDA guideline “Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics”, which is similar to the currently applied OECD guideline 405 (Iacono, 1965). A 10% dilution of test substance in USP light mineral oil (0.1 mL) was instilled into one eye of 9 New Zealand White rabbits (4 females and 5 males) each. The other eye remained untreated and served as control. Examination and scoring of effects on the eyes was performed at intervals of 1, 24, 48 and 72 h as well as 7days after test substance application. Chemosis scoring was not performed. The material did not cause irritation either in the unwashed or the washed eyes. No further local or systemic toxic effects were observed. The mean cornea, iris and conjunctivae scores after 24, 48, and 72 h were 0 for all 9 animals, respectively. Thus, the test substance was not considered as eye irritant.

In a further Draize test, the eye irritating potential of Sorbitan monooleate, ethoxylated (Tween 81 [5EO]) in rabbits was investigated (Treon et al. 1963). Each 0.1 mL of the unchanged test substance was instilled into one eye of each of 9 animals. The eyes of 6 animals remained unwashed, whereas in 3 rabbits washing of the eyes was performed 2 sec after test substance instillation. The animals were observed for 1, 24, 48 and 72 h as well as 7 days. The mean cornea, iris and conjunctivae scores were 0 for all 9 animals. Thus, the test substance was not considered to be eye irritating.

 

Conclusions for skin and eye irritation

The available human data on Sorbitan monooleate, ethoxylated (Tween 81 [5EO]) and the structurally related substance Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) do not indicate a skin irritation potential of the test substance. Similarly, no eye irritation potential of the substance was identified based on the weight of evidence of the available animal studies.

 

References (not included in IUCLID):

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 Protetio Agency, ashington, D.C. 20460

 

Fruijitier-Pölloth (2005). Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products.Toxicology 214, 1 - 38

 

Justification for selection of skin irritation / corrosion endpoint:
Hazard assessment is based on the weight of evidence from all available studies. Therefore no endpoint selection was made.

Justification for selection of eye irritation endpoint:
Hazard assessment is based on the weight of evidence from all available studies. Therefore no endpoint selection was made.

Justification for classification or non-classification

Based on substance-specific studies and read-across from a structurally similar substance, 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.