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

Endpoint summary

Description of key information

Acute toxicity: Oral LD50 (rat, m): > 20000 mg/kg bw (CAS 9005-65-6, Sorbitan monooleate, ethoxylated; Tween 81 [5EO])
Acute toxicity: Oral LD50 (rat, m): 58860 mg/kg bw (CAS 9005-65-6,polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]; Tween 80 )
Acute toxicity: Inhalation LC50 (rat, m/f): > 5.1 mg/L air (CAS 9005-64-5, sorbitan monolaurate, ethoxylated; polysorbat 21 [1 - 7EO])

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises studies which each alone are regarded insufficient for assessment (Klimisch score 4). However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with
similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI,1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute Toxicity

Justification for grouping of substances and read-across

There are only limited data available on the acute toxicity 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, 8.5., in accordance with Annex XI, 1.5., of Regulation (EC) No 1907/2006, read-across from structurally related substances Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) and sorbitan monolaurate, ethoxylated (CAS 9005-64-5, poylsorbat 21) 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 substances Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) and sorbitan monolaurate, ethxylated (polysorbat 21, CAS 9005-64-5) are 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), Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]) and sorbitan monolaurate, ethoxylated (polysorbat 21) are polyethoxylated sorbitan esters linked to oleate or laurate, with ethoxylation degrees of 3 – 5, 20 or 1 -7 EO respectively.

Target and source substances 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.

Acute oral toxicity

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

The acute toxicity of Tween 81 was investigated in 11 male rats, which were administered the undiluted test substance via oral gavage at a dose level of 20 mL/kg bw, corresponding to 20000 mg/kg bw based on a density of 1.00 g/mL (Krantz, 1945). Over a 48 h observation period, no harmful effects were observed in any of the 11 animals. No further data on body weights and gross pathology were reported. Based on the results of the study, the LD50 for rats was determined to be ≥ 20000 mg/kg bw.

In addition, very limited data for Tween 81 from a secondary source is available, in which a LD50 of ≥ 36600 mg/kg bw was defined for rats (CIR, 1984 and Marszall, 1973).

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

Tween 80 was tested in an acute toxicity study in 54 male rats, which received the test substance via oral gavage at different dose levels (Eagle and Pohling, 1956). The animals were observed for 7 days after test substance administration. No further details were given on mortality, clinical signs, body weights and gross pathology. The LD50 for rats determined from this study was reported to be of 54.5 mL/kg bw, corresponding to 58860 mg/kg bw based on a density of 1.08 g/mL (20 °C).

Inhalation

CAS 9005-64-5

An acute inhalation toxicity study was performed with sorbitan monolaurate, ethoxylated (1 - 7 EO, polysorbate 21, CAS 9005-64-5) according to OECD 403 under GLP conditions (van Huygevoort, 2012). Five male and female Wistar rats each were once exposed via nose to an aerosol of the test substance at an analytical test concentration of 5.1 mg/L for 4 h. No mortality occurred and no clinical signs were observed during the exposure and in the following observation period of 14 days. Body weight gain in males and females was within the expected range and no abnormalities were found at macroscopic post mortem examination of the animals. The LC50 was therefore considered to be higher than 5.1 mg/L.

Dermal

This information is not available.

 

Conclusions for acute toxicity

The available acute oral toxicity data on Sorbitan monooleate, ethoxylated (Tween 81 [5EO]) show that no mortality occurred in rats up to dose levels of 36600 mg/kg bw (Krantz, 1945; CIR, 1984 and Marszall, 1973). Further data on acute oral toxicity is available for the structurally related substance Tween 80 (CAS 9005-65-6 polysorbat 80 [sorbitan monooleate ethoxylated (20EO)]), for which a LD50 value of 58860 mg/kg bw was determined in rats (Eagle and Pohling, 1956). Based on a weight of evidence approach on all acute oral toxicity studies, in which dose levels were considerably above the currently applied limit dose, the LD50 for the test substance was considered to be > 2000 mg/kg bw.

No acute inhalation toxicity data is available for Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated). Therefore, assessment of acute toxicity via the inhalation route is conducted by means of read-across from the structurally related substance sorbitan monolaurate, ethoxylated (polysorbate 21, CAS9005-64-5). In the acute inhalation toxicity study with the read-across substance, no mortality and no clinical signs of toxicity were observed, leading to an LC50 of > 5.1 mg/L (van Huygevoort, 2012).

Based on these data, no acute inhalation toxicity is expected for the structurally related Sorbitan monooleate, ethoxylated (1-6.5 moles ethoxylated) .

There is no data available on acute toxicity via the dermal route.

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 acute toxicity – oral endpoint
Hazard assessment is based on the weight of evidence from all available studies. Therefore no endpoint selection was made.

Justification for selection of acute toxicity – inhalation endpoint
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is a reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – dermal endpoint
No study required since data on the oral and inhalation route are provided within the dossier and hence, the data requirements according to Annex VIII, 8.5 are met. Furthermore, dermal uptake through the intact skin is considered as low to moderate due to 1) a molecular weight ranging from 560.8 or 648.9 g/mol (for 3 and 5 ethoxy units, respectively), 2) low water solubility ranging from 30 – 100 mg/L and 3) a partition coefficient of > 4 which all indicate impeded transfer from the stratum corneum into the epidermis (see ECHA guidance R.7c: Endpoint specific guidance). QSAR analysis predicted a low dermal absorption rate of not more than 10 – 20%, depending on the amount of bound ethoxy groups and the water solubilty (please refer to IUCLID section 7.1.2). Furthermore, since the substance did not show toxicity up to the limit dose of 2000 mg/kg via the oral route and since the dermal absorption is considered less than the oral absorption, systemic acute toxicity via the dermal route is also not to be expected. Therefore, testing for acute toxicity by the dermal route is scientifically unjustified in accordance with Annex XI, Section 1.2 of Regulation (EC) 1907/2006, based on the weight of evidence from the available physicochemical and toxicological data documented in the technical dossier and the Chemical Safety Report. Hence, further testing on vertebrate animals for this property shall be omitted.

Justification for classification or non-classification

Based on substance-specific studies and read-across from structurally similar substances, the available data on the acute oral and inhalation toxicity 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.