Registration Dossier

Administrative data

Description of key information

Acute toxicity: Oral LD50 (rat, m): > 39800 mg/kg bw (Tween 61)
Acute toxicity: Inhalation LC50 (rat, m/f): > 5 mg/L air (CAS 9005-64-5,CAS 1338-39-2)

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 adequate, reliable (Klimisch score 2) and consistent studies, and is thus 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 adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). Taken together, 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 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 read-across

There is only one reliable acute oral toxicity study with Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) available. 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, 8.5.

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 analogue 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). Sorbitan stearate (CAS 1338-41-6) and Sorbitan laurate (CAS 1003-39-2) consist of sorbitan esterified either mainly with C16 and C18 fatty acids (sum of C16 and C18 min. 90%) or with C8-18 saturated and C18 unsaturated fatty acids. It is therefore considered that these source substances are structural analogue substance due to structural similarities, the presence of common functional groups and the likelihood of common breakdown products.

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). 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 reliable data only exists for acute oral toxicity, read-across to the analogue substances Sorbitan stearate (CAS 1338-41-6), Sorbitan monolaurate, ethoxylated (1-6.5 moles ethoxylated, CAS 9005- 64-5) and Sorbitan laurate (CAS 1338-39-2) was conducted.

Acute oral toxicity

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

An acute oral toxicity study with Tween 61 similar to OECD Guideline 401 was performed (Quigley, 1966). Groups of 5 male and female Wistar rats received single oral doses of 35500 or 39800 mg/kg bw. No mortalities were observed during the study period. Most of the animals in both test groups had diarrhea. In the gross pathology effects were seen in the bladder, heart, kidneys (both dose groups) and lungs (only in the higher dose group). The acute oral LD50 in rat was therefore found to be greater than 39800 mg/kg bw.

CAS 1338-41-6

For Sorbitan laurate, a study similar to OECD 401 was performed. 2 rats of each sex were orally exposed to a single dose of 2000 mg/kg bw. There were no deaths or signs of toxicity observed during the study period. The body weight gain was not influenced by the test substance administration during the observation period of 14 days. Gross examination of organs and tissues at necropsy did not reveal any abnormalities (Potokar, 1984).

 

Acute toxicity following inhalation

CAS 9005-64-5

An acute inhalation toxicity study was performed with Sorbitan monolaurate, ethoxylated (<2.5 EO, Polysorbate 21, CAS 9005-64-5) according to OECD 403 under GLP conditions. Five male and female Wistar rats each were once exposed via nose to 5 mg/L to an aerosol of the test substance for 4 hours (van Huygevoort, 2012). 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 set to be higher than 5 mg/L.

CAS 1338-39-2

An acute inhalation toxicity study was performed according to OECD 436 under GLP conditions with Sorbitan laurate (CAS 1338-39-2). Three male and female Wistar rats each were exposed via nose only to 5 mg/L test substance as aerosol for a single exposure duration of 4 hours. During exposure, slow breathing was observed among several animals approximately 3 hours after start of exposure. Clinical signs recorded between days 1 and 5 after exposure included lethargy, ventro-lateral recumbency, hunched-posture, rales, shallow respiration, piloerection, and/or chromodacryorrhoea among all animals. No clinical signs were observed afterwards and no mortalities occurred. Therefore, the LC50 was determined to be > 5000 mg/m³ (van Huygevoort, 2010)

 

Acute dermal toxicity

No data on acute toxicity following dermal contact are available. Dermal uptake of Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) through the intact skin is considered as negligible based on physicochemical properties and QSAR analysis (for details, please refer to the Statement on toxicokinetic behavior). Furthermore, the substance did not show toxicity up to the limit dose of 2000 mg/kg via the oral route, and hence, systemic acute toxicity via the dermal route is not 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.

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

Aungst B. and Shen D. D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K. K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

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): 321-401ECHA (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Office of prevention, pesticides and toxic substances.

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 acute toxicity – oral endpoint
The selected study is the most adequate and reliable study with the lowest dose descriptor.

Justification for selection of acute toxicity – inhalation 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 substance-specific data and read-across, the available data on 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.

There is no data available on acute dermal toxicity.