Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity, oral (OECD 422): NOAEL: ≥ 1000 mg/kg bw/day 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises insufficient data for assessment from the substance itself and adequate and reliable (Klimisch score 2) studies from a reference substance. 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).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity

Justification for read-across

There are no reliable data on repeated dose toxicity 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 VIII, 8.6.

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 no reliable data exist on repeated dose toxicity, read-across to the analogue substance Sorbitan stearate (CAS 1338-41-6) was conducted. In addition, subchronic and chronic toxicity of Tween 61 (Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is also referred to as Tween 61) was tested in rats (Krantz, 1948, 1949).

 

CAS 1338-41-6

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was performed similar to OECD 422 under GLP conditions with Sorbitan stearate (CAS 1338-41-6) in male and female Sprague Dawley rats (MHLW Japan 2007). 12 animals per sex were treated once daily by gavage with 40, 200, 1000 mg/kg bw/day test substance dissolved in water. Control animals received the vehicle. Females were treated 2 weeks prior to mating until Day 4 of lactation (ca. 40 days) and the males for 42 days. Ulcer was the only clinical sign seen in one male of the 200 mg/kg bw/day dose group and in one female of the 1000 mg/kg bw dose group. Female body weights were significantly decreased between day 1 and 7 of treatment in the 200 mg/kg bw dose group. Decreases in relative brain and epididymis weights were observed in males of the 200 mg/kg dose group and an increase in absolute brain weights in females of the 1000 mg/kg bw dose group. At gross pathology, spots in glandular stomach in females of the 200 mg/kg bw dose group were observed. At histopathology, no treatment-related effects were seen. As the effects described above occurred only in isolated cases in parental animals, they were considered to be by chance findings rather than treatment-related effects. Therefore the NOAEL of Sorbitan stearate for systemic toxicity was determined to be ≥1000 mg/kg bw/day.

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, Tween 61 was tested in feeding studies for repeated dose toxicity (Krantz, 1948, 1949). 50 rats were exposed to 2% Tween 61 via feed over 6, 12, 17 and 24 months. 30 rats were feed with plain diet as controls. No treatment-related effects were observed on mortality rate (unscheduled death were determined in control and test groups), body weight and weight gain, hematological parameters. In histopathology, no adverse effects on kidney and liver were observed.

 

Conclusion on repeated dose toxicity

The available data show that the analogue substance Sorbitan stearate (CAS 1338-41-6) and Tween 61 do not possess intrinsic hazardous properties in regard to repeated dose toxicity. Therefore, based in this data and the structural similarities, Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is considered to be non-hazardous after repeated exposure.

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

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 repeated dose toxicity via oral route - systemic effects endpoint:
The selected study is the most adequate and reliable study with the longest duration and the lowest dose descriptor.

Justification for classification or non-classification

Based on read-across, the available data on the repeated dose toxicity via the oral route 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 repeated dose toxicity by the inhalation and dermal routes.