Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
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, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil thestandard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to reproduction

Justification for read-across

There are no reliable data for reproductive 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, 8.7.

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 are available on reproductive toxicity, read-across to the analogue substance Sorbitan stearate (CAS 1338-41-6) was conducted.

CAS 1338-41-6

For Sorbitan stearate (CAS 1338-41-6) a combined repeated dose/developmental toxicity screening study was conducted under GLP conditions equivalent to OECD 422 in male and female Sprague-Dawley rats (MHLW Japan 2007). Seven to 12 rats were once daily orally treated with 40, 200, 1000 mg/kg bw/day of the test substance in water. Females were treated 2 weeks before mating until day 4 of lactation (about 40 days) and the males for 42 days. Control animals were treated with the vehicle. No mortality was observed. 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. No effects on oestrus cycle, copulation and conception rate were observed. 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 and no effects on reproductive function were observed, the NOAEL for systemic toxicity and fertility was therefore determined to be ≥ 1000 mg/kg bw/day.

Conclusion for reproduction toxicity

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

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


Short description of key information:
NOAEL oral (rat, fertility): ≥ 1000 mg/kg bw/day (CAS 1338-41-6)

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
NOAEL oral (rat, developmental toxicity): ≥ 1000 mg/kg bw/day (CAS 1338-41-6)
Effect on developmental toxicity: via oral route
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, similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil thestandard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity

Justification for read-across

There are no reliable data for developmental 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, 8.7.

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 are available on developmental toxicity, read-across to the analogue substance Sorbitan stearate (CAS 1338-41-6) was conducted.

CAS 1338-41-6

A combined repeated dose/developmental toxicity screening study was performed according to OECD 422 with Sorbitan stearate (CAS 1338-41-6) under GLP conditions in male and female Sprague-Dawley rats (MHLW Japan 2007). Seven to 12 rats were once daily orally treated with 40, 200, 1000 mg/kg bw/day of the test substance in water. Females were treated 2 weeks before mating until day 4 of lactation (about 40 days) and the males for 42 days. Control animals were treated with the vehicle. In parental animals no mortality was observed and no abnormalities were seen which could be related to the treatment. In the offspring, mortality was observed as follows: 2 dams of the 40 mg/kg bw/day dose group lost all pups and an additional dam lost 9/13 pups, probably because they did not lactate on day 1. No further mortalities of newborns were observed, even in the high-dose group. The number of abnormalities seen in the visceral and skeletal tissues in test animals did not differ from spontaneously occurring abnormalities in the controls except the occurrence of a filamentous tail in one pup of the 1000 mg/kg bw/day dose group. The effect was considered as not treatment-related but as common effect in Sprague-Dawley rats. With regard to the described effects, a developmental NOAEL of≥1000 mg/kg bw/day was determined.

Conclusion on developmental toxicity

Based on the available data, the analogue substance did not provide evidence that Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) negatively affects organogenesis or foetal development in utero. Thus, Sorbitan C16-18 (even numbered) fatty acid esters, ethoxylated (1-6.5 moles ethoxylated) is not considered to exhibit developmental toxicity.

 

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 Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across, the available data on toxicity to reproduction 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.