Registration Dossier

Administrative data

Description of key information

skin irritation (OECD 404): 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

Justification for read-across

There are no data on irritation towards the skin or eyes available for Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol. In accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 read-across from appropriate substances is conducted to fulfill the standard information requirements set out in Regulation (EC) No 1907/2006, Annex 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”. 

 

Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol represents an UVCB substance comprised of different Sorbitan fatty acid ester, mainly of mono-, di- and tri-esters of sorbitol, sorbitan and 1,4:3,6-dianhydro-d-glucitol esterified with natural fatty acids with a chain length ranging from of C16 – C20, mostly C18 mono-unsaturated.

 

Sorbitan fatty acid esters are known to be stepwise hydrolysed to the respective fatty acid and the alcohol moiety, which will be present mostly as the open chain isomer D-glucitol depending on the pH (Stryer, 1996). 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. 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 alcohol residue, mostly D-glucitol, is absorbed from the gastro-intestinal tract and can be metabolized by the intestinal microflora (Senti, 1986) or in the liver (Touster, 1975). Based on the common metabolic fate of 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.

 

As no data are available on skin and eye irritation of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol , read-across to reliable data on the analogue substances Sorbitan oleate (CAS 1338-43-8), Anhydro-D-glucitol trioleate (CAS 26266-58-0) and Sorbitan, (Z)-9-octadecenoate (2:3) (CAS 8007-43-0) was conducted.

 

CAS 26266-58-0

A GLP compliant OECD 404 guideline study (Harlan, 2012) was performed with Anhydro-D-glucitol trioleate (Sorbitan trioleate). 0.5 mL of the unchanged substance was applied to the clipped skin of two New Zealand white rabbits with a 2.5 x 2.5 cm gauze patch under semi-occlusive conditions for an exposure period of 4 hours. At the end of the exposure period, the gauze patch was removed, the skin site washed and immediately examined. The evaluation of irritant effects was performed at 1, 24, 48 and 72 h after patch removal. No signs of skin corrosion or irritation were observed. Mean edema and erythema scores over 24, 48, and 72 h were 0, so that the test substance was considered as not irritating under the test conditions chosen.

 

CAS 8007-43-0

For Sorbitan, (Z)-9-octadecenoate (2:3) a study performed similar to guideline OECD 404 is available, but without details on individual irritation parameters (Rzucidlo 1972). 0.5 mL of the unchanged test substance were applied to the intact and abraded skin of 6 New Zealand rabbits under semi-occlusive conditions for an exposure period of 24 h. Treated skin sites were immediately examined after removal of the patch and 72 h post-exposure. Mean edema and erythema scores were 0.78 and 1.89, respectively, calculated over 24, and 72 h, so that the test substance was considered as not irritating under the test conditions chosen. Furthermore, human patch tests did not revealed any irritating properties (Schwartz 1959, Uniqema 2002; please refer to 7.10.4).

 

CAS 1338-43-8

To assess the skin irritation potential of sorbitan oleate, the test substance was applied to the shaved intact or abraded skin of 3 animals (not further specified). The treated skin areas were observed for erythema and edema 24 and 72 hours after substance application. Well-defined erythema were observed on the treated intact skin areas in 2/3 animals 24 hours after exposure end. One of the treated skin areas exhibited a greater degree of erythema at the 72-hour reading time point, while the effect was completely reversed in the other animal. In the remaining animal, no erythema was observed. Mean erythema scores of 1, 2.5 and 0 were calculated for the respective animals. No edema was noted at any reading time point leading to an overall edema score of 0 (Rzucidlo, 1971). Based on these data, the test substance was not considered as irritating.

 

 

Eye irritation

CAS 1338-43-8

Eye irritating properties of Sorbitan laurate were characterized in 6 rabbits: 0.1 mL undiluted test substance was instilled in the eyes of the test animals. Afterwards, the eyes were evaluated 1, 24, 48 and 72 hrs after test substance application. The observation period was elongated to 7 days. The untreated eye served as control. Slight effects on conjunctivae scored with grade 1 was observed in 3/6 animals 1 hour after instillation of the test substance. At later time points, no effects on the eyes were noted leading to overall scores of 0 for cornea, iris, conjunctivae and chemosis. Based on these results, Sorbitan laurate did not exhibit eye irritation properties.

 

CAS 26266-58-0

For Anhydro-D-glucitol trioleate (Sorbitan trioleate) an OECD 405 guideline study was performed under GLP conditions (Harlan, 2012). 0.1 mL of the unchanged test substance was applied to the eyes of two New Zealand white rabbits. 1, 24, 48 and 72 h later, the animals´ eyes were examined for ocular effects. The mean irritation scores over all animals calculated for the 24, 48 and 72 h reading time points were as follows: cornea score 0, iris score 0, conjunctivae score 0.15 and chemosis score 0. Conjunctival redness was fully reversible within 48 hours.

 

CAS 8007-43-0

An eye irritation guideline-study was conducted with Sorbitan, (Z)-9-octadecenoate (2:3) equivalent to the Appraisal of the AFDO, USA (1959). 0.1 mL of the unchanged test substance was applied into one eye of 9 New Zealand White rabbits (Wanderer 1963). The untreated eye served as control. Reading points for ocular reactions were 1h post treatment and 1, 2, 3 and 7 days thereafter. No effects on cornea, iris and conjunctivae were observed (mean scores for all 6 animals over 24, 48, 72 h: 0). In the report, no data on chemosis were given.

 

Overall conclusion for skin and eye irritation

Based on the available and reliable data on skin and eye irritation, the structural analogue substances Sorbitan oleate, Anhydro-D-glucitol trioleate and Sorbitan, (Z)-9-octadecenoate (2:3) were not considered as skin or eye irritating. Therefore, Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol is not considered as skin iritant.

 

References

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

 

Iacono, J. J. (1965). [Trade name] Irritation to the Mucosa of the Rabbit Eye. Testing laboratory: Bio-Medical Research Department, Atlas Chemical Industries, San Diego, CA, USA. Report no.: G1742Eye. Owner company: Croda. Study number: 11400. Report date: 1965-05-05

 

Mezei, M. et al. (1966). Dermatitic effect of nonionic surfactants. I. Gross, microscopic, and metabolic changes in rabbit skin treated with nonionic surface-active agents. J Pharm Sci 55/6: 584-590.

 

 

Schwartz, L. (1959). Patch tests were performed on 50 subjects to determine primary irritation and sensitization to undiluted Sorbitan laurate. Report no.: G759Human. Owner company: Croda Europe Ltd., Goole, UK.

 

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, DC 20204, USA

 

Stryer, L. 1996. Biochemie. Spektrum Akademischer Verlag; Auflage: 4th edition

Suldano, S., Gramenzi, F., Cirianni, M., Vittozzi, L. (1992): Xenobiotic-metabolizing enzyme systems in test fish - IV. Comparative studies of liver microsomal and cytosolic hydrolases. Comparative Biochemistry and Physiology Part C: Comparative Pharmacology. 101(1), 117-123.

 

Touster, O. 1975: Metabolism and physiological effects of polyols (alditols). In : Physiological effects of food carbohydrates. Washington, DC: American Chemical Society. p 229-239

 

Uniqema (2002). Uniqema Toxicology Summary Report [Trade name]. Testing laboratory: Croda Europe Ltd., Goole, UK.Owner company: Croda Europe Ltd., Goole, UK. Report date: 2002-07-17.

 


Justification for selection of skin irritation / corrosion endpoint:
Hazard assessment is conducted by means of a read-across based on a 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 selection of eye irritation endpoint:
Hazard assessment is conducted by means of a read-across based on a 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

The available data on skin and eye irritation of structural analogues do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.