Registration Dossier

Administrative data

Description of key information

Acute toxicity: Oral LD50 (rat, m/f): > 2000 mg/kg bw
Acute toxicity: Inhalation LC50 (rat, m/f): > 5.27 mg/L air

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) studies from reference substances 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).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessmentleading 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, in accordance with Annex XI, 1.5, 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 and 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 assessmentleading 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, 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 are no data for acute toxicity 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 esters, 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 acute toxicity following the oral, dermal or inhalation route 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), Sorbitan, (Z)-9-octadecenoate (2:3) (CAS 8007-43-0) and Sorbitan laurate (CAS 1338-39-2) was conducted.

Acute oral toxicity

CAS 1338-43-8

For Sorbitan oleate, two reliable acute toxicity studies following oral exposure are available (Klimisch score # 2) performed similar to OECD 401. 10 rats of each sex were orally exposed to a single dose of 39800 mg/kg bw. In both studies, no mortality was observed during the study period. In the first study, animals exposed to sorbitan oleate showed clinical signs of intoxication including depression, decreased respiration, messy fur and diarrhea (Rzucidlo, 1966), latest was also observed in the second study as only clinical sign (Quigley 1966). Moreover, gross pathology revealed alterations in lungs, adrenals, kidneys, heart and stomach in several test animals (Quigley 1966).

In summary, the oral LD50 of Sorbitan oleate is greater than 39800 mg/kg bw.

 

 

CAS 26266-58-0

The acute toxic potency of Anhydro-D-glucitol trioleate was tested similar to OECD 401. 10 male and 10 female rats were orally treated with 39800 mg/kg bw via gavage. No mortality occurred during the 14 day observation period. Observed clinical signs included depression, diarrhea and pallor. At necropsy, alterations in heart, kidneys and lungs were observed in few animals (20%) (Quigley 1966).

Therefore, under the conditions of this study, the oral LD50 in male and female rats was greater than 39800 mg/kg bw.

 

 

CAS 8007-43-0

Sorbitan, (Z)-9-octadecenoate (2:3) was tested in an acute oral toxicity study performed similar to OECD 401 (Rzucidlo, 1966). 10 male and 10 female rats were exposed to 39800 mg/kg bw test substance by gavage. No mortality occurred. Decreased respiration, depression, messy fur, and diarrhea were noted within the first 96 h during the 14 day observation period. No treatment-related gross pathological findings were observed at necropsy (Rzucidlo 1966).

Under the conditions of this study, the oral LD50 in male and female rats was greater than 39800 mg/kg bw.

 

 

CAS 1338-39-2

For Sorbitan laurate, two studies similar to OECD 401 were performed (Quigley 1966, 1967), which revealed LD50 values of > 30000 mg/kg bw in male and female rats. Diarrhea was the only clinical sign observed in these studies. Furthermore, 10 rats were exposed to 16000 mg/kg bw Sorbitan laurate, which did not induce mortality. Epistaxis was the only sign of intoxication observed (Saatmen, 1977). However, due to limited documentation, the study is considered as not assignable (RL4) and was not taken into account for risk assessment.

 

Therefore, under the conditions of this study, the oral LD50 in male and female rats was greater than 2000 mg/kg bw.[MM2] 

 

Overall conclusion

In summary, based on the available and reliable data on acute oral toxicity of the read-across analogue substances, the oral LD50 of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol is considered to be greater than 2000 mg/kg bw.

 

Acute inhalation toxicity

Reliable data from the read-across analogue substances Sorbitan laurate (CAS 1338-39-2) and Anhydro-D-glucitol trioleate (CAS 26266-58-0) are available to evaluate acute toxicity following inhalation.

 

CAS 26266-58-0

Sorbitan laurate was tested according to OECD 436 under GLP conditions. 3 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).

 

CAS 1338-39-2

Moreover, a GLP compliant inhalation study was performed according to OECD 436 (GLP study) with Anhydro-D-glucitol trioleate. 3 male and female Wistar rats each were exposed via nose only to 5.27 mg/L as aerosol for a single exposure duration of 4 hours (Harlan 2012). Common abnormalities noted during the study included increased respiratory rate, hunched posture, piloerection, red/brown staining around the snout and wet fur. The animals recovered to appear normal in between 3 to 5 days post-exposure. No mortalities occurred. Thus, a LC50 > 5.27 mg/L was derived.

 

Overall conclusion

The reliable data on acute inhalation toxicity conducted with the read-across substances Sorbitan laurate and Anhydro-D-glucitol trioleate do not reveal evidences that Sorbitan fatty acid ester exhibit acute toxic properties after respiration. Therefore, Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol are not considered as hazardous following acute inhalation.

 

Acute dermal toxicity

No reliable studies on acute dermal toxicity is available for Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol . In regard to the estimated dermal absorption of 1.05 E-005 mg/cm²/h as calculated with DERMWIN (v 2.02, Epiweb 4.1), dermal uptake of Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol is considered as very low. Therefore, dermal exposure to Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitolis not expected to be associated with any adverse effects on human health as dermal absorption can be considered as negligible.

 

Overall conclusion for acute toxicity

In summary, reliable data available for the read-across analogue substances indicate a very low level of acute toxicity as oral LD50 values were greater than the threshold level of 2000 mg/kg bw. Moreover, LC50 values of > 5 mg/L were determined for acute toxicity following inhalation.

In conclusion, the reliable data did not identify a hazard for either the oral or inhalation route, and hence, Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitolis not considered as hazardous after acute exposure. Dermal absorption is considered as negligible due to the estimated dermal absorption.

 

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

 

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


Justification for selection of acute toxicity – oral 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 acute toxicity – inhalation 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 acute toxicity – dermal endpoint
Dermal uptake of Fatty acids, rape-oil, monoesters with sorbitan is considered as low. Therefore, dermal exposure to Fatty acids, rape-oil, monoesters with sorbitan is not expected to be associated with any adverse effects on human health as dermal absorption can be considered as nearly negligible.

Justification for classification or non-classification

The available data on acute toxicity 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.

No data an acute dermal toxicity are available.