Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol

Endpoint summary

Description of key information

Repeated dose toxicity, oral: toxicity studies from read-across analogues revealed no adverse effects up to the highest dose tested

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 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.

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 data on repeated dose 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 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 repeated dose toxicity 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 stearate (CAS 1338-41-6) and Sorbitan laurate (CAS 1338-39-2) was conducted.

 

CAS 1338-41-6

Subacute toxicxity

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 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.

 

Chronic toxicity

A two-year study equivalent to OECD 452 was performed with 12 rats/sex/dose exposed to 2, 5, 10 and 25% Sorbitan stearate via daily diet, corresponding to 2500, 5000, 10000 and 25000 mg/kg bw/d (based on the assumption of a mean body weight of 200 g and a mean daily food intake of 20 g per animal and day) (Fitzhugh, 1959). The test substance caused a significant increase in mortality at the 10% and 25% levels. Growth depression, kidney and common bile duct enlargement as well as slightly fatty changes in some livers along with increases in liver weights were observed at 25%. The NOAEL was therefore set at 5000 mg/kg bw/day, which is equivalent to the 5% level.

 

In addition, a second chronic study with dogs is available (Fitzhugh, 1959). Sorbitan stearate was administered to 2 Mongrel Irish terrier dogs/sex from 1 to 6 years of age via a semi synthetic diet at 5% of the total food intake, corresponding to approx.638 mg/kg bw/day, for 20 months. Feeding of 5% test substance had no adverse effect on dogs. At autopsy as well as at microscopic examination the animals showed no effects attributable to the test substance. The NOAEL was therefore set to be≥638 mg/kg bw/day (Fitzhugh, 1959).

 

A carcinogenicity study with Sorbitan stearate, performed similar to OECD 451, was conducted with 84 male and female mice (Hendy et al. 1978). Animals were treated with the test substance for 80 weeks at 0.5, 2 and 4% in diet, corresponding to 650, 2600 and 5200 mg/kg bw/d (calculated based on data given in the report: 2% = 2600 mg/kg bw/day). No effects on condition or behaviour were seen during the study period. Deaths occurred in all groups during the course of the experiment, but there was no relationship between the number of deaths at any time and the dietary level of test substance. Significant lower mean body weights were observed in male mice fed 4% test substance at week 37 when compared to controls. At week 80 there was a slight but significantly higher total erythrocyte count in male mice fed 4% test substance. In females of the same dose group, significantly lower numbers of total leucocytes over the whole study period were detected whereas the number of leucocytes in the corresponding males was higher at week 2. Afterwards the leucocyte count dit not differ significantly from that of the controls at week 52 or 80. In female animals fed 4% test substance, a significantly higher percentage of neutrophils at week 80 was observed. Fluctuations in the absolute and relative organ weights were observed in male and female animals of all test groups for the brain, liver, spleen, kidney and stomach reaching statistical significance for the relative kidney weight of both genders in the 4% dose group. An increased incidence of nephrosis was observed at histopathology in the kidneys of the male and female mice fed 4% test substance. Taking the results of this study into consideration, a NOAEL of 2600 mg/kg bw/day (corresponding to 2% in diet) was determined based on the haematological and histopathological examinations as well as organ weight changes.

 

In summary, neither short- or long term exposure studies in rodents identified hazardous properties of Sorbitan stearate as the available studies consistently lead to NOAELs ≥ 1000 mg/kg bw/day. Moreover, no adverse effects were observed in dogs treated chronically with Sorbitan stearate.

 

CAS 1338-39-2

Subchronic toxicity

An oral 90 day repeated dose study was performed similar to OECD 408 with Sorbitan laurate in male and female Wistar rats (Cater 1978). 30 animals each were fed 2.5, 5.0, 10.0% of the test substance, equivalent to 2100/2300, 4200/4500, 8000/8400 mg/kg bw/day for males/females, respectively. No mortalities or abnormal clinical signs occurred in any dose group. Mean food consumption was dose-dependently decreased during the treatment when compared to controls. A decrease in body weights was seen in the 5 and 10% dose groups 2 days after beginning of treatment which remained less until the end of the study. Haemoglobin concentration and packed cell volume were decreased in all groups in a dose dependent manner. At pathology, mean relative liver and kidney organ weights were dose dependently increased when compared to controls. All effects described were observed both sexes. At histopathology, periportal vacuolation was observed in the livers of high dosed animals and an increase of periportal fat was determined in females (5, 10% group) and males (10% group). Therefore, no NOAEL could be determined and a LOAEL of 2100 mg/kg bw/day was set.

 

Furthermore, two studies with Sorbitan laurate were performed with 25% test substance given via diet to Wistar rats for 59 and 70 days, respectively (Harris et al. 1951). In the first study, nearly all animals died, therefore a second study was performed starting with a dose level of 5% which was increased to 25% during the first 10 days. 10/14 males and 9/16 females died until the end of the treatment period in the second study. Inactivity in the experimental group animals was observed as well as nasal hemorrhages, gangrenous tails and hind legs. Body weight gain and food intake was reduced in test group animals. At gross pathology, 8/11 survivors of the test group had a fatty liver. Increased relative weights of brain, kidney, heart, spleen, lung, and liver were determined in treated animals when compared to controls. At histopathology, irritating effects in the gastrointestinal tract were observed (no further details were given) as well as degenerative alterations in kidney, necrosis in liver as well as fat globules in many liver cells, and alterations in the spleens, testes and ovaries. Due to these results, a LOAEL of 11750 mg/kg bw/day (based on an average daily uptake of 4.7 g feed and an average body weight of 100 g), corresponding to the 25% dose level, was derived. Since both studies were limited in documentation and the test systems are unsuitable, due to the increased administered doses, they were not further taken into account for risk assessment.

  

Overall conclusion for repeated dose toxicity

In summary, the available and reliable data on the structural analogue substances Sorbitan laurate and Sorbitan stearate consistently showed no or low hazardous properties after subacute and long-term exposure. Therefore, Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol is not considered as hazardous after repeated exposures.

 

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

 

Harris, R. S. et al. (1951). Nutritional and pathological effects of sorbitan laurate, polyoxyethylene sorbitan laurate, polyoxyethylene laurate, and polyoxyethylene monstearate when fed to rats. Arch of biochem and biophys 34: 249-258.

 

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 repeated dose toxicity via oral route - systemic effects 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 repeated dose 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.