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 adequate, reliable (Klimisch score 2) and consistent studies 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).
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 data for reproductive 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 reproductive 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 substance Sorbitan stearate (CAS 1338-41-6) was conducted.

 

CAS 1338-41-6

For Sorbitan stearate 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 be1000 mg/kg bw/day.

Sorbitan stearate was also investigated in a three-generation study with Wistar rats exposed via diet 12 weeks prior to mating and over a total time of 2 years (Oser 1956). 3333, 6666 and 13333 mg/kg bw/day of the test substance were administered to 12 males and 20 females in the parental generation and to 10 animals per sex in the F1, F2 and F3 generation (corresponds to 5, 10, 20% in diet; calculation based on the assumption of an average food consumption of 20 g/animal and an average body weight of 300 g). No clinical signs, effects on body weight, food consumption, organ weights were observed. At gross pathology and histopathology, no abnormalities occurred among the treated animals when compared to controls. With regard to the reproductive performance, the proportion of matings resulting in pregnancy tended to be lower at the 20% dose level in the F2 generation. In particular, the fertility index was about 20% decreased in the high-dose group when compared to controls. Therefore, a LOAEL of 13333 mg/kg bw/day and a NOAEL of 6666 mg/kg bw/day were determined for fertility.

 

Overall conclusion for reproductive toxicity

In conclusion, the available data on Sorbitan stearate did not indicateeffects on reproduction as the available studies revealed a NOAEL > 1000 mg/kg bw/day for fertility and systemic toxicity. Based on the read-across to Sorbitan stearate, Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol are not considered to exhibit hazardous properties in regard to fertility and reproduction.

 

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


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

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 studies are adequate and reliable studies 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): ≥ 1000 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies 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).
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 data for developmental 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 developmental 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 substance Sorbitan stearate (CAS 1338-41-6) was conducted.

 

A combined repeated dose/developmental toxicity screening study was performed according to OECD 422 with Sorbitan stearate 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 of1000 mg/kg bw/day was determined.

Effects of Sorbitan stearate on fetal development after oral administration to pregnant animals was also investigated in Wistar rats in a reliable but non-guideline study (Takada et al. 1986). 500 and 1000 mg/kg bw/day the test substance dissolved in squalene were orally administered to 20 rats from day 0 to day 20 of gestation. At sacrifice on day 20 of gestation, no differences between dose and control groups were observed with regard to clinical signs, body weights and post-mortem examinations of organs (not further specified). One fetus of the highest dose group showed retardation (no further details were given). As this effect was not observed in other fetuses of the same dose group, it was considered to be incidental and not treatment-related. Two fetuses of the 500 mg/kg bw dose group and one fetus of the 1000 mg/kg bw dose groups showed incomplete ossification of cervical vertebral arches. A cervical rib was observed in one control group animal, in four animals of the 500 mg/kg bw/day dose group, and in three fetuses at dosing of 1000 mg/kg bw/day. Asymmetry of sternebrae was observed in four fetuses of the 500 mg/kg bw group and five fetuses of the highest dose group. Incompletely ossified sternebrae was found in 27 fetuses at dosing of 500 mg/kg bw and in 39 fetuses at dosing of 1000 mg/kg bw/day. A lumber rib was observed in one fetus of the 500 mg/kg bw/day dose group and in three control group animals. Since the effects described occurred to the same extent in control and test group animals, the changes were not assumed to be caused by the test item, but as natural occurrence in comparison with background data of the test laboratory. In the 1000 mg/kg bw/day dose group, body weight gain of fetuses was slightly suppressed but there was no significant difference when compared to controls. Therefore, a developmental NOAEL of 1000 mg/kg bw/day was determined.

 

Overall conclusion for develomental toxicity

The available data on Sorbitan stearate did not indicate effects on intrauterine development as the available studies revealed NOAELs 1000 mg/kg bw/day for developmental toxicity. Based on the read-across to Sorbitan stearate, Fatty acids, rape-oil, mixed esters with 1,4:3,6-dianhydro-d-glucitol, sorbitan and sorbitol are not considered to affect intrauterine development.

 

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 Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected studies are adequate and reliable studies 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

The available data on reproductive and developmental 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