Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters

Endpoint summary

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): 1000 mg/kg bw/day (OECD 408)

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 origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with AnnexXI, 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

Justification for grouping of substances and read-across

There are no data available on the repeated dose toxicity via the oral route of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). In order to fulfil the standard information requirements set out in Annex IX, 8.6.2, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.

In accordance with 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).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

 

Overview of Repeated dose toxicity via the oral route.

CAS#	91031-45-7	68583-51-7	151661-88-0	1323-39-3
Chemical name	C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO)	Decanoic acid, mixed diesters with octanoic acid and propylene glycol	Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol	Stearic acid, monoester with propane-1,2-diol
Molecular weight	388.58 - 683.1	328.49 - 384.59	328.54 – 622.97	342.55
Repeated dose toxicity	WoE: RA: CAS 68583-45-7 RA: CAS 151661-88-0 RA: CAS 1323-39-3	1000 mg/kg bw/day (90 days, m/f)	1000 mg/kg bw/day (90 days, m/f)	7355 mg/kg bw/day (90 days, f) 5657 mg/kg bw/day (90 days, m)

 

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13). Structural similarity between source and target substances:

Discussion

No studies are available investigating the subchronic toxicity of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). In order to fulfil the standard information requirements set out in Annex IX, 8.6.2, in accordance with Regulation (EC) No 1907/2006 Annex XI, 1.5 read-across to the structurally related analogue substances Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0), Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) and Stearic acid, monoester with propane-1,2-diol (CAS 1323-39-3) is conducted.

Decanoic acid, mixed diesters with octanoic acid and propylene glycol was tested for subchronic oral toxicity in a 90-day study according to OECD guideline 408 in compliance with GLP and Stearic acid, monoester with propane-1,2-diol and Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol were tested using a protocol similar to OECD guideline 408 (Pittermann, 1993; Saatman, 1967; Pittermann, 1991).

Decanoic acid, mixed diesters with octanoic acid and propylene glycol and Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol, were administered to groups of 10 Wistar rats per sex and at doses of 100, 300 and 1000 mg/kg bw/day of the test material in peanut oil by gavage, 5 days/week for 13 weeks. Furthermore, additional satellite control and high-dose groups with 5 animals per sex were included in the studies for investigating the reversibility of possible effects after a 34-day post-exposure recovery period.

Stearic acid, monoester with propane-1,2-diol was administered to groups of 24 Sprague-Dawley rats per sex and dose at 1.5, 3.36 and 7.52% in the diet (calculated doses: 1158, 2571 and 5657 mg/kg bw/day (males) and 1461, 3214 and 7355 mg/kg bw/day (females)) for a period of 90 days.

Concurrent negative control groups receiving the vehicles or an isocaloric control diet (containing 7.52% mono-and diglycerides) only were included in all studies.

In all three studies, no mortality occurred in relation to the test substance.

Furthermore, in the study with Decanoic acid, mixed diesters with octanoic acid and propylene glycol, no clinical signs of toxicity or adverse effects on body weight or body weight gain in relation to the test substance were apparent. 5 animals out of different groups died at blood collection time points (no further information). Higher food consumption in the additional male high-dose group was observed due to higher body weight at start of the study. An increase in food consumption in the female high-dose group in Week 10, 12 and 13 was observed due to one animal caged individually. The water consumption of the male and female test groups showed no dose-related variations or reductions. Ophthalmoscopic, haematological and clinical examinations revealed no treatment related findings. No treatment-related changes or findings were apparent in organ weights, during gross pathology and histopathology examinations. Furthermore, the animals of the recovery groups showed no macroscopical compound-related alterations in the observed organs.

In the study with Stearic acid, monoester with propane-1,2-diol, a mild respiratory infection of the pleuro-pneumonia-like organism type was present in the weanling rats when they were assigned to the diets but the majority of the animals showed no observable signs of infection after the first few weeks on test. No significant difference in growth rate was observed in females. The mean body weight of male rats fed 1.5% of the test substance in the diet was significantly higher during Week 6 and 7. No effects on food efficiency were observed. A non-adverse increase in water consumption was seen in different groups during the study period without a dose-relationship. Blood chemical analyses, haematological determinations and urine analysis and organ to body weight or brain weight ratios showed no substance-related alternations. During gross pathology, a very high incidence of demonstrable lung involvement was observed upon necropsy. 163/192 rats showed gross lung pathology. These findings, mainly diffuse congestion and consolidation, were not related to any diet or sex but reflected a general condition of the entire group of rats. Histopathology revealed no substance-related adverse effects.

In the study with Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol no clinical signs of toxicity occurred during the study period. The total body weight gain of all groups, mean food and water consumption and the relative and absolute organ weights in all treatment groups showed no alterations when compared to controls. Haematological and biochemical parameters and ophthalmoscopic examinations showed few and slight differences to the control values and were considered incidental. The macroscopical examination of the organs displayed some spontaneous observations like discolouration of the thymus but no compound-related macroscopical effects were observed. However, in the male and female animals of all groups (including the recovery and control groups) the livers, the heart and the mandibulary lymph node showed effects which were due to a bacteriosis of unknown etiology. The liver and the heart of the recovery groups (high-dose group and control group) showed the same signs of bacteriosis and therefore prove the persistence of the bacteriosis. The histopathologic examination revealed no compound-related effects.

Thus, the resulting NOAELs of the three subchronic studies with the source substances Stearic acid, monoester with propane-1,2-diol (CAS 1323-39-3), Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) and Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) resulted in a NOAEL of ≥ 5657 mg/kg bw/day (males) and 1461, 3214 and 7355 mg/kg bw/day (females) and NOAELs of ≥ 1000 mg/kg bw/day, respectively.

Conclusion for subchronic repeated dose toxicity, oral

In summary, subchronic oral administration of the three structurally related analogue substances Stearic acid, monoester with propane-1,2-diol (CAS 1323-39-3), Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) and Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7), consistently showed no adverse systemic effects resulting in NOAELs of 1000 mg/kg bw/day and above.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is based on the weight of evidence from all available studies.

Justification for classification or non-classification

Based on read-across from analogue substances following an analogue and weight of evidence approach, all available data on repeated dose toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and the data are therefore conclusive but not sufficient for classification.