Ethane-1,2-diyl palmitate

Endpoint summary

Description of key information

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

The hazard assessment is based on the data currently available. Pursuant to ECHA decision on a compliance check CCH-D-2114546559-35-01/F new studies with the registered substance will be conducted in the future. The finalised studies will be reported in an updated dossier until 22 July 2024 and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

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

The hazard assessment is based on the data currently available. Pursuant to ECHA decision on a compliance check CCH-D-2114546559-35-01/F new studies with the registered substance will be conducted in the future. The finalised studies will be reported in an updated dossier until 22 July 2024 and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

Data matrix

Repeated dose toxicity, oral

CAS #	NOAEL (rat) [mg/kg bw/day]
624-03-3 (a)	RA: CAS 68583-51-7 RA: CAS 1323-39-3 RA: CAS 151661-88-0
627-83-8	RA: CAS 68583-51-7 RA: CAS 1323-39-3 RA: CAS 151661-88-0
151661-88-0 (b)	1000 (m,f)
1323-39-3	7355 (f) 5657 (m)
68583-51-7	1000 (m,f)
84988-75-0	RA: CAS 68583-51-7 RA: CAS 1323-39-3 RA: CAS 151661-88-0

(a) Category members subject to registration are indicated in bold font. Only for these substances a full set of experimental results and/or read-across is given.

(b) Substances not subject to registration are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

CAS 68583-51-7

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 (Pittermann, 1993).

Groups of 10 Wistar rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day of the test material in peanut oil by gavage, 5 days/week for 13 weeks. A concurrent negative control group receiving the vehicle only was included. Furthermore, additional satellite control and high-dose groups with 5 animals per sex were included in the study for investigating the reversibility of possible effects after a 34-day post-exposure recovery period. No clinical signs or mortality occurred in relation to the test substance during the study period in any animal. During the study period, 5 animals out of different groups died at blood collection time points (no further information). No adverse effects on body weight or body weight gain were noted. 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 examinations revealed no treatment related findings. No treatment-related changes in the haematological and clinical parameters and organs weights were measured. During gross pathology and histopathology no treatment-related findings were observed. Furthermore, the animals of the recovery groups showed no macroscopical compound-related alterations in the observed organs.

Based on the lack of adverse effects, a NOAEL of 1000 mg/kg bw/day (m, f) was identified in this study.

 

Repeated dose toxicity: other routes

An intramuscular repeated dose study with the test material is available. Decanoic acid, mixed diesters with octanoic acid and propylene glycol was tested in a non-guideline study for repeated dose intramuscular irritation in rabbits (Consultox Laboratories, 1976). Six New Zealand White rabbits were given 0.24 mL/kg bw/day of the undiluted test substance by intramuscular injection for 10 days. In addition, a castor oil BP control group was included in the study. The test substances were applied into the biceps of the right hind leg of each rabbit. The untreated control muscles were found to be within normal limits. The test substance seemed to be an irritant to muscles and caused muscle necrosis after repeated injections. Furthermore, some giant cell granulomata were observed after repeated treatment. Animals similarly treated with castor oil BP showed more severe effects.

 

CAS 624-03-3, CAS 627-83-3 and CAS 84988-75-0

Within the Glycol Ester category, two further subchronic repeated dose studies after oral administration are available. Therefore, the studies of the category members stearic acid, monoester with propane-1,2-diol (CAS 1323-39-3) and Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) were considered for assessment and read-across was conducted based on a category approach.

Stearic acid, monoester with propane-1,2-diol and Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol were tested in subchronic studies via the oral route following a protocol similar to OECD guideline 408 (Saatman, 1967; Pittermann, 1991).

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. Furthermore, a group receiving an isocaloric control diet containing 7.52% mono-and diglycerides was included as control group. In all treatment groups, the total fat additive in the diet was equal to 7.52% by substitution with a control fat mono-and diglycerides.

No mortality occurred during the study period in any animal. 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 showed no finding in incidence or concentration considered to be substance-related. When organ to body weight or brain weight ratios for each experimental group of rats were compared separately with the control group, no biologically relevant differences were observed. During gross pathology, a very high incidence of demonstrable lung involvement was observed upon necropsy of the rats in this study. 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.

Based on the lack of adverse effects, a NOAEL of 7.52 % in the diet equivalent to the calculated doses of 7355 mg/kg bw/day (f) and 5657 mg/kg bw/day (m) was identified in this study.

 

A study with Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol is available within the Glycol Ester group (Pittermann, 1991). Groups of 10 Wistar rats per sex and dose were given 100, 300 and 1000 mg/kg bw/day of the test material in peanut oil by gavage, 5 days/week for ca. 13.5 weeks. A concurrent negative control group receiving the vehicle only was included. Furthermore, additional satellite control and high-dose groups with 5 animals per sex and dose were included in the study for a 32-33-day recovery period. No mortality or clinical signs of toxicity occurred during the study period. The total body weight gain of all groups showed no deviation and was comparable to the control group. The mean food and water consumption in all treated groups was comparable to the control group. Relative and absolute organ weights showed no substance-related differences to the control group.

Haematological parameters showed few and slight differences to the control values and were considered incidental The biochemical examinations revealed dose-independent findings which were not considered to be substance-related. The opthalmoscopic examinations showed no compound-related effects. The absolute and relative organ weights in all groups showed no deviations and were comparable to the control. 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.

Based on the lack of adverse effects, a NOAEL of 1000 mg/kg bw/day (m, f) was identified in this study.

 

Conclusion for subchronic repeated dose toxicity, oral

In summary, subchronic oral administration of three substances of the Glycol Ester category: Stearic acid, monoester with propane-1,2-diol, Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol and Decanoic acid, mixed diesters with octanoic acid and propylene glycol, consistently showed no adverse systemic effects resulting in NOAELs of 1000 mg/kg bw/day.

 

There are no data available on the repeated dose toxicity after dermal application and inhalation of the category members.

 

References

Agency for Toxic Substances and Disease Registry (ATSDR) (1997): Toxicological Profile for Propylene Glycol. US Department of Health and Human Services. Atlanta, US.

Agency for Toxic Substances and Disease Registry (ATSDR) (2010): Toxicological Profile for Ethylene Glycol. US Department of Health and Human Services. Atlanta, US.

Gubicza, L., Kabiri-Badr, A., Keoves, E., Belafi-Bako, K. (2000): Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

Heymann, E. (1980): Carboxylesterases and amidases. In: Jakoby, W.B., Bend, J.R. & Caldwell, J., eds., Enzymatic Basis of Detoxication, 2nd Ed., New York: Academic Press, pp. 291-323.Gubicza, L. et al. (2000). Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

International Programme on Chemical Safety (IPCS) (2001): Ethylene Glycol. Poisons Information Monograph. PIM 227.

Lilja, J. et al. (2005). Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst. Chemical Engineering Journal, 115(1-2): 1-12.

Liu, Y. et al. (2006). A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis 242: 278-286.

Miller, O.N., Bazzano, G. (1965): Propanediol metabolism and its relation to lactic acid -metabolism. Annals of the New York Academy of Sciences 119, 957-973.

Radzi, S.M. et al. (2005). High performance enzymatic synthesis of oleyl oleate using immobilised lipase from Candida antartica. Electronic Journal of Biotechnology 8: 292-298.

Ritchie, A.D. (1927): Lactic acid in fish and crustacean muscle. Journal of Experimental Biology 4, 327-332.

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

Tocher, D.R. (2003): Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish. Reviews in Fisheries Science 11(2), 107-184.

WHO (2002): Ethylene Glycol: Human Health Aspects. Concise International Chemical Assessment Document 45.

Zhao, Z. (2000). Synthesis of butyl propionate using novel aluminophosphate molecular sieve as catalyst. Journal of Molecular Catalysis 154(1-2): 131-135.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the Glycol Ester Category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, all available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.