Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

Justification for read-across

There are no data for genetic toxicity available for Propyleneglycol dioleate. 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, 8.4.

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”. 

Propyleneglycol dioleate represents an UVCB substance comprised of diesters of 1,2-propyleneglycol chemically linked to mainly oleic acid (C18:1) and/or palmitic and/or stearic acid (C16, C16:1).Gylcol esters are in general known to bestepwise hydrolysed by gastrointestinal enzymes into the free fatty acid component and the respective alcohol (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972).

Based on thecommon metabolic fate of glycol esters, the read-across approach is based on the presence ofcommon functional groups, common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals,common functional groups, structural similarities and similar physico-chemical, toxicological and 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 mutagenic properties of Propyleneglycol dioleate, read-across to reliable data on the analogue substances Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol (CAS 84988-75-0), C8-C10-1,3-Butandiolester (CAS 853947-59-8) and Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1) was conducted.

 

 

Genetic toxicity (mutagenicity) in bacteria in vitro

CAS 84988-75-0

A study investigating the genetic toxicity in vitro of Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol is available. The study was conducted according to OECD guideline 471 under GLP conditions (Banduhn, 1991). In two independent experiments, the tester strains Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 and TA 1538 were tested according to the plate incorporation procedure. Concentrations from 8 to 5000 µg/plate were investigated with and without a metabolic activation system (Aroclor 1254-induced rat liver S9-mix). No increase in the number of revertant colonies was noted in any of the bacterial strains, with and without metabolic activation system. No cytotoxicity was observed up to the highest dose tested. The included positive and negative controls showed the expected results and were therefore considered as valid. Thus, under the conditions of this study, the test substance did not induce mutations in the bacterial mutation tests in the absence and presence of a metabolic activation system in any of the strains tested.

 

Genetic toxicity (cytogenicity) in mammalian cells in vitro

 

CAS 853947-59-8

An in vitro mammalian chromosome aberration test was conducted with C8-C10-1,3-Butandiolester in accordance with OECD guideline 473 under GLP conditions (Dechert, 1997). The induction of structural chromosome aberrations was evaluated in vitro in Chinese hamster lung fibroblasts (V79 cells), incubated for 18 and 28 h with and without a metabolic activation system (S9-mix from rats treated with Aroclor 1245). Concentrations of 10-100 µg/mL (18 h incubation) and 80 and 100 µg/mL (28 h incubation) of the test substance in the vehicle ethanol were applied. The solubility limit of the test substance in the vehicle ethanol in the culture medium was determined to be 100 µg/mL. In the first experiment without metabolic activation, the negative controls exhibited a mitotic index of 2.0% only and the experiment was therefore repeated. Thereafter, the negative as well as the positive controls showed the expected results and were within the range of historical control data. The frequency of polyploidy cells with and without metabolic activation was within the expected range (< 10%). In the experiments both with and without metabolic activation, a systematic influence of the test substance was observed, which led to a reduction in the mitotic index. No statistically or biologically significant increase in the incidence of chromosome aberrations was observed.

Therefore, under the conditions of the study, C8-C10-1,3-Butandiolester did not show clastogenic activity in this chromosomal aberration test with and without metabolic activation performed in Chinese hamster lung fibroblasts in vitro.

 

Genetic toxicity (mutagenicity) in mammalian cells in vitro

 

CAS 91031-31-1

Mutagenic properties of Fatty acids, C16-18, esters with ethylene glycol were characterized in an in vitro mammalian cell gene mutation study according to OECD guideline 476 under GLP conditions (Verspeek-Rip, 2010). Gene mutations in the thymidine kinase locus were investigated in L5178Y mouse lymphoma cells in the presence and absence of a metabolic activation system (Phenobarbital/β-naphtoflavone-induced rat liver S9). In the first experiment, cells were exposed for 3 h to the test substance at concentrations of 0.1-333 µg/mL (in DMSO) with and without metabolic activation. Concentrations of the second experiment without metabolic activation for an exposure time of 24 h ranged from 3-175 µg/mL and with metabolic activation (3 h; 12% S9-mix) from 0.1-333 µg/mL. The vehicle and positive controls in the study showed the expected results and were within the range of historical control data. No cytotoxicity was observed up to the precipitating concentration of 100 µg/mL and up to 333 µg/mL, respectively. There was no significant increase in the number of forward mutations at the thymidine kinase locus of L5178Y mouse lymphoma cells treated with the test material, neither in the presence nor in the absence of a metabolic activation system. Under the conditions of the study, Fatty acids, C16-18, esters with ethylene glycol did not show gene mutation activity in this test performed in L5178Y mouse lymphoma cells in vitro.

 

Conclusion on genetic toxicity

The available data on read-across analogue substances do not provide evidence that Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol (CAS 84988-75-0), C8-C10-1,3-Butandiolester (CAS 853947-59-8) or Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1) exhibit mutagenic or clastogenic properties in either bacteria or mammalian cells. Therefore, no properties for genetic toxicity are expected for Propyleneglycol dioleate.

 

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.

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.Long, C.L. et al. (1958). Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys, 77(2):428-439.

Mattson, F.H. and Volpenhein, R.A. (1972). Hydrolysis of fully esterified alcohols containing

from one to eight hydroxyl groups by the lipolytic enzymes of the rat pancreatic juice. Journal

of Lipid Research 13: 325-328

 

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.

 

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


Justification for selection of genetic toxicity endpoint
Hazard assessment is conducted by means of 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). No study was selected, since all available in vitro genetic toxicity studies were negative.

Short description of key information:
Genetic toxicity in vitro:
Ames test (OECD 471): negative with and without metabolic activation in S. typhimurium TA 98, TA 100, TA 1535, TA 1537 and TA 1538
Chromosome aberration (OECD 473): negative with and without metabolic activation in Chinese hamster lung fibroblasts (V79) cells
Gene mutation in mammalian cells (OECD 476): CAS 91031-31-1: negative with and without metabolic activation in L5178Y mouse lymphoma cells

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the analogue read-across approach, the available data on genetic 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.