Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In accordance with Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 1, a two-generation toxicity study is required if the repeated dose studies (28- or 90-day exposure) indicate adverse effects on reproductive organs and tissues. In regard to the available data on repeated dose toxicity, sufficient and reliable data (Klimisch score 2 to point to the fact that the studies were conducted on a read-across analogue substance) are available after long-term exposure to the read-across analogue substances 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) which did not reveal adverse effects on reproductive organs and tissues in rats in either sex. Therefore, performance of a two-generation study is scientifically unjustified and, in accordance with Annex XI, Section 1.2 of Regulation (EC) 1907/2006 further testing on vertebrate animals for that property shall be omitted.

 

Moreover, according to Regulation (EC) No 1907/2006, Annex IX, 8.7, Column 2, ”reproductive toxicity studies do not need to be conducted if the substance is of low toxicological activity and it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure”. As Propylenglycol dioleate is considered to be hydrolysed before absorption occurs as discussed in the toxicokientic statement (please refer to chapter 5 in the technical dossier), distribution of the intact glycol diester is not relevant but rather the absorption of the breakdown products of intestinal hydrolysis, which are considered to be either rapidly absorbed through the GI tract (propylene glycol; ATDSR, 1997, 2010; ICPS, 2001) or into the walls of the intestine villi (oleate; Lehninger, 1970). However, in accordance with the general rules set out in Regulation (EC) No 1907/2006, Annex XI, section 1.2, a weight-of-evidence approach based on the available toxicity data clearly demonstrates that Propyleneglycol dioleate exhibits no toxicological potency although absorption of the breakdown products occurs.

 

In conclusion, performance of a two-generation study is scientifically unjustified and, according to Annex XI, Section 1.2 of Regulation (EC) No 1907/2006 further testing on vertebrate animals for that property shall be omitted.

Justification for selection of Effect on fertility via oral route:
In accordance with Regulation (EC) No 1907/2006, Annex IX, 8.7.3 column 1, no two-generation study is required since no adverse effects on reproductive organs were seen in subchronic toxicity studies with structural analogues.

Effects on developmental toxicity

Description of key information

Oral (OECD 414, rat): NOAEL developmental toxicity: >900 mg/kg bw/day
Oral (OECD 414, rat): NOAEL maternal toxicity: >9000 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, partially due to read-across) 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 assessment leading 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 IX, 8.7.2.
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

Justification for read-across

There are no data on developmental 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 IX, 8.7.2.

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 pre-natal developmental toxicity after exposure to Propyleneglycol dioleate, read-across to reliable data on the analogue substances Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) and Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1) was conducted.

 

CAS 68583-51-7

Prenatal developmental toxicity of Decanoic acid, mixed diesters with octanoic acid and propylene glycol was characterised according to OECD guideline 414 under GLP conditions (Pittermann, 1994).

Groups of 24 female Sprague Dawley rats per dose level were orally dosed with 100, 300 and 1000 mg/kg bw/day by gavage from Day 6-15 of gestation. A concurrent negative control group receiving the vehicle (arachis oil) only was included in the testing as well. No maternal mortality occurred and no substance-related clinical signs of toxicity were observed. In addition, maternal body weight profiles were similar in all groups. Furthermore, at scheduled necropsy no macroscopic changes were noted in maternal animals.

No compound-related differences were observed in pre- and post-implantation loss, embryonic deaths, mean numbers of resorptions and total fetuses of the test groups in comparison to the control group. Mean fetal placental and uterus weights and body weights of live fetus exhibited no significant differences between treatment and control groups. In addition, the fetal sex ratio was not affected by treatment. No treatment-related fetal abnormalities or malformations were found at necropsy. The figures of skeletal and visceral variations in the treatment and control groups were considered to be comparable or of incidental origin due to missing dose-dependencies. Therefore, due to the lack of adverse effects in this study, the NOAEL for maternal toxicity and developmental toxicity for rats was considered to be ≥ 1000 mg/kg bw/day.

 

CAS 91031-31-1

Fatty acids, C16-18, esters with ethylene glycol was tested in an oral prenatal developmental toxicity study according to OECD guideline 414 in compliance with GLP (Pittermann, 1997).

Groups of 24 female Sprague-Dawley rats were dosed with 100, 300 and 900 mg/kg bw/day of Fatty acids, C16-18, esters with ethylene glycol via gavage from Day 6-15 of gestation. Concurrent negative control groups receiving the vehicle alone were included in all testings.

No mortalities in maternal animals and no compound-related symptoms were observed in the treatment groups. In addition, body weight and body weight gains were within the expected ranges. No compound-related differences were noted between the mean reproduction data of the test groups in comparison to the control group. At scheduled necropsy no macroscopic changes were noted in the dams of the treatment groups. Furthermore, pre-implantation loss, post-implantation loss, mean number of resorptions, embryonic deaths and total fetuses were not affected by treatment with the test substance. In addition, mean fetal placental and uterus weights were not affected. The fetal sex ratio was comparable in all groups and no treatment-related fetal abnormalities were found at necropsy. The examined fetuses showed no treatment-related malformations and the figures of visceral variations in the test groups were considered to be similar to the control group. The mean weight of live male and female fetuses in the mid-dose group was significantly increased, whereas the weights of live fetuses of the other treatment groups exhibited no significant differences. The figures of skeletal ossifications and variations showed no treatment-related deviations; thus various findings, all without dose-relationship, were considered to be incidental.

Based on the lack of adverse effects in this study, the NOAEL for maternal toxicity and developmental toxicity for rats was considered to be ≥ 900 mg/kg bw/day.

 

 

Conclusion for developmental toxicity

The available data on developmental toxicity of the read-across analogue substances Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1) and Decanoic acid, mixed diesters with octanoic acid and propylene (CAS 68583-51-7 did not show treatment-related effects on maternal animals or the offspring up to the highest tested dose level. Thus, no hazard for developmental toxicity was identified and hence, Propyleneglycol dioleate is not considered as hazardous for intrauterine development.

 

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 Effect on developmental toxicity: via oral route:
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).

Justification for selection of Effect on developmental toxicity: via inhalation route:
In accordance with Regulation (EC) No 1907/2006, Annex IX, no study is required to fulfil the data requirements.

Justification for selection of Effect on developmental toxicity: via dermal route:
In accordance with Regulation (EC) No 1907/2006, Annex IX, no study is required to fulfil the data requirements.

Justification for classification or non-classification

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