Octanoic acid, 1,1'-(1,3-propanediyl) ester

Endpoint summary

Description of key information

NOAEL oral, systemic ≥1000 mg/kg bw/d (OECD 408)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors and breakdown products and similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 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 of Propanediol dicaprylate (CAS 56519-71-2). In order to fulfill the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from a structurally related substance was 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

CAS	Chemical name	Molecular weight	Repeated dose toxicity oral
56519-71-2	Propanediol dicaprylate	328.49	RA: CAS 68583-51-7
68583-51-7	Decanoic acid, mixed diesters with octanoic acid and propylene glycol	328.49 - 384.59	Experimental result: NOAEL ≥1000 mg/kg bw/day (OECD 408)

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 endpoint for Propanediol dicaprylate (CAS 56519-71-2). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

A repeated dose toxicity study is available which was conducted with the source substance Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) in accordance with OECD guideline 408 and under GLP conditions in Wistar rats to assess the systemic toxicity at repeated doses. The substance was tested at dose levels of 0 (group 1), 100 (group 2), 300 (group 3) and 1000 (group 4) mg/kg bw/d. The test material was administered by gavage over a period of 90 days. 10 male and 10 female animals were used for each dose. In addition to the group 1 and the group 4, 5 male and 5 female animals were used to determine the reversibility of possible compound-related alterations (recovery group). All doses applied were tolerated without compound-related lethality. In each case 2 animals died earlier after the first respectively the second bloodletting. In the recovery group (1000 mg/kg bw/d), one male animal died after 35 applications without any substance related findings. No compound-related effects were observed. The mean food consumption of the male groups 2-4 showed some not dose-related variations. The mean food consumption of the female groups 2-4 showed a not dose-related decrease. The evident increase of the consumption in the group 4 in weeks 10, 12 and 13 of treatment was due to the high consumption of a single remaining animal in one cage. The mean water intake of the male groups 2-4 showed some no dose-related deviations. The mean water intake of the female groups 2-4 showed a not dose-related decrease. The evident increase of the consumption in the group 4 in weeks 10, 12 and 13 of treatment was due to reason mentioned above. The total body weight gain showed no compound-related deviations in all male and female test groups and was comparable to the controls.The haematological examinations showed no deviations in all male and female test groups. The clinical chemistry showed no deviations in all male and female test groups. The examination of the eyes by slit lamp microscope showed no compound-related effects. The absolute organ weights showed no deviations in all male and female test groups. The relative organ weights of the female group 2 showed an increase of the kidneys and a slight increase of the brain. The macroscopical examination of the organs of all groups, male and female, displayed some observations like hydrometra and edema in the area of the salivary glands which were noted as spontaneous. Possible compound-related effects were not observed. The organs of the male and female animals of the recovery group showed no macroscopical compound-related alterations after a treatment free period of 34 days. The microscopical examination of the organs of all male and female groups showed no compound-related effects, therefore no target organ was evaluated. Neither intermediate groups, nor the recovery groups were examined further. According to the study described, a daily administration of the test material up to 1000 mg/kg bw/d for male and female animals is not systemically toxic to rats. The NOAEL for this study is 1000 mg/kg bw/d.

Supportive information

The only functional group contained in the main product of 1,3-propanediol dicaprylate is the ester bond. Ester bonds are stable to acidic hydrolysis and so 1,3-propanediol dicaprylate is expected to enter the intestine unchanged. It is likely that lipases produced by the bile will initiate ester hydrolysis in the small intestine (Mattson, 1972). Any intact 1,3-propanediol dicaprylate ester that is absorbed will be rapidly cleaved by esterases in the blood (Testa, 2003). Main metabolites are expected to be 1,3-propanediol and caprylic acid. Since 1,3-propanediol caused no adverse effects upon oral administration for 90 days and caprylic acid is a naturally occurring fatty acid, subacute toxicity is not predicted for likely metabolites of propanediol dicaprylate.

 

Information on metabolites:

Subchronic oral toxicity study with 1,3-Propanediol (Gingell, 2003): NOEL = 1000 mg/kg bw

This study is published in a peer-reviewed journal by authors working for a chemical company or a contract research institute. Although not all details on the procedure are given, there is the general statement that the study was performed according the principles of Good Laboratory Practice and following the protocol given in the EPA Toxic Substances Control Act Health Effects Testing Guideline (40CFR 1989). Extensive hematological evaluations and sperm production/morphology were included because there were indications from in-vitro studies that malondialdehyde might be a metabolite. This study is therefore considered to be reliable and to give all relevant information on subchronic toxicity. Rats of the strain Crl:CD(SD)BR were treated by gavage with either 100, 300 or 1000 mg/kg bw of 1,3-propanediol for 90 days. Animals of the control group received water. For each dose group, 10 male and 10 female rats were used. The NOEL was determined to be 1000 mg/kg bw.

Caprylic acid occurs in food and is therefore part of the daily diet. In the USA, it has GRAS-status and is listed as a direct additive to food.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study 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

Based on read-across from a structurally related substance and following an analogue approach, the available data on the repeated dose toxicity 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.