3-hydroxypropyl octanoate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert Statement

Type of information:

other: Expert Statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

Expert Statement

GLP compliance:

no

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. The moderate water solubility of 808 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the molecular weight of 202 g/mol 3-hydroxypropyl octanoate might pass through aqueous pores o r could be carried through the epithelial barrier by the bulk passage of water. The moderate log Pow value is also favourable for passive diffusion. Taken together, the physiochemical properties indicate that 3-hydroxypropyl octanoate becomes bioavailable following the oral route.
Due to the low vapour pressure of 3-hydroxypropyl octanoate it is unlikely that the substance will be available as a vapour to a large extend, but if it is the case absorption via inhalation route might be possible due to the moderate water solubility and the moderate log Pow value, enabling uptake direct ly across the respiratory tract epithelium by passive diffusion.
Dermal absorption will also take place, favoured by the water solubility and the log Pow value, and als o by the size of the molecule. The anticipated adsorption is moderate to high.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of 3-hydroxypropyl octanoate favour systemic absorption following oral, inhalative and dermal uptake. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After oral uptake, the substance will undergo enzymatic hydrolysis mainly in the liver resulting in propane-1,3-diol and octanoic acid. After dermal uptake, 3-hydroxypropyl octanoate may be enzymatically hydrolized already in the skin and the metabolites are further distributed via the systemic circulation.

Details on excretion:

The substance is expected to be hydrolyzed, resulting in Propane-1,3-diol and Octanoic acid. The alcohol is completely metabolized and excreted as CO2 and H2O. Octanoic acid is expected to be metabolized either for energy production, also resulting in H2O and CO2 and thus not expected to be excreted to a significant amount via faeces or urine, but via exhaled air. As mentioned above, the fatty acid may also be used for physiological functions or stored in adipose tissues.

Metabolites identified:

yes

Remarks:

The substance is the reaction product of octanoic acid and propane-1,3-diol. The substance can easily be degraded into these substances by hydrolysis.

Details on metabolites:

The genotoxicity studies indicated no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. The substance did also not indicate a skin sensitization potential. Thus no reactive intermediates are formed.
Hydrolization of the ester mainly takes place in the liver, but also in the skin. The metabolites formed in the skin enter the blood circulation and are expected to have the same fate as the hepatic metabolites. Those metabolites are octanoic acid and propane-1,3,-diol.
Propane-1,3-diol is rapidly metabolized through alcohol and aldehyde dehydroghenase enzymes breaking down the molecule into 3-hydroxypropionaldehyde, 3-hydroxypropionic acid or malonic acid and these molecules may finally be metabolized to carbon dioxide and water (Gessner et al., 1960).

Octanoic acid is enzymatically metabolized in the liver via β-oxidation for acetyl-CoA (AcCoA) generation, which can be further oxidized in the citric acid cycle and mitochondrial electron transport chain to release energy. The other possible pathway for AcCoA is the production of ketone bodies (acetoacetate, D-β-hydroxybutyrate, and acetone), which are transported to other tissues via the bloodstream. Acetone can be exhaled, acetoacetate and D-β-hydroxybutyrate can be oxidized via the citric acid cycle for energy production in various tissues (Ebert et al., 2003, Sonnay et al., 2019) Octanoic acid may therefore be completely eliminated via metabolization into carbon dioxide and water. In addition, the fatty acid can be re-esterified with glycerol to triacylglycerides, transported via plasma and stored in adipose tissue.

Conclusions:

Bioaccumulation of the test substanceis not considered critical based on expert statement.

Executive summary:

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the dermal, oral and inhalation route is expected. The substance is expected to be enzymatically hydrolized in the body. Bioaccumulation is not to be expected to be critical, a part of the substance (fatty acid) might be used in the body for physiological and structural functions (i.e. integration into cell membranes). The fatty acid might also be utilized for energetic purposes. Excretion products of both the alcohol and the fatty acid part are H₂O and CO₂.

Description of key information

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the dermal, oral and inhalation route is expected. The molecule is expected to be enzymatically hydrolyzed, resulting in propane-1,3-diol and octanoic acid. The alcohol is considered to be completely metabolized, whereas the fatty acid may also be completely metabolized into carbon dioxide and water via ß-oxidation for energy generation. The fatty acid may also be re-esterified with glycerol to triacylglycerides, transported via plasma and stored in adipose tissue or used for physiological functions such as incorporation into cell membranes (Lehninger, 1970; Stryer, 1994).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

3-hydroxypropyl octanoate is a colourless to light yellow liquid at room temperature with a molecular weight of 202 g/mol. The substance is soluble in water (808 mg/L at 20 °C). The log Pow was determined to be 3.3. The test substance has a low vapour pressure of 0.07 Pa at 20 °C. The test substance is a mono-constituent substance.

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. The moderate water solubility of 808 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the molecular weight of 202 g/mol 3-hydroxypropyl octanoate might pass through aqueous pores or could be carried through the epithelial barrier by the bulk passage of water. The moderate log Pow value is also favourable for passive diffusion. Taken together, the physiochemical properties indicate that 3-hydroxypropyl octanoate becomes bioavailable following the oral route.

Due to the low vapour pressure of 3-hydroxypropyl octanoate it is unlikely that the substance will be available as a vapour to a large extend, but if it is the case absorption via inhalation route might be possible due to the moderate water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Dermal absorption will also take place, favoured by the water solubility and the log Pow value, and also by the size of the molecule. The anticipated adsorption is moderate to high.

Distribution

As mentioned above, the physicochemical properties of 3-hydroxypropyl octanoate favour systemic absorption following oral, inhalative and dermal uptake. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After oral uptake, the substance will undergo enzymatic hydrolysis mainly in the liver resulting in propane-1,3-diol and octanoic acid. After dermal uptake, 3-hydroxypropyl octanoate may be enzymatically hydrolized already in the skin and the metabolites are further distributed via the systemic circulation.

Metabolism

The genotoxicity studies indicated no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. The substance did also not indicate a skin sensitization potential. Thus no reactive intermediates are formed.

Hydrolization of the ester mainly takes place in the liver, but also in the skin. The metabolites formed in the skin enter the blood circulation and are expected to have the same fate as the hepatic metabolites. Those metabolites are octanoic acid and propane-1,3,-diol.

 

Propane-1,3-diol is rapidly metabolized through alcohol and aldehyde dehydroghenase enzymes breaking down the molecule into 3-hydroxypropionaldehyde, 3-hydroxypropionic acid or malonic acid and these molecules may finally be metabolized to carbon dioxide and water (Gessner et al., 1960).

 

Octanoic acid is enzymatically metabolized in the liver via β-oxidation for acetyl-CoA (AcCoA) generation, which can be further oxidized in the citric acid cycle and mitochondrial electron transport chain to release energy. The other possible pathway for AcCoA is the production of ketone bodies (acetoacetate, D-β-hydroxybutyrate, and acetone), which are transported to other tissues via the bloodstream. Acetone can be exhaled, acetoacetate and D-β-hydroxybutyrate can be oxidized via the citric acid cycle for energy production in various tissues (Ebert et al., 2003, Sonnay et al., 2019) Octanoic acid may therefore be completely eliminated via metabolization into carbon dioxide and water. In addition, the fatty acid can be re-esterified with glycerol to triacylglycerides, transported via plasma and stored in adipose tissue.

 

Excretion

Propane-1,3-diol is completely metabolized and excreted as CO₂ and H₂0. Octanoic acid is expected to be metabolized either for energy production, also resulting in H₂O and CO₂ and thus not expected to be excreted to a significant amount via faeces or urine, but via exhaled air. As mentioned above, the fatty acid may also be used for physiological and structural functions, and additionally can be stored in adipose tissues.

 

 

 

References:

 

Ebert, D., Haller, R.G. and Walton, M.E.; Energy Contribution of Octanoate to Intact Rat Brain Metabolism Measured by 13C Nuclear Magnetic Resonance Spectroscopy; Journal of Neuroscience 2 July 2003, 23 (13) 5928-5935.

 

Gessner, P.K., Parke, D.V. and Williams, R.T.: Studies in Detoxication (1960). Biochemical Journal. 74;1-5.

 

Lehninger, A.L. (1970). Biochemistry. New York: Worth Publishers, Inc.

 

Sonnay, S., Chakrabarti, A., Thevenet, J., Wiederkehr, A., Christinat, N., Masoodi, M. (2019). Differential Metabolism of Medium-Chain Fatty Acids in Differentiated Human-Induced Pluripotent Stem Cell-Derived Astrocytes. Frontiers in Physiology. June 2019, Volume 10, Article 657.

 

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