[No public or meaningful name is available]

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

In vitro metabolism in rat serum, liver and intestinal homogenates, with rates of hydrolysis

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

other: in vitro

Preliminary studies:

Ester hydrolysis did not take place when the test material was added to biological media directly without a solvent. Rapid hydrolysis was achieved when test material was added in a solution in DMSO.

Type:

metabolism

Results:

Hydrolysis by carboxyesterases

Details on absorption:

Low, due to lipophilic nature of the test substance. No hydrolysis was noted in the absence of solvent, indicating that bioavailability is very low.

Metabolites identified:

yes

Details on metabolites:

Hydrolysis occurred upon incubation with rat serum, liver and intestinal enzyme preparations, with iberation of hexanol, initially 1 mole per mole of parent compound. Mass spectroscopy identified initial formation of dihyhexyl citrate. The generation of the diester, monoester and product (citrate plus hexanol) was 0.02 h, when the concentration was 50 nmol/ml of medium. Hydrolysis as measured by generation of hexanol is 5 times faster in serum than in liver, and is slowest in intestinal preparations. Rate of hydrolysis is concentration dependent, with faster breakdown at lower concentrations than at higher. Hydrolysis of the hexyl moiety was faster than hydrolysis of the acetyl or butyryl moieties in analogue substances.
In rat liver, the half lives of ester hydrolysis and hexanol formation was 6 and 0.04 h. This is slower than in serum.
Hexanol was found to be stable during incubation with rat serum for 8 h, not showing further oxidation. Incubation of hexanol in rat liver cytosolic fraction indicated that this alcohol undergoes enzymatic modification, with half lives of 2.7, 3 and 56 hours at concentrations of 50, 150 and 3000 nmol/ml. No identification of products was presented.
Hydrolysis of the hexyl moiety is faster than that of the acetyl moiety on the citrate portion of the molecule. No hexyl citrate was formed during incubation of acetyl trihexyl citrate.

Bioaccessibility (or Bioavailability) testing results:

The substance is not highly bioavailable due to low water solubility and high lipophilicity.

Conclusions:

The in vitro hydrolysis of the test material was investigated in preparations of rat serum, liver homogenate and intestinal homogenate. The half-life of the substance was 0.02 h (at 50 nmol/ml serum), and relatively fastest in serum which is rich in carboxyesterases. The breakdown initially formed acetyl dihexyl citrate and hexanol, the latter of which was stable for 8 h in serum. Hydrolysis was slower in rat liver, at 0.3 h. Bioavailability in vivo is expected to be low, due to the low water solubility and high lipophilicity of the substance; DMSO solvent was needed to solubilize the material for this in vitro experiment.

Description of key information

Limited bioavailability; rapid metabolism by esterases.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

Molecular weight 487 (< 1000)

Water solubility: insoluble, 0.0006 mg/L (est).

Log Kow: 7.23 (est).

Lipinski Rule of 5: 1 violation

Fouda, 1982: Not bioavailable in biological fluids (serum, liver homogenate or intestinal cell homogenate) without a solvent (DMSO). Potentially soluble as micelles with bile fluids. No significant oral toxicity observed in acute and subchronic studies.