Nonanoic acid, mixed diesters, with oxybis[propanol] and dodecanoic acid

Endpoint summary

Description of key information

This toxicokinetic study (OECD 417) in Sprague-Dawley rats revealed:

- a low bioavailability, no accumulation and an inter-individual difference.

- C12-C12 and C9-C12 only detected in GI tract. C9-C9 detected in several tissues of almost all animals and absorbed into circulation to some degree.

- rapid elimination and metabolization in the digestive tract of rats.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

In accordance with the section 8.8.1 of Annex VIII in REGULATION (EC) No 1272/2008, the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available data. A toxicokinetic study (OECD 417) in Sprague-Dawley rats has been performed and described below.

 

Toxicokinetic study (OECD 417, 2019, iPhase Biosciences, K, RS)

 

ADME properties of the test substance (CAS: 2166089-27-4), dodecanoic acid mixed diesters with dipropylene glycol and nonanoic acid was tested in the Sprague-Dawley rats based on OECD guideline 417. Bio-analytical methods (LC-MS/MS) were developed and validated to determine the test substance in biological samples of SD rats. Potential metabolites of the test substance were identified using full ion scanning mode. A total of nine experimental groups (Groups #1~9) were designed in thein vivostudies as follows: a single intravenous dose group (#1), a low single oral dose group combined with initial exposure (#2), a high single oral dose group (#3), a trough repeated oral dose group (#4), a repeated oral dose group with last exposure (#5), a feces and urine excretion group (#6), a biliary excretion group (#7), a tissue distribution group (#8) and a gastrointestinal residual group (#9). In addition, threein vitrostudies were conducted on the test item, including plasma protein binding test, liver microsomal metabolism test, and recombinant CYP 450 enzymes metabolism test.

 

The test substance is composed of three components of C12 -C12 at 26.43%, C9 -C12 at 50.82%and C9 -C9 at 22.75%. In rats administrated intravenously with the test substance, the Apparent Volume of Distribution (Vz) of C12 -C12 was 0.24±0.040 L/kg, and the elimination half-life(t1/2z) of C12 -C12 was 1.02±0.18 h. C9 -C12 in plasma was also rapidly eliminated in rats. After single-dose oral exposure tothe test substance, only a small amount of C12 -C12 was absorbed into the blood. C9 -C12 was barely absorbed into circulation, and C9 -C9 was absorbed into the circulation. After single-dose oral exposure of the test substance, the 72-h cumulative excretion of C12-C12 and C9-C12 in feces only accounted for 3.88% and 1.04% of the dose administrated, and the percentage of C12 -C12 and C9 -C12 at 0.5 h was only 15.92% and 13.62% of the dose administrated, indicating that C12 -C12 and C9 -C12 were rapidly eliminated in the digestive tract. Results of in vitro studies showed that C12 -C12 and C9 -C12 were not metabolized by liver microsomes and recombinant CYP450 enzymes. C12 -C12 and C9 -C12 was almost completely bound to plasma protein with binding rate of 100%. The test substance was rapidly metabolized in the digestive tract of rats. As metabolites found in this study varied greatly in molecular weights via different administration routes, it is speculated that the diester bond of the test substance is easily broken into fragments, and new esters will be formed in the digestive tract and body by binding to fatty acids of various carbon chain lengths.