Isobutyric acid, monoester with 2,2,4-trimethylpentane-1,3-diol

Endpoint summary

Additional information

Texanol Ester-Alcohol is a mixture of the 1-substituted (61%) and 3 -substituted monoisobutyrate (37%) isomers of 2,2,4-trimethyl-1,3 -pentanediol (TMPD). An in vitro hydrolysis study conducted with Texanol Ester-Alcohol according to generally acceptable scientific standards was available for review. Samples of blood from naïve male Sprague-Dawley rats and male human volunteers were treated with aliquots of Texanol Ester-Alcohol in DMSO and held at 37°C for two hours. Nominal starting concentrations of the test material in blood were 4.6 or 2.3 mM. Samples of treated blood were withdrawn at appropriate intervals, extracted and analyzed by flame ionization gas chromatography. In vitro, Texanol Ester-Alcohol undergoes partial hydrolysis in whole rat or human blood to produce the expected diol, TMPD. Loss of the ester at the higher concentration (4.6 mM) did not follow first-order kinetics. At this concentration level, either the water solubility of the ester had been exceeded or saturation of blood esterase enzymes may have occurred. At the lower concentration level (2.3 mM), loss of the 1-substituted isomer followed first order kinetics with an average calculated half-life of 19.6 min in rats and 17.3 min in humans. For both species, the single identified product resulting from hydrolysis of the 1-substituted isomer was TMPD.  Approximately 35.5% of the starting material did not undergo hydrolysis in either rat or human blood under conditions of this study.       

Based on identification of TMPD as the primary hydrolysis product following in vitro exposure of blood samples from rats and humans to 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate, data from an in vivo study conducted in rats with 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB) should also be considered when evaluating the metabolic profile of Texanol Ester-Alcohol.  In the TXIB study, adult male Sprague-Dawley rats received a single dose of approximately 256 mg/kg bw of undiluted TXIB-3-[14]C by oral gavage and excreta and cage washings were collected for up to 22 days. A second group of rats received approximately 186.7 mg/kg bw of TMPD-3-[14]C, a potential metabolite of TXIB (and identified as a metabolite of Texanol Ester-Alcohol), and were sacrificed on Day 6. In the latter study, TMPD was rapidly absorbed from the gut and greater than 88% of the administered dose was recovered in the urine within 48 hours of dosing with only 2% recovered in the feces. Disposal of TXIB appears to involve some non-absorption and partial hydrolysis in the gut based on the occurrence of both TXIB-3-[14]C and a mono-isobutyrate ester of TMPD in the feces. The major metabolic pathway for TMPD following ingestion was by O-glucuronide formation (75%) with lesser proportions of the dose eliminated as the oxidation product 3-hydroxy-2,2,4-trimethylvaleric acid and its glucuronide (7%), unchanged TMPD (1.5%), and 2-methylmalonic acid (4%). At least half of the absorbed dose of orally administered TXIB-3-[14]C was accounted for as products of complete hydrolysis to the parent glycol TMPD, which was then metabolized by routes similar to its fate after oral ingestion.

The toxicokinetic and metabolic profile for 2,2,4-trimethyl-1,3-pentanediol (TMPD) indicates that following oral exposure in rats, the material is rapidly absorbed, metabolized, and eliminated in the urine and feces. Based on almost complete hydrolysis of the 1-substituted monoester of Texanol Ester-Alcohol to TMPD following addition of the parent material to samples of rat and human blood, it is expected that following in vivo exposure, Texanol Ester-Alcohol would be rapidly absorbed, metabolized and excreted in the urine and feces, similar to the metabolic profile obtained following in vivo exposure to TMPD or the diisobutyrate of TMPD.

To obtain further evidence that 2,2,4 -trimethyl-1,3 -pentanediol diisobutyrate (TXIB) undergoes extensive ester hydrolysis in vivo to produce the corresponding 1-substituted and 3-substituted monoisobutyrates, a proposed study will be conducted in separate groups of rats that are treated with a single oral dose of either TXIB or a mixture of the monoisobutyrates of 2,2,4-trimethylpentane-1,3-diol, wherein specific metabolites will be quantitated and the patterns of metabolites will be compared. This study will be done to determine whether data from studies using TXIB can be used to read-across to the mixture of monoisobutyrates of 2,2,4 -trimethylpentane-1,3-diol, to adequately assess safety concerns.