1-isopropyl-2,2-dimethyltrimethylene diisobutyrate

Endpoint summary

Additional information

The toxicokinetics and metabolism of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is well understood. Three non-guideline studies conducted according to generally acceptable scientific standards of the time were available for review. In the first study, adult male Sprague-Dawley rats were administered a single dose of approximately 256 mg/kg bw of undiluted [14]C-labeled 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate by oral gavage. Urine, feces, and expired air were collected for up to 22 days. At necropsy, liver, kidneys, spleen, gastrointestinal tract, fat, lungs, brain and carcass were processed for radioactivity. The test material was rapidly absorbed, metabolized and eliminated with at least 95% of the administered dose recovered in the urine (47.3-72.5%), feces (14.45-31.20%), and cage washings (11.9-16.5%) within a few days of dosing. Most urinary radioactivity was eliminated in the first 72 hours while fecal elimination was virtually complete by Day 7 after dosing. There was no radioactivity detected in expired air. Only 2.9% of the dose was found in the organs and carcass of the rat sacrificed at 8 days. This amount had decreased to 0.99% by 15 days and by 22 days, there was only 0.7% of the dose evident in tissues and carcass.

 

A similar study was conducted to identify urinary metabolites. Adult male Sprague-Dawley rats again received a single dose of approximately 256 mg/kg bw of undiluted [14]C-labeled 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate 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 [14]C-labeled 2,2,4-trimethylpentane-1,3-diol (TMPD), a potential metabolite of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate, and were sacrificed on Day 6. 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 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate appears to involve some non-absorption and partial hydrolysis in the gut based on the occurrence of both 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate-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 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate-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.

 

In a feeding study, 0.1 or 1% 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate was administered in the diet to rats of both sexes for 51 days, 99 days, or for 51days with a 47 day recovery period. Separate groups of male rats only received intraperitoneal injections of 25 or 100 mg/kg 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate or TMPD 1X/day for 7 days. For rats of both sexes fed 1% 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate for 51 days, there was an increase in p-NO2-anisole demethylase, UDP-aminophenol, and UDP-bilirubin glucuronyl transferase activities. When 0.1 or 1.0% 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate was fed in the diet to both sexes for 99 days, p-NO2-anisole demethylase activity was elevated for both sexes at the high dose while bilirubin glucuronyl transferase was elevated only in high-dose females. When both sexes were treated with 1.0% 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate for 51 days and allowed a recovery period, all liver enzyme levels returned to normal by study termination. For rats treated with 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate or TMPD by intraperitoneal injection for 7 days, demethylase activity was elevated in animals treated with 100 mg/kg bw of either 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate or TMPD. Under conditions of this study, repeated exposure to high doses of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate caused reversible adaptive changes in the livers of both sexes.   

 

The toxicokinetic and metabolic profile for 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate indicates that following oral exposure, the material is rapidly absorbed, metabolized, and eliminated in the urine and feces. Less than 1% of the administered dose was recovered in the tissues and carcass and expired air was not a route of elimination. Following oral administration, 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate is hydrolyzed primarily to the partial ester and to the parent TMPD.  Repeated exposure to high concentrations of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate by the oral or intraperitoneal routes caused transitory reversible elevations in activities of certain liver enzymes in male and female rats. These changes may explain the reversible liver enlargement observed in other studies following prolonged exposure to high doses of 1-isopropyl-2,2-dimethyltrimethylene diisobutyrate.