3,5,5-trimethylcyclohex-3-en-1-one

Endpoint summary

Additional information

Absorption

Isophorone is well absorbed via the oral and inhalative route (Dutertre-Catella, 1976). Already 10 minutes after oral administration of 1 g 14C isophorone/kg to 2 rabbits, remarkable isophorone concentrations in the blood (0-102 μg/ml) were detected, which started to decrease from 75 – 141 μg/ml after 30 minutes and 88 - 94 μg/ml after 1 hour down to less than 0.5 μg/ml at 21 hours post treatment (Dutertre-Catella, 1976). Good dermal absorption can be concluded from the systemic effects in the acute toxicity studies.

 

Distribution

In male and female rats and rabbits isophorone is rapidly distributed. One hour after a single oral administration (4 g/kg) of 14C isophorone the highest concentrations were found in the stomach, pancreas, adrenals, spleen and liver of rats and rabbits. After inhalation (400 ppm) for 4 hours, the highest concentrations were obtained in the kidney, adrenals, liver, pancreas and brain of rats immediately after the termination of inhalation (Dutertre-Catella, 1976). 48 hours after oral administration of 1 g/kg isophorone to male and female rats, only traces of isophorone could be determined in the stomach and no isophorone was measured in the other organs (Dutertre-Catella, 1976).

 

Metabolism

After oral application of 1 g isophorone (3,5,5-trimethyl-2-cyclohexene-1-one)/kg bw, one main metabolite in rats and rabbits is 5,5-dimethyl-1-cyclohexene-3-one-1-carboxylic acid. This metabolite is formed by oxidation of the 3-methyl group of isophorone and then glucuronidated (Dutertre-Catella et al., 1978). Further metabolites may be formed through hydrogenation at the 1-one or/and 2-ene-position or after further oxidation processes. Dihydroisophorone (3,5,5-rimethylcyclohexanone), isophorol (3,5,5-trimethyl-2-cyclohexen-1-ol) and 3,5,5-trimethylcyclohexan-1-ol (cis- and trans-isomer), 6-Oxoisophorone (3,5,5-trimethyl-2-cyclohexen-1,6-dione), 4-Oxoisophorone (3,5,5-trimethyl-2-cyclohexen-1,4-dione), 4-hydroxyisophorone (4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one) and 6-ydroxyisophorone (6-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one) were identified via GC/Kovats indices and GC/MS (Dutertre-Catella et al., 1978). Isophorol is eliminated as glucuronide (Dutertre-Catella et al., 1978). Dihydroisophorone is mainly found in the urine of rats, while rabbits produce primarily isophorol (Dutertre-Catella et al., 1978).

 

There are data to suggest that the glutathione system is also involved in the metabolism of isophorone. After i.p. administration of 500 mg isophorone/kg to sexually matured rats the glutathione depletion in liver, testes and epididymis was measured. In the liver 40 % reduction of the glutathione content was determined (maximum: 4 h after application), 82 % reduction was measured in testes (maximum: 4 h after application) and 72 % in the epididymis (maximum: 8 h after application) (Gandy et al., 1990).

 

Excretion

After administration of 400 ppm isophorone to rats (4 h), a part of the isophorone was expired unchanged (Dutertre-Catella, 1976). Also in the urine of orally treated rabbits and rats unreacted isophorone could be isolated (Dutertre-Catella et al., 1978).

 

Conclusion: Upon oral and inhalative administration, isophorone is well absorbed and rapidly distributed through the body of rats and rabbits. While part of the absorbed isophorone is excreted unchanged via urine and exhaled air, metabolites are mainly excreted as glucuronides. The tendency of isophorone to bioaccumulate is very low, since within 24 hours after administration more than 93% of orally administered isophorone was excreted by rats.