3,5,5-trimethylcyclohex-2-enone

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result:

Upon oral and inhalative administration, isophorone is well absorbed and rapidly distributed through the body of rats and rabbits. Dermal absorptioncan be concluded from the systemic effects in the acute dermal toxicity studies. But in an in vitro dermal absorption study with human skin disks (In Vitro Technologies, Inc., 2006) most of the applied dose of isophorone was recovered in the surface wash at the end of the incubation time. The total amount absorbed was less than 5% even after exposure for 24 hours. 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 96 hours after administration more than 80 % of orally administered isophorone was excreted by rats.

Key value for chemical safety assessment

Absorption rate - dermal (%):

5

Additional information

Absorption

Isophorone is well absorbed via oral and inhalative route (Dutertre-Catella, Thesis Universite Rene Descartes, Paris, 1976). Already 10 minutes after oral administration to 2 rabbits, remarkable isophorone concentrations in the blood were detected. Dermal absorption can be concluded from the systemic effects in the acute dermal toxicity studies (see chapter 7.2.3). But in an in vitro dermal absorption study with human skin disks (In Vitro Technologies, Inc., 2006; see chapter 7.12 ) most of the applied dose of isophorone was recovered in the surface wash at the end of the incubation time. The total amount absorbed was less than 5% even after exposure for 24 hours. The Kp value obtained indicates that isophorone is a moderate to fast penetrant. The amount of isophorone dosed onto the skin disks appeared to simulate an infinite dose under the experimental conditions used in this study. This is inferred from the observations that the total amount absorbed was less than 5% even after exposure for 24 hours and that the amount of isophorone absorbed into the receptor fluid reached a stady state.

Distribution

In male and female rats and rabbits isophorone is rapidly distributed. One hour after a single oral administration of isophorone the highest concentrations were found in the stomach, pancreas, adrenals, spleen and liver of rats and rabbits. After inhalation for 4 hours, the highest concentrations were obtained in the kidney, adrenals, liver, pancreas and brain of rats immidiately after the termination of inhalation (Dutertre-Catella, Thesis Universite Rene Descartes, Paris, 1976). 24 hours after the single oral administration of 500 mg radioactive labeled isophorone/kg to mice and rats, the highest concentrations were found in kidney, liver, lung, spleen and adrenals (Thier, R., 1991). 48 hours after oral administration 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, Thesis Universite Rene Descartes, Paris, 1976).

Metabolism

After oral application of isophorone, 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; Truhaut et al., 1970). 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 -trimethyl-cyclohexanone), isophorol (3,5,5 -trimethyl-cyclohex-2 -en-1-ol), cis- and trans-3,5,5 -trimethyl-cyclohexanol-1, 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-hydroxyisophorone (6-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one) were identified via GC/Kovats indices and GC/MS (Dutertre-Catella et al., 1976; Thier, R., 1991).

Excretion

After inhalativ administration of isophorone to rats for 4 hours, 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; Truhaut et al., 1970; Thier, R., 1991). After single as well as repeated-dose oral administration of isophorone to rats 80 % of radioactivity was excreted within 96 hours. 50 - 65 % were detected in the urine (Thier, R., 1991).