4-methylcyclohexanone

Endpoint summary

Description of key information

4-methylcyclohexanone is absorbed readily after oral administration and the same would be expected following dermal and inhalation exposure.  Once absorbed into the systemic circulation it is rapidly distributed and metabolised. A rapid onset of clinical signs confirms a rapid absorption and high recovery of the dose administered orally to rabbits in urine as conjugates indicates that the extent of absorption of 4-methylcyclohexanoneis also high.  A general distribution of 4-methylcyclohexanone into highly perfused tissues throughout the body would also be expected indicated by clinical observations suggestive of penetration into the brain and CNS together with increased liver weights with increasing dose. 4-methylcyclohexanone is metabolised primarily by reduction of the ketone to yield the corresponding secondary alcohol, followed by conjugation with predominantly glucuronic acid and some sulphate which are then excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption

Data in the scientific literature describing toxicity studies across species with 4-methylcyclohexanone and the similar compound cyclohexanone utilising different routes of administration and reporting corresponding signs of centrally mediated effects of CNS depression suggest that 4-methylcyclohexanone would also be expected to be readily absorbed into the systemic circulation through skin, the respiratory tract via inhalation and across the gastrointestinal tract.

In the 28 day repeat dose toxicity study (Dymarkowska, 2018) and the Oral Reproduction/Developmental Toxicity Screening Test (Blunt, 2018) there were dose related findings in clinical observations and increases in liver weight indicative of a dose related increase in absorption across the gastrointestinal tract and into the systemic circulation. Rapid onset with clinical signs being reported within 30 minutes of dosing confirm a rapid absorption but the extent of absorption, in terms of oral bioavailability, cannot be determined from these studies. However, in the literature cited and reviewed above, high recovery of the dose administered orally to rabbits in urine as conjugates of the secondary alcohol (75 - 89% Dose) indicates that the extent of absorption of 4-methylcyclohexanone is high. There is no reason not to expect this to be the case in rats and across other toxicology species as it is for cyclohexanone.

Distribution

With a water solubility of 22.3 g/L and Log P of 1.33 it would be expected that 4-methylcyclohexanone would distribute into tissues. Confirmation of this is indicated by the clinical observations observed during the toxicity studies suggestive of centrally mediated effects indicating penetration into the brain and CNS. Increased liver weights with increasing dose are also indicative of distribution into the liver and so it would not be unreasonable to assume a rapid more general distribution of 4-methylcyclohexanone into highly perfused tissues throughout the body. This is also suggested by the disposition kinetics of cyclohexanone obtained in the dog following intravenous administration where an initial rapid distribution phase was followed by a slower elimination phase in the concentration-time profile.

Metabolism and Excretion

The molecular weight of 4-methylcyclohexanone indicates that it would not be expected to be significantly excreted directly in bile. Its aqueous solubility and logP would allow some direct excretion in urine but information in the literature indicates that 4-methylcyclohexanone would be predominantly eliminated via metabolism and subsequent conjugation followed by excretion in urine. When rabbits were orally administered 4-methylcyclohexanone the glucuronic acid (75-86 % dose) and sulfate conjugates (0-3% dose) of the corresponding secondary alcohols were excreted in their urine. This indicates that not only the extent of absorption was high but the major clearance mechanism for 4-methylcyclohexanone is via metabolism and excretion in urine. A similar clearance mechanism would also be expected in rats and dogs as demonstrated when cyclohexanone was administered intravenously. The tolerance also shown in clinical observations on repeat dosing, together with the increased liver weights, also suggests that this metabolism and excretion mechanism is inducible.