Hydroxycyclohexyl phenyl ketone

Endpoint summary

Description of key information

Based on the physico-chemical properties and the findings in the acute and subchronic oral toxicity studies in rats, the substance is considered to be taken up by the body after ingestion, to be metabolized and to become eliminated by renal clearance. There is no danger for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No experimental data on toxicokinetics are available for the test item. Information on the toxicokinetik profile are therefore derived from physico-chemical data and results obtained in subacute and subchronic toxicity studies.

Chemistry

The test material (204.3 Da) is a white powder, slightly soluble in water (442 mg/l). The material has a densitiy of 1.17 g/cm3 and the melting point is at 46 -49 °C. A vapour pressure of 0.002 Pa indicates a low volatility. The log Pow is 2.81 (at pH 5.75).

Absorption

In acute oral and dermal toxicity studies, rats were administered to the test substance. Mortality was observed at 5000 mg/kg bw after oral administration only. Clinical signs observed after oral and dermal administration were dyspnea, exophthalmos, ruffled fur and curved body position. All (surviving) animals recovered within post observation period. Administration of the substance over a subacute period resulted in a marginal effect on liver weight and cholesterol level in males treated at 300 mg/kg/day (top dose). A 90 day treatment leads to decreased body weight and decreased body weight change in high dose males (1000 mg/kg bw). Furthermore, changes in clinical pathology, increased liver and kidney weight as well as histopathological findings in liver and kidney were observed. In regard to the results of the acute and longterm studies and considering the low molecular weight uptake of the substance from the gastro-intestinal system is most likely. Additionally, the test substance cannot undergo pH-dependent hydrolysis in the stomach, thus, the unchanged (parent) substance is taken up into the system.

In the course of a prenatal developmental toxicity study maternal effects e.g. transient clinical signs and lower body weight occurred whereas fetal development was unaffected which implicates that the substance is not able to cross the placental barrier.

According to the model of Fitzpatrick [1], the test item is moderately skin permeable.

Metabolism

In the livers of male and female animals of the mid and high dose groups treated for 90 days a minimal up to moderate centrilobular hepatocellular hypertrophy was diagnosed. This finding correlated to increased liver weights in males and females of both test groups. Furthermore, in the thyroid glands a follicular hypertrophy/hyperplasia was observed in males and females treated with 300 and 1000 mg/kg bw. The occurrence of liver cell hypertrophy is considered to be an adaptive change and a correlate for a significant microsomal enzyme induction in the liver that also may be responsible for the thyroid gland hypertrophy/hyperplasia of follicular cells due to an accelerated degradation of T4 (by induced UDP glucuronyl transferase activity) with a compensatory increase of TSH.

Thus, considering xenobiotic metabolism, reduction of the aliphatic ketone followed by glucuronidation of the hydroxyl-groups seems plausible. 

Excretion 

The low molecular weight of the substance as well as the results from longterm studies indicate that the substance will be absorbed and metabolized. Subsequently, the test substance will be excreted effectively. The primary elimination pathway of the test substance is expected to be the urinary excretion of parent compound and the glucuronidation product. Accumulation in the body is not expected.

[1] Modelling skin permeability in risk assessment––the future, D. Fitzpatrick et al, Chemosphere 55 (2004) 1309–1314