2-hydroxy-1-(4-(4-(2-hydroxy-2-methylpropionyl)benzyl)phenyl)-2-methylpropan-1-one

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Chemistry

The test material (340.4Da) is a yellowish powder, slightly soluble in water (9.9 mg/l). The melting point is at 84.3 °C and a vapour pressure of < 0.00016 hPa indicates very low volatility. The log Pow is 2.3 (at pH 4.5).

Absorption

In acute oral and dermal toxicity studies, rats were administered to the test substance. Mortality did not occur in any of the studies. Clinical signs of toxicity (transient), i.e. hunched posture, ruffled fur and emaciation were observed after oral administration in male and female animals. Gross necropsy did not reveal any findings. The LD50 is therefore considered to be > 2000 mg/kg bw.

The NOAEL in male and female rats in a subacute oral repeated dose study is 30 mg/kg bw due to adverse local irritative effects in the stomach, decreased body weight gain and lowered motor activity in the 90 mg/kg bw/day group. Discoloured feces, increased liver weights as well as liver cell hypertrophy in the (mid and) high dose group indicate systemic absorption of the substance. The test substance cannot undergo pH-dependent hydrolysis (pH 4, 7, 9), thus, it expected that the unchanged (parent) substance is taken up into the system. According to the model of Fitzpatrick [1], the test item is slightly skin permeable.

Metabolism

Treatment-related diffuse liver cell hypertrophy was recorded at 90 mg/kg body weight/day and was considered to be adaptive. This hypertrophy was associated with follicular cell hypertrophy in thyroid glands in some males and females at 90 mg/kg body weight/day. Most probably the enhanced liver cell metabolism resulted in an acceleration of thyroid hormone breakdown with consequent thyroid follicular cell hypertrophy. Xenobiotic induced thyroid hormone breakdown is often associated with an enhanced expression of CYPs P450 and UDP-glucuronyltransferases. Thus, it can be assumed that the test item will be conjugated with UGT, e.g. at its hydroxylgroups. Reduction of the keto-groups followed by conjugation is also plausible.

Excretion 

In regard to the low molecular weight the primary elimination pathway of the test substance will be the urinary excretion of the glucuronidation product. Additionally, yellowish discoloured feces after repeated dose administration could be a hint for fecal excretion of unchanged material.

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