Climbazole

Endpoint summary

Description of key information

The substance became quickly bioavailable after oral administration and was almost completely metabolised in the liver.

Upon dermal exposure for 24 hours, a maximum of 3.5% of the applied dose became systemically available. Both the parent compound and the metabolite showed a plasma half-life time of a few hours.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

3.5

Absorption rate - inhalation (%):

100

Additional information

Crinipan plasma levels in dogs treated orally with 5, 10, 20 mg/kg/day for 90 days were low compared with the dose administered, indicating a pronounced first pass metabolism (>95% of parent compound was metabolised). Concentrations of the metabolite (a secondary alcohol) exceeded those of the parent drug by a factor of 2-5. Twentyfour hours after substance administration, concentrations of both parent compound and metabolite were less than 10 ng/mL (detection limit).

 

Rapid absorption and an elimination of the parent compound mainly by biotransformation was found in rats. Peak plasma levels of the parent compound were observed 30 minutes after an oral dose of 50 mg/kg, the half life of disappearance from the plasma was 3-4 hours. A metabolite (a secondary alcohol) was identified with peak plasma levels occurring 6 hours after dosing.

 

After an oral dose of 150 mg/kg of radioactive labelled substance to mice, it was readily bioavailable (detection in plasma already after 15 minutes) and reached peak plasma levels after 8 hours.

Two in vitro studies with pig and human skin investigated the dermal absorption of crinipan.

The vast majority of applied crinipan (0.5% crinipan in hair serum and skin serum formulations, 24 h exposure) to pig skin was washed-off 24 hours post-application. A small amount penetrated into the epidermis and dermis, which slowly penetrated into the receptor fluid over the 24 h sampling period. The bioavailable portion (epidermis, dermis, receptor fluid) after 24 h was low and amounted to 2.2 and 3.5 % or 1.1 and 1.3μg/cm2 of the applied dose for hair serum and skin serum, respectively.

Similarly in human skin, almost all the crinipan in a 2% shampoo formulation (rinsed off after 0.5 h exposure period) was washed off and none of the dose penetrated through the skin into the receptor fluid during this short exposure period. A very small amount penetrated into the stratum corneum and epidermis, which resulted in a negligible penetration into the receptor fluid over the 24 h sampling period.

These results indicate that major proportion of the applied crinipan was washed-off and little amount penetrated to epidermis and dermis becoming bioavailable at about 0.15% in human (0.5 h exposure) and 2.2 -3.5% (24 h exposure) in pig skin models.