The only study which was considered appropriate for this purpose was the veterinary toxicology study "OECD TG 422 Combined Repeat-dose toxicity study with the reproduction/developmental toxicity screening test". Based on a LOEL of 10 mg/kg/d and using the procedure described in ICH Q3C(R6) to derive a PDE, a PDE of 0.5 mg/day was determined, initially.
This resulted in the following response of the SWP to the CMDh/EMA:
- Chlorobutanol levels generally used in medicinal products as excipient can be considered save for lifetime use if they are at or below the derived PDE. For short-term use higher exposures of Chlorobutanol may be acceptable based on case by case. In such cases benefit/risk consideration should be made with greatest care
- The majority of published toxicological studies were not considered suitable to derive a PDE value for chlorobutanol in general, as these studies were severely limited in terms of study design and treatment duration. Only one GLP-compliant OECD TG 422 study with chlorobutanol was identified, which was submitted to MITI in Japan. This study was considered sufficient to derive a PDE for chlorbutanol. The result from this study is:
In conclusion, a PDE of 0.5 mg/d for chlorbutanol was derived for lifetime treatment from this study, providing a safety margin of 4 times the lowest dose at which cardiac effects were observed in patients after infusion administration.
EMA: SWP response to CMDh questions on chlorobutanol