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EMA: PDE for chlorobutanol as excipient reviewed

EMA: PDE for chlorobutanol as excipient reviewed

The CMDh (EMA's Coordination Group for Mutual Recognition and Decentralized Procedures) has approached one of the EMA's Safety Working Parties (SWPs) with the following two questions regarding chlorobutanol:

  1. Can the Safety Working Party confirm that the levels of chlorobutanol commonly used in medicinal products are safe from a toxicological point of view?
  2. Is it possible to determine acceptable intake levels of chlorobutanol?

The EMA published the 15-page SWP response document to these questions on March 17, 2021.


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:

  1. 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   
  2. 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