CMDh/EMA: Update to Appendix 1 for Nitrosamines

The current version of the nitrosamine Q&A document 'Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products' from the EMA/CMDh contains three appendices (Appendices 1-3). These documents are published on the EMA website and can be viewed under 'Questions and Answers'.

Appendix 1 was compiled by the Non-clinical Working Party (NcWP), and the information provided therein regarding acceptable intakes (AIs) is based on the Carcinogenic Potency Categorisation Approach (CPCA). In December 2025, new substances were added to Appendix 1, which consists of a tabular list of substances, and some data was updated. These are marked in red in the list of Acceptable Intakes (AIs) and are clearly identifiable.

The new substances include

• N-methyl-N-nitrosoanthranilate
• N-nitroso-4-phenylpiperazine
• N-nitroso-cytisine
• N-nitroso-desbutyl-lumefantrine
• N-nitroso-desmethyl-mifepristone
• N-nitroso-desmethyl-tapentadol
• N-nitroso-selumetinib

The updated entries include

• N-nitroso-ramipril
• N-nitroso-pseudoephedrine/ N-nitrosoephedrine
• N-nitroso-perindopril
• N-nitroso-N-methyl-valaciclovir
• N-nitroso-N-desmethyl-diphenhydramine
• N-nitroso-bumetanide
• N-nitroso-berotralstat

Appendices 2 and 3, as well as Appendix 1 and the Q&A document for nitrosamines, can be viewed on the EMA website.