The acceptance Intake of Nitroso-Propranolol

Hi, everyone
I am an analyst.
Because of Inderal-LA (Propranolol Hydrochloride) capsules Pfizer recalls, I will study the nitroso-Propranolol in my drug product.

The API vender provide me the report explaining the potency of DNA damaging were similar between NDMA and NO-Propranolol and the acceptance intake should be similar to NDMA, 96 ng/ day.
Do it be correct?

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the carcinogenic potency of all the beta-blockers is still under discussion.
In Europe. Very recently EMA aknowlegded that:

All the β-blockers have a secondary amine that can undergo nitrosylation under suitable conditions to give the N-nitrosamine derivative.
• Besides carvedilol and nebivolol, all the other β-blockers have bulky (isopropyl, isopropyl with further substitution, or tert-butyl) groups at the α-position to the secondary amine.
• Carvedilol and nebivolol have CH2 groups at both α-positions, however the substituents on both sides of the amino group are large/bulky groups that render considerable steric hindrance.
• It is very likely that these factors reduce the carcinogenic potency of any related Nnitrosamine however it is recognised that further investigation is needed to completely understand this

Fourth Nitrosamine Implementation Oversight Group (NIOG) meeting

According Dobo et al:
Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N‑Nitrosamine Impurities.
Nitroso-Propanolol may be classified in group 5 and an AI of 440 ng/day may be proposed to the Health Authorities.

I remember that the position of each autority (EMA, TGA, U.S.FDA, KFDA, etc) may be different and each authority may accept the proposed limit or ask a tighter limit.
kind regards


Dear @paliog
Thank you …
I will discuss with my API vender …
and wait for the update of Nitroso-Propranolol in EMA…

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The latest EMA Nitrosamine Implementation Oversight Group meeting discussed beta blockers specifically. The industry presentation slides are a must read for anyone working with Propranolol.


The thread on propranolol may be helpful for you if you have not read it yet.


I get some information of the formation for Nitrosamine Impurity.
The Formaldehyde is catalyst …

Nitrosamines -as-Impurities-in-Drugs-Workshop-Presentation.pdf (1.8 MB)



Unlike other NDSRIs, an experimental study is available for N-Nitrosopropranolol reported in 1983 by Ilene H. Raisfeld-Danse and Jack Chen from the State University of New York at Stony Brook, New York. As per the published literature, N-Nitrosoproranolol (NNP) is unlikely to be a carcinogen. Therefore, in my opinion, comparing NNP with NDMA is absurd.


Hi …
It is good news for me …
Can you provide the paper for me…?
Thank you…so much.

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Hi Koumine,

Drug interactions. III. Formation of nitrosamines from therapeutic drugs. Formation, mutagenic properties and safety assessment of propranolol hydrochloride with respect to the intragastric formation of N-nitrosopropranolol under conditions found in pati… | Journal of Pharmacology and Experimental Therapeutics. Please use the link for reference

Thank you so much…
I think it is useful for me …