N-nitroso-Impurity C in Metamizol Drug product

Limits of Nitrosamines
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Hello dear Community
it is a pleasure to join such an amazing group

Recently we found an FDA workshop conducted back in 2021, titled : Nitrosamines as Impurities in Drugs; Health Risk Assessment and Mitigation.
The attached is one of the pages as shared

page
page1003Ă—615 31.3 KB

We cant find the exact literature reference given (Berscheid et al 1978) concluding that N-nitroso-impurity C in metamizole is not carcinogenic. Your help would be much appreciated.

Best regards
Eleni

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I believe this is the reference you are looking for:
https://onlinelibrary.wiley.com/doi/10.1002/anie.197803672

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I have found this article which seems to be relevant:
https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1365-2125.1980.tb01815.x

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It is citing

image

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Dear Naiffer

thank you for your kind input.

please note that I have also found this link, but no access is permitted right now.

[The Potential carcinogenicity of nitrosatable drugs : WHO symposium, Geneva, June 1978 - NLM Catalog - NCBI (nih.gov)] The Potential carcinogenicity of nitrosatable drugs : WHO symposium, Geneva, June 1978 - NLM Catalog - NCBI

Do you have the exact paper?

Thank you

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Thank you very much

I trust the original paper can be found here

[The Potential carcinogenicity of nitrosatable drugs : WHO symposium, Geneva, June 1978 - NLM Catalog - NCBI (nih.gov)] The Potential carcinogenicity of nitrosatable drugs : WHO symposium, Geneva, June 1978 - NLM Catalog - NCBI

Best regards

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Hi @elenipoliti this reference seems to be a book, were you able to access it online?

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There are indeed several interesting WHO or IARC symposium books from late seventies or early eighties on nitrosamine toxicology and related topics, typically combining many articles in a booklet hence the type of citation. Some books I have retrieved, but this one I haven’t read yet or retrieved yet.

However:
This procedure can help to access these publications in case they can’t be retrieved in online libraries:

  1. Use the WHO book order form to retrieve the symposium book

See also: bookorders@who.int

Most of the time the older books will be out of print and the WHO will confirm unavailability of the book.

  1. In case of an IARC publication: request a printed or digital copy to the IARC via publications@iarc.fr

If it is not out of print or has been digitalised, the IARC should be able to help to retrieve information for personal use.
If not IARC might recommend online old book shops like abebooks.com to search for copies.

This process worked for me in the past.

In Worldcat you can also see which libraries still have physical copies.
Often libraries will be able to digitalise and share the work at a cost, directly with you or with your local library.

If we are anyway talking older books worth reading on nitrosamines:
The comprehensive book from 1992 from William Lijinsky (who was working as a cancer researcher for the US government and studying nitrosation) has been reprinted in 2011 after his death in 2004 (thinking his work hadn’t been useful according to his wife in a 2023 interview).
Lijinsky, W. (1992). Chemistry and Biology of N-nitroso compounds. Cambridge Monographs on Cancer Research. Cambridge University Press, Cambridge and New York, 464 p.

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Thanks @ccdw this is very useful!!

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I am trying to get access to it through our library…

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Dear all,
@fernandaw @ccdw and @Naiffer_Host thank you for coming back to my initial post and for your kind efforts access the article.
kindly note that we proceeded with its purchase.
should you need me to upload the same for your reference please let me know.

best regards
E

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Please if you could!

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Dear all

happy Monday :slight_smile:

you may find the article attached. Hope it helps.
berscheid-et-al-1978.pdf (1.8 MB)

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Thank you @elenipoliti!!

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Dear community,

following the discution on this topic. I still have some doubts about the N-nitroso-Impurity C.

To my knoledge:
ď‚· * MNAA, reported to be positive in one strain (TA 100) Sakai etal. 1981.

  • The Negative mutagenicity studies show on the papers are on Nitrosation product (not on 4-Nitroso-N-methylaminoantipyrine), and not as per current regulatory requirements for the Enhanced Ames Test (EAT).
  • The 18-month carcinogenicity rat study is not conducted with 4- Nitroso-N-methylaminoantipyrine. However, this dietary study was performed on dipyrone and nitrite assuming formation of nitrosating product and subsequent exposure to these products including 4-Nitroso-N-methylaminoantipyrine. Considering physiological differences in rat and human gastric environment (pH and rate of Nitrosation), the human concordance of this data is questionable. Additionally, this carcinogenicity study is not robust as per the requirements mentioned in ICHM7(R2) Addendum.

So far as I understand, we would have to consider the limit following the predicted Carcinogenic Potency Categorization Approach. We classified as Class 2 - Al limit = 100 ng/day. Considering that the limit of Impurity C in the product is 0.5%, its formation, and the product as a solution of 500 mg/mL of metamizole.
How are you guys, and the industries, dealing with this situation? Am I missing some article? Or the regulatory agencies are already informed of this and the Al limits are higher?

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Hi Joao and thank you for your interest and feedback on this topic.
I am also curious to find out whether any regulatory agencies are already informed of this and what the AI to be established/ accepted.
Meanwhile you could probably review this article * 10.1021/acs.chemrestox.2c00217. I see that several discussion go through QM to provide weight of evidence for the carcinogenicity potential.
BR

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Metamizole is already banned in many countries (USA, Australia, Canada, UK, France, etc)
Metamizole (Dipyrone) Availability World Map
Moreover, in Europe EMA started a review of the safety profile of metamizole:
Review of painkiller metamizole started
It seems that N-nitroso impurity C may be the last of the problems of Metamizole…

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