Establishing acceptable intakes (AI) for complex nitrosamines (NDSRIs)

The determination of acceptable intakes (AI) for complex nitrosamines (NDSRIs) is a critical aspect of regulatory and toxicological considerations. David J. Snodin in the article “Regulatory Toxicology and Pharmacology 141 (2023) 105403011” suggests the utilization of molar units as a means to enhance the accuracy and reliability in evaluating the relative carcinogenic potency of N-nitrosamines. By employing molar units, it becomes feasible to establish a more comprehensive framework for assessing the carcinogenic potential of N-nitrosamines.

In light of these considerations, what is the community members’ opinion on the most appropriate approach for establishing acceptable intake (AI) values for complex nitrosamines (NDSRIs)?


Thanks @lucas10mauriz for bringing this topic onto the surface.

I understand currently agencies prefer molecular weight corrections rather than molarity corrections, because i assume, molarity based corrections are leading to higher AI’s due to which agency may like to stick to conservative values based on molecular weight corrections due to current uncertainty with the risk of nitrosamines.

Coming to Bassan A et al., proposal of molarity concept on the basis of free energy really makes sense. I am not sure how the agency and other stakeholders would like to foresee in adoption of this in future!

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Last February, @conudel co-authored a position paper on “Nitroso-Derivatives of ACE Inhibitors”

The discussion highlighted among others the Steric Hindrance, Carboxylic Acid Substituents (aka Polarity of the structure in connection with Potency), Metabolism (Quantum Chemical Calculation)


I want to share previous discussions in this community. Members agreed on the MW correction, but we have never heard that the corrected AI from the read-across method used to control nitrosamines so far.

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Dear @Yosukemino, upon a thorough examination of the arguments presented, it can be deduced that the overall molecular weight indeed has a significant influence on mutagenic activity, correct? However, if I understand your point correctly, the inclusion of molecular weight as a consideration when employing the read-across approach to determine an acceptable intake (AI) for structurally complex nitrosamines or those without safety data is not a subject of debate.

is it accepted by Health authority ? if it is which is this??

I have only seem @conudel and @David presented this approach, but I’m not sure if they have a reference of any regulatory agency that has accepted this approach.

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Watching with interest.
The default ng/day based on very small molecular weight nitrosamines makes so little sense scientifically when considering nitrosamines formed from drug substances that are significantly larger, and makes accurate testing even trickier.
It implies that all of the larger nitrosamines are more carcinogenic and mutagenic than the known CoC, on a basis of the number of moles present.
Correction for molecular weight seems a logical route, taking an equal potency versus the smaller nitrosamines, unless there is data to show that NDSRIs are more potent than the CoC molecules.

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And this data doesn’t exist anywhere that I’m aware of! All I’ll say for now is watch this space, we have some ongoing work to try and hammer the general argument home…


Dear @David, I understand that the calculation of Acceptable Intakes for NDSRIs is a complex task, requiring meticulous analysis of various factors. With evolving technologies and enhanced research methodologies, I am truly excited to witness the future breakthroughs that will undoubtedly refine our understanding.


At this time, we can possibly use only the surrogate studies and that is becoming difficult as there is a lack of good studies even when we find a surrogate that has good structural match. However, I think we need to see what this modified AMES assay that FDA has developed will lead to. Coming from the lab which was once directed by Willy Lijinsky, I felt that the modifications he developed worked well. At the end of the day, somebody has to start working on finding the TD50 of these nitrosamines.

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Looking forward hearing more about it…

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I want to highlight the last part of your comment. Someone needs to take the TD50 of at least some representative compounds. But who? Paying 2 to 3 million for an actual carcinogenic study (e.g.: Tg.rasH2 mouse bioassay) is not realistic, even more for generics or mid to small sized companies.


So true Diego. I personally think that the agencies should take the responsibility. We also do not want variability in the studies performed by different members of the industry to cause chaos. But we need to wait and see.


About MW correction, I add the material for break out session 2 (GroupD?) in FDA/HESI meeting. It is under discussion.

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Dear @Yosukemino, the ongoing discussion regarding the correction of the acceptable intake limit for NDSRI based on a molar basis is an important topic that requires significant progress. It is crucial for us to remain attentive and engaged in this discussion. The determination of an accurate and appropriate limit is essential for ensuring the safety and well-being of individuals consuming NDSRIs. As scientific advancements and new insights emerge, it is imperative that we continue to evaluate and reassess the existing standards. By staying informed and actively participating in this conversation, we can contribute to the advancement of knowledge and the establishment of robust guidelines. Let us strive for a comprehensive understanding and a collaborative approach to address this issue effectively.

Dear @lucas10mauriz,

Yes, you are right. And MW correction is just one of the solutions. There are a lot of issues to be solved, as members have pointed out in this thread. Now scientists are trying to approach how to determine the AI of NDSRIs. And we don’t have enough NDSRIs with robust TD50. We know NDSRIs are different from small nitrosamines, and we are trying to explain how different. Despite the MW correction looking appropriate, it may be applied after those discussions are finished, one or more years later.

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