The 18 ng/day default for NDSRIs should be re-visited?

An intriguing and thought-provoking question arises from the information presented in the Journal Pre-Proof “Acceptable Intakes (AIs) for 11 small molecule N-nitrosamines (NAs)” @jbercu. How can the reliance on the Lhasa Carcinogenicity Database (CDB) and read-across methodologies be enhanced to accommodate the assessment of novel chemical spaces, such as NA drug-substance-related impurities (NDSRIs), which may have distinct metabolic pathways and molecular characteristics?

The paper emphasizes the importance of reviewing the literature beyond the Lhasa CDB and highlights that not all studies are captured in this database. This raises concerns regarding the potential gaps in knowledge and the need for toxicologists to seek additional carcinogenicity data. The example of NDEA, with robust dose-response mutagenicity and carcinogenicity studies in rodents, further underscores the significance of comprehensive data analysis.

The revised NDEA acceptable intake (AI) of 62 ng/day, considering the most sensitive site and tumor type, suggests a downstream impact on other limits. This prompts us to question the potential consequences of adjusting the AI for NDEA on other AIs that have been established based on read-across to this compound.

Furthermore, the paper raises an important point regarding the use of more mechanistic and metabolism data in read-across methodologies, particularly in the context of defining AIs for NDSRIs. These impurities often belong to a novel chemical space and exhibit different molecular characteristics and metabolic behaviors compared to small molecule NAs. The current default AI of 18 ng/day for NDSRIs is based on small molecule NAs that are readily metabolized into toxic species. However, the larger molecular weight and unique chemistry of NDSRIs may impede metabolism around the alpha-carbon position, necessitating a re-evaluation of the default AI.

Consequently, a compelling question emerges: How can the Lhasa CDB and read-across methodologies be augmented to effectively incorporate mechanistic and metabolism data, enabling accurate and reliable assessment of carcinogenicity risks associated with novel chemical spaces like NDSRIs?

Addressing this question calls for the exploration of innovative approaches, such as the integration of predictive modeling, in vitro assays, and computational toxicology tools, to enhance the prediction of carcinogenicity and establish appropriate AI limits for NDSRIs. Additionally, it necessitates collaborative efforts among researchers, toxicologists, and regulatory authorities to ensure the utilization of the most up-to-date and comprehensive data sources, enabling a more thorough and scientifically robust evaluation of the potential risks posed by emerging chemical entities.




What I could mention is that, how to differentiate an NDSRI that should use the default 18 ng/day limit to an specific tailored one for NDSRIs. (by molecular weight?)

There are NSDRI that have low molecular weights and that are more like small dialkyl nitrosamines.

If the 18 ng/day is based on TD50s of small dialkyl nitrosamines, the default limit for NDSRI should come from a set of TD50s values of NDSRIs? Information that as of now is not available.

We need to differentiate that yes most NDSRIs are in a different chemical space than small nitrosamines, but not all. Part of the comments mentioned in the FDA/HESI workshop is that we need solutions that could move efforts now tackled in expected non cohort of concern NDSRIs to the NSDRIs that are positive in an Ames test (w/ metabolic activation) and expected then to be + in-vivo for the mechanism that nitrosamines are known for.

Finally yes, it should be revised, the topic is how? and when? I would expect it would take quite some years still for some formal changes in the limit until evidence is gathered comprehensively. Including the quoted publication.


Table 4 reference for NPIPZ: Love et al., 1977, according to the paper.

Dear @Diego_HM, I agree with you, but I admit that the subject “nitrosamines” demands a collaborative analysis, as we have made significant progress since 2018 and undoubtedly have much more to achieve. Science is dynamic, and it is crucial to foster an ongoing discussion in this field.

As David J. Snodin aptly stated: Safety assessment of NDSRIs presents a significant challenge due both to the potential for large numbers of these impurities to be detected and to the difficulties of implementing read-across for non-classical nitrosamines with complex structures. It is evident that the current concept of CoC is considered inadequate in terms of protecting human health, as it relies solely on simple structural alerts instead of compound-specific data on mutagenicity and carcinogenicity (Regulatory Toxicology and Pharmacology 141 (2023) 105403).

To address this issue, various approaches can be considered. One option is to abandon the CoC concept altogether. Alternatively, a procedure that involves a more precise identification of concerning compounds could be implemented. This can be achieved through the refinement of alert definitions based on N-nitrosamine structure-activity relationships, coupled with compound-specific data on carcinogenic potency and mutagenicity. By employing these means, a clear distinction can be made between CoC and non-CoC N-nitrosamines within the context of ICH M7 (R1) guidelines.

Do you agree?

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Hi Lucas I do agree. It is not to be pesimistic here, but to highlight that any change to a more relaxed limit, taking into account as per conservativism Health Authorities would like to maintain the more stringent limit until there is unquestionable evidence a higher limit could be used. That means generation quite a lot of evidence, that the industry is generating and regulators too, but will take some years still I would think.

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That’s the catch-22. You cannot act on tighter limits without removing entire classes of drugs from the market, which will cause more harm than is known to exist from the nitrosamines themselves.

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Kind of tricky indeed, there are limits for default nitrosamines but had not been enforced letter by letter. Because if yes, by now quite a bit of shortages would have been expected. Most recalls as of now happened by pharma companies decision rather than because an actual regulatory requeriment from what I understand.


Clearly with regret in some cases


The modus operandi of the agencies is a bit like this:

  1. do you have?
    2 how much?
    more than 18ng (or the limit that you propose )
  2. Silence…silence…
    Panic and Game over (silence )
    The panic is because everyone who makes that product is worse off or the same as you, and they don’t know what to propose. Sometimes they tell you that they will tell you something… because they are throwing out the runes and bones.