N-nitrosodicyclohexylamine (NDCHA), what do you know about it?

Limits of Nitrosamines
1

Hello everyone,

In a brief search I could not get information about the limit and carcinogenic potency of the NDCHA nitrosamine.
So, I’m very pleasure if the community can help me about N-nitrosodicyclohexylamine nitrosamine, I mean, if already there is an acceptable intake established for this impurity? Or we need apply CPCA categorization or adopt 1,5 ug/day by ICH?
Please, provide the references for this topic.

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Hi @CesarJr,
There is no established AI limit for N-Nitrosodicyclohexylamine in EMA, U.S FDA and Health Canada Appendix list. Further, no robust carcinogenicity data is available in the LCDB database. Hence, the only option is to apply CPCA - Potency Category 5 - 1500 ng/day.

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3

Hi @Sushant!
Many thanks for the reply… There really is a shortage of references for the discussion of this nitrosamine.
I appreciate your help.
If there is someone who would like to contribute to the discussion too, please, feel free for do that.

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4

There are some good surrogates of this, which you may want to look into.

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5

Hi:
Оne of the ways is CPCA analysis, article that can help you is below:
Determining Recommended Acceptable Intake Limits for N-nitrosamine Impurities in Pharmaceuticals_ Development and Application of the Carcinogenic Potency Categorization Approach _ FDA.pdf (241.0 KB)
You can use <1,5 ug/day limit for nitrosamine impurity, if Ames test in vitro is negative for that impurity. If Ames test is negative in vitro and in vivo, you can use limit of guideline ICH3B.
I am happy , if I can help you.

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6

Or if in the result of CPCA analysis potential category of impurity is 5.

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7

Ames test is an in vitro test. What in vivo test are we talking about here. Also, which agency are you talking about related to ICH Q3B control of nitrosamines?

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8

The CPCA approach was developed for NDSRIs. Is it acceptable to use CPCA approach for simple Nitrosamines like this too?

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dear Iyappan
The Carcinogenic Potency Categorization Approach (CPCA) can be used to establish the AI (unless other robust data are available that would override this AI) for any N-nitrosamines identified without sufficient substance specific data to derive a substance specific limit for lifetime exposure as recommended in ICH M7(R2) guideline

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I guess it is meant for Transgenic Rodent (OECD 488). A negative in this study is sufficient to control nitrosamines according to ICH Q3A/B for EMA and some other Health Authorities

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Agreed, but FDA is limiting themselves to 1500 ng/day. There has been some requests to FDA to accept higher than 1500 ng/day based on OECD 488.

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You don’t have to use only 1500 ng/day limit
Analytically targeted N-Nitrosamines can be calculated using acceptance intake of individual nitrosamine impurity, maximum daily dose of medical product and correction factor, which calculated based on treatment duration.

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I think that no discussion on correction factor based on treatment duration is now available in the EMA and US FDA Guidelines. Could you please explain?
Thanks

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Dear Elenipoliti:

For Example:
N-Nitrosodibenzylamine (NDBzA):
Health Agency Acceptable Intake (ng/day) 26.5
Alternative Acceptable Intake (ng/day): 1500*
*ICH M7 TTC limit of 1.5 µg/day (ICH 2017) is applied to NDBzA based on the conclusions of Jiao et al., 1997 where is shown to be 100-fold less mutagenic than NDMA and Druckery et al., 1967 where NDBzA is a non-carcinogen in rats.

Fold difference between Health Agency AI and Alternative AI=56,6 (1500/26.5=56.6)

Medical product maximum daily dose is 50 L/day (for example)
Analytically targeted for N-Nitrosodibenzylamine = 26.5/50=0,53 (ng/L)

According to ICH M7 Duration of Treatment

Table 2: Acceptable Intakes for· an Individual Impurity

 <1  month (120)       >1  to 12 Months (20)       >1 to 10 Years (10)     >10 Years to Lifetime (1,5)

For the most accurate calculation, you can use:

‘‘ICH M7 Multiplication Factors for Adjusting Lifetime AI Values to Address Less Than Lifetime Patient Exposures (Single or Multiple Nitrosamine Impurities)’’

For example <1 month Duration of Treatment and single nitrosamine impurity:
AIX80=0,53X80=42,4 (ng/L)
42,4 (ng/L) is a Lifetime Al adjusted by MAXIMUM DAILY DOSE for NDBzA (for that individual medical product).
I think I was be helpful.

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specifically for this molecule, N-nitrosodibenzylamine is reported as negative for carcinogenicity in LCDB.

moreover, based on what I have seen till now, LTL approach may be applied to claim interim limits.

please share your ideas.

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Dear Elenipoliti:
I think the main goal is to ensure patient safety.
Approaches may vary, but in my opinion, if we also consider the maximum daily dose and treatment duration in addition to the guideline criteria, the calculations will be more accurate for the individually medical product.
Approaches may vary, but if they ensure patient safety throughout the life, then the chosen approach is RIGHT.

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dear CesarJr
have you checked the entity in LCDB?
N-Nitrosodicyclohexylamine is given also as negative
Lhasa Carcinogenicity Database - Study Information

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Dear Eleni,
thank you for your addition.
Nevertheless, this information in Lhasa is not very robust, as the evaluation of the study provides more B than A
‘’
image
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Furthermore, this in-vitro study is very old.
Overall, i would be quite spectical to use it for setting a limit for the NDCHA
best regards
Christos

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19

Hi Chris
totally agree with you. it may be questionable.

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