48 Pharmaceutical Technology
®
Trends in Formulation 2022 eBook PharmTech.com
Qualit
y
variable but for the most part the TD50 values could
be comparable in some cases to those for the nitrosa-
mines. Thus, N-nitrosamides could be characterized
as a cohort of special concern due to most of the ac-
ceptable intakes (AIs) derived from the TD50s fall-
ing below the ICH M7 limit of 1.5 µg/day. Within the
N-nitrosamide class, the N-nitrosocarbamates and
N-nitrosoureas appear to be the most potent muta-
gens and carcinogens.
Conclusion
Given the difference in mechanism of activation of the
N-nitrosoamides and variable half-lives, they should
not be grouped with the N-nitrosamines but considered
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FIGURE 3. Plausible mechanism of thiolysis of Methylnitrosonitroguanidine
(MNNG) and similar N-nitrosoguanidines.
TABLE I. N-nitrosamide class potency summary and N-nitrosamine comparison.
AIs are acceptable intakes.
Class Mutagenicity/carcinogenic potency summary
†
Comparison to nitrosamines
Nitrosamides
• Most nitrosoamides are mutagenic
• Example: TD50 (dinitrosocaffeidine) = 0.18 mg/kg/day
Similar potency to some nitrosamines
and belong in a cohort of special
concern (e.g., AIs < 1.5 µg/day).
Nitrosoguanidines
• Commonly used drug cimetidine known to form a
nitroso-guanidine in the stomach after oral dosing,
not direct carcinogen
• Methylnitronitrosoguanidine (MNNG) is often used as a standard
for non-metabolic activation to a mutagen
• Example: TD50 (MNNG) = 0.553 to 0.803 mg/kg/day
• Example: TD50 (Ethyl nitrosoguanidine) = 2.84 mg/kg/day
Not as potent as the smaller alkyl
nitrosamines, but overall would still be
characterized as being in a cohort of
special concern (e.g., AIs < 1.5 µg/day).
Nitrosocarbamates
• TD50 (ethyl N-methyitrosocarbamate) = 0.127 mg/kg/day
• TD50 (n-ethyl-n-nitrosourethane) = 0.0656 to 0.0904 mg/kg/day
Similar potency to the simple alkyl
nitrosamines and belong in a cohort of
special concern (e.g., AIs < 1.5 µg/day).
Nitrosoureas
• Simple alkyl nitrosoureas are direct acting mutagens and
potent carcinogens; the larger nitrosoureas are used as
chemotherapeutic compounds.
• TD50 (simple alkyl nitrosoureas) range
= 0.037 – 0.948 mg/kg/day
Simple alkyl nitrosoureas have similar
potency to simple alkyl nitrosamines
and belong in a cohort of special
concern (e.g., AIs < 1.5 µg/day).
†
TD50 data from the LHASA Carcinogenicity Database
