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Related Concept Videos

2° Amines to N-Nitrosamines: Reaction with NaNO201:20

2° Amines to N-Nitrosamines: Reaction with NaNO2

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Secondary amines react with nitrous acid to form N-nitrosamines, as depicted in Figure 1. Nitrous acid, a weak and unstable acid, is formed in situ from an aqueous solution of sodium nitrite and strong acids, such as hydrochloric acid or sulfuric acid, in cold conditions. In the presence of an acid, the nitrous acid gets protonated. The subsequent loss of water results in the formation of the electrophile known as nitrosonium ion.
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Physical Properties of Amines01:26

Physical Properties of Amines

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Amines with low molecular weight are usually gaseous at room temperature, while those with high molecular weight are liquid or solids in nature. Usually, low molecular weight amines have a rotten fish-like smell. Diamines typically have a pungent smell. For instance, cadaverine and putrescine, depicted in Figure 1, are two molecules responsible for decaying tissue.
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1° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Overview01:26

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Nitrous acid and nitric acids are two types of acids containing nitrogen, among which nitrous acid is weaker than nitric acid. Nitrous acid with a pKa value of 3.37 ionizes in water to give a nitrite ion and the hydronium ion.
The nitrous acid is unstable. Hence, it is formed in situ from a solution of sodium nitrite and cold aqueous acids such as hydrochloric or sulfuric acid. In an acidic solution, the –OH group of nitrous acid undergoes protonation to give oxonium ion, followed by...
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A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s
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Permitted daily exposure limits for noteworthy N-nitrosamines.

George E Johnson1, Krista Dobo2, Bhaskar Gollapudi3

  • 1Swansea University Medical School, Swansea University, Swansea, Wales, UK.

Environmental and Molecular Mutagenesis
|June 5, 2021
PubMed
Summary

N-nitrosamines like NDMA and NDEA in valsartan drugs are genotoxic carcinogens. New calculations for permissible daily exposures (PDEs) offer a more robust risk assessment for patients than previous methods.

Keywords:
BMDPDEimpuritylinearnitrosaminesartan

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Area of Science:

  • Pharmacology and Toxicology
  • Carcinogenesis and Mutagenesis
  • Drug Safety and Regulation

Background:

  • N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are genotoxic carcinogens found as impurities in sartan medications.
  • These N-nitrosamines are pro-mutagens that can cause DNA damage, leading to mutations and increased cancer risk.
  • Existing acceptable daily intake (ADI) values were calculated using linear extrapolation, potentially underestimating risk at low exposure levels.

Purpose of the Study:

  • To calculate Permissible Daily Exposures (PDEs) for NDMA and NDEA using benchmark dose (BMD) modeling.
  • To compare these BMD-derived PDEs with existing ADI values.
  • To provide a more robust risk assessment for patients exposed to N-nitrosamine-contaminated sartan drugs.

Main Methods:

  • Utilized rodent cancer bioassay and in vivo mutagenicity data for NDMA and NDEA.
  • Applied benchmark dose modeling to determine points of departure (POD) for cancer and mutagenicity.
  • Calculated PDEs by adjusting PODs with appropriate uncertainty factors (UFs) following ICH M7 guidelines.

Main Results:

  • Calculated PDEs for NDMA: 6.2 μg/person/day (cancer) and 0.6 μg/person/day (mutation).
  • Calculated PDEs for NDEA: 2.2 μg/person/day (cancer) and 0.04 μg/person/day (mutation).
  • Resulting PDEs are higher than regulatory ADIs (96 ng for NDMA, 26.5 ng for NDEA), indicating a potentially safer exposure limit.

Conclusions:

  • Benchmark dose modeling provides a more robust assessment of N-nitrosamine exposure limits compared to simple linear extrapolation.
  • The calculated PDEs offer a better basis for informing risk management strategies for contaminated sartan drugs.
  • This approach enhances the protection of public health by establishing more accurate safety thresholds for drug impurities.