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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 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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Mutagenicity and Carcinogenicity01:25

Mutagenicity and Carcinogenicity

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Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
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Inorganic Nitrogen Assimilation01:22

Inorganic Nitrogen Assimilation

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Nitrogen is an essential element in biological systems, forming a crucial component of proteins, nucleic acids, and other cellular constituents. Many bacteria and archaea acquire nitrogen in the form of nitrate (NO₃⁻) or ammonia (NH₃), which are then assimilated into biomolecules through specific enzymatic pathways.Assimilatory Nitrate ReductionWhen nitrate enters the cell, it undergoes a two-step reduction process known as assimilatory nitrate reduction. Initially, the enzyme...
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1° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Overview01:26

1° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Overview

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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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Other Nuclides: 31P, 19F, 15N NMR01:16

Other Nuclides: 31P, 19F, 15N NMR

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Many organic, inorganic, and biological molecules contain spin-half nuclei such as nitrogen-15, fluorine-19, and phosphorus-31. As a result, NMR studies of these nuclei have found extensive applications in chemical and biological research.
While fluorine-19 and phosphorous-31 have high natural abundances (100%) and positive gyromagnetic ratios, nitrogen-15 has a low natural abundance and a negative gyromagnetic ratio. However, nitrogen-15 is still preferred over nitrogen-14 (which has a...
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Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs).

Joel P Bercu1, Melisa Masuda-Herrera1, Alejandra Trejo-Martin1

  • 1Gilead Sciences, Inc., Nonclinical Safety and Pathobiology (NSP), Foster City, CA, USA.

Regulatory Toxicology and Pharmacology : RTP
|May 31, 2023
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Summary

Health authorities set acceptable intakes (AIs) for N-nitrosamines (NAs) in pharmaceuticals. This study transparently evaluated NA toxicity data to clarify AI derivation, advancing risk assessment for these potential carcinogens.

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Area of Science:

  • Pharmaceutical chemistry
  • Toxicology
  • Regulatory science

Background:

  • Low levels of N-nitrosamines (NAs) detected in pharmaceuticals necessitate regulatory limits.
  • Health authorities (HAs) established acceptable intakes (AIs) to mitigate carcinogenic risks.
  • The scientific rationale for current AIs and the selection of TD50 values or read-across analogs remain unclear.

Purpose of the Study:

  • To transparently evaluate toxicity data for eleven common NAs.
  • To establish a clear methodology for deriving acceptable intakes (AIs) consistent with ICH M7 guidelines.
  • To address the lack of rationale behind existing NAs AIs.

Main Methods:

  • Comprehensive evaluation of toxicity data for eleven common N-nitrosamines (NAs).
  • Application of International Council for Harmonisation (ICH) M7 principles.
  • Calculation of AIs using TD50 values from the most sensitive organ site for substances with sufficient data.
  • Utilizing structure-activity relationships (SARs) and available carcinogenicity data for substances with insufficient experimental data to assign categorical AIs (1500, 150, or 18 ng/day).

Main Results:

  • A transparent methodology for deriving acceptable intakes (AIs) for N-nitrosamines (NAs) was developed.
  • AIs were calculated based on TD50 values for NAs with robust or sufficient carcinogenicity data.
  • Categorical AIs were assigned for NAs with insufficient carcinogenicity data, with potential for refinement through additional studies.

Conclusions:

  • The developed approach provides a clear and consistent method for deriving acceptable intakes (AIs) for N-nitrosamines (NAs).
  • This methodology enhances the scientific basis for regulatory limits of NAs in pharmaceuticals.
  • Further data, including biological and computational modeling, can refine the proposed AIs.