Nitrosamine of 7-Hydroxy-1H–quinolin–2–one

N-nitrosamines Chemistry
1

Would it be possible to generate Nitrosamine of 7-Hydroxy-1H–quinolin–2–one. If yes what will be the Potency Category ??
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2

My understanding is that this one does not count as an heteroaromatic ring, but bear in mind that it is not a nitrosamine. The nitroso derivative would be a nitrosoamide. But, if you were to categorize the compound it would be 1500 ng/day (no alpha protons on either alpha position, Category 5)

Formation is much less unlikely due to the electronwithdrawing nature of the carbonyl group (not considering the pseudoaromaticity). I would recommend testing the nitrosation of the position rather than confirmatory testing

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@JavierFernandez , Thanks for swift response.

4

If you apply the alternative approach of read-across, the most simil structure is the
1-Nitroso-2,2,4-trimethyl-1,2-dihydroquinoline polymer
with a TD50 of 3.31 mg/kg/day

If you calculate the specific AI according to ICH M7 you will obtain:

3.31 mg/kg/day ÷ 50,000 = 0.0662 μg/kg
To derive a total human daily dose:
0.0662 μg/kg/day x 50 kg body weight = 3.31 μg/day = 3310 ng/day

Because the chemical structure is different, you cannot use “as is” the above limit for your impurity, but this strongly support the proposed limit of 1500 ng/day.

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5

Due to its structural steric hinderance, having no hydrogens on its alpha carbons and the presence of a hydroxyl group (proton withdrawing group), nitrosation is not favored.

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Thanks for quick response

7

You can additionally consider that phenols react much faster with nitrosating species than secondary amines to form mostly C-NO2 derivatives, nitro- not nitroso-derivatives.

  • Rapid Nitrosation of Phenols and its Derivatives and Its Implications for Health Hazards from Dietary Nitrites (B. C. Challis, Nature, 1973)
  • Reaction of Phenol with Nitrite Ion_Pathways of Formation of Nitrophenols in Environmental Waters (P. Patnaik & J.N.Khoury , Water Res., 2004) doi:10.1016/j.watres.2003.08.022
  • On the Polarographic Determination of Phenols after Treatment with Nitrous Acid (H. Lund, Acta Chem, Scand., 1958) doi: 10.3891/acta.chem.scand.12-1444
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