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Established acceptable intake for other nitroso-structures in medicines

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Below is a list of established AI limits for some other N-nitroso-structures. N-Nitroso-structures include N-nitrosoguanidines, N-nitroso-indoles and N-nitrosoureas. These apply for all routes of administration.

Established AI limits for some nitrosamine impurities are listed separately.

Other nitroso-structures are also included in the print version below.

Established acceptable intake for other N-nitroso-structures in medicines.

N-Nitroso-structure

(CAS number, Abbreviation)

Source2

N-Nitroso-structure molecular structure

AI limit

(ng/day)1

First published

N-Nitroso-biotin /
5-((3aS,4S,6aR)-1-nitroso-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoic acid

(56859-26-8)

Biotin
Established acceptable intake for other N-nitroso-structures in medicines-Biotin

1500

24 January 2025

N-Nitroso-cimetidine /
3-cyano-1-methyl-2-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]-1-nitrosoguanidine

(73785-40-7)

Cimetidine
Established acceptable intake for other nitroso-structures in medicines Cimetidine

553

24 January 2025

N-Nitroso-clonidine /
N-(2,6-dichlorophenyl)-1-nitroso-4,5-dihydroimidazol-2-amine

(148950-49-6)

Clonidine
Clonidine Established acceptable intake for other nitroso-structures in medicines

553

24 January 2025

N-Nitroso-clonidine-2 /
N-(2,6-dichlorophenyl)-N-(4,5-dihydro-1H-imidazol-2-yl)nitrous amide

Clonidine
Clonidine 2 Established acceptable intake for other nitroso-structures in medicines

553

24 January 2025

N-Nitroso-eletriptan /
(S)-3-((1-methylpyrrolidin-2-yl)methyl)-1-nitroso-5-(2-(phenylsulfonyl)ethyl)-1H-indole

Eletriptan
N-Nitroso-eletriptan / (S)-3-((1-methylpyrrolidin-2-yl)methyl)-1-nitroso-5-(2-(phenylsulfonyl)ethyl)-1H-indole

1500

24 January 2025

N-Nitroso-melatonin /
N-(2-(5-methoxy-1-nitroso-1H-indol-3-yl)ethyl)acetamide

(278783-22-5)

Melatonin
N-Nitroso-melatonin / N-(2-(5-methoxy-1-nitroso-1H-indol-3-yl)ethyl)acetamide (278783-22-5)

1500

24 January 2025

1-Nitroso-moxonidine /
N-(4-chloro-6-methoxy-2-methylpyrimidin-5-yl)-N-(4,5-dihydro-1H-imidazol-2-yl)nitrous amide

Moxonidine
1-Nitroso-moxonidine / N-(4-chloro-6-methoxy-2-methylpyrimidin-5-yl)-N-(4,5-dihydro-1H-imidazol-2-yl)nitrous amide

553

24 January 2025

1-Nitroso-moxonidine Impurity 3 /
4-chloro-6-methoxy-2-methyl-N-(1-nitroso-4,5-dihydro-1H-imidazol-2-yl)pyrimidin-5-amine

Moxonidine
1-Nitroso-moxonidine Impurity 3 / 4-chloro-6-methoxy-2-methyl-N-(1-nitroso-4,5-dihydro-1H-imidazol-2-yl)pyrimidin-5-amine

553

24 January 2025

N-Nitroso-naratriptan /
N-methyl-2-[3-(1-methylpiperidin-4-yl)-1-nitrosoindol-5-yl]ethanesulfonamide

(1216880-64-6)

Naratriptan
N-Nitroso-naratriptan / N-methyl-2-[3-(1-methylpiperidin-4-yl)-1-nitrosoindol-5-yl]ethanesulfonamide (1216880-64-6)

1500

24 January 2025

N-Nitroso-rizatriptan /
2-(5-((1H-1,2,4-triazol-1-yl)methyl)-1-nitroso-1H-indol-3-yl)-N,N-dimethylethan-1-amine

Rizatriptan
N-Nitroso-rizatriptan / 2-(5-((1H-1,2,4-triazol-1-yl)methyl)-1-nitroso-1H-indol-3-yl)-N,N-dimethylethan-1-amine

1500

24 January 2025

N-Nitroso-sumatriptan /
1-(3-(2-(dimethylamino)ethyl)-1-nitroso-1H-indol-5-yl)-N-methylmethanesulfonamide

Sumatriptan
N-Nitroso-sumatriptan / 1-(3-(2-(dimethylamino)ethyl)-1-nitroso-1H-indol-5-yl)-N-methylmethanesulfonamide

1500

24 January 2025

N-Nitroso-tadalafil /
(2R,8R)-2-(1,3-benzodioxol-5-yl)-6-methyl-17-nitroso-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione

Tadalafil
N-Nitroso-tadalafil / (2R,8R)-2-(1,3-benzodioxol-5-yl)-6-methyl-17-nitroso-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione

1500

24 January 2025

N-Nitroso-tizanidine /
N-(5-chlorobenzo[c][1,2,5]thiadiazol-4-yl)-N-(4,5-dihydro-1H-imidazol-2-yl)nitrous amide

Tizanidine
N-Nitroso-tizanidine / N-(5-chlorobenzo[c][1,2,5]thiadiazol-4-yl)-N-(4,5-dihydro-1H-imidazol-2-yl)nitrous amide

553

24 January 2025

N-Nitroso-tizanidine Impurity 3 /
N-(5-chlorobenzo[c][1,2,5]thiadiazol-4-yl)-N-(4,5-dihydro-1H-imidazol-2-yl)nitrous amide

Tizanidine
N-Nitroso-tizanidine Impurity 3 / N-(5-chlorobenzo[c][1,2,5]thiadiazol-4-yl)-N-(4,5-dihydro-1H-imidazol-2-yl)nitrous amide

553

24 January 2025

N-Nitroso-tryptophol /
2-(1-nitrosoindol-3-yl)ethanol

(120314-14-9)

Tryptophol
N-Nitroso-tryptophol / 2-(1-nitrosoindol-3-yl)ethanol (120314-14-9)

1500

24 January 2025

N-Nitroso-zolmitriptan /
(4S)-4-[[3-[2-(dimethylamino)ethyl]-1-nitrosoindol-5-yl]methyl]-1,3-oxazolidin-2-one

Zolmitriptan
N-Nitroso-zolmitriptan / (4S)-4-[[3-[2-(dimethylamino)ethyl]-1-nitrosoindol-5-yl]methyl]-1,3-oxazolidin-2-one

1500

24 January 2025

N-Methyl-N’-nitro-N-nitrosoguanidine /
1-methyl-3-nitro-1-nitrosoguanidine

(70-25-7, MNNG)
N-Methyl-N’-nitro-N-nitrosoguanidine / 1-methyl-3-nitro-1-nitrosoguanidine (70-25-7, MNNG)

553

24 January 2025

NMI: Non mutagenic impurity should be controlled to ICH Q3A and ICH Q3B guideline limits

  1. Acceptable Intake (AI) Limit to be applied to maximum daily dose (MDD) of the drug product.

  2. Potential presence of nitroso-structure impurities with structures derived from drug substances or their related impurities. This does not mean that the impurity will be found in all products or pharmaceutical forms containing the drug substance. Please refer to EMA’s Q&A for details.

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