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Appendix 1 - Established acceptable intake for nitrosamines in medicines
Established AI limits from some nitrosamine impurities that we consider acceptable. These apply for all routes of administration and are listed in Appendix 1.
Nitrosamine structures are available in the print version of Appendix 1 below.
Appendix 1 - Established acceptable intake for nitrosamines in medicines
(CAS number, Abbreviation) | Source2 | AI limit (ng/day)1 | CPCA Potency category | First published |
---|---|---|---|---|
Default class specific threshold of toxicological concern TTC | - | 18.0 | Default limit | - |
3-((Ethyl(nitroso)amino)methyl) benzenesulfonate (N-M8) | - | 18 | 1 | 29 JULY 2024 |
N-Nitroso-N-ethyl-benzylamine / (20689-96-7, NBEA) | - | 18 | 1 | 29 JULY 2024 |
1-Methyl-4-nitrosopiperazine (16339-07-4, MeNP/MNP) | Rifampicin | 400 | 3 | 20 July 2022 Updated 24 August 2023 |
1-Nitroso-pyrrolopiperidine | - | 1500 | 4 | 24 August 2023 |
2-Nitroso-octahydrocyclopenta(c)pyrrole (54786-86-6) | Gliclazide | 1700 | 24 August 2023 | |
3-Amino-N-nitrosopiperidine (2819242-71-0) | Alogliptin | 400 | 3 | 16 October 2023 |
4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (64091-91-4, NNK) | - | 100 | 5 January 2023 | |
7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine (2892260-32-9, NTTP) | Sitagliptin | 100 | 2 | 20 July 2022 Updated 29 JULY 2024 |
Nitroso impurity C” [N-(2,6-dimethylphenyl)-2-(4-nitrosopiperazin-1-yl)acetamide] | Ranolazine | 400 | 3 | 24 August 2023 |
N-Nitroso-orphenadrine (NMOA) | Orphenadrine | 18 | 1 | 24 August 2023 |
N-Nitroso-praziquanamine / (115822-46-3) | Arpraziquantel | 1500 | 4 | 24 August 2023 |
N-Methyl-N-nitrosophenethylamine (13256-11-6, NMPEA) | - | 8.0 | 5 January 2023 | |
N-Nitroso-1,2,3,6-tetrahydropyridine (55556-92-8, NTHP) | - | 37.0 | 20 July 2022 | |
N-Nitroso derivative of rotigotine impurity B / | Rotigotine | 400 | 3 | 16 October 2023 |
N-Nitroso derivative of rotigotine impurity C / | Rotigotine | 1500 | 4 | 16 October 2023 |
N-Nitroso-2,6-pipecoloxilidide | Ropivacaine | 1500 | 4 | 24 August 2023 |
N-Nitroso-2-(7-methoxy-1-naphthyl)-N-[2-(7-methoxy-1-naphthyl)ethyl]ethylamine | Agomelatine | 100 | 2 | 29 JULY 2024 |
N-Nitroso-ambroxol | Ambroxol | 1500 | 24 August 2023 Updated 31 January 2024 | |
N-Nitroso-apixaban impurity B / | Apixaban | 1500 | 4 | 24 April 2024 |
1-(2,3-Dichlorophenyl)-4-nitrosopiperazine (2221987-86-4) | Aripiprazole | 400 | 3 | 31 January 2024 |
N-Nitroso-articaine / | Articaine | 1500 | 4 | 29 JULY 2024 |
N-Nitroso-aryl piperazine / (NDAQ) | Quetiapine | 400 | 3 | 24 August 2023 |
N-Nitroso-atomoxetine | Atomoxetine | 100 | 24 August 2023 | |
N-Nitroso-atenolol (134720-04-0) | Atenolol | 1500 | 4 | 24 August 2023 |
N-Nitroso-azacyclonol (1038-06-8) | Azacyclonol | 400 | 3 | 31 January 2024 |
N-Nitroso-desmethyl-azelastine | Azelastine | 100 | 2 | 31 January 2024 |
N-Nitroso-azithromycin | Azithromycin | NMI | 24 August 2023 | |
N-Nitroso-benazepril | Benazepril | 1500 | 5 | 24 August 2023 |
Benzydamine | 400 | 3 | 29 JULY 2024 | |
N-Nitroso-betahistine (32635-81-7) | Betahistine | 18 | 1 | 24 August 2023 |
N-Nitroso-betaxolol | Betaxolol | 1500 | 4 | 31 January 2024 |
N-Nitroso-bilastine impurity 2 / | Bilastine | 400 | 3 | 29 JULY 2024 |
N-Nitroso-bisoprolol (2820170-76-9, NBP) | Bisoprolol | 1500 | 4 | 24 August 2023 |
N-Nitroso-bumetanide (2490432-02-3, NNB) | Bumetanide | 1500 | 4 | 24 August 2023 |
N-Nitroso-bupropion (2763780-10-3) | Bupropion | 1500 | 5 | 24 August 2023 |
N-Nitroso-caspofungin / | Caspofungin | 1500 | 4 | 29 JULY 2024 |
N-Nitroso-celiprolol | Celiprolol | 1500 | 5 | 31 January 2024 |
N-Nitroso-cilazapril (1053740-92-3) | Cilazapril | 1500 | 5 | 24 August 2023 |
N-Nitroso-cinacalcet | Cinacalcet | 400 | 3 | 31 January 2024 |
1-(Diphenylmethyl)-4-nitrosopiperazine / (1698-25-5) | Cinnarizine | 400 | 3 | 29 JULY 2024 |
N-Nitroso-ciprofloxacin (864443-44-7) | Ciprofloxacin | 1500 | 4 | 24 August 2023 |
N-Nitroso-N-desmethyl-clarithromycin / | Clarithromycin | NMI | 29 JULY 2024 | |
N-Nitroso-clozapine / (156632-03-0) | Clozapine | 1500 | 5 | 24 April 2024 |
N-Nitroso-clozapine EP Impurity C / | Clozapine | 400 | 3 | 24 April 2024 |
2,2,5-Trimethyl-3-nitroso-1,3-oxazolidine (77400-46-5, TMNO) | Cyanocobalamine | 1500 | 4 | 24 April 2024 |
N-Nitroso-dabigatran etexilate (NDAB) | Dabigatran etexilate | 1500 | 5 January 2023 Updated 24 August 2023 and 24 April 2024 | |
5-Chloro-4-methyl-2-[(2S)-2-methyl-1-nitrosopyrrolidin-2-yl]-1H-benzimidazole (IDOR-1135-8758) | Daridorexant | 1500 | 5 | 31 January 2024 |
N-Nitroso-desloratadine (1246819-22-6) | Desloratadine | 400 | 3 | 24 August 2023 |
N-Nitroso-N-desmethyl dextromethorphan/ (N-DEX) | Dextromethorphan | 1500 | 4 | 29 JULY 2024 |
N-Nitroso-desmethyl-edoxaban / | Edoxaban | 100 | 2 | 29 JULY 2024 |
N-Nitroso-desmethyl trimebutine | Trimebutine | 1500 | 5 | 24 August 2023 |
N-Nitroso-trientine Impurity 1 / (2817316-41-7) | Treintine | 18 | 1 | 29 JULY 2024 |
N-Nitroso-desmethylazithromycin | Azithromycin | NMI | 24 August 2023 | |
N-Nitroso-desmethyl-chloropyramine (N-DMCP) | Chloropyramine | 18 | 1 | 24 August 2023 |
N-Nitroso-desmethyl-citalopram / | Citalopram | 100 | - | 31 January 2024 Updated 29 JULY 2024 |
N-Nitroso-desmethyl-tripelennamine | Tripelennamine | 18 | 1 | 24 August 2023 |
N-Nitroso-desvenlafaxine | Desvenlafaxine | 18 | 1 | 31 January 2024 |
N-Nitroso-diclofenac (66505-80-4) | Diclofenac | 1500 | 5 | 24 August 2023 |
N-Nitroso-diethanolamine (1116-54-7, NDELA) | - | 1900 | 5 January 2023 | |
N-Nitroso-diethylamine (55-18-5, NDEA) | - | 26.5 | 15 September 2019 | |
N-Nitroso-diisopropylamine / (601-77-4, DIPNA/NDIPA) | - | 1500 | 5 | 15 September 2019 Updated 29 JULY 2024 |
N-Nitrosodiisopropanolamine / (53609-64-6) | - | 400 | 3 | 24 April 2024 |
N-Nitroso-dimethylamine (62-75-9, NDMA) | - | 96.0 | 15 September 2019 | |
N-Nitroso-di-n-butylamine (924-16-3, NDBA) | - | 26.5 | 20 July 2022 | |
N-Nitroso-N-desmethyl-diphenhydramine / (55855-43-1) | Diphenhydramine / Dimenhydrinate | 18 | 1 | 29 JULY 2024 |
N-Nitroso-diphenylamine (86-30-6, NDPh) | - | 78000 | 5 January 2023 | |
N-Nitroso-dipropylamine (621-64-7, NDPA) | - | 26.5 | 20 July 2022 | |
N-Nitroso-dorzolamide | Dorzolamide | 1500 | 31 January 2024 | |
N-Nitroso-duloxetine (2680527-91-5, NDLX) | Duloxetine | 100.0 | 20 July 2022 | |
N-Nitroso-enalapril | Enalapril | 1500 | 5 | 24 August 2023 |
N-Nitroso-esmolol | Esmolol | 1500 | 4 | 31 January 2024 |
N-Nitroso-ethylisopropylamine / (16339-04-1, EIPNA/NEIPA) | - | 400 | 3 | 15 September 2019 Updated 29 JULY 2024 |
N-Nitroso-felodipine | Felodipine | 1500 | 5 | 24 August 2023 |
N-Nitroso-fenfluramine / (19023-40-6) | Fenfluramine | 400 | 3 | 29 JULY 2024 |
N-Nitroso-flecainide / (2901109-58-6) | Flecainide | 1500 | 4 | 24 April 2024 |
N-Nitrosofluoxetine (150494-06-7) | Fluoxetine | 100 | 5 January 2023 | |
N-Nitroso-folic acid / (26360-21-4, NFA) | Folic acid | 1500 | 4 | 24 August 2023 Updated 29 JULY 2024 |
N-Nitroso-calcium folinate | Calcium folinate / Calcium levofolinate | NMI | 31 January 2024 | |
N-Nitroso-furosemide / (2708280-93-5) | Furosemide | 1500 | 29 JULY 2024 | |
N-Nitroso-hydrochlorothiazide (63779-86-2, NHCTZ) | Hydrochlorothiazide | NMI | 24 August 2023 | |
N-Nitroso imatinib | Imatinib | 1500 | 5 | 31 January 2024 |
Indapamide impurity A / (85440-79-5) | Indapamide | 1500 | 5 | 31 January 2024 |
N-Nitroso-ethylenediamine-triacetic acid (862542-34-5) | Isosorbide mononitrate | 1500 | 4 | 31 January 2024 |
N-Nitroso-iminodiacetic acid (25081-31-6) | Isosorbide mononitrate | 1500 | 4 | 31 January 2024 |
N-Nitroso-ketamine (86144-35-6) | Ketamine | 1500 | 5 | 24 August 2023 |
N-Nitroso-labetalol (2820170-74-7) | Labetalol | 1500 | 4 | 24 August 2023 |
N-Nitroso-landiolol | Landiolol | 400 | 3 | 24 August 2023 |
N-Nitroso-leniolisib | Leniolisib | 1500 | 5 | 31 January 2024 |
N-Nitroso-levofloxacin (1152314-62-9) | Levofloxacin | 1500 | 4 | 24 August 2023 |
N-Nitroso-desethyllidocaine | Lidocaine / Lignocaine | 100 | 2 | 31 January 2024 |
N-Nitroso-lisinopril / (519175-80-5, NLP) | Lisinopril | NMI | 24 August 2023 Updated 29 JULY 2024 | |
N-Nitroso-masitinib / | Masitinib | 400 | 3 | 24 April 2024 |
N-Nitroso-mefenamic acid (2114-63-8) | Mefenamicacid | 78000 | 5 January 2023 | |
N-Nitroso-meropenem / | Meropenem | 1500 | 4 | 24 April 2024 |
N-Nitroso-methylphenidate (55557-03-4, NMPH) | Methylphenidate | 1300 | 20 July 2022 | |
N-Nitroso-ritalinic acid / | Methylphenidate | 1500 | 4 | 24 April 2024 |
N-Nitroso-metoprolol (138768-62-4) | Metoprolol | 1500 | 4 | 24 August 2023 |
N-Nitroso-mirabegron | Mirabegron | 400 | 3 | 24 August 2023 |
N-(2-Hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide / (MBL-2-NO) | Mirabegron | 400 | 3 | 29 JULY 2024 |
N-(4-Aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide / (MBL-3-NO) | Mirabegron | 400 | 3 | 29 JULY 2024 |
N-Nitroso-mirtazapine | Mirtazapine | 400 | 3 | 31 January 2024 |
N-Nitroso-morpholine (59-89-2, NMOR) | - | 127.0 | 20 July 2022 | |
N-Nitroso-moxifloxacin | Moxifloxacin | 1500 | 4 | 24 August 2023 |
N-Nitroso-nebivolol (1391051-68-5, NNEB) | Nebivolol | 1500 | 4 | 24 August 2023 |
N-Nitroso desmethyl nintedanib | Nintedanib | 400 | 3 | 31 January 2024 |
N-Nitroso-posaconazole Impurity 1 / | Posaconazole | 400 | 3 | 29 JULY 2024 |
N-Nitroso-N-ethyl-valacyclovir | Valacyclovir | 400 | 3 | 24 August 2023 |
N-Nitroso-N-methyl-valacyclovir | Valacyclovir | 400 | 3 | 24 April 2024 |
N-Nitroso-vibegron | Vibegron | 1500 | 5 | 29 JULY 2024 |
N-Nitroso-N-methyl-4-aminobutyric acid / 4-[methyl(nitroso)amino]butanoic acid (61445-55-4, NMBA) | - | 1500 | 4 | 15 September 2019 Updated 29 JULY 2024 |
N-Nitroso-N-methylaniline / (614-00-6, NMPA) | - | 100 | 2 | 31 January 2024 |
N-Nitroso-nortriptyline (55855-42-0, NNORT) | Amitriptyline, Nortriptyline | 8.0 | 20 July 2022 | |
4-Nitroso-methyl piperazine-1-carboxylate (N-nitroso PMEC) | Omecamtiv mecarbil | 400 | 3 | 29 JULY 2024 |
2-(4-Nitrosopiperazin-1-yl)ethanol (48121-20-6) | Opipramol | 400 | 3 | 29 JULY 2024 |
N-Nitroso-paroxetine (2361294-43-9) | Paroxetine | 1300 | 5 January 2023 | |
N-Nitroso-p-chloro-benzylamino-pyridine (N-CBAP) | - | 100 | 2 | 24 August 2023 |
N-Nitroso-perindopril | Perindopril | 1500 | 5 | 24 August 2023 |
N-Nitroso-phenylephrine (78658-64-7) | Phenylephrine | 100 | 2 | 24 August 2023 |
N-Nitroso-piperazine (5632-47-3, NPZ) | - | 400 | 3 | 24 August 2023 |
N-Nitrosopiperidine (100-75-4) | - | 1300 | 20 July 2022 | |
N-Nitroso-pramipexole | Pramipexole | 400 | 3 | 24 August 2023 |
N-Nitroso-propranolol (84418-35-9) | Propranolol | 1500 | 4 | 24 August 2023 |
N-Nitroso-pseudoephedrine (1850-88-0) | Pseudoephedrine | 1500 | 4 | 24 August 2023 |
N-Nitroso-pyrrolidine (930-55-2, NPYR) | - | 1700 | 5 January 2023 | |
N-Nitroso quetiapine HEEP impurity / (73486-81-4) | Quetiapine | 1500 | 31 January 2024 | |
N-Nitroso-quinapril | Quinapril | NMI | 24 August 2023 | |
N-Nitroso-ramipril | Ramipril | 1500 | 5 | 24 August 2023 |
N-nitroso ranolazine impurity 1 / | Ranolazine | 400 | 3 | 31 January 2024 |
N-Nitrosorasagiline (2470278-90-9) | Rasagiline | 100 | 2 | 20 July 2022 Updated 24 August 2023 |
N-Nitroso-reboxetine | Reboxetine | 127 | 24 August 2023 | |
N-Nitroso-ribociclib impurity 1 / | Ribociclib | 400 | 3 | 31 January 2024 |
N-Nitroso-desformyl-riociguat / | Riociguat | 100 | 2 | 29 JULY 2024 |
N-Nitroso-rivaroxaban open-ring acid | Rivaroxaban | 1500 | 4 | 31 January 2024 |
N-Nitroso-rivaroxaban amide / | Rivaroxaban | 1500 | 4 | 31 January 2024 |
Rivaroxaban Nitroso Impurity 1 / | Rivaroxaban | 1500 | 4 | 29 JULY 2024 |
Rivaroxaban Nitroso Impurity 2 / | Rivaroxaban | 1500 | 4 | 29 JULY 2024 |
Rivaroxaban Nitroso Impurity 5 / (N-Nitroso RVR-A) | Rivaroxaban | 1500 | 4 | 29 JULY 2024 |
N-Nitroso-salbutamol (2919946-71-5) | Salbutamol | 1500 | 5 | 24 August 2023 |
N-Nitroso-sertraline | Sertraline | 1500 | 24 August 2023 Updated 16 October 2023 | |
N-Nitroso-desmethyl-sildenafil | Sildenafil | 400 | 3 | 31 January 2024 |
N-Nitroso-silodosin / | Silodosin | 1500 | 4 | 24 April 2024 |
N-Nitroso-sotalol (134720-07-3) | Sotalol | 1500 | 4 | 24 August 2023 |
N-Nitroso-desmethyl sumatriptan | Sumatriptan | 18 | 1 | 31 January 2024 |
N-Nitroso-desmethyl-tamoxifen / | Tamoxifen | 18 | 1 | 24 April 2024 |
N-Nitroso-tamsulosin (2892260-31-8) | Tamsulosin | 1500 | 4 | 20 July 2022 Updated 24 August 2023 |
N-Nitroso terazosin impurity C / | Terazosin | 400 | 3 | 24 April 2024 |
N-Nitroso terazosin impurity N / (2470438-57-2) | Terazosin | 400 | 3 | 24 April 2024 |
N-Nitroso-desmethyl-terbinafine / (NDT / NHNA) | Terbinafine | 18 | 1 | 31 January 2024 |
N-Nitroso-terbinafine impurity A (296760-88-8, NTA / NMNA) | Terbinafine | 18 | 1 | 31 January 2024 |
N-Nitroso-terbinafine degradant (NTD / NHMA) | Terbinafine | 18 | 1 | 31 January 2024 |
N-Nitroso-tetracaine | Tetracaine | 400 | 3 | 31 January 2024 |
N‐Nitroso‐ticagrelor (2476859-55-7) | Ticagrelor | 1500 | 5 | 31 January 2024 |
N-Nitroso-tigecycline / | Tigecycline | NMI | 29 JULY 2024 | |
N-Nitroso-desmethyl-tramadol / | Tramadol | 18 | 1 | 29 JULY 2024 |
N-Nitroso-trandolapril / | Trandolapril | 1500 | 5 | 29 JULY 2024 |
N-Nitroso-trimetazidine (92432-50-3, NTMZ) | Trimetazidine | 400 | 3 | 24 August 2023 |
N-Nitroso-urapidil | Urapidil | 1500 | 4 | 31 January 2024 |
N-Nitroso-varenicline (2755871-02-2, NNV) | Varenicline | 400 | 3 | 20 July 2022 Updated 16 October 2023 |
N-Nitroso-desvaleryl-valsartan / (2254485-68-0) | Valsartan | NMI | 29 JULY 2024 | |
N-Nitroso-vildagliptin | Vildagliptin | 1500 | 5 | 24 August 2023 |
N-Nitroso-vortioxetine | Vortioxetine | 400 | 3 | 24 August 2023 |
CPCA: Carcinogenic Potency Categorisation Approach
- Acceptable Intake (AI) Limit to be applied to maximum daily dose (MDD) of the drug product. These limits are applicable only if a product contains a single N-nitrosamine.
- Potential presence of nitrosamine 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 4 on the risk factors for the presence of nitrosamines for details.