Nitrosamine impurities in medications: Established acceptable intake limits

Established Acceptable Intake Limits (Excel version - (1,106 KB))

Health Canada's table of established Acceptable Intake limits (Appendix 1) has been removed from the guidance document and placed in this tab.

CAS RN: Chemical Abstracts Service Registry Number
CPCA: Carcinogenic Potency Categorization Approach
AI: Acceptable Intake
-: Not applicable

Appendix 1: Established acceptable intake (AI) limits for N-nitrosamine impurities (version: 2024-07-26)
Date Most Recently Published (YYYY-MM-DD)	Related Drug Substance	N-nitrosamine (and acronym, if available)	CAS RN	CPCA Category	AI Limit (ng/day)^{Table 1 footnote *}
2024-05-31	-	N-nitroso-N-ethyl-benzylamine (NBEA)	20689-96-7	1	18
2024-05-31	Trientine	N-(2-aminoethyl)-N-(2-((2-aminoethyl)amino)ethyl)nitrous amide	-	1	18
2024-05-31	-	3-((ethyl(nitroso)amino)methyl)benzenesulfonate	-	1	18
2024-05-31	Edoxaban	N-nitroso-N-desmethyl-edoxaban	-	2	100
2024-05-31	Mirabegron	(R)-N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide	-	3	400
2024-05-31	Mirabegron	(R)-N-(4-aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide	-	3	400
2024-05-31	Posaconazole	1-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)-4-nitrosopiperazine	-	3	400
2024-05-31	Argatroban	N-nitroso-argatroban	-	4	1500
2024-05-31	Articaine	N-nitroso-articaine	-	4	1500
2024-05-31	Rivaroxaban	(S)-2-(2-((4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2-oxooxazolidin-3-yl)phenyl)(nitroso)amino)ethoxy)acetic acid	-	4	1500
2024-05-31	Rivaroxaban	(S)-N-(3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)-N-(4-(3-oxomorpholino)phenyl)nitrous amide	-	4	1500
2024-05-31	Rivaroxaban	N-(2-hydroxyethyl)-N-phenylnitrous amide	25413-76-7	4	1500
2024-05-31	Rivaroxaban	(R)-N-(3-chloro-2-hydroxypropyl)-N-(4-(3-oxomorpholino)phenyl)nitrous amide	-	4	1500
2024-03-28	Clozapine	N-nitroso-clozapine EP Impurity C	-	3	400
2024-03-28	-	N-nitroso-meglumine	62137-31-9	-	1500^{Table 1 footnote ***}
2024-03-28	Silodosin	N-nitroso-silodosin	-	4	1500
2024-03-28	Methylphenidate	N-nitroso-ritalinic acid	-	4	1500
2024-03-28	Apixaban	N-nitroso-apixaban EP Impurity B	-	4	1500
2024-03-28	Terazosin	N-nitroso-terazosin EP Impurity C	-	3	400
2024-03-28	Gliclazide	2-nitrosooctahydrocyclo-penta[c]pyrrole (Gliclazide EP Impurity B)	54786-86-6	-	1700
2024-03-28	Indapamide	(2RS)-2-methyl-1-nitroso-2,3-dihydro-1H-indole (Indapamide EP Impurity A)	85440-79-5	5	1500
2023-07-24	-	N-nitroso-piperazine	5632-47-3	3	400
2023-07-24	-	N-nitroso-pyrrolidine (NPYR)	930-55-2	-	1700
2023-04-17	-	N-nitroso-diethanolamine (NDELA)	1116-54-7	-	1900
2023-04-17	-	N-nitroso-diphenylamine (NDPh)	86-30-6	-	78000
2022-09-01	-	4-(methylnitrosamino)-1-(3-pyridyl)-1-(butanone) (NNK)	64091-91-4	-	100
2022-05-27	-	N-methyl-N-nitroso-phenethylamine (NMPEA)	13256-11-6	-	8
2022-05-27	-	N-nitroso-1,2,3,6-tetrahydropyridine (NTHP)	55556-92-8	-	37
2022-05-27	-	N-nitroso-piperidine (NPIP)	100-75-4	-	1300
2021-12-06	-	N-nitroso-dipropylamine (NDPA)	621-64-7	-	26.5
2021-12-06	-	N-nitroso-morpholine (NMOR)	59-89-2	-	127
2020-12-15	-	N-nitroso-dibutylamine (NDBA)	924-16-3	-	26.5
2024-05-31	-	N-nitroso-4-(methylamino)butyric acid (NMBA)	61445-55-4	4	1500
2019-10-02	-	N-nitroso-diethylamine (NDEA)	55-18-5	-	26.5
2024-05-31	-	N-nitroso-diisopropylamine (NDIPA)	601-77-4	5	1500
2019-10-02	-	N-nitroso-dimethylamine (NDMA)	62-75-9	-	96
2024-05-31	-	N-nitroso-ethylisopropylamine (NEIPA)	16339-04-1	3	400
2023-07-24	-	1-methyl-4-nitrosopiperazine (MNP)	16339-07-4	3	400
2023-10-20	Alogliptin	3-amino-N-nitrosopiperidine	2819242-71-0	3	400
2022-05-27	Amitriptyline	N-nitroso-nortriptyline (NNORT)	55855-42-0	-	8
2024-03-15	Aripiprazole	1-(2,3-dichlorophenyl)-4-nitrosopiperazine	2221987-86-4	3	400
2023-07-24	Atenolol	N-nitroso-atenolol	134720-04-0	4	1500
2023-07-24	Atomoxetine	N-nitroso-atomoxetine	-	-	100
2024-03-15	Azelastine	N-nitroso-desmethylazelastine	-	2	100
2023-07-24	Azithromycin	N-nitroso-azaerythromycin	-	-	-^{Table 1 footnote **}
2023-07-24	Azithromycin	N-nitroso-N- desmethylazithromycin	-	-	-^{Table 1 footnote **}
2023-07-24	Benazepril	N-nitroso-benazepril	-	5	1500
2024-03-15	Benzydamine	2-[benzyl(nitroso)amino] benzoic acid	1028-91-7	4	1500
2023-07-24	Betahistine	N-nitroso-betahistine	32635-81-7	1	18
2024-03-15	Betaxolol	N-nitroso-betaxolol	-	4	1500
2024-03-15	Bilastine	1-(2-ethoxyethyl)-2-(1-nitrosopiperidin-4-yl)-1H-benzo[d]imidazole	-	3	400
2023-07-24	Bisoprolol	N-nitroso-bisoprolol	2820170-76-9	4	1500
2024-03-15	Bumetanide	N-nitroso-bumetanide	2490432-02-3	4	1500
2023-07-24	Bupropion	N-nitroso-bupropion	2763780-10-3	5	1500
2023-07-24	Cilazapril	N-nitroso-cilazapril	1053740-92-3	5	1500
2023-10-20	Cinacalcet	N-nitroso-cinacalcet	-	3	400
2023-07-24	Ciprofloxacin	N,N'-dinitrosopiperazine	140-79-4	3	400
2024-07-26	Ciprofloxacin	N-nitroso-ciprofloxacin	864443-44-7	-	^{Footnote **}
2024-07-26	Citalopram	N-nitroso-N-desmethyl-citalopram	-	-	100
2024-05-31	Clarithromycin	N-nitroso-N-desmethyl-clarithromycin	-	-	^{Footnote **}
2023-07-24	Clozapine	N-nitroso-clozapine	156632-03-0	5	1500
2024-03-15	Dabigatran etexilate	N-nitroso-dabigatran etexilate	-	-	1500^{Table 1 footnote ***}
2024-03-15	Daridorexant	5-chloro-4-methyl-2- [(2S)-2-methyl-1-nitrosopyrrolidin-2-yl]- 1H-benzimidazole	-	5	1500
2023-07-24	Desloratadine	N-nitroso-desloratadine	1246819-22-6	3	400
2023-07-24	Desvenlafaxine	N-nitroso-N-desmethyl-desvenlafaxine	-	1	18
2023-07-24	Dextromethorphan	N-nitroso-N-desmethyl-dextromethorphan	-	4	1500
2023-07-24	Diclofenac	N-nitroso-diclofenac	66505-80-4	5	1500
2023-07-24	Diphenhydramine	N-nitroso-N-desmethyl-diphenhydramine	55855-43-1	1	18
2024-03-15	Dorzolamide	N-nitroso-dorzolamide	-	-	1500^{Table 1 footnote ***}
2023-07-24	Doxepin	N-nitroso-nordoxepin	-	1	18
2023-07-24	Doxycycline	N-nitroso-N-desmethyl-doxycycline	-	3	400
2023-07-24	Doxylamine	N-nitroso-N-desmethyl-doxylamine	-	1	18
2023-07-24	Doxylamine	N-nitroso-N-methyl-2- [1-phenyl-1-(2-pyridinyl) methoxy]ethanamine	-	1	18
2022-05-27	Duloxetine	N-nitroso-duloxetine (NDLX)	-	-	100
2023-07-24	Enalapril	N-nitroso-enalapril	-	5	1500
2023-07-24	Felodipine	N-nitroso-felodipine	-	5	1500
2023-07-24	Flecainide	N-nitroso-flecainide	-	4	1500
2023-07-24	Fluoxetine	N-nitroso-fluoxetine	150494-06-7	-	100
2023-07-24	Folic acid	N-nitroso-folic acid	26360-21-4	4	1500
2023-07-24	Frovatriptan	N-nitroso-frovatriptan	-	3	400
2023-07-24	Furosemide	N-nitroso-furosemide	2708280-93-5	4	1500
2023-07-24	Hydrochlorothiazide	N-nitroso-hydrochlorothiazide	63779-86-2	-	-^{Table 1 footnote **}
2023-07-24	Hydroxyzine	2-(2-(4-nitrosopiperazin-1-yl) ethoxy)ethan-1-ol	73486-81-4	3	400
2023-07-24	Ketamine	N-nitroso-ketamine	86144-35-6	5	1500
2023-07-24	Labetalol	N-nitroso-labetalol	2820170-74-7	4	1500
2024-03-15	Landiolol	N-nitroso-landiolol	-	3	400
2024-03-15	Leucovorin	N-nitroso-folinic acid	66505-80-4	-	-^{Table 1 footnote **}
2023-07-24	Levofloxacin	(S)-10-((2-aminoethyl) (nitroso)amino)-9-fluoro- 3-methyl-7-oxo-2,3-dihydro- 7H-[1,4]oxazino[2,3,4-ij] quinoline-6-carboxylic acid	-	4	1500
2023-07-24	Levofloxacin	N-nitroso-N-desmethyl-levofloxacin	1152314-62-9	4	1500
2023-07-24	Lidocaine	N-nitroso-desethyl-lidocaine	-	2	100
2024-05-31	Lisinopril	N-nitroso-lisinopril	519175-80-5	-	^{Footnote **}
2023-04-17	Mefenamic acid	N-nitroso-mefenamic acid	2114-63-8	-	78000
2023-07-24	Meropenem	N-nitroso-meropenem	-	4	1500
2022-05-27	Methylphenidate	N-nitroso-methylphenidate (NMPH)	55557-03-4	-	1300
2023-07-24	Metoprolol	N-nitroso-metoprolol	134720-05-1	4	1500
2023-07-24	Mirabegron	N-nitroso-mirabegron	-	3	400
2024-03-15	Mirtazapine	N-nitroso-N-desmethyl- mirtazepine	-	3	400
2023-07-24	Moxifloxacin	N-nitroso-moxifloxacin	-	4	1500
2023-07-24	Nebivolol	N-nitroso-nebivolol	1391051-68-5	4	1500
2022-05-27	Nortriptyline	N-nitroso-nortriptyline (NNORT)	55855-42-0	-	8
2023-07-24	Orphenadrine	N-nitroso-N-desmethyl- orphenadrine (NMOA)	-	1	18
2023-04-17	Paroxetine	N-nitroso-paroxetine	2361294-43-9	-	1300
2023-07-24	Penicillin G benzathine	N,N'-dinitroso-N,N'- dibenzylethanediamine	-	1	18
2023-07-24	Penicillin G benzathine	N-nitroso-N,N'- dibenzylethanediamine	-	1	18
2023-07-24	Perindopril	N-nitroso-perindopril	-	5	1500
2023-07-24	Phenylephrine	N-nitroso-phenylephrine	78658-64-7	2	100
2023-07-24	Pramipexole	N-nitroso-pramipexole	-	3	400
2023-07-24	Propranolol	N-nitroso-propranolol	84418-35-9	4	1500
2023-07-24	Pseudoephedrine	N-nitroso-pseudoephedrine	1850-88-0	4	1500
2023-07-24	Quetiapine	N-nitroso-desalkyl- quetiapine (NDAQ)	-	3	400
2023-07-24	Quinapril	N-nitroso-quinapril	158522-79-3	-	-^{Table 1 footnote **}
2023-07-24	Ramipril	N-nitroso-ramipril	-	5	1500
2024-03-15	Ranolazine	1-(2-methoxyphenoxy)- 3-(4-nitrosopiperazin-1-yl) propan-2-ol	-	3	400
2024-03-15	Ranolazine	N-(2,6-dimethylphenyl)- 2-(4-nitrosopiperazin-1-yl) acetamide	-	3	400
2023-07-24	Rasagiline	N-nitroso-rasagiline	2470278-90-9	2	100
2024-03-15	Ribociclib	N-nitroso-ribociclib	-	3	400
2023-07-24	Rifapentine	1-cyclopentyl-4- nitrosopiperazine (CPNP)	61379-66-6	3	400
2023-10-20	Rivaroxaban	(S)-5-chloro-N-(2-hydroxy-3-(nitroso(4-(3-oxomorpholino)phenyl)amino)propyl)thiophene-2-carboxamide	-	4	1500
2023-07-24	Rivastigmine	N-nitroso-N-desmethyl- rivastigmine	-	2	100
2023-07-24	Salbutamol	N-nitroso-salbutamol	-	5	1500
2024-07-26	Sertraline	N-nitroso-sertraline	-	2	100
2024-03-15	Sildenafil	N-nitroso-N-desmethyl- sildenafil	-	3	400
2024-05-31	Sitagliptin	7-nitroso-3-(trifluoromethyl)- 5,6,7,8-tetrahydro[1,2,4] triazolo-[4,3-a]pyrazine (NTTP)	2892260-32-9	2	100
2023-07-24	Sotalol	N-nitroso-sotalol	134720-07-3	4	1500
2023-07-24	Sumatriptan	N-nitroso-N-desmethyl- sumatriptan	-	1	18
2023-07-24	Tamsulosin	N-nitroso-tamsulosin	2892260-31-8	4	1500
2024-03-15	Terazosin	(4-nitrosopiperazin-1-yl) (tetrahydrofuran-2-yl)methanone	-	3	400
2023-07-24	Terbinafine	N-[(2E)-6,6-dimethyl- 2-hepten-4-yn-1-yl]- N-nitrosomethanamine	-	1	18
2023-07-24	Terbinafine	N-nitroso-N-desmethyl- terbinafine	-	1	18
2023-07-24	Terbinafine	N-nitroso-N-methyl-1- naphthylmethylamine	269760-88-8	1	18
2024-05-31	Tigecycline	N-nitroso-tigecycline	-	-	^{Footnote **}
2024-03-15	Tofacitinib	N-methyl-N-((3R,4R)- 4-methyl-1-nitrosopiperidin-3-yl) -7H-pyrrolo[2,3-d]pyrimidin-4-amine	-	3	400
2023-07-24	Trimebutine	N-nitroso-N-desmethyl- trimebutine	-	5	1500
2023-07-24	Tripelennamine	N-nitroso-N-desmethyl- tripelennamine	-	1	18
2023-07-24	Valacyclovir	N-nitroso-N-ethyl-valacyclovir	-	3	400
2023-07-24	Valacyclovir	N-nitroso-N-methyl-valacyclovir	-	3	400
2023-07-24	Valsartan	(S)-2-(((2'-(1H-tetrazol-5-yl)- [1,1′-biphenyl]-4-yl) methyl)(nitroso)amino)- 3-methylbutanoic acid	2254485-68-0	-	-^{Table 1 footnote **}
2023-07-24	Varenicline	N-nitroso-varenicline (NNV)	2755871-02-2	3	400
2023-07-24	Vortioxetine	N-nitroso-vortioxetine	-	3	400
2024-07-26	Benzydamine	3-(dimethylamino)propyl 2-(benzyl(nitroso)amino)benzoate	_	3	400
2024-07-26	Caspofungin	N-nitroso-caspofungin	_	4	1500
2024-07-26	Entacapone	N-nitroso-diethylamine (NDEA)	55-18-5	_	26.5
2024-07-26	Esmolol	N-nitroso-esmolol	_	4	1500
2024-07-26	Nintedanib	N-nitroso-N-desmethyl-nintedanib	_	3	400
2024-07-26	Riociguat	N-(4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)-N-methylnitrous amide	_	2	100
2024-07-26	Rizatriptan	N-nitroso-N-desmethyl-rizatriptan	_	1	18
2024-07-26	Tetracaine	N-nitroso-tetracaine	_	3	400
2024-07-26	Tramadol	N-nitroso-N-desmethyl-tramadol	_	1	18
2024-07-26	Trandolapril	N-nitroso-trandolapril	_	5	1500
Table 1 Notes Table 1 Note * Limit to be applied to maximum daily dose (MDD) of the drug product Return to table 1 note * referrer Table 1 Note Treat as non-mutagenic impurity and control as per ICH's Q3A and Q3B guidelines Return to table 1 note referrer Table 1 Note * Limit based on negative in vitro bacterial mutagenicity test Return to table 1 note * referrer

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Date modified:: 2024-07-26

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Nitrosamine impurities in medications: Established acceptable intake limits

Table 1 Notes

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