Herein, we report the development of an acid- and oxidant-free, continuous-flow electrochemical process towards the synthesis of N-nitrosamines from secondary amines.In this strategy, a one-electron anodic oxidation of the nitrite ion provides NO 2 radicals, which dimerise and exist in equilibrium with dinitrogen tetroxide (N 2 O 4), 46-48 a known nitrosating agent for secondary amines . An official website of the United States government. In this review, we update the current status of nitrosation pathways including basic and advanced chemistry of nitrosamine formation and chemical reactivity of nitrosamines to complement other recent publications. After a long usage history, the US FDA and EMA eventually decided to withdraw and close this over-the-counter medicine. The driving force of high carcinogenic prevalence results from metabolic hydroxylation on -position carbon of nitrosamines; however, many factors affect nitrosamine carcinogenic potency. 2017 Nov;27(6):2069-2094. doi: 10.1007/s10895-017-2146-7. The chemistry of nitrosamine formation is quite complex, Therefore, NDMA, NDEA, and other structurally-related nitrosamines are suspected by regulatory authorities to act as carcinogens in humans and were subsequently detected in other medicines belonging to the sartan family, including N-nitrosodiethylamine (NDEA), N -nitrosodiisopropylamine (NDIPA), N -nitrosoethylisopropylamine (NEIPA) and N -nitroso-N-methyl-4-aminobutyric acid (NMBA). Set by the GDPR Cookie Consent plugin, this cookie is used to record the user consent for the cookies in the "Advertisement" category . Environ Sci Technol. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Nitrosamines are a well-known group of highly potent, mutagenic impurities formed by the reaction of secondary amines with nitrite under acidic conditions1-4. In this study, seven secondary 20 amines were oxidised by chlorine, ozone, and UV-irradiation, with and without post- More interestingly, based on animal carcinogenicity data derived from 228 low-molecular-weight N-nitrosamines, 18% of those were found to have noncarcinogenic effects (Thresher et al., 2020). The site is secure. 2016 Jun;153:521-7. doi: 10.1016/j.chemosphere.2016.03.035. Referring to risk-based evaluation and manufacturers evidence-based recalls, tetrazole-containing ARBs can be contaminated with an enormous variety of nitrosamine species when diversified amine reagents are involved in the tetrazole-building step. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Specific NDMA precursors in wastewater-impacted source waters may include tertiary amine-containing pharmaceuticals or other quaternary amine-containing constituents of personal care products. Lhasa Poster: "In silico prediction of N-nitrosamine degradants in APIs that possess a secondary or tertiary amine functional group", dr Ash Ali, Science of Stability Conference 2021 Chronological events of the EU regulatory network responses and the Croatian market situation specific to NDMA and NDEA contamination in marketed pharmaceuticals have been summarized by Sedlo et al. 2014 Aug;87(6):591-606. doi: 10.1007/s00420-013-0900-y. Analysis of pilot washwater samples indicated a 59 M total N-nitrosamine concentration for a system operated with a 25% AMP/15% PZ solvent, but only 0.73 M for a 35% MEA solvent. Analysis of aqueous morpholine solutions purged with different gas-phase NO and NO(2) concentrations indicated that N-nitrosamine formation generally exceeds N-nitramine formation. The pattern element in the name contains the unique identity number of the account or website it relates to. An official website of the United States government. Stedman, G., 1959. HHS Vulnerability Disclosure, Help Preferably, the polar protic and aprotic solvents such as DCM, tetrahydrofuran (THF) and acetonitrile are selected as reaction solvents (Lpez-Rodriguez et al., 2020). Furthermore, the Singapore Health Sciences Authority (HSA) announced the metformin recall in 2019 due to NMDA contamination (https://www.hsa.gov.sg/announcements/news/hsa-recalls-three-out-of-46-metformin-medicines, accessed 04 Dec 2019). This appears to confirm that the reaction does not follow the mechanism of rapid nitrosation mentioned above. 5. This cookie is set by GDPR Cookie Consent plugin. Besides the exogenous degradation of ranitidine, endogenous decomposition via metabolism to NDMA has been noted. However, the nitrosation of secondary amines to diazonium species is rare because the process is hindered by alkyl groups. Abe Y., Yamamoto E., Yoshida H., Usui A., Tomita N., Kanno H., Masada S., Yokoo H., Tsuji G., Uchiyama N., Hakamatsuka T., Demizu Y., Izutsu K.-I., Goda Y., Okuda H. Temperature-Dependent Formation of N-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets. e.g., Loeppky RN, Outram JR, Tomasik W, Faulconer JM. Legal. For example, Group 1 assigned as N,N-dialkylnitrosoamines was considered to have structures equivalent to simple dialkyl nitrosamines such as NDMA and NDEA (Dobo et al., 2022). Four members of this class are nitric oxide (NO), nitrogen dioxide (NO2), dinitrogen trioxide/nitrous anhydride (N2O3), and dinitrogen tetroxide (N2O4) (Lpez-Rodriguez et al., 2020). Although nitrosamine does not contaminate all medicines, a number of medications have been identified as nitrosamine precursors in wastewater treatment (Shen and Andrews, 2010; Wang et al., 2015). The risks of chemical reagents or possible by-products that generate reactive genotoxic impurities such as azido and nitroso compounds, epoxides, hydrazines, alkyl halide derivatives, etc. Application of a 30-fold molar excess of sulfamic acid to nitrite at pH 2 destroyed nitrite with no significant risk of artifactual nitrosation of amines. 2009 Oct 13;367(1904):4077-95. doi: 10.1098/rsta.2009.0108. hbbd``b`F `Q v{ qH(g`bd,iHgx a The FDAs Center for Drug Evaluation and Research (CDER) has also raised awareness of NMDA contamination in metformin outside the US (https://www.fda.gov/news-events/press-announcements/statement-janet-woodcock-md-director-fdas-center-drug-evaluation-and-research-impurities-found, accessed 05 Dec 2019). Iglesias E., Casado J. Mechanisms of hydrolysis and nitrosation reactions of alkyl nitrites in various media. YOu are right. Antonsen S, Aursnes M, Gallantree-Smith H, Dye C, Stenstrm Y. Molecules. Likewise, the clinically meaningful results from Taiwan National Health Insurance Research Database demonstrated that long-term ranitidine use is associated with a higher likelihood of liver cancer development in comparison with the control groups of famotidine or proton-pump inhibitors (Wang et al., 2022). The preferred condition of nitrosation balances the pH against the basicity of the amine precursors. Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products. The AIs of Groups 2, 6, and 8 were estimated by the EMA default limit of 18ng/day due to the inadequate carcinogenicity database of their derived simple nitrosamine structures to support these groups (Dobo et al., 2022). Yes, my PhD advisor Dr. Loeppky and Vitig (Tomasik), who was a post doc in the team basically showed that tertiary amines can undergo facile nitrosation. Federal government websites often end in .gov or .mil. Furthermore, some organic nitro compounds such as bromonitromethane (Challis and Yousaf, 1990), trichloronitromethane (Demir et al., 1992), and tetranitromethane (Fan et al., 1978) can act as effective nitrosating agents. Lv J., Wang L., Li Y. The formation and control of emerging disinfection by-products of health concern. In 2019, the short commentary by Snodin and Elder (2019) focused on NDMA contamination of valsartan products. The thirteen groups of AIs were assigned from LD50 of the most potent N-nitrosamine obtained from the Lhasa Carcinogenicity Database (LCDB)) (Dobo et al., 2022). Epub 2015 Jul 1. AC's surface reactive sites react with molecular oxygen to form reactive oxygen species (ROS), which facilitate fixation of molecular nitrogen on the carbon surfaces to generate reactive nitrogen species (RNS) likely nitrous oxide and hydroxylamine that can react with adsorbed amines to form nitrosamines. CPNP is thought to arise from an intermediate step in rifapentine production. + + The nitrous acid usually arises from protonation of a nitrite.This synthesis method is relevant to the generation of nitrosamines under some biological conditions. 2013 Mar 19;47(6):2799-808. doi: 10.1021/es304893m. In such a review, the basic methodologies for nitrosamine determination were reported, and the risk assessments-based approach was outlined. Short commentary on NDMA (N-nitrosodimethylamine contamination of valsartan products. For example, the TD50 values of NDMA are 0.096mg/kg/day for the most sensitive rat species (Peto et al., 1991) and 0.189mg/kg/day for mice (https://www.nlm.nih.gov/databases/download/cpdb.html). F. Breider, I. Salihu and U. von Gunten, Theoretically, N-nitrosamines (e.g., N,N-dialkyl, cycloalkyl, and N-alkyl N-aryl analogues) undergo oxidative metabolic activation via cytochrome P450 (CYP P450) enzymes to exhibit carcinogenic effects (Fig. MeSH Keywords: Removal of chlorpheniramine and variations of nitrosamine formation potentials in municipal wastewaters by adsorption onto the GO-Fe. Philos Trans A Math Phys Eng Sci. Ohwada T., Miura M., Tanaka H., Sakamoto S., Yamaguchi K., Ikeda H., Inagaki S. Structural Features of Aliphatic NNitrosamines of 7-Azabicyclo[2.2.1]Heptanes That Facilitate N-NO Bond Cleavage. The LibreTexts libraries arePowered by NICE CXone Expertand are supported by the Department of Education Open Textbook Pilot Project, the UC Davis Office of the Provost, the UC Davis Library, the California State University Affordable Learning Solutions Program, and Merlot. They are mainly attributed to a tetrazole formation step. In aqueous solutions, both proceed smoothly and more rapidly under a basic condition while slowly undergoing hydrolysis at pH>5 to innocuous NO2 and NO3 (Lpez-Rodriguez et al., 2020). According to the risk assessment of the manufacturing process, there are two different synthetic routes proposed by DuPont (Carini et al., 1991) and Merck. Apart from small alkyl nitrosamines found in medicines such as NDMA, NDEA, and NMBA, the discovery of unique and complex N-nitroso pharmaceutical analogues, the so-called nitrosamine drug substance-related impurities (NDSRIs), have been detected in amine-based pharmaceuticals. Accessibility Chem. (2021) reported that increased gastric cancer was unrelatable to ranitidine use in South Korean patients. Possible pathways of N-Nitroso compound formation (Lpez-Rodriguez et al., 2020). CN Pat. Another direction is to tighten the sum acceptable threshold of<26.5ng/day when multiple nitrosamine impurities are presented in an individual drug product as suggested by the US FDA Guidance for Industry (2021) and USPNF (2022). The N-nitrosamines formed from 2-amines are carcinogenic, and are not generally useful as intermediates for subsequent reactions. Epub 2019 May 18. According to the US FDA guidance for industry and USP general chapter <1469>nitrosamine impurities, if multiple nitrosamine impurities are detected, their total quantity should not exceed 26.5ng/day (the AI of the most toxic nitrosamine). Chaskar A.C., Langi B.P., Deorukhkar A., Deokar H. Bismuth chloride-sodium nitrite: A novel reagent for chemoselective, Cross K.P., Ponting D.J. Specific observation of ranitidine degradation to NDMA, Presence of nitrosamine impurities in medicinal products, Short communication of the EU regulatory response and the Croatian market situation on NDMA and NDEA contamination events in pharmaceutical products. Copyright 2013 Elsevier Ltd. All rights reserved. Formation of Nitrosamine: The formation ofnitrosaminesis generally only possible when secondary or tertiary amines react with nitrous acid. Coincidently the solvents employed either were amines or contained traces of amines, and this likely afforded the observed NDMA and NDEA. Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products, Consider that this impurity may be formed also in the tablets, by reaction with nitrites presents in the excipents (typically in cellulose), Isnt this molecule prone rather to form NDMA, as a benzylic tertiary amine? Recently, updated guidelines have been announced by national authority agencies and General Chapter<1469>in the US pharmacopoeia. Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist. The reactions of nitrous acid with 1- and 2- aliphatic amines may be explained by considering their behavior with the nitrosonium cation, NO(+), an electrophilic species present in acidic nitrous acid solutions. official website and that any information you provide is encrypted Environ Sci Technol. Epub 2019 May 18. The current interim limits are applicable only when a drug product contains a single nitrosamine. Raney nickel is another reductive catalyst that cleaves the resulting NN bond (Borths et al., 2021). For this reason, triphenylphosphine is beneficial not only for inorganic decomposition but also for eradicating some organic azide by-products. Therefore, the control strategies in terms of the preventive and corrective actions not only rely on the in-depth chemistry understanding of the nitrosamine formation and decomposition, but also depend on the suitable built-in concept of control limit criteria. The perspectives on chemistry, reactivity and synthetic applications of N-nitrosamines were discussed by Beard and Swager, 2021 and Borths et al. In the article: Nitrosative Cleavage of Tertiary Amines, Smith & Loeppky, J. Copyright Clearance Center request page. J. Pham. Epub 2013 Sep 3. Rapid Nitrosamine Formation from a Tertiary Amine: The Nitrosation of 2-(N,N-Dimethylaminomethyl)Pyrrole. The total N-nitrosamine formation rate was at least an order of magnitude higher for the secondary amine piperazine (PZ) than for the primary amines 2-amino-2-methyl-1-propanol (AMP) and monoethanolamine (MEA) and the tertiary amine methyldiethanolamine (MDEA). and diagrams provided correct acknowledgement is given. EU Pat. The lowest published or calculated TD50 was chosen to establish the specific AIs for each group. Alaba P.A., Sani Y.M., Olupinla S.F., Wan Daud W.M., Mohammed I.Y., Enweremadu C.C., Ayodele O.O. Am. It is very difficult to break the aromaticity of a benzene ring; in my opinion, the mechanism in the poster is not applicable to Dapoxetine. government site. The https:// ensures that you are connecting to the ARBs containing a tetrazole ring such as valsartan, losartan, irbesartan, candesartan, and olmesartan are prone to nitrosamine contamination whereas non-tetrazole ARB analogs such as eprosartan, telmisartan, and azilsartan are unlikely to contain nitrosamine impurities. Losartan products contaminated with the losartan azido impurity 5-(4-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl) methyl)-[1,1-biphenyl]-2-yl)-1H-tetrazole (AZTT) have also been recalled. 6. However, the risk assessment is based on the risk likelihood, which requires prior knowledge of previous incident reports. Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. 24. Oral intake of ranitidine increases urinary excretion of N-nitrosodimethyl amine. N-nitrosodimethylamine (NDMA) contamination of Ranitidine Products: A review of recent findings. This synthesis method is relevant to the generation of nitrosamines under some biological conditions. Nitrosamines in pharmaceutical products arise from APIs, manufacturing processes, direct and indirect cross-contamination from solvents and equipment, and chemical degradation during storage. For example, the control of NDEA based on the LTL AI concept was proven the potential carcinogenic risk protection under the typical exposure durations of clinical trials and therapeutic medication (Bercu et al., 2021). The site is secure. Before [5][6] They usually are produced by the reaction of nitrous acid (HNO2) and secondary amines. LJY8/.6%XyvL>?'CQ%Ne-yY%x\Lm]O6r"+TT8ThMl3FinC H.a}:xnry\}{C3Q/`S}X Wi+GZlkeD]}ZYR4*%"zde:kl96JqEO7gpil:/]^`:^X^OP7)5p"w)J=ccW{[PuTr|P_VKXK>[(>'R1]plc(BZ;X-] dT*U{ Developing structure-activity relationships for. Tuesuwan B., Vongsutilers V. Nitrosamine Contamination in Pharmaceuticals: Threat, Impact, and Control. Possible root causes of 1-methyl-4-nitrosopiperazine (MNP) contamination in rifampin and 1-cyclopentyl-4-nitrosopiperazine (CPNP) contamination in rifapentine during the synthesis of active pharmaceutical ingredients. However, CHMP recommended the calculation of nitrosamine AI limits should be based on lifetime exposure but may be exceptional in case of the high-risk event of medicine shortage (Ruepp et al., 2021). Jire, J., Gibala, P., Kalek, S., Doua, M., Doubsky, J., 2021. (2021) reported the specific observation highlighted in the mechanisms for NDMA from ranitidine degradation. Nitrosation of secondary amines . In the same year, the Singapore HSA (https://www.hsa.gov.sg/announcements/news/hsa-recalls-three-out-of-46-metformin-medicines, accessed 04 Dec 2019) and US FDA (https://www.fda.gov/news-events/press-announcements/statement-janet-woodcock-md-director-fdas-center-drug-evaluation-and-research-impurities-found, accessed 05 Dec 2019) cautioned the risk of NMDA contamination in metformin preparations sold in several countries outside the US. Shen and Andrews (2010) conducted a test of nitrosamine formation potential. NDMA is a disinfection by-product of ozonation and chloramination that typically causes environmental problems (Alaba et al., 2018). As a library, NLM provides access to scientific literature. Most drug product recalls (approximately 34%) are related to NDMA contamination (Schmidtsdorff et al., 2022). 2015 Jul 21;49(14):8878-86. doi: 10.1021/acs.est.5b01365. 2019 Oct 25;4(10):2819-2824. doi: 10.1021/acssensors.9b01532. Subsequent studies showed that approximately 90% of the 300 nitrosamines tested were carcinogenic in a wide variety of animals. West DM, Wu Q, Donovan A, Shi H, Ma Y, Jiang H, Wang J. Chemosphere. Unlike ranitidine, metformin lacks a nitro functional group in its chemical structure and requires an exogenous nitrosating agent for nitrosamine formation. Safe Synthesis of Alkylhydroxy and Alkylamino Nitramines. A surrogate study is called for. Abstract Nitrosamines, a group of emerging disinfection by-products (DBPs) in drinking water, have recently caused significant concern because of their higher carcinogenic potential than that of currently regulated DBPs. Metal catalysts such as Pd/alumina, Ni/alumina, and Ru/alumina can reduce NDMA to DMA (Borths et al., 2021). The determination of two analogues of 4-(azidomethyl)-1,1-biphenyl as potential genotoxic impurities in the active pharmaceutical ingredient of several sartans containing a tetrazole group. Amines and amine-related compounds in surface waters: a review of sources, concentrations and aquatic toxicity. Endogenous nitrosamine formation can be affected by ascorbic acid,[14] either inhibiting its formation or increasing its formation, depending upon whether ascorbic acid is consumed in conjunction with it as opposed to the effect being reversed by factors related to dietary fat consumed at the same time. National Library of Medicine An official website of the United States government. You are not breaking the aromaticity of the benzene ring is this case, this is not a Phenylamine but a benzylamine. The toxicophores (structural and toxicological relationships) of MNP and CPNP (Helguera et al., 2008) suggest that these nitrosamines are less carcinogenic than NDMA. . However, the hydrolysis rate is much less rapid than the N-nitrosation process. Accessibility 591. (Resumed), 2949-2954. Pyrogenic carbon-promoted haloacetic acid decarboxylation to trihalomethanes in drinking water. The tetrazole ring is usually formed by the addition of hydrazoic acid to alkyl carbonitrile (Mihina and Herbst, 1950). This site needs JavaScript to work properly. A cleavage ratio benzyl/ethyl of 21/79 is indicated. Sedlo I., Koloni T., Tomi S. Presence of nitrosamine impurities in medicinal products. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. A combined experimental and density functional theory study of metformin oxy-cracking for pharmaceutical wastewater treatment. Accessibility On the other hand, understanding the chemistry principle and reactivity of nitrosamines can further contribute to the development of effective remediation via the chemical process as the alternative scenario to deactivate nitrosamines in pharmaceuticals. Additional moisture in wet granulation and excessive heat during the drying process initiate nitrosation reactions in the manufacturing process of metformin tablets (Nasr et al., 2021). When NDMA was raised as the first mutagenic impurity in valsartan-containing medicines in mid-2018, voluntary recalls were announced by the United States Food and Drug Administration (US FDA) (https://www.fda.gov/news-events/press-announcements/fda-announces-voluntary-recall-several-medicines-containing-valsartan-following-detection-impurity, accessed 13 Jul 2018) and the European Medicines Agency (EMA) (https://www.ema.europa.eu/en/documents/referral/angiotensin-ii-receptor-antagonists-sartan-article-31-referral-chmp-list-questions-be-addressed-api_en.pdf, accessed 16 Jul 2018). hb```#V ADX,Bo8100L8 `w``bP>Dq ?2+0fl ,3b'B4%xZ3LvzpSFpa-6i\kE{];+dxGCl`hP`0h 70TT*Jc^Xs bjc-`fH "~V rH3{G@Lw!Xg ^bh%D-c@ 8Ws Ranitidine impurity H in the solid state promptly degrades to NDMA despite lacking a dimethylamino moiety in its structure. The cookies is used to store the user consent for the cookies in the category "Necessary". Bethesda, MD 20894, Web Policies World Health Organization (WHO), 1980. Snodin D.J., Elder D.P. Pathways for. Nitrosamines have been classified based on their carcinogenic potential into four groups by the International Agency for Research on Cancer (IARC), World Health Organization (WHO) (1987). The National Formulary. Other uncategorized cookies are those that are being analyzed and have not been classified into a category as yet. You also have the option to opt-out of these cookies. In contrast, the established AIs of the remaining 9 groups (Groups 3, 4, 5, 7, and 913) were estimated according to published carcinogenicity data of corresponding N-nitrosamine analogues (Dobo et al., 2022). In pharmaceutical drug substances, the formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. However, the quenching procedure is difficult to control and is considered relatively violent. In the ICH guideline for industry M7 (R1), they are listed as a representative cohort of concern of mutagenic carcinogens and are categorized as Class 1 when known rodent carcinogenicity and mutagenicity data were characterized such as NDMA and NDEA. To facilitate the development of an analytical method for nitrosamine determination with sufficient sensitivity based on these values, we have summarized the interim limit criteria for nitrosamines in various pharmaceuticals in Table 3 (https://www.ema.europa.eu/en/documents/report/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines_en.pdf, accessed 23 Jun 2019). Unexpected role of activated carbon in promoting transformation of secondary amines to N-nitrosamines. The reaction was driven by an iminium intermediate and nitrite formation after the nitro-substitution on a secondary amine substrate (Challis and Yousaf, 1990). Brambilla G., Cavanna M., Faggin P., Maura A., Pino A., Ricci R., Robbiano L. Genotoxic effects in rodents given high oral doses of ranitidine and sodium nitrite. AZTT is formed by direct reaction between a residual azide and losartan (https://recalls-rappels.canada.ca/en/alert-recall/multiple-lots-irbesartan-losartan-and-valsartan-drugs-recalled, accessed 30 May 2021; https://www.edqm.eu/en/news/risk-presence-mutagenic-azido-impurities-losartan-active-substance, accessed 29 Sep 2021). xkLgem.8mD#%&-}>8K,.Y2@A07n2 The distinct behavior of 1, 2 & 3-aliphatic amines is an instructive challenge to our understanding of their chemistry, but is of little importance as a synthetic tool. At the same time, basic principles and recently updated information on methodologies and sample preparation techniques for trace analysis of nitrosamines in pharmaceuticals were discussed by Shaik et al. In such cases, the manufacturer must report and coordinate with the relevant authorities to evaluate clinical benefits and mutagenic risks. According to Nasr et al. FOIA They are characteristically yellow or orange . the contents by NLM or the National Institutes of Health. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). The magnitude of the catalytic effect of cationic micelles on the nitrosation reaction depended mainly of the hydrophobicity of the amine precursors (i.e., alkyl chain length), the stability and the charge of the micelles and pH. US FDA. In such cases, two approaches for AI estimation are proposed under Article 5(3) recommended by EMA (https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf, accessed 22 Sep 2021). Dattatraya J.P., Arun S.N., Deshmukh V.K., Ghawate4 V.G., Pund A.R. Nitrosamine formation from the oxidation of secondary amines Tom Bond; Michael R. Templeton Water Supply (2011) 11 (3): 259-265. https://doi.org/10.2166/ws.2011.027 Article history Views Share Tools The nitrosamines are potent carcinogens which can be formed as by-products during water treatment. The EPA is proposing revised new source performance. LinkedIn sets this cookie for LinkedIn Ads ID syncing. N -Nitrosamines (or simply "nitrosamines") are a class of compounds sharing the general structure 1 ( Chart 1 ), where the amine moiety may be derived from any organic secondary amine. government site. LinkedIn sets this cookie to store performed actions on the website. For example, nitrosamines are commonly formed by nitrosation of an amine precursor co-existing with a nitrosating agent. A review on nitrosamine impurities present in drugs. to access the full features of the site or access our, School of Architecture, Civil and Environmental Engineering (ENAC), cole Polytechnique Fdrale de Lausanne (EPFL), Lausanne, Switzerland, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Dbendorf, Switzerland, Best Papers 2018 Environmental Science: Processes & Impacts. NDMA formation has been associated with the use of quaternary amine-based coagulants and anion exchange resins, and wastewater-impaired source waters. Epub 2017 Aug 21. Wang C.-H., Chen I., Chen C.-H., Tseng Y.-T. Pharmacoepidemiological research on.