N-Nitrosomorpholine

Last updated
N-nitrosomorpholine
N nitrosomorpholine.svg
Names
Other names
4-nitrosomorpholine, alpha-acetoxy-N-nitrosomorpholine, nitrosomorpholine, NMOR, 4-nitroso-morpholine, NNM
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.155.913 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 627-564-6
KEGG
PubChem CID
UNII
UN number 2810 3077
  • InChI=1S/C4H8N2O2/c7-5-6-1-3-8-4-2-6/h1-4H2
    Key: ZKXDGKXYMTYWTB-UHFFFAOYSA-N
  • C1COCCN1N=O
Properties
C4H8N2O2
Molar mass 116.120 g·mol−1
AppearancePale yellow powder
Melting point 29 °C (84 °F; 302 K) [1]
Boiling point 435 to 436 °F at 747 mmHg
greater than or equal to 100 mg/mL in water at 66 °F
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
hepatocarcinogen
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

N-Nitrosomorpholine (NNM, NMOR) is an organic compound which is known to be a carcinogen and mutagen.

Contents

Chemistry

NMOR is a pale yellow sand-like powder below 84°F. [1] [2] NMOR is most commonly produced from morpholine, but can also be made by the reaction of dimorpholinomethane in fuming nitric acid. [3] Few reactions using NMOR as a starting material are reported in the organic synthesis literature, but it can be used as a precursor to a nitrogen-centered radical. [4]

Occurrence

NMOR is generally not used intentionally, but is instead created by the nitrosation of morpholine or morpholine derivatives which are used for several industrial purposes.

Rubber

2-(Morpholinothio)benzothiazole is used as an accelerator/stabilizer for vulcanization, or the manufacture of rubber products. It is the precursor to NMOR in the vulcanization process, as it is nitrosated by ambient sources of the nitro group present in the manufacturing process. As such, workers and others exposed to the rubber industry or its byproducts are exposed to higher levels of NMOR than the general population, raising their risk of cancer. [5]

Tobacco products

NMOR is a component of tobacco products. As of 2014, detectable levels of NMOR are present in tobacco products in the United States and China. [6] [7] The presence of NMOR and other n-nitrosoamines is not limited to cigarettes, but is found in smokeless tobacco products (snuff tobacco, Snus, etc.) as well. [8] Volatile nitrosamines, including NMOR, are detectable in the urine of tobacco smokers. [9]

Food

Morpholine oleate is used in glazing wax which covers fruit. NMOR can be generated by the nitration of morpholine, causing its presence in waxed fruits. [10] [11] Health Canada, the Canadian governmental department of public health, has stated in 2002 that this does not pose a risk to human health. [12]

Consumption of nitrate-rich diets is correlated with levels of salivary and urinary NMOR. [13] The presence of NMOR can also be observed in gastric juices. [14]

Other

NMOR has been found in several cosmetic products. [15] [16]

Health hazards

The mechanisms of carcinogenesis are not completely clear in humans. NMOR and its metabolites may induce DNA damage by directly forming reactive oxygen species or compounds which crosslink DNA. In a rat model in 2013, it was observed that NMOR is hydroxylated, probably by a P450 enzyme, alpha to the N-nitroso moiety. [17] This then decomposes into a diazonium-containing aldehyde which is capable of crosslinking DNA. [18]

Endogenous synthesis from morpholine in the digestive system is observed. NMOR can be generated from N-nitrosating species formed by salivary nitrite and stomach acid, potentially leading to more damage in individuals with acid reflux. [19] H. pylori does not induce NMOR formation in vitro, though this has yet to be confirmed in vivo. [20]

NMOR is in fact used to generate liver cancer models in rats. Along with N-diethylnitrosamine, it is the gold standard for producing hepatocarcinoma with 100% lung metastasis. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Carcinogen</span> Substance, radionuclide, or radiation directly involved in causing cancer

A carcinogen is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruses and bacteria. Most carcinogens act by creating mutations in DNA that disrupt a cell's normal processes for regulating growth, leading to uncontrolled cellular proliferation. This occurs when the cell's DNA repair processes fail to identify DNA damage allowing the defect to be passed down to daughter cells. The damage accumulates over time. This is typically a multi-step process during which the regulatory mechanisms within the cell are gradually dismantled allowing for unchecked cellular division.

<span class="mw-page-title-main">Nitrate</span> Polyatomic ion (NO₃, charge –1) found in explosives and fertilisers

Nitrate is a polyatomic ion with the chemical formula NO−
3. Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insoluble nitrate is bismuth oxynitrate.

The nitrite ion has the chemical formula NO−
2. Nitrite is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also refers to organic compounds having the –ONO group, which are esters of nitrous acid.

<span class="mw-page-title-main">Sodium nitrite</span> Chemical compound

Sodium nitrite is an inorganic compound with the chemical formula NaNO2. It is a white to slightly yellowish crystalline powder that is very soluble in water and is hygroscopic. From an industrial perspective, it is the most important nitrite salt. It is a precursor to a variety of organic compounds, such as pharmaceuticals, dyes, and pesticides, but it is probably best known as a food additive used in processed meats and in fish products.

<span class="mw-page-title-main">Nitrosamine</span> Organic compounds of the form >N–N=O

In organic chemistry, nitrosamines are organic compounds with the chemical structure R2N−N=O, where R is usually an alkyl group. They feature a nitroso group bonded to a deprotonated amine. Most nitrosamines are carcinogenic in nonhuman animals. A 2006 systematic review supports a "positive association between nitrite and nitrosamine intake and gastric cancer, between meat and processed meat intake and gastric cancer and oesophageal cancer, and between preserved fish, vegetable and smoked food intake and gastric cancer, but is not conclusive".

<span class="mw-page-title-main">Processed meat</span> Type of meat

Processed meat is considered to be any meat that has been modified in order to either improve its taste or to extend its shelf life. Methods of meat processing include salting, curing, fermentation, smoking, boiling, frying, and/or the addition of chemical preservatives. Processed meat is usually composed of pork or beef or, less frequently, poultry. It can also contain offal or meat by-products such as blood. Processed meat products include bacon, ham, sausages, salami, corned beef, jerky, hot dogs, lunch meat, canned meat, chicken nuggets, and meat-based sauces. Meat processing includes all the processes that change fresh meat with the exception of simple mechanical processes such as cutting, grinding or mixing.

<span class="mw-page-title-main">Nitrosation and nitrosylation</span> Process of converting organic compounds into nitroso derivatives

Nitrosation and nitrosylation are two names for the process of converting organic compounds or metal complexes into nitroso derivatives, i.e., compounds containing the R−NO functionality. The synonymy arises because the R-NO functionality can be interpreted two different ways, depending on the physico-chemical environment:

<span class="mw-page-title-main">NNK</span> Chemical compound

Nicotine-derived nitrosamine ketone (NNK) is one of the key tobacco-specific nitrosamines derived from nicotine. It plays an important role in carcinogenesis. The conversion of nicotine to NNK entails opening of the pyrrolidine ring.

<i>N</i>-Nitrosonornicotine Chemical compound

N-Nitrosonornicotine (NNN) is a tobacco-specific nitrosamine produced during the curing and processing of tobacco.

<span class="mw-page-title-main">Nitroso</span> Class of functional groups with a –N=O group attached

In organic chemistry, nitroso refers to a functional group in which the nitric oxide group is attached to an organic moiety. As such, various nitroso groups can be categorized as C-nitroso compounds, S-nitroso compounds, N-nitroso compounds, and O-nitroso compounds.

<span class="mw-page-title-main">Arecoline</span> Stimulant alkaloid

Arecoline is a nicotinic acid-based mild parasympathomimetic stimulant alkaloid found in the areca nut, the fruit of the areca palm. It is an odourless oily liquid. It can bring a sense of enhanced alertness and energy along with mild feelings of euphoria and relaxation.

<span class="mw-page-title-main">Smokeless tobacco</span> Tobacco product used by means other than smoking

Smokeless tobacco is a tobacco product that is used by means other than smoking. Their use involves chewing, sniffing, or placing the product between gum and the cheek or lip. Smokeless tobacco products are produced in various forms, such as chewing tobacco, snuff, snus, and dissolvable tobacco products. Smokeless tobacco is widely used in South Asia and this accounts for about 80% of global consumption. All smokeless tobacco products contain nicotine and are therefore highly addictive. Quitting smokeless tobacco use is as challenging as smoking cessation.

<span class="mw-page-title-main">Alkyl nitrite</span> Organic compounds of the form R–O–N=O

In organic chemistry, alkyl nitrites are a group of organic compounds based upon the molecular structure R−O−N=O, where R represents an alkyl group. Formally they are alkyl esters of nitrous acid. They are distinct from nitro compounds.

<span class="mw-page-title-main">Curing (food preservation)</span> Food preservation and flavouring processes based on drawing moisture out of the food by osmosis

Curing is any of various food preservation and flavoring processes of foods such as meat, fish and vegetables, by the addition of salt, with the aim of drawing moisture out of the food by the process of osmosis. Because curing increases the solute concentration in the food and hence decreases its water potential, the food becomes inhospitable for the microbe growth that causes food spoilage. Curing can be traced back to antiquity, and was the primary method of preserving meat and fish until the late 19th century. Dehydration was the earliest form of food curing. Many curing processes also involve smoking, spicing, cooking, or the addition of combinations of sugar, nitrate, and nitrite.

<span class="mw-page-title-main">DNA adduct</span> Segment of DNA bound to a cancer-causing chemical

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<i>N</i>-Nitrosodimethylamine Chemical compound

N-Nitrosodimethylamine (NDMA), also known as dimethylnitrosamine (DMN), is an organic compound with the formula (CH3)2NNO. It is one of the simplest members of a large class of nitrosamines. It is a volatile yellow oil. NDMA has attracted wide attention as being highly hepatotoxic and a known carcinogen in laboratory animals.

Tobacco-specific nitrosamines (TSNAs) comprise one of the most important groups of carcinogens in tobacco products, particularly cigarettes and fermented dipping snuff.

<i>S</i>-Nitrosothiol Organic compounds or groups of the form –S–N=O

In organic chemistry, S-nitrosothiols, also known as thionitrites, are organic compounds or functional groups containing a nitroso group attached to the sulfur atom of a thiol. S-Nitrosothiols have the general formula R−S−N=O, where R denotes an organic group.

<span class="mw-page-title-main">Semustine</span> Chemical compound

Semustine is an alkylating nitrosourea compound used in chemotherapy treatment of various types of tumours. Due to its lipophilic property, semustine can cross the blood-brain barrier for the chemotherapy of brain tumours, where it interferes with DNA replication in the rapidly-dividing tumour cells. Semustine, just as lomustine, is administered orally. Evidence has been found that treatment with semustine can cause acute leukaemia as a delayed effect in very rare cases.

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References

  1. 1 2 Zhang, Jie; Jiang, Jiewen; Li, Yuling; Wan, Xiaobing (2013). "Iodide-Catalyzed Synthesis of N-Nitrosamines via C–N Cleavage of Nitromethane". Journal of Organic Chemistry . 78 (22): 11366–11372. doi:10.1021/jo401915t. PMID   24128012 . Retrieved 10 January 2024.
  2. ↑ Borikar, Sanjay P.; Paul, Vincent (2010). "N-Nitrosation of Secondary Amines Using p-TSA-NaNO2 as a Novel Nitrosating Agent Under Mild Conditions". Synthetic Communications . 40 (5): 654–660. doi:10.1080/00397910903009448. S2CID   98412823 . Retrieved 10 January 2024.
  3. ↑ Zhang, Yu; Zou, Po; Han, Yingbin; Geng, Yongliang; Luo, Jun; Zhou, Baojing (2018). "A combined experimental and DFT mechanistic study for the unexpected nitrosolysis of N-hydroxymethyldialkylamines in fuming nitric acid". RSC Advances . 8 (34): 19310–19316. Bibcode:2018RSCAd...819310Z. doi:10.1039/C8RA03268H. PMC   9080733 . PMID   35539630.
  4. ↑ Patil, Dilip V.; Lee, Yulim; Kim, Hun Young; Oh, Kyungsoo (2022). "Visible-Light-Promoted Photoaddition of N-Nitrosopiperidines to Alkynes: Continuous Flow Chemistry Approach to Tetrahydroimidazo[1,2-a]pyridine 1-Oxides". Organic Letters . 24 (31): 5840–5844. doi:10.1021/acs.orglett.2c02402. PMID   35921551. S2CID   251317605 . Retrieved 18 January 2024.
  5. ↑ Carrier, Gaétan; Desrosiers, Marie-Claire; Adib, Georges (2011). "Cancer risk assessment for workers exposed to nitrosamines in a warehouse of finished rubber products in the Eastern Townships (Québec, Canada)" (PDF). Institut national de santé publique du Québec. Gouvernement du Québec. Archived from the original (PDF) on 3 December 2021. Retrieved 16 January 2024.
  6. ↑ Oldham, Michael J.; DeSoi, Darren J.; Rimmer, Lonnie T.; Wagner, Karl A.; Morton, Michael J. (2014). "Insights from analysis for harmful and potentially harmful constituents (HPHCs) in tobacco products". Regulatory Toxicology and Pharmacology . 70 (1): 138–148. doi:10.1016/j.yrtph.2014.06.017. PMID   24973503 . Retrieved 16 January 2024.
  7. ↑ Lv, Fang; Guo, Junwei; et al. (5 April 2016). "Determination of nine volatile N-nitrosamines in tobacco and smokeless tobacco products by dispersive solid-phase extraction with gas chromatography and tandem mass spectrometry". Journal of Separation Science . 39 (11): 2123–2128. doi:10.1002/jssc.201600037. PMID   27059265 . Retrieved 16 January 2024.
  8. ↑ Wang, Xiaoyu; Qin, Yaqiong; et al. (29 April 2021). "Smokeless tobacco analysis: Simultaneous extraction and purification of alkaloids, volatile N-nitrosamines, and polycyclic hydrocarbons for GC-MS/MS". Journal of Separation Science . 44 (13): 2642–2654. doi:10.1002/jssc.202100186. PMID   33915029. S2CID   233459643 . Retrieved 16 January 2024.
  9. ↑ Seyler, Tiffany H.; Kim, Jenny G.; Hodgson, James A.; Cowan, Elizabeth A.; Blount, Benjamin C.; Wang, Lanqing (18 March 2013). "Quantitation of Urinary Volatile Nitrosamines from Exposure to Tobacco Smoke". Journal of Analytical Toxicology . 37 (4): 195–202. doi:10.1093/jat/bkt020. PMID   23508653 . Retrieved 16 January 2024.
  10. ↑ Akbar, Syed (16 December 2016). "Toxic gloss on 'fresh' veggie plate". The Times of India . Hyderabad. Retrieved 15 February 2023.
  11. ↑ Kumar, Rupak; Kapur, Suman (2016). "Morpholine: A Glazing Agents for Fruits and Vegetables Coating/Waxing". International Journal of Science Technology and Engineering. 2 (11): 694–697. ISSN   2349-784X . Retrieved 15 February 2023.
  12. ↑ "Fact Sheet: Use of Morpholine in Apple Coatings". Government of Canada. Health Canada. 9 December 2002. Archived from the original on 27 January 2023. Retrieved 9 February 2023.
  13. ↑ van Maanen, Jan M. S.; Pachen, D. M.; Dallinga, J. M.; Kleinjans, J. C. (1998). "Formation of nitrosamines during consumption of nitrate- and amine-rich foods, and the influence of the use of mouthwashes". Cancer Detection and Prevention. 22 (3): 204–212. doi:10.1046/j.1525-1500.1998.0oa26.x. PMID   9618041 . Retrieved 11 January 2024.
  14. ↑ Dallinga, J. W.; Pachen, D. M. F. A. (1998). "Volatile N-nitrosamines in gastric juice of patients with various conditions of the gastrointestinal tract determined by gas chromatography–mass spectrometry and related to intragastric pH and nitrate and nitrite levels". Cancer Letters . 124 (2): 119–125. doi:10.1016/S0304-3835(97)00467-9. PMID   9500200 . Retrieved 11 January 2024.
  15. ↑ Schettino, Lorenzo; Benedé, Juan L.; Chisvert, Albertino (2023). "Determination of nine prohibited N-nitrosamines in cosmetic products by vortex-assisted dispersive liquid–liquid microextraction prior to gas chromatography-mass spectrometry". RSC Advances . 13 (5): 2963–2971. Bibcode:2023RSCAd..13.2963S. doi:10.1039/D2RA06553C. PMC   9850448 . PMID   36756441.
  16. ↑ Challis, B. C.; Trew, D. F.; Guthrie, W. G.; Roper, D. V. (1995). "Reduction of nitrosamines in cosmetic products". International Journal of Cosmetic Science. 17 (3): 119–131. doi:10.1111/j.1467-2494.1995.tb00115.x. PMID   19245496. S2CID   11108503 . Retrieved 18 January 2024.
  17. ↑ Fishbein, James C.; Kim, Hyun-Joong (2003). "Reexamination of the Aqueous Chemistry of N-Nitroso-3-hydroxymorpholine, a Metabolite of the Carcinogen N-Nitrosomorpholine". Chemical Research in Toxicology . 16 (6): 715–720. doi:10.1021/tx020114j. PMID   12807354 . Retrieved 18 January 2024.
  18. ↑ Fishbein, James C.; Koissi, Niangoran (2013). "Trapping of a Cross-Link Formed by a Major Purine Adduct of a Metabolite of the Carcinogen N-Nitrosomorpholine by Inorganic and Biological Reductants". Chemical Research in Toxicology . 26 (5): 732–740. doi:10.1021/tx3005289. PMC   3706203 . PMID   23587048.
  19. ↑ Winter, Jack W.; Paterson, Stuart; Scobie, Gordon; Wirz, Angela; Preston, Tom; McColl, Kenneth E. L. (2007). "N-Nitrosamine Generation From Ingested Nitrate Via Nitric Oxide in Subjects With and Without Gastroesophageal Reflux". Gastroenterology . 133 (1): 164–174. doi:10.1053/j.gastro.2007.04.047. PMID   17631140 . Retrieved 16 January 2024.
  20. ↑ Vermeer, I. T. M.; Gerrits, M. M.; et al. (31 May 2002). "Helicobacter pylori does not Mediate the Formation of Carcinogenic N-Nitrosamines". Helicobacter. 7 (3): 163–169. doi:10.1046/j.1523-5378.2002.00076.x. PMID   12047321. S2CID   27005252 . Retrieved 16 January 2024.
  21. ↑ Futakuchi, Mitsuru; Hirose, Masao; et al. (1999). "Establishment of an in vivo Highly Metastatic Rat Hepatocellular Carcinoma Model". Japanese Journal of Cancer Research . 90 (11): 1196–1202. doi:10.1111/j.1349-7006.1999.tb00695.x. PMC   5926015 . PMID   10622528.
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