O-Toluidine

Last updated
o-Toluidine
O-Toluidin.svg
Names
Preferred IUPAC name
2-Methylaniline [1]
Other names
o-Methylaniline
o-Toluidine
1-Amino-2-methylbenzene
2-Aminotoluene, 2-Toluamine
Identifiers
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.002.209 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
Properties
C7H9N
Molar mass 107.156 g·mol−1
AppearanceColorless liquid
Odor Aromatic, aniline-like odor
Density 1.004 g/cm3
Melting point −23.68 °C (−10.62 °F; 249.47 K)
Boiling point 200 to 202 °C (392 to 396 °F; 473 to 475 K)
0.19 g/100 ml at 20 °C
Vapor pressure 0.307531 mmHg (25 °C)
1.56987
Viscosity 4.4335 (20 °C)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Flammable, moderately toxic
GHS labelling:
GHS-pictogram-flamme.svg GHS-pictogram-skull.svg GHS-pictogram-exclam.svg GHS-pictogram-silhouette.svg GHS-pictogram-pollu.svg
Danger
H301, H302, H319, H331, H350, H400
P201, P202, P261, P264, P270, P271, P273, P280, P281, P301+P310, P304+P340, P305+P351+P338, P308+P313, P311, P321, P330, P337+P313, P391, P403+P233, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 3: Short exposure could cause serious temporary or residual injury. E.g. chlorine gasFlammability 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
3
2
0
Flash point 85 °C (185 °F; 358 K)
481.67 °C (899.01 °F; 754.82 K)
Lethal dose or concentration (LD, LC):
900 mg/kg (rat, oral)
323 mg/kg (rabbit, oral)
Related compounds
Related compounds
 Toluidine
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

o-Toluidine (ortho-toluidine) is an organic compound with the chemical formula CH3C6H4NH2. It is the most important of the three isomeric toluidines. It is a colorless liquid although commercial samples are often yellowish. It is a precursor to the herbicides metolachlor and acetochlor. [2]

Contents

Synthesis and reactions

o-Toluidine is produced industrially by nitration of toluene to give a mixture of nitrotoluenes, favoring the ortho isomer. This mixture is separated by distillation. 2-Nitrotoluene is hydrogenated to give o-toluidine. [2]

The conversion of o-toluidine to the diazonium salt gives access to the 2-bromo, 2-cyano-, and 2-chlorotoluene derivatives. [3] [4] [5] N-acetylation is also demonstrated. [6]

Safety

The LD50 (oral, rats) is 670 mg/kg. [2]

Binding of hemoglobin

o-Nitrosotoluene, a metabolite of o-toluidine, converts hemoglobin to methemoglobin, resulting in methemoglobinemia. [7] [8] [ ISBN missing ] [9]


o-Nitrosotoluene is suspected of causing bladder cancer in rats. [10] [11] [12] Nitrosotoluene exposure has been researched in a number of different degrees in animals. [13] [14] [15] [16]

Carcinogenicity

In the U.S., o-toluidine was first listed in the Third Annual Report on Carcinogens as 'reasonably anticipated to be a human carcinogen' in 1983, based on sufficient evidence from studies in experimental animals. The Report on Carcinogens (RoC) is a U.S. congressionally-mandated, science-based public health report that identifies agents, substances, mixtures, or exposures in the environment that pose a hazard to people residing in the United States [17] Since then, other cancer related studies have been published and the listing of o-toluidine was changed to 'known to be a human carcinogen'. o-toluidine was especially linked to bladder cancer. This was done 31 years later in the Thirteenth Report on Carcinogens (2014). [14] The International Agency for Research on Cancer (IARC) has classified o-toluidine as 'carcinogenic to humans (group 1)'. [18]

Metabolism

o-Toluidine is absorbed through inhalation and dermal contact as well as from the gastrointestinal tract. [19] [13] [20] [21]

The metabolism of o-toluidine involves many competing activating and deactivating pathways, including N-acetylation, N-oxidation, and N-hydroxylation, and ring oxidation. [22] 4-Hydroxylation and N-acetylation of toluidine are the major metabolic pathways in rats. The primary metabolism of o-toluidine takes place in the endoplasmic reticulum. Exposure to o-toluidine enhances the microsomal activity of aryl hydrocarbon hydroxylase (particularly in the kidney), NADPH-cytochrome c reductase and the content of cytochrome P-450. Cytochrome P450–mediated N-hydroxylation to N-hydroxy-o-toluidine, a carcinogenic metabolite, occurs in the liver. N-Hydroxy-o-toluidine can be either metabolized to o-nitrosotoluene or conjugated with glucuronic acid or sulfate and transported to the urinary bladder via the blood. Once in the bladder, N-hydroxy-o-toluidine can be released from the conjugates in an acidic urine environment to either react directly with DNA or be bio-activated via sulfation or acetylation by cytosolic sulfotransferases or N-acetyltransferases (presumably NAT1). [14] The postulated activated form (based on comparison with other aromatic amines), N-acetoxy-o-toluidine, is a reactive ester that forms electrophilic arylnitrenium ions that can bind to DNA. [22] [23] [10] Other activation pathways (ring-oxidation pathways) for aromatic amines include peroxidase-catalyzed reactions that form reactive metabolites (quinone-imines formed from nonconjugated phenolic metabolites) in the bladder. These metabolites can produce reactive oxygen species, resulting in oxidative cellular damage and compensatory cell proliferation. Support for this mechanism comes from studies of oxidative DNA damage induced by o-toluidine metabolites in cultured human cells (HL-60), calf thymus DNA, and DNA fragments from key genes thought to be involved in carcinogenesis (the c-Ha-ras oncogene and the p53 tumor-suppressor gene). [24] [25] Also supporting this mechanism are observations of o-toluidine-induced DNA damage (strand breaks) in cultured human bladder cells and bladder cells from rats and mice exposed in vivo to o-toluidine. [26] [27]

Figure 1: Metabolism of o-(methyl- C)-toluidine hydrochloride in the rat. Metabolism toluidine.png
Figure 1: Metabolism of o-(methyl- C)-toluidine hydrochloride in the rat.

Excretion

The main excretion pathway is through the urine where up to one-third of the administered compound was recovered unchanged. Major metabolites are 4-amino-m-cresol and to a lesser extent, N-acetyl-4-amino-m-cresol, [20] azoxytoluene, o-nitrosotoluene, N-acetyl-o-toluidine, N-acetyl-o-aminobenzyl alcohol, anthranilic acid, N-acetyl-anthranilic acid, 2-amino-m-cresol, p-hydroxy-o-toluidine. Conjugates that were formed were predominated by sulfate conjugates over glucuronide conjugates by a ratio of 6:1.

Prilocaine, an amino amide-type local anesthetic, yields o-toluidine when metabolized by carboxylesterase enzymes. [28] Large prilocaine doses can cause methemoglobinemia due to oxidation of hemoglobin by o-toluidine. [29]

Drugs List

  1. Aptocaine
  2. Asulacrine
  3. Dazepinil
  4. Methaqualone
  5. Metolazone
  6. Prilocaine
  7. Quatacaine (Tanacaine)

Related Research Articles

Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and biology.

<span class="mw-page-title-main">Aniline</span> Organic compound (C₆H₅NH₂); simplest aromatic amine

Aniline is an organic compound with the formula C6H5NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile starting material for fine chemical synthesis. Its main use is in the manufacture of precursors to polyurethane, dyes, and other industrial chemicals. Like most volatile amines, it has the odor of rotten fish. It ignites readily, burning with a smoky flame characteristic of aromatic compounds. It is toxic to humans.

<span class="mw-page-title-main">Dicarbonyl</span> Molecule containing two adjacent C=O groups

In organic chemistry, a dicarbonyl is a molecule containing two carbonyl groups. Although this term could refer to any organic compound containing two carbonyl groups, it is used more specifically to describe molecules in which both carbonyls are in close enough proximity that their reactivity is changed, such as 1,2-, 1,3-, and 1,4-dicarbonyls. Their properties often differ from those of monocarbonyls, and so they are usually considered functional groups of their own. These compounds can have symmetrical or unsymmetrical substituents on each carbonyl, and may also be functionally symmetrical or unsymmetrical.

Benzo(<i>a</i>)pyrene Carcinogenic compound found in smoke and soot

Benzo[a]pyrene (BaP or B[a]P) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of the benzopyrenes, formed by a benzene ring fused to pyrene. Its diol epoxide metabolites, more commonly known as BPDE, react with and bind to DNA, resulting in mutations and eventually cancer. It is listed as a Group 1 carcinogen by the IARC. In the 18th century a scrotal cancer of chimney sweepers, the chimney sweeps' carcinoma, was already known to be connected to soot.

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

Acenaphthylene, a polycyclic aromatic hydrocarbon is an ortho- and peri-fused tricyclic hydrocarbon. The molecule resembles naphthalene with positions 1 and 8 connected by a -CH=CH- unit. It is a yellow solid. Unlike many polycyclic aromatic hydrocarbons, it has no fluorescence.

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

Sudan I is an organic compound typically classified as an azo dye. It is an orange-red solid, used to color waxes, oils, petrol, solvents, and polishes. Historically, Sudan I used to serve as a food coloring agent, notably for curry powder and chili powder. However, along with its derivatives Sudan III and Sudan IV, the compound has been banned in many countries due to its classification as a category 3 carcinogenic hazard by the International Agency for Research on Cancer. Nevertheless, Sudan I remains valuable as a coloring reagent for non-food-related uses, such as in the formulation of orange-colored smoke.

There are three isomers of toluidine, which are organic compounds. These isomers are o-toluidine, m-toluidine, and p-toluidine, with the prefixed letter abbreviating, respectively, ortho; meta; and para. All three are aryl amines whose chemical structures are similar to aniline except that a methyl group is substituted onto the benzene ring. The difference between these three isomers is the position where the methyl group (–CH3) is bonded to the ring relative to the amino functional group (–NH2); see illustration of the chemical structures below.

In organic chemistry, an azo coupling is an reaction between a diazonium compound and another aromatic compound that produces an azo compound. In this electrophilic aromatic substitution reaction, the aryldiazonium cation is the electrophile, and the activated carbon, serves as a nucleophile. Classical coupling agents are phenols and naphthols. Usually the diazonium reagent attacks at the para position of the coupling agent. When the para position is occupied, coupling occurs at a ortho position, albeit at a slower rate.

<span class="mw-page-title-main">1,2-Naphthoquinone</span> Chemical compound

1,2-Naphthoquinone or ortho-naphthoquinone is a polycyclic aromatic organic compound with formula C
10H
6O
2. This yellow solid is prepared by oxidation of 1-amino-2-hydroxynaphthalene with ferric chloride.

<span class="mw-page-title-main">N-acetyltransferase</span> Class of enzymes

N-acetyltransferase (NAT) is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines, arylhydroxylamines and arylhydrazines. They have wide specificity for aromatic amines, particularly serotonin, and can also catalyze acetyl transfer between arylamines without CoA. N-acetyltransferases are cytosolic enzymes found in the liver and many tissues of most mammalian species, except the dog and fox, which cannot acetylate xenobiotics.

4-Aminobiphenyl (4-ABP) is an organic compound with the formula C6H5C6H4NH2. It is an amine derivative of biphenyl. It is a colorless solid, although aged samples can appear colored. 4-Aminobiphenyl was commonly used in the past as a rubber antioxidant and an intermediate for dyes. Exposure to this aryl-amine can happen through contact with chemical dyes and from inhalation of cigarette smoke. Researches showed that 4-aminobiphenyl is responsible for bladder cancer in humans and dogs by damaging DNA. Due to its carcinogenic effects, commercial production of 4-aminobiphenyl ceased in the United States in the 1950s.

4-Chloro-<i>o</i>-toluidine Chemical compound

4-Chloro-o-toluidine (4-COT, 4-chloro-2-methylaniline) is the organic compound with the formula CH3C6H3Cl(NH2). It is a colorless solid. The compound is produced as an intermediate to the pesticide chlordimeform and a precursor to some azo dyes. Production has declined after it was shown to be highly carcinogenic.

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

In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers of exposure. They are especially useful in quantifying an organism's exposure to a carcinogen. The presence of such an adduct indicates prior exposure to a potential carcinogen, but it does not necessarily indicate the presence of cancer in the subject animal.

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

Chlornaphazine, a derivative of 2-naphthylamine, is a nitrogen mustard that was developed in the 1950s for the treatment of polycythemia and Hodgkin's disease. However, a high incidence of bladder cancers in patients receiving treatment with chlornaphthazine led to use of the drug being discontinued.

<span class="mw-page-title-main">Mirosław Jan Stasik</span>

Mirosław Jan Stasik was a Polish medical doctor and research toxicologist.

4-Nitrotoluene or para-nitrotoluene is an organic compound with the formula CH3C6H4NO2. It is a pale yellow solid. It is one of three isomers of nitrotoluene.

<span class="mw-page-title-main">2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine</span> Chemical compound


PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is one of the most abundant heterocyclic amines (HCAs) in cooked meat. PhIP is formed at high temperatures from the reaction between creatine or creatinine, amino acids, and sugar. PhIP formation increases with the temperature and duration of cooking and also depends on the method of cooking and the variety of meat being cooked. The U.S. Department of Health and Human Services National Toxicology Program has declared PhIP as "reasonably anticipated to be a human carcinogen". International Agency for Research on Cancer (IARC), part of World Health Organization, has classified PhIP as IARC Group 2B carcinogen. There is sufficient evidence in experimental animals, as well as in vitro models, for the carcinogenicity of PhIP.

<span class="mw-page-title-main">2-Aminofluorene</span> Chemical compound

2-Aminofluorene (2-AF) is a synthetic arylamine. It is a white to tan solid with a melting point of 125-132 °C. 2-AF has only been tested in controlled laboratory settings thus far. There is no indication that it will be tested in industrialized settings. There is evidence that 2-aminofluorene is a carcinogen and an intercalating agent that is extremely dangerous to genomic DNA that potentially can lead to mutation if not death. Furthermore, it has been suggested that 2-aminofluorene can undergo acetylation reactions that causes these reactive species to undergo such reactions in cells. Several experiments have been conducted that have suggested 2-aminofluorene be treated with care and with an overall awareness of the toxicity of this compound.

Benzo(<i>c</i>)fluorene Chemical compound

Benzo[c]fluorene is a polycyclic aromatic hydrocarbon (PAH) with mutagenic activity. It is a component of coal tar, cigarette smoke and smog and thought to be a major contributor to its carcinogenic properties. The mutagenicity of benzo[c]fluorene is mainly attributed to formation of metabolites that are reactive and capable of forming DNA adducts. According to the KEGG it is a group 3 carcinogen. Other names for benzo[c]fluorene are 7H-benzo[c]fluorene, 3,4-benzofluorene, and NSC 89264.

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

Glycidamide is an organic compound with the formula H2NC(O)C2H3O. It is a colorless oil. Structurally, it contains adjacent amides and epoxide functional groups. It is a bioactive, potentially toxic or even carcinogenic metabolite of acrylonitrile and acrylamide. It is a chiral molecule.

References

  1. ↑ Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 669. doi:10.1039/9781849733069-FP001. ISBN   978-0-85404-182-4. The names 'toluidine', 'anisidine', and 'phenetidine' for which o-, m-, and p- have been used to distinguish isomers, and 'xylidine' for which numerical locants, such as 2,3-, have been used, are no longer recommended, nor are the corresponding prefixes 'toluidine', 'anisidino', 'phenetidine', and 'xylidino'.
  2. 1 2 3 Bowers, Joseph S. "Toluidines". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a27_159. ISBN   978-3527306732.
  3. ↑ H. T. Clarke; R. R. Read (1925). "o-Tolunitrile and p-Tolunitrile". Org. Synth. 4: 69. doi:10.15227/orgsyn.004.0069.
  4. ↑ L. A. Bigelow (1929). "o-Bromotoluene". Org. Synth. 9: 22. doi:10.15227/orgsyn.009.0022.
  5. ↑ C. S. Marvel; S. M. McElvain (1923). "o-Chlorotoluene and p-Chlorotoluene". Org. Synth. 3: 33. doi:10.15227/orgsyn.003.0033.
  6. ↑ Rolf Huisgen; Klaus Bast (1962). "Indazole". Org. Synth. 42: 69. doi:10.15227/orgsyn.042.0069.
  7. ↑ Hazardous Substances Data Bank (HSDB, online database). National Toxicology Information Program. National Library of Medicine, Bethesda, MD: U.S. Department of Health and Human Services. 1997.
  8. ↑ Clayton, G. D.; Clayton, F. E., eds. (1981). Patty's Industrial Hygiene and Toxicology. Vol. 2A (3rd rev. ed.). New York: John Wiley & Sons.
  9. ↑ Birnier, G.; Neumann, H. (1988). "Biomonitoring of aromatic amines. II: Haemoglobin binding of some monocyclic aromatic amines". Arch. Toxicol. 62 (2–3): 110–115. doi:10.1007/BF00570128. PMID   3196145. S2CID   33391149.
  10. 1 2 English, J. C.; Bhat, V. S.; Ball, G. L.; C. J., McLellan (2012). "Establishing a total allowable concentration of o-toluidine in drinking water incorporating early lifestage exposure and susceptibility". Regul. Toxicol. Pharmacol. 64 (2): 269–284. doi:10.1016/j.yrtph.2012.08.011. PMID   22940434.
  11. ↑ Eyer, P. (1983). "The Red Cell as a Sensitive Target for Activated Toxic Arylamines". Toxicology in the Use, Misuse, and Abuse of Food, Drugs, and Chemicals. Archives of Toxicology, Supplement. Vol. 6. pp. 3–12. doi:10.1007/978-3-642-69083-9_1. ISBN   978-3-540-12392-7. PMID   6578736.
  12. ↑ Hecht, S. S.; El-Bayoumy, K.; Rivenson, A.; Fiala, E. (1983). "Bioassay for carcinogenicity of 1,2-dimethyl-4-nitrosobiphenyl, o-nitrosotoluene, nitrosobenzene and the corresponding amines in Syrian golden hamsters". Cancer Lett. 20 (3): 349–354. doi:10.1016/0304-3835(83)90034-4. PMID   6627231.
  13. 1 2 Hiles, R. C.; Abdo, K. M. (1990). "5. ortho-Toluidine". In Buhler, D. R.; Reed, D. J. (eds.). Nitrogen and Phosphorus Solvents (2nd ed.). Elsevier. pp. 202–207.
  14. 1 2 3 "o-Toluidine" (PDF). Report on Carcinogens (13th ed.). US National Institute of Health.
  15. ↑ Gregg, N.; et al. (1998). o-Toluidine. World Health Organization. pp. 5–22. ISBN   92-4-153007-3. (NLM classification: QV 235.)
  16. ↑ Rubino, G. F.; Scansetti, G.; Piolatto, G.; Fira, E. (1982). "The carcinogenic effect of aromatic amines: An epidemiological study on the role of o-toluidine and 4,4′-methylenebis(2-methylaniline) in inducing bladder cancer in man". Env. Res. 27 (2): 241–254. Bibcode:1982ER.....27..241R. doi:10.1016/0013-9351(82)90079-2. PMID   7084156.
  17. ↑ Burwell, S. M. (2014). Report on Carcinogens (13th ed.).
  18. ↑ IARC Monographs . Retrieved 2016-06-13.{{cite book}}: |website= ignored (help)
  19. ↑ Cheever, K.; Richards, D.; Plotnick, H. (1980). "Metabolism of o-, m- and p-toluidine in the adult male rat". Toxicol. Appl. Pharmacol. 56 (3): 361–369. doi:10.1016/0041-008x(80)90069-1. PMID   7222020.
  20. 1 2 Son, O. S.; Everett, D. W.; Fiala, E. S. (1980). "Metabolism of o-[methyl-14C]toluidine in the F344 rat". Xenobiotica. 10 (7–8): 457–468. doi:10.3109/00498258009033781. PMID   7445517.
  21. ↑ Brock, W. J.; Hundley, S. G.; Lieder, P. H. (1990). "Hepatic macromolecular binding and tissue distribution of ortho- and para-toluidine in rats". Toxicol. Lett. 54 (2–3): 317–325. doi:10.1016/0378-4274(90)90199-v. PMID   1701932.
  22. 1 2 Riedel, K.; Scherer, G.; Engl, J.; Hagedorn, H. W.; Tricker, A. R. (2006). "Determination of three carcinogenic aromatic amines in urine of smokers and nonsmokers". J. Anal. Toxicol. 30 (3): 187–195. doi: 10.1093/jat/30.3.187 . PMID   16803653.
  23. ↑ Kadlubar, F. F.; Badawi, A. F. (1995). "Genetic susceptibility and carcinogen-DNA adduct formation in human urinary bladder carcinogenesis". Toxicol. Lett. 82–83: 627–632. doi:10.1016/0378-4274(95)03507-9. PMID   8597119.
  24. ↑ Ohkuma, Y. Y.; Hiraku, S.; Oikawa, S.; Yamashita, N.; Murata, M.; Kawanishi, S. (1999). "Distinct mechanisms of oxidative DNA damage by two metabolites of carcinogenic o-toluidine". Arch. Biochem. Biophys. 372 (1): 97–106. doi:10.1006/abbi.1999.1461. PMID   10562421.
  25. ↑ Watanabe, C; Egami, T; Midorikawa, K.; Hiraku, Y.; Oikawa, S.; Kawanishi, S; Murata, M. (2010). "DNA damage and estrogenic activity induced by the environmental pollutant 2-nitrotoluene and its metabolite". Environ. Health Prev. Med. 15 (5): 319–326. doi:10.1007/s12199-010-0146-1. PMC   2921039 . PMID   21432561.
  26. ↑ Robbiano, L.; Carrozzino, R.; Bacigalupo, M.; Corbu, C.; Brambilla, G. (2002). "Correlation between induction of DNA fragmentation in urinary bladder cells from rats and humans and tissue-specific carcinogenic activity". Toxicology. 179 (1–2): 115–128. doi:10.1016/s0300-483x(02)00354-2. PMID   12204548.
  27. ↑ Sekihashi, K.; Yamamoto, A.; Matsumura, Y.; Ueno, S.; Watanabe-Akanuma, M.; Kassie, F; Knasmuller, S.; Tsuda, S.; Sasaki, Y. F. (2002). "Comparative investigation of multiple organs of mice and rats in the comet assay". Mutat. Res. 517 (1–2): 53–75. doi:10.1016/s1383-5718(02)00034-7. PMID   12034309.
  28. ↑ Ryota Higuchi; Tatsuki Fukami; Miki Nakajima; Tsuyoshi Yokoi (2013). "Prilocaine- and Lidocaine-Induced Methemoglobinemia Is Caused by Human Carboxylesterase-, CYP2E1-, and CYP3A4-Mediated Metabolic Activation". Drug Metab. Dispos. 41 (6): 1220–1230. doi:10.1124/dmd.113.051714. PMID   23530020. S2CID   9741909.
  29. ↑ Medetalibeyoğlu A.; Koç E.S.; Beyaz O.; Edizer A. (2020). "Prilocaine-Induced Methemoglobinemia". Case Rep. Acute Med. 3 (2): 25-28. doi: 10.1159/000508403 .
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