4-Chloro-o-toluidine

Last updated
4-Chloro-o-toluidine
4-COT.svg
Names
Preferred IUPAC name
4-Chloro-2-methylaniline
Other names
2-Amino-5-chlorotoluene; 2-Methyl-4-chloroaniline; 4-Chloro-2-toluidine; 5-Chloro-2-aminotoluene; para-Chloro-ortho-toluidine; p-Chloro-o-toluidine
Identifiers
3D model (JSmol)
Abbreviations4-COT
ChemSpider
ECHA InfoCard 100.002.220 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C7H8ClN/c1-5-4-6(8)2-3-7(5)9/h2-4H,9H2,1H3
    Key: CXNVOWPRHWWCQR-UHFFFAOYSA-N
  • InChI=1/C7H8ClN/c1-5-4-6(8)2-3-7(5)9/h2-4H,9H2,1H3
    Key: CXNVOWPRHWWCQR-UHFFFAOYAG
  • Clc1cc(c(N)cc1)C
Properties
C7H8ClN
Molar mass 141.60 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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.

Contents

Production and use

It is produced by the chlorination reaction of N-acetyltoluidine followed by deprotection and separation from the 6-chloro isomer. [1] Production of 4-chloro-o-toluidine began in Germany in 1924. In Switzerland, 4-COT and its salts were produced between 1956 and 1976. Production and distribution ceased in 1979 in the US and in 1986 in Germany.

In nature, 4-COT is found in plants and animals as a metabolic product of chlordimeform. [2]

Experimental carcinogenicity and toxic effects

In chronic feeding studies (mice of both sexes), 4-COT induces hemangiosarcomas and hemangioendotheliomas. [3]

4-COT becomes covalently bound to DNA of rats and mice livers. [4]

Inhalation or skin contact with 4-COT produces acute toxic effects, initially appearing as macroscopic or microscopic haematuria. Further symptoms include dysuria, reduced bladder capacity and pain the lower abdomen. Haemorrhagic cystitis is the main symptom of acute toxicity, with methaemoglobinaemia was observed in 50% of poisoning cases. [5]

Epidemiological studies of cancer

No urinary bladder cancer was found in two of the earlier epidemiological reports of workers exposed to 4-COT in Switzerland and in the USA. [6] [7]

Stasik et al. obtained similar results in their previous mortality study carried out on a cohort of 335 male employees exposed to 4-COT at plants in Frankfurt. [8]

A subcohort of 116 subjects in the 4-COT cohort, engaged in the synthesis of 4-COT at the old production plant with presumably higher level of exposure to this monocyclic arylamine, was separated from the Frankfurt cohort of 335 men, for further research.

Stasik then conducted a retrospective study of the incidence of bladder cancer among workers restricted to this subcohort. His investigation revealed eight subjects in whom bladder carcinomas were diagnosed between 1967 and 1985. Two of them had already died. The standardized incidence rate for bladder carcinomas in the 4-COT subcohort was 73 times higher than expected.

Histologically, all tumor cases were urothelial carcinomas. [9]

Evaluation of carcinogenic risk to man

The Deutsche Forschungsgemeinschaft (German Research Council) defined 4-COT as a human carcinogen (III A1). Besides Germany, 4-COT is listed as a carcinogen in Finland and Switzerland. [10]

Further in 1990 the International Agency for Research on Cancer (IARC) classified 4-COT as a probable human carcinogen (2A).

Both assessments were based on the results of the subcohort incidence study.

Further studies of cancer

Also in China an increased incidence of bladder cancer among farm workers exposed to chlordimeform has been reported in 1990. [11]

In 1992 Popp, Norpoth et al. found seven persons suffering from bladder cancer among 49 workers involved in the synthesis of chlordimeform from 4-COT in another German plant. [12]

Ten years later Stasik carried out a follow-up study of the same 4-COT subcohort studied by him previously. His re-investigations revealed a cluster of four new cases of bladder tumors in this group. So the total evidence of bladder cancer in the 4-COT subcohort increased to 12 cases, which makes 10% of all members of this particular group. [13]

Related Research Articles

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

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise from both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

<span class="mw-page-title-main">Bladder cancer</span> Urinary system cancer that begins in the urinary bladder

Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become malignant.

<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 intensely orange-red solid that is added to colourise waxes, oils, petrol, solvents, and polishes. Sudan I has also been adopted for colouring various foodstuffs, especially curry powder and chili powder, although the use of Sudan I in foods is now banned in many countries, because Sudan I, Sudan III, and Sudan IV have been classified as category 3 carcinogens by the International Agency for Research on Cancer. Sudan I is still used in some orange-coloured smoke formulations and as a colouring for cotton refuse used in chemistry experiments.

<span class="mw-page-title-main">Transitional epithelium</span> A type of tissue

Transitional epithelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching. The transitional epithelium usually appears cuboidal when relaxed and squamous when stretched. This tissue consists of multiple layers of epithelial cells which can contract and expand in order to adapt to the degree of distension needed. Transitional epithelium lines the organs of the urinary system and is known here as urothelium. The bladder, for example, has a need for great distension.

<span class="mw-page-title-main">Alcohol and cancer</span> Relationship between cancer and the consumption of alcohol

Alcohol causes cancers of the oesophagus, liver, breast, colon, oral cavity, rectum, pharynx, and larynx, and probably causes cancers of the pancreas. Consumption of alcohol in any quantity can cause cancer. The more alcohol is consumed, the higher the cancer risk, and no amount can be considered safe. Alcoholic beverages were classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) in 1988. An estimated 3.6% of all cancer cases and 3.5% of cancer deaths worldwide are attributable to consumption of alcohol. 740,000 cases of cancer in 2020 or 4.1% of new cancer cases were attributed to alcohol.

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

Ochratoxin A—a toxin produced by different Aspergillus and Penicillium species — is one of the most-abundant food-contaminating mycotoxins. It is also a frequent contaminant of water-damaged houses and of heating ducts. Human exposure can occur through consumption of contaminated food products, particularly contaminated grain and pork products, as well as coffee, wine grapes, and dried grapes. The toxin has been found in the tissues and organs of animals, including human blood and breast milk. Ochratoxin A, like most toxic substances, has large species- and sex-specific toxicological differences.

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.

<span class="mw-page-title-main">Transitional cell carcinoma</span> Medical condition

Transitional cell carcinoma, also called urothelial carcinoma, is a type of cancer that typically occurs in the urinary system. It is the most common type of bladder cancer and cancer of the ureter, urethra, and urachus. Symptoms of urothelial carcinoma in the bladder include hematuria. Diagnosis includes urine analysis and imaging of the urinary tract (cystoscopy). Transitional cell carcinomas arise from the transitional epithelium, a tissue lining the inner surface of these hollow organs. When the term "urothelial" is used, it specifically refers to a carcinoma of the urothelium, meaning a transitional cell carcinomas of the urinary system.

<span class="mw-page-title-main">Urethral cancer</span> Medical condition

Urethral cancer is a rare cancer originating from the urethra. The disease has been classified by the TNM staging system and the World Health Organization.

<i>o</i>-Toluidine Aryl amine

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.

4,4′-Methylenebis(2-chloroaniline) is a substance used as a curing agent in polyurethane production. MOCA is an aromatic amine which is structurally similar to benzidine, a known human bladder carcinogen. MOCA has been shown to cause hepatomas in mice and rats, lung and mammary carcinomas in rats and bladder cancer in dogs. It is a proven human carcinogen standing on the WHO List of IARC Group 1 carcinogens, with a current threshold limit value of 0.01 ppm in the industrial atmosphere. Animal studies have resulted in tumor growth in the liver, lung, and bladder.

<span class="mw-page-title-main">Signet ring cell carcinoma</span> Medical condition

Signet ring cell carcinoma (SRCC) is a rare form of highly malignant adenocarcinoma that produces mucin. It is an epithelial malignancy characterized by the histologic appearance of signet ring cells.

<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.

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

Starlicide or gull toxicant is a chemical avicide that is highly toxic to European starlings and gulls, but less toxic to other birds or to mammals such as humans and pets.

<span class="mw-page-title-main">Epidemiology of cancer</span> The study of factors in cancer causes and treatments

The epidemiology of cancer is the study of the factors affecting cancer, as a way to infer possible trends and causes. The study of cancer epidemiology uses epidemiological methods to find the cause of cancer and to identify and develop improved treatments.

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

Chlordimeform is an acaricide (pesticide) active mainly against motile forms of mites and ticks and against eggs and early instars of some Lepidoptera insects. After the International Agency for Research on Cancer reported sufficient evidence that its major metabolite, 4-chloro-o-toluidine, was a carcinogen, its use has ceased and its registration has been withdrawn in most countries.

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

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

Exposure to ionizing radiation is known to increase the future incidence of cancer, particularly leukemia. The mechanism by which this occurs is well understood, but quantitative models predicting the level of risk remain controversial. The most widely accepted model posits that the incidence of cancers due to ionizing radiation increases linearly with effective radiation dose at a rate of 5.5% per sievert; if correct, natural background radiation is the most hazardous source of radiation to general public health, followed by medical imaging as a close second. Additionally, the vast majority of non-invasive cancers are non-melanoma skin cancers caused by ultraviolet radiation. Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been investigated as a possible carcinogen by the WHO's International Agency for Research on Cancer, but to date, no evidence of this has been observed.

Occupational cancer is cancer caused by occupational hazards. Several cancers have been directly tied to occupational hazards, including chimney sweeps' carcinoma, mesothelioma, and others.

Carcinogenic parasites are parasitic organisms that depend on other organisms for their survival, and cause cancer in such hosts. Three species of flukes (trematodes) are medically-proven carcinogenic parasites, namely the urinary blood fluke, the Southeast Asian liver fluke and the Chinese liver fluke. S. haematobium is prevalent in Africa and the Middle East, and is the leading cause of bladder cancer. O. viverrini and C. sinensis are both found in eastern and southeastern Asia, and are responsible for cholangiocarcinoma. The International Agency for Research on Cancer declared them in 2009 as a Group 1 biological carcinogens in humans.

References

  1. ↑ Joseph S. Bowers, "Toluidines" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005. doi : 10.1002/14356007.a27_159
  2. ↑ IARC Monograph Vol. 48, p-Chloro-o-Toluidine and its strong salts
  3. ↑ Weisburger E.K. et al., Testing of twenty-one environ. aromatic amines or derivatives for long-term toxicity or carcinogenicity, J. Environ. Pathol. Toxicol., 1987, 2, 326-356
  4. ↑ Bentley P. et al., Species differences in the toxicity of p-chloro-o-toluidine to rats and mice. Covalent binding to hepatic macromolecules and hepatic non-parenchymal cell DNA, Chem.-biol. Interact., 1986, 57, 27-40
  5. ↑ Stasik M.J., Urinary bladder cancer after 4-chloro-o-toluidine. Dtsch. med. Wschr., 1991, 116, 1444-1447 (in German)
  6. ↑ Uebelin F., Pletscher A., Aetiology and prophylaxis of industrial tumors in the dye industry, Schweiz. med. Wschr., 1954, 84, 917-928 (in German)
  7. ↑ Ott M.G., Langner R.R., A mortality survey of men engaged in the manufacture of organic dyes, J. Occupational Medicine, 1983, 225, 763-768
  8. ↑ Stasik M.J. et al., A historic cohort study of 4-chloro-2-methylaniline workers, Proceedings of the MEDICHEM Meeting, Bahia, Brazil, 1985, London, ICI plc, 2-11
  9. ↑ Stasik M.J., Carcinomas of the urinary bladder in a 4-chloro-o-toluidine cohort, Int. Arch. Occup. Environ. Health, 1988, 60, 21-24
  10. ↑ DFG Deutsche Forschungsgemeinschaft (German Research Council), Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, 1987
  11. ↑ Xue S. et al., The risk assessment of occupational exposure to chlordimeform, 23rd Intern. Congress on Occupational Health, 1990, Montreal
  12. ↑ Popp W. et al., Incidence of bladder cancer in cohort of workers exposed to 4-chloro-o-toluidine while synthesizing chlordimeform, Br. J. Ind. Med., 1992, 49, 529-531
  13. ↑ Stasik M.J., Current studies of 4-chloro-o-toluidine and chlordimeform carcinogenicity, 26th Intern. Congress on Occupational Health, 2000, Singapore
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.