Names | |
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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) | |
Abbreviations | 4-COT |
ChemSpider | |
ECHA InfoCard | 100.002.220 |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C7H8ClN | |
Molar mass | 141.60 g·mol−1 |
Density | 1,14 g/cm3 |
Melting point | 29–30 °C |
Boiling point | 240–241 °C |
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.
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]
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]
No urinary bladder cancer was found in two of the earlier epidemiological reports of workers exposed to 4-COT in Switzerland and in the US. [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]
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.
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]
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.
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.
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.
Alcohol and cancer have a complex relationship. Alcohol causes cancers of the oesophagus, liver, breast, colon, oral cavity, rectum, pharynx, and larynx, and probably causes cancers of the pancreas. Cancer risk can occur even with light to moderate drinking. The more alcohol is consumed, the higher the cancer risk, and no amount can be considered completely safe.
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.
Transitional cell carcinoma is a type of cancer that arises from the transitional epithelium, a tissue lining the inner surface of these hollow organs. It typically occurs in the urothelium of the urinary system; in that case, it is also called urothelial carcinoma. 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).
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.
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.
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a polychlorinated dibenzo-p-dioxin (sometimes shortened, though inaccurately, to simply 'dioxin') with the chemical formula C12H4Cl4O2. Pure TCDD is a colorless solid with no distinguishable odor at room temperature. It is usually formed as an unwanted product in burning processes of organic materials or as a side product in organic synthesis.
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.
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Mirosław Jan Stasik was a Polish medical doctor and research toxicologist.
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