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 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 evidenc ...

and a precursor to some azo dyes. Production has declined after it was shown to be highly carcinogenic.

Production and use

It is produced by the chlorination reaction of N-acetyl toluidine followed by deprotection and separation from the 6-chloro isomer. Production of 4-chloro-''o''-toluidine began in Germany in 1924. In

Switzerland ). Swiss law does not designate a ''capital'' as such, but the federal parliament and government are installed in Bern, while other federal institutions, such as the federal courts, are in other cities (Bellinzona, Lausanne, Luzern, Neuchâtel ...

, 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

Experimental carcinogenicity and toxic effects

In chronic feeding studies (

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

of both sexes), 4-COT induces hemangiosarcomas and

hemangioendothelioma Hemangioendotheliomas are a family of vascular neoplasms of intermediate malignancy. Signs and symptoms They have been described as masses that fall between a hemangioma and angiosarcoma. They are vascular tumors that commonly present with an enl ...

s. 4-COT becomes covalently bound to DNA of

rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...

s and mice livers.

Inhalation Inhalation (or Inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...

or skin contact with 4-COT produces

acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse eff ...

toxic effects, initially appearing as macroscopic or microscopic haematuria. Further symptoms include dysuria, reduced bladder capacity and pain the lower abdomen.

Haemorrhagic cystitis Hemorrhagic cystitis or haemorrhagic cystitis is an inflammation of the bladder defined by lower urinary tract symptoms that include dysuria, hematuria, and hemorrhage. The disease can occur as a complication of cyclophosphamide, ifosfamide and ra ...

is the main symptom of acute toxicity, with

methaemoglobinaemia Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). Complications m ...

was observed in 50% of poisoning cases.

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. Stasik ''et al.'' obtained similar results in their previous mortality study carried out on a

cohort Cohort or cohortes may refer to: * Cohort (educational group), a group of students working together through the same academic curriculum * Cohort (floating point), a set of different encodings of the same numerical value * Cohort (military unit), ...

of 335 male employees exposed to 4-COT at plants in Frankfurt. 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

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...

s 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.

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. 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 China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's most populous country, with a population exceeding 1.4 billion, slightly ahead of India. China spans the equivalent of five time zones and ...

an increased incidence of bladder cancer among farm workers exposed to chlordimeform has been reported in 1990. 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. 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.Stasik M.J., Current studies of 4-chloro-o-toluidine and chlordimeform carcinogenicity, 26th Intern. Congress on Occupational Health, 2000, Singapore

References

{{DEFAULTSORT:Chloro-o-toluidine, 4- Anilines Carcinogens Chlorobenzenes Alkyl-substituted benzenes