4-Chloro-o-toluidine
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| 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
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| Identifiers | |
3D model (JSmol)
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| Abbreviations | 4-COT |
| ChemSpider | |
| ECHA InfoCard | 100.002.220 |
PubChemCID
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| UNII | |
CompTox Dashboard(EPA)
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| Properties | |
| C7H8ClN | |
| Molar mass | 141.60g·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 theirstandard state(at 25 °C [77 °F], 100 kPa).
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4-Chloro-o-toluidine(4-COT,4-chloro-2-methylaniline) is theorganic compoundwith the formula CH3C6H3Cl(NH2). It is a colorless solid. The compound is produced as an intermediate to the pesticidechlordimeformand a precursor to someazo dyes.Production has declined after it was shown to be highlycarcinogenic.
Production and use
[edit]It is produced by thechlorination reactionof N-acetyltoluidinefollowed by deprotection and separation from the 6-chloro isomer.[1]Production of 4-chloro-o-toluidine began inGermanyin 1924. InSwitzerland,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 ametabolic productofchlordimeform.[2]
Experimental carcinogenicity and toxic effects
[edit]In chronic feeding studies (miceof both sexes), 4-COT induceshemangiosarcomasandhemangioendotheliomas.[3]
4-COT becomes covalently bound toDNAofratsand micelivers.[4]
Inhalationor skin contact with 4-COT producesacutetoxiceffects, initially appearing as macroscopic or microscopichaematuria.Further symptoms includedysuria,reducedbladdercapacity and pain the lowerabdomen.Haemorrhagic cystitisis the main symptom of acute toxicity, withmethaemoglobinaemiawas observed in 50% of poisoning cases.[5]
Epidemiological studies of cancer
[edit]No urinary bladder cancer was found in two of the earlierepidemiologicalreports of workers exposed to 4-COT in Switzerland and in the US.[6][7]
Stasiket al.obtained similar results in their previous mortality study carried out on acohortof 335 male employees exposed to 4-COT at plants inFrankfurt.[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 bladdercarcinomaswere 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 wereurothelialcarcinomas.[9]
Evaluation of carcinogenic risk to man
[edit]TheDeutsche Forschungsgemeinschaft(German Research Council) defined 4-COT as a human carcinogen (III A1). Besides Germany, 4-COT is listed as a carcinogen inFinlandand Switzerland.[10]
Further in 1990 theInternational 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
[edit]Also inChinaan increased incidence of bladder cancer among farm workers exposed to chlordimeform has been reported in 1990.[11]
In 1992 Popp, Norpothet 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 ofbladder tumorsin 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]
References
[edit]- ^Joseph S. Bowers, "Toluidines" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005.doi:10.1002/14356007.a27_159
- ^IARC Monograph Vol. 48, p-Chloro-o-Toluidine and its strong salts
- ^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
- ^Bentley P. et al., Species differences in the toxicity of p-chloro-o-toluidine to rats and mice. Covalent binding tohepaticmacromoleculesand hepatic non-parenchymalcell DNA, Chem.-biol. Interact., 1986, 57, 27–40
- ^Stasik M.J., Urinary bladder cancer after 4-chloro-o-toluidine. Dtsch. med. Wschr., 1991, 116, 1444–1447 (in German)
- ^Uebelin F., Pletscher A.,Aetiologyandprophylaxisof industrialtumorsin the dye industry, Schweiz. med. Wschr., 1954, 84, 917–928 (in German)
- ^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
- ^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
- ^Stasik M.J., Carcinomas of the urinary bladder in a 4-chloro-o-toluidine cohort, Int. Arch. Occup. Environ. Health, 1988, 60, 21–24
- ^DFG Deutsche Forschungsgemeinschaft (German Research Council), Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, 1987
- ^Xue S. et al., The risk assessment of occupational exposure to chlordimeform, 23rd Intern. Congress on Occupational Health, 1990, Montreal
- ^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
- ^Stasik M.J., Current studies of 4-chloro-o-toluidine and chlordimeform carcinogenicity, 26th Intern. Congress on Occupational Health, 2000, Singapore