For definition of Groups, see Preamble Evaluation.
VOL.: 57 (1993) (p. 271)
Chem. Abstr. Name: 4,4'-Methylenebis(2-chlorobenzenamine)
4,4'-Methylenebis(2-chloroaniline) (MOCA) was introduced in the mid-1950s in the production of high-performance polyurethane mouldings. It is used in many countries, with a total worldwide production of several thousand tonnes per year; it is used as a curing agent for roofing and wood sealing in Japan and the Far East. There was considerable occupational exposure by cutaneous absorption in the early years of use of MOCA, as revealed by urine analysis, but exposure has decreased with the implementation of control measures. Extensive environmental contamination is known to have occurred in a large area surrounding at least one factory, prior to the introduction of controls.
Three asymptomatic cases of cancer of the urinary bladder (two in men under the age of 30 among 552 workers) were identified in a factory where MOCA was produced and where screening for this cancer was undertaken in a subgroup. Although this finding suggests an excess, expected numbers could not be calculated.
MOCA was tested for carcinogenicity by oral administration in the diet in mice in one study, in rats of each sex in two studies, in male rats in a further two studies using normal and low-protein diets and in capsules in female dogs. It was also tested by subcutaneous administration to rats in one study. Oral administration of MOCA increased the incidence of liver tumours in female mice. In a series of experiments in which rats were fed either standard or low-protein diets, it induced liver-cell tumours and malignant lung tumours in males and females in one study, a few liver-cell tumours in male rats in another, lung adenocarcinomas and hepatocellular tumours in males and females in a third and malignant lung tumours, mammary gland adenocarcinomas, Zymbal gland carcinomas and hepatocellular carcinomas in a fourth. Oral administration of MOCA to female beagle dogs produced transitional-cell carcinomas of the urinary bladder and urethra. Subcutaneous administration to rats produced hepatocellular carcinomas and malignant lung tumours.
MOCA forms adducts with DNA, both in vitro and in vivo. One of the two major adducts, N-(deoxyadenosin-8-yl)-4-amino-3-chlorobenzyl alcohol, was found in rat tissues; it also cochromatographed with a DNA adduct from urothelial cells recovered from the urine of a worker in the polyurethane industry who was accidentally exposed to a high dose of MOCA. An increased frequency of sister chromatid exchange was seen in a small number of workers exposed to MOCA.
MOCA induced DNA damage in prokaryotes, cultured mammalian and human cells and in animals treated in vivo. Gene mutation was induced in bacteria and cultured mammalian cells, but not in yeast. Equivocal results for mitotic recombination were obtained in yeasts. Aneuploidy was induced in yeast and sister chromatid exchange, transformation and inhibition of intercellular communication in cultured mammalian cells. Micronuclei were induced in the bone marrow of mice treated in vivo, and sister chromatid exchange was induced in the bone marrow of rats treated in vivo.
MOCA is comprehensively genotoxic. Furthermore, (i) rats, dogs and humans metabolize MOCA to N-hydroxy-MOCA by hepatic cytochromes P450; (ii) DNA adducts are formed by reaction with N-hydroxy-MOCA, and MOCA is genotoxic in bacteria and mammalian cells; (iii) the same major MOCA-DNA adduct is formed in the target tissues for carcinogenicity in animals (rat liver and lung; dog urinary bladder) as that found in urothelial cells from a man with known occupational exposure to MOCA.
There is inadequate evidence in humans for the carcinogenicity of 4,4'-methylenebis(2-chloroaniline) (MOCA).
There is sufficient evidence in experimental animals for the carcinogenicity of 4,4'-methylenebis(2-chloroaniline) (MOCA).
4,4'-Methylenebis(2-chloroaniline) (MOCA) is probably carcinogenic to humans (Group 2A).
Overall evaluation 2A and not 2B on the basis of supporting evidence from other relevant data.
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Suppl. 7 (1987) (p. 246)
See Also: Toxicological Abbreviations