4,4'-methylenebis(cyclohexylamine)

Specific investigations: other studies

Description of key information

A human scleroderma or morphea syndrome in epoxy workers has been brought to the attention of the medical community in Japan in the 1980's.  One substance from among many was investigated in an animal experiment, of 10-28 days repeated dose oral exposure in Fisher rats at doses ranging from 25 to 100 mg/kg bw/d.  A degenerative myopathy was found at doses of 50 mg/kg bw/d and higher, and electron microscopy refined the pathology.  No scleroderma syndrome was seen after this exposure.  An association of 4-4’-methylenedicyclohexanamine in a causal relationship to this syndrome has not been proven.  The lack of attention to this effect among the industry having a history of heavy use of epoxy resins argues that the Japanese experience may have been an isolated event unassociated with this substance.

Additional information

Amine curing agents were suspected of causing human muscle disorders in workers in Japan, based on case studies of several workers in an epoxy resin polymerization factory, as reported by Yamakage, 1980, 1982. These have been described as scleroderma or morphea-type syndromes. One component of the agents used in the factory is 4-4’-methylenedicyclohexanamine, which was tested by Ohshima (1984, 1986) in a 28-day oral subchronic study with Fisher rats at doses of 25, 37.5, 50 and 75 mg/kg bw/d. Animals were monitored for clinical signs, body and organ weight changes. Clinical chemistry, hematology, and histopathologic examinations were made in selected organs and muscles. A second experiment utilized higher doses (100 mg/kg bw/d) for up to 10 days, and electron microscopy was used to examine tissue. Results indicate that animals receiving 75 mg/kg bw/d and higher doses showed suppression of body weight gain, weakness of the limb muscles, and minor changes in hematology and clinical chemistry parameters. There were few biochemical endpoints which supported muscle degeneration (no increase in CPK levels or blood protein levels). Histological examination showed no remarkable changes in most tissues (liver, kidney, spleen, heart, etc.), nor was there a reconstitution of a scleroderma or morphea-type syndrome. However, skeletal muscles showed various degrees of atrophy and degeneration or regenerative changes of muscle fibers. Electron microscopy revealed myofibril disruption, dilatation of the sarcoplasmic reticulum or mitochondria and the presence of inclusion bodies of a lamellar structure. The doses at which these effects were noted was not well described in the publication, but there were no effects described at 37.5 mg/kg bw/day or lower, hence this value is determined to be the NOAEL. It is questionable whether the muscle effect seen with one isolated chemical (4-4’-methylenedicyclohexanamine) from among many used in the factory would be the cause of the scleroderma syndrome in workers. In fact, Yamakage (1982) later proposed that this may be the result of solvent exposure, in general. There was no comprehensive assessment of chemical exposures of the workers, no report on the nutritional status or lifestyle behaviours of the workers, and no history or biochemical measurement of infectious diseases or genetic syndromes. This effect has not been reported, to our knowledge, by others who have a strong history of use of epoxy resins.

In summary, while the report of a scleroderma or morphea syndrome in epoxy workers has been brought to the attention of the medical community, the association of 4-4’-methylenedicyclohexanamine in a causal relationship to this syndrome has not been proven. The lack of attention to this effect among the industry having a history of heavy use of epoxy resins argues that this may have been an isolated event unassociated with this substance.