2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine)

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Occupational Scleroderma-Like Disorder Occurring in Men Engaged in the Polymerization of Epoxy Resins

Author:

Yamakage, A. et al.

Year:

1980

Bibliographic source:

Dermatologica 161, 33-44

Reference 2

Title:

Sklerodermie und Sklerodermie-ähnliche Erkrankungen durch Umweltsubstanzen (Scleroderma and Scleroderma-like Diseases due to Environmental Substances)

Author:

U.-F. Haustein and V. Ziegler

Year:

1986

Bibliographic source:

Dermatosen 34, Heft 3

Materials and methods

Study type:

clinical case study

Endpoint addressed:

other: skin sclerosis

Test guideline

Qualifier:

no guideline required

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine)

EC Number:

229-962-1

EC Name:

2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine)

Cas Number:

6864-37-5

Molecular formula:

C15H30N2

IUPAC Name:

4-[(4-amino-3-methylcyclohexyl)methyl]-2-methylcyclohexan-1-amine

Method

Type of population:

occupational

Subjects:

- Number of subjects exposed: 2
- Sex: male
- Age: 48 years (case 1) and 30 years (case 2)
- Race: caucasian
- Demographic information:factory in Japan

Case 1:
A 48-year-old Japanese male was first in September 1976. His family history was unremarkable. He had been operated on at the age of 25 because of pulmonary tuberculosis, but during the past years he has been in good health. Since the end of May 1975, he had been engaged in the polymerization process of epoxy resins at a factory in Japan.

Case 2:
A 41-year-old Japanese male who had also begun similar duties at the same factory as case 1 beginning in May 1975.

Ethical approval:

not applicable

Route of exposure:

inhalation

Reason of exposure:

unintentional, occupational

Exposure assessment:

not specified

Examinations:

- Haematology: peripheral blood cell count and differential
- Lung function parameters: pulmonary function tests
- Other: urinalysis, BUN, serum electrolytes, uric acid, liver function, cholesterol, CPK, aldolase, fibrinogen, ASO and protein electrophoresis, Electrocardiogram and chest X-ray
Biopsies of skin and muscles were taken from the upper arm and gluteal region. For electron microscopic observations, part of the remaining skin specimen was fixed.

Results and discussion

Clinical signs:

Case 1: Toward the end of June (1975), the patient developed fatigue and a burning sensation on the skin. Some days later, he felt an itching over the entire body. In August, he noticed an edema on the thighs, which lasted for a month. When the edema subsided, an indurative skin change developed on the lower legs causing difficulty in walking. The skin sclerosis extended gradually to other parts of the body such as the fingers, forearms, upper arms, thighs and buttocks. Hair of the scalp, axillae and genitalia began to diminish, accompanied by a diffuse darkening of the skin surface. Meanwhile, the itching improved. Body weight had dropped from 56 kg prior to this disease to 41 kg at the first examination by us. On examination the skin of the patient showed a diffuse, sclerodermatous induration over the whole body. In addition, a considerable grade of erythema and a brownish pigmentation were seen along with telangiectatic spots. There was also marked weakness and atrophy of the muscles of the body and extremities with no pain. The skin and muscle changes were especially conspicuous on the buttocks and lower back. Further, there was a total loss of the hairs of the scalp, axillae and genitalia.

Case 2: In the middle of July 1975, the patient noted an edema on the lower legs and dorsum of the feet and later also on the forearms. In November the edema was somewhat improved, but hair loss on the scalp and extremities appeared instead. In January 1976, the skin of the upper arms, forearms and lower legs became scleroedematous. 2 months later, he noticed a marked weakness of the muscles of the extremities and body. On examination, the patient showed similar, but less remarkable skin changes than those of case 1. In both of the cases, joints of the extremities including the hands and fingers demonstrated a slight contracture in a flexed position with considerable arthralgia. A slight grade of impotency was also a complaint on first examination.

Results of examinations:

- Urine analysis: within normal limits
- Haematology: within normal limits
- Lung function parameters: pulmonary function tests revealed diminished vital capacity in both patients
- Other: urinalysis, BUN, serum electrolytes, uric acid, liver function, cholesterol, CPK, aldolase, fibrinogen, ASO and protein electrophoresis were within normal limits. Electrocardiogram and chest X-ray also showed normal features

Both patients demonstrated abnormal flattening of the wave in plethysmograms, although they did not complain of Raynaud's phenomenon, and acrocyanosis was not seen . The lymphocyte subpopulation as well as IgG, IgM and 1gA values lay within the normal range in both patients. They had been sensitized to DNCB-patch and proved positive in Mantoux-R. ANA was not detected in the serum.

Light and electron microscopic studies of the skin lesions revealed a similarity to generalized morphea rather than to systemic scleroderma.

Effectivity of medical treatment:

The patients were treated with a protease and small doses of prednisolone. Three months after the first examination, the patients showed slight improvement in walking and muscle weakness. By June 1977, the hair of the scalp was restored to nearly normal .

Any other information on results incl. tables

Four compounds out of the chemicals used in the polymerization process of epoxy resins were selected, as possible causative agents of the skin sclerosis, as described be low, and the immune responses of the patients were examined. The 48 hour patch test resulted in a positive reaction (+ +) only with a 0.01% of bis-(4-amino-3-methyl-cyclohexyl) methane in one of the patients (case 2). The other patient failed to respond to any compound tested, including the amine.

The epoxy resin vapor to which the patients were exposed consisted of 9 chemicals. Five of them have been safely used in the factory for a long while. Thus the other 4 compounds were suspected of being the causative agent at the time this disease occurred. An experimental skin sclerosis in the mouse was tried to produce using the compounds (Bis (4-amino-3-methyl-cyclohexyl) methane; Diglycysylaniline, Tetrabromobisphenol A glycysyl ether, Dibromocresylglycysyl ether). The agents were finally dissolved in either 20% ethanol or acetone to a concentration of 0.2% and, after their sterilization through a Millipore filter, 0.1 mL of each of the agents was injected intraperitoneally into mice of DD strain for either 10 or 17 consecutive days . As control, the solvent alone was injected. 2 days after the final injection, the animals were sacrificed by decapitation. The dorsal skin near the shoulder was cut off for histological examinations, which were carried out using the double-blind method. Histologically, a change similar to the skin sclerosis of the patients was observed with a high incidence in miceinjected with bis(4-amino-3 - methyl-cyclohexyl) methane. However, the other compounds(oligomers of epoxy resins) also showed sclerotic skin changes in some mice examined.