Amine-curing agent for epoxy resin, bis (4-amino-3-methylcyclohexyl) methane (commercial name; Laromin C) has been suspected to have induced in the workers some toxic signs such as collagen disease like scleroderma or polymyositis. Subacute toxicity of this agent was studied in rats following repeated oral administration. The agent was given orally at 5 dose levels (25 mg/kg to 100 mg/kg per one dose) for periods ranging from 10 days to 4 weeks. After the completion of administration, clinico-biochemical tests and histopathological examinations were carried out. In a few cases, skeletal muscles and choroid plexus of the brain were examined by electronmicroscopy. Clinico-biochemical tests revealed some elevation of muscle-derived components such as GOT and CPK as seen in the myopathic diseases. Histologically, various degrees of atrophy, degeneration and regeneration of muscle fibers and a numerical increase of interstitial cells were observed in the skeletal muscles. Electronmicroscopical examination of the gastrocnemius muscle revealed intrasarcoplasmic osmiophilic round-shaped inclusion bodies, sometimes with lamellar structure, which were suggestive of some lipidosis. The epithelial cells of choroid plexus in the brain ventricles represented various degrees of vacuolar changes lightmicroscopically, which were suggested to be dilated smooth endoplasmic reticulum electronmicroscopically. Although scleroderma-like changes were not observed in our experiments, the results suggest that this amine-curing agent for epoxy resin could be one of the causative agents which induced toxic lesions like some collagen diseases including muscle lesions in the workers. In addition, it is considered that the agent may have systemic toxic effects.

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Changes in the levels of urea cycle enzymes and polyamine metabolism in the liver of rats treated with α-naphthylisothiocyanate (ANIT), an inducer of experimental cholestasis, were studied. Activities of arginase increased approximately two-fold compared to the control values during the period of 24-72 hours after oral administration of ANIT (100 mg/kg), while activities of ornithine carbamyltransferase and ornithine aminotransferase decreased. The activity of ornithine decarboxylase was elevated by approximately 20-and 10-fold at 12 and 60 hours, respectively, after ANIT administration. Putrescine concentration doubled 24-48 hours after the ANIT administration, but spermidine level rose more slowly and reached the level of 1.5-fold of the control level in 36-72 hours. Spermine concentration decreased initially but increased in 96 hours. These results suggest that the increased activity of urea cycle accounts for the increase in the ornithine content and that the putrescine and spermidine acts as the initiator of recovery of the liver damaged by ANIT treatment.

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We examined the effects of chinoform (CF) on the spinal reflexes and the descending influences on the spinal reflexes from the locus coeruleus (LC) and the nucleus raphe magnus (NRM) in rats. The spinal reflex potential was recorded from the L5 ventral root following stimulation of the L5 dorsal root, and the effects of electrical stimulation of the LC and the NRM were tested in anesthetized rats. CF was suspended in Tween 80 and administered for two days (400 mg/kg, i. p./day) before the measurement of the spinal reflexes. In all rats treated with CF, death or motor incoordinations such as abnormal gait and hindlimb ataxia were observed. However, the control and CF-treated groups are not different in the amplitude and shape of the reflexes and in the influences of the LC and the NRM on the reflexes from the LC and the NRM. These results suggest that segmental spinal reflexes and descending influences from the LC and the NRM are not affected in rats suffered from motor incoordination by acute CF.

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Toxicokinetic parameters of γ-chlordane (GCD) after oral administration of various doses of radio-rabelled GCD (50μg/kg-10 mg/kg) were compared. Absorption of GCD were about 80% in both 0.1 and 1.0 mg/kg groups. Distributions of GCD (50μg/kg and 10 mg/kg) into the liver and kidney were rapid and those into adipose tissues were relatively slow. Concentrations of GCD in adipose tissues became highest at 16 hr after administration and became about 10 times more than those in the liver. The initialconcentrations of GCD calculated by two-compartment open model in high dose group (10 mg/kg) were about 200-300 times higher than those in low dose group (50μg/kg). Half lives of GCD in low dose group had a tendency to be a little longer than those in high dose group. This difference seemed to be caused by the accumulation of oxychlordane in low dose group.

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To investigate the teratogenicity of 4-bromophenyl chloromethyl sulfone (BCS), doses of 0, 5, 35 and 245 mg/kg/day of the test substance were administered by oral gavage to Wistar-Imamichi rats from days 6 to 15 of gestation. The results were as follows: 1) The treated dams did not exhibit any toxic symptoms or mortality attributable to the test substance. 2) The following changes were noted in the treated dams : dose-dependent reduction of body weight gain and food intake in 35 and 245 mg/kg groups, and decreased water intake, reduced brain and thymus weights and increased relative weights of liver and kidney in the 245 mg/kg group. 3) Fetal toxicity, increase of mortality and body weight depression, caused by the test substance was not observed. 4) External, skeletal and visceral examination of the fetuses did not reveal any abnormalities ascribed to the test substance. With regard to ossification, the incidence of fetuses with delayed ossification of the 2nd and 5th sternebrae was significantly higher than in the control group. In summary, dams given BCS in doses of 35 mg/kg and 245 mg/kg displayed toxic manifestations. Fetuses showed slightly delayed ossification. However, the test substance was concluded to be free of any lethal or teratogenic effects.

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The plasma levels and urinary excretion of batroxobin administered to 6 species of animals were examined by an enzyme immunoassay method. Defibrinogenating effect of batroxobin was also studied in those species. The plasma levels of immunoreactive batroxobin disappeared exponentially in all the animals and differences in half-life were observed to occur according to species. The elimination half-life of immunoreactive batroxobin in the plasma was the largest in dogs, followed by rats, monkeys, guinea pigs, mice and rabbits. The extent of the defibrinogenating effect was also noted to vary according to the species, being greatest in dogs and then monkeys, mice, rats, guinea pigs and rabbits. Following the continuous infusion of batroxobin into dogs, its level in the plasma remained high over a considerable period of time and the defibrinogenating effect lasted in corresponding to its plasma level. The urinary excretion of immunoreactive batroxobin was quite small in these species, being 0.2-1.9% of the original dose.

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