Short-term oral and dermal toxicity of MCPA and MCPP.

The herbicieds 2-methyl-4-chlorophenoxy acetic acid (MCPA) and 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP or mecoprop) were tested for 90 days in rats. The compounds were added to the diet at levels of 0, 50, 400, and 3200 ppm. Growth, food intake, mortality, haematology, blood and liver chemistry, organ weights and histopathology were used as criteria. The main effects of both compounds were growth retardation and elevated relative kidney weights at levels of 400 ppm and more. The 50 ppm dose level can be considered as a no-toxic-effect level in the 90-day study. In subacute dermal studies in rabbits during 3 weeks the dosages were 0, 0.5, 1.0 and 2 g MCPA or MCPP per kg body weight. Therafter followed a recovery period of 2 weeks. Growth, mortality, skin reaction, haematology, organ weights (MCPP) and histopathology were recorded and determined. Both compounds caused slight to moderate erythema at all dose levels, whereas elasticity of the skin was decreased. In both experiments the skin returned to normal during the recovery period. Weight loss was observed at all dose levels. In the MCPA experiment high mortality and histopathological changes in the liver, kidneys, spleen and thymus were recorded at the two highest dose levels. The cause of this could have been either the treatment with MCPA or a dysbacteria infection which developed during the experiment. Oral and intraperitoneal acute toxicity of MCPP for the rat were found to be 1210 and 402 mg/kg, respectively. After a single oral or dermal application of MCPA to the rabbit, the compound was excreted unchanged in the urine.

Short-term toxicity of 1-naphthaleneacetic acid in rats.

In a 90-day feeding study, 4 groups of 10 male and 10 female rats received in the diet 0,200, 1000 and 5000 ppm 1-naphthaleneacetic acid (1-NAA). Growth and food intake was reduced significantly only in males on 5000 ppm. Haematological examination yielded essentially negative results except for a non-significant reduction at the 1000 and 5000 ppn levels in the leucocyte count, mainly due to a reduction in neutrophils. No significant effects were observed in the renal concentration test, urinalysis, renal histochemistry or histology of a wide range of organs at any level of 1-NAA tested. Increased relative weights of thyroid, testes, brain and liver were confined to the 5000 ppm level. The increase in relative liver weight was not accompanied by histological liver damage and was associated with elevated liver microsomal enzyme activity. The loss of glucose 6-phosphatase (G6Pase) and increase in glucose 6-phosphate dehydrogenase (G6PDH) seen histochemically in the centrilobular region of the liver in males on 5000 ppm, accompanied by glycogen depletion in the liver, could however be indicative of liver damage. On the basis of conventional criteria, a no-effect level of 1000 ppm would have been indicated by this study but in view of liver glycogen depletion at all levels tested a no-effect level was not established.

Long-term toxicity and reproduction studies with metaldehyde in rats.

Rats received 0, 200, 1000 and 5000 ppm metaldehyde in the diet for 2 years. Reproduction studies over three generations using the same dietary levels were carried out. In the third litter of each generation attention was paid to possible embryotoxic or teratogenic effects. The parameters studied included growth, food intake, behaviour and survival, haematology, clinical biochemistry, organ weight, histopathology, reproductive performance and teratogenicity. At 5000 ppm the relative liver weight was increased and this was accompanied by an increase in liver microsomal enzyme activity. The most striking observation was a dose-related development of posterior paralysis in females due to a transverse lesion of the spinal cord. The latency period was more than 550 days. Three rats with posterior paralysis showed a transverse lesion of the spinal cord. No significant histological damage to other organs was seen. The tumour incidence was not increased in any of the metaldehyde dosage groups. The reproduction study confirmed the findings of the long-term test. Posterior paralysis appeared in at least 50% of the females on 5000 ppm metaldehyde in all 3 generations. Some were affected at 1000 ppm but none at 200 ppm. Histologically, a fracture or distortion of thoracic vertebrae and subsequent compression of the spinal cord was found. The onset of paralysis was related to the time of delivery. The reproductive performance was susceptibility in this respect to metaldehyde. Apart from one male rat on 200 ppm with clinical posterior paralysis without transverse lesions in the spinal cord, this level was without toxic effects both in the long-term and 3-generation reproduction study.

Toxicity of methylmercury chloride in rats. III. Long-term toxicity study.

Four groups, each of 25 male and 25 female weanling rats, were given dietary levels of 0, 0.1, 0.5 and 2.5 ppm MeHgCl for 2 years. Observations were made on behaviour, growth, food intake, haematology, serum enzymes, urinalysis, microsomal liver enzymes, organ weights and histology with special reference to the nervous system, histochemistry of the kidneys and cerebellum and on tissue Hg concentrations. Significant findings included a slight growth reduction in females at 2.5 ppm, increased relative kidney weight at 2.5 ppm and histochemical changes in kidney enzymes at 2.5 ppm. No effect was seen on the nature or incidence of pathological lesions or tumours at any level. From the results obtained in the short-term, reproduction and long-term studies, the no-toxic effect level for rats appears to be between 0.1 and 0.5 ppm MeHgCl in the diet. Exposure of the Dutch population does not appear to present a health hazard at the moment because the mean intake of total Hg is still far below the intake deemed to be safe.

Toxicity of methylmercury chloride in rats I. Short-term study.

In the range-finding test, 6 groups of 4 male and 4 female weanling rats were given dietary levels of 0, 0.1,0.5, 2.5, 12.5 and 250 ppm methylmercury chloride (MeHgCl) for 2 weeks. Signs of central nervous system toxicity, weight loss and high mortality appeared at 250 ppm but not at lower levels. No haematological changes were observed at 0.1-12.5 ppm. The relative weights of the liver in females on 2.5 and 12.5 ppm and of the kidneys in females on 12.5 ppm were significantly increased; the effects in males were less marked. Total mercury concentration in the kidneys increased proportionally with increasing dietary levels of MeHgCl. In the short-term test, 5 groups of 15 male and 10 female weanling rats were given dietary levels of 0, 0.1, 0.5, 2.5 and 25 ppm MeHgCl for 12 weeks. Toxic signs, weight loss and restricted food intake were observed at 25 ppm starting from week 9 onwards. Haematological, serum enzyme and urinalysis changes were seen at 25 ppm. Liver microsomal enzyme activity was increased non-significantly and liver glycogen was depressed at 25 ppm. Organ weight changes were evident at 25 ppm and histological changes seen in the spleen, kidneys, brain, spinal cord and peripheral nerves were confined to the 25 ppm level. Histochemical changes in kidney enzymes occured at 2.5 and 25 ppm. Hg concentrations in blood, hair, kidneys, liver and brain were higher at 12 weeks than 6 weeks and generally increased with increasing MeHgCl level in the diet.

Toxicity of methylmercury chloride in rats. II. Reproduction study.

A reproduction study over 3 generations of rats was carried out in which groups of 20 female and 10 male rats received in the diet 0, 0.1, 0.5 and 2.5 ppm MeHgCl. The parameters studied included growth, food intake, haematology, serum and urinalysis, organ weights and reproductive performance, No effect was exerted on fertility index, lactation index or on the 21-day body weights of pups but the viability index was impaired at 2.5 ppm in the F1 and F2 generations. Weight gain reductions observed at 12 weeks for the 2.5 ppm level were not accompanied by reductions in food intake. At 6 months, Fla females on 2.5 ppm showed a reduced leucocyte count whilst P males on 0.5 and 2.5 ppm showed an increase in neutrophils and a decrease in lymphocytes. The relative weights of the kidneys, heart, spleen brain and thyroid were increased at 2.5 ppm and in some cases the increases of kidney weights were inconsistently seen at the 0.1 and 0.5 ppm levels. No significant histological changes were seen at any level. In a special 7-week study involving the F3a generation, weanling rats obtained from the four different F2a groups, each comprising 20 females and 10 males, were all transferred to diets containing 25 ppm MeHgCl. Toxicity signs were evident at 7 weeks. No evidence was obtained of increased susceptibility to the toxicity of MeHgCl in successive generations.

Health risk assessment of environmental exposure to 1,1,1-trichloroethane.

In 1986 a survey was published by CEFIC on the occurrence of chlorinated solvents in ambient air, in surface water, and in ground water. The present article concentrates on 1,1,1-trichloroethane (1,1,1-T), and puts into perspective the environmental occurrence and the toxicity. Critical toxicological data are briefly discussed. As no evidence of a carcinogenic effect of 1,1,1-T is apparent, the no-adverse-effect levels in chronic inhalation exposure in rats (875 ppm) and mice (1500 ppm) form the basis for the estimation of potential risk to human health. Environmental exposure to 1,1,1-T is mainly via the atmosphere (120 micrograms/day); the contributions of drinking water (2 micrograms/day) and food (3 micrograms/kg) are negligible. Safety margins are calculated by comparing the no-adverse-effect levels in rat and mouse studies with the total body burden. Safety margins are also calculated after converting no-adverse-effect levels into estimated internal dose levels by physiologically based pharmacokinetic modeling. Safety margins vary with the starting point, but are of the order of 10(5) for the general population and more than 10(4) for the population close to industrial activities. It may be concluded that the risk of a potential health effect resulting from environmental exposure to 1,1,1-trichloroethane is negligible.