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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.

In a comparative study 0, 50, 200, 1000 and 3000 ppm (parts per million) of five acaricides, tetrasul (2,4,5,4′-tetrachlorodiphenylsulphide), V110 (2,4,5,4′-tetrachlorodophenylsulphoxide), tetradifon, chlorfenson and kelthane were given to groups of 10 male and 10 female rats in separate 90-day toxicity experiments. Growth, food intake, mortality, haematology, blood and liver biochemistry, organ weight, histopathology, number of liver parenchymal cells per surface unit and the diameter of liver-cell nuclei were used as criteria. The acaricides investigated, with the exception of kelthane, induced both functionally and structurally the same liver alterations. SER (smooth endoplasmic reticulum) whorls were found in the higher dose-levels of all 5 compounds. In all compounds, except kelthane, enlarged thyroids were found accompanied by histological alterations. Tetrasul was more toxic than V110, followed by tetradifon. Chlorfenson was equally as toxic as tetrasul. Kelthane can be regarded as the most toxic of this group of compounds. The 50-ppm dosage appeared to be a no-toxic effect level only in the case of tetradifon.

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 ppm 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-phosphate (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.

Hexachlorobenzene Toxicity in Pigs. den Tonkelaar, E. M., Verschuuren, H. G., Bankovska, J., de Vries, T., Kroes, R., and van Esch, G. J. (1978). Toxicol. Appl. Pharmacol. 43 , 137–145. A 90-day toxicity study was carried out in which pigs received 0.05, 0.5, 5.0, and 50 mg/kg/day of hexachlorobenzene (HCB). Special attention was given to the induction of porphyria and microsomal liver enzymes and the concentration of HCB in blood and tissues. Animals given the highest dose (50 mg/kg) showed clinical signs associated with porphyria and died during the experiment. At lower dosages these signs were not observed. An increased excretion of coproporphyrin was found in the 5.0- and 0.5-mg/kg groups, as well as induction of microsomal liver enzymes accompanied by increased liver weight (at 5.0 mg/kg) and characteristic histopathological changes in the liver. The concentration of HCB in blood and tissues was elevated at all dosages. Concentrations in fat were approximately 500 times greater than those in blood, while the concentration in liver was higher than in the kidneys and brain. Under the conditions of this experiment, a no-effect level was judged to be 0.05 mg/kg/day of HCB.

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.

Pentachlorophenol (PCP) was fed to rats at dietary levels of 0, 25, 50 and 200 ppm for 12 weeks. Growth was decreased in the group of female rats fed 200 ppm. The treatment had no effect on food intake and behaviour. Liver weight was increased at the 50 and 200 ppm dose levels accompanied by an increased activity of microsomal liver enzymes. In week 6 higher haemoglobin and haematocrit values were found in the groups of males fed 50 and 200 ppm. In week 11 the haemoglobin values and the number of erythrocytes were decreased in the same groups of males. A possible explanation is discussed. A striking dose-related decrease of calcium deposits in the kidney is found. The no-toxic-effect level for all criteria is considered to be 25 ppm.

A toxicological investigation was carried out in order to repeat and extend the findings of Bukhman (Vop. Pitan. 1962, 21, 68) concerning the toxicity of propyl gallate in fasting rats. Rats were given a diet containing 0·002 or 0·004% propyl gallate or α-tocopherol. After 13 wk some of the animals were sacrificed, while the remaining rats were placed on a partial starvation diet until death. The survival time was recorded. Chemical determinations of water, protein and fat content were made on the sacrificed animals as well as on those that died. No difference in survival time or in protein and fat utilization was found between the control groups and the groups which received propyl gallate or α-tocopherol. The results of Bukhman could not be confirmed.

Short-term toxicity studies have been carried out in rats and guinea-pigs fed diets containing triphenyltin acetate (TPTA), triphenyltin hydroxide (TPTH) or triethyltin hydroxide (TETH) for 90 days at levels ranging from 0 to 50 ppm. The lowest dietary levels found to retard growth in rats and guinea-pigs respectively are as follows: 5 and 10 ppm for TETH; 25 and 5 ppm for TPTA; 50 and 20 ppm for TPTH. An increase in mortality was found in the following groups: rats on 10 ppm or more of TETH; guinea-pigs on 20 and 50 ppm TPTA and on 50 ppm TPTH. In rats and guinea-pigs given TETH, paralysis and pronation of the hindlegs developed. These toxic signs were not found in the TPTA- and TPTH-treated animals. This observation was correlated with the finding that only the TETH-treated animals developed interstitial oedema of the central nervous system. The water content of the brain and spinal cord was increased in rats and guinea-pigs at respective minimum levels of 5 and 10 ppm of TETH and in guinea-pigs on 20 ppm TPTA. In female rats given 50 ppm TPTA or TPTH the water content of the spinal cord was only increased. The changes in organ weights which could be related to the administration of the organotin compounds were confined to an increase of brain weight in rats and guinea-pigs given TETH, and in guinea-pigs given 5 ppm or more of TPTA and a decrease of thymus and/or spleen weights in rats and guinea-pigs receiving TETH. Guinea-pigs given 5–20 ppm TPTA or 2·5–20 ppm TPTH displayed lymphopenia accompanied in a number of animals by histological changes in the lymphopoietic system, viz. atrophy of the white pulp of the spleen was found. This possibly induced a decrease of general resistance, so that a mycotic infection developed in the animals. Hitherto, damage to the central nervous system was considered to be the most sensitive criterion for assessing the toxicity of organotin compounds, but the present work shows that the effect on lymphopoiesis is a more sensitive index of toxic action for triphenyltin compounds.