Tomoko Fujitani

Sub-acute toxicity of piperonyl butoxide in F344 rats

Piperonyl butoxide, alpha-[2-(2-Butoxyethoxy)ethoxy]-4,5-methylenedioxy- 2-propyltoluene, is a pesticide synergist. F344 rats of both sex were maintained on diets containing 0, 0.6, 1.2 or 2.4% of piperonyl butoxide for 13 weeks. At the end of experimental period, they were necropsied. Selected organs were weighted and serum was analyzed by clinical chemistry. In male and female rats of the 2.4%-group, body weight gains were depressed, macroscopically, hepatomegaly was marked and liver weights were significantly higher than those of the control group. In male and female rats of all treated groups, relative kidney weights were significantly increased in a dose-dependent manner. Rats of the 2.4%-group had increased levels of albumin, cholesterol, urea nitrogen and gamma-glutamyl transpeptidase. Examination of livers of the male 2.4%-group by light microscopy showed enlarged hepatocytes with glassy cytoplasm and fatty deposition. On occasion, there was coagulative necrosis of a few hepatocytes in the periportal area and oval cell proliferation. The kidney of treated rats showed atrophy of epithelium in the proximal convoluted tubules. These results indicated that toxicity of piperonyl butoxide in rats was directed primarily to the liver and kidney.

Flame retardant tetrabromobisphenol A induced hepatic changes in ICR male mice

Tetrabromobisphenol A (TBBPA) is widely used throughout the world as flame retardant for electronic equipment or building materials, and is detected in air at the dismantling plant, sewage sludge, sediment or human serum samples. In the present study, we examined the effects of TBBPA on the liver when administered to mice for 14 consecutive days. Groups of 7 (control group) or 8 (treated group) Crlj:CD1 (ICR) male mice were given 0 (control), 350, 700 or 1400mg/kg body weight/day TBBPA (99.1% pure) in olive oil for 14 days. The serum concentration of total-cholesterol in high-dose (1400mg/kg BW) group was higher than those of the control group. Absolute and relative liver weights were dose-dependently increased, and were significantly increased in high-dose (1400mg/kg BW) group. The histological findings showed that the slight enlargement of the hepatocytes, inflammatory cell infiltrations and focal necrosis of hepatocytes were more marked in liver of treated groups (from 350mg/kg BW) than in control group. The present data suggest the possibility of inducing hepatic lesion by TBBPA dosing.

Subacute toxicity of piperonyl butoxide in ICR mice.

Piperonyl butoxide, alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltol uene, is a pesticide synergist. ICR mice of both sexes were maintained on diet containing 0, 0.1, 0.3 or 0.9% of piperonyl butoxide for 20 days. At the end of the experimental period, they were necropsied. Selected organs were weighed and serum chemistries were analyzed. In male and female mice of the 0.9% group, body weight, kidney and spleen weight were depressed in comparison to those of control group. Liver weight of the 0.3 and 0.9% group of both sexes were significantly higher than those of control group. Mice of the 0.9% group of both sexes had increased serum levels of cholesterol, total protein, gamma-glutamyl transpeptidase. Histological examination of livers from mice of the 0.9% group by light microscopy showed enlarged hepatocytes, anisonucleosis and single cell necrosis. The results indicated that subacute toxicity of piperonyl butoxide in ICR mice was directed primarily at liver.

Hemotoxicity of chlorpropham (CIPC) in F344 rats.

Chlorpropham[Isopropyl-N-(3-chlorophenyl)carbamate; CIPC] is a widely used sprout suppressant. Groups of ten male and ten female F344 rats were given 0, 7500, 15,000 or 30,000 ppm of CIPC in the diet for 13 weeks. Body weight gain of male and female rats in the 30,000 ppm-group was depressed. Spleen and liver weights of male and female rats in the treated groups were dose-dependently increased. Red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular hemoglobin concentration and platelet count were decreased in male and female rats of the treated groups. Methemoglobin level, mean corpuscular volume and mean corpuscular hemoglobin were increased in male and female rats of the treated groups. Those hematological changes were dose-dependent and were marked in the 15,000 and 30,000 ppm-groups. White blood cell count of male and female rats in the 30,000 ppm-group were significantly higher than those of the control group. Congestion, increased hemosiderin deposition, increased extramedullary hemopoiesis, lymphoid atrophy and fibrosis were seen in spleen of male and female rats of all treated groups in a dose-dependent manner. Hemopoietic cell hyperplasia was marked in bone marrow of male and female rats in all treated groups. The results suggested that the erythrocyte is one of the primary targets of CIPC toxicity in rats.

Developmental toxicity evaluation of piperonyl butoxide in CD-1 mice

Piperonyl butoxide was administered to pregnant mice by gavage at a level of 0 (control), 1065, 1385 and 1800 mg/kg body weight only on day 9 of gestation. The animals were sacrificed on day 18 of gestation. Early and late foetal deaths were significantly increased in the higher dose groups and those effects were significantly dose-related. The average body weights of male and female foetuses were significantly reduced in a dose-related fashion. The external malformation of oligodactyly in forelimbs was significantly increased in higher treatment groups in a dose-related manner. The dose levels of piperonyl butoxide in the present study produced adverse effects on developmental parameters.

Chronic toxicity studies of piperonyl butoxide in CD-1 mice : Induction of hepatocellular carcinoma'

Male and female CD-1 mice (51-104 mice/group) were administered piperonyl butoxide (alpha-[2-(2-butoxyethoxy)ethoxy-4,5-methylenedioxy-2-propyltol uene) in the diet at levels of 0 (control), 0.6 and 1.2% for 52 weeks (1 year). Hepatocellular carcinomas were induced in treated groups in a dose-dependent manner. The incidences of hepatocellular carcinoma were 11.3 and 52.0% in male mice given 0.6 and 1.2% piperonyl butoxide, and 41.2% in female mice given 1.2%. Piperonyl butoxide is thus a hepatocarcinogen to mice as it is known to be to rats.

Developmental Toxicity Study of Piperonyl Butoxide in CD Rats

Piperonyl butoxide was administered to pregnant rats by gavage at a level of 0 (control), 630, 1065, and 1800 mg/kg bw on days 11-12 of gestation. The animals were killed on day 20 of gestation. Average maternal body weight gain (gestational days 11-20) was significantly reduced in the 1065 and 1800 mg/kg bw groups. Total resorption rate was significantly increased in the 1800 mg/kg bw group and those effects were significantly dose-related. The average fetal body weight of each sex was significantly reduced in the 1065 and 1800 mg/kg bw groups. External limb deformity (oligodactyly, syndactyly, and polydactyly) was significantly increased in the 1065 and 1800 mg/kg bw groups in a dose- related manner. The dose levels of piperonyl butoxide in the present study produced limb deformities in rats.

Chronic toxicity of thiabendazole (TBZ) in CD-1 mice

Male and female CD-1 mice (50 mice per group) were administered thiabendazole (TBZ) in diet at levels of 0 (control), 0.031, 0.125 and 0.5% for 78 weeks. A life time study was terminated after 78 weeks due to enhanced strain specific mortality. There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 0.5% group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. It is concluded that TBZ is not carcinogenic to CD-1 mice of both sexes. However, caution should be exercised in the long-term application of high TBZ doses.

Hepatotoxicity of piperonyl butoxide in male F344 rats

Male F344 rats were given 0, 0.6, 1.2 or 2.4% of piperonyl butoxide in the diet. At 1, 2, 4 or 12 weeks after the beginning of the experiment, liver and kidney weight and serum clinical parameters were determined and livers and kidneys were examined with light microscopy. From 1 or 2-12 weeks, distinct increase of liver weight, changes in serum clinical parameters for liver damage, oval cell proliferation, bile duct hyperplasia, single cell necrosis, enlarged and vacuolated hepatocytes, enlarged nuclei and anisonucleosis were seen in treated rats. From 4-12 weeks, cell infiltration, focal necrosis, multinucleated hepatocytes and prominent nucleoli of hepatocytes were seen in treated rats. At 12 weeks microgranulomas were seen in treated rats. Especially in rats of the 2.4% group at 12 weeks, severe enlargement of hepatocytes, severe enlargement of nuclei and multinucleated hepatocyte were seen, suggesting preneoplastic alteration. Relative kidney weights and serum urea nitrogen levels were increased in treated rats from 1 or 2-12 weeks and at 12 weeks, atrophy of proximal tubules, dilation of tubules, cell infiltration, fibrosis and accumulation of yellow-brown pigment in the proximal tubular cells were seen.

Thiabendazole induces urinary tract toxicity in male ICR mice

Male ICR mice were administered thiabendazole (TBZ) in the diet at concentration of 0 (control), 0.8, 1.2 and 1.6% for 44 weeks. The mortality was 10, 6, 40 or 90% in control, 0.8, 1.2 or 1.6% TBZ group, respectively. In dead mice, the gross findings included the abnormalities of kidney such as atrophy, hydronephrosis or swelling in 2, 67, 95 or 96% of the 0, 0.8, 1.2 or 1.6% TBZ group, respectively. In surviving mice at the end of study, the right kidney weight of treated groups was significantly lower than that of control group. The urinary bladder weight of treated groups was significantly higher than that of control group. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis or urinary bladder and thickening of the bladder wall. Microscopic findings in the kidneys of treated mice included nephrosis, hydronephrosis and hyperplasia of transitional epithelium of renal pelvis and/or papilla. In the urinary bladder, hyperplasia or squamous metaplasia of transitional epithelium were found in treated mice. Administration of TBZ in the diet for 44 weeks results in nephrosis and calculus formation in the renal pelvis and urinary bladder of male ICR mice, and is associated with hyperplasia of transitional epithelium of renal pelvis or urinary bladder.