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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.

Animals

Reproductive and neurobehavioural effects in three-generation toxicity study of piperonyl butoxide administered to mice.

Piperonyl butoxide (PB) was administered continuously to mice from 5 weeks of age in the F0 generation to weaning of the F2 generation. PB was administered in the diet at levels of 0 (control), 0.1, 0.2, 0.4 and 0.8%. Selected reproductive, developmental and behavioural parameters were measured. Litter size and litter weight were reduced in higher-dosed groups, and the body weight of the pups in the lactation period was reduced in dosed pups in each generation. The survival index at postnatal day 21 of the group receiving 0.8% PB was reduced in each generation. The developmental and behavioural parameters in the lactation period were little different from those of the controls, apart from olfactory orientation in the F1 generation. However, in the F2 generation mice, surface righting, cliff avoidance and olfactory orientation were adversely affected in treatment groups. The results suggest that PB had adverse effects on reproductive, developmental and behavioural parameters of mice, with increasing effects in subsequent generations of offspring.

Administration, Oral

Effect of piperonyl butoxide on disposition of di-2-ethylhexyl phthalate by rainbow trout.

1. Piperonyl butoxide in vitro inhibits the oxidation and hydrolysis of di-2-ethylhexyl phthalate, and the hydrolysis of the butyl ester of 2,4-dichloro-phenoxyacetic acid by liver homogenate fractions and serum from rainbow trout. 2. The rates of oxidation and hydrolysis of di-2-ethylhexyl phthalate by liver homogenates from rainbow trout pre-exposed to piperonyl butoxide (1 mg/l) were considerably lower than those by liver homogenates from control trout. 3. Disposition of di-2-ethylhexyl [14C]phthalate in rainbow trout in vivo was modified by pre-exposure to piperonyl butoxide. The piperonyl butoxide-treated trout had lower levels of 14C in bile and higher levels of 14C in blood and muscle than control trout. 4. Muscle of control and piperonyl butoxide-exposed trout showed similar concentrations of mono-2-ethylhexyl phthalate but the concentration of di-2-ethylhexyl phthalate in muscle from piperonyl butoxide-exposed trout was three times the control value.

Animals

Effects of piperonyl butoxide on F1 generation mice.

Piperonyl butoxide (PB), used in Japan as a pesticide synergist and food additive, was administered to mice from 5 weeks of age in the F0 generation to 9 weeks of age in the F1 generation, in the diet at levels of 0 (control), 0.15, 0.30 and 0.60%, and some reproductive, developmental and behavioral parameters were measured. Some parameters of open field activity were reduced in the treatment groups; in particular, ambulation and rearing were significantly reduced in F0 generation male mice and in 3-week-old F1 generation male mice. The weight of the pups was significantly reduced and litter weight tended to be reduced in the treatment groups. Body weight of dosed pups was reduced in the lactation period. Of the developmental parameters, olfactory orientation was significantly reduced as compared to controls. The dose levels of PB in this study, therefore, had an effect on some reproductive, developmental and behavioral parameters in mice.

Animals

Evaluation of three candidate cypermethrin-piperonyl butoxide formulations compared with Scourge against adult Culex quinquefasciatus.

Cypermethrin-piperonyl butoxide formulations (1:1, 1:5, 1:10) were evaluated in a laboratory wind tunnel against colony reared, susceptible adult Culex quinquefasciatus mosquitoes. Scourge (4% resmethrin:12% piperonyl butoxide) was used as the standard for comparison. Based on the LC90 data, the 3 cypermethrin-piperonyl butoxide formulations were 2.6-3.7x more toxic than Scourge 24-h posttreatment.

Animals

Piperonyl butoxide as a tool in aquatic toxicological research with organophosphate insecticides.

Experiments were conducted to determine the effects of piperonyl butoxide, a synthetic methylenedioxyphenyl inhibitor of cytochrome(s) P450, on the toxicity of organophosphate insecticides to three cladoceran test species: Ceriodaphnia dubia. Daphnia magna, and Daphnia pulex. Coadministration of piperonyl butoxide effectively reduced the acute toxicity of four metabolically activated organophosphates (parathion, methyl parathion, diazinon, and malathion) and did not affect the toxicity of three organophosphates not requiring metabolic activation (dichlorvos, chlorfenvinphos, and mevinphos). These results indicate that piperonyl butoxide may be an effective tool in toxicological research focused upon identifying specific compounds responsible for toxicity in complex aqueous mixtures.

Animals

Differences in the effects of piperine and piperonyl butoxide on hepatic drug-metabolizing enzyme system in rats.

An i.p. administration of rats with piperine (100 mg/kg) and piperonyl butoxide (400 mg/kg) produced a significant decrease in hepatic cytochrome P-450, and activities of benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 1 hr after the treatment. Twenty-four hr later, these parameters along with cytochrome b5 and NADPH-cytochrome c reductase remained depressed only in piperine-treated rats. In contrast, piperonyl butoxide caused a significant induction of these parameters with the exception of cytochrome b5 and aminopyrine N-demethylase, which were up by 36 and 33% over their respective controls but not significantly. These results point up that effect of piperine on hepatic mixed-function oxidases is monophasic while that of piperonyl butoxide is biphasic.

Alkaloids

Carcinogenesis bioassay of technical-grade piperonyl butoxide in F344 rats.

The insecticide synergist piperonyl butoxide--alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltoluene--was tested for carcinogenicity in inbred F344 rats in a 2-year study employing doses of 10,000 and 5,000 ppm of the compound administered continuously in the feed. Although a statistically significant dose-related increase in the incidence of lymphoreticular neoplasia was associated with administration of the compound to females, the incidence of that class of neoplasm was higher in control males than in treated males. The finding of statistical significance in one sex is not considered by itself to constitute sufficient evidence of a biologic effect to justify an indictment of carcinogenic action. However, inasmuch as the chief use of this substance is to alter the in vivo metabolism of other chemicals, its possible role as a cocarcinogen should be carefully considered in any risk-benefit evaluation aimed at setting policies regarding its uses.

Animals

Effects of piperonyl butoxide on hydroxylation of 2-acetylaminofluorene in hamster liver.

Single i.p. injection of piperonyl butoxide induces a dose dependent and prolonged inhibition of hamster liver acetylaminofluorene hydroxylation. However, this slight inhibition is the result of a 61% inhibition of acetylaminofluorene-7-hydroxylase activity and a 10 fold stimulation of acetylaminofluorene N-hydroxylase activity. This was confirmed by in vivo experiments. The DNA and RNA binding of acetylaminofluorene-C14 increased 2.1 and 2.4 fold, respectively, 16 hrs after treatment with acetylaminofluorene-C14 in combination with piperonyl butoxide.

2-Acetylaminofluorene

Effects of piperonyl butoxide on dimethylnitrosamine metabolism and toxicity in Swiss mice.

The effects of piperonyl butoxide (PB) on the metabolism and toxicity of dimethylnitrosamine (DMN) in Swiss mice were determined. PB, at doses of 10 and 20 mg/kg, inhibited DMN demethylase 45 min after treatment by 18 and 37%. These inhibitory effects were marked 0.5 hr after PB (640 mg/kg) treatment and reached maximal effects at 2 hr when there was 55% inhibition of enzyme activity. The inhibition by PB continued for 24 hr where enzyme activity was suppressed by 35%. At 48 hr after treatment there was stimulation of enzyme activity. Enzyme kinetic determinations showed no change in Km but Vmax decreased from 129 to 49 mumol CH2O/min-g liver. PB (640 mg/kg) inhibited DMN (500 mg/kg; im) mutagenicity in the host-mediated assay, decreasing the mutant frequency by 42%. Paradoxically, PB (640 mg/kg) had no effect on the alkylation of nucleic acids or proteins in mouse liver, kidney, lung, or spleen. In addition, pretreatment with PB (640 mg/kg) had no effect on the LD50 of DMN.

Alkylation

Potentiation of methylmercury toxicity by piperonyl butoxide.

Methylmercury (MeHg) is an extremely potent neurotoxin about 25% of which is degraded in vivo to inorganic mercury. Piperonyl butoxide (PB) is a widely used pesticidal synergist which inhibits many mammalian detoxification reactions. In a preliminary experiment with the high doses of PB and MeHg, PB induced a 12% decrease in mean survival time and a 20% decrease in mean latency time to neurotoxicity. The weight loss in PB-MeHg group was far greater than the control MeHg group. In a dose response experiment, mean survival times in rats fed 40 ppm MeHg-C1 were 5.75, 5.3, and 5.0 weeks at 0, 0.5, and 1% PB, respectively. By the ninth week 25% of rats fed 20 ppm MeHg-C1 showed neurotoxicity and 63% of the 0.5% PB fed showed neurotoxicity with some mortality. In experiments at 20 ppm MeHg-C1 both PB fed groups weighted considerably less than corresponding controls.

Animals

Effects of piperonyl butoxide on the toxicity and hepatocarcinogenicity of 2-acetylaminofluorene and 4-acetylaminobiphenyl, and their n-hydroxylated derivatives, following administration of newborn mice.

Neonatal ICR/Ha mice were injected subcutaneously with a single dose of 25, 50 and 100 microgram of 4-acetylaminobiphenyl (AAB), N-hydroxy-4-acetylaminobiphenyl (N-OH-AAB), 2-acetylaminofluorene (AAF), or N-hydroxy-2-acetylaminofluorene (N-OH-AAF) alone or together with 2,5% piperonyl butoxide (PB) in tricaprylin, negative control groups were injected with tricaprylin, and positive control groups were injected with 30 microgram of 7,12-dimethylbenz(a)anthracene (DMBA), alone or with PB. PB induced synergistic toxicity in the various groups of mice injected with the nonhydroxylated and hydroxylated amine carcinogens, or with DMBA, as compared with groups injected with carcinogen alone. AAB, N-OH-AAB, AAF, and N-OH-AAF all induced dose-related hepatocarcinogenicity in male, but not female mice, which was not consistently influenced by concomitant administration of PB. DMBA control groups developed pulmonary adenomas and lymphomas in both sexes, and hepatomas in males, whose incidences were not modified by PB.

2-Acetylaminofluorene