Acute toxicity of aristolochic acid in rodents

The acute toxic effects of aristolochic acid (AA) were tested in rats and mice of both sexes. Oral or intravenous administration in high doses was followed by death from acute renal failure within 15 days. Histologically, the predominant features were severe necrosis affecting the renal tubules, atrophy of the lymphatic organs and large areas of superficial ulceration in the forestomach, followed by hyperplasia and hyperkeratosis of the squamous epithelium. The LD₅₀ ranged from 56 to 203 mg/kg orally or 38 to 83 mg/kg intravenously, depending on species and sex.Dedicated to Dr. Rolf Madaus on the occasion of his 65th birthday.     

Structure-activity relationships of some pyrethroids in rats

The intravenous toxicity to the rat of 36 pyrethroids has been examined. With two exceptions they cause either (1) T-syndrome, consisting of aggressive sparring, sensitivity to external stimuli, fine progressing to gross whole body tremor and prostration or (2) CS-syndrome, consisting of pawing and burrowing behaviour, salivation, coarse tremor, progressing to sinuous writhing (choreoathetosis) and clonic seizures. The two exceptions presented a TS-syndrome with salivation associated with the T-syndrome. No clearcut relationship between chemical structure and symptoms of poisoning has emerged through some generalisations are discussed.     

Acute toxicity of pyridostigmine in rats: histological findings

To assess the morphological changes due to pyridostigmine (Pyr), sublethal doses of Pyr (20 and 40 mg/ kg body weight) were given to adult rats through a gastric tube. Within 24 h, acute focal necroses, leukocytic infiltrates and marked changes in the motor endplates appeared in the skeletal muscle. The changes were more evident in the diaphragm than in the quadriceps muscle. The acetylcholinesterase activity in the whole blood and in the erythrocytes was reduced to considerably less than onehalf of the normal value.The histological changes induced by Pyr have not been reported to date, but are similar to those observed in experimental poisoning with other anticholinesterase agents such as carbamates and organophosphates.Abbrevations Pyr Pyridostigimine - ACh Acetylcholine - AChE Acetylcholinesterase     

Sexual behaviour of adult rats after a single neonatal injection of reserpine

To investigate whether reserpine given in the critical period of sexual differentiation of the rat brain affects adult sexual behaviour, female and male rats were given a single injection of reserpine on the fourth day after birth, and their sexual behaviour was tested at maturity. In the 11 consecutive daily tests for spontaneous sexual behaviour the reserpine treated female animals showed fewer regular behavioural and vaginal oestrous cycles than the control animals. 19 % of the reserpinized and none of the control animals had prolonged oestrous behaviour without a coincident prolonged vaginal cycle. The reseptivity quotients of the reserpine treated animals were reduced. In the tests for hormone induced sexual behaviour after ovariectomy no statistically significant differences between the number of animals responding or between the receptivity quotients occurred. The tests for spontaneous sexual behaviour in males showed that the reserpinized animals needed fewer intromissions to ejaculate than the controls. The significance of these findings is discussed.     

硝酸羟胺急性、亚慢性染毒大鼠毒作用靶器官的研究

目的研究硝酸羟胺(hydroxylammonium nitrate,HAN)的急性毒性及亚慢性染毒大鼠后主要毒作用的靶器官。方法急性毒性实验中经腹腔对大鼠进行单次染毒,观察动物中毒症状,计算HAN的LD50和95%的可信限;亚慢性毒性实验中,分别以HAN 71、42、8 mg/kg不同剂量和生理盐水经腹腔染毒动物,连续染毒13周后脱颈椎处死3/4动物,剩余1/4动物停止染毒再饲养4周后同法处死,观察大鼠中毒症状和脏器的组织病理学改变,探讨HAN主要毒作用靶器官。结果HAN腹腔染毒大鼠的LD50为139.3 mg/kg,95%可信限为132.3~146.7 mg/kg。HAN亚慢性染毒后,动物体重无明显变化,各染毒组动物脾脏脏器系数明显高于对照组(P<0.05);组织病理学检查表明,HAN可引起含铁血黄素在体内的大量沉积,主要位于肝、脾和肾内,对组织脏器的损伤主要以氧化性损伤为主,主要靶器官为肺、肝、脾和肾。结论HAN属于中等毒性物质,长期接触对机体有一定的毒性作用。     

Toxicological assessment of combined lead and cadmium: Acute and sub-chronic toxicity study in rats

The exposure to chemical mixtures is a common and important determinant of toxicity and receives concern for their introduction by inhalation and ingestion. However, few in vivo mixture studies have been conducted to understand the health effects of chemical mixtures compared with single chemicals. In this study, the acute and 90 day sub-chronic toxicity tests of combined Pb and Cd were conducted. In the acute toxicity test, the LD₅₀ value of Pb(NO₃)₂ and CdCl₂ mixture by the oral route was 2696.54 mg/kg by Bliss method. The sub-chronic treatment revealed that the low-dose combination of Pb and Cd exposures can significantly change the physiological and biochemical parameters of the blood of Sprague–Dawley (SD) rats with dose–response relationship and causes microcytic hypochromic anemia and the damages of liver and kidney of the SD rats to various degrees. Histopathological exams showed that the target organs of Pb and Cd were testicle, liver, and kidneys. These observations suggest that Pb and Cd are practically additive-toxic for the SD rats in oral acute toxicity studies. The lowest observed adverse-effect level in rats may be lower than a dose of 29.96 mg/(kg bw day) when administered orally for 90 consecutive days.     

Acute and sub-chronic toxicity studies of honokiol microemulsion

The purpose of this study was to investigate the acute and sub-chronic toxicity of honokiol microemulsion. In the acute toxicity tests, the mice were intravenously injected graded doses of honokiol microemulsion and were observed for toxic symptoms and mortality daily for 14 days. In the sub-chronic toxicity study, rats were injected honokiol microemulsion at doses of 100, 500, 2500 μg/kg body weight (BW) for 30 days. After 30 days treatment and 14 days recovery, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity tests, the estimated median lethal dosage (LD₅₀) was 50.5 mg/kg body weight in mice. In the sub-chronic toxicity tests, the non-toxic reaction dose was 500 μg/kg body weight. In each treatment group, degeneration or/and necrosis in vascular endothelial cells and structure change of vessel wall can be observed in the injection site (cauda vein) of a few animals while there were no changes in the vessels of other organs. The overall findings of this study indicate that the honokiol microemulsion is non-toxic up to 500 μg/kg body weight, and it has irritation to the vascular of the injection site which should be paid attention to in clinical medication.     

The increase of cardiac beta 1-subtype of beta-adrenergic receptors in adult rats following neonatal 6-hydroxydopa treatment

An analysis of Hofstee plots of specific [3H]dihydroalprenolol ([3H]DHA) binding in the presence of various concentrations of practolol showed that KD and Bmax in beta 1-subtype adrenoceptors were 19.2-fold lower and 2.76-fold higher than those in beta 2-subtype in adult rat hearts, respectively. Neonatal treatment with 6-hydroxydopa produced a significant increase only in Bmax in beta 1-adrenoceptors without changing Bmax and KD in beta 2-receptors. "Up' regulation in the density of beta 2-type of adrenoceptors seems to be caused by the 6-hydroxydopa-induced sympathetic lesion.     

Acute and sub-chronic toxicity studies of the extract of Thunberg Fritillary Bulb

The aim of this study was to investigate the acute and sub-chronic toxicity of extract of Thunberg Fritillary Bulb. For the acute toxicity tests, graded doses of the extract were administered orally to mice. The animals were observed for toxic symptoms and mortality daily for 14 days. In the sub-chronic toxicity study, rats were orally administered the extract at doses of 1 and 3 mg/kg body weight (BW) for 26 weeks. After 26 weeks, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity tests, the estimated median lethal dosage (LD₅₀) was 52.2 mg/kg body weight in the mice. In the sub-chronic toxicity tests, a dose of 1 mg/kg body weight presented no toxicity. Above the 1 mg/kg dose, the main adverse signs observed in male rats were body or head tremor and spontaneous motor activity reduction. There were no other significant changes observed in hematology, blood biochemistry, organ weight and organ histology. The overall findings of this study indicate that the extract of Thunberg Fritillary Bulb is non-toxic up to 1 mg/kg body weight, which can be considered a safe application dose.     

Acute toxicity evaluation of a thiazolo arene ruthenium (II) complex in rats

Recently, a series of thiazolo arene ruthenium complexes were found to be highly cytotoxic in vitro, on both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. The most active compound of the series, [(η⁶-p-cymene)Ru(L)Cl]Cl (L = 1-(2-(2-(3-chlorobenzylidene)hydrazinyl)-4-methylthiazol-5-yl)ethanone), was selected for an in vivo study in order to assess its safety profile.The ruthenium complex was administered to female Crl:WI rats orally, by gastric intubation and intraperitoneal injection. The hematological parameters and the histopathological changes in liver, kidneys, spleen and brain were investigated after a 14-days treatment. The substance was very well tolerated orally, with a LD₅₀ value of over 2000 mg/kg body weight. Symptoms were observed only in the first day after intraperitoneal administration of the highest dose, with a LD₅₀ value between 300 and 2000 mg/kg bw. The hematological profile was not modified at any of the tested doses, after both oral and intraperitoneal acute administration. Structural modifications (moderate lymphocytolysis) were identified only in the spleen at the highest tested dose. In conclusion, the thiazolo arene ruthenium complex was very well tolerated orally and had a low acute toxicity after intraperitoneal administration in Crl:WI rats The results justify further investigation to determine the in vivo therapeutic potential of this promising ruthenium complex.     

Synthesis, acute toxicity, and analgesic activity of new derivatives of pyrrole

Ten pyrrole derivatives (including six new compounds) were synthesized and evaluated as potential platform for analgesic agents' development. Acute intraperitoneal toxicity and analgesic activity studies (acetic acid writhing test) were performed on mice with acetylsalicylic acid used as a reference substance. Products 3c, 3d, 3e, and 3h exhibited a dose-dependent activity demonstrating 1.5 to 2.5-fold better protections than the reference. The most prospective compounds comprised salicylic acid moieties, whose 4-substituted derivatives were related to lower acute toxicity and considerable activity. 4-[3-(Ethoxycarbonyl)-2-methyl-5-(3,4-dimethoxy-phenyl)-1H-pyrrol-1-yl]-2-hydroxy-benzoic acid 3c was pointed out as the most prospective substance due to its lower acute toxicity (378 mg/kg body weight, intraperitoneally) and highest analgesic activity (up to 89.3% protection) in a dose range of 1/10 to 1/40 parts of LD(50).     

Acute toxicity of pinnatoxins E, F and G to mice

The acute toxicities to mice of pinnatoxins E, F and G, members of the cyclic imine group of phycotoxins, by intraperitoneal injection and/or oral administration, have been determined. These substances were all very toxic by intraperitoneal injection, with LD₅₀ values between 12.7 and 57 μg/kg. Pinnatoxin E was much less toxic by oral administration than by intraperitoneal injection, but this was not the case for pinnatoxin F. The median lethal doses of the latter substance by gavage and by voluntary intake were only 2 and 4 times higher than that by injection. The high oral toxicity of pinnatoxin F raises concerns as to the possibility of adverse effects of this substance in shellfish consumers, although it should be noted that no toxic effects in humans have been recorded with pinnatoxins or with any other compound of the cyclic imine group.     

皖南蝮蛇毒蛋白C激活物的急性毒性作用的研究

目的:探讨蛇毒蛋白C激活物(protein Cactivator,PCA)对大、小鼠的急性毒理反应。方法:大鼠采用上下剂量增减法,小鼠采用半数致死量法,观察实验动物症状、体征、死亡时间和累积死亡率。结果:PCA尾静脉注射大鼠(剂量17.5～175mg/kg)、小鼠(剂量为6.25～11mg/kg)的中毒表现为不同程度的口鼻泡沫状出血、呼吸困难、心率加快、走路不稳、蜷缩、昏厥性抽搐;大、小鼠尾静脉注射PCA的LD50及其95%可信限分别为29.57(17.5～55)mg/kg和8.05(7.55～8.54)mg/kg;大体解剖可见双肺有片块状出血,病理镜检显示出血主要累及肺泡、支气管等。其他器官未见明显异常。结论:皖南蝮蛇毒PCA的毒性主要是抗凝过度导致的出血,肺出血引起的急性呼吸衰竭是实验动物死亡主要原因。     

Acute toxicity of high concentrations of carbon dioxide in rats

Subterranean storage of carbon dioxide (CO₂) has been proposed to diminish atmospheric increases of this greenhouse gas. To contribute to risk assessment of accidental release associated with handling, transport and storage, rats were exposed to high concentrations (targets 40, 43 and 50 volume %) of CO₂. The oxygen concentrations dropped as a result, but were not supplemented. For each concentration, pairs of animals were exposed for different exposure durations to derive an exposure concentration–duration relation in which mortality is described as a function of Cⁿ × t (probit relation). A very high “n” value for the probit function could be derived from the data obtained at 40% and 43% CO₂, which indicates that for exposure durations longer than 30 min the LC50 decreases hardly with increasing exposure duration. Below 30 min the LC50 seemed to increase with decreasing exposure durations. The variability in the data of 43% and 50% CO₂, however, did not allow to derive a meaningful value of “n”.     

Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids

Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of the present study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL(50)) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Our studies suggest that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.     

Acute oral toxicity of nickel compounds

Acute oral toxicity studies were conducted on samples of nine unique nickel compounds and two complex materials to comply with the data and classification requirements of the new Registration, Evaluation, and Authorization of Chemicals Regulation (REACH) in Europe. The samples tested in this study confirmed the overall low oral toxicity of nickel substances and demonstrated a wide range of LD₅₀ values extending from 310 to >11,000 mg/kg. This variation highlights the differences in toxicological properties between various forms of nickel and underscores the importance of Ni(II) ion bioavailability in determining toxicity. The relative acute oral toxicity of the various nickel substances was found to be: nickel fluoride, nickel sulfate, nickel chloride, nickel acetate > nickel sulfamate > nickel hydroxycarbonate > nickel dihydroxide ?$?$ nickel subsulfide, nickel oxides, nickel ash, nickel mattes. Based on these data, four nickel compounds would receive a Category 4 acute toxicity classification according to the European Regulation on Classification, Labelling and Packaging of Chemical Substances and Mixtures (CLP), while the rest of the nickel substances tested fit the criterion for no classification. These data also provided the in vivo verification needed to perform read-across for additional oral toxicity endpoints and nickel substances.     

Prenatal toxicity of acyclovir in rats

Pregnant rats were treated during organogenesis with s.c. injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown-rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crownrump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 we found a similar but slightly more pronounced outcome. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively we measured maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 M). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (± SD) of 60.3±14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6±16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. We conclude that acyclovir, at doses leading to plasma concentrations well above the therapeutic level in the dam, interferes with the embryonic development in the rat. Acyclovir induces typical gross structural abnormalities which have been first observed using a whole embryo culture system.     

Acute inhalation toxicity of eugenol in rats

The acute toxicity of inhaled eugenol was assessed by exposure of three groups of five male and five female rats to a submicron aerosol of eugenol for 4 h followed by a 14-day observation period. A fourth group, also of five male and five female rats and exposed to air only under similar conditions, served as a control group for comparison. The three concentrations of eugenol to which the different groups were exposed were 2.58, 1.37 and 0.77 mg/l. The mass median aerodynamic diameters and geometric standard deviations of the aerosols were, respectively, 0.82 m (g 2.26), 0.88 m (g 2.05) and 0.9 m (g 1.87). Clinical signs observed during exposure consisted principally of moderately increased salivation and restlessness (indicative of irritation) and abnormal breathing patterns. The signs were graded, being less marked in animals exposed to the lower concentrations of eugenol. All three groups, exposed to high, medium and low levels of eugenol, lost weight overnight following exposure. Associated with the weight loss were marked reductions in food and water intake. The responses appeared to be largely independent of the concentration of eugenol inhaled, although there was some evidence of a graded effect on water intake. There was rapid recovery, with food and water consumption data comparable with control values throughout most of the remainder of the 14-day observation period. Also, by the end of the observation period, group mean body weights were comparable. Upon sacrifice and macroscopic examination of the animals, abnormalities were detected in the lungs only of a few animals: 3/10 control, 2/10 eugenol 2.58 mg/l, and 2/10 eugenol 0.77 mg/l. These consisted of dark red/red (raised) areas up to 4×4 mm. Such abnormalities are not uncommon in the lungs of laboratory maintained rats and their presence with equal incidence in control animals suggests that they are unlikely to be related to inhalation of eugenol. Lung weight to body weight ratio values for all groups were similar, providing no evidence of any persistent effect of eugenol on the lungs of the rats. Similarly, histopathological examination of the lung failed to reveal any treatment-related changes. A few incidental lesions present were considered spontaneous in origin and therefore of no toxicological importance.     

Acute and 90-day subchronic toxicity studies of Silk peptide E5K6, in Sprague-Dawley rats

Acute and 90-day subchronic oral toxicity studies of Silk peptide E5K6 were performed in Sprague-Dawley rats. In the acute toxicity study, Silk peptide E5K6 was administered orally to male and female rats at a single dose of 2000 and 5000 mg/kg. Mortality, clinical signs and body weight changes were monitored for 14 days. There were no treatment-related changes in these parameters. Therefore, the Approximate Lethal Dose (ALD) of Silk peptide E5K6 in male and female rats is higher than 5000 mg/kg. In the subchronic toxicity study, Silk peptide E5K6 was administered orally to male and female rats for 90 days at a single dose of 500, 1000, and 2000 mg/kg. There were no toxicologically significant changes in clinical signs, body weight, food and water consumptions, ophthalmoscopic examination, urinalysis, hematological and serum biochemical examinations, necropsy findings, organ weights and histopathological examination of all of the animals treated with Silk peptide E5K6. These results suggest that the oral No Observed Adverse-Effect Level (NOAEL) of Silk peptide E5K6 is greater than 2000 mg/kg/day in both sexes and the target organs were not established.     

In vitro covalent binding of the pyrethroids cismethrin,cypermethrin and deltamethrin to rat liver homogenate and microsomes

Phenobarbital-induced rat liver homogenate and microsomes were used to study covalent binding of l4C-labelled (at the alcohol moiety) cismethrin, ¹⁴C-labelled (at the alcohol and acid moieties) cypermethrin, and ¹⁴C-labelled (at the alcohol and acid moieties) deltamethrin. Covalent binding was dependent on pyrethroid concentration. With liver homogenate, inhibition of esterases by tetraethylpyrophosphate and of mitochondrial respiration by rotenone or potassium cyanide only slightly altered the covalent binding level. With microsomes, inhibition of cytochrome P-450 and mixed function oxidases by carbon monoxide and piperonyl butoxide reduced the covalent binding so far as to be nearly absent. Eighty percent inhibition of epoxide hydrolase decreased the covalent binding by 50%. The comparison of data between alcohol and acid labelling of the same pyrethroid suggested that, in vitro, the whole molecule is bound to proteins and that hydrolysis can occur afterwards. The experiments stress the role of cytochrome P-450-dependent monoxygenases in the covalent binding process.