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PubMed1985

Toxicological studies of hydroxypropylmethylcellulose acetate succinate--acute toxicity in rats and rabbits, and subchronic and chronic toxicities in rats.

The acute toxicity (in rabbits and rats) and the subchronic and chronic toxicities (in rats) of Hydroxypropylmethylcellulose acetate succinate (HPMCAS), a potentially useful pharmaceutical excipient, were investigated. 1) In the acute toxicity study (single oral dose of 2.5 g/kg), no deaths or behavioral abnormalities were observed. Thus, LD50 is higher than 2.5 g/kg. 2) In the subchronic toxicity study (0.63, 1.25 or 2.5 g/kg daily as a single oral dose in the morning, 6 days per week (not Sunday) for 2 months), no significant behavioral abnormality was observed. There was some decrease in body weight gain in rats of both sexes, but the effect was not statistically significant. 3)In the chronic toxicity study (1.25 or 2.5 g/kg daily as a single oral dose in the morning, 6 days per week (not Sunday) for 6 months), no significant behavioral abnormality was observed. There was some decrease in body weight gain in male rats, but it was not statistically significant. 4)Various biochemical and physiological abnormalities in rats were noted in all groups (including the control groups) in the toxicity studies, but there appeared to be no significant dose-related finding attributable to the administration of HPMCAS.

Administration, Oral↗

PubMed1994

[Single-dose toxicity study and twenty-eight-days intravenously repeated dose toxicity study of desethyl-piperacillin in rats].

Desethyl-piperacillin (desethyl-PIPC) is an active metabolite of PIPC which was newly found in clinical field. We carried out a single intravenous toxicity study at the dosage of 2000 mg/kg, and 28-days intravenous toxi-city study at the daily dosage of 400 mg/kg followed by 28-days recovery study using both sexes of rats. The following results were obtained. In the single dose toxicity study, no deaths occurred in rats injected 2000 mg/kg of desethyl-PIPC, therefore it is presumed that minimal lethal dose of desethyl-PIPC is over 2000 mg/kg in both sexes. As clinical signs, decrease in locomotor activity, deep breath and loose stool were observed. In the patho-logical study, dilatation of cecal lumen was observed macroscopically, but no significant changes were observed histologically. In the repeated dose toxicity study, loose stool, increase in water consumption, dilatation of cecal lumen and increase in its weight were noted. These abnormal findings were considered to be due to antimicrobial activity of desethyl-PIPC. In addition, decrease in the ratio of serum gamma-globulin and increase in the ratio of alpha 1-globulin were observed, but A/G ratio was not affected. After withdrawal of desethyl-PIPC administration, these abnormal findings tended to disappear. As mentioned above, the minimal lethal dose of desethyl-PIPC is over 2000 mg/kg in the single dose toxicity study and abnormal signs were slight in the repeated dose toxicity study at the dosage of 400 mg/kg of desethyl-PIPC for 28 days in rats. It is, therefore, concluded that desethyl-PIPC is a low toxic metabolite of PIPC.

Alpha-Globulins↗

PubMed1981

[Studies of toxicity of hydrocortisone 17-butyrate 21-propionate -5. Chronic toxicity in rats by percutaneous administration (author's transl)].

Chronic toxicity of a new synthetic corticosteroid, hydrocortisone 17-butyrate 21-propionate (HBP), was investigated in rats of both sexes. HBP was percutaneously given to rats with 0.1%, 0.5% cream and ointment at the daily dose level of 150 mg per 100 g body weight for 6 months. For the comparison, the percutaneous toxicity with 0.12% betamethasone 17-valerate (BV) cream and ointment, and 0.1% hydrocortisone 17-butyrate (HB) cream and ointment at the daily dose level of 150 mg per 100 g body weight were studied. Rats receiving HBP showed the dose-dependent changes such as the suppression of body weight gain and food intake, emaciation, decrease in the number of white blood cells and lymphocytes, total protein, increase in the number of red cells, hematocrit, hemoglobin, blood sugar and total cholesterol, regressive changes in adrenal cortex, lymphatic and hematopoietic tissues and skin, and gastric erosion, which have been well known as toxic effects of synthetic corticosteroids. These findings were comparatively high toxic in male, and almost disappeared in rats elapsed recovery time of month after withdrawal of HBP. The toxicities of HBP, BV and HB were qualitatively same. However, the grade of effects of HBP toxicity was similar to that of HB, weaker than of BV.

Administration, Topical↗

PubMed2001

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (3)--One- and three-month repeated oral dose toxicity studies in rats].

One- or three-month repeated oral dose toxicity studies of Cefmatilen hydrochloride hydrate (S-1090) in rats were conducted. Doses were set at 80, 200, 500 and 1250 mg potency/kg/day in the one-month toxicity study, and 100, 300 and 1000 mg potency/kg/day in the three-month toxicity study. Body weights increased favorably and no deaths occurred in all treated groups of both studies. The changes observed in both studies were soft feces, abdominal distention, increased food and water consumption, decreases of urine volume and pH, and a decrease of blood neutrophils in almost all treated groups, reddish-brown feces (due to chelated products of S-1090 and its decomposition products with Fe3+ in the diet) in groups dosed at 300 mg potency/kg or more, and a lower mature granulocyte ratio in the bone marrow in groups dosed at 1000 mg potency/kg or more. In necropsy, cecal enlargement with a large amount of muddy content was observed in all treated groups of both studies. In the three-month toxicity study, elevated drug-metabolizing enzyme activities were noted in the liver of the males in the 1000 mg potency/kg group. These changes were slight except for the cecal enlargement and the rats recovered well with drug withdrawal. Since no toxicologically significant changes were noted in either study, the NOAEL of S-1090 was estimated to be 1250 mg potency/kg/day in the one-month toxicity study and 1000 mg potency/kg/day in the three-month toxicity study.

Administration, Oral↗

PubMed2000

Studies on the toxic interaction between monensin and tiamulin in rats: toxicity and pathology.

The characteristics of the toxic interaction between monensin and tiamulin were investigated in rats. A three-day comparative oral repeated-dose toxicity study was performed in Phase I, when the effects of monensin and tiamulin were studied separately (monensin 10, 30, and 50 mg/kg or tiamulin 40, 120, and 200 mg/kg body weight, respectively). In Phase II, the two compounds were administered simultaneously to study the toxic interaction (monensin 10 mg/kg and tiamulin 40 mg/kg b.w., respectively). Monensin proved to be toxic to rats at doses of 30 and 50 mg/kg. Tiamulin was well tolerated up to the dose of 200 mg/kg. After combined administration, signs of toxicity were seen (including lethality in females). Monensin caused a dose-dependent cardiotoxic effect and vacuolar degeneration of the skeletal muscles in the animals given 50 mg/kg. Both compounds exerted a toxic effect on the liver in high doses. After simultaneous administration of the two compounds, there was a mild effect on the liver (females only), hydropic degeneration of the myocardium and vacuolar degeneration of the skeletal muscles. The alteration seen in the skeletal muscles was more marked than that seen after the administration of 50 mg/kg monensin alone.

Administration, Oral↗

PubMed1975

[Investigations on toxic fractions of swine erysipelas bacteria (erysipelothrix rhusiopathiae). 1. Communication: Toxicity investigation on a phenol water extract in chicken embryos (author's transl)].

The watersoluble fractions (WESTPHAL et al., 1952 a, b) of twelve Erysipelothrix rhusiopathiae strains, which differed in virulence were tested for toxicity for ten day old chick-embryos by the route of i.v. injection. The LD50-values ranged from 108 mug to 0.01 mug toxin dry weight/embryo. The different toxicity of these extracts for chick-embryos was compared with the virulence of the corresponding strains in swine: The extracts of four strains with high virulence were very toxic for chick-embryos (LD50:0,01 mug to 0.207 mug) The extracts of four non-virulent strains were low-, respectively non-toxic (LD50:10.95 mug to 108 mug) The extract of one virulent strain showed an intermediate degree of toxicity (LD50:2.8 mug) In tese nine strains there was a correlation between virulence for swine and the toxicity of the extracts for chick-embryos. But this relation could not be found for three other strains.

Animals↗

PubMed1990

Heavy metal toxicity in a N2-fixing cyanobacterium, Anabaena doliolum: regulation of toxicity by certain environmental factors.

The toxic effects of chromium and tin salts on growth, 14C uptake, heterocyst differentiation, and nitrate reductase, nitrogenase, and glutamine synthetase activities of Anabaena doliolum and their regulation by pH, salinity, extracellular metabolites (spent), and organic acids have been studied. The toxicity of the test metals was lowered at alkaline pH and increased at acidic pH. NaCl at 20 mM was found to decrease metal toxicity. Extracellular metabolites (spent) in a 1:1 ratio (v/v) with fresh culture medium and organic acids were found to reduce metal toxicity. Among the various organic acids studied, humic acid was the most effective in regulating metal toxicity, apparently due to its multiple binding sites for metal cations. This study demonstrated that environmental factors, such as pH, salinity, extracellular metabolites, and organic acids, can mediate the toxicity of heavy metals to A. doliolum in a laboratory microcosm.

Acids↗

PubMed1989

Changes in serum thyroid hormone and thyroglobulin levels after surgical treatments for toxic and non-toxic goiter.

We assessed changes in serum total tri-iodothyronine (TT3), total thyroxine (TT4), free thyroxine (FT4), reverse tri-iodothyronine (rT3), thyroid stimulating hormone (TSH), and serum thyroglobulin (hTg) levels in 20 patients with toxic diffuse goiter who received subtotal thyroidectomy after metabolic control with antithyroid drugs and 22 patients with non-toxic solitary nodular goiter who received lobectomy only. In the first 2 days postoperatively the toxic diffuse goiter group had approximately a 50% decrease in the mean serum TT3 concentration, and a 28% decrease in the mean serum TT4 concentration. In the same period, the non-toxic nodular goiter group had approximately a 30% decrease in mean serum TT3 concentration, and a 15% decrease in mean serum TT4 concentration. The toxic diffuse goiter group and the non-toxic nodular goiter group each had transient elevations of the mean serum rT3 concentration, amounting to 34% and 48% respectively. Neither group had any change in the mean serum FT4 level, while both showed a several-fold elevation of serum hTg. At the 6th week postoperatively in both groups, the mean serum TT3 level had returned to the preoperative value, the mean serum TT4, rT3 and hTg levels were significantly lower than preoperative values, and the mean serum FT4 level remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1984

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-6. Toxicity of metabolites of miocamycin: subacute toxicity of Mb2 in rats.

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. At previous study, the acute and subacute toxicity of Mb1 and acute toxicity of Mb2 were performed that those metabolites did not exhibit any lethal toxicity even at the maximum physically applicable dose. The object of this study was to examine subacute toxicity in male and female rats after repeated p.o. administration of Mb2 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is, therefore, concluded that Mb2 exerted no toxic effects in this subacute toxicity.

Animals↗

PubMed1984

[Studies on the pharmacological bases of fetal toxicity of drugs (VII). Enhancement effect of bacterial pyrogen on the fetal toxicity of salicylic acid].

We reported previously that the acute and fetal toxicities of aspirin (ASA) were enhanced by bacterial endotoxin (LPS). In order to clarify the mechanism of the enhancement by LPS, the effects of LPS on the toxicities of salicylic acid (SA), the main metabolite of ASA, were investigated in rats. The following results were obtained: 1) The acute toxicity of SA was significantly potentiated by LPS in male rats. The LD50 of SA with LPS was about one third of that of SA alone. 2) The increase of maternal body weight was inhibited significantly after administration of SA (383 mg/kg, p.o.) with LPS (20 micrograms/kg, i.v.), but not after administration of SA alone. 3) The fetal toxicity of SA including fetal death, resorption, growth retardation and skeletal variations was slightly observed in the dam receiving a single dose of SA on the 15th day of pregnancy, but it was markedly increased by LPS (20 micrograms/kg, i.v.). 4) The half-life period of SA in plasma was increased significantly by the co-administration of LPS in male rats after administration of ASA or SA. All of these phenomena in the rats given SA closely resembled the phenomena previously reported in the rats given ASA. These results suggest that SA might play a main role in the acute and fetal toxicities of ASA, and one of the mechanism of the enhancement effect by LPS on ASA-induced fetal toxicity might be related to the increase of SA concentration in the fetus.

Animals↗

PubMed1982

[Toxicological study of amikacin following intravenous drip infusion. 1. Acute toxicity in rats, rabbits and dogs, and subacute toxicity in rabbits].

Acute toxicity of amikacin sulfate (AMK) was studied in rats, rabbits and dogs following 1 hour drip intravenous infusion (1 hour d.i.v.), and compared with those after intravenous injection (i.v.). Subacute toxicity was studied in rabbits following 1 hour d.i.v. of AMK at doses of 400, 200, 100 and 25 mg/kg for 36 days. Acute toxicity: Acute toxicity of AMK by 1 hour d.i.v. was extremely diminished as compared with that by i.v. judging from LD50, the toxicity was approximately 1/6 in rats and approximately 1/2 in rabbits and dogs. No difference was observed between males and females. Subacute toxicity: 1. No death was found in all rabbits. 2. At the doses of 25 mg/kg and 100 mg/kg, there were no significant changes or signs recognized as toxicological effects of AMK. 3. At the dose of 200 mg/kg, very slight renal damages were observed histopathologically in all the 5 rabbits. 4. At the dose of 400 mg/kg, slight or moderate renal damages were observed in all the rabbits. Those were mainly dilatation of renal proximal tubules, hydropic swelling and degeneration of renal proximal tubular epithelium. No significant impairment effect of AMK was found in heart, lung, liver and other organs. 5. From these results, it is considered that the maximum no effect dose from a view point of safety is about 100 mg/kg in this study.

Amikacin↗

PubMed1981

Drug metabolism and fetal toxicity: changes in fetal toxicity of aminopyrine by variation of drug metabolizing enzyme activity in mice.

The influence of hepatic drug-metabolizing enzyme activity on the fetal toxicity of aminopyrine (AM, 200 mg/kg s.c.) was examined in mice. We used the hepatic enzyme inhibitors metyrapon (40 mg/kg s.c.) and SKF-525-A (20 mg/kg s.c.), simultaneously administered with AM on days 7-9 of pregnancy. As hepatic enzyme-inducers we used 3-methyl-cholanthrene (3-MC, 2 mg/kg s.c.) and CoCl2 (40 mg/kg s.c.) were administered on days 5-7 of pregnancy followed by AM on days 7-9. The fetal toxicity of the enzyme inducers and inhibitors was not significantly different from controls. Fetal toxicity of AM (57.1%) was slightly increased and decreased by metyrapon (26.8%). Pretreatment with CoCl2 markedly increased the fetal toxicity of AM (88.6%), particularly by an increase in new abnormalities but the decrease in AM toxicity by SKF-525-A was unclear. The induction of AM N-demethylase and aniline hydroxylase activity was observed in liver microsomes from pregnant mice treated with phenobarbital and AM. From these findings, it appears that the fetal toxicity of AM was altered according to induced changes in maternal hepatic drug metabolizing enzyme activities.

Aminopyrine↗

PubMed1996

Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine.

PURPOSE: It is well known that acute exposure to high concentrations of glutamate is toxic to central mammalian neurons. However, the effect of a chronic, minor elevation over endogenous glutamate levels has not been explored. The authors have suggested that such chronic exposure may play a role in glaucomatous neuronal loss. In the current study, they sought to explore whether a chronic, low-dose elevation in vitreal glutamate was toxic to retinal ganglion cells and whether this toxicity could be prevented with memantine, a glutamate antagonist. METHODS: Rats were injected serially and intravitreally with glutamate to induce chronic elevations in glutamate concentration. A second group of rats was treated with intraperitoneal memantine and glutamate. Control groups received vehicle injection with or without concurrent memantine therapy. After 3 months, the animals were killed, and ganglion cell survival was evaluated. RESULTS: Intravitreal injections raised the intravitreal glutamate levels from an endogenous range of 5 to 12 microM glutamate to 26 to 34 microM. This chronic glutamate elevation killed 42% of the retinal ganglion cells after 3 months. Memantine treatment alone had no effect on ganglion cell survival. However, when memantine was given concurrently with low-dose glutamate, memantine was partially protective against glutamate toxicity. CONCLUSIONS: These data suggest that minor elevations in glutamate concentration can be toxic to ganglion cells if this elevation is maintained for 3 months. Furthermore, memantine is efficacious at protecting ganglion cells from chronic low-dose glutamate toxicity.

Animals↗

PubMed2005

A review of interspecies toxicity extrapolation in birds and mammals and a proposal for long-term toxicity data.

Terrestrial risk assessments for pesticide exposure is generally based on a limited number of toxicity data. The protection target for these assessments requires an extrapolation from species for which toxicity data are available to other species with unknown sensitivity to be able to protect these as well. Our ability to extrapolate toxicity endpoints between species is a major source of uncertainty in risk assessment. Most analyses of interspecies extrapolation in avian risk assessments have dealt with acute toxicity data. It was suggested that, in the absence of a strong rationale to the contrary, we should assume that reproductive data is at least as variable as acute data and that strategies developed for acute data could be applied to long term toxicity data as well. Considering only the two main bird test species for which reproduction data are available (Mallard and Northern Bobwhite), a comparison of the interspecies standard deviation for both acute and reproduction data suggests that the two are equally variable. Analysis of a very limited data set also suggests that this conclusion holds regardless of which endpoint is triggered in the reproduction study. However, the relative sensitivity of the two species established from acute test data appears to be reversed in the case of reproductive data. In addition there seems to be no reason to believe that bodyweight is a factor in helping birds cope with the rigors of chronic dosing, which is in contrast with the acute dosing situation. This suggests that the best extrapolation technique for reproduction test data should be independent of phylogeny and independent of bodyweight scaling. The simplest such method is the one that was proposed by Luttik and Aldenberg (1995, 1997) for both birds and mammals.

Animals↗

PubMed2002

Cyst-based toxicity tests XIV--application of the ostracod solid-phase microbiotest for toxicity monitoring of river sediments in Flanders (Belgium).

In view of the need for rapid and low-cost solid-phase assays for contaminated sediments, a new 6-day "culture/maintenance-free" microbiotest has been developed with the freshwater ostracod crustacean Heterocypris incongruens at the Laboratory for Biological Research in Aquatic Pollution at the Ghent University in Belgium. The sensitivity of the Ostracodtoxkit F has been compared with that of the 10-day sediment contact test with the amphipod crustacean Hyalella azteca and the two pore water assays (on the anostracan crustacean Thamnocephalus platyurus and the microalgae Raphidocelis subcapitata) selected by the Flemish Environmental Agency for initial hazard assessment of contaminated sediments. The exercise was performed on 26 sediments collected at random from various rivers of the Flemish hydrographic basin in Belgium. The toxicity data ranged from nontoxic to highly toxic for the solid-phase assays and showed that the mortality of the two test biota varied from "nearly identical" to "substantially different," depending on the sediment. The correlation coefficient for the data pairs was weakly positive (r = 0.60), mainly because of 5 samples for which a low mortality had been noted with the ostracod versus a much higher mortality for the amphipod. However, for 4 out of the 5 samples of concern, a substantial growth inhibition was recorded for H. incongruens, showing that this assay eventually performed as did the amphipod test in detecting the toxic character of the sediments. The comparison of toxicity data of the two solid-phase assays with those of the two pore water tests again confirmed that both types of bioassay provided complementary (nonredundant) information. On the basis of its various advantages (independence of stock culturing/maintenance, user-friendliness, precision, and time and cost savings) the new ostracod microbiotest appears to be a promising tool for routine toxicity assessment of contaminated sediments.

Amphipoda↗

PubMed2000

Priority assessment of toxic substances in life cycle assessment. Part II: assessing parameter uncertainty and human variability in the calculation of toxicity potentials.

Toxicity potentials are standard values used in life cycle assessment (LCA) to enable a comparison of toxic impacts between substances. This paper presents the results of an uncertainty assessment of toxicity potentials that were calculated with the global nested multi-media fate, exposure and effects model USES-LCA. The variance in toxicity potentials resulting from input parameter uncertainties and human variability was quantified by means of Monte Carlo analysis with Latin Hypercube sampling (LHS). For Atrazine, 2,3,7,8-TCDD and Lead, variation, expressed by the ratio of the 97.5%-ile and the 2.5%-ile, ranges from about 1.5 to 6 orders of magnitude. The major part of this variation originates from a limited set of substance-specific input parameters, i.e. parameters that describe transport mechanisms, substance degradation, indirect exposure routes and no-effect concentrations. Considerable correlations were found between the toxicity potentials of one substance, in particular within one impact category. The uncertainties and correlations reported in the present study may have a significant impact on the outcome of LCA case studies.

Environmental Exposure↗

PubMed2003

Is the OECD acute worm toxicity test environmentally relevant? The effect of mineral form on calculated lead toxicity.

In a series of experiments the toxicity of lead to worms in soil was determined following the draft OECD earthworm reproduction toxicity protocol except that lead was added as solid lead nitrate, carbonate and sulphide rather than as lead nitrate solution as would normally be the case. The compounds were added to the test soil to give lead concentrations of 625-12 500 microg Pb g(-1) of soil. Calculated toxicities of the lead decreased in the order nitrate> carbonate> sulphide, the same order as the decrease in the solubility of the metal compounds used. The 7-day LC50 (lethal concentration when 50% of the population is killed) for the nitrate was 5321+/-275 microg Pb g(-1) of soil and this did not change with time. The LC50 values for carbonate and sulphide could not be determined at the concentration ranges used. The only parameter sensitive enough to distinguish the toxicities of the three compounds was cocoon (egg) production. The EC50s for cocoon production (the concentration to produce a 50% reduction in cocoon production) were 993, 8604 and 10246 pg Pb g(-1) of soil for lead nitrate, carbonate and sulphide, respectively. Standard toxicity tests need to take into account the form in which the contaminant is present in the soil to be of environmental relevance.

Animals↗

PubMed2000

Structure-toxicity relationships for aliphatic compounds encompassing a variety of mechanisms of toxic action to Vibrio fischeri.

QSARs based upon the logarithm of the octanol-water partition coefficient, log P, and energy of the lowest unoccupied molecular orbital, ELUMO were developed to model the toxicity of aliphatic compounds to the marine bacterium Vibrio fischeri. Statistically robust, hydrophobic-dependent QSARs were found for chloroalcohols and haloacetonitriles. Modelling of the toxicity of the haloesters and the diones required the use of terms to describe both hydrophobicity and electrophilicity. The differences in intercepts, slopes, and fit of these models suggest different electrophilic mechanisms occur between classes, as well as within the diones and haloesters. In order to model globally the toxicity of aliphatic compounds to V. fischeri, all the data determined in this study were combined with those determined previously for alkanones, alkanals, and alkenals. A highly predictive two-parameter QSAR [pT15 = 0.760(log P) - 0.625(ELUMO) - 0.466; n = 63, s = 0.462, r2 = 0.846, F = 171, Pr > F = 0.0001] was developed for the combined data that models across classes and is independent of mechanisms of action. The toxicity of these compounds to V. fischeri compares well to the toxicity (50% population growth inhibition) to the ciliate Tetrahymena pyriformis (r2 = 0.850).

Bacterial Toxins↗