The acute intraperitoneal toxicity of cypermethrin

This study determined the effects of acute cypermethrin toxicity in the rat and its dose-response characteristics The intraperitoneal LD50 of cypermethrin from the study was 44.0 mg/kg body weight. The symptoms of toxicity were muscular weakness, swaying gait and respiratory distress; pallor and prostration occurred at higher doses and convulsions preceded death, apparently due to respiratory failure.     

Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dogs

Because information regarding efficacious treatment of acute isoniazid (INH) toxicity is incomplete and controversial, diazepam and pyridoxine were investigated as iv antidotes in rats and dogs following administration of po lethal doses of INH. There is a marked species variation in the lethality of INH; the lowest consistently lethal dose is 1500 mg/kg for rats and 75 mg/kg for dogs. Of the two species, the dog more closely approximates man's sensitivity to the lethal effect of INH overdose (80–150 mg/kg). Species variation was also observed in the effects of the antidotes. Diazepam exerted dose-related protection against convulsions in rats; paradoxically, survival was increased by the lowest dose (1 mg/kg) but not by higher doses. In dogs, however, diazepam failed to prevent convulsions but provided dose-related protection against death. Pyridoxine, in rats, did not protect against INH toxicity, but in dogs it showed dose-related effectiveness against convulsions, and all doses (75–300 mg/kg) prevented lethality. Significantly, the highest dose of pyridoxine tested in rats (750 mg/kg) was substantially below the optimal pyridoxine-to-INH antidotal ratio recommended for man (a dose that at least equals the amount of INH ingested), but that dose of pyridoxine would be larger than its LD50 for rats. Combined administration of diazepam with pyridoxine protected against convulsions and death in rats and dogs. Used concurrently, the two antidotes are clearly synergistic for controlling the manifestations of experimental INH overdose. These results have important implications for the management of acute INH intoxication in man.     

Acute toxicity of propoxyphene salts

The acute toxicity of oral and parenteral doses of propoxyphene HCl was studied in laboratory animals. Large iv, im, or ip doses of propoxyphene HCl produced clonic and tonic convulsions in mice, rats, and dogs. Death from oral doses of propoxyphene HCl was preceded by convulsions in dogs but not in rodents or rabbits. Other effects included hypoactivity and body rigidity in rodents, and salivation, ataxia, and weakness in dogs. Animals given lethal doses of propoxyphene showed profound respiratory depression, which was judged to be the primary cause of death. Respective LD50 values for propoxyphene HCl in the mouse, rat, and dog were 28, 15, and 29 mg/kg iv and 282, 230, and 100 mg/kg po.     

Toxicity Studies with Fluindarol, 2-[p-(trifluoromethyl)phenyl]1, 3-indandione,an Agent with Anticoagulant Properties (BS 7616 D)

The phenylindandione derivative fluindarol was subjected to a toxicological investigation in view of its possible use as an anticoagulant in man. The acute oral LD50 in rats and rabbits was 198 and 123 mg/kg, respectively. The acute intraperitoneal LD50 in the rat was 125 mg/kg. Dogs survived single oral doses of up to 2810 mg/kg; if the drug was given for four consecutive days, an oral LD50 of 118 mg/kg was obtained. In a four-week experiment in the rat, doses ranging from 108 to 7 mg/kg caused mortality which occurred sooner and more frequently in the females than the males; the organs showed haemorrhages and at the higher dose levels the liver showed parenchymal necrosis. Similar results were obtained with chlorindione, which tended to be somewhat less toxic. It was confirmed that a distinction should be made between the “toxicity” of an anticoagulant which is due to its pharmacological properties and true organ toxicity. Fluindarol was considered too toxic for clinical use.     

Reproductive, acute and subacute toxicity studies with nefopam in laboratory animals.

Nefopam hydrochloride, a compound with non-narcotic analgesic activity, was evaluated for its acute and subacute toxicity in mice, rats, and dogs. Potential teratogenic effects in mice and rabbits and its effect on general reproduction and postnatal development in rats were also studied. The LD50 by various routes of administration showed that in all three species oral LD50 values (80–178 mg/kg) were greater than im LD50 values (30–57 mg/kg) which were higher than iv LD50 values (20–45 mg/kg). A comparative oral acute toxicity study did indicate a strain difference in rats. Repeated daily administration of nefopam hydrochloride to rats and dogs at doses up to 10 mg/kg/day parenterally and 80 mg/kg/day orally revealed no toxic effects except for mild tissue irritation at injection sites and slight weight loss in some dogs receiving the high dose. Reproduction studies did not reveal any effects on fertility, lactation, or pup development and viability.     

Comparison of acute toxicities of deoxynivalenol (vomitoxin) and 15-acetyldeoxynivalenol in the B6C3F1 mouse

The acute toxic effects of deoxynivalenol (DON) and 15-acetyldeoxynivalenol (15-ADON) were compared in the B6C3F1 female mouse after oral and intraperitoneal exposure. Using the abbreviated procedure of Lorke (Archs Toxicol. 1983, 54, 275), LD50 values for DON were estimated to be 78 mg/kg (oral) and 49 mg/kg (ip) whereas the LD50 values for 15-ADON were 34 mg/kg (oral) and 113 mg/kg (ip). Acute doses of these toxins resulted in extensive necrosis of the gastro-intestinal tract, bone marrow and lymphoid tissues, and focal lesions in kidney and cardiac tissue. The minimum doses required for these histopathological effects were consistent with LD50 estimations. The results indicate that 15-ADON was more or less toxic than DON depending on the route of administration. Risk assessments for DON should therefore consider the potential for 15-ADON occurrence and toxicity in food and feed.     

Toxicity and neuropharmacology of cyclopiazonic acid

Cyclopiazonic acid (CPA) was found to have many pharmacological properties in common with the antipsychotic drugs chlorpromazine and reserpine. Thus, in mice CPA at ip doses of 5-14 mg/kg body weight produced hypokinesia, hypothermia, catalepsy, ptosis, sedation without loss of righting reflex, tremor, gait disturbance, dyspnoea, opisthotonus, atypical convulsion and prolonged barbiturate-induced sleep. The ip LD50 of CPA was found to be 13 +/- 0.05 mg/kg. The tremors induced by near-lethal doses of CPA were associated with voluntary or forced movements (action tremors); they worsened during the days following treatment, but they were weak compared with the exhausting and continuous tremors of the whole body caused by 20 mg tremorine/kg (used for comparison). When death occurred only 24-259 min after administration of CPA (11-14 mg/kg), it was preceded by dypsnoea, cyanosis, opisthotonus and clonic leg movements and tonic extension of hind legs (convulsions). When death was delayed (2-6 days after CPA administration), it was preceded by prostration, ptosis, hypothermia, tremor and cessation of food and water intake resulting in cachexia; convulsions were not seen in this group of mice. CPA did not affect the rate of convulsion or death caused by either maximal electroshock or metrazol administration but it did delay the onset of metrazol-induced seizures. In rabbits, 10 mg CPA/kg body weight initially produced tachycardia, tachypnoea and sedation with an activated electroencephalogram. Of three rabbits given 10 mg CPA/kg one died, and in this rabbit slow delta waves were seen just before and during a brief period with clonic leg movements. In this animal death was accompanied by tonic extension of the hind legs, respiratory arrest and cardiac fibrillation; and epileptiform EEG was not seen at any time. The unexpected EEG activation with sedation in rabbits treated with CPA was similar to the effect of reserpine on EEG.     

The evaluation of the acute toxicity and long term safety of hydroalcoholic extract of Sapthaparna (Alstonia scholaris) in mice and rats

The acute and sub-acute toxic effects of various doses of hydroalcoholic extract of Alstonia scholaris (ASE) was studied in mice and rats. The acute toxicity in mice depended on the season of collection of plant. The highest acute toxicity was observed in the ASE prepared from the summer collection followed by winter. The least toxicity was observed in the extract prepared from the bark of A. scholaris collected in the monsoon season. The administration of different doses of ASE showed a dose dependent increase in the toxicity in all species of mice. The Swiss albino mice were found to be the most sensitive followed by the DBA and C(57)BL. The crossbred mice were resistant when compared to the pure inbred strains. The oral administration of ASE was non-toxic up to a dose of 2000 mg/kg b. wt., while maximum number of animals succumbed to death after administration of 1100 mg/kg ASE by intraperitoneal route. The rats were more sensitive than the mice as the LD(50) dose of ASE was lesser for the former than the latter. The sub-acute toxicity in the rats was carried out with 120 and 240 mg/kg b. wt. ASE (1/10th and 1/5th of the LD(50) dose of ASE). The 240 mg was observed to be more toxic than 120 mg/kg ASE since it caused mortality and deformity in various organs of the recipient animals. The various biochemical parameters like AST, ALT, ACP, ALP, CK, LDH, creatinine, urea, ammonia, glucose and LPx were higher at 240 mg/kg ASE when compared with the 120 mg and the non-drug treated animals. In contrast, the total protein, albumin, DNA, RNA, cholesterol, glucose, glutathione, total thiols declined in the 240 mg/kg ASE treated animals when compared with non-drug treated controls. The hematological analysis showed a dose dependent decrease in the RBC, WBC, hemoglobin, neutrophils and monocytes, while a significant increase in the lymphocytes, eosinophils and basophils was observed. The observed toxic effect of ASE may be due to the presence of echitamine. Our studies shows that at high doses, A. scholaris exhibited marked damage to all the major organs of the body.     

Acute and subacute toxicology and safety evaluation of triphenyl tin hydroxide (Vancide KS).

The acute oral LD50 in Sprague-Dawley rats was determined to be 171 mg/kg (100-295) for males and 268 mg/kg (205-344) for females. 2. A 1 ppm dietary supplement of Vancide KS for 90 days did not induce any abnormalities in weanling Sprague-Dawley rats. The parameters evaluated were serum glutamic-oxaloacetic transaminase (SGOT), hematocrit, differential white blood cell count, food consumption, and weight gain, along with histologic studies of the myocardium, spleen, liver, kidney, stomach, and small intestine. A 500 ppm diet was lethal. Weanling and older rats subjected to 1000 and 10,000 ppm diets died within 5 days. 3. Vancide KS induced no acute dermal toxicity, nor did it exhibit percutaneous absorption in New Zealand strain albino rabbits. 4. Vancide KS induced no chronic dermal toxicity in New Zealand strain albino rabbits. 5. Vancide KS was not shown to be teratogenic. It exhibited an antifertility action, especially in Sprague-Dawley rats dosed on day 1 through day 7 of timed-pregnancy. 6. Vancide KS was shown to be an eye irritant which induces corneal opacity. 7. Acute oral toxicity studies in Sprague-Dawley rats indicate that Vancide KS should be classified as a toxic substance as defined in the regulations under the Federal Hazardous Labeling Act. 8. The intravenous administration of 25 mg/kg of Vancide KS to New Zealand strain albino rabbits induced death preceded by topic convulsions. 9. Vancide KS did not induce skin sensitization in male adult guinea pigs.     

Oral and intraperitoneal acute toxicity studies of yessotoxin and homoyessotoxins in mice.

The acute toxicity of yessotoxin (YTX), homoyessotoxin (homoYTX) and 45-hydroxy-homoyessotoxin (45-OH-homoYTX) has been studied in comparison to that of okadaic acid (OA), the main diarrhogenic toxin, both after intraperitoneal (i.p.) and oral administration. After i.p. administration, homoYTX and YTX showed similar lethality (LD(50)=444 microg/kg and 512 microg/kg), higher than that of OA (LD(50)=225 microg/kg), while 750 microg/kg of 45-OH-homoYTX did not cause death. OA induced the already known toxic signs: before death, mice were motionless and cyanotic; small intestine and liver damage were shown at post-mortem. Mice treated with YTX and homoYTX were restless and jumped before death; necroscopy did not show major changes. After oral treatment, 2 mg/kg of OA induced diarrhoea and body weight loss, causing 4/5 deaths; necroscopy and/or histology revealed degenerative lesions to small intestine, forestomach and liver (confirmed by increased plasma transaminase), but no myocardium alterations. On the contrary, the oral treatment with YTX (1 and 2 mg/kg) and its derivatives (1 mg/kg) did not cause any death or signs of toxicity, except some ultrastructural myocardiocyte alterations, adjacent to capillaries, such as cytoplasmic protrusions (YTX, 1 and 2 mg/kg), fibrillar alteration (YTX, 1 mg/kg) or mitochondria assemblage (45-OH-homoYTX). Altogether, our data show that YTX and its derivatives are less toxic than OA after acute oral and i.p. treatments, at doses which may represent up to 100 times of the possible human daily intake.     

Toxicology of tetraethylene glycol Di-N-heptanoate

Tetraethylene Glycol-Di-N-Heptanoate (TEGDH), a chemical added to polymers to improve flexibility, has a very low acute toxicity following both oral administration and inhalation in rats. The oral LD50 is 25 g/kg in females and greater than 25 g/kg in males. Its approximate lethal concentration for a 4-hr. inhalation exposure is 14.2 mg/L with no mortalities occurring at 13.7 mg/L. The chemical produces mild to moderate irritation on rabbit skin, is not an eye irritant in the rabbit, and is not a sensitizer in the guinea pig. Repeated exposures by the oral route (28 consecutive doses of 1 g/kg) or by inhalation (6 hr/day, 5 days/week for 4 weeks at 1 mg/L) failed to produce any significant adverse response in rats. The material appears to have very low toxicity both when given orally or by inhalation and when the treatment is either acute (single dose) or subchronic (4 weeks).     

Toxicology of Ietraethylene Glycol Di-N-Heptanoate

ABSTRACT

Tetraethylene Glycol-Dl-N-Heptanoate (TEGDH), a chemical added to polymers to improve Flexibility, has a very low acute toxicity Following both oral administration and inhalation in rats. The oral LD50 is 25 g/kg in Females and greater than 25 g/kg in males. Its approximate lethal concentration For a 4-hr. inhalation exposure is 14.2 mg/L with no mortalities occurring at 13.7 mg/L. The chemical produces mild to moderate irritation on rabbit skin, is not an eye irritant in the rabbit, and is not a sensitizer in the guinea pig. Repeated exposures by the oral route (28 consecutive doses oF 1 g/kg) or by inhalation (6 hr/day, 5 days/week For 4 weeks at 1 mg/L) Failed to produce any significant adverse response in rats. The material appears to have very low toxicity both when given orally or by inhalation and when the treatment is either acute (single dose) or subchronic (4 weeks).     

Acute toxicity of aversectin C : various routes of administration and dosage forms

The acute oral, cutaneous, and inhalation toxicity of aversectin C was studied on white unbred rats and mice. The compound was less toxic for rats than for mice, the LD50 for oral administration being 90 and 33 mg/kg, respectively. Aversectin C exhibited a maximum acute toxicity upon the inhalation in rats (LD50 = 40 mg/kg), while a minimum toxicity level was observed for the cutaneous application in rats (1700 mg/kg).     

Toxicological studies on isepamicin (HAPA-B). I. Acute toxicity test in the mouse, rat and dog

Acute toxicity of isepamicin (HAPA-B), a new aminoglycoside antibiotic, in mice, rats and dogs was examined in comparison with amikacin (AMK) and gentamicin (GM). Intravenous LD50 values of HAPA-B were 234 mg/kg in male and 236 mg/kg in female for mice, 489 mg/kg in male and 476 mg/kg in female for rats and 720-864 mg/kg for dogs. Those of AMK were 183 mg/kg in male and 181 mg/kg in female for mice, 420 mg/kg in male and 417 mg/kg in female for rats. Those of GM were 50 mg/kg in male and 47 mg/kg in female for mice, 119 mg/kg in male and 124 mg/kg in female for rats. Intraperitoneal LD50 values of HAPA-B were 2,244 mg/kg in male and 2,272 mg/kg in female for mice, 1,664 mg/kg in male and 1,591 mg/kg in female for rats. Intramuscular LD50 values of HAPA-B were 2,508 mg/kg in male and 2,632 mg/kg in female for mice, 2,088 mg/kg in male and 2,111 mg/kg in female for rats and greater than 1,800 mg/kg for dogs. Those of AMK were 1,247 mg/kg in male and 1,334 mg/kg in female for mice, 2,324 mg/kg in male and 2,244 mg/kg in female for rats. Those of GM were 359 mg/kg in male and 360 mg/kg in female for mice, 559 mg/kg in male and 557 mg/kg in female for rats. Subcutaneous LD50 values of HAPA-B were 3,321 mg/kg in male and 3,320 mg/kg in female for mice, 3,451 mg/kg in male and 3,392 mg/kg in female for rats. Oral LD50 values of HAPA-B were more than 5,000 mg/kg in mice and rats. Ataxia, acratia, dyspnea and convulsions were observed following administration by all routes, except for oral route, of all drugs in mice, rats and dogs. The cause of early death was due to respiratory paralysis which is the typical acute toxic sign of aminoglycoside antibiotics, and that of late death was due to renal injuries. BUN and creatinine values of surviving dogs after day 14 increased after administration by either intravenous or intramuscular routes. Disintegration, necrosis and calcification of epithelial cells of the proximal convoluted tubuli were observed in rats which died during the course of the study, and atrophy, dilatation and eosinophilic degeneration in epithelial cells of the proximal convoluted tubuli and thickening of Bowman's capsule were observed in surviving dogs.     

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-10. Toxicity of metabolites of miocamycin: acute toxicity of Mb12 in mice

We evaluated acute toxicity and estimated LD50 values of Mb12, one of the main metabolites of MOM, in male and female mice after single oral administration. Observations were continued for 1 week after treatment. The LD50 values were calculated according to Litchfield-Wilcoxon's method. It is concluded that LD50 values of Mb12 were 5,750 mg/kg (4,914.5-6,727.5 mg/kg) in male mice and 4,950 mg/kg (4,194.9-5,841.0 mg/kg) in female mice, respectively.     

Experimental toxicology of ASTA Z 7557 (INN mafosfamide)

Summary The LD 50 of Z 7557 in mice was between 500 and 625 mg/kg after i.v. and around 2310 mg/kg after oral administration. The corresponding LD 10 was around 435 mg/kg (i.v.) or 1100–1250 mg/kg (p.o.), respectively.The LD 50 values in rats were in the range of 250–310 mg/kg after i.v. administration and around 1000–1250 mg/kg if given orally.With repeated daily i.v. injections only 70% of the daily dose contributed to lethality. A second administration of Z 7557 to rats after reversal of all toxic signs from the first administration induced the same symptoms and degree of toxicity as the initial injection.Reversible myelosuppression was the predominant feature of toxicity in mice and rats, but at equimolar doses this myelotoxicity was less than half that of cyclophosphamide (CP). First signs of immunosuppression were seen only at 100 mg/kg i.v.No severe urotoxicity was observed in rats with single i.v. doses up to 192 mg/kg. This might be due to the fast and complete renal excretion of the thiol moiety of Z 7557, whereas the activated oxazaphosphorine component occurred in the urine only to a much smaller amount, as could be shown by a pilot pharmacokinetic study.In conclusion, Z 7557 appeared to have an overall tolerance in rats and mice similar to cyclophosphamide but was clearly less toxic with respect to the bone marrow, the immune system and the urinary tract.     

Acute toxicity of seeds of the sapodilla (Achras sapota L.)

An aqueous extract of the sapodilla seed (Achras sapota L.) was acutely toxic to mice and rats (i.p. LD50 = 190 and 250 mg/kg, respectively) with symptoms of dyspnoea, apnoea and convulsions. Soxhlet extraction and chromatographic separation of the seed constituents yielded a brown amorphous solid containing saponin. This was heat-stable and toxic by the i.p. route (LD50 = 30-50 mg/kg) but non-toxic by the oral route in mice and rats. It is proposed that the toxicity of the sapodilla seed is due mainly to the saponin content.     

The acute toxicity of cyclopentadienyl manganese tricarbonyl in the rat

The acute toxicity of cyclopentadienyl manganese tricarbonyl (CMT) was studied in Sprague-Dawley rats. CMT was found to produce convulsions and pulmonary edema. The ED50s for convulsion were 32 mg/kg (95% C.I. 24-42 mg/kg) p.o. and 20 mg/kg (95% C.I. 15-26 mg/kg) i.p. The LD50s for p.o. and i.p. administration were 22 mg/kg (95% C.I. 19-26 mg/kg) and 14 mg/kg (95% C.I. 10-20 mg/kg), respectively. Approximately 13-16% of the administered dose was recovered in the urine from 0 to 48 h post-dosing. The majority of this material was present as an organometallic form of manganese other than CMT. Phenobarbital pretreatment prevented the convulsions and pulmonary damage produced by a 50 mg/kg i.p. dose of CMT. Rats pretreated with CMT (5 mg/kg, i.p.) for 3 days exhibited convulsions but no deaths after treatment with a 34 mg/kg p.o. dose of CMT. These results suggest that CMT does not require metabolic activation to produce toxic effects, and that prior exposure to CMT produces tolerance.     

Comparative evaluation of acute toxicity of ivermectin by two methods after single subcutaneous administration in rats

Ivermectin was evaluated for its acute toxicity after single subcutaneous (s/c) administration by 'Acute Toxic Class' method as per OECD 423 and by conventional acute toxicity test using probit analysis in rats. 'Acute toxic class' method yielded LD(50) in category 2 i.e. between 5 and 50mg/kg which was comparable with conventional method where it was found to be 51.5mg/kg. Post mortem lesions were observed in the form of congestion of liver, which showed centrilobar necrosis and hemorrhages on histopathological analysis in both the methods. This study suggests, 'Acute Toxic Class' method may be used instead of conventional method to study acute toxicity of injectable preparations. Similarly the LD(50) of around 50mg/kg indicated a wide margin of safety (250x) considering therapeutic dose of ivermectin as 200microg/kg.     

Acute and subacute toxicity of cytochalasin E in the rat

Cytochalasin E, a minor toxic metabolite of the fungus Aspergillus clavatus, is acutely toxic to rats, mice, and guineapigs. The LD50 values for a single ip administration of cytochalasin E were: 1-day-old rats, 0.98 mg/kg; adolescent rats, 2.60 mg/kg; mice, 4.60 mg/kg, and guinea-pigs, 0.5–1.5 mg/kg. The toxicity of cytochalasin E was reduced in adolescent rats when administered orally (LD50 9.10 mg/kg) and was increased when administered by the intrathoracic route (LD50 1.30 mg/kg). Rats receiving a fatal ip dose of cytochalasin E died within 2–18 hr with 2–3 ml fluid in the peritoneal cavity. Intrathoracic administration of cytochalasin E killed rats within 2–8 hr and resulted in accumulation of 2.5–3.5 ml pleural fluid. Rats receiving the toxin orally died within 4–18 hr with 1.0–1.5 ml gastric fluid. Histopathologic examination revealed congestive degenerative changes, necrosis of liver, kidney, spleen, pancreas, and small intestine, brain edema, pulmonary hemorrhages, and injury to vascular walls.