Subchronic toxicity of vomitoxin in Sprague-Dawley rats

Purified vomitoxin was incorporated into the diet at a level of 20 ppm and fed to male Sprague-Dawley rats ad lib. for 90 days. Few clinical signs of toxicity were observed. Rats in the vomitoxin treatment group were less efficient in converting feed into body mass, but there was no feed refusal. Terminal body weight was reduced in the vomitoxin treatment group. There were no statistically significant effects on serum enzyme levels, haematological parameters or tissue lesions, or on liver detoxification systems, as reflected in levels of microsomal cytochrome P-450 or in glutathione S-transferase activity.     

Subchronic toxicity of Sipjeondaebo-tang (SDT) in Sprague-Dawley rats

Sipjeondaebo-tang (SDT, Juzen-taiho-to in Japanese), a traditional Korean herbal medicine, is used as a supplemental treatment for the adverse effects of chemotherapy, radiation therapy, and surgical treatment. However, limited information is available about the long-term safety of SDT. Therefore, we evaluated the potential adverse effects of SDT in Sprague-Dawley rats over a period of 13-weeks. The SDT was administered once daily by gavage to male and female rats at dose levels of 0, 250, 500, 1000 and 2000 mg/kg/day for 13 weeks. The SDT treatment did not result in any toxicologically significant changes in mortality, clinical signs, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights, histopathology, estrus cycle, serum testosterone levels and sperm analysis. We concluded that the 13-week repeated oral administration of SDT did not cause any adverse effects in rats at dose levels of ≤ 2000 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level (NOAEL) was more than 2000 mg/kg/day for both genders. Here, we demonstrated the safety of a 13-week repeated oral dose and considered that it is a safe herbal medicine for human consumption.     

Comparative distribution,pharmacokinetics and placental permeabilities of all-trans-retinoic acid, 13-cis-retinoic acid,all-trans-4-oxo-retinoic acid,retinyl acetate and 9-cis-retinal in hamsters

Pregnant hamsters were given a single oral dose (35 mol/kg) of all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxo-retinoic acid, 9-cis-retinal or all-trans-retinyl acetate during the early primitive streak stage of development. The radioactivity associated with the acidic retinoids was distributed to all tissues sampled (including placenta and fetus), with the largest accumulation in the liver and the least accumulation in fat. Radioactivity from 9-cis-retinal or retinyl acetate concentrated in the liver and lung. The all-trans-retinoic acid was oxidized in vivo to all-trans-4-oxo-retinoic acid and isomerized to 13-cis-retinoic acid; 13-cis-retinoic acid was oxidized to 13-cis-4-oxo-retinoic acid and isomerized to all-trans-retinoic acid. No parent 9-cis-retinal or retinyl acetate could be detected in maternal plasma. Plasma concentrations of the parent acidic retinoids reached their maxima within 60 min and then followed exponential decay. Of all the retinoids examined here, 13-cis-retinoic acid showed the largest area under the plasma curve, the slowest clearance and the longest elimination t 1/2. Total plasma radioactivity, consisting of unidentified metabolites, remained elevated at 4 days after dosing. Maternal peak circulating concentrations of the parent retinoids, total radioactivity, plasma pharmacokinetic parameters or the total concentrations of residual radioactivity in fetal tissues could not be correlated with the differential teratogenic potencies of these retinoids.     

Subchronic toxicity studies of the aqueous extract of Aristolochiae fructus in Sprague-Dawley rats

The subchronic toxicity of Aristolochiae fructus containing aristolochic acids (AAs), a natural component in the Aristolochiaceae family, was investigated. The A. fructus was daily administered by gavage to male and female rats for 90 d at dose levels of 21.35, 213.5, and 2135 mg/kg (equivalent to 0.05, 0.5, and 5 mg/kg as AAs, respectively). During the test period, clinical signs, mortality, body weights, food and water consumption, hematology, serum biochemistry, organ weights, and histopathology were examined. Significant decreases in body weight gain were noted in the high-dose group receiving both the aqueous extract of A. fructus and AAs. Decreases in food consumption were noted beginning at 50 d and did not recover in the high-dose group of aqueous extract of A. fructus and AAs. Irrespective of dose, water consumption was not affected. There was no mortality or adverse clinical signs, hematology, or serum biochemistry in the treatment groups versus control. Nephrotoxicity and hyperplasia of epithelial cells in the forestomach were observed in rats receiving the highest dose of aqueous extract of A. fructus and at doses of >or= 0.5 mg/kg/day AAs. For both genders, the no-observed-adverse-effect level (NOAEL) for A. fructus based on this subchronic study in rats was considered to be 21.3 mg/kg/d.     

Subchronic oral toxicity of 4-chloro-alpha, alpha, alpha-trifluorotoluene in Sprague-Dawley rats

The subchronic oral toxicity of 4-chloro-alpha, alpha, alpha-trifluorotoluene (CTT) was assessed in Sprague-Dawley rats. Four groups of six male and six female rats were treated daily for 28 days, by gavage, with doses of 0, 10, 100 and 1000 mg CTT/kg body weight using olive oil as a vehicle. No clinical signs were observed, other than salivation in the high-dose group in the last week. The males of this group showed a significant decrease in body-weight gain without a concurrent decrease in food consumption. In males, there were significant dose-dependent increases in blood cholesterol and triglycerides, suggestive of alterations in lipid metabolism. The females showed only a small dose-related increase in serum lactate dehydrogenase. Specific histological alterations were found in the males given 1000 mg/kg/day, namely hyaline droplet nephrosis, along with a significant increase in relative kidney weight, and an increase in lipid vacuoles in the adrenal cortex. Slight nephrosis was also observed in males given 100 mg/kg. Both male and female rats showed a significant increase in relative liver weight at a dose of 1000 mg CTT/kg. CTT appears to have a low subchronic oral toxicity. Neither pathological nor biochemical alterations were found at 10 mg/kg body weight/day and this can be defined as the no-observable-effect level (NOEL).     

Subchronic toxicity of plant sterol esters administered by gavage to Sprague-Dawley rats.

The purpose of this study was to investigate the potential subchronic toxicity of plant sterol esters by a 13-week repeated oral dose in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 1000, 3000 and 9000 mg/kg/day for 13 weeks. At the end of treatment period, 10 rats/sex/group were sacrificed, while six rats/sex in the negative control and highest dose groups were sacrificed after a 4-week recovery period. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. Slight decreases in body weight gain were noted at lower doses but were only statistically different from the control animals in the highest dose group. In histopathological examinations, an increase in the incidence of cardiomyopathy with mononuclear cell infiltration was observed in males of the 9000 mg/kg group. Decreased body weight gain and increased incidence of cardiomyopathy observed in the highest dose group were not recovered until the end of the recovery period. There were no adverse effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings and organ weights in any treatment group. Based on these results, it was concluded that the 13-week repeated oral dose of plant sterol esters resulted in the suppression of body weight gains in both sexes and cardiomyopathy in males at a dose level of 9000 mg/kg/day. The target organ was determined to be heart in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 3000 mg/kg/day for both sexes.     

Subchronic 90 day toxicity of dichloroacetic and trichloroacetic acid in rats

Male Sprague-Dawley rats were treated with either dichloroacetic acid (DCA) or trichloroacetic acid (TCA) in the drinking water at levels of 0, 50, 500 and 5000 ppm for a period of 90 days to determine the toxicities associated with subchronic exposure. All animals were sacrificed and examined for gross and histopathologic lesions, serochemical changes, immune dysfunction, hepatic peroxisomal and mixed function oxidase enzyme induction and organ-body weight changes. Animals treated with DCA had decreased body weight gains (500 and 5000 ppm) and decreased total serum protein (all doses). Rats given either TCA (5000 ppm) or DCA (500 or 5000 ppm) had increased liver and kidney organ to body weight ratios. Rats offered DCA had significantly elevated alkaline phosphatase (500 and 5000 ppm) and alanine-amino transferase (5000 ppm). No consistent immunotoxicity was observed in animals exposed to either compound. Rats treated with 5000 ppm TCA or DCA had significantly increased hepatic peroxisomal beta-oxidation activity. These data, along with histopathologic changes, suggest that TCA and DCA produce substantial systemic organ toxicity to the liver and kidney during a 90-day subchronic exposure, although only at doses greater than those expected to occur in the environment.     

Subchronic hepatotoxicity evaluation of 1,2,4-tribromobenzene in Sprague-Dawley rats

Male Sprague-Dawley rats were exposed to 1,2,4-tribromobenzene (TBB) by gavage for 5 days, 2, 4, and 13 weeks at 0, 2.5, 5, 10, 25, or 75 mg/kg per d. There were no TBB exposure-related clinical signs of toxicity or changes in body weight. Liver weight increases were dose and exposure time related and statistically significant at ≥10 mg/kg per d. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were dose and time related. The 75 mg/kg per d group had minimally increased mitoses within hepatocytes (5 days only). Hepatocyte vacuolation was observed (13 weeks) and was considered TBB exposure related at ≥25 mg/kg per d. Concentrations of blood TBB increased linearly with dose and at 13 weeks, ranged from 0.5 to 17 μg/mL (2.5-75 mg/kg per d). In conclusion, rats administered TBB doses of 10-75 mg/kg per d for 13 weeks had mild liver effects. A no observed adverse effect level of 5 mg/kg per d was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥10 mg/kg per d.     

Subchronic nose-only inhalation study of propylene glycol in Sprague-Dawley rats

Groups of nineteen Sprague-Dawley rats of each sex were exposed by a nose-only inhalation to 0.0, 0.16, 1.0 or 2.2 mg propylene glycol/litre air, for 6 hr/day, 5 days/wk for 90 days. There were no significant differences in respiratory rates, minute volumes or tidal volumes between any of the groups during aerosol exposure. The uniformity of respiratory parameters between dose groups implied that the delivered doses were proportional to the exposure concentrations. The mean terminal body weights were not significantly different from controls for any group of male animals. The mean body weights of the females exposed to 2.2 mg/litre were significantly less than those of female controls from day 50 onwards. This effect, in female rats, was consistent with a decrease in feed consumption for the high-exposure female rats beginning on study day 43. Statistically significant differences between the treated and control groups in certain haematological parameters, serum enzyme activities, other serum chemistry parameters and organ weights did not show clear dose relationships. There was a significant increase in the number of goblet cells or an increase in the mucin content of the existing goblet cells in the nasal passages of the medium- and high-exposure animals. Exposure to the above concentrations of propylene glycol caused nasal haemorrhage and ocular discharge in a high proportion of animals, possibly as a result of dehydration of the nares and eyes.     

Subchronic oral toxicity of strychnine in rats

In recent years strychnine has been used for the treatment of nonketotic hyperglycinemia, a rare metabolic disease in infants. Since no information on repeated dose toxicity of this drug was available, a subacute oral toxicity study in rats was conducted. Strychnine hydrochloride was administered orally to rats for 4 weeks in aqueous 0,2 % solution. The study showed no organ and tissue damage or functional disorders. The difficulty to conduct meaningful repeated-dose toxicity studies with drugs exhibiting potent pharmacological actions and a steep dose-effect curve are discussed.     

Subchronic inhalation toxicity of azinphos-methyl in rats

Azinphos-methyl was evaluated for its subchronic inhalation toxicity. The exposure of rats to concentrations of 0.195, 1.24, and 4.72 mg/m³, respectively, for 12 weeks, 6 hrs daily, 5 times weekly, resulted in effects only in those animals which inhaled aerosols of the highest concentration. This group showed a significant depression of the cholinesterase activity in plasma and erythrocytes. The males of this group had a lower body weight gain. The results are in agreement with the established maximum allowable concentration of 0.2 mg/m³.     

丹红注射液对大鼠亚慢性毒性试验研究

目的研究连续iv给予丹红注射液对SD大鼠产生的亚慢性毒性作用。方法 SD大鼠80只,雌雄各半,随机分为对照组和丹红注射液600、200、60 mg/kg剂量组,每组20只,连续iv给药13周,以其体质量、血液生化学、血液学、脏器相对质量、组织病理学检查为指标,全面评价其对大鼠的毒性作用。结果丹红注射液600 mg/kg组大鼠体质量增长明显延缓,肾功能指标(BUN、Cr)明显增加,组织病理学检查表明肾脏发生病变。结论 iv给予丹红注射液600 mg/kg对大鼠有明显的肾脏毒性。     

Subchronic toxicity of trinitrotoluene in Fischer 344 rats rats

This study was conducted to evaluate the toxicity of trinitrotoluene (TNT) in Fischer 344 rats when administered in the diet for 13 weeks. Groups of 10 rats per sex received TNT at doses of 1, 5, 25, 125 or 300 mg/kg/day. Thirty rats per sex served as untreated controls. Toxicologic endpoints included clinical signs, body weight, food consumption, hematology, clinical biochemistry, organ weights and gross/histopathology. Toxic effects following 125 mg/kg/day or greater included decreased food intake and body weight gain, elevated serum cholesterol levels, and anemia (reduced hemoglobin, hematocrit and RBC counts). Splenomegaly, hepatomegaly/hepatocytomegaly and testicular atrophy with degeneration of the seminiferous tubular epithelium were also seen at 125 and 300 mg/kg/day. Hemosiderin-laden macrophages, congestion of the splenic red pulp, methemoglobin production indicative of the oxidizing activity of TNT and/or its metabolites, and the lack of bone marrow toxicity suggested hemolysis as the mechanism of anemia.     

Subchronic inhalation toxicity of dimethylformamide in rats and mice

Fisher F344 rats and B6C3F1 mice were exposed to concentrations of 0, 150, 300, 600 and 1200 ppm of dimethylformamide (DMF) for 6 hours a day, 5 days a week for 12 weeks. Detailed clinical observations were obtained weekly and body weights biweekly on all animals. Clinical chemistry and hematology evaluations were made on all rats and approximately half the mice at terminal sacrifice. Gross necropsy examinations were made on all animals. Histopathologic evaluations were conducted on selected tissues of animals of both species at all dose levels. Few overt signs of toxicity were seen in either rats or mice. There was a dose related depression in body weight gain in rats that was significant at the 1200 ppm level from the second week of study onwards. A total of 11 mice died or were sacrificed moribund during the study, 8 from the high dose and 2 from the 600 ppm dose level. Both clinical chemistry (in rats only) and gross necropsy observations, and histopathology of tissues indicate the possibility that liver may be the target in specific organ toxicity. The no-effect DMF dose was below the 150 ppm level for both rats and mice and the maximum tolerated dose was below the 600 ppm level.     

Subchronic oral toxicity of ubiquinol in rats and dogs

Ubiquinol is the two-electron reduction product of ubiquinone (coenzyme Q(10) or CoQ(10)) and functions as an antioxidant in both mitochondria and lipid membranes. In humans and most mammals, including dogs, the predominant form of coenzyme Q is coenzyme Q(10), whereas the primary form in rodents is coenzyme Q(9) (CoQ(9)). Therefore, the subchronic toxicity of ubiquinol was evaluated and compared in Sprague-Dawley rats and beagle dogs. In the initial rat study, males and females were given ubiquinol at doses of 0, 300, 600, or 1200 mg/kg or ubiquinone at 1200 mg/kg by gavage for 13 weeks. This was followed by the second study, where females were given with doses of 75, 150, 200, or 300 mg/kg/day in order to determine a no observed adverse effect level (NOAEL). In the dog study, the test material was administered to males and females at dose levels of 150, 300, and 600 mg/kg, and ubiquinone was included at 600 mg/kg. Clinical observations, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, blood biochemistry, gross findings, organ weights, and histopathological findings were examined. In both species, determination of plasma and liver ubiquinol concentrations, measured as total coenzyme Q(10), were performed. There were no deaths or test article-related effects in body weight, food consumption, ophthalmology, urinalysis, or hematology in rats. Histopathological examinations revealed test article-related effects on the liver, spleen, and mesenteric lymph node in female rats but not in male rats. In the liver, fine vacuolation of hepatocytes was observed in the ubiquinol groups at 200 mg/kg and above. These changes were judged to be of no toxicological significance because they were not considered to induce cytotoxic changes. Microgranuloma and focal necrosis with accumulation of macrophages were observed in the ubiquinol groups at 300 mg/kg and above. These findings were accompanied by slight increases in blood chemistry enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]), which was suggestive of either potential hepatotoxicity or a normal physiological response to ubiguinol loading. Microgranuloma, and focal necrosis were judged to be only adverse effects induced by test article based on their incidence and pathological characteristics. These changes observed in liver were thought due to uptake of the administered ubiquinol by the liver as an adaptive response to xenobiotics, and the microgranulomas and focal necrosis were considered the results of excessive uptake of ubiquinol, which exceeded the capacity for adaptive response. Based on these findings the NOAEL in rats was conservatively estimated to be 600 mg/kg/day for males and 200 mg/kg/day for females. In dogs, there were no deaths or ubiquinol-related toxicity findings during the administration period. No test article-related effects were observed in body weight, food consumption, ophthalmology, electrocardiogram, urinalysis, hematology, or blood chemistry. Histopathological examination revealed no effects attributable to administration of ubiquinol or ubiquinone in any organs examined. Based on these findings, a NOAEL for ubiquinol in male and female dogs was estimated to be more than 600 mg/kg/day under the conditions of this study.     

Subchronic inhalation toxicity of p-nitroaniline and p-nitrochlorobenzene in rats

For evaluation of subchronic toxicity of the two single-ring nitroaromatics, p-nitroaniline (PNA) and p-nitrochlorobenzene (PNCB), groups of 10 male and 10 female Sprague-Dawley rats were exposed to an aerosol/vapor of PNA in isopropanol at target concentrations of 0, 10, 30, or 90 mg/m³ or to PNCB vaporized from a solution in ethylene glycol monoethyl ether at target concentrations of 0, 5, 15, or 45 mg/m³ for 6 hr/day, 5 days/week for 4 weeks. Clinical signs of toxicity, body weights, results of ophthalmoscopic exam, hematology and clinical chemistry tests, organ weights, gross and histopathological changes were recorded. Exposure to PNA or PNCB resulted in a dose-related increase in blood methemoglobin levels. Mean red blood cell counts, hematocrit, and hemoglobin were significantly decreased in mid and high level animals exposed to PNCB. Mean spleen weights (absolute and relative to body weight) were significantly increased at the high dose levels in the two studies. A slight increase in spleen weights was also observed at the low concentration level in the PNA study. Absolute and relative liver weights also were increased among animals exposed to 45 mg/m³ PNCB. Microscopic changes were observed mainly in the spleen and included an increase in intensity of extramedullary hematopoiesis and hemosiderosis with both compounds. Spleens of animals exposed to PNCB also exhibited congestion. Neither PNA nor PNCB exhibited significant toxicological effects other than those of methemoglobinemia, anemia, and splenic changes classically associated with nitroaromatics at levels significantly above presently accepted occupational standard. Our data suggest that the current TLV for PNA which is 3 mg/m³ will provide adequate protection to the workers. OSHA's PEL of 1 mg/m³ for PNCB is to be preferred over the current TLV of 3 mg/m³ to provide a comparable margin of safety.     

Subchronic oral toxicity study of gamma-glycidoxypropyltrimethoxysilane in rats

The subchronic toxicity (28 days) of orally administered gamma-Glycidoxypropyltrimethoxysilane (GPTS) was studied in laboratory rats. The test material was administered daily for four weeks to groups of 10 male and 10 female Sprague-Dawley rats by gavage at dose levels of 0, 40, 400, and 1,000 mg/kg. Mortality, behavioral reactions, growth and food consumption were observed and measured along with hematology, blood biochemistry, absolute and relative organ weights. No overt signs of toxicity or behavioral abnormalities were observed in any of the test animals during the course of the study. There were no treatment related mortalities and no significant differences were observed in mean body weight, food consumption, absolute or relative organ weights of control and treated rats. Also, there were no meaningful differences in hematology, urinalysis or clinical blood chemistry values between control and treated animals. Gross and histopathologic examinations of organs or tissues from both control and GPTS treated animals did not reveal any treatment related changes. These results suggest that it is unlikely that serious injury would result from the ingestion of GPTS in amounts normally encountered incidental to its industrial use.     

Subchronic oral toxicity of cellulose acetate in rats

Cellulose acetate was administered by way of a dietary admixture to Sprague-Dawley rats (20/sex/group) at dose levels of 0, 500, 2500 and 5000 mg/kg body weight/day for 94-96 days. Physical observations, body weight and food consumption measurements were made before testing and throughout the study. Ophthalmoscopic examinations were conducted on all animals before testing and just prior to study termination. Haematology, clinical chemistry and urinalysis were performed at 1.5 and 3 months on 10 animals/sex/group. After 3 months of treatment the animals were killed, terminal body weights and organ weights were measured and ratios calculated. Histopathological examination of tissues from the control and high-dose groups was conducted. The evaluation of physical observations, ophthalmology, body weight, food consumption, haematology, clinical chemistry, organ-to-body-weight ratios, gross pathology and histopathology revealed no evidence of an adverse effect related to treatment with cellulose acetate.     

Subchronic toxicity of a fluoroalkylethanol mixture in rats

The objective of this study was to evaluate the subchronic toxicity of a commercial fluoroalkylethanol mixture, which is an intermediate in the production of fluoroorganic compounds that are used as protectants and surfactants. The test substance was administered daily by gavage to Sprague-Dawley rats as a suspension in aqueous methylcellulose. The dosages were 0, 25, 100, or 250 mg kg(-1) day(-1). A 1- and 3-month recovery period was included to evaluate the reversibility of toxic effects. No test substance-related mortality or neurotoxicity occurred. Body weights and/or nutritional parameters were significantly reduced at 100 and 250 mg kg(-1) day(-1), and these effects were reversible. Broken and absent teeth were observed in rats dosed with 250 mg kg(-1) day(-1), and microscopic tooth lesions (ameloblast degeneration/disorganization) occurred at 100 and 250 mg kg(-1) day(-1) and persisted with decreased severity throughout recovery. Decreased red cell mass parameters occurred at 90 days in the 250 mg kg(-1) day(-1) group, but red cell counts were normal thereafter during recovery. A persistent elevation of liver weights was seen in groups given > or =100 mg kg(-l) day(-1). The increased weights correlated with microscopic hepatocellular hypertrophy only in males and females administered 250 mg kg(-1) day(-1). Hepatic beta-oxidation was increased in a dose-dependent manner and persisted through 1 month of recovery at 250 mg kg(-1) day(-1). Increased kidney weights were observed at 25 (females only), 100, and 250 mg kg(-1) day(-1). These elevated weights persisted in the high dose after recovery and correlated with microscopic tubular hypertrophy (males only). Thyroid follicular hypertrophy was present at 100 and 250 mg kg(-1) day(-1) but was not present after recovery. Total fluorine in whole blood increased with continuous dosing and achieved steady state in approximately 42 days. Both plasma and urine fluoride levels were elevated in a dose-dependent manner. Under the conditions of the study, the no-observed adverse effect level for this mixture was 25 mg kg(-1) day(-1) for subchronic toxicity.