Subchronic Oral Toxicity Evaluation of Lanthanum： A 90-day, Repeated Dose Study in Rats

Objective The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level（NOAEL）,which is a critical factor in the establishment of an acceptable dietary intake（ADI）.Methods In accordance with the Organization for Economic Co-operation and Development（OECD） testing guidelines,lanthanum nitrate was administered once daily by gavage to Sprague-Dawley（SD） rats at dose levels of 0,1.5,6.0,24.0,and 144.0 mg/kg body weight（BW） per day for 90 days,followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups.Outcome parameters were mortality,clinical symptoms,body and organ weights,serum chemistry,and food consumption,as well as ophthalmic,urinary,hematologic,and histopathologic indicators.The benchmark dose（BMD） approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum.Results Significant decreases were found in the 144.0 mg/kg BW group in the growth index,including body weight,organ weights,and food consumption.This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day.Importantly,the 95% lower confidence value of the benchmark dose（BMDL） was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males.Conclusion The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements（REEs）.

Combined Subchronic Toxicity of Bisphenol A and Dibutyl Phthalate on Male Rats

Objective To evaluate the combined subchronic toxicity of bisphenol A（BPA） and dibutyl phthalate（DBP） in male Sprague Dawley（SD） rats.Methods Forty 4‐week‐old male rats weighing 115‐125 g were randomly divided into BPA‐treated,DBP‐treated group,BPA＋DBP‐treated and control groups and fed with a soy‐ and alfalfa‐free diet containing 285.4 ppm BPA,285.4 ppm DBP,285.4 ppm BPA plus 285.4 ppm DBP,and a control diet,respectively,for 90 consecutive days.At the end of the study,the animals were sacrificed by exsanguination via the carotid artery under diethyl etherane aesthesia and weighed.Organs,including liver,kidneys,spleen,thymus,heart,brain,and testis underwent pathological examination.The androgen receptor（AR）,gonadotropin‐releasing hormone receptor（GNRHR）,and progesterone hormone receptor（PR） genes from the hypothalamus were detected by real‐time PCR.The biomedical parameters were analyzed.Results No significant difference was found in food intake,body weight,tissue weight,organ/brain weight ratio,and biomedical parameters among the four groups（P〉0.05）.However,BPA and DBP up‐regulated AR,PR and GNRHR expression levels in rats and showed a synergistic or an additive effect in the BPA＋DBP group.Conclusion The combined subchronic toxicity of BPA and DBP is synergistic or additive in male SD rats.

Acute and subchronic toxicity as well as evaluation of safety pharmacology of modified pulsatilla granules

The present study investigated acute and subchronic toxicity and safety pharmacology of modified pulsatilla granules（MPG）to provide a basis for a comprehensive understanding of MPG toxicity.The results of acute toxicity testing showed that the median lethal dose of MPG was more than 5 000 mg kg^-1,suggesting that MPG was considered as practically non-toxic.The subchronic toxicity study for 30 days was conducted by daily oral administration at doses of 375,750 and 1 500 mg kg^-1 in Sprague-Dawley rats.The results of subchronic toxicity study showed that the body weight and relative organ weight were not significantly changed by administration of MPG.The clinical chemistry study showed that MPG could induce kidney and liver damages.In histopathological,mild lesions in liver and kidney were also observed,suggesting that the liver and kidney might be potential target organs of MPG.In the safety pharmacology study,MPG did not exhibited any side effects to rats in cardiovascular system,respiratory system and central nervous system.These results suggested that MPG could be considered safe for veterinary use.

Effects of Subchronic Aluminum Exposure on Amino Acids Neurotransmitters in Chicken Brain

To investigate the effects of aluminium （Al） exposure on amino acid neurotransmitters, the chickens with different levels of subchronic Al poisoning were estabolished by continuous peritoneal injection of fixed volume and different concentrations of gradient of aluminium trichloride （AlCl3）. The levels of amino acid neurotransmitters in chicken brains were determined by high performance liquid chromatography （HPLC） after being exposed of Al for 60 days, and Al levels in serum and brain tissue were determined by atomic absorption spectrophotometry （AAS）. The results showed that Glu levels increased with the increase of Al, but there was no significant difference compared with the control. The levels of Al, Asp, Gly, GABA and Tau were significantly higher in Al-treated groups than those in the control. The results indicated that Al intoxication led to excitatory neurotoxicity.

Subchronic Toxicity Study on Soy Isoflavones in Rats

Objective To investigate the subchronic toxicity of soy isoflavones （SIF） in male rats. Method Fifty Sprague-Dawley rats were randomly divided into 5 groups, 10 rats per group. SIF were given to rats in different groups by gavage at dose of 0, 0.2, 0.5, 1.5, and 4.5 g/kg bw, respectively for 13 weeks. Clinical manifestations, body weight, and food consumption were observed weekly. At the end of the study, urinalysis, hematology, clinical chemistry, total testosterone, and follicle-stimulating hormone were tested, and histopathological examinations were performed. Results No mortality, ophthalmic abnormalities or treatment-related clinical signs were identified during the study. As compared with the control group, significantly lower body weights and food consumption were observed in 1.5 and 4.5 g/kg bw groups. In clinical chemistry tests, triglyceride was significantly decreased and high-density lipoprotein cholesterol was significantly increased in all SIF-treated groups. Total testosterone levels were significantly lower in 0.50, 1.50, and 4.5 g/kg bw dose groups than in the control group. Microscopic examination showed that the mammary glands exhibited hyperplasia and excreted latex in rats of the 4.5 g/kg bw group. No changes attributable to treatment of SIF in other parameters were found. Conclusion SIF at high dosages caused significant endocrine disruption in male rats. The no observed adverse effect level （NOAEL） of SIF to male rats in this study is considered to be 0.20 g/kg bw.

Subchronic Oral Toxicity of Silica Nanoparticles and Silica Microparticles in Rats

Objective To investigate the subchronic oral toxicity of silica nanoparticles（NPs） and silica microparticles（MPs） in rats and to compare the difference in toxicity between two particle sizes.Methods Sprague-Dawley rats were randomly divided into seven groups： the control group; the silica NPs low-, middle-, and high-dose groups; and the silica MPs low-, middle-, and high-dose groups [166.7,500, and 1,500 mg/（kg·bw·day）]. All rats were gavaged daily for 90 days, and deionized water was administered to the control group. Clinical observations were made daily, and body weights and food consumption were determined weekly. Blood samples were collected on day 91 for measurement of hematology and clinical biochemistry. Animals were euthanized for necropsy, and selected organs were weighed and fixed for histological examination. The tissue distribution of silicon in the blood, liver,kidneys, and testis were determined.Results There were no toxicologically significant changes in mortality, clinical signs, body weight,food consumption, necropsy findings, and organ weights. Differences between the silica groups and the control group in some hematological and clinical biochemical values and histopathological findings were not considered treatment related. The tissue distribution of silicon was comparable across all groups.Conclusion Our study demonstrated that neither silica NPs nor silica MPs induced toxicological effects after subchronic oral exposure in rats.

Acute and subchronic toxicity of hydroxylammonium nitrate in Wistar rats

Hydroxylammonium nitrate(HAN) is a major constituent in a class of liquid monopropellants and is extensively used in nuclear industry and space propulsion.Previous toxicological studies have focused on oral,inhalation and dermal routes of exposure to HAN-based propellant blends.In this study,acute and subchronic toxicity of HAN in Wistar rats by intraperitoneal injections were evaluated.In this acute study,doses of HAN at 115,125,135,147,160 or 174 mg/kg were administered.No adverse effects were observed during a 14-day period and at gross histopathological examination.In the subchronic study,HAN at 7,14 or 28 mg/kg were administered for 13 weeks.The treatment with HAN caused significant changes in the weight of spleen,in the level of hematological parameters,total bilirubin,direct bilirubin,uric acid and carbondioxidecombining power and histopathological damages of the lung,liver,spleen and kidney.Overall,the study suggests that 13-week HAN treatment caused abnormal hematological changes and tissue lesions,and the risk of toxicity to mammals is not negligible.

A Subchronic Toxicity Study on Lactobacillus Fermentum GM 090 in Rat

Lactobacillus fermentum （L. fermentum） is one of seven species in the genus Lactobacillus[1]. With a long history of safe use in fermented food production, Lactobacillus is considered as one of the most beneficial probiotics[23]. The most well-known potential health benefit is improving digestion and immune function[4.s]. Other beneficial functions of Lactobacillus strains include managing lactose intoleranceIs], lowering cholesterol and blood pressureIs], reducing inflammation[~], and prevention of cancerIs＇7]. L. fermentum is usually found during malt whisky fermentation]8]. L. fermentum CP34 was found to have the significant effect of decreasing the serum antigen-specific IgE levels compared to a control group[9].

Subchronic Oral Toxicity of Pyridostigmine Bromide in Rats

This study evaluated the oral toxicity of pyridostigmine bromide in Sprague-Dawley rats when administered for 13 weeks by daily gavage. Groups of 10 rats/sex received doses of 0, 5, 15, 30, or 60 mg/kg/day. Toxicity was limited to exaggerated cholinergic stimulation at doses of 15 mg/kg/day or greater. Significant findings included tremors and inhibition of RBC acetylcholinesterase. Thus, 5 mg/kg/day of pyridostigmine bromide appears to be the no observed toxic effect level under the conditions of the present investigation.

Effects of Subchronic Aluminum Exposure on Liver Function in Rats

Effects of subchronic aluminum （Al） exposure on the function of rat liver were investigated in this experiment. A total of 48 male Wistar rats （4 weeks old） were randomly divided into four groups： experimental groups were orally exposed to 64.18, 128.36, 256.72 mg. kg^-1 body weight aluminum trichloride （AlCl3） in drinking water, and the control group with distilled water. The experiment lasted for 120 days. The activities of superoxide dismutase （SOD） and glutathione peroxidase （GSH-PX）, the concentration of malondialdehyde （MDA） in serum and liver, and alanine transarninase （ALT） and aspartate aminotransferase （AST） activities in serum were detected in all groups. The results showed that the activities of ALT, AST in serum and the concentrations of MDA in liver in the Al-treated groups significantly increased compared with the control group; the activities of GSH-PX and SOD in high-dose Al-treated group were significantly lower than those in control group. Our findings indicated that subchronic AI exposure could result in injures of lipid peroxidation and function in liver.

A 180-Day Subchronic Oral Toxicity Study of Total Flavones of <i>E. leptorrhizum</i>Stearn in Rats

A subchronic oral toxicity was conducted to evaluate the safety of total flavones of E. leptorrhizum Stearn in Sprague-Dawley rats. The test article was administered once daily by gavage in male and female rats at dose levels of 24, 48, and 96 mg/kg body weight/day for 180 days. 90 and 180 days after administration, ten and tweedy animals (each half of male and female) of each group were tested. 28 days after withdrawal, five male and female rats were tested. There were no significant toxicological changes shown in daily clinical signs, body weight, food consumption, hematology parameters, blood biochemistry, organ weights and histopathological examination except leukocyte differential count. It was concluded that the no-observed-effect level (NOEL) for total flavones of E. leptorrhizum Stearn was >96 mg/kg in SD rats.

Antihyperglycemic and subchronic toxicity study of Moringa stenopetala leaves in mice

Objective:To evaluate the antihyperglycemic activity and subchronic toxicity of an extract ofMoringa stenopetala(M.stenopetala)leaves in mice.Methods:Antihyperglycemic activities of various solvent subfractions and chromatographic fractions were investigated in alloxan induced diabetic mice.All fractions were administered intragastrically using oral gavage at a dose of 500 mg/kg.For the subchronic toxicity investigation of the 70%ethanol extract of M.stenopetala leaves,a daily dose of 300 or 600 mg/kg body weight was administered to mice over 96 d.Some hematological and plasma biochemical parameters were measured as indices of organ specific toxicity.Preliminary phytochemical screening and antioxidant activity investigation was done using thin layer chromatography method.Results:Among the solvent subfractions of the 70%ethanol extract tested only butanol subfraction exhibited significant reduction of blood glucose level(P<0.05)at 2 h(53.44%)and 4.5 h(46.34%)in diabetic mice and it was further fractionated chromatographically.This resulted in isolation of three chromatographic fractions(fraction 1,2,and 3)which exhibited maximal blood glucose reduction(P<0.01)at 6 h(77.2%),at 4.5 h(69.1%)and at 4.5 h(71.96%)after administration.Furthermore,these fractions exhibited comparable antioxidant activity,and preliminary phytochemical screening indicated the presence of phenolic compounds which may be phenolic glycoside in all fractions.The subchronic toxicity study of the 70%ethanol extract of M.stenopetala leaves revealed that there were no significant differences in body weight,between controls and treated mice.Hematological analysis showed no differences in most parameters examined.Furthermore,it did not significantly affect plasma creatinine,urea,cholesterol,triglycerides and CA125 levels.It also did not significantly affect the plasma T3,T4 and THS level.It,however,caused a significant dose-dependent increases in aspartate aminotransferase and alkaline phosphatase.The plasma alanine aminotransferase increased in a dose dependent manner,though not significant.Conclusions:The present study revealed that the crude ethanol extract and solvent-solvent fractions as well as chromatographic fractions have antihyperglycemic effect.Furthermore,the crude ethanol extract have some effect on liver of the mice on subchronic administration.Therefore,further study should be done to identify the active principal compound responsible for antihyperglycemic effect and to rule out the safety in other animal model.

A subchronic toxicity test of ethyl acetate extract from endophytic fungus Penicillium sp. of kunyit putih(Curcuma zedoaria) against Swiss albino mice

Ethyl acetate extract of endophytic fungus from Penicillium sp. of kunyit putih showed antibacterial activity in vivo but no acute toxicity. However, the extract may have toxic effects on major organs for long-term consumption. This study was carried out in order to test sub-chronic toxicity of the ethyl acetate from endophytic fungus Penicillium sp. of kunyit putih against mice(Mus musculus). A total of 50 male mice were divided into five groups. Groups Ⅰ, Ⅱ, Ⅲ and Ⅳ were orally administered with ethyl acetate extracts of 250, 500, 1000 and 2000 mg/kg body weight(BW), respectively. Group Ⅴ was used as a control without extract treatment. A toxic symptom was observed by analyzing several parameters, namely change in BW, hematologic and biochemical properties(SGOT & SGPT), macroscopic organs, and relative organ weight. The results showed that there was toxic symptom and statistically significant difference in the parameters of SGOT, SGPT and heart weight between treated and control groups. Based on analysis, we concluded that ethyl acetate extract from endophytic fungus Penicillium sp. of kunyit putih had subchronic toxicity effect.

Subchronic oral toxicity evaluation of ethanolic whole plant extract of Eleucine indica on haematological and biochemical indices in Wistar albino rats

Objective:To evaluate the effect of ingestion of ethanolic whole plant extract of Eleucine indica on haematological and biochemical parameters of Wistar albino rats.Methods:Subchronic toxicity study was carried out by oral administration of different doses(200,400 and 600 mg/kg body weight)of the extract on alternate-day basis to different groups of rats for 28 days.The animals were subsequently sacrificed and blood samples were collected by cardiac puncture for haematological and biochemical analyses.Results:Haematological indices were preserved and the extract showed significant(P<0.01–0.001)haemostatic potentials.There was significant reduction(P<0.05–0.001)in total bilirubin,aspartate aminotransferase(P<0.001),alanine transaminase(P<0.05),alkaline phosphatase(P<0.001)and blood glucose(P<0.001)compared to control.The level of total protein increased significantly(P<0.05–0.001).Kidney functions were,however,intact.Conclusions:The results obtained indicated that ingestion of Eleucine indica whole plant extract for a long period of time reduces both bleeding and clotting times,reduces blood sugar and shows no apparent toxic effect on liver and kidneys.The results of this study may be useful as a basis for clinical trials in humans.

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