Acute and sub-chronic toxicity studies of honokiol microemulsion

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

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

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

Safety assessment of vitacoxib: Acute and 90-day sub-chronic oral toxicity studies

Vitacoxib, is a newly developed coxibs NSAID (selective inhibitors of cyclooxygenase-2). To date, no experimental data have been published concerning its safety for use as an additive in the human diet. In the present study, we assessed the acute and sub-chronic toxicity of vitacoxib administered by gavage. The acute toxicity tests in Sprague Dawley (SD) rats and ICR mice demonstrated that vitacoxib at a dose of 5000 mg/kg BW failed to alter any of the parameters studied. In the 90-day sub-chronic toxicity test, vitacoxib was administered to SD rats at the doses of 0 (control), 5, 10, 20, 30, and 60 mg/kg BW. The results demonstrated that there were no significant differences for most indexes of sub-chronic toxicity throughout the experiment at the dose of 5–20 mg/kg BW, indicating no apparent dose-dependent. However, there were significant histopathology changes in the liver and kidney, and alterations in some biochemical parameters in the 60 mg/kg BW group. Based on these findings, the gavage LD₅₀ was determined to be > 5000 mg/kg in SD rats and ICR mice, and the 90-day gavage no-observed-adverse-effect level (NOAEL) of vitacoxib was considered to be 20 mg/kg BW under the present study conditions.     

丹参多糖的急性和亚急性毒性试验研究

目的 检测丹参多糖的急性毒性与亚急性毒性,为丹参多糖的安全性做出初步评价.方法 预试验中,以剂量8、6、4.5 g·kg-1,对小鼠等容积[0.2 mL·(10 g)-1]一次性灌胃给药,若死亡数≥30%,按改良寇氏法设计试验测定半数致死量(LD50),否则,按倍比稀释法测定最大耐受量(MTD);对大鼠口服灌药高(6 g·kg-1)、中(3 g·kg-1)、低(1.5 g·kg-1)剂量的丹参多糖,14 d后进行常规行为观察、血生化检测、免疫脏器系数和心、肝、脾、肾、肺、胃的大体肉眼观察以及病理学检查.结果 急性毒性预试验中小鼠无1例死亡,未测出半数致死量,最大耐受量结果显示小鼠灌服丹参多糖最大耐受量为15 g·kg-1,相当于临床用药的200倍;亚急性毒性试验中,大鼠各检测指标与正常对照组相比,均无统计学差异.结论 丹参多糖无毒,可安全使用.     

The sub-chronic toxicity in rats of isoparaffinic solvents

Results from a 13-week inhalation study in rats on a C10–C12 isoparaffinic solvent are compared to the results of repeated inhalation and oral toxicity studies of four other isoparaffinic hydrocarbon solvents. Statistically significant findings which were consistent across all studies included: nephropathy and small but significant changes in hematological parameters in male rats and liver enlargement in both male and female rats. The male rat kidney changes were due to an alpha 2u globulin process and not relevant for human health or risk assessment. The liver enlargement without pathologic changes or elevations in liver enzyme markers was considered to be an adaptive response. The reason for the reductions in hematological parameters that were observed in males only is not clear, but it is suggested that these were either due to normal variation or a secondary consequence of the nephropathy. The overall No Observed Adverse Effect Concentration (NOAEC) was the highest concentration tested in the study, >10,000 mg/m³. Because of the overall pattern of response, this solvent is considered to be representative of low aromatic C9–C14 aliphatic solvents in general. The data are useful for risk assessment and other purposes including the development of occupational exposure recommendations.     

The sub-chronic toxicity of regular White Spirit in rats

Hydrocarbon solvents are mostly complex substances (UVCB) with carbon numbers in the range of approximately C5–C20. One of the most common types is a C9–C14 aliphatic solvent containing approximately 20% aromatics and commonly known as White Spirit in Europe and mineral spirits in the US. In previous repeated inhalation toxicity studies, White Spirit was reported to cause minimal systemic effects in most animal species with few effects other than male rat-specific kidney changes at levels up to approximately 2000 mg/m³. In the present study male and female rats were exposed to White Spirit vapors, 6 h/day, 5 days/week for 13 weeks at levels of approximately 2000, 4000, or 8000 mg/m³ to assess the potential for effects at higher exposure levels. All of the rats survived the treatment period. In life observations were largely restricted to acute central nervous system (CNS) effects in the high exposure group. Terminal body weights of high exposure groups animals were significantly below control values. Statistically significant differences in the clinical and hematological observations were small and within normal physiological limits. Weights of some organs including liver, spleen and kidneys were elevated, but microscopic examination indicated that the only pathological effects were changes in the kidneys of the male rats, consistent with an α2u-globulin-mediated process, which is gender and species-specific and not relevant to humans. The overall no observed adverse effect level (NOAEC) was 4000 mg/m³.     

Evaluation of the safety of primary metabolites of cyadox: Acute and sub-chronic toxicology studies and genotoxicity assessment

Cyadox (CYA) is a synthetic antimicrobial agent, belonging to quinoxaline (QdNO) family. Cy1 (bidesoxy cyadox), Cy2 (N4-desoxycyadox) and Cy10 (N1-desoxycyadox) are the primary metabolites of CYA. In our present study, an acute toxicity test, a sub-chronic toxicity test, and a battery of three genotoxicity tests were carried out according to standard protocols. The LD50 of the metabolites were above 5000 mg/kg b.w. The maximum tolerated dose (MTD) of Cy1 and Cy-M (mixture of Cy2 and Cy10) in rats, and the MTD of Cy1, Cy2 and Cy10 in mice were above 6000 mg/kg b.w./day. In subchronic study, rats were separately administered Cy1 and Cy-M at the dose levels of 0, 50, 150 and 2500 mg/kg diet for 90 days, with CYA (2500 mg/kg) as a control. Significant decreases in body weight and changes in clinical serum biochemistry were observed in the high-dose group of Cy1 and Cy-M, as well as CYA. Significant changes in relative weights of organs at 150 and 2500 mg/kg diet of Cy1 and CYA were noted. Additionally, the high-dose groups of Cy1, Cy-M and CYA showed pathological changes near the hepatic portal area. There was no evidence for genotoxic activity of any of the three metabolites in the bacterial reverse mutation test, mouse bone marrow micronucleus assay or an in vitro assay for clastogenicity. Based on the subchronic study, the target organ of the primary metabolites was the liver, and the no-observed-adverse-effect level for Cy1 and Cy-M was 150 mg/kg diet.     

Safety assessment of methanol extract of red dragon fruit (Hylocereus polyrhizus): Acute and subchronic toxicity studies

Recently, the fruits of Hylocereus polyrhizus, known as red dragon fruit, have received much attention from growers worldwide. However, there is little toxicological information regarding the safety of repeated exposure to these fruits. The present study evaluated the potential toxicity of a methanol extract of H. polyrhizus fruit after acute and subchronic administration in rats. In the acute toxicity study, single doses of fruit extract (1250, 2500 and 5000 mg/kg) were administered to rats by oral gavage, and the rats were then monitored for 14 days. In the subchronic toxicity study, the fruit extract was administered orally to rats at doses of 1250, 2500 and 5000 mg/kg/day for 28 days. There was no mortality or signs of acute or subchronic toxicity. There was no significant difference in body weight, relative organ weight or hematological parameters in the subchronic toxicity study. Biochemical analysis showed some significant changes, including creatinine, globulin, total protein and urea levels. No abnormality of internal organs was observed between treatment and control groups. The lethal oral dose of the fruit extract is more than 5000 mg/kg and the no-observed-adverse-effect level (NOAEL) of the extract for both male and female rats is considered to be 5000 mg/kg per day for 28 days.     

Acute and 30-day oral toxicity studies of administered carnosic acid

Purpose

Increasing interest in carnosic acid (CA) is due to its pharmacological properties. The aim of this study was to evaluate the acute and 30-day oral toxicity of CA.

Methods

The acute oral toxicity study in Kuming mice design followed the OECD-guidelines 423, and a 30-day chronic oral toxicity study in Wistar rats based on the enhanced OECD test guideline 407 were performed.

Results

The oral lethal dose (LD50) for mice was 7100 mg/kg of body weight in the acute toxicity study. The histopathological changes were observed in the heart, liver and kidney for the survival mice treated with a single dose CA. For the sub chronic toxicity study, CA administered for 30 days produced slightly reductions in the weight gain pattern, which did not reach the significant level when compared with the control values. With respect to serum biochemistry test, decreased total serum protein levels, but conversely increased aspartate aminotransferase (AST) levels were detected in the high-dose and moderate-dose groups. Histopathologically, light pathological changes were observed in the heart, liver, and kidney of rats treated with the high-dose CA.

Conclusion

The present work suggests that a short-term oral administration of CA has a relatively low toxicity profile.     

A 13-week sub-chronic dietary toxicity study of a cruciferin-rich canola protein isolate in rats

The objective was to evaluate the safety of a cruciferin-rich canola protein isolate (Puratein^®) when fed as a protein source at various dietary levels to rats for 13-weeks. The study included four groups (20 animals/sex/group) of young Sprague Dawley rats. They were fed ad libitum with an AIN-93 G based protein-free diet added respectively with 5%, 10% and 20% (w/w) Puratein^® (test article) or 20% (w/w) vitamin-free casein (control article). Protein levels were adjusted in all groups at 18% using vitamin-free casein. Body weights, food consumption, locomotor activity and behavioral and clinical pathology parameters were recorded at various points of the study, followed by macroscopic examination, determination of organ weights and microscopic tissue examination. There were no test article-related effects on body weight, food consumption, clinical observations, functional observational battery, motor activity, clinical pathology, or ophthalmic examinations. A slightly higher thyroid/parathyroid weight (g/100 g BW) noted in the 20% Puratein^® group was not correlated with histopathological changes. The no-observed-effect-level (NOEL) was 10%, whereas the no-observed-adverse-effect-level (NOAEL) was the highest fed level of 20%, equivalent to 11.24 g/kg BW/day for males and 14.11 g/kg BW/day for females. The cruciferin-rich canola protein isolate (Puratein^®) was considered safe under the conditions tested.     

银杏苁蓉配方急性毒性和亚慢性毒性实验研究

目的观察银杏苁蓉配方的毒性。方法按照《保健食品检验与评价技术规范》2003年版中的相关规定,进行银杏苁蓉片的急性毒性实验和90d喂养实验。结果银杏苁蓉配方的大鼠最大耐受剂量(MTD)大于15g·kg~(-1)·bw~(-1),属无毒级;将受试物掺入饲料中,自由摄取连续90d,大鼠体质量和食物利用率均无异常改变,各项血常规和生化指标均在本实验室正常指标值范围内,高剂量组和对照组动物各脏器的病理组织检查亦未见明显病变,未观察到有害作用(NOAEL),剂量为0.7g·kg~(-1)·bw~(-1)。结论可以判断银杏苁蓉配方为无毒物,未见急性毒性和亚慢性毒性。     

Toxicity evaluation of hydroalcoholic extract of Ferula gummosa root

Traditionally, people use harvested Ferula gummosa for medicinal purposes. However, no information about its safety and toxicity is available. In the present study, the toxicological profile of sub-chronic oral administration of hydroalcoholic extract of F. gummosa radix is evaluated in rats. The extract was orally administrated at 100 and 600 mg/kg to male rats for 28 days. After 28 days, clinical signs, mortality, body weights, food and water consumption, organ weights, hematology, serum biochemistry, as well as histopathological and neurobehavioral changes were examined. Also, the sedative effect of this extract was evaluated in mice at the doses of 100, 600, and 800 mg/kg. Its cytotoxicity against human stroma-vascular cells and human renal epithelial cells were also evaluated. No lethality or adverse toxic signs were seen during the experimental period. There were no significant changes in body and organ weights, hematology, serum biochemistry, and histopathological examination. The extract decreased the rotarod performance, but did not increase pentobarbital-induced hypnosis. Also, F. gummosa extract significantly decreased cell viability at the concentrations of higher than 400 μg/mL. In conclusion, the sub-chronic toxicity study of F. gummosa hydroalcoholic extract demonstrated the extract to be safe for the tested dosage and route of administration.     

Acute and subacute toxicity studies on triptolide and triptolide-loaded polymeric micelles following intravenous administration in rodents

Except its anti-tumour effects, triptolide (TP) also shows multiple pharmacological side activities, such as immune-suppressive and male anti-fertility. To increase the therapeutic index of TP, a novel polymeric micelle system containing TP (TP-PM) has been developed to treat tumour. Our previous studies have demonstrated the good anti-tumour efficacy of TP-PM. This paper investigated the acute toxicity in mice and subacute toxicity in rats of TP-PM and TP. Results demonstrated that the LD₅₀ for TP-PM and TP administered intravenously were 1.06 mg/kg and 0.83 mg/kg in mice, respectively. In subacute toxicity study, TP-PM and TP were administered intravenously at the dose levels of 0.1 mg/kg and 0.3 mg/kg for 14 d. Compared to the control, there was significant decrease in the serum AST activities, the testis ACP activities, thymus index, testis index, and significant increase in spleen index, and obvious histopathological changes in rats treated with TP, however, the toxicities of TP-PM on liver, kidney, testis and spleen are slighter than TP. Compared to TP, TP-PM significantly increased the ACP activity of the testis and decreased the MDA level in serum. So, the polymeric micelles may be a novel drug delivery carrier of TP for reducing the toxicities of TP.     

Acute and repeated dose toxicity studies of recombinant saxatilin, a disintegrin from the Korean snake (Gloydius saxatilis).

To examine the toxicological effect of saxatilin, a disintegrin isolated from the venom of a Korean snake (Gloydius saxatilis), recombinant saxatilin was highly expressed as a biologically active form in Pichia pastoris, and was successfully purified to homogeneity from the culture broth supernatant. The molecular and biological properties of the recombinant protein were the same as those of its natural form. Plasma half-life of the protein in rat was determined to 13.8 min. The maximum tolerated dose of the recombinant saxatilin was examined in ICR mice. The determined LD(50) values were 400 and 600 mg/kg of the body weight of a male and female mouse, respectively. To investigate the repeated dose toxicity of saxatilin in mice, the test item was intravenously administered to groups of ICR mice every day for 4 weeks. We observed a decrease in locomotor activity, piloerection, and crouching in clinical findings, a decrease of red blood cells (RBCs) in hematology, and hyperplasia of the spleen in histology related to administration of the test item. These results suggest that the target organ of intravenous administration of the test item is the spleen. The no adverse effect level (NOAEL) in this test for both males and females is considered to be 3mg/kg. Our results also indicate that recombinant saxatilin is non-toxic at an administration dose with an anti-platelet effect, and might be a potential anti-adhesion therapeutic agent for thrombosis, cancer, restenosis, cataract, and osteoporosis.     

Evaluation of the sub-chronic toxicity of a standardized flavonoid extract of safflower in rats

Carthamus tinctorius L., or safflower, is an annual herbaceous crop belonging to the family Asteraceae, which is cultivated throughout China and used as a traditional Chinese medicine. Our previous study revealed anti-Parkinson's disease effects of an isolated standardized safflower flavonoid extract (SAFE). The purpose of this study is to evaluate the potential sub-chronic toxicity of SAFE. Male and female Sprague Dawley rats received three doses of SAFE (100, 300, and 500 mg/kg) q.d. by gavage for four weeks. Body weights were measured during the experiment, and blood samples were collected once per week for hematological and serum biochemical parameters. Major organs were examined after execution and histopathological analyses were performed. Body weight gain in the administration groups showed no decline compared to the control group. However, there were changes in values of aspartate transaminase (p < 0.05), alanine transaminase (p < 0.05), and blood glucose (p < 0.05) between treatments. SAFE influenced parameters related to platelets in rats receiving SAFE for both sexes under different dosages (p < 0.05). No histopathological changes were observed. SAFE might have influence on conglomeration of platelets, transaminases, and blood glucose. SAFE caused no significant toxicity and further studies may be needed to ensure safety of SAFE.     

Acute toxicity of pinnatoxins E, F and G to mice

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

二巯丁二酸对小鼠的急性毒性作用

目的探讨二巯丁二酸（DMSA）对小鼠的急性毒性作用。方法20只昆明小鼠，雌雄各半，体质量（21．2±2．3）g，适应性喂养3d，按体质量随机分为对照组和实验组，给药前禁食12h，实验组每只小鼠于24h内分4次经口给予DMSA160mg，对照组给予等体积的去离子水，观察1周，然后摘除眼球取血，置于肝素化试管，5000r／min，离心5min，取血浆；处死小鼠，取其脑、心脏、肝脏和肾脏，0．9％氯化钠溶液清洗。测定抗氧化酶系统、过氧化产物、血尿素氮、血肌酐及氨基转移酶水平。结果（1）试验观察期内小鼠出现消化道症状，进食减少，体质量降低，腹腔轻度积水，此外未见其他明显中毒症状；（2）脑组织、肝脏和肾脏超氧化物歧化酶（SOD）活性降低，但差异无统计学意义（P〉0．05），谷胱甘肽过氧化物酶（GSH—PX）活性明显降低（P〈0．01），肝脏丙二醛（MDA）显著性升高（P〈0．01）；（3）血尿素氮和肌酐水平显著性升高（P〈0．001）；血氨基转移酶升高（P〈0．001），而肝肾氨基转移酶无显著性变化。结论二巯丁二酸抑制机体抗氧化系统，对肝脏和肾脏具有毒性作用。     

Acute toxicity of gymnodimine to mice.

The acute toxicity of the phycotoxin gymnodimine to female Swiss mice by intraperitoneal injection and by oral administration has been determined. Gymnodimine was highly toxic by injection, the LD50 being only 96 microg/kg. Animals either died within 10 min of injection or made a full recovery with no perceptible long-term effects. Gymnodimine was also toxic after oral administration by gavage (LD50 755 microg/kg), but was much less toxic when administered with food. No signs of toxicity were seen in mice voluntarily ingesting food containing gymnodimine at a level sufficient to give a dose of approximately 7500 microg/kg. Pre-treatment with physostigmine or neostigmine protected against injected gymnodimine, suggesting that the latter exerts its toxic effects via blockade of nicotinic receptors at the neuromuscular junction. The low toxicity of gymnodimine when ingested with food suggests that this compound is of low risk to humans, a conclusion that is consonant with anecdotal evidence for the absence of harmful effects in individuals consuming shellfish contaminated with gymnodimine.     

Toxicological studies on aqueous extract of Gmelina arborea in rodents

Context:?Gmelina arborea Roxb. (Verbenaceae) is an important medicinal plant in the traditional system of medicine of India. The plant is used in the treatment of snake-bites, fever, piles, and diabetes. However, there is little toxicological information available regarding its safety after exposure. The present study was designed to evaluate acute and repeated dose toxicity of the aqueous extract of Gmelina arborea stem bark.

Materials and methods:?In the acute toxicity test, Swiss albino mice were treated with aqueous extract (300, 2000, and 5000?mg/kg), orally. Animals were observed periodically during the first 24?h after administration of the extract, and daily thereafter for 14 days. In the repeated dose toxicity study, the aqueous extract of Gmelina arborea (300, 1000, and 2000?mg/kg per day) was administered orally for a period of 28 days in Wistar rats. The effects on body weight, food and water consumption, organ weight, hematology, clinical biochemistry, as well as histology, were studied.

Results and conclusion:?Aqueous extract did not produce mortality, changes in behavior or any other physiological activities in mice, for any of the selected doses. There were no significant differences in the body weight, organ weights and feeding habits between control and treated animals. Hematological and biochemical analysis showed no marked differences in any of the parameters examined in either the control or treated groups. Pathologically, neither gross abnormalities nor histopathological changes were observed. The aqueous extract of Gmelina arborea was found safe in acute and repeated dose toxicity studies when tested in rodents.