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The purpose of this study was to investigate the NOAEL of the nickel ion and provide with basic data for the biological evaluation of those medical devices containing nickel. Five groups SD rats were repeatedly exposed during 14 d respectively to nickel at first stage doses of 4.9, 3.7, 2.5 mg/(kg.d), and the second stage doses of 1.2, 0.25 mg/(kg.d) by the intravenous route. The results showed that the NOAEL of nickel ion is 0.25 mg/(kg.d) for SD rats, and the result was verified by subchronic systemic toxicity test of nickel alloy. The threshold of toxicological concern (TTC) of nickel is 150 μg/d (based on application of 100-fold uncertainty factor and a body weight of 60 kg)deduced by these data.
Subject(s)
Animals , Rats , Equipment and Supplies/adverse effects , Nickel/toxicity , No-Observed-Adverse-Effect Level , Rats, Sprague-Dawley , Risk AssessmentABSTRACT
Abstract The present study was aimed to characterize the chemical profile and evaluate the cytotoxicity and sub-chronic toxicity of the hydroethanolic extract of the xylopodium Mandevilla velame (A.St.-Hil.) Pichon, Apocynaceae. Chemical profile was analyzed by high performance liquid chromatography. Cytotoxic potential of hydroethanolic extract of the xylopodium M. velame was evaluated using Chinese hamster ovary cells. The sub-chronic assessment was done on rats with hydroethanolic extract of the xylopodium M. velame (50, 200 and 800 mg/kg) was orally administered daily for 30 consecutive days. High performance liquid chromatography analysis confirmed the presence of gallic acid, ellagic acid, catechin, epigallocatechin gallate, naringin, myricetin, quercetin and naringenin. hydroethanolic extract of the xylopodium M. velame tested concentrations did not alter the viability of Chinese hamster ovary cells. In the sub-chronic test, 50 and 200 mg/kg were safe, but there were significant changes in relation to weight gain and water consumption by animals that received 800 mg/kg of hydroethanolic extract of the xylopodium M. velame. Among the haematological and biochemical parameters evaluated, only the number of neutrophils, lymphocytes, and creatinine concentration were changed at 800 mg/kg. Phytochemical profile of hydroethanolic extract of the xylopodium M. velame revealed the presence of phenolics and flavonoid compounds. The in vitro cytotoxicity assay result demonstrated that hydroethanolic extract of the xylopodium M. velame had no cytotoxic effects in Chinese hamster ovary cells. In the in vivo models, hydroethanolic extract of the xylopodium M. velame was shown to be relatively safe after sub-acute administration in rats which is relation to that the population daily takes a total dose of the plant xylopodium decoction or infusion about 23.29 times lower than the no-observed-adverse effect level dose in rats.
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Objective To observe the protective and regeneration-promoting effects of Ruyi Zhenbao Pill (RZP) on nerve injury in zebrafish.Methods The zebrafish model of central nervous injury was induced by mycophenolate mofetil,the model of peripheral motor nerve and axonal injury was induced by ethanol,and the model of myelin damage was induced by ethidium bromide.The variations of central nerve,axon and myelin sheath fluorescence intensity,and peripheral motor nerve length in zebrafish,which exposed to the different concentration (10.0,33.3,and 100.0 μ.g/mL) of RZP,were observed with fluorescence microscope.The effective protection rates of RZP on zebrafish central nerve and axone,and the regeneration-promoting effect on peripheral motor nerve and myelin sheath were analyzed and calculated with the image processing software NIDS-Element's.Results In 10.0,33.3,and 100.0 μg/mL RZP groups,the zebrafish central nervous injury protective rates were 2％,24％,and 50％ (P ＜ 0.001),respectively,the peripheral nerve regeneration promoting rates were 44％ (P ＜ 0.05),49％ (P ＜ 0.01),and 93 ％ (P ＜ 0.001),the axonal injury recovery rates were 3％,29％ and 48％ (P ＜ 0.05),and the myelin sheath regeneration promoting rates were 36％ (P ＜ 0.01),37％ (P ＜ 0.001),and 41％ (P ＜ 0.001),compared with model group.Conclusions RZP could not only protect the central nervous and axonal injury,but also promote the regeneration of peripheral nerve and myelin sheath in zebrafish.
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BACKGROUND/OBJECTIVES: Turanose, α-D-glucosyl-(1→3)-α-D-fructose, is a sucrose isomer which naturally exists in honey. To evaluate toxicity of turanose, acute and subchronic oral toxicity studies were conducted with ICR mice. MATERIALS AND METHODS: For the acute oral toxicity study, turanose was administered as a single oral dose [10 g/kg body weight (b.w.)]. In the subchronic toxicity study, ICR mice were administered 0, 1.75, 3.5, and 7 g/kg b.w. doses of turanose daily for 13 weeks. RESULTS: No signs of acute toxicity, including abnormal behavior, adverse effect, or mortality, were observed over the 14-day study period. In addition, no changes in body weight or food consumption were observed and the median lethal dose (LD₅₀) for oral intake of turanose was determined to be greater than 10 g/kg b.w. General clinical behavior, changes in body weight and food consumption, absolute and relative organ weights, and mortality were not affected in any of the treatment group for 13 weeks. These doses also did not affect the macroscopic pathology, histology, hematology, and blood biochemical analysis of the mice examined. CONCLUSION: No toxicity was observed in the acute and 13-week subchronic oral toxicology studies that were conducted with ICR mice. Furthermore, the no-observed-adverse-effect level is greater than 7 g/kg/day for both male and female ICR mice.
Subject(s)
Animals , Female , Humans , Male , Mice , Body Weight , Hematology , Honey , Mice, Inbred ICR , Mortality , No-Observed-Adverse-Effect Level , Organ Size , Pathology , Sucrose , ToxicologyABSTRACT
In the development process from the preclinical stage to the subsequent clinical phase,one critical risk controlling step is the determination of the first-in-human (FIH) dose.There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs,therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals.This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL,MABLE,and PK/PD model.The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe,although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented.It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product.Early communication between sponsors and regulators is always beneficial.
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In the development process from the preclinical stage to the subsequent clinical phase,one critical risk controlling step is the determination of the first-in-human (FIH) dose.There is difference in the mechanisms of action and toxic risks between biopharmaceuticals and small molecule drugs,therefore different considerations will be involved in the determination of the FIH dose for biopharmaceuticals.This paper presents the overall review of the preclinical studies supporting the determination of FIH dose and the approaches based on the NOAEL,MABLE,and PK/PD model.The experience-based views that the MABLE-based FIH dose for immune activating products would be reasonably safe,although the NOAEL approach remains conservative and widely used for a majority of biopharmaceuticals are also presented.It is suggested that sponsors should determine the appropriate and safe FIH dose by diverse approaches according to the characteristics of product.Early communication between sponsors and regulators is always beneficial.
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Objective To observe toxic symptoms and signs , toxic damage extents and reversibility in rats after oral administration of Tangwang Mingmu granules .Methods Four dose groups with 40 rats in each group were designed in this study, including control group fed with distilled water and three groups at different dosages of the test drug .Tangwang Mingmu granules were orally administered to SD rats at the dosage of 8.4, 4.2 and 2.1 g/kg for 3 weeks and 14.0, 8.4 and 4.2 g/kg for 23 weeks, for 26 consecutive weeks .The general state of the rats was observed every day , while body mass and food consumption were calculated once a week .Halfway through and at the end of the administration (13 and 26 weeks) and after four weeks of recovery, parameters of body mass, hematology, hematological biochemistry, organ/body mass ratio and histopathology were measured .Results Compared with the control group at the same time-point, body mass of male rats in the other three groups was slightly reduced .Food consumption in high and medium dose groups was reduced (P<0.05), MCHC, ALT, TBIL and Na +in high dose group were decreased (P<0.05), TP, ALB and D-BIL were increased (P<0.05), the mean body mass and relative organ weight of thymus in medium dose male rats were decreased (P<0.05), relative organ weight of the liver and kidney in high dose male rats was increased (P<0.05), and focal chronic inflammation to different extent was observed in the liver , kidney and prostate gland .No dose-effect relationship was found in these perturbations that were all within the normal range of animals .No significant drug-related pathological changes were found.Conclusion The NOAEL of Tangwang Mingmu granules is considered to be 14.0 g/kg body mass/day (equal to 50 times the proposed clinical adult dosage ) for the 26-week repeated dose oral toxicity study in male andfemale rats.
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Objective To study the subacute inhalation toxicity of Ivermectin TC, and obtain its non-observed adverse effect level(NOAEL).Methods It was performed on the doses of Ivermectin TC 190, 380, 750 mg/m3, the solvent control group (0.03%Tween-80 solution) , the control group and additional group ( there were 6 female and 6 male Sprague-Dawley rats for each group) .The animals inhaled with nose-only exposure for 4 weeks (4 h/d, 5 d/week) .The additional group should be observed another 14 days after exposing.At the end of experiment, the rats were killed, the routine and biochemical detection, the body weight and organ to body weight ratios were all measured.Results In the high exposure group, clinical signs of rats included hair fluffy, dull, salivation, tremors were recorded at the exposure period;in female rats, feed efficiency was decreased, ALT and liver to body weight ratio were increased; in male rats, BUN and ALT were increased, CHOL and body weight for the 4th week were decreased.Histopathological examinations revealed that swelling in the liver cell was seen in some female rats at high exposure group.Conclusion The results suggested that the NOAEL of Ivermectin TC in SD rats was 380 mg/m3(4 h/d for 28 days).
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Introduction: One of the most frequent problems found in medicinal plants is the absence of clinical, toxicological, and pharmacological studies. Valeriana pavonii is one of the species used in Colombia as an anxiolytic. Further study of this specie is rendered to add information in the toxicological area. Objective: The acute and subchronic oral toxicity of V. pavonii ethanolic extract was evaluated in Wistar rats of both sexes. Materials and methods: The rats were distributed into four groups: the control group received the vehicle (0.5 mL/100 g of corporal weight) and the other three groups received increasing levels of the dosage for 90 days to evaluate characteristics like physical exam, laboratory test (blood chemistry and haematology), and anatomopathological findings. Results: This study reveals that there were no signs of toxicity, mortality, or significant alterations attributable to the ethanolic extract of V. pavonii. Conclusions: The Not Observed Adverse Effect Levels (NOAEL) of V. pavonii ethanolic extract were 2000 and 1000 mg/kg of body weight for the acute and subchronic toxicity studies, respectively.
Introducción: Uno de los problemas más frecuentes asociados con el uso de plantas medicinales es la ausencia de evidencias farmacológicas, toxicológicas y clínicas. Valeriana pavonii es una de las especies más utilizadas popularmente en Colombia con fines ansiolíticos. Es necesario avanzar en el estudio de esta especie para aportar información en el campo toxicológico. Objetivos: Evaluar la toxicidad oral aguda y sub-crónica del extracto etanólico de V. pavonii en ratas Wistar de ambos sexos. Materiales y métodos: En cada uno de los estudios se distribuyeron ratas en cuatro grupos; un grupo control que recibió únicamente vehículo (0.5 ml/100 g de peso corporal) y tres grupos correspondientes a niveles crecientes de dosis, así: para el estudio de toxicidad aguda se administraron en dosis única 20, 200 y 2000 mg/kg con un período de observación de 14 días y para el de toxicidad sub-crónica, dosis diarias de 250, 500 y 1000 mg/kg durante 90 días. Se evaluaron los parámetros de examen físico, los exámenes de laboratorio (química sanguínea y hematología) y el estudio anatomopatológico. Resultados: No se presentaron signos de toxicidad, letalidad ni alteraciones significativas atribuibles al consumo del extracto etanólico de V. pavonii, según el examen físico, el examen anatomopatológico y el análisis de las pruebas de química sanguínea y hematología. Conclusiones: Los valores de nivel sin efectos adversos observados (NOAEL) del extracto etanólico de V. pavonii, fueron 2000 y 1000 mg/kg de peso corporal para los estudios de toxicidad aguda y sub-crónica, respectivamente. No se encontraron valores de nivel más bajo de efecto adverso observado (LOAEL).
Subject(s)
Animals , Rats , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/toxicity , Plants, Medicinal/toxicity , Toxicity Tests/classification , Toxicity Tests/statistics & numerical data , Toxicity Tests/methods , Toxicity Tests/veterinary , Valerian , Valerian/toxicity , Ethanol/pharmacology , Ethanol/toxicityABSTRACT
Aedes aegypti mosquito is one of the most notorious vectors of dangerous diseases like dengue hemorrhagic fever and chikangunya. One method of control of the vectors is by the use of semiochemicals or pheromones. The pheromone n-heneicosane (C21) has been proved to be effective in attracting the female Aedes aegypti to lay eggs in the treated water and the growth of the larva is controlled by insect growth regulator diflubenzuron (DB). This study was planned to assess the safety of C21 alone and the combination with DB. Acute toxicity tests were carried out using two doses, viz., 1600 and 3200 mg/kg and two routes of exposure oral and intra-peritoneal. Dermal toxicity test was carried out in both male and female rats at the dose of 3200 mg/kg. Primary skin irritation test was carried out in rabbits. Sub-acute (90 days) dermal toxicity studies in male and female rats at the dose of 1 and 2 mg/kg via the per-cutaneous route were also studied. Sub-acute (90 days) toxicity test through the oral route was carried out, at doses 125, 250 and 500 mg/kg in male and female rats. The calculated LD50 by ip route and dermal route was more than 5 g/kg in mouse and rats of both the sexes. In the primary skin irritation test no significant changes were noted. In the sub-acute toxicity studies even 500 mg/kg dose was not able to produce toxic response in rats when they were dosed daily for 90 days. The established no observed adverse effect level (NOAEL) was more than 500 mg/kg.
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In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.
Subject(s)
Animals , Rats , Chemistry, Clinical , Hematology , Japan , Jurisprudence , No-Observed-Adverse-Effect Level , Organ Size , UrinalysisABSTRACT
In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.