Alternative Methods for the Median Lethal Dose (LD50) Test: The Up-and-Down Procedure for Acute Oral Toxicity

Toxicological assessment is a mandatory research step in the development of new insecticidal drugs. At the All-Russian Research Institute of Veterinary Entomology and Arachnology, a prototype of the insecticidal bait Mukhnet IF was obtained with an active ingredient content of 0.06% ivermectin and 0.015% fipronil, which showed a highly effective effect against houseflies. This work presents the results of the study of acute oral toxicity of the above agent. For this, male white mice with a live weight of 16-26 g were selected. They were kept on a starvation diet for one day in individual houses with water. The drug was given in mg/kg body weight the next day. A total of 33 doses have been tested, ranging from 100 mg/kg to 40,000 mg/kg. The animals were observed for 14 days. According to the research results, it was revealed that at doses up to 20,000 mg/kg there were no signs of intoxication, but when tested at 25,000 mg/kg in some mice, these signs were noted, and at 30,000, 35,000 and 40,000 mg/kg deaths were recorded 20±10, 45±30 and 60±20%, respectively. It was not possible to test the drug over the last above dose due to incomplete eaten by mice. According to the degree of danger for warm-blooded animals, the drug belongs to the 4th class of low-hazard drugs (average lethal dose of 5000 mg/kg or more) in accordance with the classification of GOST 12.1.007-76. When analyzing the literature data on the toxicological characteristics of preparations containing ivermectin and chlorfenapyr, it was revealed that the insecticidal agent in its acute toxicity for warm-blooded animals is comparable to known analogues.

Download Full-text

Sensitivity of The Stripe-Faced Dunnart, Sminthopsis Macroura (Gould 1845), To The Phenyl Pyrazole Insecticide, Fipronil, Toxicological Signs And Implications For Pesticide Risk Assessments In Australia

10.21203/rs.3.rs-890972/v1 ◽

2021 ◽

Author(s):

Paul Story ◽

Lyn A Hinds ◽

Steve Henry ◽

Andrew C. Warden ◽

Greg Dojchinov

Keyword(s):

Lethal Dose ◽

Risk Assessments ◽

Eutherian Mammal ◽

Oral Toxicity ◽

Median Lethal Dose ◽

Agricultural Pesticides ◽

Sminthopsis Macroura ◽

The Difference ◽

Ld50 Value ◽

Female Responses

Abstract A lack of toxicity data quantifying responses of Australian native mammals to agricultural pesticides prompted an investigation into the sensitivity of the stripe-faced dunnart, Sminthopsis macroura (Gould 1845) to the insecticide, fipronil (5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl pyrazole, CAS No. 120068-37-3). Using the Up-And-Down method for determining acute oral toxicity in mammals, derived by the Organisation for Economic Cooperation and Development (OECD), median lethal dose estimates of 990 mg kg− 1 (95% confidence interval (CI) = 580.7–4770.0 mg kg− 1) and 270.4 mg kg− 1 (95% CI = 0.0 - >20000.0 mg kg− 1) were resolved for male and female S. macroura respectively. The difference between median lethal dose estimates for males and females may have been influenced by the increased age of two female dunnarts. Further modelling of female responses to fipronil doses used the following assumptions: (a) death at 2000 mg kg− 1, (b) survival at 500 mg kg− 1 and (c) a differential response (both survival and death) at 990 mg kg− 1. This modelling revealed median lethal dose estimates for female S. macroura of 669.1 mg kg− 1 (95% CI = 550–990 mg kg− 1; assuming death at 990 mg kg− 1) and 990 mg kg− 1 (95% CI = 544.7–1470 mg kg− 1; assuming survival at 990 mg kg− 1). These median lethal dose estimates are 3–10-fold higher than the only available LD50 value for a similarly sized eutherian mammal, Mus musculus (L. 1758; 94 mg kg− 1) and that available for Rattus norvegicus (Birkenhout 1769; 97 mg kg− 1). Implications for pesticide risk assessments in Australia are discussed.

Download Full-text

ACUTE ORAL TOXICITY STUDY OF ETHANOLIC EXTRACT OF ACTINOSCIRPUS GROSSUS (L.F.) GOETGH. AND D.A. SIMPSON

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i7.21688 ◽

2018 ◽

Vol 11 (7) ◽

pp. 321

Author(s):

Savin Chanthala Ganapathi ◽

Rajendra Holla ◽

Shivaraja Shankara Ym ◽

Ravi Mundugaru

Keyword(s):

Body Weight ◽

Lethal Dose ◽

Ethanolic Extract ◽

Female Rats ◽

Test Substance ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Healthy Female ◽

Ld50 Value ◽

Toxic Potential

Objective: To study the acute oral toxicity of ethanolic extract of Actinoscirpus grossus (L.f.) Goetgh. and D.A. Simpson in Wistar albino rats.Methods: Ethanolic extract of the plant was assessed for single dose acute toxicity by employing Organisation for Economic Co-Operation and Development(OECD) guidelines 425 using Acute Oral Toxicity(AOT) software. The dosed (up or down as per the requirement) rats were observed for 14 days for general appearance, behavior, mortality, and necropsy. A total of 5 healthy female rats of body weight 225±25 g were used.Results: The test substance did not produce any mortality up to the dose of 2000 mg/kg per oral.Conclusion: Test substance is without any toxic potential even at the dose of 2000 mg/kg in animals and the Lethal Dose (LD50) value of A. grossus (L.f.) Goetgh. and D.A. Simpson was found to be more than 2000 mg/kg body weight.

Download Full-text

Acute, Subacute, and Genotoxicity Assessments of a Proprietary Blend of Garcinia mangostana Fruit Rind and Cinnamomum tamala Leaf Extracts (CinDura®)

Journal of Toxicology ◽

10.1155/2020/1435891 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Sundararaju Dodda ◽

Venkata Krishnaraju Alluri ◽

Trimurtulu Golakoti ◽

Krishanu Sengupta

Keyword(s):

Body Weight ◽

Wistar Rats ◽

Lethal Dose ◽

Toxicity Study ◽

Mouse Bone Marrow ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Garcinia Mangostana ◽

Cinnamomum Tamala ◽

Fruit Rind

The present communication describes a battery of toxicity studies that include an acute oral toxicity, a subacute twenty-eight-day repeated oral dose toxicity, and genotoxicity studies on a herbal formulation CinDura® (GMCT). This proprietary herbal composition contains the extracts of the Garcinia mangostana fruit rind (GM) and the Cinnamomum tamala leaf (CT). The toxicological evaluations were performed following the Organization for Economic Cooperation and Development (OECD) guidelines. The acute oral toxicity study in Wistar rats suggests that the median lethal dose of CinDura® is at least 2000 mg/kg body weight. Acute dermal and eye irritation tests in New Zealand white rabbits indicate that the test item is nonirritant to the skin and eyes. A twenty-eight-day repeated dose oral toxicity study was conducted in male and female Wistar rats using daily doses of 250, 500, and 1000 mg/kg body weight, followed by a fourteen-day reversal period for two satellite groups. The CinDura®-supplemented animals did not show any sign of toxicity on their body weights, organ weights, and on the hematobiochemical parameters. The gross pathology and histopathological examinations indicated no treatment-related changes in the experimental animals. Overall, the no-observed-adverse-effect level (NOAEL) of the herbal blend is 1000 mg/kg body weight, the highest tested dose. Also, the results of the bacterial reverse mutation test and the erythrocyte micronucleus assay in mouse bone marrow suggest that CinDura® (GMCT) is neither mutagenic nor clastogenic.

Download Full-text

A Tutorial for Analysing the Cost-effectiveness of Alternative Methods for Assessing Chemical Toxicity: The Case of Acute Oral Toxicity Prediction

Alternatives to Laboratory Animals ◽

10.1177/026119291404200204 ◽

2014 ◽

Vol 42 (2) ◽

pp. 115-127 ◽

Cited By ~ 5

Author(s):

Hedvig Norlen ◽

Andrew P. Worth ◽

Silke Gabbert

Keyword(s):

Cost Effectiveness ◽

Alternative Methods ◽

Acute Oral Toxicity ◽

Chemical Toxicity ◽

Toxicity Prediction ◽

Oral Toxicity ◽

The Cost

Download Full-text

QSAR and Classification Study on Prediction of Acute Oral Toxicity of N-Nitroso Compounds

International Journal of Molecular Sciences ◽

10.3390/ijms19103015 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3015 ◽

Cited By ~ 14

Author(s):

Tengjiao Fan ◽

Guohui Sun ◽

Lijiao Zhao ◽

Xin Cui ◽

Rugang Zhong

Keyword(s):

External Validation ◽

Lethal Dose ◽

Nitroso Compounds ◽

Acute Oral Toxicity ◽

Classification Models ◽

Toxicity Data ◽

Oral Toxicity ◽

Qsar Studies ◽

Dragon Descriptors

To better understand the mechanism of in vivo toxicity of N-nitroso compounds (NNCs), the toxicity data of 80 NNCs related to their rat acute oral toxicity data (50% lethal dose concentration, LD50) were used to establish quantitative structure-activity relationship (QSAR) and classification models. Quantum chemistry methods calculated descriptors and Dragon descriptors were combined to describe the molecular information of all compounds. Genetic algorithm (GA) and multiple linear regression (MLR) analyses were combined to develop QSAR models. Fingerprints and machine learning methods were used to establish classification models. The quality and predictive performance of all established models were evaluated by internal and external validation techniques. The best GA-MLR-based QSAR model containing eight molecular descriptors was obtained with Q2loo = 0.7533, R2 = 0.8071, Q2ext = 0.7041 and R2ext = 0.7195. The results derived from QSAR studies showed that the acute oral toxicity of NNCs mainly depends on three factors, namely, the polarizability, the ionization potential (IP) and the presence/absence and frequency of C–O bond. For classification studies, the best model was obtained using the MACCS keys fingerprint combined with artificial neural network (ANN) algorithm. The classification models suggested that several representative substructures, including nitrile, hetero N nonbasic, alkylchloride and amine-containing fragments are main contributors for the high toxicity of NNCs. Overall, the developed QSAR and classification models of the rat acute oral toxicity of NNCs showed satisfying predictive abilities. The results provide an insight into the understanding of the toxicity mechanism of NNCs in vivo, which might be used for a preliminary assessment of NNCs toxicity to mammals.

Download Full-text

Insulin-mimetic macromolecular poly-N-vinylpyrrolidone-based vanadium metallocomplexes. Part 1. Synthesis of macromolecular vanadium metallocomplex and its acute oral toxicity evaluation

Butlerov Communications ◽

10.37952/roi-jbc-01/19-59-7-24 ◽

2019 ◽

Vol 59 (7) ◽

pp. 24-30

Author(s):

Alexey G. Ivanov ◽

◽

Veronika A. Prikhodko ◽

Veronika A. Mukhina ◽

Nadezhda V. Kirillova ◽

...

Keyword(s):

Lethal Dose ◽

Structural Features ◽

Antidiabetic Drugs ◽

Vanadium Complexes ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Vanadium Compounds ◽

Insulin Mimetic ◽

In Vivo Experiments

Diabetes mellitus (DM) is a severe chronic disease affecting virtually all kinds of metabolic processes in the human body. As incidence and prevalence of DM are increasing worldwide, WHO estimates the number of people living with diabetes to be as high as half a billion and still rising. Long-term health complications of DM, such as diabetic nephropathy, retinopathy, neuropathy, and cardiovascular pathology, although preven-table in most cases, are known to be severe, potentially life-threatening and often irreversible, which makes the search for new effective antidiabetic drugs a research priority and one of the most pressing issues in health care today. To date, the insulin-mimetic properties of vanadium compounds have been the subject of quite a significant number of studies. In vivo experiments have shown that vanadium, acting in an insulin-like fashion, takes part in the regulation of glucose and lipid metabolism. In particular, vanadium stimulates glucose uptake and metabolism in insulin target tissues, increases the intensity of glycogen and lipid biosynthesis, and inhibits that of gluconeogenesis, glycogenolysis, and lipolysis. Organic vanadium complexes are known to be less toxic than its inorganic salts, which are characterized by a number of potentially serious adverse effects, mainly but not exclusively on the central nervous system and the kidneys; in addition to lower toxicity, organic vanadium compounds have been found to have higher bioavailability when to compared to those of inorganic nature. Such observations clearly hold promise for the development of an entirely novel therapeutic class of antidiabetic drugs. The aims of this study are to obtain new polymeric vanadyl(VO2+) derivatives based on poly-N-vinylpyrrolidone (PVP) that would exert hypoglycemic effect in vivo, and to explore the possibilities of using such compounds or formulations derived thereof for type 2 DM prophylaxis and/or treatment. This work gives a method of obtaining and isolation of an oxovanadium(IV)-polymer metallocomplex, and describes the structural features of said compound, confirmed experimentally. The results of the acute oral toxicity study revealed that the newly synthesized compound is of low toxicity, having a median lethal dose (LD50) that is at a level well above those typical of inorganic vanadium salts.

Download Full-text

Estimation of acute oral toxicity in rates by determination of the approximate lethal dose rather than the LD50

Journal of Applied Toxicology ◽

10.1002/jat.2550060302 ◽

1986 ◽

Vol 6 (3) ◽

pp. 145-148 ◽

Cited By ~ 74

Author(s):

Gerald L. Kennedy ◽

Rayanne L. Ferenz ◽

Bruce A. Burgess

Keyword(s):

Lethal Dose ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Approximate Lethal Dose

Download Full-text

Evaluation of antibacterial and acute oral toxicity of Impatiens tinctoria A. Rich root extracts

PLoS ONE ◽

10.1371/journal.pone.0255932 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0255932

Author(s):

Sileshi Degu ◽

Abiy Abebe ◽

Negero Gemeda ◽

Adane Bitew

Keyword(s):

Ethyl Acetate ◽

Plant Extracts ◽

Aqueous Ethanol ◽

Ethyl Acetate Extract ◽

Fungal Infections ◽

Biological Activities ◽

Lethal Dose ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Root Extracts

The high prevalence of morbidity and mortality from bacterial infections, together with the growing threat of antibacterial resistance, necessitated the development of alternative new drugs from traditional medicine. In Ethiopia, Impatiens tinctoria A. Rich has been traditionally used for the treatment of fungal infections such as ringworms that cause tinea pedis and it have also different medical values. Scientific information on its biological activity against a broad range of bacteria and safety data is scant, compared to its folklore data. In this study, we evaluated antibacterial activities and acute oral toxicity of aqueous, ethanol and ethyl acetate root extracts of Impatiens tinctoria A. Rich. Aqueous, ethanol and ethyl acetate extracts of the plant were evaluated using agar hole diffusion and agar dilution methods. Biological activities of the plant extracts were expressed as a zone of inhibition diameter, minimum inhibitory concentration (mg/ml), and minimum bactericidal concentration (mg/ml). The safety studies were performed by oral acute toxicity study according to the organization of economic cooperation and development test Guidelines 420.Gram-positive bacteria were more susceptible to the extracts compared to gram-negative bacteria, especially against S. aureus and S. epidermidis, which are commonly found in the skin. Ethyl acetate extract was more potent than ethanol and aqueous extracts. The 50% lethal dose (LD50) of tested mice was above 9600 mg/kg. This study provides a scientific basis for the antibacterial activity of the root extracts of I. tinctoria A. Rich, where, the ethyl acetate extract showed the most promising activity. Therefore, the antibacterial potential and practical non-toxicity of the study plant extracts suggested the possibility of using it for the development of antimicrobial drugs by further studying the plant in different directions.

Download Full-text