Exploring Greater Flexibility for Chronic Toxicity Study Designs to Support Human Safety Assessment While Balancing 3Rs Considerations.

Chronic repeated-dose toxicity studies are required to support long-term dosing in late-stage clinical trials, providing data to adequately characterize adverse effects of potential concern for human safety. Different regulatory guidances for the design and duration of chronic toxicity studies are available, with flexibility in approaches often adopted for specific drug modalities. These guidances may provide opportunities to reduce time, cost, compound requirement and animal use within drug development programs if applied more broadly and considered outside their current scopes of use. This article summarizes presentations from a workshop at the 43rd Annual Meeting of the American College of Toxicology (ACT) in November 2022, discussing different approaches for chronic toxicity studies. A recent industry collaboration between the Netherlands Medicines Evaluation Board (MEB) and UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) illustrated current practices and the value of chronic toxicity studies for monoclonal antibodies (mAbs) and evaluated a weight of evidence (WOE) model where a 3-month study rather than a 6-month study might be adequate. Other topics included potential opportunities for single-species chronic toxicity studies for small molecules, peptides and oligonucleotides and whether a 6-month duration non-rodent study can be used more routinely than a 9-month study (similar to ICH S6(R1) for biological products). Also addressed were opportunities to optimize recovery animal use if warranted and whether restriction to one study only (if at all) can be applied more widely within and outside ICH S6(R1).

CaC2-induced ripening: Unveiling the bitter truth behind sweet fruit.

Fruit ripening is a natural, irreversible process crucial for developing luscious flavor and appealing appearance. Fruits are lauded for their health benefits, forming a key part of a balanced diet. Regrettably, the continued use of calcium carbide (CaC2) to ripen fruit persists in various regions due to its low cost and perceived effectiveness. This method raises significant concerns about health, safety, and the resultant fruit quality and flavor. CaC2 and CaC2-ripened fruits contain harmful substances like inorganic arsenic and phosphorus hydrides, posing considerable health risks including chronic toxicity upon consumption or exposure to acetylene released during CaC2 application. Ensuring food safety requires adherence to regulatory standards governing harmful substances in food. Thus, understanding the risks of consuming CaC2-ripened fruit is crucial for crafting strategies to protect consumers' nutritional well-being and food safety. This review presents a comprehensive analysis of the impacts and apprehensions regarding use of CaC2 as a ripening agent in fresh fruit.

Occurrence and ecological risk assessment of 16 plasticizers in the rivers and estuaries in Japan.

Owing to growing concerns about the adverse effects of phthalate plasticizers, non-phthalate plasticizers are being increasingly used as their replacement. However, information on the residual environmental concentrations and ecological risks posed by these plasticizers is limited. In this study, we analyzed the environmental contamination of 11 phthalates and 5 non-phthalate plasticizers in Class A and B rivers in Japan. In the considered river water samples, phthalates and non-phthalates were detected in the following order of detection frequency: phthalates (DEHP > DMP > DMEP > BBP > DNPP > DNP > DEEP > DBEP = DNOP) and non-phthalates (ATBC > DEHS > DEHA > TOTM = DIBA). Phthalate plasticizers were the most abundant and included DEHP (157-859 ng/L), DMP (

Safer and greener chemicals for the aquatic ecosystem: Chemometric modeling of the prolonged and chronic aquatic toxicity of chemicals on Oryzias latipes.

In the modern era, chemicals and their products have been used everywhere like agriculture, healthcare, food, cosmetics, pharmaceuticals, household products, clothing industry, etc. These chemicals find their way to reach the aquatic ecosystem (directly/indirectly) and cause severe chronic and prolonged toxic effects to aquatic species which is also then translated to human beings. Prolonged and chronic toxicity data of many chemicals that are used daily is not available due to high experimentation testing costs, time investment, and the requirement of a large number of animal sacrifices. Thus, in silico approaches (e.g., QSAR (quantitative structure-activity relationship)) are the best alternative for chronic and prolonged toxicity predictions. The present work offers multi-endpoint (five endpoints: chronic_LOEC, prolonged_14D_LC50, prolonged_14D_NOEC, prolonged_21D_LC50, prolonged_21D_NOEC) QSAR models for addressing the prolonged and chronic aquatic toxicity of chemicals toward fish (O. latipes). The statistical results (R2 =0.738-0.869, QLOO2 =0.712-0.831, Q(F1)2 =0.618-0.731) of the developed models show that they were robust, reliable, reproducible, accurate, and predictive. Some of the features that are responsible for prolonged and chronic toxicity of chemicals towards O. latipes are as follows: the presence of substituted benzene, hydrophobicity, unsaturation, electronegativity, the presence of long-chain fragments, the presence of a greater number of atoms at conjugation, and the presence of halogen atoms. On the other hand, hydrophilicity and graph density descriptors retard the aquatic chronic and prolonged toxicity of chemicals toward O. latipes. The PPDB (pesticide properties database) and experimental and investigational classes of drugs from the DrugBank database were also screened using the developed model. Thus, these multi-endpoint models will be helpful for data-gap filling and provide a broad range of applicability. Therefore, this research will aid in the in silico QSAR (quantitative structure-activity relationship) prediction (non-animal testing) of the prolonged and chronic toxicity of untested and new toxic chemicals/drugs/pesticides, design and development of eco-friendly, novel, and safer chemicals, and help to protect the aquatic ecosystem from exposure to toxic and hazardous chemicals.

Toxicity assessment of Cucurbita pepo cv Dayangua and its effects on gut microbiota in mice.

BACKGROUND: Cucurbita pepo cv Dayangua (CPD) is an edible plant with diverse pharmacological properties. The current research on CPD has primarily focused on initial investigations of its chemical composition and pharmacological effects, and no comprehensive toxicity assessment has been conducted to date. METHODS: In the present study, the toxicity of CPD was evaluated through both acute and sub-chronic oral toxicity tests in mice. 16S rDNA sequencing was used to analyze the composition of the gut microbiota of mice at different time points to observe the effect of CPD on these microbial communities. RESULTS: In the acute toxicity test, CPD exhibited low toxicity, with a median lethal dose (LD50) > 2000 mg/kg. The sub-chronic toxicity test indicated that CPD administration at doses of 200, 400, and 600 mg/kg did not cause mortality or significant organ damage in mice. Furthermore, analysis of the gut microbiota after gavage administration of CPD at 400 and 600 mg/kg revealed an improved abundance of some beneficial gut bacteria. CONCLUSIONS: In summary, no acute or sub-chronic toxic effects were observed in mice following the oral administration of CPD. CPD did not affect the structure and diversity of the gut microbiota and may contribute to an increase in the number of beneficial gut bacteria.

Differential Toxicity of Arsenic in Daphnia pulex Under Phosphorus and Food Limitation.

The on-going anthropogenic degradation of freshwater habitats has drastically altered the environmental supply of both nutrients and common pollutants. Most organisms living in these altered habitats experience interactive effects of various stressors that can initiate adjustments at multiple levels impacting their fitness. Hence, studies measuring response to a single environmental parameter fail to capture the complexities of the status quo. We tested both the individual and the interactive effect of arsenic (As) exposure, food quantity, and dietary phosphorus (P)-supply on six life-history traits (Juvenile Growth Rate; Adult Growth Rate; Age and Size at Maturity, Lifespan, and Fecundity) as surrogates for organismal fitness in the keystone aquatic grazer Daphnia pulex. We also tested the effect of food quantity and P-supply on somatic As accumulation in Daphnia. Our results indicated an influence of P-supply on neonatal growth and an influence of As and food quantity on growth and maintenance later in life. Maturation was strongly influenced by all three variables, with no reproduction observed in the presence of two or more environmental stressors. We found a strong interaction between As and dietary P, with increased P-supply intensifing the toxicity effect of As. No such effects were seen between As and food quantity, indicating a differential role of quantity versus quality on As toxicity. We found a nominal effect of diet on somatic As accumulation. The results from the present study emphasize the importance of considering such interactions between co-occurring environmental stressors and the dietary status of organisms, to better predict and manage impacts and risks associated with common environmental toxicants in highly vulnerable ecosystems. Environ Toxicol Chem 2024;00:1-13. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Comprehensive Toxicological Assessment of Halobenzoquinones in Drinking Water at Environmentally Relevant Concentration.

Halobenzoquinones (HBQs), an emerging unregulated category of disinfection byproduct (DBP) in drinking water, have aroused an increasing concern over their potential health risks. However, the chronic toxicity of HBQs at environmentally relevant concentrations remains largely unknown. Here, the occurrence and concentrations of 13 HBQs in drinking water from a northern megacity in China were examined using ultrahigh performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UHPLC-MS/MS). Four HBQs, including 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ), 2,3,6-trichloro-1,4-benzoquinone (TriCBQ), and 2,5-dibromo-1,4-benzoquinone (2,5-DBBQ), were detected beyond 50% occurrence frequency and at median concentrations from 4 to 50 ng/L. The chronic toxicity of these four HBQs to normal human colon and liver cells (FHC and THLE-2) was investigated at these concentrations. After 90 days of exposure, 2,5-DBBQ and 2,6-DCBQ induced the highest levels of oxidative stress and deoxyribonucleic acid (DNA) damage in colon and liver cells, respectively. Moreover, 2,5-DBBQ and 2,6-DCBQ were also found to induce epithelial-mesenchymal transition (EMT) in normal human liver cells via the extracellular signal regulated kinase (ERK) signaling pathway. Importantly, heating to 100 °C (boiling) was found to efficiently reduce the levels of these four HBQs in drinking water. These results suggested that environmentally relevant concentrations of HBQs could induce cytotoxicity and genotoxicity in normal human cells, and boiling is a highly efficient way of detoxification for HBQs.

Acute and sub-chronic toxicity study of novel polyherbal formulation in non-alcoholic fatty liver using Wistar rats.

Aim: This study assessed the acute and sub-chronic toxicity of a novel polyherbal formulation tablet in Wistar rats Materials & methods: Acute toxicity and sub-chronic toxicity was assessed following OECD (Organisation for the Economic Co-operation and Development) guidelines based on 423 and 408. Results & conclusion: No mortality and toxicity showed in rats during acute toxicity. The LD50 of the extract was at 2000 mg/kg. In sub-chronic study, both sex rats were orally administered at 250, 500,1000 and 2000 mg/kg for 90 days and revealed no significant difference (p < 0.05) in hematological and other parameters compared with the control. Histopathology study did not reveal morphological alteration. The No observed adverse effect level of the tablet was observed until 2000 mg/kg.

Non-alcoholic fatty liver disease (NAFLD) affects around 25% of individuals globally and has become the most common long-term liver problem. The reasons why people get this disease can be different for each person. By studying natural substances, scientists have discovered that some compounds help treat the disease some of these substances can also be harmful. By studying natural substances, scientists have discovered that some compounds help treat the disease some of these substances can also be harmful. People are also trying out traditional medicines more and more, and we need to make sure they're safe. To determine whether a medication is secure, we conducted experiments in accordance with the OECD guidelines. One test examines whether a high dose of the drug is lethal. The goal is to determine the optimal dose, which is neither too low nor too excessive. Another test investigated what happens if these rats take the medicine every day for a long time. Variables such as blood tests and tissue samples are collected to make sure the medicine does not make the rats sick. In this case, we tested a medicine called a 'PHF tablet' for 90 days, and it didn't make the animals sick. They found that you can take a relatively high dose without any adverse effects.

Elevated temperature magnifies the acute and chronic toxicity of clothianidin to Eisenia fetida.

Pesticide residue and thermal stress resulting from global climate change are parallel stressors for soil fauna. However, it remains ambiguous how elevated temperatures and pesticides can interact to threaten soil fauna. In the study, the acute and chronic clothianidin (CTD) toxicity to earthworms (Eisenia fetida) at different temperatures, and the effect of increasing temperature on antioxidant defense mechanisms in response to CTD were investigated. The acute toxicity of CTD was exacerbated by increased temperature in both filter paper contact tests (a decrease in the 48-h median lethal concentration (LC50) from 0.077 µg/cm2 at 20 °C to 0.009 µg/cm2 at 30 °C) and natural soil tests (a decrease in the 48-h LC50 from 0.774 mg/kg at 20 °C to 0.199 mg/kg at 30 °C). Exposure to CTD or high temperature (30 °C) triggered reactive oxygen species (ROS) overgeneration and increased antioxidant enzyme activities in earthworms; and the effect was particularly pronounced after exposure to both higher temperatures and CTD. At 20 and 25 °C, there was no significant change in the growth and reproduction of E. fetida after 56-d exposure to CTD-contaminated soil. However, the combined effect of CTD and high temperature (30 °C) significantly reduced the weight change rate, cocoon number, hatching rate, and number of juveniles on day 56. These results indicated that elevated temperature could aggravate acute and chronic CTD toxicity to earthworms. The findings emphasize that evaluating changes in pesticide toxicity under global warming is worth further investigation.

Mechanistic insights into the parental co-exposure of T-2 toxin and epoxiconazole on the F1 generation of zebrafish (Danio rerio).

Mycotoxins and pesticides frequently coexist in agricultural commodities on a global scale. The potential transgenerational consequences induced by these substances pose a significant threat to human health. However, there is a lack of data concerning the effects of co-contamination by these chemicals in the F1 generation following parental exposure. This investigation delved into the mixture effects of T-2 toxin (T-2) and epoxiconazole (EPO) on the offspring of zebrafish (Danio rerio). The findings revealed that exposure across generations to a combination of T-2 and EPO resulted in toxicity in the larvae of the F1 generation. This was demonstrated by a significant increase in the levels or activities of malondialdehyde (MDA), thyroxine (T4), Caspase3, and cas9, along with a decrease in the levels of cyp19a, ERα, and ERß. These outcomes suggested that cross-generational exposure to T-2 and EPO in D. rerio disrupted oxidative balance, induced cell apoptosis, and affected the endocrine system. Moreover, these effects were magnified when the F1 generation was continuously exposed to these compounds. Notably, these adverse effects could persist in subsequent generations without additional exposure. This study underscored the potential dangers associated with the simultaneous presence of T-2 and EPO on the development of fish offspring and the resulting environmental hazards to aquatic ecosystems. These findings emphasized the significant health risks posed by cross-generational exposure and highlighted the need for additional legislative measures to address these concerns.

Effects of pyroligneous acid on acute, chronic, and cyto-genotoxicity to earthworms (Eisenia fetida).

The pyroligneous acid (PA), or wood vinegar, is a byproduct of wood carbonization during the slow pyrolysis process. PA is recognized globally as a safe compound for agriculture due to its various beneficial properties, such as antioxidant, antibacterial, antifungal, and termiticidal properties. However, the impact of different PA concentrations on beneficial soil organisms, such as earthworms has not been investigated. The present study aims to understand the effects of different PA concentrations on earthworm Eisenia fetida. The earthworms were exposed to nine different concentrations of PA in soils, including their control. The acute toxicity assay was performed after 14 days of exposure, and the chronic toxicity assay was performed up to 8 weeks after exposure. The results from the acute toxicity assay demonstrated no significant effect on earthworm mortality. The chronic toxicity assay showed that lower PA concentrations (0.01-0.2% of weight/weight PA in soil) promoted cocoon and juvenile production in soils, whereas higher PA concentrations (0.5 and 1%) had a negative effect. These findings highlight the potential of PA to enhance soil fertility at lower concentrations, up to 0.2%, by stimulating worm activity and subsequent manure production. The outcomes of this study have significant implications for the careful management of PA concentrations within agricultural operations.

Antihypertensive Potential of Japanese Quail (Couturnix Couturnix Japonica) Egg Yolk Oil (QEYO) in Sprague Dawley Rats.

Oils from animal sources have been used for centuries in the management of diseases. This research was conducted to screen the ex vivo and in vivo toxicity of quail egg yolk oil (QEYO) extracts and assess their effects on the management of hypertension in rats. QEYO was extracted using gentle heating (GH) and n-hexane (NHN). The extracts were subjected to toxicity testing using the hen's egg test on chorioallantoic membrane (HET-CAM) and bovine corneal histology test. Acute and sub-chronic toxicity (28 days) were evaluated in rats. Hypertension was induced in rats by administering 80 mg/kg of Nω-L-Arginine Methyl Ester (L-NAME) per day for 28 days. Treatments commenced on the 14th day; Nifedipine at 30 mg/kg and 1 mL of distilled water were administered as positive and negative controls. Blood pressure (BP), lipid profiles, and oxidative stress markers were quantified. No irritation was observed using the HET-CAM test in the egg treated with both extracts. Bovine corneal histology showed no lesions in all treated groups. No signs of toxicity were observed in either acute or sub-chronic toxicity studies. A significant reduction in blood pressure was observed in rats treated with the extracts (p < 0.05). Changes in total cholesterol (TC), triglycerides (TGs), low-density lipoproteins (LDLPs), and high-density lipoproteins (HDLPs) were not significant compared to the control (p > 0.05). Oxidative stress markers (SOD and CAT) increased significantly in the treated groups compared to the control, while the malondialdehyde levels decreased (p < 0.05). QEYO was safe in both ex vivo and in vivo studies and can be said to have the potential to lower blood pressure as well as cardio-protective effects in hypertensive rats. This research provides evidence based on which QEYO could be used safely as an adjuvant therapy in eye drops and cosmetics and can be considered an effective choice for preventing hypertension.

Safety assessment of crude aqueous methanol extract of Annona senegalensis stem bark: acute and sub-chronic toxicity studies.

Annona senegalensis Pers., (wild custard apple), is a shrub used traditionally to treat respiratory and skin diseases. Previous studies have demonstrated its anti-malaria, anti-snake envenomation and anti-cancer activities. However, its toxicological profile remains limited, particularly in male and female animals. This study aims to evaluate the safety of crude aqueous methanol extract of Annona senegalensis stem bark (AMEAS) through acute and sub-chronic toxicity studies. The stem bark of A. senegalensis was collected, air-dried, pulverized, and extracted using 70% methanol. Phytochemical screening, elemental analysis, and acute toxicity evaluation were carried out on AMEAS. Sub-chronic toxicity study was conducted on Wistar rats of both sexes at different doses administered orally for 28 days. Elemental analysis revealed the presence of heavy metals and essential mineral elements with the highest contents being calcium (59.88%) and potassium (25.39%). Acute toxicity testing showed no mortality up to 5000 mg/kg, suggesting an LD50 greater than 5000 mg/kg. In the sub-chronic toxicity study, no mortality or significant harmful effects were observed. The blood glucose decreased from 13.68 mMol/L at 250 mg/kg to 10.71 mMol/L at 1000 mg/kg, much lower than the distilled water group (17.06 mMol/L). In conclusion, the extract appeared to be well-tolerated, with no obvious adverse effects. AMEAS is rich in Calcium (Ca) and potassium (K). It has been shown to have LD50 greater than 5000 mg/kg and is assumed to be safe. On repeated use, AMEAS may cause hypoglycemia and weight loss which may be useful in managing diabetes and obesity respectively.

Safety of Oral Carica papaya L. Leaf 10% Ethanolic Extract for Acute and Chronic Toxicity Tests in Sprague Dawley Rats.

Carica papaya L. leaves, traditionally utilized in dietary supplements and pharmaceuticals, exhibit a broad spectrum of potentially therapeutic properties, including anti-inflammatory, antimalarial, and wound healing properties. This study examined the acute and chronic toxicity of 10% ethanolic-extracted C. papaya leaf in Sprague Dawley rats. The acute toxicity assessment was a single oral dose of 5000 mg/kg body weight, while the chronic toxicity assessment included daily oral doses of 100, 400, 1000, and 5000 mg/kg over 180 days. Systematic monitoring covered a range of physiological and behavioral parameters, including body and organ weights. End-point evaluations encompassed hematological and biochemical analyses, along with gross and histopathological examinations of internal organs. Findings revealed no acute toxicity in the C. papaya leaf extract group, although a significant decrease in uterine weight was observed without accompanying histopathology abnormalities. In the chronic toxicity assessment, no statistically significant differences between the control and the C. papaya leaf extract groups were detected across multiple measures, including behavioral, physiological, and hematological indices. Importantly, histopathological examination corroborated the absence of any tissue abnormalities. The study results indicate that C. papaya leaf extract exhibited no adverse effects on the rats during the 180-day oral administration period, affirming its potential safety for prolonged usage.

Unveiling the multilevel impact of four water-soluble polymers on Daphnia magna: From proteome to behaviour (a case study).

The ubiquitous presence of water-soluble polymers (WSPs) in freshwater environments raises concerns regarding potential threats to aquatic organisms. This study investigated, for the first time, the effects of widely used WSPs -polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyacrylic acid (PAA), and polyethylene glycol (PEG)- using a multi-level approach in the freshwater biological model Daphnia magna. This integrated assessment employed a suite of biomarkers, evaluation of swimming behaviour, and proteomic analysis to investigate the effects of three environmentally relevant concentrations (0.001, 0.5, and 1 mg/L) of the tested WSPs from molecular to organismal levels, assessing both acute and chronic effects. Our findings reveal that exposure to different WSPs induces specific responses at each biological level, with PEG being the only WSP inducing lethal effects at 0.5 mg/L. At the physiological level, although all WSPs impacted both swimming performance and heart rate of D. magna specimens, PAA exhibited the greatest effects on the measured behavioural parameters. Furthermore, proteomic analyses demonstrated altered protein profiles following exposure to all WSPs, with PVA emerging as the most effective.

Role of benzophenone-3 additive in the effect of polyethylene microplastics on Daphnia magna population dynamics.

The adverse effects of microplastics (MPs) on Daphnia magna have been extensively studied; however, their population-level effects are relatively unknown. This study investigated the effect of polyethylene MP fragments (33.90 ± 17.44 µm) and benzophenone-3 (BP-3), which is a widely used plastic additive (2.91 ± 0.02% w/w), on D. magna population dynamics in a 34-day microcosm experiment. In the growth phase, neither MP nor MP/BP-3 fragments changed the population size of D. magna compared with the control. However, MP/BP-3 fragments significantly reduced (p < 0.05) the population biomass compared to that of the control, whereas MP fragments did not induce a significant reduction. The MP/BP-3 group had a significantly higher (p < 0.05) neonate proportion than that in the control and MP groups. MP/BP-3 fragments upregulated usp and downregulated ecrb, ftz-f1, and hr3, altering gene expression in the ecdysone signaling pathway linked to D. magna growth and development. These findings suggested that BP-3 in MP/BP-3 fragments may disrupt neonatal growth, thereby decreasing population biomass. In the decline phase, MP fragments significantly decreased (p < 0.05) the population size and biomass of D. magna compared with the control and MP/BP-3 fragments. This study highlights the importance of plastic additives in the population-level ecotoxicity of MPs.

Toward a Mechanism-Driven Integrated Framework to Link Human Exposure to Multiple Toxic Metal(loid) Species with Environmental Diseases.

The ongoing anthropogenic pollution of the biosphere with As, Cd, Hg and Pb will inevitably result in an increased influx of their corresponding toxic metal(loid) species into the bloodstream of human populations, including children and pregnant women. To delineate whether the measurable concentrations of these inorganic pollutants in the bloodstream are tolerable or implicated in the onset of environmental diseases urgently requires new insight into their dynamic bioinorganic chemistry in the bloodstream-organ system. Owing to the human exposure to multiple toxic metal(loid) species, the mechanism of chronic toxicity of each of these needs to be integrated into a framework to better define the underlying exposure-disease relationship. Accordingly, this review highlights some recent advances into the bioinorganic chemistry of the Cd2+, Hg2+ and CH3Hg+ in blood plasma, red blood cells and target organs and provides a first glimpse of their emerging mechanisms of chronic toxicity. Although many important knowledge gaps remain, it is essential to design experiments with the intent of refining these mechanisms to eventually establish a framework that may allow us to causally link the cumulative exposure of human populations to multiple toxic metal(loid) species with environmental diseases of unknown etiology that do not appear to have a genetic origin. Thus, researchers from a variety of scientific disciplines need to contribute to this interdisciplinary effort to rationally address this public health threat which may require the implementation of stronger regulatory requirements to improve planetary and human health, which are fundamentally intertwined.

Sub-chronic oral toxicity study of the alkaloid rich fraction from Luffa cylindrica fruit in Sprague-Dawley rats.

The loofah/sponge gourd Luffa cylindrica (L.), a member of the Cucurbitaceae family, is one of the neglected medicinal plants. Traditionally, Luffa cylindrica is prescribed for inducing labor. It has a long history of use in China for the treatment of fever, diabetes, dyspnea, and dysentery. This study investigated the toxicity profile of the alkaloid-rich fraction of Luffa cylindrica (ARF-LC) for the first time in Sprague Dawley rats. A total of 80 rats (40 male and 40 female rats) aged 13 weeks old and weighing 200-220 g were selected for this study. In SD rats, sub-chronic oral toxicity was investigated at doses of 100, 200, and 400 mg/kg/d for a total of 90 days, followed by a 30-day recovery period. The results showed no variation in body weight among the three dose groups compared to the control group. Treatment-related adverse events, such as alterations in hematology and serum biochemistry parameters and the histology of the liver were sporadic in the high-dose rats but within the reference range. However, these changes disappeared after the doses were withdrawn during the recovery period. In conclusion, the "no observed adverse effect level" (NOAEL) of oral administration of ARF-LC in SD rats was considered 400 mg/kg/d and can be studied for its potential in further in vivo chronic investigations.

Chronic aquatic toxicity assessment of diverse chemicals on Daphnia magna using QSAR and chemical read-across.

We have modeled here chronic Daphnia toxicity taking pNOEC (negative logarithm of no observed effect concentration in mM) and pEC50 (negative logarithm of half-maximal effective concentration in mM) as endpoints using QSAR and chemical read-across approaches. The QSAR models were developed by strictly obeying the OECD guidelines and were found to be reliable, predictive, accurate, and robust. From the selected features in the developed models, we have found that an increase in lipophilicity and saturation, the presence of electrophilic or electronegative or heavy atoms, the presence of sulphur, amine, and their related functionality, an increase in mean atomic polarizability, and higher number of (thio-) carbamates (aromatic) groups are responsible for chronic toxicity. Therefore, this information might be useful for the development of environmentally friendly and safer chemicals and data-gap filling as well as reducing the use of identified toxic chemicals which have chronic toxic effects on aquatic ecosystems. Approved classes of drugs from DrugBank databases and diverse groups of chemicals from the Chemical and Product Categories (CPDat) database were also assessed through the developed models.

Sub-chronic oral toxicity of a water-soluble extract of Centella asiatica (Centell-S) in Wistar rats.

BACKGROUND: Centell-S, a water-soluble extract from Centella asiatica, is predominantly composed of madecassoside and asiaticoside, exceeding 80% w/w. Pursuing its development as an herbal medicinal product, Centell-S underwent sub-chronic toxicity assessment adhering to OECD GLP 408 standards. METHODS: In a study involving 100 Wistar rats, varying doses of Centell-S (50, 200, or 800 mg/kg/day) or a vehicle control were administered orally over 90 days. To evaluate Centell-S's safety profile, assessments included clinical observations, health examinations, clinical biochemistry analyses, and detailed anatomical pathology evaluations were conducted. RESULTS: Over the 90 days of treatment, the administration of Centell-S did not lead to any fatalities in the test animals. Clinical observations did not reveal any signs indicative of toxic effects. Notably, an increase in total white blood cell and lymphocyte counts was observed in both sexes, yet these levels returned to normal following a two-week discontinuation period post-treatment. CONCLUSIONS: Under the specific conditions of the OECD GLP 408, Repeated Dose 90-day Oral Toxicity Study in Rodents, the no observed adverse effect level (NOAEL) of Centell-S was 800 mg/kg/day. These findings are promising for the continued development of Centell-S as a phytopharmaceutical for clinical applications.