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  1. Christapher PV, Parasuraman S, Asmawi MZ, Murugaiyah V
    Regul Toxicol Pharmacol, 2017 Jun;86:33-41.
    PMID: 28229903 DOI: 10.1016/j.yrtph.2017.02.005
    Medicinal plant preparations may contain high levels of toxic chemical constituents to potentially cause serious harm to animals and/or humans. Thus, toxicity studies are important to assess the toxic effects of plant derived products. Polygonum minus is used traditionally for different ailments in Southeast Asia. This study was conducted to establish the acute and subchronic toxicity profile of the methanol extract of P. minus leaves. The acute toxicity study showed that the methanol extract of P. minus is safe even at the highest dose tested of 2000 mg/kg in female Sprague Dawley rats. There were no behavioural or physiological changes and gross pathological abnormalities observed. The subchronic toxicity study of methanol extract of P. minus at 250, 500, 1000 and 2000 mg/kg were conducted in both sexes of Sprague Dawley rats. There were no changes observed in the extract treated animal's body weight, food and water intake, motor coordination, behaviour and mental alertness. The values of haematological and biochemical parameters were not different between the treated and control animals. The relative organ weights of extract-treated animals did not differ with that of control animals. Based on the present findings, the methanol extract of P. minus leaves could be considered safe up to the dose of 2000 mg/kg.
  2. Gorain B, Choudhury H, Tekade RK, Karan S, Jaisankar P, Pal TK
    Regul Toxicol Pharmacol, 2016 Dec;82:20-31.
    PMID: 27815174 DOI: 10.1016/j.yrtph.2016.10.020
    Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients.
  3. Mohamad Shalan NAA, Mustapha NM, Mohamed S
    Regul Toxicol Pharmacol, 2017 Feb;83:46-53.
    PMID: 27871867 DOI: 10.1016/j.yrtph.2016.11.022
    Noni (Morinda citrifolia) leaf and fruit are used as food and medicine. This report compares the chronic toxicity of Noni fruit and edible leaf water extracts (two doses each) in female mice. The 6 months study showed the fruit extract produced chronic toxicity effects at the high dose of 2 mg/ml drinking water, evidenced through deteriorated liver histology (hepatocyte necrosis), reduced liver length, increased liver injury marker AST (aspartate aminotransferase) and albumin reduction, injury symptoms (hypoactivity, excessive grooming, sunken eyes and hunched posture) and 40% mortality within 3 months. This hepatotoxicity results support the six liver injury reports in humans which were linked to chronic noni fruit juice consumption. Both doses of the leaf extracts demonstrated no observable toxicity. The hepatotoxicity effects of the M. citrifolia fruit extract in this study is unknown and may probably be due to the anthraquinones in the seeds and skin, which had potent quinone reductase inducer activity that reportedly was 40 times more effective than l-sulforaphane. This report will add to current data on the chronic toxicity cases of Morinda citrifolia fruit. No report on the chronic toxicity of Morinda citrifolia fruit in animal model is available for comparison.
  4. Ho YB, Abdullah NH, Hamsan H, Tan ESS
    Regul Toxicol Pharmacol, 2017 Aug;88:72-76.
    PMID: 28554823 DOI: 10.1016/j.yrtph.2017.05.018
    This study aims to determine concentrations of mercury in facial skin lightening cream according to different price categories (category I:
  5. Choudhury H, Gorain B, Tekade RK, Pandey M, Karmakar S, Pal TK
    Regul Toxicol Pharmacol, 2017 Dec;91:179-189.
    PMID: 29080846 DOI: 10.1016/j.yrtph.2017.10.023
    Oral paclitaxel (PTXL) formulations freed from cremophor® EL (CrEL) is always in utmost demand by the cancerous patients due to toxicities associated with the currently marketed formulation. In our previous investigation [Int. J. Pharm. 2014; 460:131], we have developed an oral oil based nanocarrier for the lipophilic drug, PTXL to target bioavailability issue and patient compliance. Here, we report in vivo antitumor activity and 28-day sub-chronic toxicity of the developed PTXL nanoemulsion. It was observed that the apoptotic potential of oral PTXL nanoemulsion significantly inhibited the growth of solid tumor (59.2 ± 7.17%; p 
  6. Sengupta P, Chatterjee B, Pal TK
    Regul Toxicol Pharmacol, 2017 Dec;91:151-158.
    PMID: 29107617 DOI: 10.1016/j.yrtph.2017.10.029
    The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR-γ receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination of its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to the coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the in vivosafety of the combination.
  7. Leong YH, Isa ASM, Mohamed Mahmood M, Moey CEJ, Utar Z, Soon YI, et al.
    Regul Toxicol Pharmacol, 2018 Jun;95:280-288.
    PMID: 29567329 DOI: 10.1016/j.yrtph.2018.03.011
    This study aimed to investigate the oral acute and subacute toxicity of Poly [3-hydroxybutyrate-co-4-hydroxybutyrate], P(3HB-co-4HB) in the form of nanoparticles in Sprague-Dawley rats. Acute oral administration of P(3HB-co-4HB) nanoparticles was performed as a single dose up to 2000 mg/kg in six female rats for 14 days. Subacute toxicity study via oral administration for 28 days at doses of 0 (control), 500, 1000 and 2000 mg/kg in rats (10 rats in each group, female:male = 1:1) was conducted. The estimated lethal dose (LD50) of P(3HB-co-4HB) nanoparticles was >2000 mg/kg. No mortality, unusual changes in behaviour, adverse clinical signs, abnormal changes in body weights or food consumption were observed on all animals treated with P(3HB-co-4HB) nanoparticles during 14 days of the acute toxicity study. In the subacute test, there was no mortality and toxicologically significant changes in clinical signs, body weights, food consumption, hematology, clinical biochemistry, urinalysis, macroscopic findings, organ weights as well as histopathological examination were observed.
  8. Raslan R, Hassim MH, Chemmangattuvalappil NG, Ng DKS, Ten JY
    Regul Toxicol Pharmacol, 2020 Oct;116:104753.
    PMID: 32745583 DOI: 10.1016/j.yrtph.2020.104753
    Consumers are commonly exposed to numerous chemical ingredients found in various formulated products especially household and personal care products. Therefore, identification of hazardous ingredients contained in those products should be performed at the early stages of product design to reduce the high cost of redesigning the products at the final stage. Thus, a systematic safety and health risk assessment methodology is required for the product formulation design. In this work, a two-step index-based methodology is presented to estimate the severity of the hazards and the magnitude of risks. In Tier 1 assessment, potential hazards of the ingredients were identified by following the Product Ingredient Safety Index (PISI). The basic toxicology information of ingredients was required for this assessment. In Tier 2 assessment, the extent of risks of the ingredients via dermal and inhalation exposure routes were evaluated. At this stage, the concentration of ingredients and the amount of exposure were considered. The value of Margin of Exposure (MOE) was used as an indicator in the development of Product Ingredient Exposure Index (PIEI). To demonstrate the proposed methodology, a case study on the evaluation of potential hazards and the risks from ingredients used in personal care product formulations were performed.
  9. Lakshmanan H, Raman J, Pandian A, Kuppamuthu K, Nanjian R, Sabaratam V, et al.
    Regul Toxicol Pharmacol, 2016 Aug;79:25-34.
    PMID: 27177820 DOI: 10.1016/j.yrtph.2016.05.010
    Senecio candicans DC. (Asteraceae) is used as a remedy for gastric ulcer and stomach pain in the Nilgiris, district, Tamil Nadu. The present investigation was carried out to evaluate the sub-chronic toxicity of an aqueous extract of Senecio candicans (AESC) plant in Wistar albino rats. The study was conducted in consideration of the OECD 408 study design (Repeated Dose 90-Day Oral Toxicity Study in Rodents) and the extract was administered via gavage at doses of 250, 500 or 750 mg/kg body weight per day for 90-days. Hematological, biochemical parameters were determined on days 0, 30, 60 and 90 of administration. Animals were euthanized after 90 d treatment and its liver and kidney sections were taken for histological study. The results of sub-chronic study showed significant increase (P 
  10. Hor SY, Ahmad M, Farsi E, Yam MF, Hashim MA, Lim CP, et al.
    Regul Toxicol Pharmacol, 2012 Jun;63(1):106-14.
    PMID: 22440551 DOI: 10.1016/j.yrtph.2012.03.006
    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.
  11. Rampal KG, Mohd Nizam J
    Regul Toxicol Pharmacol, 2006 Nov;46(2):131-5.
    PMID: 16899331
    In Malaysia exposures in the workplace are regulated under the Factories and Machinery Act (FMA), 1967 and also under the more comprehensive Occupational Safety and Health Act (OSHA) enacted in 1994. With OSHA 1994 the philosophy of legislating safety and health in the workplace changed from one that was very prescriptive and containing detailed technical provisions under FMA, 1967 to one that is more flexible and encourages self-regulation under OSHA 1994. OSHA 1994 is supported by regulations, codes of practices and guidelines to further clarify the provisions in the Act. Under the FMA 1967 emphasis was on safety while with OSHA 1994 there has been equal emphasis on addressing health hazards in the workplace. Regulations for occupational exposures are developed by the Department of Occupational Safety and Health with tripartite and stakeholder consultation. When developing these regulations International Labor Organization Conventions, laws of other countries and occupational exposure standards adopted internationally are reviewed. The government also conducts surveys to collect information on both exposures and health effects in workplaces to have better understanding on specific occupational health problems. Effective law enforcement is crucial in ensuring compliance to safety and health law. The challenge at the moment is to ensure all employers and employees, particularly those in the small and medium enterprises, understand and comply with the provisions stipulated in the legislation.
  12. Ibrahim AH, Khan MS, Al-Rawi SS, Ahamed MB, Majid AS, Al-Suede FS, et al.
    Regul Toxicol Pharmacol, 2016 Nov;81:457-467.
    PMID: 27756558 DOI: 10.1016/j.yrtph.2016.10.004
    Fermented Virgin Coconut Oil (FVCO) is widely used in the Southeast Asia as food and traditional medicine. The objective of the present study is the evaluation of chronic safety of the commercialized FVCO of Malaysia and other Southeast Asian countries. A single dose of 5000 mg/kg of FVCO was administered orally in rats (each group, n = 5) for the acute toxicity study and 175, 550 and 2000 mg/kg for sub-chronic and chronic studies (each group, n = 10), respectively. The behavior, mortality, and body weight of the rats were assessed to determine the toxic effects of FVCO. The haematology, biochemistry and histopathology of the treated rats were evaluated. The treated rats were safe with the dose of 5000 mg/kg in acute, sub-chronic and chronic indication. Abnormal clinical signs and morphology (gross necroscopy), changes of organ weight, anomalous haematology and biochemistry indexes were not found in comparison with the control (p > 0.05). In general, food and water intake were higher in the treated rats related to control. It was concluded that the presence of the antioxidant active compounds of FVCO might be the reason of safety. The structure activity relationship (SAR) provides a comprehensive mechanism to determine the safety that is the presence of the electron donating phenolic groups, carbonyl groups, and carboxylic acid in the ortho and meta position of the aromatic rings. The SAR showed the antioxidant properties of myristic acid and lauric acid determined by GC-MS analysis. This result suggests the safety of FVCO for chronic use, nutritional activity that FVCO formulation complies the requirements of regulatory agencies.
  13. Balakumar P, WitnessKoe WE, Gan YS, JemayPuah SM, Kuganesswari S, Prajapati SK, et al.
    Regul Toxicol Pharmacol, 2017 Mar;84:35-44.
    PMID: 27993652 DOI: 10.1016/j.yrtph.2016.12.007
    This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection.
  14. Zakaria A, Ho YB
    Regul Toxicol Pharmacol, 2015 Oct;73(1):191-5.
    PMID: 26190304 DOI: 10.1016/j.yrtph.2015.07.005
    This study aimed to determine the heavy metals (lead, cadmium, and chromium) concentration in lipsticks of different price categories sold in the Malaysian market and evaluate the potential health risks due to daily ingestion of heavy metals in lipsticks. A total of 374 questionnaires were distributed to the female staff in a public university in Malaysia in order to obtain information such as brand and price of the lipsticks, body weight, and frequency and duration of wearing lipstick. This information was important for the calculation of hazard quotient (HQ) in health risk assessment. The samples were extracted using a microwave digester and analyzed using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). The concentrations of lead, cadmium, and chromium in lipsticks ranged from 0.77 to 15.44 mg kg(-1), 0.06-0.33 mg kg(-1), and 0.48-2.50 mg kg(-1), respectively. There was a significant difference of lead content in the lipsticks of different price categories. There was no significant non-carcinogenic health risk due to the exposure of these heavy metals through lipstick consumption for the prolonged exposure of 35 years (HQ < 1).
  15. Sengupta P, Das A, Ibrahim F, Mandal UK, Chatterjee B, Mahmood S, et al.
    Regul Toxicol Pharmacol, 2016 Aug 26;81:155-161.
    PMID: 27569202 DOI: 10.1016/j.yrtph.2016.08.009
    It has been reported that the major cause of mortality in diabetes is cardiovascular diseases and contribution of hypertension is significant in this context. Pioglitazone, a thiazolidinedione class of therapeutic agent is used to treat type 2 diabetes mellitus. Telmisartan, an angiotensin receptor blocker antihypertensive has been reported to have beneficial effect if co-administered with pioglitazone for the management of diabetes complications. The present research work aims to evaluate the safety/toxicity profile of this combination in rat model. The investigation was carried out after co-administering the drugs to the rats for 28 days at three dose levels of 50, 100 and 150 mg/kg covering low to high dose ranges. Various hematological and biochemical parameters were studied in addition to the histopathology of the major organs in order to evaluate the toxicity profile of the combination. Absence of mortality and histopathological changes as well as unaltered hematological and biochemical parameters was observed. This preliminary investigation concludes that the combination of pioglitazone and telmisartan can primarily be stated as safe in animals, even at the dose level which is several folds higher than the intended human dose. Thus, this combination can be explored in future to develop a rational therapy regimen to treat hypertensive diabetic patients.
  16. Thangavelu L, Balusamy SR, Shanmugam R, Sivanesan S, Devaraj E, Rajagopalan V, et al.
    Regul Toxicol Pharmacol, 2020 Jun;113:104640.
    PMID: 32169672 DOI: 10.1016/j.yrtph.2020.104640
    Acacia catechu (A. catechu) or Khair (Hindi) is used in several herbal preparations in the Ayurvedic system of medicine in India. Traditionally, this drug is beneficial against several gastrointestinal and stomach related ailments, and leprosy. The present investigation was carried out to evaluate the sub-acute oral toxicity of the ethanolic extract of A. catechu seeds in Wistar albino rats. Results obtained from the quantitative chemical analysis of A. catechu seed extract were compared with commercially available standards. A. catechu seed extract was administered orally at the doses of 250, 500 and 1000 mg/kg b.w. daily for 28 days. General behavior, bodyweight and mortality were examined during the entire study period. At the end of 28 days, hematological and biochemical parameters along with the relative organ weights were determined. It was observed that the extract did not induce death or any significant changes in the body weight, relative weight of vital organs and in hematological parameters for up to a dose of 1000 mg/kg. The oral administration of the plant extract did not produce any significant changes in the levels of glucose. In addition, there were no significant changes in the activity of both hepatotoxic and nephrotoxic marker enzymes in the serum. Oral administration of A. catechu also did not produce any significant changes in the levels of oxidative markers. Furthermore, the findings from the biochemical studies were, well corroborated with the histological findings.
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