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1.  Antioxidant and Toxicity Studies of 50% Methanolic Extract of Orthosiphon stamineus Benth 
BioMed Research International  2013;2013:351602.
The present study evaluated the antioxidant activity and potential toxicity of 50% methanolic extract of Orthosiphon stamineus (Lamiaceae) leaves (MEOS) after acute and subchronic administration in rats. Superoxide radical scavenging, hydroxyl radical scavenging, and ferrous ion chelating methods were used to evaluate the antioxidant properties of the extract. In acute toxicity study, single dose of MEOS, 5000 mg/kg, was administered to rats by oral gavage, and the treated rats were monitored for 14 days. While in the subchronic toxicity study, MEOS was administered orally, at doses of 1250, 2500, and 5000 mg/kg/day for 28 days. From the results, MEOS showed good superoxide radical scavenging, hydroxyl radical scavenging, ferrous ion chelating, and antilipid peroxidation activities. There was no mortality detected or any signs of toxicity in acute and subchronic toxicity studies. Furthermore, there was no significant difference in bodyweight, relative organ weight, and haematological and biochemical parameters between both male and female treated rats in any doses tested. No abnormality of internal organs was observed between treatment and control groups. The oral lethal dose determined was more than 5000 mg/kg and the no-observed-adverse-effect level (NOAEL) of MEOS for both male and female rats is considered to be 5000 mg/kg per day.
doi:10.1155/2013/351602
PMCID: PMC3899703  PMID: 24490155
2.  Safety Assessment of Zigbir®: A Polyherbal Formulation in Sprague-Dawley Rats 
Journal of Toxicology  2012;2012:589520.
The safety of Zigbir®, a polyherbal formulation intended for use as food supplement, was evaluated in Sprague-Dawley rats treated orally at the dose of 2000 mg/kg in acute and at 250, 500, and 1000 mg/kg for 90 days in subchronic toxicity study. The median lethal dose of Zigbir® was found to be more than 2000 mg/kg, and fourteen-day repeated dose toxicity study revealed it to be safe up to 1000 mg/kg. The subchronic study did not show any mortality or treatment-related adverse clinical signs. The treated animals exhibited normal feed intake and comparable body weight gain except for a decrease in females of 500 and 1000 mg/kg groups. Ocular examination revealed no abnormalities. Further, Zigbir® administration in rats did not induce any major changes in urinalysis, hematological, and biochemical evaluations except for minor alterations in few parameters at different dose levels. Gross and histopathological findings did not show any lesions attributable to Zigbir® administration. The no observed effect level of Zigbir® was found to be 500 and 250 mg/kg in male and female Sprague-Dawley rats.
doi:10.1155/2012/589520
PMCID: PMC3483787  PMID: 23125854
3.  Safety Assessment of Ocimum Basilicum Hydroalcoholic Extract in Wistar Rats: Acute and Subchronic Toxicity Studies 
Objective(s)
Ocimum basilicum L. is widely used in folk medicine of many countries including . Both O. basilicum and its oil extract have received considerable attention for their potential medicinal properties, but there are a few reports about possible toxicity of this plant. Therefore, in the present study, acute and subchronic toxicity of O. basilicum hydroalcohlic extract have been evaluated in Wistar rats.
Materials and Methods
For the acute toxicity assessment, five groups of 10 animals (5 male, 5 female) received four different single dose of extract orally, the animals were, then, kept under observation for 14 days. For subchronic toxicity, the animals were divided into four groups (5 male, 5 female) and were gavaged daily by 50, 200 and 500 mg/kg of extract. Mortality, clinical signs, body weight changes, food and water consumption, and hematological and biochemical parameters were monitored during the study period. On the 45th day, animals were sacrificed and gross findings, weight of liver and left kidney and liver histological markers were assessed.
Results
The results of acute study indicated that LD50 of O. basilicum is higher than 5 mg/kg. In subchronic study, no adverse effects were observed on serum parameters in male and female rats. The hematological results showed a reduction in the hematocrit, platelets and RBC in both sexes. No abnormalities were observed in other parameters.
Conclusion
Based on the results of this study, present data suggest that hematologic system could serve as a target organ in oral toxicity of this plant.
PMCID: PMC3586872  PMID: 23493182
Acute toxicity; Ocimum basilicum; Rats; Subchronic toxicity
4.  Acute and Subchronic Toxicity Study of Tud-Rak-Ka-Sai-Puu Recipe in Rats 
Acute and subchronic toxicities of Tud-Rak-Ka-Sai-Puu (TR) recipe were studied in male and female rats. After 14 days of a single oral administration of test substance (5,000 mg/kg body weight), measurement of the body and organs weights, necropsy and health monitoring were performed. No signs and differences in the weights and behavior were observed relative to the control rats, suggesting that TR recipe in the dose of 5,000 mg/kg body weight does not produce acute toxicity. The subchronic toxicity was determined by oral feeding in male and female rats daily with the test substance at 2, 20, 200 and 2,000 mg/kg body weight for 90 days. No defects of animal behavior were observed in the test groups. Both test and control groups (on the 90th day) as well as the satellite group (on the 118th day) were analyzed by measuring their final body and organ weights, taking necropsy, and examining hematology, blood clinical chemistry, and microanatomy. These results together with the information of signs, behavior and health monitoring can lead to a conclusion that an oral administration of TR recipe at 2, 20, 200 and 2,000 mg/kg body weight for 90 days did not cause subchronic toxicity.
PMCID: PMC3746368  PMID: 24082336
Acute toxicity; Subchronic toxicity; Tud-Rak-Ka-Sai-Puu Recipe
5.  Acute and Subchronic Toxicity of Chantaleela Recipe in Rats 
Acute and subchronic toxicities of Chantaleela recipe were studied in both male and female rats. Oral administration of the extract at a single dose of 5,000 mg/kg body weight (5 females, 5 males) did not produce signs of toxicity, behavioral changes, mortality or differences on gross appearance of internal organs. The subchronic toxicity was determined by oral feeding the test substance at the doses of 600, 1,200 and 2,400 mg/kg body weight for 90 days (10 females, 10 males). No signs of abnormalities were observed in the test groups as compared to the controls. The test and control groups (on the 90th day) and the satellite group (on the 118th day) were analyzed by measuring their final body and organ weights, taking necropsy, and examining hematological parameters, blood clinical chemistry and histopathology features. The results suggest that Chantaleela recipe did not cause acute or subchronic oral toxicities to female and male rats.
PMCID: PMC3746366  PMID: 24082334
Acute toxicity; Subchronic toxicity; Chantaleela recipe
6.  Acute and 28-Day Subchronic Oral Toxicity of an Ethanol Extract of Zingiber zerumbet (L.) Smith in Rodents 
The objective of this study was to evaluate the acute and subacute toxicity (28 days) of the ethanol extract of Z. zerumbet rhizomes (EEZZ) via the oral route in Wistar rats of both sexes. In the acute toxicity study, Wistar rats were administered a single dose of 15 g kg−1 of body weight by gavage, and were monitored for 14 days. EEZZ did not produce any toxic signs or deaths; the 50% lethal dose must be higher than 15 g kg−1. In the subchronic toxicity study, EEZZ was administered by gavage at doses of 1000, 2000 and 3000 mg/kg daily for 4 weeks to Wistar rats. The subacute treatment with EEZZ did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups. Necropsy and histopathological examination, did not reveal any remarkable and treatment related changes. A no-observed adverse-effect level for EEZZ is 3000 mg kg−1 for rats under the conditions of this study. Hence, consumption of EEZZ for various medicinal purposes is safe.
doi:10.1155/2012/608284
PMCID: PMC3320105  PMID: 22536288
7.  Acute and subchronic toxicological evaluation of Stachys lavandulifolia aqueous extract in Wistar rats 
Stachys lavandulifolia (S. lavandulifolia) is a plant that has been widely used as an herbal medicine in Iran. Unfortunately, despite the prevalent medicinal uses of the plant, there are no reports on the possible toxic effects of S. lavandulifolia. In the present study the potential toxicity of S. lavandulifolia after acute and subchronic administration in rats was evaluated. Rats were orally treated with single doses of S. lavandulifolia aqueous extract and screened for signs of toxicity two weeks after administration. In the sub-chronic toxicity study, S. lavandulifolia was administered for 45 days. Mortality, clinical signs, body weight changes were assayed during the study. After 45 days animals were sacrificed and hematological and biochemical parameters, as well as weight of some organs were measured. All of the rats treated with different concentrations of water extracts of S. lavandulifolia were alive for all 14 days of observation. No hematological changes were observed a part from significant increase in WBC and neutrophils counts. Moreover, serum aspartate aminotransferase (AST) and creatinine significantly increased. Histopathological examinations showed fatty change, degeneration of hepatocytes and renal glomerular atrophy in the male rats. In the female rats, atrophy of hepatocytes and dilatation of sinusoids in liver, hyperemia and degeneration of renal epithelium mostly in cortical region were observed. Based on the results of this study no observed adverse effect level (NOAEL) of the total aqueous extract of S. lavandulifolia considered to be 250 and 100 mg/kg/day for the male and female rats, respectively.
PMCID: PMC4311280  PMID: 25657785
Stachys lavandulifolia; Rat; Acute; Subchronic; Toxicity
8.  Acute and subchronic toxicity as well as evaluation of safety pharmacology of eucalyptus oil-water emulsions 
Essential oil has performed a variety of indirect services used as insect/pest repellent. The present study investigated the acute and subchronic toxicity of eucalyptus oil emulsion in water (EOE). In addition, we conduct safety pharmacology evaluation of EOE to supplement the toxicity tests and provide a basis for a comprehensive understanding of the toxicity of EOE. Acute administration of EOE was done as single dose from 2772 mg to 5742 mg of EOE per kg/bodyweight (b.wt.) and subchronic toxicity study for thirty days was done by daily oral administration of EOE at doses of 396, 792 and 1188 mg/kg b.wt. In SPF SD rats. The acute toxicity study showed the LD50 of EOE was 3811.5 mg/kg. The subchronic toxicity study suggested the high-dose and middle-dose EOE slowed down the growth of male rats. The clinical pathology showed the high-dose and middle-dose EOE could cause damage to liver and kidney. The safety pharmacology indicated that EOE had no side effects on rats. These results suggest that EOE is a safe veterinary medicine for external use.
PMCID: PMC4307427  PMID: 25663980
Essential oil; acute toxicity; subchronic toxicity; safety pharmacology
9.  Preclinical Safety of the Root Extract of Polygala tenuifolia Willdenow in Sprague-Dawley Rats and Beagle Dogs 
The root of Polygala tenuifolia Willdenow has been used for the treatment of insomnia, depression, and amnesia. However, the toxicological properties of the herb have been overlooked, because it has been used for a long time for various purposes. In this study, we evaluated the preclinical safety of the root extract in rats and beagle dogs. First, the acute oral toxicity was tested in both rats and dogs. In the rats, only one female of 2 g/kg died, but no treatment-related death or clinical and gross findings were observed after the administration. No toxicological changes or mortalities related to the test substance were also observed after the administration in the dogs. Although vomiting, discoloration, or hemorrhage was found in some dogs, there were no serious abnormalities. Second, the subchronic toxicity was investigated in the rats. Two animals were found dead in the female group of 1,000 mg/kg/day, but there were no abnormal findings associated with the test substance. There also were no adverse effects on the clinical signs, body weight, and hematological and biochemical findings. Therefore, our results showed that the acute or subchronic toxicity of the root extract of Polygala tenuifolia might not be toxic to rats and dogs.
doi:10.1155/2014/570134
PMCID: PMC4238171  PMID: 25431613
10.  Comparative acute and subchronic toxicity of ethylene glycol monopropyl ether and ethylene glycol monopropyl ether acetate. 
The acute toxicity of ethylene glycol monopropyl ether (EGPE) and ethylene glycol monopropyl ether acetate (EGPEA) was determined in a series of standardized tests. The oral LD50 in rats was 3089 and 9456 mg/kg EGPE and EGPEA, respectively. Skin irritation was slight following an occluded single dose application of either compound to the guinea pig abdomen. The dermal LD50 for guinea pigs was 1 to 5 mL/kg and greater than 20 mL/kg EGPE and EGPEA, respectively. EGPE produced a very weak positive sensitization response in one of five guinea pigs. No positive response was elicited when 10 guinea pigs were similarly challenged with EGPEA. EGPE produced transient moderate to severe eye irritation in rabbits while EGPEA produced slight eye irritation. Subchronic toxicity was determined in a series of oral and inhalation studies. Groups of 10 male rats were dosed with 15, 7.5, 3.75 or 1.88 mmole/kg EGPE and 30, 15 or 7.5 mmole/kg EGPEA by gavage 5 days/week for 6 weeks. Hemoglobinuria was seen at least once at all dose levels of both compounds. EGPE had little effect on feed consumption or body weight gain, while body weight gain was reduced in the two high dose groups exposed to EGPEA and feed consumption was reduced at all dose levels. Hematologic changes were seen at all dose levels of both compounds. Absolute and/or relative spleen weights were increased at all but the lowest EGPE dose level and at all EGPEA dose levels. Gross and histopathologic examinations revealed significant effects on the spleen of animals exposed to EGPE and on the spleen, liver, kidney and testes of animals exposed to EGPEA. The no-observed effect level (NOEL) for splenic changes was 1.88 mmole/kg EGPE. A NOEL for hematology was not established. The NOEL for liver and testicular changes were 15 and 7.5 mmole/kg EGPEA, respectively while a NOEL for hematologic, splenic and renal changes was not established. Groups of 10 rats (5M, 5F) were exposed to 800, 400, 200 or 100 ppm EGPE or EGPEA 6 hr/day, 5 days/week for a total of 11 exposures. Body weight gains in all exposure groups were comparable to controls. Hemoglobinuria was seen only after the first or second exposure in males and females exposed to 800 ppm EGPE and in males exposed to 400 ppm EGPE. Males and females exposed to 800 ppm EGPEA and females exposed to 400 and 200 ppm EGPEA also exhibited hemoglobinuria.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC1568291  PMID: 6499801
11.  Acute and Subchronic Toxicity Study of Euphorbia hirta L. Methanol Extract in Rats 
BioMed Research International  2013;2013:182064.
Despite Euphorbia hirta L. ethnomedicinal benefits, very few studies have described the potential toxicity. The aim of the present study was to evaluate the in vivo toxicity of methanolic extracts of E. hirta. The acute and subchronic oral toxicity of E. hirta was evaluated in Sprague Dawley rats. The extract at a single dose of 5000 mg/kg did not produce treatment related signs of toxicity or mortality in any of the animals tested during the 14-day observation period. Therefore, the LD 50 of this plant was estimated to be more than 5000 mg/kg. In the repeated dose 90-day oral toxicity study, the administration of 50 mg/kg, 250 mg/kg, and 1000 mg/kg/day of E. hirta extract per body weight revealed no significant difference (P > 0.05) in food and water consumptions, body weight change, haematological and biochemical parameters, relative organ weights, and gross findings compared to the control group. Macropathology and histopathology examinations of all organs including the liver did not reveal morphological alteration. Analyses of these results with the information of signs, behaviour, and health monitoring could lead to the conclusion that the long-term oral administration of E. hirta extract for 90 days does not cause sub-chronic toxicity.
doi:10.1155/2013/182064
PMCID: PMC3872372  PMID: 24386634
12.  Acute and subchronic toxicological evaluation of Echinophora platyloba DC (Apiaceae) total extract in Wistar rats 
Clinics  2012;67(5):497-502.
OBJECTIVE:
Echinophora platyloba DC is a widely used herbal medicine and food seasoning in Iran. It is claimed to exert antimicrobial, antifungal, and antispasmodic effects. Despite the prevalent use of this plant as a food and medicine, there are no reports on its possible toxic effects. To evaluate the safety of E. platyloba, we tested its acute and sub-chronic toxicity in male and female Wistar rats.
METHODS:
Rats were orally treated with four different single doses of E. platyloba total extract and screened for signs of toxicity two weeks after administration. In the sub-chronic toxicity study, E. platyloba was administered for 45 days. Mortality, clinical signs, body weight changes, hematological and biochemical parameters, gross findings, organ weights, and histological markers were monitored during the study.
RESULTS:
We found no mortality and no abnormality in clinical signs, body weight, or necropsy findings in any of the animals in the acute study. The results of the subchronic study showed no significant difference in hematological parameters in either sex. There was a significant increase in lactate dehydrogenase in the female groups. A significant increase in the relative lung weight of female rats was noted at 500 mg/kg. Histopathological examinations revealed intra-alveolar hemorrhage in the male rats (500 mg/kg). In the females, congestion of the alveolar capillaries (at 500 mg/kg) and liver bridging necrosis (at 200 mg/kg) were significantly increased.
CONCLUSION:
The no observed adverse effect level of E. platyloba was determined to be 200 and 50 mg/kg for male and female rats, respectively.
doi:10.6061/clinics/2012(05)15
PMCID: PMC3351248  PMID: 22666795
Echinophora Platyloba; Rat; Acute Toxicity; Subchronic Toxicity
13.  Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs 
Toxicology  2011;289(2-3):141-150.
CP-31398 (N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160 mg/kg/day (0, 240, 480, or 960 mg/m2/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40 mg/kg/day (0, 200, 400, or 800 mg/m2/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The Maximum Tolerated Dose (MTD) for subchronic oral administration of CP-31398 is 80 mg/kg/day (480 mg/m2/day) in rats and 20 mg/kg/day (400 mg/m2/day) in dogs. Although only modest and apparently reversible toxicities (microscopic changes in rats; reductions in body weight gain and alterations in red cell parameters in dogs) were seen in the low dose groups, No Observed Adverse Effect Levels (NOAELs) for CP-31398 could not be established for either species. The toxicity of CP-31398 suggests that this agent may not be suitable for use in cancer prevention. However, should in vivo antitumor efficacy be achievable at doses that do not induce limiting toxicity, CP-31398 may have utility as a cancer therapeutic. Modification of the primary sites of CP-31398 metabolism (N-demethylation of the alkyl side chain; hydroxylation and O-demethylation of the styryl benzene group) may result in the development of CP-31398 analogs with comparable pharmacologic activity and reduced toxicity.
doi:10.1016/j.tox.2011.08.009
PMCID: PMC3195508  PMID: 21864638
CP-31398; N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride; p53; chemopreventive agent; chemotherapeutic agent
14.  Assessment of Oral Toxicity and Safety of Pentamethylchromanol (PMCol), A Potential Chemopreventative Agent, in Rats and Dogs 
Toxicology  2010;273(1-3):19-28.
2,2,5,7,8-pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000 mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN↑and PT↓) and hyperkeratosis of the nonglandular stomach in the 2000 mg/kg/day dose group (in one or both sexes). In the 500 mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100 mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800 mg/kg/day (4 male dogs/dose group). PMCol treatment at 800 mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200 mg/kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50, 200 and 800 mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-hour recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100 mg/kg/day and 50 mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100 mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500 mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent.
doi:10.1016/j.tox.2010.04.011
PMCID: PMC2927641  PMID: 20430063
chemoprevention; vitamin E; pentamethylchromanol; toxicity; oral; rat; beagle dog
15.  The Effect of Route of Administration in Thymoquinone Toxicity in Male and Female Rats 
The maximum tolerated dose for intraperitoneal injection and oral ingestion of thymoquinone was determined in male and female Wistar rats. A range of dose levels of thymoquinone: 20, 30 and 40 mg/kg body weight for intraperitoneal injection and 200, 300 and 500 mg/kg body weight for oral ingestion were tested for acute toxicity in rats. The results showed that the maximum tolerated dose for intraperitoneal injection was 22.5 mg/kg in male rats and 15 mg/kg in females, whereas for oral ingestion it was 250 mg/kg in both male and female rats. There were different signs of toxicity shown in rats which received intraperitoneal injection from those that received oral ingestion of thymoquinone. Rats which received intraperitoneal injection of thymoquinone showed toxicity signs which were related to acute pancreatitis. Meanwhile, rats which received oral ingestion of thymoquinone showed transient toxicity signs. Two deaths were reported at dose of 500 mg/kg as a result of bowel obstruction complications. The data presented in this study indicate that the route of administration of thymoquinone could have an influence on thymoquinone toxicity outcome in both genders.
doi:10.4103/0250-474X.106060
PMCID: PMC3574528  PMID: 23440704
Acute pancreatitis; acute toxicity; adynamic ileus; thymoquinone
16.  Toxicologic Assessment of a Commercial Decolorized Whole Leaf Aloe Vera Juice, Lily of the Desert Filtered Whole Leaf Juice with Aloesorb 
Journal of Toxicology  2013;2013:802453.
Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL) aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies—examined grossly and microscopically—that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks.
doi:10.1155/2013/802453
PMCID: PMC3608129  PMID: 23554812
17.  Genotoxicity and acute and subchronic toxicity studies of a standardized methanolic extract of Ficus deltoidea leaves 
Clinics  2013;68(6):865-875.
OBJECTIVE:
Ficus deltoidea leaves have been used in traditional medicine in Southeast Asia to treat diabetes, inflammation, diarrhea, and infections. The present study was conducted to assess the genotoxicity and acute and subchronic toxicity of a standardized methanol extract of F. deltoidea leaves.
METHODS:
Sprague Dawley rats were orally treated with five different single doses of the extract and screened for signs of toxicity for two weeks after administration. In the subchronic study, three different doses of the extract were administered for 28 days. Mortality, clinical signs, body weight changes, hematological and biochemical parameters, gross findings, organ weights, and histological parameters were monitored during the study. Genotoxicity was assessed using the Ames test with the TA98 and TA100 Salmonella typhimurium strains. Phytochemical standardization was performed using a colorimeter and high-performance liquid chromatography. Heavy metal detection was performed using an atomic absorption spectrometer.
RESULTS:
The acute toxicity study showed that the LD50 of the extract was greater than 5000 mg/kg. In the subchronic toxicity study, there were no significant adverse effects on food consumption, body weight, organ weights, mortality, clinical chemistry, hematology, gross pathology, or histopathology. However, a dose-dependent increase in the serum urea level was observed. The Ames test revealed that the extract did not have any potential to induce gene mutations in S. typhimurium, either in the presence or absence of S9 activation. Phytochemical analysis of the extract revealed high contents of phenolics, flavonoids, and tannins. High-performance liquid chromatography analysis revealed high levels of vitexin and isovitexin in the extract, and the levels of heavy metals were below the toxic levels.
CONCLUSION:
The no-observed adverse effect level of F. deltoidea in rats was determined to be 2500 mg/kg.
doi:10.6061/clinics/2013(06)23
PMCID: PMC3674303  PMID: 23778480
Ficus deltoidea; Oral Toxicity; OECD; Genotoxicity; Isovitexin; Vitexin
18.  Evaluation of Oral Subchronic Toxicity of Soshiho-Tang Water Extract: The Traditional Herbal Formula in Rats 
Soshiho-tang (Xiao-chai-hu-tang in Chinese and Sho-saiko-to in Japanese) has been widely used for its various pharmacological effects, which include anti-inflammatory, antioxidant, antihepatic fibrosis, and antitumor properties. To evaluate the safety of Soshiho-tang water extract (SST), we tested its subchronic toxicity in male and female Crl:CD (SD) rats. Rats were orally treated with four different doses (0, 500, 1000, and 2000 mg/kg/day) of SST administered for 13 weeks. Mortality, clinical signs, body weight changes, food and water consumption changes, ophthalmology, urinalysis, hematological and biochemical parameters, gross findings, organ weights, and histological markers were monitored during the study. The SST treatment did not result in any toxicologically significant changes in mortality, clinical signs, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematological and serum biochemical parameters, gross findings, organ weights, or histopathology. Histological analysis did not show any liver or kidney alteration. We concluded that the 13-week repeated oral administration of SST did not cause any adverse effects in rats at dosage levels of ≤2000 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level was concluded to be 2000 mg/kg/day for both sexes.
doi:10.1155/2013/590181
PMCID: PMC3616347  PMID: 23573136
19.  Toxicity and carcinogenicity studies of boric acid in male and female B6C3F1 mice. 
Environmental Health Perspectives  1994;102(Suppl 7):93-97.
Toxicity and potential carcinogenicity studies of boric acid were investigated in mice to verify in a second rodent species that this was a noncarcinogenic chemical. Earlier chronic studies in rats indicated boric acid was not a carcinogen. The chemical is nominated for testing because over 200 tons are produced annually, there are multiple uses for the product, and there is potential for widespread human exposure, both orally and dermally. Both sexes of B6C3F1 mice were offered diets mixed with boric acid for 14 days, 13 weeks, or 2 years. Dietary doses used in the acute, 14-day study were 0, 0.62, 1.25, 2.5, 5, and 10%; those in the subchronic, 13-week study were 0, 0.12, 0.25, 0.50, 1, and 2%; and doses in the 2-year, chronic study were 0, 0.25, and 0.50% in the diet. Mortality, clinical signs of toxicity, estimates of food consumption, body weight gain, and histopathologic examination of selected tissues constituted the variables measured. In the 14-day study mortality was proportional to dose and time of exposure in both sexes, occurring in dose groups as low as 2.5% and as early as 7 days of exposure. Body weights were depressed more than 10% below controls in the higher dose groups of both sexes. Mortality in the 13-week study was confined to the two highest dose groups in male mice and to the 2%-dose group in females. Body weight depression from 8 to 23% below those of controls occurred in the 0.50% and higher dose groups of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1566652  PMID: 7889889
20.  Gastroprotective and anti-Helicobacter pylori potential of herbal formula HZJW: safety and efficacy assessment 
Background
A traditional Chinese Medicine (TCM) formula, HZJW, has been applied in clinics in China for gastrointestinal disorders. However, the therapeutic mechanism underlying its efficacy and safety remained to be defined. The present investigation was undertaken to evaluate the formula HZJW for its gastroprotective potential, possible effect on Helicobacter pylori along with safety to justify its anti-ulcer action and safe clinical application.
Methods
The gastroduodenal cytoprotective potential was evaluated in rodent experimental models (HCl/Ethanol and NSAID-induced ulcer protocols). The anti-H. pylori property was assessed by agar dilution assay in vitro and analysis in vivo including rapid urease test, immunogold test and histopathology. For toxicity assessment, acute toxicity study was performed according to fixed dose procedure with a single oral administration of HZJW to mice. In the oral chronic toxicity, rats (80 males, 80 females) were administrated HZJW orally in 0, 1000, 2500, or 5000 mg/kg/day doses for 26 weeks (n = 40/group of each sex). Clinical signs, mortality, body weights, feed consumption, ophthalmology, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined at the end of the 13- and 26-week dosing period, as well as after the 4-week recovery period.
Results
In the HCl/Ethanol-induced ulcer model, it was observed that oral administration with HZJW (260, 520 and 1040 mg/kg) and ranitidine (250 mg/kg) significantly reduced the ulcerative lesion index (116.70 ± 36.4, 102.20 ± 18.20, 84.10 ± 12.1 and 73.70 ± 16.70) in a dose-dependent manner, respectively, with respect to control group (134.10 ± 31.69). Significant inhibition was also observed in ulcerative index from aspirin-induced ulcer model, with decreases of 35.40 ± 5.93, 31.30 ± 8.08, 26.80 ± 8.27and 20.40 ± 6.93 for the groups treated with HZJW and ranitidine, in parallel to controls (41.60 ± 10.80). On the other hand, treatment with HZJW efficaciously eradicated H. pylori in infected mice in rapid urease test (RUT) and immunogold antibody assay, as further confirmed by reduction of H. pylori presence in histopathological analysis. In the in vitro assay, MICs for HZJW and amoxicillin (positive control) were 125 and 0.12 μg/mL respectively. The LD50 of HZJW was over 18.0 g/kg for mice. No drug-induced abnormalities were found as clinical signs, body weight, food consumption, hematology, blood biochemistry, ophthalmology and histopathology results across three doses. No target organ was identified. The No Observed Adverse Effect Level (NOAEL) of HZJW was determined to be 5,000 mg/kg/day for both sexes, a dose that was equivalent to 50 times of human dose.
Conclusions
These results suggested the efficacy and safety of HZJW in healing peptic ulcer and combating H. pylori, which corroborated their conventional indications and contributed to their antiulcer pharmacological validation, lending more credence to its clinical application for the traditional treatment of stomach complaints symptomatic of peptic ulcer disease (PUD). HZJW might have the potential for further development as a safe and effective alternative/complementary to conventional medication in treating gastrointestinal (GI) disorders.
doi:10.1186/1472-6882-13-119
PMCID: PMC3679842  PMID: 23721522
HZJW; TCM; Cytoprotective; Helicobacter pylori; Gastroduodenal ulcer; Safety
21.  Toxicology of haloacetonitriles. 
Haloacetonitriles are by-products of water chlorination and may form in vivo from the reaction of residual chlorine with endogenous compounds such as amino acids. Dibromoacetonitrile (DBAN) was negative in selected mutagenic assays; dichloroacetonitrile (DCAN) was mutagenic in S. typhimurium, but not in S. cerevisiae. Both DBAN and DCAN may be carcinogenic. There is a paucity of basic toxicological data for these compounds. The studies described were conducted to determine the acute, subacute, and subchronic toxicity of DBAN and DCAN. The acute oral LD50 values (mg/kg) in mice and rats are: DBAN, mice: 289 (M), 303 (F); DBAN, rats: 245 (M), 361 (F); DCAN, mice: 270 (M), 279 (F); DCAN, rats: 339 (M), 330 (F). Death was preceded by slowed respiration, depressed activity, prostration, and coma. There were no apparent compound-related gross pathological effects. DBAN (in corn oil) was administered by gavage to male and female CD rats for 14 or 90 days at levels of 23, 45, 90, and 180 mg/kg/day or 6, 23, and 45 mg/kg/day, respectively. Mortality was 100% at 180 mg/kg and 40% (M) and 20% (F) at 90 mg/kg/day. Compound-related mortality was 10% (M) and 5% (F) at 45 mg/kg and 0% (M) and 10% (F) at 23 mg/kg during the 90-day study. No consistent, significant, adverse compound-related effects on any of the parameters evaluated were evident. Possible target organs might be spleen, thymus, and liver. The no-observed adverse-effect level (NOAEL) for 14 days was 45 mg/kg/day and for 90 days was 23 mg/kg/day. DCAN (in corn oil) was administered by gavage to male and female CD rats for 14 or 90 days at levels of 12, 23, 45, and 90 mg/kg/day or 8, 33, and 65 mg/kg/day, respectively. There were no deaths during the 14-day study. Compound-related mortality was 50% (M) and 25% (F) at 65 mg/kg, 10% (M) and 5% (F) at 33 mg/kg, and 5% (M) and 0% (F) at 8 mg/kg during the 90-day study. Body weights were significantly lower at 90 and 65 mg/kg/day; weight and ratios of spleen and gonads and cholesterol levels were significantly lower at 90 mg/kg/day. No consistent, significant adverse compound-related effects on any of the parameters evaluated were evident. The NOAEL for 14 days was 45 mg/kg/day and for 90 days was 8 mg/kg/day.
PMCID: PMC1474335  PMID: 3816722
22.  Safety Assessment of TLPL/AY/03/2008, A Polyherbal Formulation in Sprague Dawley Rats 
Toxicology International  2013;20(1):77-86.
Objectives:
TLPL/AY/03/2008 is a polyherbal formulation intended for treatment of osteoarthritis, rheumatoid arthritis, lumbago, spondylitis etc., Acute and repeated dose 90-days studies were conducted to evaluate the safety profile of TLPL/AY/03/2008 in rats.
Materials and Methods:
In acute study, TLPL/AY/03/2008 was orally administered to Sprague Dawley rats at 2000 mg/kg. In repeated dose study, TLPL/AY/03/2008 was administered to rats at 200, 500 and 1000 mg/kg through oral gavage for 90 days and assessed for treatment related changes in body weight, feed consumption, hematological, biochemical and pathological parameters. Histopathological examination was conducted for tissues from control and the high dose groups and was extended to target organs from the lower dose and recovery groups.
Results:
In acute study, the test item did not produce any mortality or adverse clinical signs. In the 90-days oral toxicity study, animals did not exhibit any toxicity symptoms and no deaths were observed. No significant changes were found in hematological and biochemical endpoints. Also, toxicologically significant alterations in relative organ weights were not observed. Microscopic findings of mild to marked, diffuse hepatocellular degeneration (vacuolar changes with granular of cytoplasm and pyknotic nuclei of hepatocytes) was noticed in males at 1000 mg/kg body weight. Animals of recovery group (1000 mg/kg) did not show any changes when compared with control group animals indicating the complete reversal.
Conclusions:
Based on the findings of the study, the median lethal dose of TLPL/AY/03/2008 was found to be more than 2000 mg/kg. The No Observed Adverse Effect Level (NOAEL) of TLPL/AY/03/2008 can be considered as 1000 mg/kg in both male and female rats, under the experimental conditions and doses employed.
doi:10.4103/0971-6580.111539
PMCID: PMC3702132  PMID: 23833442
Acute; polyherbal; subchronic; toxicity; TLPL/AY/03/2008
23.  Toxicity Profile of a Nutraceutical Formulation Derived from Green Mussel Perna viridis 
BioMed Research International  2014;2014:471565.
The short-term (acute) and long-term (subchronic) toxicity profile, mean lethal dose 50 (LD50), and no-observed-adverse-effect level (NOAEL) of a nutraceutical formulation developed from green mussel Perna viridis, which showed in vitro and in vivo anti-inflammatory properties, were evaluated in the present study. The formulation was administered to the male and female Wistar rats at graded doses (0.5, 1.0, and 2.5 g/kg body weight) for two weeks of acute toxicity study and 0.5, 1.0, and 2.0 g/kg body weight for 90 days in subchronic toxicity study. The LD50, variations in clinical signs, changes in body weight, body weight, food/water consumption, organ weight (liver, kidney, spleen, and brain), hematology, serum chemistry, and histopathological changes were evaluated. The LD50 of the formulation was 5,000 mg/kg BW. No test article related mortalities as well as change in body weight, and food and water consumption were observed. No toxicity related significant changes were noted in renal/hepatic function, hematological indices, and serum biochemical parameters between the control and treated groups. Histopathological alterations were not observed in the vital organs of rats. The subchronic NOAEL for the formulation in rats is greater than 2000 mg/kg. This study demonstrated that the green mussel formulation is safe to consume without any adverse effects in the body.
doi:10.1155/2014/471565
PMCID: PMC4066681  PMID: 24995298
24.  Lipid-Lowering Effects of Tetradecylthioacetic Acid in Antipsychotic-Exposed, Female Rats: Challenges with Long-Term Treatment 
PLoS ONE  2012;7(11):e50853.
Background
Psychiatric patients often require chronic treatment with antipsychotic drugs, and while rats are frequently used to study antipsychotic-induced metabolic adverse effects, long-term exposure has only partially mimicked the appetite-stimulating and weight-inducing effects found in the clinical setting. Antipsychotic-induced effects on serum lipids are also inconsistent in rats, but in a recent study we demonstrated that subchronic treatment with the orexigenic antipsychotic olanzapine resulted in weight-independent increase in serum triglycerides and activation of lipogenic gene expression in female rats. In addition, a recent long-term study in male rats showed that chronic treatment with antipsychotic drugs induced dyslipidemic effects, despite the lack of weight gain.
Aims
In the current study, we sought to examine long-term effects of antipsychotic drugs on weight gain, lipid levels and lipid composition after twice-daily administration of antipsychotics to female rats, and to investigate potential beneficial effects of the lipid-lowering agent tetradecylthioacetic acid (TTA), a modified fatty acid.
Methods
Female rats were exposed to orexigenic antipsychotics (olanzapine or clozapine), metabolically neutral antipsychotics (aripiprazole or ziprasidone), or TTA for 8 weeks. Separate groups received a combination of clozapine and TTA or olanzapine and TTA. The effects of TTA and the combination of olanzapine and TTA after 2 weeks were also investigated.
Results
The antipsychotic-induced weight gain and serum triglyceride increase observed in the subchronic setting was not present after 8 weeks of treatment with antipsychotics, while lipid-lowering effect of TTA was much more pronounced in the chronic than in the subchronic setting, with concomitant upregulation of key oxidative enzymes in the liver. Unexpectedly, TTA potentiated weight gain in rats treated with antipsychotics.
Conclusion
TTA is a promising candidate for prophylactic treatment of antipsychotic-induced dyslipidemic effects, but a more valid long-term rat model for antipsychotic-induced metabolic adverse effects is required.
doi:10.1371/journal.pone.0050853
PMCID: PMC3511315  PMID: 23226405
25.  Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7 
Toxicology Mechanisms and Methods  2011;21(7):520-532.
Menaquinone-7 (MK-7) is part of a family of vitamin K that are essential co-factors for the enzyme γ-glutamyl carboxylase, which is involved in the activation of γ-carboxy glutamate (Gla) proteins in the body. Gla proteins are important for normal blood coagulation and normality of bones and arteries. The objective of this study was to examine the potential toxicity of synthetic MK-7 in BomTac:NMRI mice and in Sprague-Dawley rats. In an acute oral toxicity test, mice were administered a single oral dose of 2000 mg/kg body weight (limit dose) and no toxicity was observed during the 14-day observation period. In the subchronic oral toxicity test in rats, animals were administered MK-7 for 90 days by gavage at the following doses: 0 (vehicle control, corn oil), 2.5, 5, and 10 mg/kg body weight/day. All generated data, including clinical observations, ophthalmology, clinical pathology, gross necropsy, and histopathology, revealed no compound-related toxicity in rats. Any statistically significant findings in clinical pathology parameters and/or organ weights noted were considered to be within normal biological variability. Therefore, under the conditions of this experiment, the median lethal dose (LD50) of MK-7 after a single oral administration in mice was determined to be greater than the limit dose level of 2000 mg/kg body weight. The no observed adverse effect level (NOAEL) of MK-7, when administered orally to rats for 90 days, was considered to be equal to 10 mg/kg body weight/day, the highest dose tested, based on lack of toxicity during the 90-day study period.
doi:10.3109/15376516.2011.568983
PMCID: PMC3172146  PMID: 21781006
Menaquinone-7; acute oral toxicity; 90-day oral subchronic toxicity study; histopathology

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