Thirteen-week oral toxicity study of fermented ginseng, GBCK25, in Sprague-Dawley rats.

Ginseng (Panax ginseng) is commonly used in Asia as a medicinal herb. In particular, fermented ginseng, GBCK25, has been recently developed to increase ginsenoside absorption. It also has other beneficial biological effects such as hemodynamic and anti-inflammation functions. Here, we investigated the potential toxicity of GBCK25 in Sprague-Dawley rats following 13 weeks of GBCK25 treatment by oral gavage at doses of 250, 500, or 1000 mg/kg/day and reversible toxic effects over a 4-week recovery phase. Ten male and female rats per group were randomly allocated to the main toxicology groups and five male and female rats per group were allocated to the 0 and 1000 mg/kg/day recovery groups, respectively. There was no mortality; significant clinical toxicity or microscopic findings; and changes in body weight, food consumption, hematological parameters, serum biochemistry, or absolute and relative organ weights in any of the groups. In conclusion, there were no toxicological changes upon repeated oral gavage of GBCK25 at doses of 250, 500, or 1000 mg/kg/day in Sprague-Dawley rats over 13 weeks. The no-observed-adverse-effect level of GBCK25 was 1000 mg/kg/day in both sexes of Sprague-Dawley rat.

A 13-Week Repeated Oral Dose Toxicity Study of ChondroT in Sprague-Dawley Rats.

BACKGROUND: ChondroT, a new herbal medication, consists of Angelica grosseserrata Maxim., Lonicera japonica Thunb., Angelica gigas Nakai, Clematis terniflora var. manshurica (Rupr.) Ohwi, and Phellodendron amurense Rupr. (6:4:4:4:3). Our previous studies have shown that ChondroT exhibits significant anti-arthritic and anti-inflammatory effects. In this study, we aimed to assess the toxicological safety assessment of ChondroT. METHODS: This study was designed to assess the safety of ChondroT after repeated oral administration. Male and female Sprague-Dawley rats were treated with ChondroT at oral doses of 0, 500, 1000, and 2000 mg/kg for 13 weeks. Mortality, clinical signs, body weight changes, food consumption, ophthalmological findings, urinalysis, hematological and blood-chemical parameters, necropsy findings, organ weights, and histological markers were recorded throughout the study period. Rats were also monitored for an additional 4 weeks to determine the recovery time. RESULTS: No death occurred and no significant changes in food consumption, ophthalmologic findings, and urinalysis were found. Although there were alterations in clinical signs, body weights, hematological parameters, blood-chemical parameters, necropsy findings, organ weights, and histological markers, they were not considered to be toxicologically significant. CONCLUSIONS: The results suggest that the no-observed adverse effects level (NOAEL) was 2000 mg/kg/day for the test substance. ChondroT, a new complex herbal medication composed of five plants, can therefore be used safely at the NOAEL.

Timeline of changes in adaptive physiological responses, at the level of energy expenditure, with progressive weight loss.

Diet-induced weight loss (WL) is associated with reduced resting and non-resting energy expenditure (EE), driven not only by changes in body composition but also potentially by adaptive thermogenesis (AT). When exactly this happens, during progressive WL, remains unknown. The aim of this study was to determine the timeline of changes in RMR and exercise-induced EE (EIEE), stemming from changes in body composition v. the presence of AT, during WL with a very-low-energy diet (VLED). In all, thirty-one adults (eighteen men) with obesity (BMI: 37 (sem 4·5) kg/m2; age: 43 (sem 10) years) underwent 8 weeks of a VLED, followed by 4 weeks of weight maintenance. Body weight and composition, RMR, net EIEE (10, 25 and 50 W) and AT (for RMR (ATRMR) and EIEE (ATEIEE)) were measured at baseline, day 3 (2 (sem 1) % WL), after 5 and 10 % WL and at weeks 9 (16 (sem 2) %) and 13 (16 (sem 1) %). RMR and fat mass were significantly reduced for the first time at 5 % WL (12 (sem 8) d) (P<0·01 and P<0·001, respectively) and EIEE at 10 % WL (32 (sem 8) d), for all levels of power (P<0·05), and sustained up to week 13. ATRMR was transiently present at 10 % WL (-460 (sem 690) kJ/d, P<0·01). A fall in RMR should be anticipated at ≥5 % WL and a reduction in EIEE at ≥10 % WL. Transient ATRMR can be expected at 10 % WL. These physiological adaptations may make progressive WL difficult and will probably contribute to relapse.

The Ramazzini Institute 13-week study on glyphosate-based herbicides at human-equivalent dose in Sprague Dawley rats: study design and first in-life endpoints evaluation.

BACKGROUND: Glyphosate-based herbicides (GBHs) are the most widely used pesticides worldwide, and glyphosate is the active ingredient of such herbicides, including the formulation known as Roundup. The massive and increasing use of GBHs results in not only the global burden of occupational exposures, but also increased exposure to the general population. The current pilot study represents the first phase of a long-term investigation of GBHs that we are conducting over the next 5 years. In this paper, we present the study design, the first evaluation of in vivo parameters and the determination of glyphosate and its major metabolite aminomethylphosphonic acid (AMPA) in urine. METHODS: We exposed Sprague-Dawley (SD) rats orally via drinking water to a dose of glyphosate equivalent to the United States Acceptable Daily Intake (US ADI) of 1.75 mg/kg bw/day, defined as the chronic Reference Dose (cRfD) determined by the US EPA, starting from prenatal life, i.e. gestational day (GD) 6 of their mothers. One cohort was continuously dosed until sexual maturity (6-week cohort) and another cohort was continuously dosed until adulthood (13-week cohort). Here we present data on general toxicity and urinary concentrations of glyphosate and its major metabolite AMPA. RESULTS: Survival, body weight, food and water consumption of the animals were not affected by the treatment with either glyphosate or Roundup. The concentration of both glyphosate and AMPA detected in the urine of SD rats treated with glyphosate were comparable to that observed in animals treated with Roundup, with an increase in relation to the duration of treatment. The majority of glyphosate was excreted unchanged. Urinary levels of the parent compound, glyphosate, were around 100-fold higher than the level of its metabolite, AMPA. CONCLUSIONS: Glyphosate concentrations in urine showed that most part of the administered dose was excreted as unchanged parent compound upon glyphosate and Roundup exposure, with an increasing pattern of glyphosate excreted in urine in relation to the duration of treatment. The adjuvants and the other substances present in Roundup did not seem to exert a major effect on the absorption and excretion of glyphosate. Our results demonstrate that urinary glyphosate is a more relevant marker of exposure than AMPA in the rodent model.

Late onset postpartum psychoses.

It has been known since the eighteenth century that postpartum psychoses can begin several weeks after childbirth, not during the first fortnight. There are almost 400 non-organic episodes in the literature, starting more than 3 weeks after the birth; some of them are recurrent. The distinction of this disorder from early onset puerperal psychosis is supported by the distribution of onsets (which shows a steep fall after 14-15 days), survey data and the association with later pregnancies, not the first. Marcé believed that these late onsets were related to the resumption of menstruation. This is a hypothesis worth investigating.

Acute and subchronic (13-week) toxicity of fermented Acanthopanax koreanum extracts in Sprague Dawley rats.

The biological fermentation of plants is usually used to improve their product properties, including their biological activity. Acanthopanax koreanum is a plant indigenous to Jeju, Korea; however, fermented A. koreanum (FAK) has not been guaranteed to be safe. Therefore, in this study, a safety evaluation of aqueous extracts of FAK was performed using Sprague Dawley rats. The acute toxicity of FAK did not influence animal mortality, body weight changes or the animals' clinical appearance at a concentration of 5000 mg/kg body weight. Using doses of 500, 1000 and 2000 mg/kg/day in a subchronic (13-week) toxicity study, the administration of FAK in male rats increased their body weight, food consumption, absolute liver weight, liver-associated enzymes and total cholesterol content. However, these effects of FAK were not considered toxic because the changes were not accompanied by any evidence of clinical signs or any change in the histopathological examination. On the other hand, the FAK-treated female rats did not exhibit significant changes in their body weight, food consumption, absolute and relative organ weights or liver enzymes. These results suggest that the acute oral administration of FAK is non-toxic to rats, and 13 weeks of repeated dosing demonstrated no FAK-related toxicity at a concentration of 2000 mg/kg. Therefore, the no-observed-adverse-effect level (NOAEL) of FAK was determined to be 2000 mg/kg/day for both male and female rats.

Evaluating the toxicity of the roots of Asarum heterotropoides var. mandshuricum extracted using the decoction method: Genotoxicity, single-dose toxicity, and 13-week repeated-dose toxicity studies.

ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Asarum heterotropoides F. Maekawa var. mandshuricum F. Maekawa (AR) is a traditional herbal medicine used across Asia, including Korea, China, and Japan. AR exhibits a range of biological activities, such as anti-inflammatory, anti-cancer, cold treatment, and anti-nociceptive effects. Various extraction methods, including decoction, which utilizes traditional knowledge and techniques. The AR decoction extract expected to contain fewer toxicants and have reduced toxicity due to the use of hot water in the extraction process. However, scientific evidence on the toxicity of AR decoction extracts is lacking, necessitating further studies for safe usage. AIM OF THE STUDY: This study aimed to evaluate the genotoxicity and toxicity of single and repeated administration of AR decoction extracts. MATERIALS AND METHODS: The genotoxicity was assessed using a bacterial reverse mutation (Ames test), an in vitro mammalian chromosome aberration test (CA test), and an in vivo micronucleus test (MN test) in Sprague-Dawley (SD) rats. The general toxicity was evaluated through single-dose and 13-week repeated-dose toxicity studies. In the single-dose toxicity study, 40 SD rats were orally administered AR decoction extract at doses of 1000, 2000, and 5000 mg/kg. In the 13-week repeated-dose toxicity study, 140 SD rats received daily oral doses of 0, 250, 500, 1000, 2000, and 5000 mg/kg of AR decoction extract. RESULTS: The genotoxicity tests revealed that AR decoction extract was not genotoxic. The single-dose toxicity study showed no changes in body weight, clinical pathology, or macroscopic findings, with the approximate lethal dose (ALD) exceeding 5000 mg/kg. The 13-week repeated-dose toxicity study demonstrated no treatment-related changes in body weight, general symptoms, hematology, clinical chemistry, or urinalysis. Histopathological findings revealed hyperplasia of squamous cells in the forestomach after AR decoction extract administration, a treatment-related effect that resolved during the recovery period. The no observed adverse effect level (NOAEL) for both male and female rats was estimated to be 2000 mg/kg. CONCLUSIONS: This study establishes the non-toxic dose of AR decoction extract, providing a foundation for further non-clinical and clinical evaluations AR safety.

Evaluation of genotoxicity and 13-week subchronic toxicity of root of Asarum heterotropoides var. seoulense (Nakai) Kitag.

ETHNOPHARMACOLOGICAL RELEVANCE: Asarum heterotropoides var. seoulense (Nakai) Kitag is a traditional herbal medicine used in Korea and China. It is effective in aphthous stomatitis, local anesthesia, headache, toothache, gingivitis, and inflammatory diseases. However, information on the toxicity of the root of Asarum heterotropoides var. seoulense (Nakai) Kitag (AR) is limited. Therefore, preclinical toxicity studies on AR are needed to reduce the risk of excessive intake. AIM OF THE STUDY: We aimed to evaluate genotoxicity and the potential toxicity due to repeated administration of AR powder. MATERIALS AND METHODS: In vitro bacterial reverse mutation assay (Ames), in vitro chromosomal aberration assay (CA), and in vivo micronucleus (MN) assay in ICR mice were conducted. As positive results were obtained in Ames and CA assays, alkaline comet assay and pig-a gene mutation test were conducted for confirmation. For evaluating the general toxicity of AR powder, a 13-week subchronic toxicity test was conducted, after determining the dose by performing a single and a 4-week dose range finding (DRF) test. A total of 152 Sprague-Dawley (SD) rats were orally administered AR powder at doses of 0, 150, 350, 500, 1000, and 2000 mg/kg/day in the 13-week subchronic toxicity test. Hematology, clinical chemistry, urinalysis, organ weight, macro-, and microscopic examination were conducted after rat necropsy. RESULTS: AR powder induced genotoxicity evidenced in the Ames test at 187.5, 750, 375, and 1500 µg/plate of TA100, TA98, TA1537, and E. coli WP2uvrA in the presence and absence of S9, respectively; CA test at 790 µg/mL for 6 h in the presence of S-9; 75 µg/mL for 6 h in the absence of S-9, and 70 µg/mL for 22 h in the absence of S-9 in the stomach in the comet assay but not in MN and pig-a assays. In the 13-week subchronic toxicity study, clinical signs including irregular respiration, noisy respiration, salivation, and decreased body weight or food consumption were observed in males and females in the 2000 mg/kg/day group. In hematology tests, clinical chemistry, urinalysis, organ weight, and macroscopic examination, changes were observed in the dose groups of 500 mg/kg/day and above. Microscopic examination revealed hyperplasia of the stomach as a test-related change. Hepatocellular adenoma and changes in liver-related clinical chemistry parameters were observed. The rat No Observed Adverse Effect Level (NOAEL) was 150 mg/kg/day in males and <150 mg/kg/day in females. CONCLUSIONS: AR powder is potentially toxic to the liver and stomach and should be used with caution in humans. A long-term study on carcinogenicity is necessitated because DNA damage or changes in tissue lesions were observed in SD rats.

Repeated oral dose toxicity and genotoxicity of a standardized Quisqualis indica extract.

Quisqualis indica L. of Combretaceae family is a traditional medicine that is widely used for various gastrointestinal discomfort including stomach pain, constipation, and digestive problem. In this study, the potential repeated dose toxicity and genotoxicity of a standardized Quisqualis indica L. extract (HU033) were determined under good laboratory practice conditions. For the repeated dose toxicity test, HU033 was orally administered to Sprague-Dawley (SD) rats at doses of 500, 1000, and 2000 mg/kg/day for 13 consecutive weeks. The genotoxicity of HU033 was determined with a standard battery of genotoxicity test, including an in vitro bacterial reverse mutation test, an in vitro chromosomal aberration test, and an in vivo micronucleus test. After 13 weeks of repeated dose of HU033 by oral administration, there was no treatment related adverse clinical sign including food consumption, organ weights, and histopathological findings or significant decrement in bodyweight. The no-observed-adverse-effect level of HU033 was higher than 2000 mg/kg in both male and female SD rats. No target organs were identified. In addition, no evidence of HU033 genotoxicity was detected based on results from the bacterial reverse mutation test, chromosomal aberration test, and micronucleus test. Based on results of this study, HU033 could be safely used in food and medical products within the tested dose range.

Toxicological evaluation of the red mold rice extract, ANKASCIN 568-R: 13-week chronic toxicity, and genotoxicity studies.

ANKASCIN 568-R is an extract derived from red mold rice (RMR) fermented using Monascus purpureus NTU 568. RMR fermented using M. purpureus NTU 568 prevents cardiovascular diseases and decreases blood lipid levels. This study evaluates the safety of ANKASCIN 568-R, since it has not determined yet. After daily oral ANKASCIN 568-R for 13 consecutive weeks, we evaluated the toxicity tolerance of Sprague-Dawley rats and performed dose formulation analysis on monascin and ankaflavin. The dose formulation analysis showed that ANKASCIN 568-R concentrations were lower than the target concentration and out of range ( ± 15%) at week 8 and on the last dosing day for both monascin (all dose groups) and ankaflavin at the 100 mg/kg dose. The lowest reported concentrations for the low, middle, and high dose formulations were 34.7, 115.2, and 398.1 mg/mL, respectively. We also evaluated the genotoxicity of ANKASCIN 568-R and showed no genotoxicity potential at all ANKASCIN 568-R doses investigated. The no observed adverse effect level of ANKASCIN 568-R was determined to be 796.2 mg/kg/day. This study revealed the first toxicity evaluation data of ANKASICN 568-R, and the data demonstrated ANKASICN 568-R was safe and can be used in daily life.

Assessment of General Toxicity of the Glycyrrhiza New Variety Extract in Rats.

The Glycyrrhiza radix (Licorice) is one of the most commonly used medicinal plants in Asian countries, such as China, India, and Korea. It has been traditionally used to treat many diseases, including cough, cold, asthma, fatigue, gastritis, and respiratory tract infections. A Glycyrrhiza new variety, Wongam (WG), has been developed by the Korea Rural Development Administration and revealed pharmacological effects. However, the potential adverse effects of WG have not been revealed yet. This study evaluates the general toxicity of the WG extract through a single and repeated oral dose toxicity study in Sprague-Dawley rats. After single oral dose administration, no significant toxicological changes or mortality was observed up to 5000 mg/kg. Over a 4-week repeated oral dose toxicity study, no adverse effects and target organs were observed up to 5000 mg/kg/day. Over a 13-week repeated oral dose toxicity study, no mortality or toxicological changes involving ophthalmology, water consumption, or hematology were observed up to 5000 mg/kg/day. Although other parameters were changed, the alterations in question were not considered toxicologically significant, since responses remained within normal ranges and were not dose-dependent. In conclusion, the no-observed-adverse-effect level (NOAEL) of WG was higher than 5000 mg/kg/day, and no target organs were identified in rats.

Nutritional and 13-Week Subchronic Toxicological Evaluation of Lignosus rhinocerotis Mycelium in Sprague-Dawley Rats.

Lignosus rhinocerotis (Tiger's Milk mushroom) is a novel mushroom with sclerotium belonging to the Polyporaceae family and has been reported widely to possess anti-cancer, anti-cough, antioxidant, gastro-protective, immuno-modulating, and neurite-stimulating properties. As numerous studies have proven the tremendous medicinal values of L. rhinocerotis, it is necessary to understand its nutrition as well as its safety for the recipient. Previous research on L. rhinocerotis has mainly focused on the naturally occurring sclerotium and may have overlooked mushroom mycelia from submerged liquid fermentation, which ensures a high uniform quantitative biomass production as well as a high biological value. Hence, this is the first report on the evaluation of nutrition and 13-week repeated oral toxicity of L. rhinocerotis mycelium (LRM). The LRM powder contained 9.0 ± 4.2% moisture, 1.9 ± 1.3% ash, 1.6 ± 2.2% crude lipid, 8.4 ± 5.3% crude protein, 79.3 ± 4.6% carbohydrate, and 364 kcal/100 g energy. The total free amino acid ranged from 349 to 5636 mg/100 g and the umami index of freeze-dried LRM powder was 0.37. For safety assessment, ninety-six rats were divided into four groups, each consisting of twelve male and twelve female rats. Test articles were administered by oral gavage to rats at 850, 1700, and 3400 mg/kg body weight/day for 13 weeks and reverse osmosis water was used as the control. All animals survived to the end of the study. During the experiment period, no abnormal changes were observed in clinical signs, body weight, or ophthalmological examinations. No adverse or test article-related differences were found in urinalysis, hematology, or serum biochemistry parameters between the treatment and control groups. Necropsy and histopathological examination indicated no treatment-related changes. According to the above results, the no-observed-adverse-effect level (NOAEL) of L. rhinocerotis was identified to be greater than 3400 mg/kg body weight (BW)/day in Sprague-Dawley rats.

Evaluation of subchronic repeated administration toxicity of ammonium nitrate in rats.

Ammonium nitrate is a chemical mostly used in agriculture and munitions to produce fertilizers and explosives, respectively. Its annual production and consumption exceed ten million tons. Despite is diverse uses, large production and consumption, and occupational risk, information on the toxicity that results from oral exposure to ammonium nitrate is limited. In this study, the safety of ammonium nitrate was therefore evaluated by observing its subchronic toxicity in rats. Ammonium nitrate (0, 100, 300 and 1000 mg/kg/day) was orally administered by gavage to rats at 5 times/week for 13 weeks. Reversibility of the effects of 1000 mg/kg/day was assessed in rats after 2 weeks. Mortality, clinical signs, body weight, and food consumption were monitored. Hematology, serum chemistry, urinalysis, organ weight, necropsy, and histopathology were performed. Salivation was intermittently observed in both sexes receiving 300 and 1000 mg/kg/day ammonium nitrate, which normalized 2 weeks post-treatment. Urine volume increased in both sexes receiving 1000 mg/kg/day ammonium nitrate. Urine pH decreased in both sexes of all dosing groups when compared with the concurrent control group. Urinary changes normalized 2 weeks post-treatment. Blood urea nitrogen levels increased in males receiving 1000 mg/kg/day, but normalized 2 weeks later. Potassium level in males and sodium and chloride levels in both sexes receiving 1000 mg/kg/day ammonium nitrate decreased, but normalized 2 weeks later. Hypertrophy of zona glomerulosa in the adrenals was observed in both sexes receiving 1000 mg/kg/day and in females receiving 300 mg/kg/day ammonium nitrate. After a 2-week recovery period, the same lesion was observed in one female receiving 1000 mg/kg/day ammonium nitrate. Our results indicate that ammonium nitrate induces reversible salivation, increases BUN levels, induces acidic diuresis with decreases in sodium, potassium, and chloride levels, and induces ZG hypertrophy. These results shed light on the toxicity profile of ammonium nitrate.

Toxicological Evaluation of Saposhnikoviae Radix Water Extract and its Antihyperuricemic Potential.

Although the dried root of Saposhnikovia divaricata (Turcz.) Schischk. (Umbelliferae) is a popular medicinal plant in East Asia, there has been no systemic toxicological evaluation of a water extract of Saposhnikoviae Radix (SRE). In this experiment, an oral acute and 13-week subchronic toxicological evaluations of SRE (500-5,000 mg/ kg body weight) were performed in both sexes of Crl:CD(SD) rats. Based on the results from mortality, clinical signs, effects on body weight and organ weight, clinical biochemistry, hematology, urinalysis, and histopathology, significant acute, 4-week repeated dose range finding (DRF) and 13-week subchronic toxicity of SRE was not observed in either sex of rats; thus, the no observed adverse effect level (NOAEL) was 5,000 mg (kg/day). To identify anti-hyperuricemia potential of SRE, the suppressive effect of SRE was determined in mice challenged with potassium oxonate (PO; 250 mg/kg) via intraperitoneal injection for 8 days (each group; n = 7). SRE supplementation suppressed the uric acid level in urine through significant xanthine oxidase (XO) inhibitory activity. Kidney dysfunctions were observed in PO-challenged mice as evidenced by an increase in serum creatinine level. Whereas, SRE supplementation suppressed it in a dose-dependent manner. Collectively, SRE was safe up to 5,000 mg (kg/day) based on NOAEL found from acute and 13-week subchronic toxicological evaluations. SRE had anti-hyperuricemia effect and lowered the excessive level of uric acid, a potential factor for gout and kidney failure.

Toxicological safety evaluation of freeze-dried Protaetia brevitarsis larva powder.

White-spotted flower chafer (Protaetia brevitarsis) is an edible insect and its larva was used as a traditional Asian medicine. It's a promising material as a novel food source because of its nutritional components. In this study, as part of the preclinical toxicity program, we evaluated the toxicity of freeze-dried P. brevitarsis larva powder to develop a novel food material. In a single-dose oral toxicity study in rats, there were no changes in mortality, clinical observations, and body weight in rats administered 5000 mg/kg P. brevitarsis larva powder. In a 13-week oral repeated dose toxicity study in rats, there were no adverse effects or changes in mortality, clinical observations, body weight, food consumption, ophthalmology, clinical pathology, necropsy, organ weight, and histopathology at doses of 300, 1000, and 3000 mg/kg/day. In identification of allergic reactions, P. brevitarsis larva powder induced no increases of serum immunoglobulin E and histamine concentrations over 13 weeks of oral administration in rats. In a genotoxicity assessment, P. brevitarsis larva powder didn't provoke bacterial reverse mutations, chromosomal aberrations, and micronucleated reticulocytes. Therefore, freeze-dried P. brevitarsis larva powder shows no evidence of toxic and mutagenic changes under the experimental conditions of the present in vitro and in vivo studies.

A thirteen-week oral toxicity study of So-ochim-tang-gami-bang, a traditional Korean medicine, in Sprague-Dawley rats.

ETHNOPHARMACOLOGICAL RELEVANCE: So-ochim-tang-gamibang (SOCG) is a traditional Korean medicine formulated to control internal energy flow (Qi) and has been prescribed to improve stress-induced depressive disorders. AIM OF THE STUDY: SOCG has been used in clinical practice for the last two decades and its efficacy against stress-induced thoracic pain has been suggested. Although SOCG has been used as an herbal formula in Korean medicine, its toxicity has not yet been evaluated. In this study, we evaluated the safety of SOCG through a 13-week general toxicity study in rats. MATERIAL AND METHODS: SOCG was administered by oral gavage to rats at doses of 0 (control), 800, 2000, and 5000mg/kg/day over a 13-week period. Toxicity testing was conducted by evaluating mortality, clinical signs, body weight, food consumption, urinalysis, hematology, serum biochemistry, organ weight, necropsy, and histopathology compared with the concurrent control. RESULTS: SOCG-related changes were noted in clinical signs and urinalysis. The observed clinical signs were compound-colored stool and salivation. Urinalysis results revealed brown or amber colored urine and elevated levels of protein. However, these changes were not considered to be adverse. CONCLUSIONS: The no-observed-adverse-effect-level of SOCG was determined to be above 5000mg/kg in both male and female rats. The result of this study can lay the foundation for the application of SOCG in humans and prove useful for detailed investigations on the toxicity or pharmacological effects of SOCG.

Safety and toxicological evaluation of Meratrim®: an herbal formulation for weight management.

Meratrim is a unique dietary ingredient consisting of extracts from Sphaeranthus indicus flower heads and Garcinia mangostana fruit rind. Clinical studies have demonstrated that Meratrim is effective and well-tolerated in weight management. Herein we assessed the broad spectrum safety of Meratrim in a battery of in vitro and animal toxicological studies including a sub-chronic repeated-dose 13-week oral toxicity study to determine the no-observable-adverse-effect-level (NOAEL). The LD50 levels of Meratrim in Sprague-Dawley (SD) rats, as determined by the acute oral and dermal toxicity studies, were >5000 and >2000 mg/kg body weight, respectively. The primary skin and eye irritation tests classified Meratrim as non-irritating to the skin and mildly irritating to the eye. Genotoxicity studies showed that Meratrim is non-mutagenic. In the repeated-dose 13-week oral toxicity study, SD rats were orally gavaged with Meratrim at 0, 250, 500 or 1000 mg/kg/day. No morbidity, mortality, or significant adverse events were observed either during the course of the study or on the 13th week. The NOAEL of Meratrim was concluded to be 1000 mg/kg of body weight/day in male and female SD rats. These results, combined with the tolerability of Meratrim in the human clinical trials, demonstrate the broad spectrum safety of Meratrim.

Study on a 4-week recovery test of sweet bee venom after a 13-week, repeated, intramuscular dose toxicity test in sprague-dawley rats.

OBJECTIVES: This study was performed to check for reversibility in the changes induced by a 13-week, repeated, dose toxicity test of Sweet Bee Venom (SBV) in Sprague-Dawley (SD) rats. METHODS: Fifteen male and 15 female SD rats were treated with 0.28 mg/kg of SBV (high-dosage group) and the same numbers of male and female SD rats were treated with 0.2 mL/kg of normal saline (control group) for 13 weeks. We selected five male and five female SD rats from the high-dosage group and the same numbers of male and female SD rats from the control group, and we observed these rats for four weeks. We conducted body-weight measurements, ophthalmic examinations, urinalyses and hematology, biochemistry, histology tests. RESULTS: (1) Hyperemia and movement disorder were observed in the 13-week, repeated, dose toxicity test, but these symptoms were not observed during the recovery period. (2) The rats in the high-dose group showed no significant changes in weight compared to the control group. (3) No significant differences in the ophthalmic parameters, urine analyses, complete blood cell counts (CBCs), and biochemistry were observed among the recovery groups. (4) No changes in organ weights were observed during the recovery period. (5) Histological examination of the thigh muscle indicated cell infiltration, inflammation, degeneration, necrosis of muscle fiber, and fibrosis during the treatment period, but these changes were not observed during the recovery period. The fatty liver change that was observed during the toxicity test was not observed during the recovery period. No other organ abnormalities were observed. CONCLUSION: The changes that occurred during the 13-week, repeated, dose toxicity test are reversible, and SBV can be safely used as a treatment modality.

Thirteen-Week Oral Dose Toxicity Study of G. bimaculatus in Sprague-Dawley Rats.

Gryllus bimaculatus (Gb) was orally administered at doses of 0, 0.04, 0.2, 1 and 5 g/kg bw/day for 13 consecutive weeks. There were no observed clinical signs or deaths related to treatment in all the groups tested. Therefore, the approximate lethal oral dose of G. bimaculatus was considered to be higher than 5 g/kg in rats. Throughout the administration period, no significant changes in diet consumption, ophthalmologic findings, organ weight, clinical pathology (hematology, clinical chemistry, coagulation, and urinalysis) or gross pathology were detected. Minor changes were found in hematological parameters for the 5 g/kg Gb-treated group (triglyceride reduction of 35.8%), but all changes were within normal physiological ranges. Microscopic examination did not identify any treatment-related histopathologic changes in the organs of Gb-treated rats in the high dose group. From these results, one can conclude that the no-observed adverse effect level (NOAEL) of G. bimaculatus is higher than 5 g/kg bw/day in rats.