scholarly journals Clinical and Morphological Aspects in Assessing the Safety of OSPL-502 with Repeated Dose Administration

2018 ◽  
Vol 6 (9) ◽  
pp. 1581-1587
Author(s):  
Sergey A. Zhuchkov ◽  
Alexandr S. Kinzirsky ◽  
Irina V. Koroleva ◽  
Yuriy B. Vicharev
Keyword(s):  
Toxic Effect ◽  
Adrenal Glands ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Repeated Administration ◽  
Test Substance ◽  
Sprague Dawley ◽  
Adverse Effect Level ◽  
Pharmacological Substance ◽  
Effect Level

BACKGROUND: OSPL-502 is a new potential medicinal drug which stimulates a cognitive function. It is necessary to reveal clinical manifestations of its general toxic effect and determine organs that are most heavily affected by this pharmacological substance. AIMS: To describe and estimate clinical and histopathological changes in the organism of experimental animals in response to the repeated administration of pharmacological substance OSPL-502. MATERIAL AND METHODS: The study was conducted by the OECD Guidelines (Test No. 407) on Sprague-Dawley rats. The drug was administered at the dose of 20, 60 and 180 mg/kg. RESULTS: The repeated doses of OSPL-502 have not caused any toxic effects on the growth of body weight, food and water consumption of the tested animals, or affected the musculoskeletal system and exploratory behaviour of the rats in the doses of 20 and 60 mg/kg. The dose of 180 mg/kg (1800 times larger than the therapeutic dose) has shown clinical signs of toxicity in females but has not resulted in the death of the animals. Due to morphological methods, we have found histostructural changes in the liver, kidneys and adrenal glands of the rats that were treated with the test substance in the maximum dose. These changes are reversible and reduce within 14 days after the admission of the studied substances is cancelled. CONCLUSION: OSPL-502 at the dose of 180 mg/kg has a weakly pronounced toxic effect, the dose of 60 mg/kg is the threshold, and that of 20 mg/kg is no-observable-adverse-effect-level (NOAEL); the liver, kidneys and adrenal glands can be considered target-organs for the tested substance.

Studies of the Toxicological Potential of Capsinoids: II. A 26-Week Daily Gavage Dosing Toxicity Study of CH-19 Sweet Extract in Rats

2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 11-27 ◽  
Author(s):  
Terutaka Kodama ◽  
Eri Watanabe ◽  
Takeshi Masuyama ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
...  
Keyword(s):  
Clinical Signs ◽  
Toxicity Study ◽  
High Dose ◽  
Test Substance ◽  
Sprague Dawley ◽  
Oral Toxicity ◽  
Test Article ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Dose Levels

A 26-week oral toxicity study of capsinoids-containing CH-19 Sweet extract was conducted in Sprague-Dawley rats (20 males and 20 females per group) at 6 weeks of age. The test substance was administered by gavage for 26 weeks at dose levels of 0 (vehicle), 1.25, 2.5, and 5.0 ml/kg/day. The concentration of capsinoids in the CH-19 Sweet extract employed was 71.25 to 73.15 mg/ml, resulting in dose levels of capsinoids of 89.06 to 91.44, 178.13 to 182.88, and 356.25 to 365.75 mg/kg, respectively. Adverse test article–related changes were only observed in males, not in females, and within the males, only at the high dose (5.0 ml/kg). Within that group (high-dose males), increases were observed in the numbers of segmented neutrophils, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities, liver weights, and in the incidence and severity of hepatocellular focal necrosis. No test substance–related changes were detected in clinical signs, body weight, food consumption, water intake, ophthalmology, or urinalysis. No adverse test article–related changes were observed in low- or mid-dose males or in females at any dose. Based on the results of this chronic gavage study, the target organ was the liver and the no observed adverse effect level (NOAEL) for CH-19 Sweet extract in the rat was 2.5 ml/kg/day in males and 5.0 ml/kg/day in females (178.13 to 182.88 mg/kg and 356.25 to 365.75 mg/kg as capsinoids, respectively).

Safety of a novel galacto-oligosaccharide: Genotoxicity and repeated oral dose studies

2009 ◽  
Vol 28 (10) ◽  
pp. 619-630 ◽  
Author(s):  
T. Kobayashi ◽  
N. Yasutake ◽  
K. Uchida ◽  
W. Ohyama ◽  
K. Kaneko ◽  
...  
Keyword(s):  
Oral Dose ◽  
Kluyveromyces Lactis ◽  
Clinical Signs ◽  
Chinese Hamster ◽  
Metabolic Activation ◽  
Blood Chemistry ◽  
Control Group ◽  
Sprague Dawley ◽  
Adverse Effect Level ◽  
Effect Level

A series of safety tests were undertaken on a novel galacto-oligosaccharide (GOS) produced from lactose by a two-step enzymatic process involving Sporobolomyces singularis and Kluyveromyces lactis. Bacterial reverse mutation and chromosomal aberration tests, with or without metabolic activation, were performed. These tests showed no mutagenesis in the Ames assay or in Escherichia coli WP2uvrA, and no chromosomal aberrations in cultured fibroblast cells from Chinese hamster lungs (CHL/IU). Micronuclei were not induced in the reticulocytes of mouse peripheral blood following oral administration of GOS. In a 90-day repeated oral dose toxicity study in rats, GOS was administered at 0, 500, 1000 and 2000 mg/kg to male and female Sprague-Dawley rats. There were no GOS-related changes in clinical signs, body weight, water intake, feed intake, urinalysis, ophthalmology, haematology, blood chemistry, organ weights, gross pathology or histopathology in any of the treatment groups compared to the control group. The no observed adverse effect level (NOAEL) of GOS was at least 2000 mg/kg/day in both males and females.

Subchronic Hepatotoxicity Evaluation of 1,2,4-Tribromobenzene in Sprague-Dawley Rats

2012 ◽  
Vol 31 (3) ◽  
pp. 250-256 ◽  
Author(s):  
Darol E. Dodd ◽  
Linda J. Pluta ◽  
Mark A. Sochaski ◽  
Kathleen A. Funk ◽  
Russell S. Thomas
Keyword(s):  
Adverse Effect ◽  
Body Weight ◽  
Exposure Time ◽  
Clinical Signs ◽  
Liver Weight ◽  
Sprague Dawley ◽  
Significant Incidence ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level

Male Sprague-Dawley rats were exposed to 1,2,4-tribromobenzene (TBB) by gavage for 5 days, 2, 4, and 13 weeks at 0, 2.5, 5, 10, 25, or 75 mg/kg per d. There were no TBB exposure-related clinical signs of toxicity or changes in body weight. Liver weight increases were dose and exposure time related and statistically significant at ≥10 mg/kg per d. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were dose and time related. The 75 mg/kg per d group had minimally increased mitoses within hepatocytes (5 days only). Hepatocyte vacuolation was observed (13 weeks) and was considered TBB exposure related at ≥25 mg/kg per d. Concentrations of blood TBB increased linearly with dose and at 13 weeks, ranged from 0.5 to 17 µg/mL (2.5-75 mg/kg per d). In conclusion, rats administered TBB doses of 10-75 mg/kg per d for 13 weeks had mild liver effects. A no observed adverse effect level of 5 mg/kg per d was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥10 mg/kg per d.

Studies of the Toxicological Potential of Capsinoids: IV. Teratology Studies of CH-19 Sweet Extract in Rats and Rabbits

2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 41-57 ◽  
Author(s):  
Bruce K. Bernard ◽  
Eri Watanabe ◽  
Terutaka Kodama ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
...  
Keyword(s):  
Body Weight ◽  
Sex Ratio ◽  
Food Consumption ◽  
Clinical Signs ◽  
Pathological Finding ◽  
High Dose ◽  
Corpora Lutea ◽  
Test Substance ◽  
Sprague Dawley ◽  
Adverse Effect Level

In order to evaluate the safety of CH-19 Sweet extract that contains capsinoids, teratology studies were conducted in pregnant Sprague-Dawley rats (20 rats per group) and pregnant New Zealand white rabbits (17 to 22 animals per group). The test substance was administered to rats by gavage for 11 days on gestation days 7 to 17 at doses of 0 (vehicle), 1.25, 2.5, and 5.0 ml/kg and to rabbits for 13 days on gestation days 6 to 18 at doses of 0 (vehicle), 0.25, 0.5, and 1.0 ml/kg. As the concentration of capsinoids in CH-19 Sweet extract was 72.2 to 75.05 mg/ml, the resulting dose of capsinoids administered to rats was 90.25, 180.5, and 361 mg/kg, and to rabbits was 18.76, 37.53, and 75.05 mg/kg in the vehicle, low-, mid-, and high-dose groups, respectively. In the rat study, no deaths occurred in any group and there were no test substance–related changes or abnormalities in clinical signs, body weight, food consumption, or gross pathological findings. There were no test substance–related changes in the number of corpora lutea, number or index of implantations, index of embryofetal deaths, number of live fetuses, sex ratio, fetal body weight at the end of the gestation period, or abnormalities in the placenta of live fetuses. There were no test substance–related abnormalities or variations in the external, skeletal, or visceral examinations of live fetuses. It was concluded that the test article caused neither teratogenic effects nor abnormalities in the progression of ossification. In the rabbit study, there were no test substance–related effects on clinical signs, body weight, food consumption, or necropsy findings. There were neither test substance–related abortions nor test substance–related effects on the number of corpora lutea, or number or index of implantations. There were no test substance–related effects on the number of dead embryos/fetuses, the number of live fetuses, sex ratio, body weight of live fetuses, or gross pathological finding in the placentas. There were no test substance–related external abnormalities or incidences of visceral or skeletal abnormalities or variations, and there were no test substance–related effects on the progress of ossification in any group. The authors concluded the no observed adverse effect level (NOAEL) of CH-19 Sweet extract containing capsinoids on pregnant animals and fetal development/growth was >5.0 ml/kg/day (>361 mg/kg/day as capsinoids) in rats and >1.0 ml/kg/day (>75.05 mg/kg/day as capsinoids) in rabbits.

scholarly journals Eurycoma longifolia—Infused Coffee—An Oral Toxicity Study

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3125
Author(s):  
Norzahirah Ahmad ◽  
Bee Ping Teh ◽  
Siti Zaleha Halim ◽  
Nor Azlina Zolkifli ◽  
Nurulfariza Ramli ◽  
...  
Keyword(s):  
Body Weight ◽  
Clinical Signs ◽  
Sprague Dawley ◽  
Oral Toxicity ◽  
Eurycoma Longifolia ◽  
Dependent Relationship ◽  
Adverse Effect Level ◽  
Chronic Study ◽  
Effect Level ◽  
Gender Groups

Coffee infused with the additive Eurycoma longifolia, also known as Tongkat ali (TA), has become widely available in the Malaysian market. Safety evaluations for consumption of the products have been called for due to the herbal addition. This study investigates the acute, subacute and chronic effects of a commercial TA coffee in Sprague Dawley rats when given in a single, repeated and prolonged dosage. The dosages of 0.005, 0.05, 0.30 and 2 g/kg body weight (BW) were used in the acute study and 0.14, 0.29 and 1 g/kg BW were used in the repeated dose studies. The in-life parameters measured were food and water intake, body weight and clinical observations. Blood were collected for hematology and clinical biochemistry analyses. All animals were subjected to full necropsies. Non-toxicity-related changes were observed in the food and water consumption parameters. Body weight showed normal increments and none of the animals had any clinical signs of toxicity. Microscopically assessed organ tissues did not reveal any abnormalities. There was significant decrease of platelet count in all the chronic study male treated groups. Significant elevation of renal profile parameters in both gender groups given 0.29 g/kg BW, along with liver and lipid profile elevation in some female groups of the chronic study were noted. No dose-dependent relationship was apparent in the dosage range tested, though these changes may suggest an initial safety indication to the TA coffee. The study concludes that the no observed adverse effect level (NOAEL) for this commercial TA coffee was 1 g/kg BW.

Studies of the Toxicological Potential of Capsinoids: IX. Teratology Studies of Dihydrocapsiate in Rats and Rabbits

2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 119-136 ◽  
Author(s):  
Bruce K. Bernard ◽  
Eri Watanabe ◽  
Terutaka Kodama ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
...  
Keyword(s):  
Body Weight ◽  
Sex Ratio ◽  
Food Consumption ◽  
Clinical Signs ◽  
Pathological Finding ◽  
Corpora Lutea ◽  
Test Substance ◽  
Sprague Dawley ◽  
Adverse Effect Level ◽  
Rat Study

In order to determine the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS no. 205687-03-2), teratology studies were conducted in pregnant Sprague-Dawley rats (18 to 20 animals per group) and pregnant New Zealand white rabbits (20 to 21 animals per group). The test substance was administered by gavage for 11 days, from days 7 to 17 of gestation in rats, and for 13 days from days 6 to 18 of gestation in rabbits, at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. In the rat study, no deaths occurred in any group and there were no test substance–related changes or abnormalities in clinical signs, body weight, food consumption, or gross pathological findings. There were no test substance–related changes in the number of corpora lutea, number of implantations, index of implantations, index of embryofetal deaths, and number, sex ratio, or body weight of live fetuses at the end of the gestation period and there were no abnormalities in the placentae of live fetuses. There were no test substance–related abnormalities or variations in the external, skeletal, or visceral examinations of live fetuses. There were no abnormalities in ossification. En toto, it was concluded there were no teratogenic effects in the rat study. In the rabbit study, there were no test substance–related effects on clinical signs, body weight, food consumption, or necropsy findings in any group. There were neither test substance–related abortions nor test substance–related effects on the number of corpora lutea, number of implantations, or implantation index in any group. There were no test substance–related effects on the number of dead embryos/fetuses, the number, sex ratio, or body weight of live fetuses, or gross pathological finding of placentae. There were no test substance–related external abnormalities, or incidence of visceral or skeletal abnormalities or variations, and there were no test substance–related effects on the progress of ossification in any group. Based upon these data, the no observed adverse effect level (NOAEL) of dihydrocapsiate for general toxicity in dams, reproductive functions of dams, and embryofetal development was judged to be 1000 mg/kg/day both in rats and rabbits.

scholarly journals Subchronic Toxicity Studies of 2,4,6-Trichlorophenol in Sprague-Dawley Rats

1990 ◽  
Vol 9 (5) ◽  
pp. 497-506 ◽  
Author(s):  
J. Peter Bercz ◽  
Merrel Robinson ◽  
Lillian Jones ◽  
Norbert P. Page ◽  
Michael J. Parnell ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Body Weight ◽  
Adrenal Glands ◽  
Corn Oil ◽  
Clinical Chemistry ◽  
Sprague Dawley ◽  
Weight Changes ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level

2,4,6-Trichlorophenol (TCP) has been found in drinking water as a result of its use as a fungicide and due to its inadvertent production in the water purification process. This study was conducted since information on the toxicity from repeated ingestion was inadequate. Male and female Sprague-Dawley rats were gavaged with TCP administered in corn oil (2 ml/kg body weight) for 90 consecutive days at dose levels of 0, 80, 240, and 720 mg/kg per day. Treatment-related effects were observed at the highest dose (720 mg/kg/day) and consisted of salivation, urine stains on the fur, increase in absolute and relative weights of the kidneys, liver, adrenal glands, and testes. At this dose, increases were seen in serum protein, albumin, and alanine aminotransferase (ALT), with a decrease in urinary pH. Some effects observed at 240 mg/kg per day were an increase in the absolute and relative weights of the liver and adrenal glands in females, relative liver weights in males, and an increase in serum albumin in males. No treatment-related effects were observed at 80 mg/kg per day. No mortality or significant effects were observed at any dose level for body weight, food consumption, ophthalmic lesions, hematology, gross pathology, or histopathology. Based on clinical chemistry and organ weight changes, it appears that the liver, kidney, and adrenal glands were target organs for systemic toxicity to TCP in this study, although this was not correlated with histopathology lesions. It was concluded that 240 mg/kg/day represents a lowest observed adverse effect level (LOAEL), although the toxic effects were minimal. The no observed adverse effect level (NOAEL) for subchronic exposure to TCP by the oral route was 80 mg/kg per day.

scholarly journals Evaluation of Subchronic Oral Dose Toxicity of Freeze-Dried Skimmed Powder of Zophobas atratus Larvae (frpfdZAL) in Rats

Foods ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 995
Author(s):  
Sun Young Kim ◽  
Kyu-Won Kwak ◽  
Eun-Sung Park ◽  
Hyung Joo Yoon ◽  
Yong-Soon Kim ◽  
...  
Keyword(s):  
Animal Feed ◽  
Clinical Signs ◽  
Sprague Dawley ◽  
Freeze Dried ◽  
Body Weights ◽  
Adverse Effect Level ◽  
Mealworm Beetle ◽  
Good Laboratory ◽  
Effect Level ◽  
Zophobas Atratus

Zophobas atratus (Coleoptera: Tenebrionidae), the giant mealworm beetle, is known as an edible insect containing a high protein content which may serve as new sources of human food and animal feed. However, potential toxicity and food safety analyses of Z. atratus have not been previously investigated. Therefore, in this study, we aimed to evaluate toxicity of freeze-dried skimmed powder of Z. atratus larvae (frpfdZAL), known as the super mealworm. Toxicological assessments were performed at the doses of 1250, 2500, and 5000 mg/kg/day in a 2- and a 13-week oral repeated-dose toxicity study of frpfdZAL in male and female Sprague-Dawley (SD) rats in accordance with the Organisation for Economic Co-operation and Development (OECD) guidelines and the principles of Good Laboratory Practice (GLP). No toxicological changes in clinical signs, body weights, water and food consumption, urinalysis, hematology, clinical biochemistry, gross findings, and histopathological examinations were observed. In conclusion, the no-observed-adverse-effect level (NOAEL) of frpfdZAL was 5000 mg/kg/day and target organ was not identified in both sexes of rats. In addition, frpfdZAL did not induce increases of serum ImmunoglobulinE (IgE), an identifier of allergic reactions in rats. Collectively, these results suggest that frpfdZAL is safe with no adverse effects, and able to be applied as an edible ingredient or other biological uses.

Evaluation of the Developmental Toxicity of Linalool in Rats

2008 ◽  
Vol 27 (2) ◽  
pp. 183-188 ◽  
Author(s):  
Valerie T Politano ◽  
Elise M Lewis ◽  
Alan M Hoberman ◽  
Mildred S Christian ◽  
Robert M Diener ◽  
...  
Keyword(s):  
Body Weight ◽  
Developmental Toxicity ◽  
Clinical Signs ◽  
Feed Consumption ◽  
Corpora Lutea ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Weight Gains ◽  
Adverse Effect Level ◽  
Effect Level

The developmental toxicity of linalool, a widely used fragrance ingredient, was evaluated in presumed pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 250, 500, or 1000 mg/kg/day linalool were administered by gavage on gestational days 7 to 17. The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. There were no maternal deaths, clinical signs, or gross lesions that were considered related to linalool. During the dosage period, mean relative feed consumption was significantly reduced by 7% and mean body weight gains were reduced by 11% at 1000 mg/kg/day. During the postdosage period, feed consumption values at 1000 mg/kg/day were significantly higher than vehicle control values, which corresponded to the increase in body weight gains during this period. Caesarean section and litter parameters, as well as fetal alterations, were not affected by linalool at any of the three dosages tested. On the basis of these data, the maternal no observed adverse effect level (NOAEL) of linalool is 500 mg/kg/day, whereas the developmental NOAEL is ≥ 1000 mg/kg/day. It is concluded that linalool is not a developmental toxicant in rats at maternal doses of up to 1000 mg/kg/day.

scholarly journals A 4-Week Repeated Oral Dose Toxicity Study of Ssanghwa-Tang in Crl:CD Sprague Dawley Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Sae-Rom Yoo ◽  
Hyekyung Ha ◽  
Mee-Young Lee ◽  
Hyeun-kyoo Shin ◽  
Su-Cheol Han ◽  
...  
Keyword(s):  
Safety Information ◽  
Experimental Period ◽  
Serum Biochemistry ◽  
Toxicity Study ◽  
Herbal Formula ◽  
Sprague Dawley ◽  
Organ Weights ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level

Ssanghwa-tang (SHT), a traditional herbal formula, has been widely used to recover fatigue or consumptive disease after an illness. Along with much attention to herbal formula, the concerns about the safety and toxicity have arisen. To establish the safety information, SHT was administrated in Crl:CD Sprague Dawley rats at a daily dose of 0, 1000, 2000, and 5000 mg/kg for 4 weeks. During the test periods, we examined the mortality, clinical observation, body weight change, food consumption, organ weights, hematology, serum biochemistry, and urinalysis parameters. No changes of mortality and necropsy findings occurred in any of the groups during the experimental period. In either sex of rats treated with SHT at 5000 mg/kg/day, changes were observed in food intake, reticulocyte, total bilirubin, some urinalysis parameters, and relative organ weights. The results indicated that SHT did not induce toxic effects at a dose level up to 2000 mg/kg in rats. This dosage was considered no observed adverse effect level (NOAEL) and was appropriate for a 13-week subchronic toxicity study.

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