Studies of the Toxicological Potential of Capsinoids: VII. A 13-Week Toxicity Study of Dihydrocapsiate in Rats

2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 79-100 ◽  
Author(s):  
Terutaka Kodama ◽  
Eri Watanabe ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
Masahiro Mochizuki ◽  
...  
Keyword(s):  
Food Consumption ◽  
Water Intake ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Toxicity Study ◽  
Female Rats ◽  
High Dose ◽  
Test Article ◽  
Body Weights ◽  
Toxicological Significance

To evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2), a 13-week gavage toxicity study was conducted in Sprague-Dawley rats (10/sex/group). Test subjects received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle by gavage and were observed for antemortem and postmortem signs of toxicity, which included changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. No changes attributable to the test article were observed in clinical signs, body weights, food consumption, water intake, ophthalmology, urinalysis, hematology, or histopathology. A number of sporadic blood chemistry differences were observed at the high dose between treated and controls, but were not of toxicological significance and were not attributable to the test article. These included increased alanine aminotransferase (ALT) activity in males; increased total protein in males and females; increased calcium, percentage of albumin fraction, and A/G (albumin/globulin) ratio and decreased percentage of γ-globulin fraction in female rats. An effect, which was attributable to the test article, was increases in both absolute and relative liver weights in the high dose (both sexes). In the absence of histopathological changes attributable to the test article, the liver weight changes were considered adaptive (physiological) in nature and not of toxicological significance. It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both male and female rats in this 13-week gavage study.

Studies of the Toxicological Potential of Capsinoids: VIII. A 13-Week Toxicity Study of Commercial-Grade Dihydrocapsiate in Rats

2008 ◽  
Vol 27 (3_suppl) ◽  
pp. 101-118 ◽  
Author(s):  
Eri Watanabe ◽  
Terutaka Kodama ◽  
Takeshi Masuyama ◽  
Shoji Tsubuku ◽  
Akira Otabe ◽  
...  
Keyword(s):  
Food Consumption ◽  
Water Intake ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Toxicity Study ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Sprague Dawley ◽  
Organ Weights

Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100,300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses ≤300 mg/kg or in females at any of the doses tested (≤1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study.

Subchronic Toxicity of Thalidomide in Rodents After 13 Weeks of Oral Administration

1999 ◽  
Vol 18 (5) ◽  
pp. 337-352 ◽  
Author(s):  
Steve K. Teo ◽  
Nancy J. Trigg ◽  
Mary E. Shaw ◽  
J. Michael Morgan ◽  
Steve D. Thomas
Keyword(s):  
Food Consumption ◽  
Dose Response ◽  
Clinical Chemistry ◽  
Female Rats ◽  
Male Rats ◽  
Lumbar Spinal Cord ◽  
High Dose ◽  
Significant Finding ◽  
Lower Body ◽  
Body Weights

The subchronic toxicology of thalidomide was determined in CD-1 mice and F344 rats. Animals (10/sex/dose) were orally dosed at 30,300, and 3000 mg/kg/day over 13 weeks. Control animals were given 1% carboxymethylcellulose. No thalidomide-related mortality occurred throughout the study. Some species and sex differences were seen. In mice, thalidomide had no effect on body weight, food consumption, ophthalmic function or clinical chemistry/hematology, but a dose-dependent orange-pink urine was observed in both sexes. The discoloration was probably due to chromogenic breakdown products of thalidomide. The only significant finding in the mouse study was dose-related hepatic centrilobular hypertrophy in the males. This appeared only at the highest dose in the females. The hypertrophy was correlated with increased liver weight for the high dose of both sexes suggesting enzyme induction. In rats, thalidomide produced lower body weights in both sexes compared to control with a dose-response more evident in males. Male rats dosed at 30, 300, and 3000 mg/kg had body weights that were 8, 11, and 19% below control weight just before necropsy. Corresponding female rats were only 6–7% below control weights at all dose levels. Lower food consumption was observed in male rats and varied between 6–13% below control with no dose-response. Decreased forelimb strength was noted in males and could be due to the lower body weights. Functional observational battery tests and histopathology of the sural nerve and lumbar spinal cord sections suggested that the rat did not develop thalidomide-induced peripheral neuropathy. Mild anemia and leukopenia were seen only in some treated males. A decrease in total and free T4 was more consistent in females. Both sexes had lower thymus weights with no histological correlate compared to control. The no-observed-adverse-effect level for mice and female rats were 3000 mg/kg and 30 mg/kg for male rats.

scholarly journals Studies of the Toxicological Potential of Capsinoids XIV: A 26-week Gavage Toxicity Study of Dihydrocapsiate in Rats

2010 ◽  
Vol 29 (2_suppl) ◽  
pp. 27S-54S ◽  
Author(s):  
Terutaka Kodama ◽  
Takeshi Masuyama ◽  
Takashi Kayahara ◽  
Shoji Tsubuku ◽  
Takumi Ohishi ◽  
...  
Keyword(s):  
Food Consumption ◽  
Water Intake ◽  
Clinical Chemistry ◽  
Recovery Period ◽  
Clinical Signs ◽  
Medium Chain Triglyceride ◽  
Clinical Pathology ◽  
Toxicity Study ◽  
Sprague Dawley ◽  
Organ Weights

To further evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate, CAS No. 205687-03-2), a 26—week gavage toxicity study was conducted in Sprague-Dawley rats (20/sex/group). Test animals received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle (medium-chain triglyceride) by gavage and were observed for antemortem and postmortem signs of toxicity including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. After the end of the dosing period, reversibility was assessed (10/sex/group for the control and 1000 mg/kg groups) following a 4-week recovery period. There were no adverse or toxicological changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, blood chemistry, organ weights, or histopathology. It was concluded that the no observable adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both sexes in this 26—week gavage study.

scholarly journals Chronic Toxicity and Carcinogenic Potential of Tris-(1,3-Dichloro-2-propyl) Phosphate in Sprague-Dawley Rat

2000 ◽  
Vol 19 (2) ◽  
pp. 119-125 ◽  
Author(s):  
Ralph I. Freudenthal ◽  
Richard T. Henrich
Keyword(s):  
Body Weight ◽  
Food Consumption ◽  
Microscopic Examination ◽  
Chronic Toxicity ◽  
Clinical Chemistry ◽  
Female Rats ◽  
High Dose ◽  
Sprague Dawley ◽  
Carcinogenic Potential ◽  
Body Weights

The Flammable Fabrics Act of 1953 and its amendments established a need for flame-resistant fabrics. Tris-(1,3-dichloro-2-propyl) phosphate (TDCPP) was briefly used in apparel fabrics to assist in the compliance with federal flammability standards, and continues to be used as a flame retardant in flexible polyurethane foams. A chronic toxicity and carcinogenicity bioassay was conducted in Sprague-Dawley rats to determine the toxicologic and carcinogenic potential of TDCPP after repeated exposure. Four groups of animals, each consisting of 60 male and 60 female rats, received via their diet a daily dose of either 0, 5, 20, or 80 mg TDCPP per kg body weight for up to 24 months. Diets were adjusted after each weekly (first 13 weeks) or biweekly (weeks 14 through 104) body weight and food consumption measurement to achieve and maintain the indicated doses. Ten animals per sex were taken from each group for interim sacrifice at the end of the 12th month. Body weights, food consumption, clinical signs, and hematological and clinical chemistry parameters were measured periodically, and ophthalmoscopic examinations were conducted on all animals. After complete postmortem examination of all animals, microscopic examination of all tissues was conducted for the control and high-dose animals. Liver, kidneys, testes, and adrenal glands were examined from all animals. Mortality was significantly higher and body weights were significantly lower in the high-dose group when compared to control animals. Certain hematology parameters, such as hemoglobin, hematocrit, and total erythrocyte values, were decreased in the high-dose animals. Ophthalmoscope examination revealed no treatment-related changes. Microscopic examination revealed a higher incidence of benign neoplasms and non-neoplastic alterations in several organs of the mid and high dose animals. The no-observed-adverse-effect level (NOAEL) for chronic toxicity and neoplastic activity was the dietary dose of 5 mg/kg/day.

Tamarind Seed Polysaccharide

2013 ◽  
Vol 32 (3) ◽  
pp. 198-208 ◽  
Author(s):  
James T. Heimbach ◽  
Hiroshi Egawa ◽  
Palma Ann Marone ◽  
Mark R. Bauter ◽  
Elke Kennepohl
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Consumption ◽  
Body Weight Gain ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Female Rats ◽  
Feed Consumption ◽  
Test Substance ◽  
Tamarind Seed

Forty male and 40 female Crl:SD® CD® IGS rats were fed diets containing 0, 40 000, 80 000, or 120 000 ppm tamarind seed polysaccharide (equivalent to 3450.8, 6738.9, or 10 597.1 mg/kg bw/day and 3602.1, 7190.1, or 10 690.7 mg/kg bw/day for males and females, respectively) for 28 days. Animals were observed for adverse clinical signs, body weight, feed consumption, hematology and clinical chemistry parameters, urinalysis values were recorded, and at the end of the study the rats underwent a full necropsy. Functional Observational Battery (FOB) and Motor Activity (MA) tests were performed on all animals. There were no mortalities, no clinical or ophthalmologic signs, body weight, body weight gain, food consumption and food efficiency, FOB or MA findings associated with the administration of tamarind seed polysaccharide. Initial statistically significant decreases in body weight gain and food consumption resolved after the first week and were considered the result of reduced palatability. There were no adverse changes in hematology, coagulation, clinical chemistry or urinalysis parameters in male or female rats considered the result of test substance administration. At necropsy, there were no macroscopic, histopathological findings, estrus cycle, or organ weight changes deemed related to administration of the test substance. Under the conditions of this study and based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for tamarind seed polysaccharide in the diet was the highest concentration tested of 120 000 ppm (equivalent to 10 597 mg/kg bw/day and 10 691 mg/kg bw/day for male and female rats, respectively).

Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): V. A 13-Week Toxicity Study of Tripeptides-Containing Casein Hydrolysate in Male and Female Rats

2005 ◽  
Vol 24 (4_suppl) ◽  
pp. 41-59 ◽  
Author(s):  
Seiichi Mizuno ◽  
John H. Mennear ◽  
Keiichi Matsuura ◽  
Bruce K. Bernard
Keyword(s):  
Body Weight ◽  
Food Consumption ◽  
Low Dose ◽  
Clinical Signs ◽  
Casein Hydrolysate ◽  
Toxicity Study ◽  
Once Daily ◽  
Organ Weights ◽  
Test Article ◽  
Weight Gains

The objective of this multiple-dose toxicity study was to assess the toxicological potential of two tripeptides, L-valyl-L-prolyl-L-proline (VPP) and L-isoleucyl-L-prolyl-L-proline (IPP), when administered once daily for 91 consecutive days to rats. The test article, powdered casein hydrolysate (CH) known to contain 0.6% VPP plus IPP, was prepared using Aspergillus oryzae protease. Prior to administration to the rats by oral gavage, the test article was suspended in sterile water. Groups of 12 male and 12 female Charles River rats were administered once daily doses of 0, 40, 200, or 1000 mg of CH (0, 0.2,1.2, or 6 mg VPP plus IPP/kg body weight [BW]). Antemortem evaluative parameters included gross observations of behavior and clinical signs; food consumption and body weight gains; ophthalmologic examinations; clinical pathology (hematology, clinical chemistry); and urinalysis. Postmortem parameters included determination of absolute and relative (to fasting body weight) organ weights and histopathological evaluation of approximately 50 organs and tissues from each animal. All rats survived until the scheduled termination of the study and no treatment-related clinical signs were observed. Food consumption was unaffected by administration of CH. All animals gained weight and there were no statistical differences between groups with respect to weight gains. There were no meaningful changes in hematological or coagulation parameters. Mid- and high-dose males (but not females) had slightly (<2%) increased mean serum chloride concentrations, but because the difference was so small and it was observed in only one sex, the authors considered its association with CH administration to be doubtful. Urinalysis revealed the occasional presence of crystals, leukocytes, and epithelial cells in animals from all experimental groups. Similarly, ophthalmic changes (lenticular clouding) were observed in both control and dosed animals. Mean relative (to body weight) kidney weight was decreased by 8 % in low-dose males and mean relative uterus weight was elevated 46 % in low-dose females. Absolute organ weights were not affected. Only naturally occurring microscopic changes were observed in all groups and none could be attributed to CH administration. It was concluded that, under the conditions of these experiments, the maximally tolerated dose (MTD) and the no-observable-effect level (NOEL) for powdered CH administered once daily for 13 weeks was greater than 1000 mg/kg BW/day or greater than 6 mg of VPP plus IPP/kg BW/day. There was no evidence of target organ toxicity associated with administration of the tripeptides. This corresponds to an margin of safety (MOS) of 60 based upon current thinking regarding incorporation in food.

A Subchronic Toxicity Study of Phosflex 51B in Sprague-Dawley Rats

2001 ◽  
Vol 20 (5) ◽  
pp. 269-274 ◽  
Author(s):  
Ralph I. Freudenthal ◽  
David Brandwene ◽  
Welmoed Clous
Keyword(s):  
Food Consumption ◽  
Clinical Chemistry ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Sprague Dawley ◽  
Significant Treatment ◽  
Sprague Dawley Rats ◽  
The Mean ◽  
Microscopic Pathology

Phosflex 51B is a flame retardant plasticizer that is blended with polyvinyl chloride films to effectively control product flammability. Its composition places it in the butylated triphenyl phosphate category. Previous studies have shown Phosflex 51B to have low acute toxicity, to lack teratogenic and mutagenic activity, and to not induce delayed peripheral neuropathy. The present study was conducted to determine the toxicity of Phosflex 51B after repeated dietary exposure. Four groups, each consisting of 20 male and 20 female Sprague-Dawley rats, received rodent diet containing either 0, 100, 400, or 1600 ppm for 90 days. Parameters measured include body weight, food consumption, clinical observations, hematology, clinical chemistry, and cholinesterase activity. Tissues were examined at necropsy for gross changes and were processed for microscopic pathology. There were no significant treatment-related effects on body weights, food consumption, hematology and clinical chemistry, or cholinesterase values. A significant increase was observed in the absolute and relative mean weights of livers in high-dose male rats, the mean relative fiver weights of the high-dose female animals, the mean relative kidney weights of the high-dose male rats, and the mean absolute weights of the adrenal glands from high-dose female rats. Neither gross nor microscopic pathology examinations revealed tissue changes in these organs or in any other organs. Although increases in fiver, kidney, and adrenal weights were observed in certain animals in the 1600-ppm high-dose group, the administration of Phosflex 51B did not result in significant treatment-related adverse effects at dietary dose levels of 100 and 400 ppm. The no-observable-effect level (NOEL) in this study is 400 ppm.

The Subchronic Oral Toxicity of Ethane, 1,2-Bis(pentabromophenyl) (Saytex 8010) in Rats

2002 ◽  
Vol 21 (3) ◽  
pp. 165-170 ◽  
Author(s):  
M. L. Hardy ◽  
D. Margitich ◽  
L. Ackerman ◽  
R. L. Smith
Keyword(s):  
Corn Oil ◽  
Clinical Chemistry ◽  
Recovery Period ◽  
Clinical Signs ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Low Grade ◽  
Oral Toxicity ◽  
Effect Level

Ethane, 1,2-bis(pentabromophenyl) (EBP; CAS no. 8452–53–9) dose levels of 0, 100, 320 and 1000 mg/kg/day administered to rats by gavage in corn oil for 90 consecutive days produced no compound-related clinical signs of systemic toxicity, ocular lesions, or alterations in urinalysis, clinical chemistry, and hematology values in the treated or recovery groups. No biologically or toxicologically significant differences were observed in body weights, body weight gains, and food consumption. Statistically significant differences were found between control and high-dose animals in mean absolute or relative liver weights. Histomorphological evaluation showed in male rats low-grade liver changes consisting of minimal to slight hepatocellular vacuolation (high-dose males) and minimal to slight centrilobular hepatocytomegaly (high- and possibly mid-dose males). These changes had resolved by the end of the 28-day recovery period. No treatment-related changes were found in the livers of female rats. No treatment-related histomorphologic changes were present in any of the other tissues examined in either sex, except for evidence of aspirated test article in individual rats. The 90-day EBP no-adverse-effect level in the rat was 1000 mg/kg/day, and was consistent with that of the preceding 28-day study (no-effect level 1250 mg/kg/day). EBP's lack of toxicity is likely related to poor bioavailability due to its high molecular weight and low solubility.

Subchronic Oral Toxicity Study of Mixed Tocopheryl Phosphates in Rats

2007 ◽  
Vol 26 (5) ◽  
pp. 475-490 ◽  
Author(s):  
R. Gianello ◽  
W. C. Hall ◽  
E. Kennepohl ◽  
R. Libinaki ◽  
E. Ogru
Keyword(s):  
Small Intestine ◽  
Lymph Node ◽  
Low Dose ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Female Rats ◽  
High Dose ◽  
Test Substance ◽  
Foreign Material ◽  
Dose Dependent

Rats were fed diets containing 0%, 1 %, 3%, or 5% mixed tocopheryl phosphates for 90 days. No abnormal clinical signs related to treatment appeared. Some statistically significant changes in hematology and clinical chemistry parameters appeared, but the majority were not dose dependent, occurred in only one sex or group, and/or remained within the historical control range for this strain of rat. A statistically significant apparent reduction in blood protein was observed in animals treated with the tocopheryl phosphates, but further investigation showed that the test substance interfered with the protein assay. Repeat analysis using a method unaffected by plasma test substance levels showed no difference in plasma proteins among all groups. Gross necropsy revealed no abnormalities; reduced relative heart and epididymal weights were observed, but were not dose dependent and were considered incidental. Histopathological changes occurred only in the mesenteric lymph node and small intestine. Foreign material in a crystal-like form appeared in macrophages in both organs, and increased in a dose-related fashion. In the lymph node, sinus histiocytosis increased with dose, but the severity was similar between the control and low-dose groups. Foreign-body granulomatous inflammation, associated with Maltese cross birefringence of the crystals was seen in the mid- and high-dose animals, but not the low-dose group. Similarly, the small intestine showed increasing amounts of foreign material and inflammation in the mid- and high-dose but not in the 1 % diet. The 1 % diet (equivalent to 587 and 643 mg mixed tocopheryl phosphates/kg body weight/day for male and female rats, respectively) was considered the no observed adverse effect level.

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).

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