Subchronic and Chronic Toxicity/Carcinogenicity Feeding Studies with Lactitol in Rats

1992 ◽  
Vol 11 (2) ◽  
pp. 165-188 ◽  
Author(s):  
E. J. Sinkeldam ◽  
R.A. Woutersen ◽  
V.M.H. Hollanders ◽  
H.P. Til ◽  
A. Van Garderen-Hoetmer ◽  
...  
Keyword(s):  
Histopathological Examination ◽  
Clinical Chemistry ◽  
Hematological Parameters ◽  
Calcium Content ◽  
Study Groups ◽  
Female Rats ◽  
Male Rats ◽  
Negative Results ◽  
Urine Composition ◽  
Chronic Study

The toxicity and possible carcinogenicity of lactitol, a lactose-derived reduced calorie sugar substitute, were examined in Wistar Cpb:WU rats. In a first 13-week study, groups of 10 weanling rats of each sex were fed diets containing 0, 5, 10, or 20% lactitol, or 25% lactose. In a second 13-week study, groups of 20 rats of each sex received diets with 0, 10, or 20% lactitol, or 25% lactose starting from an age of 3 months. In a lifetime toxicity/cancerogenicity study with in utero exposure, groups of 50 rats of each sex consumed diets with 0, 2, 5, or 10% lactitol, or 20% lactose for 130 weeks. Satellite groups of 10 rats/group received the same diet but were sacrificed after 53 weeks. Subchronic and chronic ingestion of lactitol and lactose was generally well tolerated and an effect on mortality rate was not seen. Body weight gains were slightly decreased in a dose-related manner in all experiments. Dose-related cecal enlargement was observed consistently with lactitol and lactose. Examinations for hematological parameters and urine composition did not reveal any treatment-related abnormalities. The clinical chemistry examinations revealed increased plasma alkaline phosphatase (AP) levels in rats fed 5 or 10% lactitol, or 20% lactose. Slight (microscopic) cytoplasmic alterations in the staining pattern of hepatocytes were observed in the first but not the second 13-week study in a number of male rats of the 10 and 20% lactitol groups. In the chronic study, a statistically significant increase in bile duct hyperplasia was noted in female rats fed 5 or 10% lactitol, or 20% lactose. Measurement of femur calcium content in terminated female rats revealed a dose-related, yet statistically nonsignificant decrease in the lactitol groups and lowest levels in the 20% lactose group. The histopathological examination of rats treated with lactitol and lactose for their lifetime showed an increased incidence of (1) pelvic nephrocalcinosis (5% lactitol females, and 10% lactitol and 20% lactose males and females), (2) adrenomedullary proliferative changes (10% lactitol and 20% lactose males), and (3) hyperplastic and neoplastic changes of Leydig cells (10% lactitol and 20% lactose males). Results from other studies suggest that nephrocalcinosis and adrenal medullary proliferative disease represent sequelae of a chronic, treatment-related hyperabsorption of calcium which does not occur in man. The mechanism of the testicular effect is not yet identified. However, lactitol gave completely negative results in standard tests for mutagenicity and clastogenicity, and no testicular effects or other neoplastic response was observed in lactitol-fed mice. Since Leydig cell tumors occur in humans at an extremely low rate despite the ingestion of substantial amounts of lactose with ordinary meals, the observation made in rats lacks apparent relevance for man.

scholarly journals 14-Day Repeated Intraperitoneal Toxicity Test of Ivermectin Microemulsion Injection in Wistar Rats

2020 ◽  
Vol 7 ◽  
Author(s):  
Zhen Dong ◽  
Shou-ye Xing ◽  
Ji-yu Zhang ◽  
Xu-zheng Zhou
Keyword(s):  
Toxicity Test ◽  
Wistar Rats ◽  
Histopathological Examination ◽  
Clinical Chemistry ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Toxic Injury ◽  
Male And Female Rats ◽  
Initial Stage

To evaluate the safety of ivermectin microemulsion injection, 100 Wistar rats were injected intraperitoneally at 0.38 g/kg, 0.19 g/kg, and 0.1 g/kg for 14 days. The 14-day repeated toxicity test of ivermectin microemulsion injection was systematically evaluated by clinical observation, organ coefficient, hematological examination, clinical chemistry examination, and histopathological examination. The results showed that no rats died during the test. At the initial stage of treatment, the rats in the high dose group had mild clinical reaction, which disappeared after 4 days. Clinical chemistry showed that the high dose of ivermectin microemulsion could cause significant changes in ALT and LDH parameters in male rats; high and medium doses could increase the liver coefficients of male and female rats. The toxic target organ may be the liver as indicated by histopathological findings. No significant toxic injury was found in the heart, liver, spleen, lung, kidney, brain, ovary, and testes of all groups of rats. No drug-related toxic effects were found at low doses, and thus the NOVEL of ivermectin microemulsion injection was 0.19 g/kg.

The effect of dexamethasone on mucosal immunity of uterine tissue during pregnancy in rat

2019 ◽  
Vol 20 (1) ◽  
pp. 75-84
Keyword(s):  
Early Pregnancy ◽  
Histopathological Examination ◽  
Early Period ◽  
Interleukin 10 ◽  
Treated Group ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Uterine Tissue ◽  
Leukocytic Infiltration

Disturbances in early pregnancy immunity affect embryo development, endometrial receptivity, placental development, fetal growth and lead to subfertility, dexamethasone is a synthetic glucocorticoid used for treatment of various complications. Immune cells and cytokines were examined during the early pregnancy in twenty-four female rats and six male rats for mating. Rats were grouped into two group control and dexamethasone treated by a dose of 50µgm/kgm body weight daily starting from one week before mating and persisted for one week after pregnancy. Blood samples were collected from each rat at 5hrs and at 1,3,7 day of pregnancy. Extracted RNA was subjected to real time PCR to determine mRNA levels for immune related genes interleukin1a(IL1A) and interleukin 10(IL10). Histopathological examination was done to uterus in order to detect leukocyte infiltration in uterine tissue. Results showed that significant increase in white blood cell count mainly eosinophil at 5hrs and lymphocyte at three and seven day of pregnancy of dexamethasone treated group. Moreover, TNF, C-reactive protein and progesterone were increased mainly at seven day of pregnancy of dexamethasone treated group. Similarly, interleukin 1alpha and interleukin 10 significantly increased at 5hrs and one day of pregnancy of dexamethasone treated group. In contrast, serum levels of total antioxidant capacity and estrogen were decreased significantly at 5hrs and seven day in dexamethasone treated group. Histopathological examination of uterus revealed leukocytic infiltration especially neutrophil and few eosinophils at five hours and one day of gestation then eosinophil become absent at 3day and seven day of dexamethasone group. Epithelial height and uterine gland diameter significantly increased at 5hrs, three day and seven days of gestation of dexamethasone treated group. The present investigation demonstrated that using of dexamethasone by dose of 50µgm/kgm during early pregnancy had a conflicting impact on some immune cytokines and parameters and may reflect a harmful response of immune system toward early period of pregnancy

scholarly journals EFFECT OF YOHIMBINE ON CLOMIPRAMINE-INDUCED SEXUAL DYSFUNCTION IN MALE RATS

2017 ◽  
Vol 10 (2) ◽  
pp. 92
Author(s):  
Devangam Sheshadri Shekar
Keyword(s):  
Sexual Behavior ◽  
Sexual Dysfunction ◽  
Histopathological Examination ◽  
Red Light ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Testicular Damage

Object: The present investigation has been carried out to find out the effect of yohimbine on clomipramine-induced sexual dysfunction in male rats.Methods: The male rats were treated with clomipramine and yohimbine simultaneously for 60 days. During the treatment, all the male rats werechallenged with the female rats which are in estrous phase and their sexual behavior was observed under dim red light. Half of the animals in each group and remaining on 60 day were sacrificed, blood was collected and serum separated. Testis was collected and preserved in 10% formalin forsubsequent histopathological examination. thResults: The study reveals that yohimbine failed to antagonize the clomipramine-induced sexual dysfunction in male rats in all aspects, except thepartial improvement in the sexual behavior.Conclusion: Yohimbine a well-known aphrodisiac failed to antagonize the clomipramine-induced sexual dysfunction in male rats. The decrease intestosterone levels, a decrease in spermatozoa count were continued even in the presence of yohimbine except improvement in the sexual behaviorparameters. Hence, yohimbine could not be a safe antidote against clomipramine-induced sexual dysfunction in male rats.Keywords: Yohimbine, Clomipramine, Testosterone, Male rat sexual competence, Testicular damage.

Acute and sub-chronic toxicity of the aqueous extract of Ficus vogelii (Miq.) Miq. stem bark in rats

2021 ◽  
Vol 10 (2) ◽  
pp. 89-97
Author(s):  
EL Lappa ◽  
◽  
C Bogning Zangueu ◽  
EL Nguemfo ◽  
JJ Kojom Wanche ◽  
...  
Keyword(s):  
Body Weight ◽  
Aqueous Extract ◽  
Chronic Toxicity ◽  
Hematological Parameters ◽  
Lethal Dose ◽  
Relative Weight ◽  
Stem Bark ◽  
The Body ◽  
Female Rats ◽  
Male Rats

Ficus vogelii is a medicinal plant mainly found in tropical Africa and reported to treat inflammatory complaints. This study aims to evaluate the acute and sub-chronic toxicity of the aqueous extract of Ficus vogelii stem bark in wistar rats. For acute study, aqueous extract at a single dose of 5000 mg/kg body weight was administered to female rats and observed for 14 days. In the sub-chronic study, the extract was administered daily to both sex rats at the doses of 100, 200, 400, and 600 mg/kg body weight for 28 consecutive days. Body weight was measured weekly, while hematological, biochemical, and histopathological parameters were analyzed after euthanize. Aqueous extract of Ficus vogelii at all tested doses didn’t produced any mortality or significant change on the body weight and relative weight of rats on acute and sub-chronic studies. The lethal dose 50 was estimated greater than 5000 mg/kg (DL50˃5000 mg/kg). Hematological parameters were recorded non-significant in all treated rats. Aqueous extract at 600 mg/kg significantly changed transaminases and alkaline phosphatase activities, these changes were reversible in satellites. The concentrations of bilirubin was increased at 200 and 600 mg/kg in male rats, at 100, 400 mg/kg in female rats. The levels of lipids markers didn’t changed, except the significant decrease of LDL-cholesterol. Histological examination didn’t showed any change in the architecture of the liver and kidney of rats treated compared to control. Thus aqueous extract of Ficus vogelii stem bark didn’t produced adverse effects in rats after oral acute and sub-chronic treatment.

Investigation of the effects of bisphenol-A exposure on lymphoid system in prenatal stage

2020 ◽  
Vol 36 (7) ◽  
pp. 502-513
Author(s):  
Işil Aydemir ◽  
Caner Özbey ◽  
Oktay Özkan ◽  
Şadiye Kum ◽  
Mehmet İbrahim Tuğlu
Keyword(s):  
Lymph Node ◽  
Bisphenol A ◽  
Tissue Damage ◽  
Corn Oil ◽  
Histopathological Examination ◽  
Female Rats ◽  
Male Rats ◽  
High Dose ◽  
Organ Function ◽  
Pregnant Rats

Bisphenol-A (BPA) used in the production of plastic materials is a temperature-soluble agent. It also has a steroid hormone-like activity; therefore, it poses a danger to human health. In our study, we aimed to investigate the effects of BPA on lymph node and spleen in male rats exposed to this agent during prenatal stage. The pregnant female rats were divided into four groups: control, sham, low dose (300 µg/kg BPA), and high dose (900 µg/kg BPA). BPA was dissolved in 1 mL of corn oil and administered to the pregnant rats every day during pregnancy. On the 21st and 45th day after the birth, male rats’ lymph node and spleen samples were taken and histopathological examination was performed. Samples were stained with hematoxylin and eosin to determine the general histological appearance, and with CD3 and CD20 immunohistochemically. The results of staining were evaluated by H-score, and statistical analysis was performed. In the samples, BPA applications were not found to cause significant tissue damage. But there was a significant decrease in the immunoreactivities of CD3 and CD20 after BPA applications in both 21st and 45th day samples. After high dose BPA administration, decreased CD3 immunoreactivity was statistically significant. It is thought that BPA does not cause histologically significant tissue damage, but it may impair organ function at cellular level. The investigation of molecules involved in organ function will be useful in revealing the mechanisms that will cause dysfunction.

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.

Subchronic Toxicity Study of Dicyclopentadiene Vapor in Rats

1992 ◽  
Vol 8 (6) ◽  
pp. 353-367 ◽  
Author(s):  
Christopher Bevan ◽  
William M. Snellings ◽  
Darol E. Dodd ◽  
Gerard F. Egan
Keyword(s):  
Epithelial Cells ◽  
Clinical Chemistry ◽  
Recovery Period ◽  
Proximal Tubules ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Weight Changes ◽  
High Exposure ◽  
Excretion Rates

Fischer 344 rats were exposed by inhalation to 0, 1, 5 or 50 ppm dicyclopentadiene (DCPD) vapor 6 hr/day, 5 days/week for 13 weeks, followed by a 13-week recovery period. Animals were euthanized following completion of exposure at 2, 6, or 13 weeks and at postexposure weeks 4 or 13. No mortality, overt signs, body weight changes, hematologic or clinical chemistry values were related to DCPD exposure. In the high-exposure male rats, relative liver weights were significantly increased but with no accompanying histopathologic changes. Exposure to DCPD produced adverse kidney effects in male, but not female, rats as evidenced by the excretion of epithelial cells in the urine. Histologic changes were localized to the proximal tubules of the kidney and included increased accumulation of protein droplets, regenerative epithelium, and the presence of intraluminal proteinaceous material. In addition, several alterations in renal function were observed. Urinary Na+ excretion rates were decreased and urinary K+ excretion rates were increased throughout the exposure period; however, glucose was not present in the urine, and creatinine clearance was normal. The ability of the kidney to concentrate urine was also impaired. After the recovery period, many of the treatment-related kidney effects were not observed, including the presence of hyaline droplets in the proximal tubules and epithelial cells in the urine. These findings indicate an overall low degree of systemic toxicity following sub-chronic inhalation exposure of dicyclopentadiene at exposure levels up to 50 ppm. The only effect that was observed was a male rat-specific nephropathy that is characteristic of the hyaline droplet nephropathy produced by a diverse group of compounds.

Discussion on rationality of administration of Angong Niuhuang Pills from pharmacological and toxicological perspectives

2020 ◽  
Author(s):  
Jianzhao Chen ◽  
Yushuang Chai ◽  
Yuanfeng He ◽  
Jisheng Huang ◽  
Ting Wan ◽  
...  
Keyword(s):  
Normal Control ◽  
Ischemia Reperfusion ◽  
Hematological Parameters ◽  
Scientific Basis ◽  
Neurological Function ◽  
Female Rats ◽  
Male Rats ◽  
Control Group ◽  
Toxicology Study ◽  
Body Weights

Abstract Background: Investigate the different treatment course of ANP from pharmacology and toxicology to provide scientific basis for clinic use. Method: In pharmacology study, cerebral ischemia-reperfusion model was made; rats were divided into six groups, Sham, model, aspirin 25 mg/kg, ANP 270 mg/kg (1 day, 4 days and 7 days) groups. Rats were fed for 30 days. Neurological function, cerebral infraction volume, brain histopathology, cytokines were detected; in toxicology study, rats were divided into four groups, normal control, ANP (550, 1640, 4910 mg/kg) group. ANP was daily administered by gavage for 30 days. Detection indicators included appearance, behavior, excrement character, food-intake, body weight, hematological parameters, etc. In addition, biomarkers such as TBA, GSTα, Cystatin C, clusterin, GSH, S-100B and MBP were also detected. Result: In pharmacology study, compared with model group, the neurological function scores of ANP 270mg/kg (1 day, 4 days and 7 days) were decreased (P<0.11 or P<0.05); the volume of ANP 270mg/kg (1 day and 7 days) were decreased (P<0.05); the R value of ANP 270mg/kg (1 day, 4 days and 7 days) groups were decreased (P<0.11 or P<0.05); the serum content of IL-1β, TNFα and NO of ANP 270 mg/kg(1 day, 4 days and 7 days) groups were decreased (P< 0.05); the brain content of IL-1β and NO of ANP 270 mg/kg(1 day, 4 days and 7 days) groups were decreased (P<0.05). In toxicology study, no mortality, ophthalmic abnormalities were identified. Compared with normal control group, body weights were significantly lower in ANP 4910 mg/kg group; TBA was significantly increased in ANP 4910mg/kg group; liver organ coefficient of female rats of ANP 4910 mg/kg group was increased (P < 0.05); kidney organ coefficient of male rats of ANP 1640mg/kg, 4910 mg/kg groups were increased (P < 0.05), these all recovered after drug withdraw for 8 weeks. Conclusion: The effect of ANP 270 mg/kg (7 days) was much better than ANP (1 day and 4 days). ANP 550mg/kg is non toxicity dose. So, ANP is taken one pill peer day for 7 days is safety and effective, it can be used as the scientific basis for clinic use.

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.

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