Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): III. Single- and/or Repeated-Dose Toxicity of Tripeptides-Containing Lactobacillus helveticus-Fermented Milk Powder and Casein Hydrolysate in Rats

2005 ◽  
Vol 24 (4_suppl) ◽  
pp. 13-23 ◽  
Author(s):  
Masafumi Maeno ◽  
Yasunori Nakamura ◽  
John H. Mennear ◽  
Bruce K. Bernard
Keyword(s):  
Body Weight ◽  
Single Dose ◽  
Clinical Chemistry ◽  
Casein Hydrolysate ◽  
Fermented Milk ◽  
Lactobacillus Helveticus ◽  
Female Rats ◽  
Repeated Dose ◽  
Male And Female ◽  
Dose Study

The objective of these studies was to assess the toxicological potential of orally administered tripeptides in rats. The studies employed powdered L-valyl-L-prolyl-L-proline (VPP)- and L-isoleucyl-L-prolyl-L-proline (IPP)-containing test articles, including (1) powdered Lactobacillus helveticus-fermented milk (FM), (2) pasteurized casein hydrolysate (CH) generated by Aspergillus oryzae protease, and (3) synthesized VPP. All test articles were administered by oral gavage to male and female Sprague-Dawley rats. Specific goals of the single-dose and repeated-dose studies were to (1) identify doses that produce evidence of systemic and/or local (i.e., gastrointestinal) toxicity (e.g., lowest-observable-effect level [LOEL]); (2) estimate the maximally tolerated oral dose (MTD) ; and (3) identify specific target organs for toxicity of these tripeptides. Single doses of CH (2000 mg/kg), powdered FM (2000 or 4000 mg/kg), or VPP (40, 200, or 400 mg/kg) were administered 14 days prior to study termination. No treatment regimen caused either antemortem (gross observations, body weight, and food consumption parameters) or postmortem (necropsy) evidence of either systemic or local toxicity. In the repeated-dose study, powdered FM (0, 500, 1000, or 2000 mg/kg body weight [BW]/day) was administered by gastric gavage to male and female rats for 28 consecutive days. Antemortem evaluative parameters included gross observations, ophthalmic examinations, and clinical pathology (clinical chemistry, hematology, and urinalysis). Post mortem parameters included necropsy, determination of organ weights, and microscopic examination of major organs. There was neither in-life nor postmortem evidence that powdered FM administration caused physiological or toxicological changes. Under the conditions of these experiments, the single-dose LOEL of powdered FM, CH, and VPP were found to be greater than 4000,2000, and 400 mg/kg, respectively. The results of the repeated-dose study do not support identification of a target organ for powdered FM toxicity. Similarly, there was no evidence to support establishment of either the LOEL or MTD; both being greater than 2000 mg/kg/day for up to 28 consecutive days.

Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): IV. Assessment of the Repeated-Dose Toxicological Potential of Synthesized L-Valyl-L-prolyl-L-proline in Male and Female Rats and Dogs

2005 ◽  
Vol 24 (4_suppl) ◽  
pp. 25-39 ◽  
Author(s):  
Yasunori Nakamura ◽  
Izuki Bando ◽  
John H. Mennear ◽  
Bruce K. Bernard
Keyword(s):  
Body Weight ◽  
Clinical Chemistry ◽  
Clinical Pathology ◽  
Female Rats ◽  
Male Rats ◽  
Repeated Dose ◽  
High Dose ◽  
Male And Female ◽  
Organ Weights ◽  
Male And Female Rats

The objective of these repeated-dose, 8-week studies was to assess the toxicological potential of a synthetic tripeptide, L-valyl-L-prolyl-L-proline (VPP), when administered to Charles River rats and Beagle dogs. Groups of 20 male and 20 female rats were fed powdered diets containing sufficient VPP to afford daily doses of 0, 2, 8, or 16 mg/kg body weight (BW)/day. Groups of five male and five female dogs were administered 0, 2, 8, or 16 mg/kg BW/day in hard gelatin capsules. Antemortem evaluative parameters for both species included grossly observable clinical signs, body weight and food consumption, clinical pathology (hematology, clinical chemistry, urinalysis), and ophthalmological examinations. Dogs also received electrocardiographic examinations. Postmortem evaluations in both species included complete necropsy, determination of major organ weights, and histopathological examination of specimens from approximately 50 organs and tissues. All rats and dogs survived to the scheduled termination of the studies and neither species exhibited evidence of VPP effects on appetite or body weight gain/maintenance. Ophthalmic examinations revealed occasional lens clouding in rats, but this occurred in all groups and was not attributable to VPP. Some clinical pathology parameters in both species were occasionally altered, but there was no evidence that this was dose-related. Electrocardiographic examinations in dogs revealed no VPP-associated changes. Mid- and high-dose male rats (but not females) had slightly reduced mean pituitary and kidney weight parameters, whereas mid- and high-dose females had slightly increased mean uterus:body weight ratios. There were no microscopic correlates for these minor changes. Ten percent to 20 % of all female rats (but not males) exhibited corticomedullary mineralization of the kidney and gliosis of the optic nerve, and 10% to 20% of males (but not females) had thymic hemorrhage. Postmortem evaluations of dogs revealed no VPP-related effects on organ weights or either macro- or microscopic appearances of organs. The results of these studies provided no evidence of either local or systemic toxicity. Similarly, there was no evidence of neurotoxicity that might have been detected by the appearance of physical or behavioral changes during gross observations of animals. Although these results do not identify target organs for VPP toxicity, the no-observable-effect level and maximally tolerated dose are both greater than 16 mg/kg/day when administered to male and female rats and dogs for 8 consecutive weeks. Based upon food enhancement levels of VPP currently being evaluated, the resultant margin of safety (160) is substantial.

scholarly journals Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): VI. Effects of Lactobacillus helveticus-fermented Milk Powder on Fertility and Reproductive Performance of Rats

2005 ◽  
Vol 24 (4_suppl) ◽  
pp. 61-89 ◽  
Author(s):  
Takahiro Kurosaki ◽  
Masafumi Maeno ◽  
John H. Mennear ◽  
Bruce K. Bernard
Keyword(s):  
Adverse Effect ◽  
Body Weight ◽  
Sex Ratio ◽  
Reproductive Performance ◽  
Clinical Signs ◽  
Fermented Milk ◽  
Lactobacillus Helveticus ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats

The objective of these studies was to assess the effects of the tripeptides, L-valyl-L-prolyl-L-proline (VPP) and L-isoleucyl-L-prolyl-L-proline (IPP), on reproductive capabilities of male and female rats. The specific goals of the experiments were (1) to determine the effects of orally administered tripeptides on (a) fertility and reproductive behavior in both sexes of rats, (b) embryo-fetal development in pregnant rats, and (c) pre- and postnatal development of rats exposed to tripeptides in utero and during lactation; and (2) to estimate the no-observable-adverse-effect doses of tripeptides in maternal and fetal rats. During the conduct of these classical segment I, II, and III studies, the test material was powdered Lactobacillus helveticus-fermented milk (FM), which contains the tripeptides, VPP and IPP. FM (0, 500, 1000 or 2000 mg/kg body weight [BW]/day—equivalent to 0, 0.8, 1.6, or 3.3 mg/kg BW/day of VPP plus IPP) was administered to males by oral gavage from 4 weeks prior to mating until sacrifice, and to females from 2 weeks prior to mating through day 20 of lactation. Evaluative parameters included monitoring grossly observable clinical signs; food consumption and body weight gains; mating behavior and fertility indices of both sexes; implantation and maintenance of embryos; sex ratio of live pups ; fetal viability; incidences of external, visceral or skeletal variations; growth and behavioral development; as well as reproductive capabilities of Fi offspring exposed to FM during gestation and lactation. All animals were subjected to macroscopic examination at termination of their segment of the studies. Clinical signs, body weights, and food consumption were unaffected by administration of FM. During segment I, the test agent had no effect on estrus cycle, mating behavior, fertility index, or reproductive competence of either males or females. The results of segment II experiments revealed no effects of FM on postimplantation survival-loss, sex ratio or birth weights of live fetuses, and there was no evidence of treatment-associated developmental or teratological effects. During segment III, FM was without effect on pup viability, behavioral and sexual maturation, and reproductive capability of the F1 generation. Under the conditions of these experiments, the no-observable-adverse-effect level (NOAEL) of FM on reproductive performance in male and female rats is greater than 2000 mg/kg BW/day, the equivalent of 3.3 mg/kg BW/day of VPP plus IPP.

scholarly journals A 28-Day Repeated Dose Toxicological Study of an Aqueous Extract of Morus Alba L.

2016 ◽  
Vol 35 (6) ◽  
pp. 683-691 ◽  
Author(s):  
Tennille K. Marx ◽  
Róbert Glávits ◽  
John R. Endres ◽  
Philip A. Palmer ◽  
Amy E. Clewell ◽  
...  
Keyword(s):  
Body Weight ◽  
Animal Studies ◽  
Clinical Pathology ◽  
Morus Alba ◽  
Water Soluble ◽  
Female Rats ◽  
Repeated Dose ◽  
Oral Toxicity ◽  
Male And Female ◽  
Male And Female Rats

Morus alba L. (white mulberry) leaves are one of the oldest recognized traditional Chinese medicines. More recently, M alba leaves and their constituents, particularly iminosugars (or azasugars), have garnered attention for their ability to maintain normal blood glucose concentrations, an effect identified in both animal studies and human clinical trials. Reducose (Phynova Group Limited) is a commercial water-soluble extract of M alba leaves standardized to 5% 1-deoxynojirimycin (DNJ), an iminosugar with α-glucosidase inhibition properties. Although there is an extensive history of consumption of M alba leaves by humans and animals worldwide, suggesting that the leaves and their extracts have a relatively good safety profile, we are unaware of safety assessments on an extract containing a higher amount of DNJ than that occurs naturally. The current 28-day repeated dose oral toxicity study in rats, conducted according to Organisation for Economic Co-operation and Development guidelines, was carried out to assess the safety of Reducose. Male and female Hsd.Han Wistar rats (4 groups of 10 animals/sex) were administered Reducose via gavage at doses of 0, 1,000, 2,000 and 4,000 mg/kg body weight (bw)/d. No treatment-related mortality or adverse effects (per clinical observations, body weight/weight gain, food consumption, ophthalmoscopy, clinical pathology, gross pathology, organ weights, or histopathology) were observed, and no target organs were identified. The no observed adverse effect level was determined to be 4,000 mg/kg bw/d for both male and female rats, the highest dose tested.

Trans-1,1,1,4,4,4-hexafluoro-2-butene (HFO-1336mzz-E) (2018)

2019 ◽  
Vol 35 (3) ◽  
pp. 204-210
Keyword(s):  
Body Weight ◽  
Female Rats ◽  
Male Rats ◽  
Repeated Dose ◽  
Exposure Level ◽  
Inhalation Study ◽  
Male And Female ◽  
Range Finding ◽  
Male And Female Rats ◽  
Dose Inhalation

Trans-1,1,1,4,4,4-hexafluoro-2-butene (HFO-133mzz-E) is an odorless gas that finds uses as a foam transfer agent, heat transfer fluid, and specialty gas. The acute 4-h LC50 (in rats) for HFO-133mzz-E is > 17,000 ppm; it was not an eye or dermal irritant in 3- and 13-week repeated-dose inhalation studies in rats at concentrations up to 1.5% (15,000 ppm). HFO-133mzz-E was not a cardiac sensitizer at 70,000 ppm in a standard epinephrine challenge study in Beagle dogs. In a 3-week, repeated-dose (non-GLP) inhalation range-finding study in male and female rats, HFO-133mzz-E concentrations of 7500 and 15,000 ppm were determined to be well-tolerated. In the follow-up, GLP-compliant, 28-day repeated-dose inhalation study (as per OECD 412), male and female rats were exposed to 0, 1000, 10,000, or 15,000/20,000 ppm (20,000 ppm concentration was decreased to 15,000 ppm after week 1 because of deaths and body weight loss). The study no-observed-adverse-effect level (NOAEL) was established at 10,000 ppm based on reduced body weight gain and mortality observed at 15,000 ppm. In a 90-day GLP-compliant repeated-dose study (as per OECD 413), male and female rats were exposed to 0, 1000, 5000, 7500, or 15,000 ppm HFO-133mzz-E. Three male rats exposed to 15,000 ppm HFO-133mzz-E died during exposure; clinical signs such as restlessness, blepharospasm, and myoclonic jerks were also observed, during the first month of the study, at 15,000 ppm. There were no significant gross or histopathological organ/tissue lesions attributable to HFO-133mzz-E exposure. The study NOAEL was established at 7500 ppm. In a GLP prenatal developmental study (OECD 414), groups of time-mated nulliparous female rats were exposed via inhalation to 0, 1000, 5000, 7500, or 15,000 ppm HFO-1336mzz-E beginning on gestation day (GD) 6 up to and including GD 19. Under the conditions of this study, the NOAEL for maternal and fetal effects was established at 7500 ppm. HFO-1336mzz-E was not genotoxic in either in vitro or in vivo assays. Based on the results of the 90-day inhalation study, 7500 ppm was determined to be the NOAEL and was selected as the point of departure for the derivation of the 8-h time-weighted average (TWA), health-based workplace environmental exposure level (WEEL) value. This subchronic inhalation NOAEL was adjusted to account for duration of exposure, interindividual variability, and intraindividual variability. The resulting 8-h TWA WEEL value of 400 ppm is fully expected to provide a significant margin of safety against the production of any potential adverse health effects in workers following long-term inhalation exposure to HFO-1336mzz-E.

scholarly journals 90-Days Repeated Dose Oral Toxicity Study on Majoon-e-Nisyan

2020 ◽  
Vol 15 ◽  
pp. 22-33
Author(s):  
Masud Shaikh ◽  
Syed Shoeb Ahmed ◽  
Mohd Urooj ◽  
Uzma Viquar ◽  
Munawwar Husain Kazmi ◽  
...  
Keyword(s):  
Body Weight ◽  
Histopathological Examination ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Female Rats ◽  
Feed Consumption ◽  
Control Group ◽  
Male And Female ◽  
Male And Female Rats ◽  
Dose Levels

Majoon-e-Nisyan (MJN) is a polyherbal semisolid compound formulation. Its description is present in various Unani literatures. It is used in Unani medicine for its therapeutic efficacy against amnesia. There is no report regarding its safety on long term administration. Therefore, toxicological evaluation of MJN is carried out in rats. Majoon-e-Nisyan was subjected to 90-days repeated oral dose toxicity studies as per OECD guide line 408. Wistar rats were treated at three dose levels i.e., 500, 1000 and 2000 mg/kg bw and one vehicle treated group. MJN and vehicle were orally administered daily for 90 days and animal were observed for clinical signs of toxicity, mortality, body weight and feed consumption. On completion of 90-days, blood samples were collected and analyzed for hematology and biochemistry. Necropsy was performed on all survived animals and vital organs were collected and subjected to histopathology. No post dose adverse effect was reported on survival of both male and female rats after oral administration of MJN for 90 days. No incidence of mortality was reported in MJN treated male and female rats at all tested dose levels. No abnormal clinical signs were observed in MNJ treated animals at 500, 1000 and 2000 mg/kg bw as compared to animals of control group. No significant changes were observed in biochemistry, hematology and histopathological examination. No incidence of mortality, adverse changes in clinical signs of toxicity or body weight gain of rats was noted. No changes in clinical chemistry, hematology, and histopathology were observed in MJN-treated or control group. Therefore, NOAEL for MJN may be considered more than 2000 mg/kg bw in rats. Subject Classification Numbers: Pharmacology, Toxicology.

Effects of Dehydroepiandrosterone Acetate on Metabolism, Body Weight and Composition of Male and Female Rats

1986 ◽  
Vol 116 (10) ◽  
pp. 1977-1983 ◽  
Author(s):  
Anthony R. Tagliaferro ◽  
James R. Davis ◽  
Stephen Truchon ◽  
Nancy Van Hamont
Keyword(s):  
Body Weight ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats

scholarly journals Toxicity Evaluation of a Traditional Polyherbal Unani Formulation Jawarish Shahi in Rats

2018 ◽  
Vol 7 (5) ◽  
pp. 412-418
Author(s):  
Mohd Urooj ◽  
◽  
Mohammad Ahmed Khan ◽  
G. Thejaswini ◽  
Munawwar Husain Kazmi ◽  
...  
Keyword(s):  
Body Weight ◽  
Feed Intake ◽  
Clinical Signs ◽  
Female Rats ◽  
Control Group ◽  
Sprague Dawley ◽  
Male And Female ◽  
Salix Caprea ◽  
Male And Female Rats ◽  
Dose Levels

Jawarish Shahi (JS) is a compound polyherbal Unani pharmacopoeial formulation indicated for Khafqan (Palpitation), Nafkh-e-Shikam (Flatulence) and Waswas (Insanity; false perception and hallucinations). Jawarish Shahi contains herbs like Halela (Terminalia chebula), Amla (Emblica officinalis), Kishneez (Coriandrum sativum), Elaichi Khurd, (Elettaria cardamomum), and Bed Mushk (Salix caprea). The present study was carried out as per OECD 408 guidance to evaluate 90 days repeated oral dose toxicity in male and female Sprague Dawley rats. The study was performed at dose levels 1028 and 2000 mg/kg bw. No adverse effects were reported with respect to body weight, feed intake, behavior and clinical signs indicative of systemic toxicity. The expected growth pattern was observed in body weight and feed intake as compared to control group at both dose levels in male and female rats. There were few significant alterations with respect to hematology, and clinical biochemistry, however the results were within normal range thus considered toxicologically insignificant. The microscopic examination of different organ/tissue showed that no histopathological changes were observed. The findings of the study showed that No Observed Adverse Effect Level (NOAEL) for JS is greater than 2000 mg/kg body weight

scholarly journals Reproductive toxicity of triazole fungicides cyproconazole and epoxiconazole when exposed to male and female wistar rats during gametogenesis

2021 ◽  
Vol 54 (1) ◽  
pp. 52-61
Author(s):  
NR Shepelskaya ◽  
YaV Kolyanchuk
Keyword(s):  
Body Weight ◽  
Reproductive Toxicity ◽  
Reproductive Function ◽  
Female Rats ◽  
Male Rats ◽  
Corpora Lutea ◽  
Disruptive Effect ◽  
Male And Female ◽  
Two Samples ◽  
Adverse Effect Level

Aim. Studying the effect of generic pesticides cyproconazole (98 %) and two samples of epoxiconazole (epoxiconazole 1 — 95,75 % and epoxiconazole 2 — 98,7 %) on the reproductive system of male and female Wistar Han rats at the level of the organism when exposed during gametogenesis, identification and characterization of their hazard, as well as assessment of the risk of reproductive toxicity of these compounds. Materials and Methods. The test samples were administered daily (5 days a week) by oral gavage at doses of 0.2 and 2.0 mg/kg for cyproconazole and 0.5 and 2.0 mg/kg for epoxiconazoles during 11 weeks for males, and 10 weeks for females. Also, there were kept intact males and females, intended for crossover mating with experimental animals. After the end of the exposure, functional indicators of the state of the gonads and the ability of animals to reproduce offspring were studied. The duration and the frequency of each stage of the estrous cycle in female rats and the number of motile sperm, the total amount of sperm and the number of abnormal forms of germ cells of the male rats were studied. The reproductive function state in females was evaluated on day 20th of pregnancy. Thereby the number of corpora lutea in the ovaries, number of alive, dead and resorbed foetuses and embryos, the foetus weight, total weight of litters were registered. The studies were carried out in accordance with the recommendations of the Bioethics Commission and the Centre’s standard operating procedures, developed in accordance with the recommendations and requirements of Good Laboratory Practice (GLP). Conclusions. Test substances at a maximum dose of 2.0 mg/kg of body weight have reproductive toxicity and endocrine-disruptive effect, exerting a significant antiandrogenic effect on males and antiestrogenic effect on female rats. No-observed-adverse-effect-level (NOАEL) for gonadal and reproductive toxicity for male and female Wistar Han rats were established. They are 0.2 mg/kg body weight for cyproconazole and 0.5 mg/kg body weight for epoxiconazole. Key Words: azole fungicides, cyproconazole, epoxiconazole, reproductive toxicity, antiandrogenic and antiestrogenic effects, Wistar Han rats.

scholarly journals Subchronic Toxicity Assessment of Phytolacca americana L. (Phytolaccaceae) in F344 Rats

2020 ◽  
Vol 15 (7) ◽  
pp. 1934578X2094165
Author(s):  
Hyoung-Yun Han ◽  
Kang-Hyun Han ◽  
Jun-Ho Ahn ◽  
Se-Myo Park ◽  
Soojin Kim ◽  
...  
Keyword(s):  
Body Weight ◽  
Adverse Effects ◽  
Clinical Chemistry ◽  
Toxicity Assessment ◽  
Phytolacca Americana ◽  
Subchronic Toxicity ◽  
Experimental Conditions ◽  
Male And Female ◽  
Long Term Treatment ◽  
F344 Rats

Phytolacca americana L. is traditionally used in Korea, Japan, and China as a diuretic, antibacterial, antiviral, anticancer, and anti-inflammatory agent, and also in the treatment of hepatitis B, psoriasis, edema, and rheumatism. In this study, we evaluated the subchronic toxicity of an aqueous extract of P. americana (PAAE) in male and female F344 rats. The rats were orally administered PAAE (0, 500, 1000, and 2000 mg/kg body weight) once daily for 13 weeks. Mortality rate, body weight, food consumption, and organ weights were measured and assessed. Additionally, ophthalmological, hematological, and histopathological parameters were evaluated. Urinalysis and necropsy were also performed. The clinical chemistry values for potassium in the treated female groups (500, 1000, and 2000 mg/kg/ body weight/day) were higher than those in the control. Further, the relative weights of the kidneys in the treated female groups (1000 and 2000 mg/kg/ body weight/day) were higher than those in the control. However, these changes were not consistent in either sex, and no abnormalities were found in the corresponding pathological findings. Thus the results showed no adverse effects in all the parameters assessed. The findings show that after 13 weeks of treatment, the “no-observed-adverse-effect level” of PAAE is 2000 mg/kg body weight in both male and female F344 rats under the experimental conditions applied. Although treatment-related adverse effects were not seen, potassium-level changes in the blood should be examined to establish the safety profile of PAAE after long-term treatment.

scholarly journals Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats

Life Sciences ◽  
2007 ◽  
Vol 81 (12) ◽  
pp. 1024-1030 ◽  
Author(s):  
SuJean Choi ◽  
Briana DiSilvio ◽  
JayLynn Unangst ◽  
John D. Fernstrom
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Chronic Infusion
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