A 90-day oral (dietary) toxicity and mass balance study of corn starch fiber in Sprague Dawley rats

A toxicological assessment of spermidine trihydrochloride produced using an engineered strain of Saccharomyces cerevisiae

A 28-day oral dose toxicity study in Wistar rats enhanced to detect endocrine effects of decabromodiphenyl ether (decaBDE)

Re-evaluation of the reduced heart weights in male rats in a 28-day oral repeated-dose toxicity study of tetramethylammonium hydroxide

Introduction: Caffeine, one of the most ubiquitous ingredients found in beverages and other ingested food products, has a long history of safe use. As a member of the methylxanthine class of stimulants, caffeine is not devoid of unwanted side effects at any serving level. Caffeine safety has been the subject of a safety workshop by FDA and the Institute of Medicine in the past decade. Thus, investigation into an alternate stimulant with similar pharmacology but improved safety is warranted. Paraxanthine (1,7-dimethylxanthine) is the predominant metabolite of caffeine in humans with similar stimulant properties. The few toxicity studies that are available for paraxanthine suggest that the molecule is relatively safe, although thorough characterization of its safety is required prior to widespread incorporation into foods/beverages.Methods: The aim of this study was to evaluate the toxicity of paraxanthine (Rarebird, Inc.) relative to caffeine through a battery of toxicological studies conducted in accordance with international guidelines. These studies evaluated the potential mutagenicity (bacterial reverse mutation, in vitro mammalian chromosomal aberration), genetic toxicity (in vitro mammalian cell gene mutation) and acute, sub-acute and sub-chronic oral toxicity of paraxanthine in Sprague Dawley rats.Results/Discussion: There was no evidence of genetic toxicity or mutagenicity in the in vitro studies. An acute oral LD50 of 829.20 mg/kg body weight (bw) was established. There was no mortality or treatment-related adverse effects in the 14-day repeat dose oral toxicity study, wherein rats received low, mid, or high doses of paraxanthine (50, 100, or 150 mg/kg bw, n = 5 rats/sex/group). The same findings were observed in the subchronic repeat-dose 90-day oral toxicity study at daily doses of paraxanthine of 100, 150, or 185 mg/kg bw which were compared to caffeine at 150 or 185 mg/kg bw (n = 10 animals/sex/group). However, mortality was reported in two animals in the high dose caffeine-treated animals. Therefore, the no observed adverse effect level (NOAEL) from the 90-day study was determined to be 150 mg/kg bw for caffeine and 185 mg/kg bw for paraxanthine for both male and female Sprague Dawley rats. These findings may suggest that paraxanthine could be a safer alternative to caffeine in humans.

The main objective of this 28-day oral gavage toxicity study in the rat was to investigate which of the current and/or additional parameters of the OECD Test Guideline 407 would reliably and sensitively detect the endocrine-mediated effects of the nonsteroidal antiestrogen tamoxifen. In addition, as this study was performed using two subgroups of five animals of each sex run concurrently, it enabled an assessment of the intralaboratory reproducibility while also assessing the potential value of using ten animals of each sex per group instead of using the standard five animals of each sex per group stipulated by the current guideline. Tamoxifen was administered daily by gavage to groups of 7-week-old Wistar rats for at least 28 days at dose levels of 5, 30, or 200 microg/kg body weight. Additional parameters specified in the enhanced OECD Test Guideline 407 were spermatozoa enumeration and morphology of the cauda epididymis, hormonal analysis of the thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) levels, monitoring of the estrous cycle during week 4 of treatment to ensure females were in diestrus on the day of terminal sacrifice, organ weight of ovary, uterus, thyroid gland, prostate gland (ventral and dorsolateral parts), seminal vesicles with coagulation glands and pituitary gland, and microscopic investigation of the pituitary gland, vagina, mammary gland, seminal vesicles with coagulating glands, epididymis, and prostate gland (ventral and dorsolateral parts). Overall, 200 microg/kg per day was considered to be the Maximum Tolerated Dose (MTD) in both sexes, resulting in a marked reduction of body weight gain, together with slight effects on clinical signs, hematology, plasma chemistry, and microscopic changes in some endocrine tissues. Five micrograms per kilogram per day represented the No Observed Adverse Effect Level (NOAEL) in males and the No Observed Effect Level (NOEL) in females. At the intermediate dose level (30 microg/kg per day), the current OECD Test Guideline 407 was appropriate to detect the specific endocrine-related changes induced by tamoxifen in females, based on the histopathology findings observed in the ovary and the uterus. The additional parameters which were found to be changed in females (thyroid hormone levels, ovary and uterus weights, and histopathology of vagina) provided supplementary information further confirming tamoxifen-mediated endocrine effects. In males, when data from the current Test Guideline 407 were considered at the intermediate dose level, specific endocrine effects were only indicated on the basis of the histopathology findings observed in the prostate gland. The additional parameters examined which were found to be changed (prostate gland and seminal vesicle weights, and histopathology of seminal vesicle and mammary gland) were necessary to confirm the specific tamoxifen-mediated endocrine effects. Hence, amongst the additional parameters contained in the enhanced OECD Test Guideline 407, organ weights and histopathological examination of endocrine-related organs were the most helpful in confirming the detection of tamoxifen-mediated endocrine effects. The reproducibility evaluation showed that a group size of five animals of each sex consistently allowed the detection of endocrine effects with the current Test Guideline in both sexes at the high dose level and in females at the intermediate dose level. Doubling the animal number from five to ten of each sex per dose level did not notably increase the sensitivity of detection of endocrine-mediated effects.

17alpha-methyltestosterone: 28-day oral toxicity study in the rat based on the "Enhanced OECD Test Guideline 407" to detect endocrine effects.

A toxicological assessment of tri-betahydroxybutyrin for use as a novel food ingredient.

Fungal-derived food products align with sustainable food supply principles and offer a sustainable and nutritious option for consumers. Rhizomucor pusillus strain CBS 143028 has emerged as a candidate food ingredient. Fermentation of R. pusillus CBS 143028 results in a mycelium biomass mainly comprising fungal proteins, cell wall components, and micronutrients. Although R. pusillus has a history of safe use in the production of food enzymes and in traditional fermented foods, the fungal biomass obtained after fermentation of R. pusillus CBS 143028 is considered a novel food and requires a thorough safety assessment. To this end, a 90-day oral toxicity study was conducted in which Wistar rats (10/sex/group) were provided diets containing 0, 100,000, 200,000, or 300,000 ppm of R. pusillus mycelium. Standard toxicity study parameters as given in OECD Test Guideline 408 were examined. The mean achieved dosages of R. pusillus mycelium were 6398, 12,738, or 19,668 mg/kg body weight/day for males and 7235, 14,949, or 22,461 mg/kg body weight/day for females in the low-, mid-, and high-dose groups, respectively. Although statistically significant differences were reported, these effects were not considered biologically relevant or test article-related due to atypical values in the control groups, the lack of a dose response relationship, or were attributed to normal biological variation. Thus, the no-observed-adverse-effect level (NOAEL) was established at 300,000 ppm (corresponding to 19,668 and 22,461 mg/kg body weight/day for males and females, respectively), the highest concentration tested.

Safety evaluation of Nostoc flagelliforme (nostocales, cyanophyceae) as a potential food

BackgroundNuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats.MethodsAcute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed.ResultsIn acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment.ConclusionAcute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects in NK satellite group. In conclusion, NK was found to be non-toxic in the tested doses and experimental conditions.

Naturally sweet proteins have no glycemic effect and offer a fundamentally new approach to sweetness and health for individuals seeking to reduce their added sugar intake. However, unlike many commercial sweeteners, little research has been performed on the potential safety implications of adding these uniquely sweet proteins to food and beverages. In this study, a naturally sweet protein found in the West African Oubli plant ( Pentadiplandra brazzeana), referred to as Oubli fruit sweet protein or brazzein, was expressed in Komagataella phaffii (formerly Pichia pastoris) and produced via precision fermentation, and a safety and risk assessment was undertaken for its use as a sweetener in food and beverages. Potential consumption levels of brazzein were estimated to be 3 mg/kg body weight/day based on the National Health and Nutrition Examination Survey. The safety of brazzein derived from K. phaffii was evaluated through in silico allergenicity, in vitro genotoxicity (reverse mutation and mammalian micronucleus assays), and a 90-day dietary oral toxicity study in rats. There was no indication of allergenicity in the in silico analyses. Brazzein was non-genotoxic in the in vitro assays and showed no adverse effects in the 90-day oral toxicity study up to the highest dose tested, where the no-observed-adverse-effect level (NOAEL) was 978 and 985 mg/kg body weight/day in males and females, respectively. The totality of evidence in the in silico allergenicity, in vitro genotoxicity, and 90-day dietary toxicity studies demonstrates that brazzein derived from K. phaffii is considered safe for use as a sweetener in food and beverages.

Objectives:The present work was aimed to study the phytochemical composition of the Sapindus laurifolius leaves and toxicological effect of the Sapindus laurifolius leaf extract in a systematic way using Wistar albino rats as a model animal. Materials and Methods :The identification of phytoconstituents present in the leaf extract was performed using High performance thin layer chromatography (HPTLC). In toxicity studies, the acute oral toxicity study was conducted as per the guidelines of Organization for Economic Co-operation and Development (OECD 423 Acute Toxic Class Method) for testing of chemicals. In repeated dose 28-day oral toxicity study (OECD 407), methanolic leaf extract administered at the dose of 50, 200 and 800 mg/kg BW and limit dose of 1000 mg/kg BW. Results: Saponins, flavanoids, glycosides and bitter principles were the major phytoconstituents identified. In acute toxicity study, the LD cut-off values were found to be more than 2g/kg in leaf extract. In repeated dose 28-day oral toxicity, significant 50 (P<0.05) increase in AST, ALT, BUN and creatinine, significant (P<0.05) increase in total protein was noticed. The histopathological changes confined to liver, kidney and intestine, revealed mild to moderate hepatotoxicity, severe nephrotoxicity and increased goblet cell activity. The changes were found to correlate with increased dose of leaf extract. Conclusion:The phytochemical analysis of Sapindus laurifolius revealed the presence of saponins, glycosides, flavonoids and bitter principles.The acute oral toxicity study of S. laurifolius methanolic leaf extract in rats resulted in no toxicity even at the highest dose, but in repeated 28-day oral toxicity study revealed mild to moderate hepatotoxicity, severe nephrotoxicity and intestinal damage.

Introduction:Metriviv syrup is a poly-herbal formulation used as uterine tonic and for treating gynecological ailments such as infertility, leucorrhea, and menstrual disorders. There is no scientific data on the safety of this formulation available, therefore, its detail toxicity study in female albino rats was conducted.Aims and Objective:Acute toxicity and repeated dose 28 days oral toxicity study of metriviv syrup in female rats.Material and Methods:In oral acute toxicity study, syrup metriviv was administered orally once only at the dose of 2000mg/kg in rats in a sequential manner. For repeated dose toxicity study, Metriviv syrup was administered orally for 28 consecutive days in albino rats at three dose levels, i.e., TED, TEDx5 and TEDx10 dose levels (1.35, 0.75, 13.5 ml/kg, twice a day respectively).Results and Observation:Results of acute toxicity study showed that drug did not produce any behavioral changes, signs of toxicity and mortality up to the dose of 2000 mg/kg in rats. In repeated dose 28-day oral toxicity study, Metriviv did not produce any signs of toxicity and changes in behavioral parameters. Metriviv did not affect cellular as well as non-cellular elements of the blood to significant extent. Serum biochemical profile and histological study clearly indicated that the test formulation is not likely to produce any serious changes at lower dose level while produced mild-to-moderate changes at TEDx10 dose level and same was reverted in recovery study after discontinuation of the drug.Conclusion:The study concluded that metriviv syrup is safe to administer up to dose of 2000 mg/kg in female rats during acute toxicity. In repeated dose 28-day oral toxicity study, test drug at TEDx10 has only mild-to-moderate adverse potential for liver and kidney while did not have any major toxic effects at therapeutic dose level in female albino rats.

Perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and their salts Scientific Opinion of the Panel on Contaminants in the Food chain.

Objective: The aim of the present study was to perform an acute toxicity study to obtain information on the possible adverse effects from a single oral administration of Oleanolic acid in Wistar rats as the onset of toxicity, and to determine the range of exposure (to the LD50 cut-off criteria). Following a sub-chronic 90-days Repeated toxicity study by oral route to determine any potential indication of its dose response relationship and determine no observed effect level (NOEL)/ no-observed adverse effect level (NOAEL)/ low observed effect level (LOEL)/ low observed adverse effect level (LOAEL). Methods: A dose level of 2000mg/kg body weight was employed as step one for single acute study. Based on the survival pattern of the previously dosed animals after 48 hours, same dose 2000 mg/kg body weight) was repeated for Step 2 as a confirmatory test. For the 90-day toxicity study, the highest dose was determined as 1000mg/kg Body weight, and the middle and lower doses were 500 and 250mg/kg Body weight respectively. The rat group was held for a 14-day recovery period after the last dose administration, to observe for any persistence or reversal of toxic effects. Results: Results of the acute toxicity study showed no mortality on the dose level of 2000mg/kg body weight with no significant clinical and body weight changes. During the 90-day Repeated dose oral sub-chronic toxicity study, no rats died. There were no significant clinical changes related to the test item in terms of functional evaluation, body weight, food and water consumption, ophthalmological tests, urine analysis, necropsy findings, or organ weight, Hematology, and biochemistry at the highest dose level of 1000 mg/kg bwt. Conclusion: It is concluded that LD50 Cut-off Value of “Oleanolic acid” in from acute oral toxicity study in Wistar Rats is 2000 mg/kg b.wt. In addition, 90 days study have showed no significant changes with respect to any hematological or blood chemical analyses in 1000, 500 and 250 mg/kg bwt groups. Based on histopathological findings, clinical signs and other parameters, it may be concluded that upon repeated once oral administration for consecutive 90 days, the Oleanolic acid (Pentacyclic Triterpenoid) extracted from Lantana camara roots at the dose level of 1000 mg/kg body weight have caused no adverse effect in both sexes of Wistar Rats.