A 90-day Sub-chronic Oral Toxicity Assessment of Mulberry Extract in Sprague Dawley Rats
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ABSTRACT:
SUBMITTER: Hong M
PROVIDER: S-EPMC8613892 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Regular consumption of polyphenol-rich fruits and vegetables is associated with beneficial health outcomes. To increase polyphenol intakes, consumers are increasingly using herbal and botanical dietary supplements containing concentrated polyphenol extracts. However, the safety of this consumption modality has not been vetted. To address this, ovariectomized Sprague-Dawley (OVX-SD) rats were orally gavaged with purified blueberry polyphenols at 0-1000 mg total polyphenols/kg bw/d for 90d. No differences in behavior, body weight, or food consumption were observed. No tumors or macroscopic changes were observed, and histopathological analyses showed no differences among groups. Although several statistically significant differences between treatment and control groups were observed in urine (color and pH) and blood (monocyte count, total cholesterol, and chloride ion concentration) analyses, these parameters were within normal ranges and not considered biologically significant. Intestinal permeability assessed via FITC-dextran showed increased intestinal permeability in the highest dose, though no morphological differences were found throughout the gastrointestinal tract. Given the lack of other systemic changes, this finding is likely of minimal physiological importance. These results indicate a NOAEL for blueberry polyphenols in OVX-SD rats is ≥ 1000 mg total polyphenols/kg bw/d, which translates to a 70 kg human consuming ~10 g polyphenols. Keywords: Blueberry, Polyphenol, Sub-chronic toxicity.
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Project description:A 90-day oral toxicity study of γ-oryzanol, a rice-derived triterpenoid ferulate, was performed by oral gavage administration to male and female Sprague-Dawley rats at doses of 0, 1000, and 2000 mg/kg body weight/day. All rats administered γ-oryzanol survived throughout the study period. Both male and female rats showed no toxicologically significant changes of the general signs, examination findings, body weight, food consumption, functional observational battery results, ophthalmological findings, urinalysis, hematology tests, clinical chemistry tests, organ weights, and necropsy findings. Moreover, there were no histopathological changes related to administration of γ-oryzanol in males and females from the 2000 mg/kg body weight/day group. In conclusion, the no observed adverse effect level (NOAEL) of γ-oryzanol exceeded 2000 mg/kg body weight/day for both male and female rats under the conditions of this study.
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Project description:Cannabinoids are extracted from Cannabis sativa L. and are used for a variety of medicinal purposes. Recently, there has been a focus on the cannabinoid Cannabidiol (CBD) and its potential benefits. This study investigated the safety of a proprietary extract of C. sativa, consisting of 9% hemp extract (of which 6.27% is CBD) and 91% olive oil. The mutagenic potential of the hemp extract was evaluated with the AMES assay inclusive of a hepatic drug metabolizing mix (S9) rich in CYP enzymes. The test article did not elicit evidence of bacterial mutagenicity. GLP compliant 14-day and a 90-day toxicity study were conducted. Olive oil was used as a control. The 90-day study had a 28-day recovery period. Treatments for the 14-day non-recovery range-finding study were 0, 1000, 2000 and 4000 mg test article/kg body weight (bw)/day for 14 days. There was a non-statistically significant (p > 0.05) decrease in body weights for the male and female rats receiving the test article. Hypoactivity, hyperactivity, reduced food consumption and piloerection were observed in the rats receiving 4000 mg test article/kg bw. Histopathology showed an increase in the size of liver cells (hypertrophy) around the central vein (centrilobular) in Groups 3 (3/10) and 4 (5/10) that correlated with increased liver weights. In the 90-day study, 8 groups of rats were dosed with 0, 200, 400 and 800 mg test article/kg bw/day. Groups 5 to 8 had a 28-day recovery. There were no test article-linked changes in clinical observations, physical examinations, Functional Observation Battery, ophthalmology, Motor Activity Assessment, hematology, clinical chemistries and macropathology (all groups). With the exception of the liver and adrenal gland, no test article-linked pathology was observed. For all rats receiving the test article, histopathology showed hypertrophy of liver cells around the central vein. The increase of liver weight is most likely caused by hypertrophy due to up-regulation of the hepatic drug metabolizing enzymes. The hepatocellular hypertrophy was completely reversed in 28 days and was not considered to be an adverse effect. Vacuolization of the adrenal zona fasciculata was observed in the control and 800 mg test article/kg bw groups. The vacuolization of the zona fasciculata was of the same incidence and severity in treatment and control male rats and correlated with an increased in the weights of the adrenal glands. In addition, a statistically significant increase (p<0.05) in adrenal-to-body weight ratios was observed for females receiving 800 mg test article/kg bw. This increase in adrenal-to-body weight ratio did not correlate with any of the pathology findings. The NOAEL for the test article is 800 mg/kg bw/day for female and 400 mg/kg bw/day for male Sprague Dawley rats.
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Project description:Bisphenol A (BPA) is a high production volume industrial chemical to which there is widespread human oral exposure. Guideline studies used to set regulatory limits detected adverse effects only at doses well above human exposures and established a no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day. However, many reported animal studies link BPA to potentially adverse effects on multiple organ systems at doses below the NOAEL. The primary goals of the subchronic study reported here were to identify adverse effects induced by orally (gavage) administered BPA below the NOAEL, to characterize the dose response for such effects and to determine doses for a subsequent chronic study. Sprague Dawley rat dams were dosed daily from gestation day 6 until the start of labor, and their pups were directly dosed from day 1 after birth to termination. The primary focus was on seven equally spaced BPA doses (2.5-2700 μg/kg bw/day). Also included were a naïve control, two doses of ethinyl estradiol (EE2) to demonstrate the estrogen responsiveness of the animal model, and two high BPA doses (100,000 and 300,000 μg/kg bw/day) expected from guideline studies to produce adverse effects. Clear adverse effects of BPA, including depressed gestational and postnatal body weight gain, effects on the ovary (increased cystic follicles, depleted corpora lutea, and antral follicles), and serum hormones (increased serum estradiol and prolactin and decreased progesterone), were observed only at the two high doses of BPA. BPA-induced effects partially overlapped those induced by EE2, consistent with the known weak estrogenic activity of BPA.
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Project description:Novel forms of fibrillated cellulose offer improved attributes for use in foods. Conventional cellulose and many of its derivatives are already widely used as food additives and are authorized as safe for use in foods in many countries. However, novel forms have not yet been thoroughly investigated using standardized testing methods. This study assesses the 90-day dietary toxicity of fibrillated cellulose, as compared to a conventional cellulose, Solka Floc. Sprague Dawley rats were fed 2 %, 3 %, or 4 % fibrillated cellulose for 90 consecutive days, and parallel Solka Floc groups were used as controls. Survival, clinical observations, body weight, food consumption, ophthalmologic evaluations, hematology, serum chemistry, urinalysis, post-mortem anatomic pathology, and histopathology were monitored and performed. No adverse observations were noted in relation to the administration of fibrillated cellulose. Under the conditions of this study and based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for fibrillated cellulose was 2194.2 mg/kg/day (males) and 2666.6 mg/kg/day (females), corresponding to the highest dose tested (4 %) for male and female Sprague Dawley rats. These results demonstrate that fibrillated cellulose behaves similarly to conventional cellulose and raises no safety concerns when used as a food ingredient at these concentrations.
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Project description:Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.
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Project description:To evaluate the acute and chronic 28-day repeated-dose oral toxicity of Guixiong Yimu San (GYS) in mice and rats, high-performance liquid chromatography (HPLC) was used to determine the stachydrine hydrochloride in GYS as the quality control. In the acute toxicity trial, the mice were administered orally at a dose rate of 30.0 g GYS/kg body weight (BW) three times a day. The general behavior, side effects, and death rate were noticed for 14 days following treatment. In the subacute toxicity trial, the rats were administered orally at a dose rates of30.0, 15.0, and 7.5 g GYS/kg BW once a day for 28 days. The rats were monitored every day for clinical signs and deaths; changes in body weight and relative organ weights (ROW) were recorded every week, hematological, biochemical, and pathological parameters were also examined at the end of treatment. The results showed that the level of stachydrine hydrochloride in GYS was 2.272 mg/g. In the acute toxicity trial, the maximum-tolerated dose of GYS was more than 90.0 g/kg BW, and no adverse effects or mortalities were noticed during the 14 days in the mice. At the given dose, there were no death or toxicity signs all through the 28-day subacute toxicity trial.The oral administration of GYS at a dose rate of 30.0 g/kg/day BW had no substantial effects on BW, ROW, blood hematology, gross pathology, histopathology, and biochemistry (except glucose), so 30.0 g/kg BW/day was determined as the no-observed-adverse-effect dosage.
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Project description:The use of flavoring substances is an important element in the development of reduced-risk products for adult smokers to increase product acceptance and encourage switching from cigarettes. In a first step towards characterizing the sub-chronic inhalation toxicity of neat flavoring substances, a study was conducted using a mixture of the substances in a base solution of e-liquid, where the standard toxicological endpoints of the nebulized aerosols were supplemented with transcriptomics analysis. The flavor mixture was produced by grouping 178 flavors into 26 distinct chemical groups based on structural similarities and potential metabolic and biological effects. Flavoring substances predicted to show the highest toxicological effect from each group were selected as the flavor group representatives (FGR). Following Organization for Economic Cooperation and Development Testing Guideline 413, rats were exposed to three concentrations of the FGR mixture in an e-liquid composed of nicotine (23 µg/L), propylene glycol (1520 µg/L), and vegetable glycerin (1890 µg/L), while non-flavored and no-nicotine mixtures were included as references to identify potential additive or synergistic effects between nicotine and the flavoring substances. The results indicated that the inhalation of an e-liquid containing the mixture of FGRs caused very minimal local and systemic toxic effects. In particular, there were no remarkable clinical (in-life) observations in flavored e-liquid-exposed rats. The biological effects related to exposure to the mixture of neat FGRs were limited and mainly nicotine-mediated, including changes in hematological and blood chemistry parameters and organ weight. These results indicate no significant additive biological changes following inhalation exposure to the nebulized FGR mixture above the nicotine effects measured in this sub-chronic inhalation study. In a subsequent study, e-liquids with FGR mixtures will be aerosolized by thermal treatment and assessed for toxicity.
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Project description:N-Butylbenzenesulfonamide (NBBS) is widely used as a plasticizer in polyacetals, polyamides, and polycarbonates and has been found in ground water and effluent from wastewater treatment sites. The compound is lipophilic and distributes rapidly to the brain but also clears rapidly and shows little evidence of accumulation. Limited studies in the literature report neurotoxicity of NBBS in rabbits and rats. Adult Sprague-Dawley male rats (Harlan) received corn oil vehicle or NBBS (100, 200, or 400mg/kg/d) via oral gavage (5 ml/kg bwt) daily/5d/week for 27 d. Deaths were observed in the 400mg/kg/d dose group in the first 5d and dosing was decreased to 300 mg/kg/d. No alterations were observed in gait, locomotor activity, and rearing behavior. No histological lesions were observed in the testis, seminal vesicles, coagulating gland, epididymis, and prostate. In the liver, minimal centrilobular hypertrophy was evident in all rats of the high dose group. Contrary to previous reports, there was no evidence of peripheral nerve lesions or gliosis in the hippocampus or cerebellum. mRNA levels for glial fibrillary acidic acid protein, interferon gamma, CXCR-3, intracellular adhesion molecule-1, and CD11b were not altered in the hippocampus while Iba-1 levels were decreased. These data do not support previous reports of neurotoxicity for NBBS within a 4-week exposure regimen; however, neuropathological injury occurring over an extended period of exposure cannot be ruled out and given the potential for human exposure requires further examination.
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