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Shizuoka-shi, Japan

Matsumoto M.,Japan National Institute of Health Sciences | Serizawa H.,Bozo Research Center Inc | Sunaga M.,Safety Research Institute for Chemical Compounds Co. | Kato H.,Japan National Institute of Health Sciences | And 5 more authors.
Journal of Toxicological Sciences | Year: 2012

Three female Crl:CD(SD) rats/group were dosed with single wall carbon nanotube (SWCNT) or multi wall carbon nanotube (MWCNT) four times by gavage at a total of 50 mg/kg bw or 200 mg/kg bw (four equally divided doses at one-hour intervals). Acute oral doses of SWCNT and MWCNT caused neither death nor toxicological effects, and thus the oral LD50 values for SWCNT and MWCNT were considered to be greater than 50 mg/kg bw and 200 mg/kg bw, in rats respectively. Five or ten Crl:CD(SD) rats/sex were dosed with SWCNT once daily by gavage at a dose of 0 (control), 0.125, 1.25 or 12.5 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 12.5 mg/kg bw/day groups). Six or twelve Crl:CD(SD) rats/sex were dosed with MWCNT once daily by gavage at a dose of 0 (control), 0.5, 5.0 or 50 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 50 mg/kg bw/day groups). Based on no toxicological effects, the no observed adverse effect levels (NOAELs) of repeated dose toxicity of SWCNT and MWCNT were considered to be 12.5 mg/kg bw/day and 50 mg/kg bw/day (the highest dose tested), respectively. It was suggested that SWCNT and MWCNT dosed by gavage reached the gastro-intestinal tract as agglomerates and were mostly excreted via feces. Source


Ishida S.,Bozo Research Center Inc | Sarada M.,BML Inc. | Seki H.,BML Inc. | McGirr L.,Intertek | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2013

l-Ornithine monohydrochloride was evaluated in two in vitro genotoxicity assays and a rat 90-day oral toxicity study.No evidence of genotoxicity was observed in the reverse bacterial mutation assay or the chromosome aberration test at doses of up to 5000. μg/plate or 1686. μg/mL, respectively, both in the presence and absence of metabolic activation.Rats were administered l-ornithine monohydrochloride at dietary concentrations of 0 (basal diet), 1.25%, 2.5%, or 5.0% for 90. days. No changes in body weight, food consumption, ophthalmoscopy, or hematology were observed. Transient increases in water intake and urinary volume, and a decrease in specific gravity were observed in males receiving 5.0% l-ornithine monohydrochloride; however, these were likely attributable to the central role of ornithine in the urea cycle and the consequent increase in urea production. A decrease in serum chloride concentration and an increase in urinary chloride excretion were observed; however, these were likely attributable to administration of the hydrochloride salt of ornithine and were not considered to be of any toxicological significance. No remarkable findings were noted at necropsy.Based on the results of the study, a no-observed-adverse effect level (NOAEL) of 3445 and 3986. mg/kg body weight/day was established for male and female rats. © 2013 Elsevier Inc. Source


Nakamura R.,Asubio Pharma Co. | Nishimura T.,Asubio Pharma Co. | Ochiai T.,Asubio Pharma Co. | Nakada S.,Daiichi Sankyo | And 2 more authors.
Journal of Toxicologic Pathology | Year: 2013

In rats, it is sometimes difficult to distinguish malignant reticuloses from astrocytomas in routine histopathological assessment. In the present study, four spontaneous brain neoplasms developing in the cerebrum of one Wistar Hannover rat and three Sprague-Dawley rats were immunohistochemically examined using microglia and macrophage markers. Histopathologically, these neoplasms were localized mainly in the cerebral cortex, hypothalamus or piriform lobe, and the portions showing solid growth did not show characteristic cellular arrangement but had an indistinct boundary with the surrounding brain parenchyma. Neoplastic cells had oval or pleomorphic small nuclei with abundant eosinophilic cytoplasm. Two cases showed neoplastic cell infiltration into the meninges and perivascular spaces. Silver staining showed lack of reticulin fiber production in the stroma of the neoplasms. Immunohistochemically, the neoplastic cells were strongly positive for Iba-1 and sporadically positive for CD68 in all four cases. On the basis of these results, all the neoplasms examined here could be distinguished from astrocytomas and diagnosed as malignant reticuloses. Thus, immunohistochemical demonstration of microglia/macrophage characters, such as using Iba-1, is considered to be helpful for differential diagnosis of malignant reticuloses from astrocytomas among spontaneously occurring primary brain neoplasms in rats. ©2013 The Japanese Society of Toxicologic Pathology. Source


Ohishi T.,Tokyo University of Agriculture and Technology | Ohishi T.,Bozo Research Center Inc | Wang L.,Tokyo University of Agriculture and Technology | Akane H.,Tokyo University of Agriculture and Technology | And 6 more authors.
Reproductive Toxicology | Year: 2012

To examine the effects of developmental manganese (Mn)-exposure on hippocampal neurogenesis, pregnant rats were treated with MnCl2·4H2O in the diet at 32, 160 or 800ppm from gestation day 10 to day 21 after delivery. Serum concentrations of thyroid-related hormones were examined in offspring exposed to MnCl2·4H2O at 800 or 1600ppm. Immunohistochemical analysis revealed increased doublecortin-positive cells in the subgranular zone of the dentate gyrus on postnatal day (PND) 21 following exposure to MnCl2·4H2O at 800ppm, indicating an increase of type-3 progenitor or immature granule cells. Reelin-positive cells, suggestive of γ-aminobutyric acid-ergic interneurons in the dentate hilus, also increased at 800ppm on PND 21. Brain Mn concentrations increased in offspring on PND 21 at 160 and 800ppm, whereas brain concentrations in the dams were unchanged. Serum concentrations of triiodothyronine and thyroxine decreased at 800 and 1600ppm, whereas thyroid-stimulating hormone increased only after exposure at 800ppm. All changes disappeared on PND 77. Thus, maternal exposure to MnCl2·4H2O at 800ppm mildly and reversibly affects neurogenesis targeting late-stage differentiation in the hippocampal dentate gyrus of rat offspring. Direct effects of accumulated Mn in the developing brain might be implicated in the mechanism of the development of aberrations in neurogenesis; however, indirect effects through thyroid hormone fluctuations might be rather minor. © 2012 Elsevier Inc. Source


Katsumata T.,Bozo Research Center Inc | Ishibashi T.,Nippon Oil Corporation | Kyle D.,Kyle Consulting Services
Toxicology Reports | Year: 2014

Astaxanthin is believed to be beneficial to human health because it possesses strong antioxidant properties. A natural astaxanthin-rich carotenoid extract (ARE) was produced by a well-controlled fermentation of a natural bacteria Paracoccus carotinifaciens, followed by the extraction and enrichment of the final product comprising mixture of carotenoids that is predominantly astaxanthin. The aim of this study was to evaluate the sub-chronic toxicity of the ARE using 6 week old Sprague-Dawley SPF rats [Crl:CD(SD)]. The test article was suspended in olive oil and administered daily to the rats by oral gavage for 13 weeks at doses of 0 (olive oil), 250, 500 or 1000. mg/kg/day. Each group consisted of 10 animals of each sex. No deaths occurred and no treatment-related changes were observed in the detailed clinical observations, manipulative tests, grip strength, motor activity, body weights, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weight, necropsy or histopathology. Dark-red feces were observed throughout the administration period in all treated groups due to excretion of the colored test article. Based on these results, it was concluded that the no observed adverse effect level (NOAEL) for ARE was at least 1000. mg/kg/day for male and female rats, respectively. © 2014 The Authors. Source

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