High-dose Female Rats Research Articles

Four-week intravenous repeated dose toxicity study of vitacamphorae injection in rats.

The study was undertaken to evaluate the safety of vitacamphorae (VCP) injection in Sprague-Dawley (SD) rats. Rats were intravenously administered with VCP at the doses of 0, 5, 15, and 50mg/kg/day (equivalent to 0, 5, 15, and 50 times the clinical equivalent dose) for 4weeks, respectively. In addition, we also tested oxidative stress-related parameters and cytokine levels in rat serum. In the current study, intravenous administration of VCP at a dose of 50mg/kg/day caused significant pathophysiological responses in rats. Compared with the control group, different doses of VCP exposure had no significant effect on body weight, food consumption, and clinic pathology of rats after 4weeks of VCP administration. Rats in high-dose group (50mg/kg/day) showed general symptoms of convulsions after VCP administration. The toxicological significance of VCP exposure in the spleen of high-dose female rats was observed, which showed a significant increase in the relative spleen weights (P < 0.01) and mild lymphocyte proliferation in splenic pathology. Furthermore, the results of oxidative stress and cytokine detection showed that the levels of antioxidant enzymes SOD increased in each administration group, but the levels of a series of pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-12, and IFN-γ also increased in these groups. Above changes caused by VCP exposure can be reversed after 4weeks of recovery. Overall, the results showed that the no-observed-adverse-effect-level (NOAEL) of VCP injection for 4-week toxicity was 15mg/kg/day.

Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis-stimulating agent in monkeys and rats

EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025mg/kg. The study findings at 0.2mg/kg for rats and 0.3mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical studies.

A peripherally restricted P2Y12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

BackgroundTicagrelor is an orally available, direct acting and reversible P2Y12 receptor antagonist approved for treatment of acute coronary syndrome. The objectives of these studies were to (1) evaluate the Ticagrelor 2-year rat carcinogenicity bioassay data; (2) investigate potential mode of action (MOA) and (3) interpret human relevance. MethodsThe following studies were done (1) rat two-year carcinogenicity study in male and female rats, (2) in vitro and in vivo genotoxicity assays, (3) quantitative whole body autoradiography (QWBA; male and female rats), (4) in vitro pharmacological profiling for more than 300 assays, and (5) in vivo ovariectomized rat assay. ResultsThe carcinogenicity study indicated Ticagrelor increased uterine tumor incidence while decreasing mammary and pituitary tumors/hyperplasia incidences in only high dose female rats. However, this altered tumor incidences were not P2Y12 target related since marketed non-reversible P2Y12 receptor antagonists were not associated with alter tumor incidences. MOA studies determined Ticagrelor exposure in the anterior pituitary and Ticagrelor was (1) non-genotoxic, (2) peripherally-restricted, (3) a dopamine transport (DAT) inhibitor with an IC50 lower than systemic free exposure in the rat carcinogenic study and more than a log higher than the free systemic exposure seen in clinical trials and (4) an inhibitor of estradiol-induced prolactin secretion. DiscussionSimilar to Ticagrelor, centrally active dopamine agonists induce the same altered tumor incidence patterns that according to literature do not translate into the clinical setting, with a MOA involving decreased prolactin secretion. The Ticagrelor MOA data and literature suggest that altered dopamine levels in the hypophyseal part of the hypothalamus–hypophyseal axis (by Ticagrelor) will result in similar altered tumor incidences in rat that do not translate into the clinical setting, based on qualitative species differences. In conclusion Ticagrelor increased uterine tumors in the rat carcinogenesis study by a MOA consistent with reduced dopamine inhibition of prolactin, which is not a patient safety risk.

Lung Function Changes in Sprague-Dawley Rats After Prolonged Inhalation Exposure to Silver Nanoparticles

The antimicrobial activity of silver nanoparticles has resulted in their widespread use in many consumer products. However, despite the continuing increase in the population exposed to silver nanoparticles, the effects of prolonged exposure to silver nanoparticles have not been thoroughly determined. Accordingly, this study attempted to investigate the inflammatory responses and pulmonary function changes in rats during 90 days of inhalation exposure to silver nanoparticles. The rats were exposed to silver nanoparticles (18 nm diameter) at concentrations of 0.7 × 106 particles/cm3 (low dose), 1.4 × 106 particles /cm3 (middle dose), and 2.9 × 106 particles /cm3 (high dose) for 6 h/day in an inhalation chamber for 90 days. The lung function was measured every week after the daily exposure, and the animals sacrificed after the 90-day exposure period. Cellular differential counts and inflammatory measurements, such as albumin, lactate dehydrogenase (LDH), and total protein, were also monitored in the acellular bronchoalveolar lavage (BAL) fluid of the rats exposed to the silver nanoparticles for 90 days. Among the lung function test measurements, the tidal volume and minute volume showed a statistically significant decrease during the 90 days of silver nanoparticle exposure. Although no statistically significant differences were found in the cellular differential counts, the inflammation measurements increased in the high-dose female rats. Meanwhile, histopathological examinations indicated dose-dependent increases in lesions related to silver nanoparticle exposure, such as infiltrate mixed cell and chronic alveolar inflammation, including thickened alveolar walls and small granulomatous lesions. Therefore, when taken together, the decreases in the tidal volume and minute volume and other inflammatory responses after prolonged exposure to silver nanoparticles would seem to indicate that nanosized particle inhalation exposure can induce lung function changes, along with inflammation, at much lower mass dose concentrations when compared to submicrometer particles.

Comparative chronic toxicity and carcinogenicity of acrylonitrile by drinking water and oral intubation to Spartan® Sprague–Dawley rats

Comparative chronic toxicity and carcinogenicity of acrylonitrile by drinking water and oral intubation to Spartan® Sprague–Dawley rats

A subchronic toxicity study of Phosflex 51B in Sprague-Dawley rats.

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 liver 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 liver, 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.

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate. Matthews, H. B., Eustis, S. L., and Haseman, J. (1993). Fundam. Appl. Toxicol. 20, 477-485.Previous short-term studies of tris(2-chloroethyl)phosphate (TRCP), a flame retardant used in industrial and consumer products, demonstrated that repeated administration of 350 mg TRCP/kg body wt by oral gavage resulted in necrosis of pyramidal neurons in the CA1 region of the hippocampus of F344 rats, but not in B6C3F1 mice. The 2-year studies reported here were designed to characterize the chronic toxicity and potential carcinogenicity of TRCP in each sex of F344 rats and B6C3F1 mice. Groups of 60 rats per sex received 0, 44, or 88 mg/kg by oral gavage, once per day, 5 days per week, for up to 103 weeks. Groups of 60 mice per sex received 0, 175, or 350 mg/kg by oral gavage on the same dosing schedule. Each of these groups contained 10 animals which were euthanized at 66 weeks. The principal toxic effects of chronic exposure of rats to TRCP occurred in the brain and kidney. In contrast to the findings in the 16-week studies, a hippocampal lesion was not observed in the brain, although degenerative lesions were widely distributed in the gray and white matter of the brain stem and cerebral cortex of high-dose female and, to a lesser extent, male rats. These findings suggest that the hippocampal necrosis may be dependent upon the size of the individual doses or may have a pathogenesis different from that of the lesions in the brain stem and cerebral cortex. The other primary effect of chronic exposure was a dose-dependent increased incidence of renal tubule hyperplasia and adenoma. Renal tubule neoplasms, primarily adenomas, were observed in 4% of control, 10% of low-dose, and 50% of high-dose male rats and in 0% of control, 4% of low-dose, and 10% of high-dose female rats. There were also marginal increases in mononuclear cell leukemia and in thyroid follicular neoplasms in dosed male and female rats that were not clearly related to TRCP administration. Mice were less sensitive to TRCP than rats and lesions attributable to chemical administration in mice were limited to a dose-dependent increased incidence of karyomegaly (nuclear enlargement) in epithelial cells of proximal tubules in the inner cortex and outer stripe of the outer medulla of the kidneys both sexes. Marginal increases in the incidence of renal tubule neoplasms in male mice and harderian gland neoplasms in female mice were not considered clearly related to TRCP administration.

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate

Previous short-term studies of tris(2-chloroethyl)phosphate (TRCP), a flame retardant used in industrial and consumer products, demonstrated that repeated administration of 350 mg TRCP/kg body wt by oral gavage resulted in necrosis of pyramidal neurons in the CA1 region of the hippocampus of F344 rats, but not in B6C3F1 mice. The 2-year studies reported here were designed to characterize the chronic toxicity and potential carcinogenicity of TRCP in each sex of F344 rats and B6C3F1 mice. Groups of 60 rats per sex received 0, 44, or 88 mg/kg by oral gavage, once per day, 5 days per week, for up to 103 weeks. Groups of 60 mice per sex received 0, 175, or 350 mg/kg by oral gavage on the same dosing schedule. Each of these groups contained 10 animals which were euthanized at 66 weeks. The principal toxic effects of chronic exposure of rats to TRCP occurred in the brain and kidney. In contrast to the findings in the 16-week studies, a hippocampal lesion was not observed in the brain, although degenerative lesions were widely distributed in the gray and white matter of the brain stem and cerebral cortex of high-dose female and, to a lesser extent, male rats. These findings suggest that the hippocampal necrosis may be dependent upon the size of the individual doses or may have a pathogenesis different from that of the lesions in the brain stem and cerebral cortex. The other primary effect of chronic exposure was a dose-dependent increased incidence of renal tubule hyperplasia and adenoma. Renal tubule neoplasms, primarily adenomas, were observed in 4% of control, 10% of low-dose, and 50% of high-dose male rats and in 0% of control, 4% of low-dose, and 10% of high-dose female rats. There were also marginal increases in mononuclear cell leukemia and in thyroid follicular neoplasms in dosed male and female rats that were not clearly related to TRCP administration. Mice were less sensitive to TRCP than rats and lesions attributable to chemical administration in mice were limited to a dose-dependent increased incidence of karyomegaly (nuclear enlargement) in epithelial cells of proximal tubules in the inner cortex and outer stripe of the outer medulla of the kidneys both sexes. Marginal increases in the incidence of renal tubule neoplasms in male mice and harderian gland neoplasms in female mice were not considered clearly related to TRCP administration.

Carcinogenicity study in rats of phytic acid ‘Daiichi’, a natural food additive

The carcinogenicity of phytic acid ‘Daiichi’ (PA), a natural food additive, was examined in Fischer 344 rats of both sexes. PA was added to the drinking-water of groups of 60 male and 60 female rats at levels of 1.25 or 2.5% for 100 108 wk. There was a dose-dependent reduction in the mean final body weights of rats treated with PA. Necrosis and calcification of the renal papillae were observed in PA-treated rats, but not in the controls. The incidences of necrosis (calcification) were as follows: one (three) out of 57 males given 2.5% PA; one (none) out of 59 males given 1.25% PA; 10 (17) out of 55 females given 2.5% PA; six (six) out of 58 females given 1.25% PA. Renal papillomas occurred in three of the high-dose male rats, four of the high-dose female rats, and three of the low-dose female rats. The development of papillomas seemed to be related to calcification and necrosis of the renal papillae induced by PA. While many other tumours developed in all groups, including the controls, the organ distribution of these neoplasms and their histological characteristics did not differ significantly from those known to occur spontaneously in this strain of rats.

Chronic toxicity studies with thiram in Wistar rats and beagle dogs

Groups of 64 male and 64 female Wistar rats were given thiram at constant dietary doses of 0, 3, 30, and 300 ppm (0, 0.1, 1.2, and 11.6 mg/kg/day for males and 0, 0.1, 1.4, and 13.8 mg/kg/day for females) for 104 weeks. Eight males and eight females in each group were killed after Weeks 13, 26, and 52. For the dog study, four male and four female beagle dogs were allotted to each group and treated with the compound at 0, 0.4, 4, and 40 mg/kg/day for 104 weeks. The dogs in the 40 mg/kg/day group had severe toxic signs, including nausea or vomiting, salivation, and occasional clonic convulsion, and all were subjected to unscheduled necropsy before Day 203 of treatment. The dogs also had ophthalmological changes such as fundal hemorrhage, miosis, and desquamation of the retina which were consistent with the retinal lesions shown by histopathology. The rats of the high-dose group had retarded growth with a slightly decreased food intake. Anemia was evident in highdose female rats and in middle- and high-dose dogs. Liver failure in male and female dogs and kidney damage in female dogs were detected in middle- and high-dose groups by blood biochemistry and/or histopathology. Regressive changes of the sciatic nerve accompanied by atrophy of the calf muscle were seen in female rats of the high-dose group but not in male rats. In high-dose rats, progression of myocardial lesions of the heart and chronic nephrosis of the kidney were depressed in males and females, respectively. Female rats of the middle- and high-dose groups had decreased occurrences of mammary fibroadenoma and decreased development of skin masses.

Chronic Toxicity Studies with Thiram in Wistar Rats and Beagle Dogs

Chronic Toxicity Studies with Thiram in Wistar Rats and Beagle Dogs. Maita, K., Tsuda, S., and Shirasu, Y. (1991). Fundam. Appl. Toxicol. 16, 667–686. Groups of 64 male and 64 female Wistar rats were given thiram at constant dietary doses of 0, 3, 30, and 300 ppm (0, 0.1, 1.2, and 11.6 mg/kg/day for males and 0, 0.1, 1.4, and 13.8 mg/kg/day for females) for 104 weeks. Eight males and eight females in each group were killed after Weeks 13, 26, and 52. For the dog study, four male and four female beagle dogs were allotted to each group and treated with the compound at 0, 0.4, 4, and 40 mg/kg/day for 104 weeks. The dogs in the 40 mg/kg/day group had severe toxic signs, including nausea or vomiting, salivation, and occasional clonic convulsion, and all were subjected to unscheduled necropsy before Day 203 of treatment. The dogs also had ophthalmological changes such as fundal hemorrhage, miosis, and desquamation of the retina which were consistent with the retinal lesions shown by histopathology. The rats of the high-dose group had retarded growth with a slightly decreased food intake. Anemia was evident in high-dose female rats and in middle- and high-dose dogs. Liver failure in male and female dogs and kidney damage in female dogs were detected in middle- and high-dose groups by blood biochemistry and/or histopathology. Regressive changes of the sciatic nerve accompanied by atrophy of the calf muscle were seen in female rats of the high-dose group but not in male rats. In high-dose rats, progression of myocardial lesions of the heart and chronic nephrosis of the kidney were depressed in males and females, respectively. Female rats of the middle- and high-dose groups had decreased occurrences of mammary fibroadenoma and decreased development of skin masses.

No evidence of toxicity or carcinogenicity of pentaerythritol tetranitrate given in the diet to F344 rats and B6C3F1 mice for up to two years

Toxicology and carcinogenesis studies of pentaerythritol tetranitrate (PETN), an organic nitrate used in explosives and as a therapeutic agent for angina pectoris, were conducted by administering diets containing PETN,NF (National Formulary Grade, a 1:4 mixture of PETN and lactose) to both sexes of F344 rats and B6C3F1 mice in 14-day, 13-week and 2-year studies. PETN was found to be essentially non-toxic in 14-day and 13-week studies at dietary concentrations as high as 10,000 ppm; the weight gain of female rats was lower than that of controls at 5000 and 10,000 ppm in the 13-week study. In the 13-week studies, one in ten high-dose female rats had an adenoma of the Zymbal gland and one in ten high-dose female mice had a hepatocellular adenoma. Dietary concentrations chosen for the 2-year studies were 5000 and 10,000 ppm for male rats and male and female mice, and 1240 and 2500 ppm for female rats. In the 2-year studies, there were no adverse effects on survival or body weight gains in either sex of rats or mice. No neoplastic or non-neoplastic lesions were considered to be related clearly to PETN administration. Neoplasms of the Zymbal gland occurred at low incidences in PETN-exposed groups of both sexes of rats in the 2-year study.

A 13-week vapor inhalation study of 3,3-dimethyl-2-butanol in Sprague-Dawley rats.

Four groups of male and female Sprague-Dawley rats were exposed for 13 weeks to 3,3-dimethyl-2-butanol (PA) at concentrations of 0.00, 0.20, 1.00 or 5.00 mg/l (1 mg/l = 240 ppm). Exposures were for 6 hr per day, 5 days per week with sacrifices at 7 and 13 weeks of exposure, and at 4 weeks after exposure. The test animals were evaluated for abnormalities in physiology, behaviour, clinical laboratory parameters, and gross and microscopic morphology. No abnormalities were detected in electrocardiograms, respiratory indices, spontaneous activity, passive avoidance activity and open-field behaviour. Clinical signs related to PA exposure included alopecia, ataxia and lacrimation. There were no biologically significant between-group differences in body-weights during the study. The clinical laboratory data demonstrated a 30% increase in serum cholesterol and bilirubin at 7 weeks in high-dose males and an increase in urea nitrogen in intermediate and high-dose males at 13 weeks. There were no abnormalities in hematologic or coagulation parameters. At necropsy there were no significant gross abnormalities; however, examination of organ weights revealed enlarged kidneys in high-dose male rats at 13 weeks, enlarged ovaries in high-dose female rats at 13 weeks, and microscopic study of tissue sections revealed minimal to mild renal tubular injury in high and possibly intermediate dose males at several sacrifices. These findings suggest that the primary target organ of PA, when given by inhalation, is the kidney in male rats and possibly the ovary in female rats. The renal changes in the high-dose males were not fully reversible during the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice

These studies were performed to assess the chronic toxicity and oncogenicity of ethylene glycol (EG) in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-1 mice per sex were fed diets yielding approximate dosages of 1.0, 0.2, or 0.04 g/kg/day of EG. Two separate control groups in each study received no EG. Mortality rate was increased in high-dose male rats all of which died by 475 days. The following effects were also observed in high dose male rats: reduced body weight gain, increased water intake, increased blood urea nitrogen and creatinine, reduced erythrocyte count, reduced hematocrit and hemoglobin, increased neutrophil count, increased urine volume, reduced specific gravity and pH. Urinary calcium oxalate crystals and increased kidney weight were seen in all high-dose rats. Uric acid crystals were seen in the urine of high-dose female rats at 18 and 24 months. Histopathologic changes in high-dose male rats included tubular cell hyperplasia, tubular dilation, peritubular nephritis, parathyroid hyperplasia, and generalized soft tissue mineralization. Fatty change of the liver was seen in high- and intermediate-dose female rats. No clinical signs, or gross or microscopic evidence of toxicity was seen in mice at the dosages used. Water intake and clinical pathologic parameters were not measured in the mouse study. In these studies there was no evidence of an oncogenic effect of EG in rodents.

Effects of chronic inhalation of dimethyl ether in the rat

Dimethyl ether (DME) is a colourless gas with an ethereal odour. It is used mainly as a liquid refrigerant and an aerosol dispersant. Little or no data exist on the toxicology of this material. In the present study, groups of male and female rats were exposed to 0.02%, 0.2% and 2% v/v of DME in air, 6 h/day, 5 days/week for 30 weeks. At the end of the study the high-dose level male rats showed a significant reduction on liver weight compared with the control group; this was accompanied by raising SGPT levels. In high-dose female rats there was no significant effect on liver weight but the SGPT levels were raised above control values. No histological abnormalities were observed in the liver or in any other organ.