CKD‐501, a novel selective PPARγ agonist,shows no carcinogenic potential in ICR mice following oral administration for 104 weeks

CKD‐501 is a peroxisome proliferator‐activated receptor gamma (PPARγ) agonist that is effective for the treatment of diabetes. However, its carcinogenic potential remains controversial. The current carcinogenicity study was conducted over a period of 104 weeks in ICR mice. Three groups, each consisting of 60 male and 60 female mice, received oral CKD‐501 dosages of 0.2, 1.0 or 6.0 mg kg^?1day^–1. The mortality rates of the male control, 0.2, 1.0 and 6.0 mg kg^–1 day^–1 treated groups were 60%, 68%, 58% and 67%, respectively and 57%, 68% and 67% in the female control, 0.2 and 1.0 mg kg^?1 day^–1 treated groups. It was 67% in the female 6.0 mg kg^?1 day^–1 treated group, which was terminated at week 98 due to its increased mortality rate. No significant treatment‐related effects were observed on the survival rates, with the exception of females in the 6.0 mg kg^?1 day^–1 group. Body weights increased in females receiving 1.0 and 6.0 mg kg^?1 day^–1 due to the class effects of the PPARγ agonist. Differences were not found in hematology parameters between the CKD‐501‐treated groups and their corresponding controls, but the histopathological evidence did not reveal any findings attributed to CKD‐501. Treated animals exhibited non‐neoplastic findings (adipocyte proliferation, bone marrow hypoplasia cardiomyopathy), but all of these were expected changes for this class of compound. There were no treatment‐related neoplastic changes in this study. The results of this study therefore demonstrate a lack of carcinogenicity following oral administration of CKD‐501 to ICR mice for 104 weeks. Copyright © 2013 John Wiley & Sons, Ltd.     

Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment

Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2‐year bioassay for TBBPA. The objective of the present study was to develop a cancer‐based and a non‐cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2‐year and 13‐week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg^?1 day^?1 based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg^?1 day^?1 based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E^?7 to 3.9 E^?6 mg kg^?1 day^?1 based on age‐adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E ^?7 to 8.4 E^?5 mg kg^?1 day^?1. Resulting margin of exposure (MOE) values were > 800 000 for non‐cancer endpoints and > 32 000 000 for cancer‐based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA. Copyright © 2015. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.     

Safety assessment of aditoprim acute,subchronic toxicity and mutagenicity studies

Aditoprim (ADP), a new developed dihydrofolate reductase (DHFR) inhibitor, has great potential in clinical veterinary medicine because of its greater pharmacokinetic properties than structural analogs. Preclinical toxicology studies were performed to assess the safety of ADP including an acute oral toxicity test, a subchronic toxicity test and five mutagenicity tests. In the acute oral toxicity test, ADP was administered singly by oral gavage to Wistar rats and Kunming mice. The LD₅₀ calculated was 1400 mg kg^–1 body weight (BW) day^–1 in rats and 1130 mg kg^–1 BW day^–1 in mice. In a subchronic study, Wistar rats were administered ADP at dose levels of 0, 20, 100 and 1000 mg kg^–1 diet for 90 days. Significant decreases were observed on body weight and food efficiency in the high‐dose group. Treatment‐related changes in clinical serum biochemistry were found in the medium‐ and high‐dose groups. Significant increases in the relative weights of livers and kidneys in females and testis in males in the 1000 mg kg^–1 diet, and significant decrease in relative weights of livers in males in the 100 mg kg^–1 diet were noted. Histopathological observations revealed that the 1000 mg kg^–1 ADP diet could induce lymphocytic infiltration and hepatocytic necrosis near the hepatic portal area. The genotoxicity of ADP was negative in tests, such as the bacterial reverse mutation assay, mice bone marrow erythrocyte micronucleus assay, in vitro chromosomal aberration test, in vitro cho/hgprt mammalian cell mutagenesis assay and mice testicle cells chromosome aberration. Based on the subchronic study, the no‐observed‐adverse‐effect level for ADP was a 20 mg kg^–1 diet, which is about 1.44‐1.53 mg kg^–1 BW day^–1 in rats. Copyright © 2015 John Wiley & Sons, Ltd.     

Evaluation of the Developmental Toxicity of 8-2 Telomer B Alcohol

The potential maternal and developmental toxicity of 8-2 Telomer B Alcohol was assessed in rats. Groups of 22 time-mated female Crl:CD (SD)IGS BR rats were administered oral gavage doses as suspensions of 8-2 Telomer B Alcohol in aqueous 0.5% methylcellulose from day 6 through 20 of gestation (G) at daily doses of either 0, 50, 200, or 500 mg/kg. Under the conditions of this study, adverse maternal toxicity was produced at 500 mg kg^{? 1} day^{? 1} and consisted of maternal mortality, decreased body weights and body weight gains, and increased clinical observations of toxicity. One litter at 500 mg kg^{? 1} day^{? 1} consisted of one early resorption and was believed to be secondary to overt maternal toxicity, although single conceptus litters occur historically in this strain of rats. Developmental toxicity at 500 mg kg^{? 1} day^{? 1} consisted of increased fetal skeletal variations (delayed pelvic bone ossification and wavy ribs). At 200 and 500 mg kg^{? 1} day^{? 1}, there were transient reductions in maternal feed consumption. In addition, there were slight increases in the incidence of delayed fetal skull bone ossification at 200 and 500 mg kg^{? 1} day^{? 1}. The no-observed-adverse-effect level (NOAEL), defined as the highest dose at which adverse effects attributable to the test substance were not detected, for both maternal and developmental toxicity, is considered to be 200 mg kg^{? 1} day^{? 1}. Thus, 8-2 Telomer B Alcohol is not considered to be a selective developmental toxicant in rats. The transient and quantitative nature of the observations in the 200 mg/kg group supports the conclusion that these findings were not adverse.     

Evaluation of the Reproductive and Developmental Toxicity of a Fluoroalkylethanol Mixture

The objective of these studies was to evaluate the reproductive and developmental toxicity of a commercial fluoroalkylethanol mixture, which is an intermediate in the production of fluorotelomers. The test substance was administered daily by gavage to Sprague–Dawley rats as a suspension in 0.5% aqueous methylcellulose. In a one-generation reproductive toxicity study, rats (20 per sex per group) were given dosages of 0, 25, 100, or 250 mg kg^{? 1} day^{? 1} for a period of 74 days prior to cohabitation, and during mating, gestation, and lactation. Body weights, feed consumption, clinical signs, gross pathology, sperm parameters, estrous cyclicity, and reproductive performance were evaluated for the P₁ generation. The F₁ offspring were evaluated during the lactation period for growth and survival and given a gross pathology examination at weaning. A subset of the offspring were retained; body weights, feed consumption, clinical signs, and age at onset of vaginal opening and preputial separation were evaluated, and gross pathology was performed on postnatal day 60. In the developmental toxicity study, groups of time-mated Sprague–Dawley female rats were given the test substance as a suspension in 0.5% aqueous methylcellulose at daily dosages of 0, 50, 200, or 500 mg kg^{? 1} day^{? 1} by gavage on gestation days 6–20. During the in-life portion of the study, growth parameters and clinical observations were made. On gestation day 21, dams were euthanized, and the thoracic and abdominal viscera were examined. The uterine contents were removed and examined, and fetuses were evaluated for any alterations. In the reproduction study, litter size at birth, number of live pups per litter on day 0 and 4 of lactation, and pup weights during lactation were reduced in groups administered ≥ 100 mg kg^{? 1} day^{? 1}. No other reproductive parameters were affected. There were no adverse reproductive effects observed at 25 mg kg^{? 1} day^{? 1}. In the developmental toxicity study, reduced maternal body weight parameters, increased perineal fur staining, and increased fetal skeletal alterations were observed at 500 mg kg^{? 1} day^{? 1}. There was no maternal or developmental toxicity at 50 or 200 mg kg^{? 1} day^{? 1}. Under the conditions of the studies, the no-observed adverse effect levels for this mixture were 25 mg kg^{? 1} day^{? 1} for subchronic toxicity and reproductive parameters and 200 mg kg^{? 1} day^{? 1} for developmental toxicity end points. No functional reproductive or developmental effects were observed at dose levels that did not adversely affect adult animals.     

Physicochemical analysis and repeated-dose 90-days oral toxicity study of nanocalcium carbonate in Sprague-Dawley rats

Abstract

In our previous studies of nanocalcium carbonate, in which we performed physicochemical analysis, genotoxicity, acute single-dose and repeated-dose 14-day oral toxicity testings in Sprague-Dawley (SD) rats, nanocalcium carbonate did not show a difference in toxicity compared to vehicle control. Here, we provide the first report of a repeated-dose 90-day oral toxicity test of nanocalcium carbonate in Sprague-Dawley rats, with physicochemical comparison of micro and nanocalcium carbonate. We find that the two particles differ in size, hydrodynamic size, and specific surface area, with no differences in components, crystalline structure and radical production. In terms of ionization ability, nanocalcium carbonate was slightly more ionized within 1% than microcalcium carbonate at pH 5 and pH 7. In the repeated-dose 90-day oral toxicity test of nanocalcium carbonate, there was no significant toxicity, and similar blood concentrations of Ca²⁺ compared to the vehicle control group. Based on our results, although nanocalcium carbonate has different physicochemical properties, nanocalcium carbonate does not differ from microcalcium carbonate in terms of toxicity. Based on the results, we suggest that the no-observed-adverse-effect level (NOAEL) of nanocalcium carbonate is 1000?mg kg^?1 day^?1 in SD rats according to the maximum dose (OECD guideline 408). However, the NOAEL might be higher than 1000?mg kg^?1 day^?1 because there were no adverse effects revealed by consistent pathological findings or biochemical parameter changes. To justify a safe concentration of nanocalcium carbonate, which is a low toxicity chemical, more data is required on dose levels above 1000?mg kg^?1. Our findings may be useful for creating safety guidelines for the use nanocalcium carbonate.     

Oral Toxicity Study of 2-Pentenenitrile in Rats with Reproductive Toxicity Screening Test

A combined repeated-dose toxicity study with reproduction was conducted with 2‐pentenenitrile (2-PN). Rats (10/sex per dose level) were dosed with 2-PN once daily by gavage at dose levels of either 0, 1, 3, or 10 mg kg^?1 day^?1 for 28 days, prior to and during cohabitation, and through day 3 of lactation. General clinical observations were recorded daily; body weights were recorded weekly. A neurobehavioral evaluation consisting of a functional observational battery and motor activity was conducted in all parental rats (10/sex per group). Clinical pathology parameters (hematology, clinical chemistry, coagulation) were measured in parental rats. Pup weights and clinical signs were recorded at birth and on lactation day 4. Parental rats were given a gross pathological examination, organ weights were obtained, and histological examination was conducted for the control and 10 mg kg^?1 day^?1 groups. No effects were seen with regard to mortality, clinical signs, functional observational battery and motor activity, hematology, or organ weights. Females receiving 10 mg/kg and males from all dose groups showed lower body weight gains and feed efficiency. Increased albumin concentrations were seen in both sexes given 10 mg/kg. Females in the 10 mg/kg group showed degeneration of the olfactory mucosa. No effects on the numbers of pups born, number surviving to lactation day 4, pup weight, and no gross anatomical development changes were observed. Under the conditions of this study, the no-observed-effect level (NOEL) for systemic toxicity in rats was 3 mg kg^?1 day^?1, based on degeneration of olfactory mucosa in females at 10 mg kg^?1 day^?1. The NOEL for reproductive and neurobehavioral toxicity in rats and for toxicity to offspring was 10 mg kg^?1 day^?1, the highest dose level tested.     

Activity of Alkaloid Extract of Carica papaya. Seeds on Reproductive Functions in Male Wistar Rats

ABSTRACT

Activity of the alkaloid extract of Carica papaya. Linn seed on male reproductive physiology was investigated. Male rats were divided into two groups. Each group of 20 male rats was further divided into 4 subgroups of 5 rats. Each rat was treated with C. papaya. seed extract (10, 50, and 150 mg kg^?1day^?1) daily for 3 days for fecundity study, semen analysis, and testis histopathology, respectively. Twenty male rats treated with C. papaya. seed extract (10, 50, and 150 mg kg^?1 day^?1), abstained from sex for 7 days and divided into 4 groups, were mated with fertile female rats: another set of 30 male rats, divided into 4 groups, treated with the seed extract (10, 50, and 150 mg kg^?1 day^?1), respectively, was used for semen analysis and testis histopathology. The results showed that oral administration of C. papaya. seed extract prevented ovum fertilization, reduced sperm cell counts, revealed sperm cell degeneration, and induced testicular cell lesion. These observations led to the conclusion that C. papaya. seed extract oral administration could induce reversible male infertility and therefore could be used for pharmaceutical development of a male contraceptive.     

Skeletal Muscle Atrophy Induced by Intramuscular Repeated Dose of Botulinum Toxin Type A in Rats

Botulinum toxin type A was intramuscularly administered to Sprague–Dawley rats once a day for 28 days at doses of 1, 3, and 9 ng kg^?1 day^?1 to investigate the possibility of unanticipated toxicity of repeated dose. A dose-related decrease in body weight gain was noted and lasted throughout the 4-week recovery period. Paralytic gait was a common clinical sign observed in the animals dosed at ≥3 ng kg^?1 day^?1 and muscle atrophy at 9 ng kg^?1 day^?1. Decreased creatinine was monitored in both males and females treated at 9 ng kg^?1 day^?1. Microscopic examination of the quadriceps femoris muscle, the test article application site, confirmed the muscle atrophy with a decrease in myofiber diameter and an increase of myofiber nuclei and intermyofiber connective tissue. Although antibody against botulinum toxin type A was detected in the sera from both males and females at 9 ng kg^?1 day^?1, no immunogenicity-related changes or lesions were noted. In conclusion, no other side effects of the botulinum toxin type A injection except the decrease in body weight gain and the muscle atrophy at the administration site were noted in the 28-day intramuscular repeated dose study.     

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg^?1 day^?1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg^?1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg^?1 day^?1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg^?1 day^?1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.     

Effects of oral exposure to the phthalate substitute acetyl tributyl citrate on female reproduction in mice

Acetyl tributyl citrate (ATBC), is a phthalate substitute used in food and medical plastics, cosmetics and toys. Although systemically safe up to 1000 mg kg⁻¹ day⁻¹, its ability to cause reproductive toxicity in females at levels below 50 mg kg⁻¹ day⁻¹ has not been examined. This study evaluated the effects of lower ATBC exposures on female reproduction using mice. Adult CD‐1 females (n = 7–8 per treatment) were dosed orally with tocopherol‐stripped corn oil (vehicle), 5 or 10 mg kg⁻¹ day⁻¹ ATBC daily for 15 days, and then bred with a proven breeder male. ATBC exposure did not alter body weights, estrous cyclicity, and gestational and litter parameters. Relative spleen weight was slightly increased in the 5 mg kg⁻¹ day⁻¹ group. ATBC at 10 mg kg⁻¹ day⁻¹ targeted ovarian follicles and decreased the number of primordial, primary and secondary follicles present in the ovary. These findings suggest that low levels of ATBC may be detrimental to ovarian function, thus, more information is needed to understand better the impact of ATBC on female reproduction. Copyright © 2016 John Wiley & Sons, Ltd.     

A 28-Day Repeated Dose Toxicity Study of Ultraviolet Absorber 2-(2′-Hydroxy-3′,5′-di-tert-butylphenyl) benzotriazole in Rats

To examine the possible repeated-dose toxicity of an ultraviolet absorber, 2-(2′-hydroxy-3′,5′-di-tert-butylphenyl)benzotriazole (HDBB), CD(SD)IGS rats were administered HDBB by gavage at a dose of 0 (vehicle: corn oil), 0.5, 2.5, 12.5, or 62.5 mg kg^?1 day^?1 for 28 days. At the completion of the administration period, a decrease in red blood cells, hemoglobin, and hematocrit was noted only in males at 2.5 mg/kg and more. Blood biochemical changes were noted at 0.5 mg/kg and more in males and at 62.5 mg/kg in females. Histopathologic changes were observed principally in the liver (vacuolar degeneration and hypertrophy of hepatocytes, bile duct proliferation, etc.) and in the heart (degeneration and hypertrophy of myocardium and cell infiltration). These changes were noted at 0.5 mg/kg and more in males and at 12.5 mg/kg and more in females. At higher doses, hypertrophy of tubular epithelium in the kidneys and diffuse follicular cell hyperplasia in the thyroids in both sexes and increased severity of basophilic tubules in the kidneys and extramedullary hematopoiesis in the spleen in males were also detected. After the 14-day recovery period, these changes mostly recovered in females but not in males. Based on these findings, no observed adverse effect level (NOAEL) was concluded to be less than 0.5 mg kg^?1 day^?1 in male rats and 2.5 mg kg^?1 day^?1 in female rats.     

Horseradish extract promotes urinary bladder carcinogenesis when administered to F344 rats in drinking water

Horseradish extract (HRE), consisting mainly of a mixture of allyl isothiocyanate and other isothiocyanates, has been used as a food additive. To evaluate the potential hazards of HRE, a 104‐week chronic study, a 2‐week analysis of cell proliferation in the urinary bladder and a medium‐term promotion bioassay of HRE were conducted with administration at concentrations of up to 0.04% HRE in the drinking water to male F344 rats. In the 104‐week chronic study with 32 male rats per group, no treatment‐related increases in the incidences of neoplastic lesions in any organ, including urinary bladder, were observed, except for simple hyperplasia in the urinary bladder in rats treated with HRE at concentrations of more than 0.01% (5.0 mg kg⁻¹ body weight day⁻¹). In the promotion study, HRE treatment after N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine initiation caused a clear increase in papillary or nodular hyperplasia, papilloma, and urothelial carcinoma of the urinary bladder in the groups given HRE for 13 weeks at doses higher than 0.005%, 0.01%, and 0.04% (2.7, 5.4 and 20.5 mg kg⁻¹ body weight day⁻¹), respectively. In the 2‐week cell proliferation analysis, treatment with HRE at concentrations greater than 0.005% (3.9 mg kg⁻¹ body weight day⁻¹) caused transient increases in 5‐bromo‐2′‐deoxyuridine labeling indices in the urothelium. Although clear tumor induction was not observed, administration of relatively low‐dose HRE increased cell proliferation in the urothelium and exerted obvious promoting effects on rat urinary bladder carcinogenesis. Further studies are needed to elucidate the mode of action of HRE in the rat urinary bladder to facilitate data extrapolation from the present study and provide insights into risk assessment. Copyright © 2017 John Wiley & Sons, Ltd.     

TOXICOKINETIC EVALUATION OF A SELEGILINE TRANSDERMAL SYSTEM IN THE DOG

The toxicology and toxicokinetics of a selegiline transdermal system (STS) were evaluated in a 3 month dog study of daily 24 h applications of placebo 4, 8, or 12 STSs in 32 male and 32 female beagle dogs. Each STS delivered approximately 5 mg selegiline over 24 h. No drug-related signs of toxicity were noted in any group with respect to clinical observations, dermal effects, body weight, food consumption, hematology, urinalysis data, or ophthalmoscopic or electrocardiographic examinations. Clinical chemistry data revealed no consistent adverse effects except for an increase in alanine aminotransferase in dogs receiving 8 and 12 STSs. Histological evaluation of tissues revealed the presence of pigment in the Kupffer cells of dogs treated with 8 and 12 STSs. There were no pathology findings suggestive of hemolysis or cholestasis. The no-effect level (NOEL) was 4 STSs (2·9 mg kg⁻¹ d⁻¹). There were no degenerative or life-threatening toxic effects up to 12 STSs (8·5 mg kg⁻¹ d⁻¹). Gender-related differences in steady-state plasma levels were not observed. Steady-state plasma concentrations were similar to maximum plasma concentrations obtained in single-dose studies, suggesting that drug accumulation was not evident. Simulation of systemic exposure following oral administration of 16·8 mg kg⁻¹ d⁻¹ from previous toxicology studies indicated that selegiline exposure following 12 STSs is sixfold greater while N-desmethylselegiline, L-amphetamine, and L-methamphetamine exposure is 0·5, 0·15, and 0·14 times the exposure in the oral study. The threefold difference in NOEL between oral and transdermal studies in the dog (0·8 versus 2·9 mg kg⁻¹ d⁻¹) is probably related to greater L-amphetamine and L-methamphetamine exposure following oral administration. The reduction in metabolite formation, relative exposure of selegiline in the dog at the NOEL compared to oral toxicology studies, and margin of safety provided, given that the expected clinical dose is less than the dosage of oral Eldepryl^™ (0·15 mg kg⁻¹ d⁻¹), documents the safety of the selegiline drug substance and indicates that additional toxicologic findings with the STS may not be expected. © 1997 by John Wiley & Sons, Ltd.     

Brain‐targeted distribution and high retention of silver by chronic intranasal instillation of silver nanoparticles and ions in Sprague–Dawley rats

The wide applications of silver nanoparticles (AgNPs) have been concerned regarding their unintentional toxicities. Different exposure modes may cause distinct accumulation, retention and elimination profiles, which are closely related with their toxicities. Unlike silver accumulation profiles through other regular administration modes, the biodistribution, accumulation and elimination of AgNPs by intranasal instillation are not fully understood. This study conducted intranasal instillation of polyvinylpyrrolidone‐coated AgNPs in neonatal Sprague–Dawley rats at doses of 1 and 0.1 mg kg^?1 day^?1 for 4 and 12 weeks, respectively. The 4‐week recovery was also designed after the 12‐week exposure. Silver concentrations in the main tissues or organs were periodically monitored. Parallel exposures using silver ion were performed for the comparative studies. No physiological alterations were observed in AgNP exposures. In comparison, 1 mg kg^?1 day^?1 silver ions decreased body weight gain and caused mortality of 18.2%, showing ionic silver had a relatively higher toxicity than AgNPs. A relatively higher silver accumulation was observed in silver ion groups than AgNP groups. The silver ion release could not fully explain silver accumulation in AgNP exposures, showing silver distribution caused by particulate silver occurred in vivo. The highest silver concentration was in the liver at week 4, while it shifted to the brain after a 12‐week exposure. Dose‐related silver accumulation occurred for both AgNP and silver ion groups. The time course revealed a uniquely high concentration and retention of brain silver, implying chronic intranasal instillation caused brain‐targeted silver accumulation. These findings provided substantial evidence on the potential neuronal threat from the intranasal administration of AgNPs or silver colloid‐based products. Copyright © 2015 John Wiley & Sons, Ltd.     

Two‐generation reproduction and teratology studies of feeding aditoprim in Wistar rats

Aditoprim, a new bacteriostatic agent that belongs to diaminopyrimidines, has a broad antimicrobial spectrum, good antibacterial activity and excellent pharmacokinetics. To evaluate the reproductive toxicity and teratogenic potential of aditoprim, different concentrations of aditoprim were administered to Wistar rats by feeding diets containing 0, 20, 100 and 1000 mg kg^–1, respectively. Each group consisting of 18 males and 25 females (F₀) was treated with different concentrations of aditoprim through a 13‐week period before mating and during mating, gestation, parturition and lactation. At weaning, 20 males and 25 females of the F₁ generation weanlings per group were selected randomly as parents for the F₂ generation. Selected F₁ weanlings were exposed to the same diet and treatment as their parents. At 1000 mg kg^–1 dose group, body weights in F₀ and F₁ rats, fetal body weight on day 21 (0, 4 and 21) after birth and number of viable fetuses in the F₀ and F₁ generation significantly decreased. Teratogenicity study was performed in combination with the F₁ generation of a two‐generation reproduction study. F₁ parents of the reproduction study were mated after weaning of the F_2a pups. Pregnant female rats were subjected to cesarean section on gestational day 20 for teratogenic examination. At 1000 mg kg^–1 group, body weights, fetal body lengths, tail lengths, litter weights and number of viable fetuses were significantly decreased. No obvious external, skeletal or visceral malformations in fetuses were noted in any groups in the teratogenic test. The no‐observed‐adverse‐effect level for reproduction/development toxicity of aditoprim was 100 mg kg^–1 diet (about 7.89–9.25 mg kg^–1 body weight day^–1). Copyright © 2015 John Wiley & Sons, Ltd.     

Disposition of LY333531, a selective protein kinase C β inhibitor,in the Fischer 344 rat and beagle dog

1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the β-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg^?1 oral dose of ¹⁴C-LY333531. Urine, faeces, bile and plasma were collected and analysed for ¹⁴C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5?mg kg^?1 oral dose of ¹⁴C-LY333531 to the male rat produced C_max and AUC_0-∞ for LY333531 of 14.7 ng ml^?1 and 60.8ng h ml^?1, respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C_max and AUC_0-∞ of LY333531 were higher, producing 245 ± 94 ng ml^?1 and 1419 ± 463ng h ml^?1, respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog.     

Thirteen week toxicity study of dietary l‐tryptophan in rats with a recovery period of 5 weeks

Although l ‐tryptophan is nutritionally important and widely used in medical applications, toxicity data for its oral administration are limited. The purpose of this study was to evaluate the potential toxicity of an experimental diet containing added l ‐tryptophan at doses of 0 (basal diet), 1.25%, 2.5% and 5.0% when administered to Sprague–Dawley rats for 13 weeks. There were no toxicological changes in clinical signs, ophthalmology, urinalysis, hematology, necropsy, organ weight and histopathology between control rats and those fed additional l ‐tryptophan. Body weight gain and food consumption significantly decreased throughout the administration period in males in the 2.5% group and in both sexes in the 5.0% group. At the end of the dosing period, decreases in water intake in males in the 5.0% group and in serum glucose in females in the 5.0% group were observed. The changes described above were considered toxicologically significant; however, they were not observed after a 5 week recovery period, suggesting reversibility. Consequently, the no‐observed‐adverse‐effect level of l ‐tryptophan in the present study was 1.25% for males and 2.5% for females (mean intake of l ‐tryptophan: 779 mg kg^–1 body weight day^–1 [males] and 1765 mg kg^–1 body weight day^–1 [females]). As the basal diet used in this study contained 0.27% of proteinaceous l ‐tryptophan, the no‐observed‐adverse‐effect level of overall l ‐tryptophan was 1.52% for males and 2.77% for females (mean intake of overall l ‐tryptophan: 948 mg kg^–1 body weight day^–1 (males) and 1956 mg kg^–1 body weight day^–1 (females)). We conclude that l ‐tryptophan has a low toxicity profile in terms of human use.     

Evaluation of the effects of deltamethrin on the fetal rat testis

Pregnant Sprague–Dawley rats were administered deltamethrin, at doses 0.1, 1, 5 or 10 mg kg^?1 day^?1, or di‐n‐hexyl phthalate (DnHP) (250 mg kg^?1 day^?1), by gavage, from gestational day 13 to 19. Maternal toxicity was observed at 10 mg kg^?1 day^?1, as evidenced by transient clinical signs of neurotoxicity and reductions in body weight, body weight gain and corrected weight gain. Deltamethrin had no statistically significant effect on the incidence of post‐implantation loss, fetal weight or anogenital distance in the male fetuses. Unlike DnHP, deltamethrin induced no changes in the expression of several genes involved in cholesterol transport or in the steroid synthesis pathway in the testes of gestational day 19.5 male fetuses (SRB1, StAR, P450scc, 3βHSD, P450 17 A1, 17βHSD). Fetal testicular levels of P450scc and P450 17 A1 protein were also unaffected by deltamethrin. No statistically significant differences were observed in the ex vivo fetal testicular production of testosterone and androstenedione after deltamethrin exposure, whereas DnHP markedly reduced these parameters. The deltamethrin metabolite, 3‐phenoxybenzoic acid, was detected in amniotic fluid. In summary, our results demonstrate that in utero exposure to deltamethrin during the period of sexual differentiation had no significant effect on the testosterone synthesis pathway in the male rat fetus up to a maternal toxic dose. Copyright © 2016 John Wiley & Sons, Ltd.     

Deep sea minerals prolong life span of streptozotocin‐induced diabetic rats by compensatory augmentation of the IGF‐I‐survival signaling and inhibition of apoptosis

Consumption of deep sea minerals (DSM), such as magnesium, calcium, and potassium, is known to reduce hypercholesterolemia‐induced myocardial hypertrophy and cardiac‐apoptosis and provide protection against cardiovascular diseases. Heart diseases develop as a lethal complication among diabetic patients usually due to hyperglycemia‐induced cardiac‐apoptosis that causes severe cardiac‐damages, heart failure, and reduced life expectancy. In this study, we investigated the potential of DSM and its related cardio‐protection to increase the life expectancy in diabetic rats. In this study, a heart failure rat model was developed by using streptozotocin (65 mg kg^?1) IP injection. Different doses of DSM‐1× (37 mg kg^?1 day^?1), 2× (74 mg kg^?1 day^?1) and 3× (111 mg kg^?1 day^?1), were administered to the rats through gavages for 4 weeks. The positive effects of DSM on the survival rate of diabetes rats were determined with respect to the corresponding effects of MgSO₄. Further, to understand the mechanism by which DSM enhances the survival of diabetic rats, their potential to regulate cardiac‐apoptosis and control cardiac‐dysfunction were examined. Echocardiogram, tissue staining, TUNEL assay, and Western blotting assay were used to investigate modulations in the myocardial contractile function and related signaling protein expression. The results showed that DSM regulate apoptosis and complement the cardiomyocyte proliferation by enhancing survival mechanisms. Moreover DSM significantly reduced the mortality rate and enhanced the survival rate of diabetic rats. Experimental results show that DSM administration can be an effective strategy to improve the life expectancy of diabetic subjects by improving cardiac‐cell proliferation and by controlling cardiac‐apoptosis and associated cardiac‐dysfunction. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 769–781, 2016.