Developmental toxicity of N-methyl-2-pyrrolidone administered orally to rats.

The developmental toxicity of N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given NMP at doses of 0 (distilled water), 125, 250, 500, and 750 mg/kg/day, by gavage, on gestational days (GD) 6 through 20. Significant decreases in maternal body weight gain and food consumption during treatment, and a reduction in absolute weight gain were observed at 500 and 750 mg/kg. The incidence of resorptions per litter was significantly higher than control at 500 mg/kg, and rose to 91% at 750 mg/kg. Examination of the foetuses revealed treatment-related malformations, including imperforate anus and absence of tail, anasarca, and malformations of the great vessels and of the cervical arches. The incidence of malformed foetuses per litter, and of litters with malformed foetuses was significantly increased at 500 and 750 mg/kg. At 250 mg/kg, one foetus showed malformations similar to those recorded at higher dosages. There was a dose-related decrease in foetal body weights (male, female, and total) that reached statistical significance at 250 mg/kg. A significant increase in incomplete ossification of skull bones and of sternebrae was also present at 500 and 750 mg/kg. In summary, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 250 and 125 mg/kg/day, respectively. Thus, oral administration of NMP produced developmental toxicity below maternally toxic levels.     

Prenatal developmental toxicity evaluation of Withania somnifera root extract in Wistar rats

Context: Withania somnifera (L) Dunal (Solanaceae) is an important traditional herbal medicine used for thousands of years and is considered as the Indian ginseng. Reports on the effect of Withania somnifera root (WSR) extract on the developing foetus of pregnant rats including mortality, structural abnormalities, changes in growth and effects on dams are not available. Objective: The present study was performed to evaluate the prenatal developmental toxicity potential of WSR extract in rats. Materials and methods: WSR extract was given orally to pregnant rats during the period of major organogenesis and histogenesis (days 5 to 19 of gestation) at the dose levels of 500, 1000 and 2000?mg/kg/day. Clinical observations including mortality, moribundity, behavioural changes, signs of overt toxicity, body weight, gross pathological changes of dams and foetal analyses including external malformations, skeletal and soft tissue malformations were evaluated. Results: No evidence of maternal or foetal toxicity was observed. WSR extract caused no changes (p?Discussion and conclusion: Under the conditions of the study, the no-observed-effect level (NOEL) of WSR extract for maternal and developmental toxicity was concluded to be at least 2000?mg/kg/day.     

Lack of beneficial effects on the NO-donor, molsidomine, in the L-NAME-induced pre-eclamptic syndrome in pregnant rats.

1. In pregnant rats, chronic NO-synthase inhibition induces the development of a pre-eclamptic syndrome, characterized by an increase in maternal blood pressure, a loss of vascular refractoriness to pressor stimuli, a reduction in litter size and a decrease in pups (and maternal) weight. We investigated whether a NO-donor, molsidomine, administered during NO synthase inhibition, could restore a normal pregnancy. 2. Pregnant rats were given daily, starting from day 14 of gestation, saline (controls), or L-NAME (50 mg kg-1 d-1), or molsidomine (15 or 30 mg kg-1 d-1), or the L-NAME + molsidomine combinations. Maternal blood pressure and body weight, litter size, pups weight and vascular reactivity to pressor stimuli (angiotensin II, noradrenaline, electrical stimulation of the spinal cord) were investigated. 3. L-NAME alone, as compared to controls, increased maternal blood pressure, reduced litter size (-59%), increased foetal reabsorptions (+ 625%) and decreased foetal weight (-10%). Vascular reactivity to pressor stimuli was enhanced. 4. Molsidomine alone, as compared to controls, dose-dependently decreased maternal blood pressure but had no effect vascular reactivity and, whatever the dose, on foetal outcome. 5. The L-NAME-molsidomine combinations dose (of molsidomine)-dependently limited the rise in maternal blood pressure induced by L-NAME alone but unexpectedly, dose-dependently and significantly worsened pregnancy evolution, e.g., at 30 mg kg-1 d-1: litter size (-80%), foetal reabsorptions (+ 1025%), foetal weight (-24%). Vascular reactivity to pressor stimuli was paradoxically further enhanced. 6. Thus, in a chronic NO deprivation-induced model of pre-eclampsia in rats, molsidomine, possibly because of its hypotensive action, worsens the foetal outcome, which questions the usefulness of NO-donors in pre-eclamptic women.     

Effects of aminopentol on in utero development in rats.

Aminopentol (AP1), the backbone and main hydrolysis product of the mycotoxin fumonisin B1 (FB1), is present in corn-based foods which are consumed daily as a substantial part of the diet in some areas of the world. The toxicity of FB1 has been attributed to altered sphingolipid metabolism, but the toxicity of AP1 is less certain. Epidemiological correlations and in vitro studies have suggested that AP1 can increase neural tube defects (NTDs), but no in vivo developmental study of AP1 was done prior to this study. AP1 was given once daily to rats by gavage on gestation days (GD) 3-16 at doses of 0, 15, 30, 60, or 120 mg/kg. Reproductive and developmental parameters were measured at GD 17, one day after the last dose, and on GD 20. In addition, on GD 17, maternal and fetal tissues were analyzed for sphingolipid content. Conclusions: AP1 reduced dam body weight gain, but was less toxic than FB1. AP1 was not teratogenic, did not affect tissue sphingolipid ratios, did not alter reproduction or development of fetuses, and produced no dose-related histopathological effects in dams.     

Study of the teratogenic potential of FD & C Yellow No. 5 when given by gavage to rats

FD & C Yellow No. 5 (tartrazine) was given to Osborne-Mendel rats by gavage at dose levels of 0, 60, 100, 200, 400, 600 or 1000 mg/kg body weight/day on days 0–19 of gestation. No maternal or developmental toxicity was observed when the rats were killed on day 20. The mean daily food consumption for the entire period of gestation was significantly greater in the females given 1000 mg/kg body weight/day than in the controls, but maternal body-weight gain was not affected. No dose-related effects were observed in implantations, foetal viability or external foetal development. Foetal skeletal and visceral development was similar among foetuses from all groups. At the doses given, FD & C Yellow No. 5 was neither toxic nor teratogenic.     

Prenatal and postnatal development of rats following the maternal treatment with testosterone during the late period of embryogenesis

Sprague-Dawley derived female albino rats were administered subcutaneously 0.5, 1.5, or 3.0 mg/kg of testosterone acetate in sesame oil at single daily doses, from day 13 until day 16 of pregnancy (day 0 = spermatozoa). The pregnant females were either killed shortly before term or allowed to litter and raise their offspring. Increased rates of prenatal death were observed in the three experimental groups of both these experiments. Reduced body weight of foetuses and, respectively, young rats after weaning was recorded for the intermediate and high dose groups. Embryo-lethality and delay of either foetal or postnatal development occurred at some dose-relationship and in association with slight to moderate loss of maternal body weight during the period of treatment. No teratogenic potency of testosterone was found and no changes of the female sexual organs were observed in the foetuses or young rats.     

An experimental evaluation of possible teratogenic potential in Boerhaavia diffusa in Albino rats.

The present study was undertaken to evaluate any possibility of teratogenic effects in Boerhaavia diffusa (Punarnava), a widely used herbal medicine for renal and urinary tract diseases by Ayurvedic physicians in India. The ethanolic extract of Boerhaavia diffusa (BDE) was administered daily in a dose of 250 mg/kg, body weight p.o., to pregnant albino female rats during the entire period of gestation. BDE was found to be devoid of any teratogenic effect as litter size and survival rate of foetuses were the same as for the normal control group and no foetal anomaly could be detected.     

Developmental toxicity assessment of the new fluoroquinolone antibacterial DW-116 in rabbits

DW-116 is a newly developed fluoroquinolone antibacterial with a broad spectrum against both Gram-positive and Gram-negative bacteria. We have reported recently that DW-116 is embryotoxic and teratogenic in rats. The present study was conducted to investigate the teratogenicity of DW-116, together with maternal toxicity and developmental toxicity using New Zealand White rabbits. The test chemical was administered by gavage to pregnant rabbits from gestational day (GD) 6 through to GD 18 at dose levels of 0, 5, 19.5 and 76.1 mg kg(-1) day(-1). All does were subjected to caesarean section on day 28 of gestation and their foetuses were examined for external, visceral and skeletal abnormalities. In the 76.1 mg kg(-1) group, a minimal maternal toxicity, as evidenced by decreased body weight gain during treatment period, was observed in pregnant rabbits. Significant embryo-foetal toxicity, including increased number of foetal deaths and delayed foetal ossification, was seen. However, no treatment-related morphological changes were detected in foetal external, visceral and skeletal examinations. There were no adverse effects on either pregnant dams or embryo-foetal development at 19.5 and 5 mg kg(-1). It was concluded that administration of DW-116 during the major organogenetic period in rabbits produced decreased maternal body weight gain, increased number of foetal deaths and foetal developmental delay but no evidence of teratogenicity. The no-observed-adverse-effect levels (NOAELs) of DW-116 are considered to be 19.5 mg kg(-1) day(-1) for does and embryo-foetuses, respectively.     

Developmental toxicity study of Aquacoat ECD ethylcellulose aqueous dispersion administered orally to rats.

A developmental rat toxicity study of Aquacoat((R)) ECD was performed as part of a program to evaluate the safety of the product. Groups of 25 presumed-pregnant Charles River Sprague-Dawley CD rats received doses of 0, 903, 2709 and 4515mg/kg/day (dry weight basis) of Aquacoat ECD administered undiluted once daily via oral gavage on days 6-15 of gestation. All surviving dams underwent caesarean sectioning on day 20 of gestation. Foetuses were weighed, sacrificed and subject to external, visceral and skeletal evaluations. No test material-related maternal deaths occurred; one high-dose female died on day 14 due to gavage error. The only treatment-related clinical sign noted among dams receiving 2709mg/kg/day and greater was pale faeces which was attributed to the presence of the test material in the faeces. No statistically significant differences were noted among the measured maternal parameters. Foetal sex ratios and body weights were similar in all groups. The results of external and visceral foetal evaluations revealed no treatment-related alterations. The only statistically significant findings noted during the skeletal evaluation were increased litter incidences of incompletely ossified or wavy ribs noted among foetuses receiving 4515mg/kg/day, and a significant increase in the litter incidence of thickened ribs at doses of 2709 and 4515mg/kg/day. Given the nature of these findings and the lack of effects on any other parameter measured in this study, they were not considered adverse effects of treatment. Under the conditions of this study, the maternal and foetal no-observed-adverse-effect level (NOAEL) is in excess of 4515mg/mg/day.     

Efficacy of royal jelly against the oxidative stress of fumonisin in rats.

Fumonisins (FB) are mycotoxins produced by Fusarium verticillioides, frequently associated with corn. It produces toxicity, including teratogenicity, equine leukoencephalomalacia, porcine pulmonary edema, hepatic or renal damage in most animal species and perturb sphingolipid metabolism. The aim of the present study was to evaluate the protective effects of royal jelly (RJ) against FB toxicity. Sixty male Sprague-Dawley rats were divided into six treatment groups including the control group; group fed FB-contaminated diet (200mg/kg diet) and the groups treated orally with RJ (100 or 150mg/kg body weight) with or without FB for 3 weeks. FB alone decreased body weight gain, feed intake, GPX and SOD. Whereas it increased in ALT, AST, triglycerides, cholesterol, HDL, LDL, createnine and uric acid levels. Animals received FB showed severe histological and histochemical changes in liver and kidney tissues. Cotreatment with FB plus RJ resulted in a significant improvement in all the tested parameters and the histological and histochemical pictures of the liver and kidney. These improvements were pronounced in animals fed FB-contaminated diet plus the high dose of RJ. It could be concluded that RJ have a protective effects against FB toxicity and this protection was dose dependent.     

Developmental toxicity evaluation of inhaled citral in Sprague-Dawley rats.

Citral is a commonly used fragrance and flavour ingredient that has demonstrated a potential for teratogenicity in chick embryo screening studies. To investigate potential mammalian developmental toxicity, pregnant Sprague-Dawley rats were exposed to citral by inhalation for 6 hr/day on gestation days 6-15 at mean concentrations of 0, 10 or 34 ppm as vapour, or 68 ppm as an aerosol/vapour mixture. Dams were killed on gestation day 20 and the foetuses were removed and evaluated for gross, visceral and skeletal malformations. Exposure to 68 ppm was maternally toxic, with reduced body-weight gains, ocular opacity, breathing difficulty, nasal discharge and salivation noted in the dams. No maternal toxicity was seen at the lower vapour exposure levels. The number of corpora lutea, implantations, resorptions, foetal viability, litter size, and sex ratio were not adversely affected by citral at any exposure level tested, and no exposure-related malformations were observed. At a maternally toxic exposure level, a slight reduction in mean foetal body weight and a slight increase in the incidence of hypoplastic bones were noted. Results of this study indicate that citral does not produce developmental toxicity in the rat when administered by inhalation at concentrations up to a maternally toxic exposure level.     

Study of the teratogenic potential of FD & C Red No. 40 when given by gavage to rats

Osborne-Mendel rats were intubated with FD & C Red No. 40 at dose levels of 0, 30, 75, 150, 300, 600, or 1000 mg/kg body weight/day on days 0-19 of gestation. No developmental toxicity was observed when the animals were killed on day 20 of gestation. No dose-related changes were seen in maternal daily observations, food consumption, body-weight gain or implantations, or in foetal viability, body weight, body length, sex distribution or external variations. Skeletal and soft-tissue development appeared similar in foetuses of all groups. The isolated increases that occurred in the number of male foetuses, number of females with two or more resorptions, number of litters with three or more sternebral variations and incidence of 14th rib bud are considered random occurrences and were not related to dosage.     

Vitamin D ameliorates fluoride-induced embryotoxicity in pregnant rats

We have evaluated the ameliorative effect of vitamin D on fluoride-induced embryotoxicity in pregnant rats. Oral administration of sodium fluoride (NaF; 40 mg/kg body weight) from days 6 to 19 of gestation caused, as compared with control, significantly lowered body weight, feed consumption, absolute uterine weight and number of implantations. As compared with the control, higher incidence of skeletal (presence of wavy ribs, 14th rib, dumbbell-shaped 5th sternebrae, incomplete ossification of skull) and visceral (subcutaneous haemorrhage) abnormalities was recorded in the foetuses of fluoride-treated pregnant rat. Vitamin D (2 ng/0.2 ml olive oil/animal/day po) treatment significantly ameliorated the fluoride-induced reductions in body weight, feed consumption and absolute uterine weight. As compared with fluoride-treated alone, the total percentage of skeletal and visceral abnormalities observed in foetuses was significantly lowered in fluoride plus vitamin D-treated animals. These findings suggest that vitamin D treatment significantly reduced the severity and incidence of fluoride-induced embryotoxicity. The ameliorative effect of vitamin D against skeletal and visceral abnormalities could be due to stimulation of intestinal absorption of calcium and phosphate, thus raising the plasma calcium and phosphate concentrations.     

Developmental toxicity of isomalt in rats

The sugar replacer isomalt, a 1:1 mixture of the disaccharides glucopyranosylsorbitol and glucopyranosylmannitol, was incorporated in the diet of rats. Female Bay FB:30 rats were adapted to isomalt by feeding them a diet containing a gradually increasing amount of isomalt for several days, prior to mating. Subsequently, they were mated. Isomalt was fed continuously in concentrations of 2.5, 5 and 10% up to day 20 of pregnancy. In addition, one group of female Wistar rats was mated and fed 10% isomalt incorporated in the diet from day 0 up to day 20 of pregnancy, without previous adaptation to isomalt. Finally, one group of untreated female Wistar rats served as controls. Half of the number of females in each group was selected for caesarian section on day 20 of pregnancy. The other half was allowed to litter and rear their pups for 2 weeks (Wistar rats) or 3 weeks (Bay FB:30 rats). In the females of the Bay FB:30 rats, a decreased body-weight gain and food consumption were observed in the 5 and 10% isomalt group. Minor retardation in the development of the foetuses was observed in the 10% isomalt group only with the Bay FB:30 rats and was therefore considered to be related to maternal toxicity. In addition, a dose-related increase in the incidence of wavy ribs occurred in foetuses of the Bay FB:30 rats. However, none of the observed effects were persistent in neonates. Isomalt appeared to have slight toxic effects in the dams of the Bay FB:30 strain but no toxicity in the offspring. In Wistar rats no toxicity and no effects on maternal performance or on embryonic, foetal or neonatal development were seen. Isomalt, when fed at dietary levels up to 10%, did not induce structural or functional teratogenic effects in rats of either the Wistar or the Bay FB:30 strain.     

The effect of prednisolone on the foetotoxicity of cadmium in pregnant mice

The effects of prednisolone was investigated on the foetotoxicity of cadmium. CFLP female mice were given a single i.p. dose of 2.5 mg cadmium (Cd) per kg body weight on day 5 or 9 of gestation. This treatment significantly decreased both the number of live foetuses and foetal weights on day 18 of gestation. Prednisolone (0.1 mg kg-1) given daily from the day of cadmium treatment death, prevented the effects of cadmium on foetal weights in both groups, and on the number of live foetuses when cadmium was given on day 9 of gestation. When Cd was given on day 13 of gestation similar treatment with prednisolone did not influence either litter size or the weights of 1-day-old pups.     

A teratology study on vomitoxin (4-deoxynivalenol) in rabbits

Diets containing 4-deoxynivalenol (vomitoxin) of greater than 98% purity were fed to rabbits on days 0-30 of gestation. The dietary concentrations of 4-deoxynivalenol were 0, 0.00075, 0.0015, 0.003, 0.006, 0.012 and 0.024% and the daily intakes of deoxynivalenol were 0, 0.3, 0.6, 1.0, 1.6, 2.0 and 1.8 mg/kg body weight/day, respectively. A pair-fed group was given a feed intake equivalent to that in the 1.6-mg/kg group. The only significant effects that were observed in foetuses examined at day 30 of gestation occurred only at doses that caused reductions in both the body weight and feed intake of does. The foetal effects consisted of a 100% incidence of resorption in the 1.8- and 2.0-mg/kg groups and decreased mean foetal weight in the 1.0- and 1.6-mg/kg and pair-fed groups. The doses that did not appear to be maternotoxic (0.6 and 0.3 mg/kg) did not show any adverse effects in foetuses at term. Vomitoxin given in the diet during pregnancy failed to show any evidence of teratogenic potential in rabbits.     

Foetal development in rats FED AIN-76A diets supplemented with excess calcium

This study was designed to evaluate the developmental effects of moderate dietary calcium increases in rats fed nutritionally adequate diets. Female Charles River CD/VAF Plus rats were given 0.50 (control), 0.75, 1.00 or 1.25% dietary calcium as calcium carbonate in AIN-76A diets for 6 wk before mating, during mating and for 20 days of gestation. On gestation day 20, the animals were killed and caesarean sections were performed. Both the non-pregnant and pregnant rats in the 0.75, 1.00 and 1.25% groups ate slightly more than did the control group during most of the intervals measured, but not all the increases were statistically significant. There was no consistent pattern of increase or decrease in weight gain. No dose-related changes were found in maternal clinical findings, the average number of implantations, resorptions and viable foetuses, or foetal length or weight. Under the conditions of the study, there were no statistically significant increases as compared with the control group in the litter incidence regarding specific external, visceral or skeletal variations of the foetuses. Dietary calcium was neither foetotoxic nor teratogenic at the concentrations used.     

Maternal-foetal distribution studies in late pregnancy. II. Distribution of [1-14C]acrylamide in tissues of beagle dogs and miniature pigs

[carbonyl-14C]Acrylamide was administered iv as a single dose (5 mg/kg) to pregnant beagle dogs and miniature pigs late in gestation. After a 2-hr equilibration period, the animals were killed and foetuses were removed for determination of the amount of radioactivity in maternal and foetal tissues. In total, six dog litters (33 foetuses) and seven pig litters (45 foetuses) were examined. In dogs, acrylamide was distributed readily to both maternal and foetal tissues with a placental distribution factor of 17.7%. The blood/brain distribution factor was insignificant (5.9%) in maternal dogs and 0% in the foetuses. Maternal liver was the largest depot of the administered acrylamide in the dog, followed by the maternal kidney. In pigs, the placental distribution factor was 31%, and the blood/brain distribution factor was insignificant in both maternal and foetal pigs. Liver and kidney of maternal pigs also contained the greatest amount of radioactivity. Although there appears to be some placental protection of the foetuses from the xenobiotic in the maternal circulation, foetal brain would be exposed to the effect of any acrylamide present in the foetal circulation, since the foetuses of both species had blood/brain distribution factors that were either small or zero, reflecting the absence of a blood-brain barrier.     

Oral developmental toxicity study of methylsulfonylmethane in rats.

Methylsulfonylmethane (MSM) is a metabolite of dimethyl sulfoxide, and occurs naturally at low levels in many foods. MSM has received wide attention as a dietary supplement to promote joint health. The objective of these studies was to determine the developmental toxicity potential of MSM when administered orally to pregnant rats during the period of major organogenesis and histogenesis. In a preliminary dose-finding study, distilled MSM microprill (i.e., microspherical pellets of MSM) was administered by oral gavage at dose levels of 0 (vehicle control), 50, 250, 500, and 1000 mg/kg/day to 8-9 sperm-positive female Sprague-Dawley rats/group/day on gestation days 6-20. No evidence of maternal or fetal toxicity was observed. For the definitive developmental study, four groups of 24-25 timed-bred primiparous female rats were administered 0, 50, 500, or 1000 mg MSM/kg/day via gavage on gestation days 6-20. Maternal feed consumption, body weight, body weight gain, uterus weight and corrected body weight/body weight gain were unaffected by treatment. No evidence of maternal toxicity, and no significant differences in litter viability, litter size, or litter body weight were detected. Fetal evaluations failed to show any biologically significant increase in the incidence of anomalies in the MSM treated groups, and no malformations were seen in any of the fetuses. No evidence of fetal mortality, alterations to growth, or structural alterations were observed in the fetuses of dams administered 50-1000 mg/kg/day. Therefore, under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 1000 mg/kg/day.     

A teratogenic study of carbaryl in Swiss albino mice

To study the teratogenicity of carbaryl, groups of 10 pregnant mice were dosed, by gavage, with 0, 100, 150 or 200 mg carbaryl/kg body weight, in corn oil, on day 8 or day 12 of pregnancy or daily (as daily doses) from day 6 to day 15. The two higher doses were toxic to both dams and foetuses regardless of the timing of treatment. Treated dams generally showed reduced weight gains but total weight gain was significantly reduced only for dams given 200 mg carbaryl on day 8 or day 12 of gestation. Maternal mortality was increased in most groups given 150 or 200 mg carbaryl. Carbaryl treatment tended to reduce litter size, to increase the percentage of resorbed foetuses, and to reduce foetal weight. There were increased incidences of open eye, of certain visceral abnormalities, and of reduced ossification in virtually all treated groups. The variety of abnormalities in treated foetuses reflected the dysmorphogenic potential of the pesticide. More aberrations were seen in foetuses from dams treated throughout organogenesis than in those from dams given a single dose.