Evaluation of teratogenic potential of sodium sulfite in rats

The teratogenicity of sodium sulfite was examined in Wistar rats. The pregnant rats were fed diets containing 5, 2.5, 1.25, 0.63 or 0.32% of sodium sulfite heptahydrate(Na2SO3.7H2O) ad libitum from day 8 to 20 of pregnancy. Maternal toxicity, as evidenced by decreased body weight gain and decreased food consumption was observed at the 5% group, but no clinical signs of toxicity were observed. A significant reduction in the fetal body weight of both sexes was observed in all dose groups except 2.5% group. No significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the sodium sulfite-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any dose level. However, several types of skeletal and internal variations as well as delayed ossifications were observed in some groups treated with sodium sulfite, but the incidences were not significantly different from controls. Also, some fetuses with dilatation of the renal pelvis and the lateral ventricle were found in all groups except 1.25% group, but there was no dose-response. The live birth index and survival rate of offspring within 4 weeks and their body weight gain at 3 weeks after birth were not affected by sodium sulfite-treatment. In conclusion, sodium sulfite (0, 0.32, 0.63, 1.25, 2.5 or 5.0% as Na2SO3.7H2O) administered in the diet to Wistar rats during days 8-20 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity.     

Placental and fetal toxicity of albendazole sulphoxide in Wistar rats

This work characterized the effects of albendazole sulphoxide (ABZSO) on placental and fetal parameters in Wistar rats on day 20 of gestation. ABZSO was fed in laboratory chow at 0, 2.5, 5, 10, 20 or 30 mg/kg/d from day 6 to 15 of gestation to pregnant rats. Data of resorptions, placental and fetal characteristics and fetal skeletal malformations were recorded. Resorption percentages in the 20 and 30 mg/kg/d groups were significantly higher compared to the control group. Placentas of ABZSO-treated rats had lower weight and smaller size than untreated rats. The fetal weight and size were lower in the 5 mg/kg/d dose compared to no treatment. In the 5, 10 and 20 mg/kg/d groups, reductions in ossification process were observed. ABZSO induced malformations and/or fetal death when orally administered to pregnant rats. This data contributes to characterization of the reproductive toxicity of ABZSO, the main active metabolite of albendazole.     

Effect of aluminosilicates and bentonite on aflatoxin-induced developmental toxicity in rat.

Numerous studies have established that aflatoxin is a potent developmental toxin in animals. Previous research has demonstrated that a phyllosilicate clay, hydrated sodium calcium aluminosilicate (HSCAS or Novasil), tightly binds and immobilizes aflatoxins in the gastrointestinal tract of animals and markedly reduces the bioavailability and toxicity of aflatoxin. Our objective in this study was to utilize the pregnant rat as an in vivo model to compare the potential of HSCAS and bentonite to prevent the developmental toxicity of aflatoxin. Aluminosilicates (HSCAS) and bentonite were added to the diet at a level of 0.5% (w/w) and fed to the pregnant rat throughout pregnancy (i.e. days 0-20). Test animals were fed an aflatoxin-contaminated diet (2.5 mg kg(-1) diet) with or without sorbents during gestation days 6-15. Evaluations of toxicity were performed on day 20. These included maternal (mortality, body weights, feed intake and litter weights), developmental (embryonic resorptions and fetal body weights) and biochemical (ALT, AST and AP) evaluations. Sorbents alone were not toxic and aflatoxin alone resulted in significant maternal and developmental toxicity. Animals treated with phyllosilicate (plus aflatoxin) were comparable to controls following evaluations for resorptions, live fetuses and fetal body weights, as well as biochemical parameters. While bentonite plus aflatoxin resulted in significant reduction in fetal body weight, none of the fetuses from HSCAS or bentonite plus aflatoxin-treated groups had any gross, internal soft tissue or major skeletal malformations.     

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.     

Subchronic toxicity study of dietary N-acetylglucosamine in F344 rats.

A subchronic toxicity study of N-acetylglucosamine (GlcNAc), a monomeric form of chitin, was conducted in groups of 10 male and 10 female F344 rats fed pelleted diets containing 0, 0.625, 1.25, 2.5 or 5% concentrations for 13 weeks. All animals survived until the end of the experiment. Slight, non-significant increase in body weights was observed in males receiving 0.625, 1.25 or 2.5% from week 4 until the end of the experiment, when significant elevation was found for the males receiving 0.625, 1.25 or 2.5% at the terminal sacrifice to result in decreased relative weights of many organs in these cases. However, there were no obvious indications of toxicity in any group receiving GlcNAc in terms of clinical signs, food intake, hematology, serum biochemistry, and histopathological findings. Thus, it was concluded that orally administered GlcNAc exerts no obvious toxicity to F344 rats at concentrations up to 5% in the diet for 13 weeks. Based on the present toxicity data, > or =5% was determined to be a no-observed-adverse-effect level, translated into 2476 and 2834 mg/kg/day for male and female rats, respectively.     

Teratology study of diethylene glycol mono-n-butyl ether in rats

The teratogenicity of diethylene glycol mono-n-butyl ether (DEGMBE) was studied in Wistar rats. The pregnant rats were fed a diet containing DEGMBE from day 0 through day 20 of pregnancy. The dietary concentrations of DEGMBE were 0, 0.04, 0.2 and 1% and the daily intakes of DEGMBE were 0, 25, 115 and 633 mg/kg, respectively. In the DEGMBE-treated groups, the maternal body weight gain during pregnancy was significantly reduced, but neither decrease in food consumption during pregnancy nor any clinical sign of toxicity was observed. No significant differences between the DEGMBE-treated groups and the control group were found in the pre- and postimplantation losses, the number of live fetuses per litter, the sex ratio of live fetuses, the fetal body weight and the placental weight. External, skeletal and internal examinations of the fetuses revealed no evidence of teratogenesis. In the postnatal development of the offspring from the dams given DEGMBE, a high survival rate and good growth of the offspring were noted. It could be concluded that DEGMBE has no adverse effects on the pre- and postnatal development of the offspring in rats.     

Co-consumption of selenium and vitamin E altered the reproductive and developmental toxicity of methylmercury in rats

Methylmercury (MeHg), an environmental contaminant primarily found in fish and seafood, may pose long-term health risks to pregnant women and their developing children. The objective of this study was to determine whether co-consumption of nutritional supplements would alter the effects of MeHg on reproductive and developmental toxicity using a rodent model. Adult female rats were fed a diet containing additional selenium (1 ppm), additional vitamin E (225 IU/kg) or a combination of the two for 4 weeks before oral dosing of MeHg (1.25 mg/kg/day). Treatment with MeHg and dietary supplementation continued throughout pregnancy after which the dams were allowed to deliver their offspring. In addition to routine evaluations including periodic body weight measurements and daily clinical signs observations, dams and pups were evaluated for auditory startle habituation and pups were evaluated for developmental landmarks and reflexology. The dams and offspring were euthanized approximately 4 weeks after birth of the offspring. Results indicated that treatment with MeHg caused adverse effects on both reproduction of the dams and decreased progeny survival. However, the dams showed significant improvement in body weight gain during lactation and average auditory startle response time when the diet was enriched with both selenium and vitamin E. The combination of both vitamin E and Se also resulted in a significant increase in post-natal survival when compared to MeHg-treated group. There was no nutrient effect on the MeHg toxicity shown in offspring physical landmarks, performance in reflex tests and assessment of simple auricular startle response. Also, accelerated development as indicated by earlier opening in the pups of the supplemental diet groups was observed. These results suggest that antioxidant nutrients in the diet may alter MeHg reproductive and developmental toxicity. The underlying and human health implications warrant further investigations.     

Developmental toxicity of dibutyltin dichloride in cynomolgus monkeys

Dibutyltin dichloride (DBTCl) has been shown to be teratogenic in rats. The present study was conducted to determine the teratogenic potential of DBTCl given to pregnant monkeys during the entire period of organogenesis. Cynomolgus monkeys were dosed once daily by nasogastric intubation with DBTCl at 0, 2.5 or 3.8 mg/kg on days 20-50 of pregnancy, the whole period of organogenesis. The pregnancy outcome was determined on day 100 of pregnancy. In both DBTCl-treated groups, a significant increase in the incidence of pregnant females with soft stool and/or diarrhea, and with yellowish stool was observed. Maternal body weight gain at 3.8 mg/kg and food consumption at 2.5 and 3.8 mg/kg were decreased during the administration period. The survival rate of fetuses at terminal cesarean sectioning was decreased in the DBTCl-treated groups and significantly decreased at 2.5 mg/kg. There were no changes in the developmental parameters of surviving fetuses, including fetal body weight, crown-rump length, tail length, sex ratio, anogenital distance and placental weight, in the DBTCl-treated groups. No external, internal or skeletal malformations were found in the fetuses in any group. Although internal and skeletal variations were found, no difference in the incidence of fetal variation was noted between the control and DBTCl-treated groups. No effect on skeletal ossification was observed in fetuses in the DBTCl-treated groups. The data demonstrate that DBTCl is embryolethal but not teratogenic in cynomolgus monkeys.     

Protein malnourishment: a predisposing factor in acrylamide toxicity in pregnant rats.

Exposure to acrylamide (3-10 mg/kg body weight) was found to be lethal for protein-deficient pregnant rats as evidenced by their increased mortality. It had no such effect on the normal protein diet fed pregnant and nonpregnant rats and the protein-malnourished nonpregnant rats. Protein deficiency during pregnancy caused a significant decrease in the activity of brain monoamine oxidase and acetylcholinesterase and striatal [3H]spiperone binding, known to label dopamine receptors; had no significant effect on the binding of 3H-QNB (quinuclidinyl benzilate) to cerebellar and [3H]diazepam to frontocortical membranes, known to label muscarinic and benzodiazepine receptors, respectively; and had no significant effect on brain glutathione (GSH) levels in comparison with pregnant rats fed normal protein diet. Exposure to acrylamide (2 mg/kg body weight) in protein-malnourished pregnant rats caused a marked decrease in the activity of monoamine oxidase and acetylcholinesterase and also in the binding of [3H]spiperone, [3H]QNB, and [3H]diazepam to striatal, cerebellar, and frontocortical membranes, respectively. Kinetic studies revealed that decreased binding of these ligands in the specific brain regions were due to decreased receptor sites (Bmax). A reduction in the brain glutathione content was also observed in these animals in comparison with those fed a low-protein diet during pregnancy. Pregnant rats fed a normal-protein diet on acrylamide exposure, however, showed no such biochemical changes in comparison with the pregnant rats fed normal protein diet. Also, no effect on any of the parameters studied was observed in the adult nonpregnant rats fed a low-protein diet (for 18 d) and those exposed to the monomer (d 6-17) fed either a normal- or low-protein diet in comparison with respective controls. The results indicate that pregnancy under conditions of malnutrition modifies the susceptibility of pregnant rats toward acrylamide.     

Peri- and postnatal developmental toxicity of the fluoroquinolone antibacterial DW-116 in rats.

DW-116 is a fluoroquinolone antibacterial developed by Dong-Wha Pharmaceutical Industry Co. The aim of this study is to determine the potential adverse effects of this chemical on pregnancy, delivery and lactation of dams and on peri- and postnatal development of F1 offspring. The test chemical was orally administered to pregnant rats from day 16 of pregnancy, through parturition and throughout the period of lactation up to weaning (postnatal day 21) at dose levels of 0, 10, 50, or 250 mg/kg/day. The progeny were examined at birth and subsequently to weaning. Mortality, body weight change, physical signs of postnatal development (pinna detachment, incisor eruption, fur development, eye opening, testis descent and vaginal opening) and behavioral function (righting reflex, negative geotaxis, grip-strength, pupillary reflex, acoustic startle response, rotating rod test, open field test and water-filled T-maze test) were evaluated. When the exposed offspring reached maturity (11 weeks old) their reproductive capacity was assessed. Maternal toxicity was observed only in the highest dose group and was limited to decreased food consumption during the late stage of pregnancy. However, this change was not observed during the lactation period. There were no adverse effects on mortality, clinical signs, body weight, necropsy findings, organ weight of dams in any treatment group. No adverse effects on the offspring were seen with the low and middle doses tested, but the highest dose increased postnatal mortality. The number of stillborn was also increased at the highest dose but the difference was not statistically significant. Meanwhile, no treatment-related effects were observed in clinical sign, developmental and behavioral landmarks and necropsy findings at any dose levels tested. There were no treatment-related effects on the mating of the F1 generation and resulting F2 offspring. The results of this study indicate that the peri- and postnatal administration of DW-116 to female rats results in an increase in postnatal mortality at a minimally maternotoxic dose, i.e., 250 mg/kg/day. Under the experimental conditions, the no-observed-adverse-effect level for peri- and postnatal developmental toxicity was considered to be 50 mg/kg/day.     

Reproductive and developmental toxicity studies of S-1090, cefmatilen hydrochloride hydrate (2)--A study on oral administration during the period of organogenesis in rats

Cefmatilen hydrochloride hydrate (S-1090) was administered daily by gavage to female rats at doses of 100, 300 or 1000 mg potency/kg/day from Days 7 to 17 of pregnancy to assess its effects on dams and on development of the embryo-fetuses and offspring. Loose or reddish-brown feces were observed in dams of all the S-1090 dosing groups. Body weight gain was increased from the early stage of administration to the end of pregnancy, food consumption was transiently decreased at the early stage of administration, and water consumption was increased from the middle to the end of pregnancy in all the S-1090 dosing groups. However, no effects on pregnancy, parturition and lactation were observed. Necrospy revealed an increased cecum weight in pregnant and lactating dams of all the S-1090 dosing groups. No effects of S-1090 were observed in viability, growth, incidences of external, skeletal and visceral anomalies, and degree of ossification in F1 fetuses. No effects of S-1090 were observed in such parameters as viability, incidence of external and skeletal anomalies, physical development, sensory functions/reflexes, behavior and reproductive function in F1 offspring. No adverse effects were observed in F2 offspring. On the basis of these results, the no observed adverse effect levels of S-1090 are estimated to be less than 100 mg potency/kg/day for maternal general toxicity, 1000 mg potency/kg/day for maternal reproductive toxicity and the developmental toxicity in the embryo-fetuses and offspring under the conditions of the present study.     

Developmental toxicity of dimethylformamide in the rat following inhalation exposure.

Dimethylformamide (DMF) is a widely used industrial solvent. DMF has been reported to be a developmental toxin when given to rodents by injection or following dermal administration. In this study, groups of pregnant rats were exposed by inhalation to either 0 (control), 30, or 300 ppm DMF from gestation day 6 through 15. In the 300 ppm rats, both maternal weight gain during gestation and fetal weights were lower than those of the controls. Fetal resorptions were not increased in this group. No significant differences among either maternal or fetal rats were seen in the 30 ppm group compared to controls. Both fetal and maternal toxicity were noted at 300 ppm and the no observed effect level under these experimental conditions was 30 ppm for both the dams and the conceptuses. DMF did not produce malformations in the rat fetus even at a level that was toxic to the dam.     

Cisplatin exposure induces mitochondrial toxicity in pregnant rats and their fetuses.

High levels of cis-diamminedicholorplatinum II (cisplatin)-DNA adducts have previously been observed at term in mitochondrial DNA (mtDNA) from organs of pregnant rats, and from their offspring, after administration of a single injection of cisplatin 15 mg/kg body weight (bw) to the pregnant rat on day 18 of gestation. The consequences of such DNA damage may be clinically relevant as cisplatin is given to pregnant women discovered to have ovarian cancer during pregnancy. In this study, kidneys, livers, and brains of exposed pregnant rats and their offspring were examined for mitochondrial functional integrity. Consistent with previous literature, the most severe toxicity occurred in maternal kidney, where oxidative phosphorylation (OXPHOS) enzyme activities were significantly (approximately 50%) impaired for Complexes II, III, and IV, mtDNA levels in drug-exposed animals were higher than in the unexposed controls, and abnormal mitochondrial morphology was observed by transmission electron microscopy (TEM). In fetal kidneys and livers, cisplatin exposure did not alter mitochondrial morphology or mtDNA quantity, but specific activities of OXPHOS Complexes II and IV were significantly decreased. Fetal brain sustained no discernible mitochondrial toxicity. Therefore, cisplatin-induced mitochondrial toxicity in maternal rat kidney is severe, while damage to mitochondria in fetal kidney and liver, occurring as a result of the transplacental drug exposure, appears to be mild.     

Developmental and reproductive toxicity evaluation of toluene vapor in the rat II. Developmental toxicity

The developmental toxicity of toluene was evaluated via whole body inhalation exposure, in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) from gestation day (GD) 6–15 inclusive, 6 h/day, at concentrations of 0, 250, 750, 1500 and 3000 ppm (0, 938, 2812, 5625 and 11250 mg/m³). Doses were selected from a preliminary study performed over a range of concentrations from 0 to 5000 ppm, in which maternal and fetal toxicity were observed at 2000 ppm and above. This study has been cited in various regulatory documents and is presented here to allow greater accessibility to results and conclusions.

Toluene induced clinical signs in pregnant dams (ataxia, hyper-responsivity, increased water intake, decreased food consumption) at 3000 ppm, ataxia and hyper-responsivity at 1500 ppm, and reduced maternal body weight gain at 1500 during the exposure period only and at 3000 ppm from initiation of exposure to GD20. At Caesarean section on GD20, no adverse effects on implantation, number and viability of fetuses, or fetal sex distribution were observed. Litter weight and mean fetal weight was reduced at 3000 ppm and mean fetal weight was reduced at 1500 ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Mean fetal weight was also reduced at 250 ppm but not at 750 ppm. Extensive statistical analysis of fetal body weight data support the conclusion that there is no toxicologically significant dose-related effect on fetal body weight at or below 750 ppm. Low incidences (≤2.5%) of various malformations occurred in the 250, 1500, and 3000 ppm groups; there was no increase in the incidence of specific or total malformations with increased exposure and thus these were not attributed to toluene.

In this Toluene study, the maternal toxicity NOAEL was 750 ppm with a defined maternal and developmental toxicity LOAEL of 1500 ppm.     

复脑苏I段生殖毒性研究

目的：观察复脑苏对SD大鼠的I段生殖毒性。方法：采用SD大鼠，雌雄各80只，分为3个剂量组（7．5、15．0和30mg／kg）和一个对照组（0．85％生理盐水），每组20只大鼠。雄鼠于交配前28d给药；雌鼠于交配前14d给药，给药至妊娠后第6天。实验组和对照组给药容量为1mL／100g体重，均采用尾静脉给药。雄鼠于交配后剖杀；1／2孕鼠于妊娠第14天剖杀，另1／2自然分娩。观察雄鼠、雌鼠和F1代仔鼠的相关指标。结果：复脑苏在各受试剂量下，对雄性大鼠的精子发生无明显影响，表现为活精子数、精予畸形率、脏器系数与对照组比较无统计学差异（P〉0．05）；病理学检查显示，未引起睾丸、附睾明显的病理学改变。复脑苏在各受试剂量下，对雌性大鼠的生殖功能也未见明显影响，表现为交配率、受孕率、流产率、活胎率、吸收胎率与对照组比较差异无统计学意义（P〉0．05）；也不影响仔鼠的出生存活率和哺育存活率。结论：在受试剂量下复脑苏对雄性和雌性大鼠无生殖毒性。     

Sucrose-rich feeding during rat pregnancy-lactation and/or after weaning alters glucose and lipid metabolism in adult offspring

1. Adverse fetal and early life environments predispose to the development of metabolic disorders in adulthood. The present study examined whether offspring of normal Wistar dams fed a high-sucrose diet (SRD) developed impaired lipid and glucose homeostasis when fed a control diet (CD) after weaning. In addition, we investigated whether there were more pronounced derangements in lipid and glucose homeostasis when offspring of SRD-fed Wistar were fed an SRD after weaning compared with those in offspring of CD-fed dams weaned on an SRD. 2. During pregnancy and lactation, female rats were fed either an SRD or CD. After weaning, half the male offspring from both groups were fed a CD or SRD, up to 100 days of age (CD-CD, CD-SRD, SRD-SRD and SRD-CD groups). 3. Final bodyweight was similar between all groups, although offspring of SRD-fed dams had lighter bodyweight at birth. Plasma lipid and glucose levels were significantly higher (P < 0.05) without changes in insulin levels in the CD-SRD, SRD-SRD and SRD-CD groups compared with the CD-CD group. Dyslipidaemia in the CD-SRD and SRD-SRD groups resulted from increased secretion of very low-density lipoprotein triacylglycerol, as well as decreased triacylglycerol (TAG) clearance that was associated with increased liver TAG content (P < 0.05) compared with the CD-CD group. The hypertriglyceridaemia observed in the SRD-CD group was mostly associated with decreased TAG clearance. Altered glucose and insulin tolerance were observed when the SRD was fed during any period of life. 4. These data support the hypothesis that early life exposure to SRD is associated with changes in lipid and glucose metabolism, leading to an unfavourable profile in adulthood, regardless of whether offspring consumed an SRD after weaning.     

Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats

Butyl benzyl phthalate (BBP) was administered in the diet at 0, 750, 3750, and 11,250 ppm ad libitum to 30 rats per sex per dose for two offspring generations, one litter/breeding pair/generation, through weaning of F2 litters. Adult F0 systemic toxicity and adult F1 systemic and reproductive toxicity were present at 11,250 ppm (750 mg/kg per day). At 11,250 ppm, there were reduced F1 and F2 male anogenital distance (AGD) and body weights/litter during lactation, delayed acquisition of puberty in F1 males and females, retention of nipples and areolae in F1 and F2 males, and male reproductive system malformations. At 3750 ppm (250 mg/kg per day), only reduced F1 and F2 offspring male AGD was present. There were no effects on parents or offspring at 750 ppm (50 mg/kg per day). The F1 parental systemic and reproductive toxicity no observable adverse effect level (NOAEL) was 3750 ppm. The offspring toxicity NOAEL was 3750 ppm. The offspring toxicity no observable effect level (NOEL) was 750 ppm, based on the presence of reduced AGD in F1 and F2 males at birth at 3750 ppm, but no effects on reproductive development, structures, or functions.     

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.     

Studies on the pharmacological bases of fetal toxicity of drugs. (VI) Teratogenic effects of trypan blue and related compounds in rats

The teratogenicity of trypan blue and its related compounds was studied in Wistar rats and the following results were obtained: 1) o-Tolidine, 1-amino-8-naphthol-3, 6-disulfonic acid or 1-nitronaphthalene-3, 6-disulfonic acid was injected subcutaneously on day 7 of pregnancy (sperm = day 0). No fetotoxicity was observed in any group. 2) The main fractions, blue fraction (blue fr.) and red fraction (red fr.), were separated from commercial trypan blue (C-TB) by silica gel column chromatography. C-TB, blue fr. or red fr. was injected into pregnant rats subcutaneously on day 7 of pregnancy. The incidence of malformed fetuses after injection of blue fr. was higher than that of C-TB, and the types of malformations induced by C-TB and blue fr. were similar. However, no fetotoxicity was detected after injection of red fr. 3) Blue fr. or red fr. was injected into the exocoelom on day 11 of pregnancy. The incidence of malformed fetuses in the group injected with blue fr. (2.5 micrograms/embryo) was 39%, and the types of malformations were abnormal tail and vertebrae, which were also observed after injection of C-TB or blue fr. into pregnant rats. No significant teratogenic effect was observed after injection of red fr. From these data, it was concluded that the teratogenic effect of C-TB might be due to the blue fr., but not the red fr.     

Effect of period of exposure on the developmental toxicity of butyl benzyl phthalate in rats.

The objective of the present study was to determine if periods of exposure would modify the developmental toxicity of butyl benzyl phthalate (BBP). Pregnant Wistar rats were given BBP at a dose of 2.0% in the diet on days 0-20, days 0-7, days 7-16 or days 16-20 of pregnancy. Food consumption and body weight gain were decreased in the pregnant rats given BBP. All dams given BBP on days 0-20 exhibited complete resorption of all the implanted embryos. Post-implantation loss in the pregnant rats given BBP on days 0-7 or 7-16 was higher than that in the control and pair-fed pregnant rats. No increase in post-implantation loss was found in the pregnant rats given BBP on days 16-20. Pre-implantation loss in the BBP-treated groups was comparable to the control and pair-fed groups. Striking teratogenicity was detected in fetuses of the dams given BBP on days 7-16. Cleft palate and fusion of the sternebrae were predominantly observed. About 95% of the fetuses in this group had cleft palate. The incidence of malformations in this group was significantly and markedly higher than that in the control and pair-fed groups.