Teratogenic vulnerability of Wistar rats to diphenyl ditelluride

The effect of single maternal subcutaneous (s.c.) injection of 0.12 mg/kg diphenyl ditelluride, (PhTe)2, diluted in canola oil at days 6, 10 or 17 of gestation were evaluated in Wistar rats. The reduction of body weight gain was statistically significant at GD9, for the dams that received (PhTe)2, at GD6; at GD13, for the dams that received (PhTe)2, at GD10, and at GD20, for the dams that received (PhTe)2, at GD17, when compared to respective control groups. External and internal fetal soft tissues examination was performed on day 20 of gestation. Single maternal injection at day 10 of gestation resulted in appearance of malformation in fore- and hind-limbs, absent or short tail, subcutaneous blood clots, exophthalmia, hydrocephalus and absence of the cranial bone and cutaneous tissue in fetuses on day 20 of gestation. Besides, (PhTe)2 reduced fetal body and cerebral weight, kidney length, measurements of body dimension and provoked 73% of fetal mortality. Subcutaneous administration of (PhTe)2 on day 17 of gestation was associated with 94% mortality, hydrocephalus and edema. Histological evaluations of fetal brain demonstrated displaced brain tissue with absence of the cranial bone and cutaneous tissue when diphenyl ditelluride was administered in GD10. Histological evaluation of fetal head exposed at GD17 revealed a decrease of the brain volume with consequent dilation of the lateral ventricles and the adjacent tissues were thinner than that of control group tissues. No fetal changes were observed after administration of (PhTe)2 at day 6 of gestation. Thus, (PhTe)2 can be teratogenic to rat fetuses and toxic for dams. The late fetal stages of rat prenatal development appeared uniquely sensitive to organic tellurium exposure.     

Gestational age dependency in the prenatal toxicity and in the disposition kinetics of the novel anticonvulsant HEPP (D,L-3-hydroxy-3-ethyl-3-phenylpropionamide) after subcutaneous administration in pregnant rats

HEPP (D,L-3-hydroxy-3-ethyl-3-phenylpropionamide) is a novel anticonvulsant with promising anticonvulsant profile, which is being actively researched. The potential maternal and embryo/fetal toxicities of HEPP were evaluated in pregnant rats following subcutaneous (s.c.) administration during organogenesis (gestation days 6 through 14, GDs 6-14) and the fetal period (GDs 14-21). Single- and multiple-dose pharmacokinetics were also evaluated at the same periods in order to establish possible correlations with some maternal or embryo/fetal toxicity end points. Embryotoxicity was mainly indicated by a significant dose-concentration dependency in the increase in resorptions, high percentage of fully resorbed litters, and decrease in embryo body weights during the GD6-14 dosing period. No gross external alterations were observed in live fetuses. There was no indication of maternal toxicity; but a marked increase in maternal body weight was evident following dosing from GD14 to GD21. The maternal plasma profile following single subcutaneous dose of 50 mg/kg on both GD14 and GD21 showed a monoexponential elimination pattern. Statistically significant differences between treatments (GD14 versus GD21) were observed in elimination (k(el) = 0.12 versus 0.15 h(-1)), absorption (k(a) = 2.01 versus 3.14 h(-1)), maximum plasma concentration time points (T(max) = 1.49 versus 1.01 h); maximum plasma concentration (C(max) = 40.23 versus 36.31 microg/ml) and areas under the concentration-time curve (AUCs(0-infinity) = 421.88 versus 274 microg h/ml. Based on comparisons of C(max), T(max), and AUCs(0-infinity) between the actual data and single intraperitoneal (i.p.) data previously published, the s.c. administration exhibited slower disposition and higher absorbed amount. After multiple-dose administrations of 50 and 100 mg/kg every 12 h (07:00 and 19:00 h), steady-state plasma levels were lower than the computer prediction, and only slight accumulation was observed. In both dosing periods HEPP levels were similar in mothers and offspring at steady-state conditions. The high incidence of embryo death and reduced embryo weight at GD6-14 dosing compared to GD14-21 dosing suggest that embryos are more sensitive to the deleterious effects of HEPP than fetuses; however, the faster elimination observed at late gestation could also contribute to the lower toxicity observed during the fetal period. Because the maternal HEPP plasma levels and the AUC values were positively correlated with embryo/fetal toxicity end points, both pharmacokinetic parameters could be reliable indicators of offspring exposure and consequently of potential toxicity. These data suggest that the length of time that HEPP is present in the maternal plasma at a sufficiently high concentration could be determinant of adverse effects in the offspring.     

Sub-chronic exposure of adult male rats to diphenyl ditelluride did not affect the development of their progeny.

The present study was undertaken to evaluate the toxicity of diphenyl ditelluride [(PhTe)(2)] exposure on the progeny of Wistar male rats. Male rats were exposed to (PhTe)(2) subcutaneously for 4 weeks (wk) at the dose of 0.006 mg/kg and 8-wk at the dose of 0.003 mg/kg, prior to mating with unexposed females. The body and sex organ weights of male rats were not affected in both 4- and 8-wk (PhTe)(2)-exposed groups. The gravid uterus weight and the body weight gain (overall or corrected) during the pregnancy were not statistically different to those obtained from females mated with control males. The number of implantation sites, resorptions and live and dead fetuses were not affected by male exposure to (PhTe)(2). Fetal body weight and crown-rump length were not affected, as well. Examination of the fetuses from both exposed groups for external and skeletal changes did not reveal any male-mediated effect of (PhTe)(2). The current study indicated that (PhTe)(2) given sub-chronically (4- or 8-wk) to male rats had no adverse effects on their progeny.     

Potential renal and hepatic toxicity of diphenyl diselenide,diphenyl ditelluride and Ebselen for rats and mice

The occupational importance of tellurium and selenium is growing rapidly, but the biochemistry of exposure is poorly understood. Here we report the potential toxic effects of diphenyl diselenide (PhSe)(2), diphenyl ditelluride (PhTe)(2) and Ebselen in rats and mice. The results suggest that (PhTe)(2) is more toxic in rats than mice. (PhSe)(2), (PhTe)(2) and Ebselen are more toxic by intraperitoneal (i.p.) than subcutaneous (s.c.) route. Calculated LD(50) for (PhTe)(2), i.p., was 0.65 micromol/kg in rats and 150 micromol/kg in mice, and LD(50), s.c., was 0.9 micromol/kg in rats and >500 micromol/kg in mice. Calculated LD(50) for Ebselen, i.p., was 400 micromol/kg in rats and 340 micromol/kg in mice and LD(50), s.c., was >500 micromol/kg in both mice and rats. (PhTe)(2) at small doses increased 2-fold serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in rats. LD(50) for all organochalcogens administrated in mice inhibited blood delta-ALA-D activity. The present study provides evidence for liver and renal toxicity of (PhTe)(2).     

Effects of prenatal exposure to the environmental pollutant 2-bromopropane on embryo-fetal development in rats

2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered subcutaneously to pregnant rats at dose levels of 0, 250, 500, and 1000 mg/kg per day. All dams were subjected to caesarean section on GD 20 and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, maternal toxicity included an increase in the incidence of abnormal clinical signs, a suppression in the body weight and body weight gain, and a decrease in the food intake. Developmental toxicity included an increase in the fetal deaths, a decrease in the litter size, and a reduction in the fetal body weight. In addition, an increase in the incidence of fetal external, visceral, and skeletal abnormalities was seen. In the 500 mg/kg group, minimal developmental toxicity including decreased fetal body weight and increased fetal ossification delay was observed. There were no adverse effects on either pregnant dams or embryo-fetal development in the 250 mg/kg group. These findings suggest that a 14-day subcutaneous dose of 2-BP is embryotoxic and teratogenic at a maternally toxic dose (i.e., 1000 mg/kg per day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 500 mg/kg per day) in Sprague-Dawley rats. In the present experimental conditions, the no-observed-adverse-effect level (NOAEL) of 2-BP is considered to be 500 mg/kg per day for dams and 250 mg/kg per day for embryo-fetal development.     

The Evaluation of the Developmental Toxicity of Hydrochlorothiazide in Mice and Rats

Timed-pregnant CD-1 outbred albino Swiss mice and CD Sprague-Dawleyrats were administered hydrochlorothiazide (HCTZ, USP) in cornoil by gavage during major organogenesis, Gestational Days (GD)6 through 15. The doses administered were 0, 300, 1000, or 3000mg/kg/day for mice and 0, 100, 300, or 1000 mg/kg/day for rats.Maternal clinical status was monitored daily during treatment.At termination (GD 17, mice; GD 20, rats), confirmed pregnantfemales (20–27 per group, mice; 36–39 per group,rats) were evaluated for clinical status and gestational outcome;each live fetus was examined for external, visceral, and skeletalmalformations. In mice, no maternal mortality was observed.However, clinical signs including dehydration, pioerection,lethargy, and single-day weight loss appeared to be doserelated.HCTZ had no effect on maternal weight gain or water consumption,gravid uterine weight, relative maternal liver weight, or relativematernal kidney weight. There was no definitive evidence ofembryotoxicity or fetal toxicity for mice on GD 17. Thus, theno observed adverse effect level (NOAEL) for both maternal anddevelopmental toxicity was 3000 mg/kg/day. In rats, HCTZ hadno effect on maternal survival, clinical signs, or water consumption.Clinical signs were not dose-related. Maternal weight gain duringtreatment was depressed at 1000 mg/kg/day. Gravid uterine weightand relative maternal liver weight were unaffected. Relativematernal kidney weight was slightly (7–8%) increased atall dose levels, but there was no evidence of a dose response.Thus, the maternal NOAEL for rats was 300 mg/kg/day, based ondecreased maternal weight gain during treatment at 1000 mg/kg/day. HCTZ had no effect on prenatal mortality, fetal growth,or morphological development in rats. The developmental NOAELwas l000 mg/kg/day. In summary, oral administration of HCTZto mice at doses up to 3000 mg/kg/day and rats at doses up to1000 mg/kg/day during organogenesis produced no evidence ofdevelopmental toxicity in either species, in spite of mild maternaltoxicity in rats at 1000 mg/kg/day.     

Effects of melamine on pregnant dams and embryo‐fetal development in rats

There are worldwide concerns regarding the potential adverse effect of melamine. This study investigated the potential effects of melamine on pregnant dams and embryo‐fetal development in Sprague–Dawley rats following maternal exposure on gestational days (GD) 6–20. Melamine was administered to pregnant rats by gavage at doses of 0, 200, 400 and 800 mg kg^?1 per day (n = 8–10 for each group). All dams were subjected to a Caesarean section on GD 21 and their fetuses were examined for morphological abnormalities. With administration of melamine at 800 mg kg^?1 per day, maternal toxicity manifested as increased incidences of clinical signs and death, lower body weight gain and food intake, and increases in heart, adrenal gland and kidney weights. Histopathological examinations revealed an increase in incidences of congestion, tubular necrosis/degeneration, crystals, casts, inflammatory cells in tubules, tubular dilation and tubular hyaline droplets in the maternal kidneys, while fetal kidneys (one fetus/litter) did not show any histopathological changes. Developmental toxic effects included a decrease in fetal weight, an increase in the incidence of skeletal variations and a delay in fetal ossification. No treatment‐related maternal or developmental effects were observed at doses ≤400 mg kg^?1 per day. These results show that 15‐day repeated oral dosing of melamine is embryo‐/fetotoxic at a maternotoxic dose, but not teratogenic in rats. The no‐observed‐adverse‐effect level of melamine for pregnant dams and embryo‐fetal development is considered to be 400 mg kg^?1 per day. Copyright © 2011 John Wiley & Sons, Ltd.     

Developmental toxicity of N-methyl-2-pyrrolidone in rats following inhalation exposure.

The developmental toxicity of inhaled N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats. Pregnant rats were exposed whole body to NMP vapours at concentrations of 0, 30, 60 and 120 ppm, 6 h/day, on gestational days (GD) 6 through 20. Maternal body weight gain was significantly decreased at 60 and 120 ppm on GD 6-13 and maternal food consumption was reduced at 120 ppm on GD 13-21. No significant difference in the gestational weight change corrected for the weight of the gravid uterus was observed, whatever NMP concentration. There were no adverse effects on embryo/fetal viability or evidence of teratogenicity at any concentration tested. Fetal toxicity indicated by reduced fetal weight was observed at 120 ppm. Thus, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 30 and 60 ppm, respectively.     

Developmental toxic potential of 1,3-dichloro-2-propanol in Sprague–Dawley rats

This study investigated the potential adverse effects of 1,3-dichloro-2-propanol (1,3-DCP) on pregnant dams and the embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague–Dawley rats. The test chemical was administered to pregnant rats by gavage at dose levels of 0, 10, 30, and 90 mg/kg per day (n = 10 for each group). All dams underwent Caesarean sections on GD 20, and their fetuses were examined for morphological abnormalities. Maternal toxicity was noted at 90 mg/kg/day. Manifestations of toxicity included clinical signs of illness, lower body weight gain, decreased food intake, and increases in the weight of the adrenal glands and the liver. Developmental toxic effects including decreases in fetal body weight and increases in visceral and skeletal variations also occurred at the highest dose. At 30 mg/kg, only a minimal maternal toxicity, including a decrease in maternal food intake and an increase in the liver weight, was observed. No adverse maternal or developmental effects were observed at 10 mg/kg/day. These results revealed that a 14-day repeated oral dose of 1,3-DCP was minimally embryotoxic but not teratogenic at a maternal toxic dose (90 mg/kg/day), and was not embryotoxic at a minimally maternal toxic dose (30 mg/kg/day) in rats. Because the developmental toxicity of 1,3-DCP was observed only in the presence of maternal toxicity, it is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of 1,3-DCP is considered to be 10 mg/kg/day for dams and 30 mg/kg/day for embryo-fetal development.     

Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in rats.

Dexamethasone (DEX) has been shown to elicit growth stunting and cleft palate in rat fetuses. This investigation characterized DEX dosimetry as various pharmacokinetic parameters and evaluated their impact on developmental toxicity endpoints. DEX pharmacokinetics was evaluated as a single dose on either gestation day (GD) 9 or 14, as well as on GD 14 after multiple daily dosing from GD 9 to GD 14. An additional set of pregnant rats was dosed with DEX on GD 9 through GD 14, pharmacokinetic evaluation was conducted on GD 14 through GD 16, and teratological evaluation was conducted following sacrifice on GD 20. For all pharmacokinetic evaluations, a subcutaneous (sc) injection of 0.8 mg DEX/kg body weight together with 50 microCi 3H-DEX was administered to Sprague-Dawley rats. Blood, urine, and feces were collected for 24 or 48 h. At GD 20 sacrifice, maternal tissues as well as fetal brain and liver samples were collected as part of the laparotomy. All samples were assayed using scintillation spectrometry. DEX pharmacokinetic parameters remained similar whether dosing occurred early (GD 9) or late (GD 14) in organogenesis, or dosing occurred on multiple sequential days (GD 9-14). DEX produced maternal and fetal weight loss, fetal lethality, and cleft palate. DEX a-half-life was positively correlated with the percentage of implants affected [(number of non-live + number with cleft palate)/number of implants]/litter. Neither the area under the concentration-time curve (AUC), the maximum maternal plasma concentration (Cmax), nor the terminal phase beta-half-life correlated with any fetal outcome parameters. The correlation between the percentage of the litter that was affected and half-life was improved if AUC was added in a stepwise multiple regression. These data suggest that the length of time that DEX is present in the maternal plasma at a sufficiently high concentration (i.e., slower tissue distribution of DEX) appears to be important in determining the risk of an adverse outcome in the offspring.     

Metabolism and pharmacokinetics of bisphenol A (BPA) and the embryo-fetal distribution of BPA and BPA-monoglucuronide in CD Sprague-Dawley rats at three gestational stages.

The pharmacokinetics of bisphenol A (BPA), including the quantification of the major BPA metabolite BPA-monoglucuronide conjugate (BPA-glucuronide) was studied in Sprague-Dawley rats at different stages of gestation. 14C-BPA was administered orally at 10 mg BPA/kg body weight (0.2 mCi/rat) to nongravid rats and to other groups on gestation days (GD) 6, 14, and 17. GD 0 was when the vaginal smear was sperm positive or a copulatory plug was observed. Radioactivity derived from 14C-BPA was quantified in the maternal blood, selected tissues, and the embryo or fetus. BPA and BPA-glucuronide were quantified in maternal plasma and excreta. Additional rats were dosed orally at 10 mg 14C-BPA/kg (0.2 mCi/rat or 0.5 mCi/rat) on GD 11, 13, and 16 to further study the distribution of BPA and BPA-glucuronide to the embryo/fetal tissue. The tissue distribution, metabolism, or the rates or routes of excretion of BPA, or the plasma concentration-time profiles of BPA-glucuronide did not appear to be altered at any stage of gestation as compared to nonpregnant rats. In the GD 11 group, neither BPA nor BPA-glucuronide was detected in the yolk sacs or embryos, except for trace concentrations of BPA-glucuronide in the yolk sacs at 15 min postdosing. In the GD 13 group, both BPA and BPA-glucuronide were detected in the yolk sacs of the conceptus but not in the embryos/fetuses, except for BPA at 15 min. For the animals dosed with 0.2 mCi/rat on GD 16, both analytes were detected in the placentae at 15 min and 12 h, but not at 96 h. Traces of both analytes were detected in fetal tissue in two of five specimens at 15 min only. In rats dosed on GD 16 with 0.5 mCi/rat, the BPA-glucuronide and BPA concentrations in maternal plasma at 15 min were 1.7 and 0.06 mug equivalents (eq)/g plasma, respectively. At the same time postdosing in these animals, the placental BPA-glucuronide concentrations were lower (0.34 mug eq BPA [as glucuronide]/g), and the BPA concentrations were about equivalent (0.095 mug/g). Fetal BPA-glucuronide and BPA concentrations were markedly lower, 0.013 and 0.018 mug eq/g, respectively. Therefore, no selective affinity of either yolk sac/placenta or embryo/fetus for BPA or BPA metabolites relative to maternal plasma or tissues was observed in this study.     

2,3,7,8-Tetrachlorodibenzo-p-dioxin in Pregnant Long Evans Rats: Disposition to Maternal and Embryo/Fetal Tissues

Prenatal exposue to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)interfereswith fetal development at doses lower than those causing overttoxicity in adult animals. In a multigeneration study (Murrayet al., 1979), female rats that were administered 0.01 µgTCDD/kg/day in their diet did not experience reduced fertility;however, reduced fertility was seen in the F₁ and F₂ generations.Exposure to TCDD during development produces alterations inthe reproductive system of the developing pups, such as delayedpuberty and reduced sperm counts in males (Mably et al., 1992a;Gray et al., 1995) and malformations in the external genitaliaof females (Gray and Ostby, 1995). Therefore, the objectivesof this study were to determine maternal and fetal tissue concentrationsof TCDD that are associated with the adverse reproductive effectsseen by Gray and co-workers. Pregnant Long Evans rats receiveda single oral dose of 1.15 µg [₃H]TCDD/kg on GestationDay (GD) 8 and maternal as well as fetal tissue concentrationsof TCDD were measured on GD9, GD16, and GD21. On GD9, the highestlevel of TCDD localized in the maternal liver (25.1% dose).In addition, the amount reaching all the embryos on GD9 was0.01% of the administered dose, which resulted in a concentrationof 0.02% dose/g . The amount of TCDD reaching the fetal compartment(fetuses + placentas) increased to 0.12% dose/tissue on GD16and 0.71% by GD21. The concentration of TCDD within the fetalcompartment (0.01% dose/g) on GD16 was comparable to that foundin the maternal blood and spleen. Concentrations of TCDD ina single embryo/fetus were 39.6, 18.1, and 22.1 pg/g on GD9,GD16, and GD21, respectively. Estimates of hepatic half-lifeof elimination in pregnant rats suggested that TCDD may be eliminatedfaster in pregnant LE rats. Therefore, measurements of biliaryelimination were made in pregnant and nonpregnant LE rats tocompare rates of metabolism; however, biliary elimination ofTCDD is not affected by pregnancy. In conclusion, this doseadministered during a critical period of organogenesis causesadverse effects on the developing reproductive system of rodents.This dose produced a body burden of 22.1 pg TCDD/g within asingle fetus on GD21. This indicates that low-level TCDD exposureduring the perinatal stage of life can produce adverse effectswithin the developing pups.     

Developmental toxicity assessment of arsenic acid in mice and rabbits

To evaluate potential effects of exposure to inorganic arsenic throughout major organogenesis, CD-1 mice and New Zealand White rabbits were gavaged with arsenic acid dosages of 0, 7.5, 24, or 48 mg/kg/d on gestation days (GD) 6 through 15 (mice) or 0, 0.19, 0.75, or 3.0 mg/kg/d on GD 6 through 18 (rabbits) and examined at sacrifice (GD 18, mice; GD 29, rabbits) for evidence of toxicity. Two high-dose mice died, and survivors at the high and intermediate doses had decreased weight gains. High-dose-group fetal weights were decreased; no significant decreases in fetal weight or increases in prenatal mortality were seen at other dosages. Similar incidences of malformations occurred in all groups of mice, including controls. At the high dose in rabbits, seven does died or became moribund, and prenatal mortality was increased; surviving does had signs of toxicity, including decreased body weight. Does given lower doses appeared unaffected. Fetal weights were unaffected by treatment, and there were no effects at other doses. These data revealed an absence of dose-related effects in both species at arsenic exposures that were not maternally toxic. In mice, 7.5 mg/kg/d was the maternal No-Observed-Adverse-Effect-Level (NOAEL); the developmental toxicity NOAEL, while less well defined, was judged to be 7.5 mg/kg/d. In rabbits, 0.75 mg/kg/d was the NOAEL for both maternal and developmental toxicity.     

Developmental toxicity of copaiba tree (Copaifera reticulata Ducke, Fabaceae) oleoresin in rat

The oleoresin of the copaiba tree (Copaifera sp., Fabaceae) is traditionally used in Brazilian herbal medicine to treat a variety of illnesses and symptoms. This study, conducted according to the OECD Guideline 414, provides data on the developmental toxicity of oleoresin from C. reticulata (COPA-R) in rats. Pregnant Wistar rats (25 per dose group) were treated by gavage with COPA-R (0, 500, 1000 and 1250 mg/kg bw/day) on gestation days (GD) 6-19 and Caesarean sections performed on GD20. Implantations, living and dead fetuses and resorptions were recorded. Half of the fetuses from each litter were examined for visceral abnormalities and the remaining were cleared and stained for skeleton evaluation. COPA-R was maternally toxic (reduced food intake and weight gain) and embryotoxic (lower fetal body weight and increased occurrence of fetal skeleton variations) at the two highest doses, but did not cause embryo deaths or fetal malformations at any dose level. The study derived an oral no-observed-adverse-effect-level (NOAEL) for maternal and developmental toxicity induced by COPA-R of 500 mg/kg bw/day. The results suggest that copaiba oleoresin does not pose a health risk to pregnant women when used according to the recommended doses (up to five drops, three times a day).     

Developmental exposure to fenproporex: reproductive and morphological evaluation

This study was designed to evaluate the maternal toxicity and teratogenicity of fenproporex, one of the most widely-used anorectic drugs in many countries, including Brazil. Three periods of exposure were evaluated: (a) 30 days before mating; (b) from gestational day (GD) 0 to 14; and (c) 30 days before mating and during pregnancy, until GD 14. Female mice from experimental groups received, by gavage, 15 mg/kg of fenproporex. Treatment with fenproporex increased ambulation of dams in the open-field test and did not influence the mobility in the forced-swimming test. There was no significant difference in maternal weight gain between the controls and fenproporex-treated groups, although fenproporex treatment reduced the gravid uterus weight. No significant difference was observed in postimplantation loss, fetal viability and sex ratio. In addition, this compound did not impair intra-uterine growth. The reduction in the number of implantations in the groups receiving fenproporex indicates that this drug may have an adverse effect on implantation. Fenproporex treatment also increased the number of fetuses presenting small kidneys and cervical ribs. The present results indicate that fenproporex, in the dose and exposure periods tested, appears to exhibit a low maternal toxicity and teratogenic potential in mice.     

Comparative embryotoxicities of butyl benzyl phthalate, mono-n-butyl phthalate and mono-benzyl phthalate in mice and rats: in vivo and in vitro observations

The embryotoxic effects of butyl benzyl phthalate (BBP) and its two main metabolites mono-n-butyl (MBP) and mono-benzyl (MBzP) phthalate were evaluated in OF1 mice and Sprague-Dawley rats, in vivo and in whole embryo culture. In vivo, pregnant mice and rats received a single oral dose (0.9-5.4 mmol/kg) of either of these compounds on GD 8 and 10, respectively, and their fetuses were examined externally on GD 18 and 21, respectively. In mice, BBP, MBP and MBzP caused concentration-related embryolethality and malformations. In rats, MBP and MBzP did not show developmental toxicity. Some teratogenicity and a slight increase in post-implantation loss were observed after BBP administration, but mice were more susceptible to its toxic effects than were rats. In vitro, GD 8 mouse embryos and GD 10 rat embryos were cultured for 46 h in the presence of the test compounds (0.5 to 3-5mM). The cultured mouse embryos did not appear intrinsically more sensitive to MBP and MBzP, than the rat embryos. Altogether, these results suggest that the species sensitivity observed in vivo after an oral administration of BBP, MBP or MBzP during early organogenesis, might be due to maternal factors, i.e. toxicity and/or kinetics.     

Rat embryonic palatal shelves respond to TCDD in organ culture

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a highly toxic environmental contaminant, is teratogenic in mice, inducing cleft palate (CP) and hydronephrosis at doses which are not overtly maternally or embryo toxic. Palatal shelves of embryonic mice respond to TCDD, both in vivo and in organ culture, with altered differentiation of medial epithelial cells. By contrast, in the rat TCDD produces substantial maternal, embryonic, and fetal toxicity, including fetal lethality, with few malformations. In this study the possible effects of maternal toxicity on induction of cleft palate were eliminated by exposure of embryonic rat palatal shelves in organ culture. The shelves were examined for specific TCDD-induced alterations in differentiation of the medial cells. On Gestation Day (GD) 14 or 15 palatal shelves from embryonic F344 rats were placed in organ culture for 2 to 3 days (IMEM:F12 medium, 5% FBS, 0.1% DMSO) containing 0, 1 x 10(-8), 1 x 10(-9), 1 x 10(-10), or 5 x 10(-11) M TCDD. The medial epithelial peridermal cells degenerated on shelves exposed to control media or 5 x 10(-11) M TCDD. Exposure to 10(-10), 10(-9), and 10(-8) M TCDD inhibited this degeneration in 20, 36, and 60% of the shelves, respectively, and was statistically significant at the two highest doses. A normally occurring decrease in [3H]TdR incorporation was inhibited in some GD 15 shelves cultured with 10(-10) and 10(-9) M TCDD. The medial cells of TCDD-exposed shelves continued to express high levels of immunohistochemically detected EGF receptors. The altered differentiation of rat medial epithelium is similar to that reported for TCDD-exposed mouse medial cells in vivo and in vitro. However, in order to obtain these responses, the cultured rat shelves require much higher concentrations of TCDD than the mouse shelves. Thus TCDD induces the same effects at a cellular level in medial epithelium of rats and mice, but cleft palate is not seen in rats because the level required to produce the cellular effects would result in maternal and embryonic toxicity including fetal lethality.     

Embryotoxicity and Fetotoxicity of Orally Administered Tridiphane in Mice and Rats

Embryotoxicity and Fetotoxicity of Orally Administered Tridiphanein Mice and Rats. HANLEY, T. R., Jr., JOHN-GREENE, J. A., HAYES,W. C., and RAO, K. S. (1987). Fundam. Appl. Toxicol. 8, 179–187.Tridiphane [2-(3,5-dichlorophenyl)-2-(2,2,2-trichloroethyl)oxirane],a broad-leaf herbicide, was evaluated for its potential effectson mouse and rat embryonal and fetal development. Pregnant CF-1mice were given 0, 25, 75, or 250 mg tridiphane/kg/day on Days6 through 15 of gestation. Significant maternal toxicity wasobserved in both the 75- and 250-mg/kg/day dose groups. An increasedpercentage of females given 250 mg/kg/day showed implantationsites only after staining of the uterus, suggesting a toxiceffect on the embryo during the early stages of development,possibly secondary to maternal toxicity. Increases in some skeletalvariants were noted at the 75-mg/kg dose level; however, a teratogeniceffect was not observed. An additional group of mice was given250 mg/kg/day on Days 8 through 15 of gestation. Maternal toxicitywas also observed among these mice as manifested by significantlyelevated (+50%) liver weight; however, there was a substantialincrease in the number of females with full-term litters followingthis shorter dosing period. An increase in the occurrence ofcleft palate in these offspring associated with low fetal bodyweights was also observed. Pregnant Sprague-Dawley rats weregiven 0, 30, 100, or 200 mg/kg/day of tridiphane on Days 6 through15 of gestation. Maternal toxicity was observed among rats given200 mg/kg. Increased incidences of two minor skeletal variants,lumbar spurs and extra ribs, were observed in the 200-mg/kg/daydose group, and an increase in lumbar spurs was observed at100 mg/kg/day. Thus, tridiphane was embryotoxic and inducedcleft palate in mice only at the maternally toxic dose levelof 250 mg/kg/day. Slight fetotoxicity (increased skeletal variants)was observed in mice at 75 mg/kg, a dose which also produceda significant elevation of liver weight in the maternal animal.In rats, slight fetotoxicity was observed at the maternallytoxic dose of 200 mg/kg/day, and very slight fetotoxicity at100 mg/kg/day. Neither test species showed evidence of significantdevelopmental toxicity at dose levels which were not toxic tothe dam. Thus, the no observed effect levels (NOELs) for tridiphaneunder these test conditions were 25 and 30 mg/kg/day for miceand rats, respectively.     

Teratogenic effects of diphenyl diselenide in Wistar rats

Diphenyl diselenide is an organoselenium compound with potential therapeutic use. The present study evaluates the effects of single maternal subcutaneous injection of 50 and 100 mg/kg diphenyl diselenide [(PhSe)₂] at gestational days (GD) 6, 10 or 17 in Wistar rats. The highest dose of (PhSe)₂ was also administered at GD 7–12. External and internal fetal soft-tissue examination was performed at GD 20. No mortality was observed in fetuses or dams at any (PhSe)₂ treatment group. Neither did exposure to (PhSe)₂ cause significant changes to fetal body weight, organ weight, or fetal size when administered at GD 6–8, 10–12 or 17. Exposure to 100 mg/kg (PhSe)₂ at GD 9 produced significant changes in fetal biometry (crown-rump (CR) length) and body weight. No significant increase in the proportion of fetuses with external visible abnormalities was observed in groups exposed to (PhSe)₂. Skeletal anomalies were observed in fetuses in the GD 9–11 treatment groups and included incomplete ossification of cranial bones, misshapen and incomplete ossification of sternebrae, reduced sternebrae number, wavy and extra ribs, incomplete ossification of fore and hindpaw bones and incomplete ossification of sacral and caudal bones. We conclude that maternal administration of (PhSe)₂ during GD 7–12 led to increased incidences of these skeletal variations or anomalies, but did not cause externally visible malformations in rat fetuses.     

Effects of 2-bromopropane on pregnant dams and embryo-fetal development in the ICR mouse

2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones (CFCs) which have a great potential to destroy the ozone layer and to warm the earth’s environment. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo–fetal development after maternal exposure during the gestational days (GD) 6–17 in ICR mice. The test chemical was administered subcutaneously to pregnant mice at dose levels of 0, 500, 1000, and 1500 mg/kg per day. All dams were subjected to caesarean section on GD 18 and their fetuses were examined for external, visceral and skeletal abnormalities. Throughout the study period, no treatment-related deaths were found in the groups treated with 2-BP. Pregnant mice of the 1000 and 1500 mg/kg groups showed treatment-related clinical signs such as rough fur and swelling, induration, crust formation, and ulceration in the injection sites which were dose dependent in incidence and severity. A decrease in fetal weight, an increase in fetal malformation, and an increase in fetal ossification delay were found at a dose level of 1500 mg/kg per day in a dose-dependent manner. On the contrary, there were no adverse effects on body weight, body weight gain, gravid uterine weight, food consumption, gross finding at any dose tested. In addition, no treatment-related effects on the number of corpora lutea, implantations, resorptions, dead fetuses, live fetuses, and sex ratio of live fetuses were observed. These findings suggest that 2-BP was embryotoxic and teratogenic at a minimally maternally toxic dose (i.e., 1500 mg/kg per day) in ICR mice. In the present experimental conditions, the no-observed-adverse-effect level of 2-BP is considered to be 500 mg/kg per day for dams and 1000 mg/kg per day for fetuses, respectively.