Developmental toxicity of pentostatin (2'-deoxycoformycin) in rats and rabbits

The developmental toxicity of the potent adenosine deaminase (ADA) inhibitor, pentostatin (2'-deoxycoformycin), was investigated in pregnant rats and rabbits administered daily iv doses during organogenesis. Rats received 0, 0.01, 0.10, or 0.75 mg/kg on gestation days 6-15 and rabbits received 0, 0.005, 0.01, or 0.02 mg/kg on gestation days 6-18 and maternal and fetal parameters were evaluated on gestation day 21 (rats) or 30 (rabbits). Live fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal body weight gain and food consumption were significantly suppressed at doses of 0.10 and 0.75 mg/kg during the treatment period but returned to control levels during posttreatment. Increased postimplantation loss and decreased numbers of live fetuses, litter size, and fetal body weight were observed at 0.75 mg/kg. A statistically significant increase in the incidence of vertebral malformations occurred at 0.75 mg/kg. The incidence of certain skeletal variations (extra presacral vertebrae, extra ribs, hypoplastic vertebrae) was also increased at 0.75 mg/kg. Ossification of cervical centra was reduced at 0.75 mg/kg compared with controls. In rabbits, marked maternal toxicity (death, body weight loss, and decreased food consumption) and reproductive toxicity (abortion and premature delivery) occurred in all pentostatin-treated groups. However, there were no significant effects on number of live fetuses, pre- or postimplantation loss, litter size, or fetal body weights in the animals with live litters. There was also no apparent increase in the incidence of malformations or variations in the live fetuses of pentostatin-treated rabbits. Thus, these studies demonstrate developmental toxicity of pentostatin in rats and rabbits, and teratogenicity in rats, at maternally toxic doses.     

Effects of an antisense oligonucleotide inhibitor of human ICAM-1 on fetal development in rabbits

The potential for reproductive toxicity of an antisense oligonucleotide designed to inhibit ICAM-1 was evaluated as part of the safety assessment for this compound. The human active ICAM-1 inhibitor (ISIS 2302) is not pharmacologically active in rabbits. Female rabbits were treated once daily on Day 6 through 18 of gestation. Rabbits were treated with 0, 1, 3, and 9 mg/kg ISIS 2302 by daily i.v. injection. Reproductive indices evaluated included estrus cycling, litter parameters, fetal development, and fetal body weight. Concentrations of oligonucleotide in plasma following the last dose, and in selected maternal target organs, placenta, and fetal tissues at scheduled necropsy were also measured. Maternal toxicity was evident as a decreased maternal body weight gain, decreased food consumption, and scant feces at doses > or =3 mg/kg. Increased spleen to body weight ratio and increased mononuclear cell infiltrates were indicative of a proinflammatory effect of ISIS 2302 at the 9 mg/kg dose level. Despite the maternal toxicity, there were no changes in litter parameters or fetal development in rabbits treated with ISIS 2302. The only change was a decrease in fetal body weight at the 9 mg/kg dose level, which was attributed to the maternal toxicity observed. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no oligonucleotide measured in placenta or fetal tissues. Thus, there was no dose-dependent exposure and maternal toxicity to ISIS 2302, but no reproductive toxicity in rabbits, and exposure of fetus or pups is negligible.     

Developmental toxicity evaluation of sodium thioglycolate administered topically to Sprague-Dawley (CD) rats and New Zealand White rabbits

BACKGROUND: Sodium thioglycolate, which has widespread occupational and consumer exposure to women from cosmetics and hair‐care products, was evaluated for developmental toxicity by topical exposure during the embryonic and fetal periods of pregnancy METHODS: Timed‐mated Sprague–Dawley rats (25/group) and New Zealand White (NZW) rabbits (24/group) were exposed to sodium thioglycolate in vehicle (95% ethanol:distilled water, 1:1) by unoccluded topical application on gestational days (GD) 6–19 (rats) or 6–29 (rabbits) for 6 hr/day, at 0, 50, 100, or 200 mg/kg body weight/day (rats) and 0, 10, 15, 25, or 65 mg/kg/day (rabbits). At termination (GD 20 rats; GD 30 rabbits), fetuses were examined for external, visceral, and skeletal malformations and variations. RESULTS: In rats, maternal topical exposure to sodium thioglycolate, at 200 mg/kg/day (the highest dose tested) on GD 6–19, resulted in maternal toxicity, including reduced body weights and weight gain, increased relative water consumption and one death. Treatment‐related increases in feed consumption and changes at the application site occurred at all doses, in the absence of increased body weights or body weight change. Fetal body weights/litter were decreased at 200 mg/kg/day, with no other embryo/fetal toxicity and no treatment‐related teratogenicity in any group. In rabbits, maternal topical exposure to sodium thioglycolate on GD 6–29 resulted in maternal dose‐related toxicity at the dosing site in all groups; no maternal systemic toxicity, embryo/fetal toxicity, or treatment‐related teratogenicity were observed in any group. CONCLUSIONS: A no observed adverse effect level (NOAEL) was not identified for maternal toxicity in either species with the dosages tested. The developmental toxicity NOAEL was 100 mg/kg/day (rats) and ≥65 mg/kg/day (rabbits; the highest dose tested). The clinical relevance of theses study results is uncertain because no data were available for levels, frequency, or duration of exposures in female workers or end users. Birth Defects Research Part B 68:144–161, 2003. © 2003 Wiley‐Liss, Inc.     

Conduct and interpretation of a dermal developmental toxicity study with KBR 3023 (a prospective insect repellent) in the Sprague-Dawley rat and Himalayan rabbit

KBR 3023, 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxyethyl)piperidine, a prospective insect repellent being developed by Bayer Corporation, was evaluated for developmental toxicity in the Sprague-Dawley rat and Himalayan rabbit. As the intended human usage of the test compound is topical, the test systems were exposed to the compound via the dermal route. Specifically, the animals were fitted with Elizabethan collars, to reduce the likelihood of oral ingestion, and dermally administered either 0, 50, 200, or 400 mg KBR 3023/kg (rat), and 0, 50, 100, or 200 mg KBR 3023/kg (rabbit) on gestation days 0-19 (rat) and 0-28 (rabbit). Maternal toxicity, as demonstrated by clinical signs and changes in body weight gain and food consumption during gestation, was characterized. Animals were sacrificed on gestation day 20 (rat) and 29 (rabbit), at which time fetuses were removed by cesarean section and a gross maternal necropsy was performed. All fetuses were evaluated for external anomalies. With rats, approximately half of each litter was examined for visceral effects; the other half underwent a skeletal examination. With rabbits, all fetuses underwent both visceral and skeletal examinations. No effects were observed on maternal body weight gain or food consumption in either the rat or rabbit. In the rat, dermal effects (scaling/sloughing), were observed at the dose site of all test substance-treated groups from approximately gestation day 7 until termination of the study. Also noted were an increase in both absolute and relative liver weights in rats in the 400-mg/kg dose group. In the rabbit, dermal effects (slight erythema, squamous and cracked skin) were noted at the dose site of virtually all does administered the test compound, from approximately gestation day 7 until termination. Also observed in the rabbits was a potentially compound-related increase in soft stool, particularly at the highest dose level. In both species, there were no statistically significant effects on any reproductive parameters, or any embryonic endpoints, including pre/post-implantation loss and resorptions. There were no statistically significant effects on litter size or fetal or placental weights. No test compound-related external, visceral, or skeletal findings were observed. No effect on the individual fetal or litter incidence of total malformations or variations was observed and there was no difference in the incidence of malformations between males and females. KBR 3023 Technical, administered as described in these studies, produced maternal effects in the rat (liver weight) at a dose of 400 mg/kg, and in the rabbit (soft stool) in the 200-mg/kg dose group. No developmental toxicity was observed at any dose level.     

Developmental toxicity of orally administered 2',3'-dideoxycytidine in mice

2',3'-Dideoxycytidine (DDC), a potent inhibitor of human immunodeficiency virus (HIV), is presently undergoing clinical trials as a promising anti-AIDS drug. Since there are very limited published animal toxicity data available, and nucleoside analogues are being considered for treatment of HIV-infected pregnant women, a study was conducted in mice to investigate the potential adverse developmental effects of this drug. DDC, suspended in 0.5% methyl cellulose, was administered via gavage twice per day during gestation days (gd) 6 through 15 to C57Bl/6N mice in a total dose of 0, 200, 400, 1,000, or 2,000 mg/kg/day. Maternal weight gain during the gestation and treatment period, as well as gravid uterine weight, decreased significantly in the 2,000 mg group, but weight gain, corrected for gravid uterine weight, was not affected by DDC. The percent resorptions per litter increased significantly in the highest dose group, and there were fewer live litters because of complete litter resorption in six dams. Among litters with live fetuses, the mean litter size was significantly reduced in the 2,000 mg group. Average fetal body weight per litter decreased significantly in the 1,000 and 2,000 mg groups. The number of fetuses with any malformation, the number of litters with one or more malformed fetuses and the percent of malformed fetuses per litter increased significantly in the 1,000 and 2,000 mg groups. There was an increase in malformations at 400 mg/kg/day; however, it was not statistically significant. In conclusion, DDC produced developmental toxicity (malformations, reduced fetal body weight, and resorptions) in the absence of overt maternal toxicity except for body weight changes due to resorptions and reduced fetal weights.     

Evaluation of the developmental toxicity of lenalidomide in rabbits

BACKGROUND: Lenalidomide, a thalidomide analog, is indicated for treatment of patients with deletion-5q myelodysplastic syndromes or multiple myeloma. NZW rabbits were used because of sensitivity to thalidomide's teratogenicity. METHODS: Range-finding and pulse-dosing studies preceded a full developmental toxicity study in New Zealand white (NZW) rabbits (25/group) given lenalidomide (0, 3, 10, or 20 mg/kg/day) or thalidomide (180 mg/kg/day) by stomach tube on gestation days (GD) 7-19. Clinical signs, body weights, and feed consumption were recorded daily from GD 7. On GD 29, standard maternal necropsy, uterine content, and fetal evaluations were carried out. RESULTS: In all studies, thalidomide was selectively toxic to development. In the pulse-dosing study, lenalidomide did not affect development at 100 mg/kg/day. Increases in C(max) and AUC(0-24 hr) values for lenalidomide were slightly less than dose-proportional; lenalidomide occurred in the fetuses. At 10 and 20 mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights and increased postimplantation losses and fetal variations (morbidity/purple-discolored skin, undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal ossification). Thalidomide selectively reduced fetal body weight, increased postimplantation loss and caused characteristic limb and other dysmorphology. CONCLUSIONS: The maternal and developmental NOAELs for lenalidomide are 3 mg/kg/day. Unlike thalidomide, lenalidomide affected embryo-fetal development only at maternally toxic dosages, confirming that structure-activity relationships may not predict maternal or developmental effects. No fetal malformations were attributable to lenalidomide.     

Teratogenicity of carbamazepine in rats

The teratogenicity of carbamazepine (CBZ) was investigated in Sprague-Dawley CD rats at doses of 0, 200, 400, and 600 mg/kg administered by gavage in corn oil on days 7-18 of gestation in a dosage volume of 2 ml/kg. The CBZ-600 dose was maternally toxic in that dams in this group weighed 30.6% less than controls by E20. This group had significantly increased resorptions, reduced live fetal weight (51.6% less than controls), and increased skeletal and visceral abnormalities. The CBZ-400 dose also significantly reduced maternal weight gain during gestation to 26.6% less than controls by E20. No significant increase in resorptions occurred in this group; live fetuses weighted 42.9% less than controls and showed an increase in visceral, but not skeletal, abnormalities. The CBZ-200 dose did not significantly affect maternal weight gain or increase resorptions or fetal abnormalities but did reduce fetal body weight (20.3% less than controls). Maternal serum total CBZ concentrations 1 hr after the final dose were 22.9, 27.9, and 34.4 micrograms/ml for the 200, 400, and 600 mg/kg groups, respectively. These levels were little changed 6 h post-treatment. CBZ was 65-70% serum protein bound across dose groups. Human therapeutic levels of CBZ are 4-12 micrograms/ml and the drug is typically 80% serum protein bound. This suggests that abnormalities in rats occur at concentrations well above the human therapeutic range. However, a no-effect level was not found for fetal body weight. Further experiments will be required to determine how much lower doses will need to be in order to find a no-effect level for fetal body weight. Nevertheless, the present data suggest that CBZ is not potent at inducing malformations in rats.     

Evaluation of the protective activity of deferiprone, an aluminum chelator, on aluminum-induced developmental toxicity in mice

BACKGROUND: Since deferiprone can be an effective chelating agent for the treatment of aluminum (Al) overload, in the present study we investigated whether this chelator could protect against Al-induced maternal and developmental toxicity in mice. METHODS: A single oral dose of Al nitrate nonahydrate (1,327 mg/kg) was given on gestation day 12, the most sensitive time for Al-induced maternal and developmental toxic effects in mice. At 2, 24, 48, and 72 hr thereafter, deferiprone was given by gavage at 0 and 24 mg/kg. Cesarean sections were performed on day 18 of gestation and fetuses were examined for malformations and variations. RESULTS: Aluminum-induced maternal toxicity was evidenced by significant reductions in body weight gain, corrected body weight change, and food consumption. Developmental toxicity was evidenced by a significant decrease in fetal weight per litter and an increase in the total number of fetuses and litters showing bone retardation. No beneficial effects of deferiprone on these adverse effects could be observed. By contrast, a more pronounced decrease in maternal weight gain and corrected body weight change, as well as a higher number of litters with fetuses showing skeletal variations was noted in the group exposed to Al nitrate and treated with deferiprone at 24 mg/kg. CONCLUSIONS: According to the current results, deferiprone would not be effective to prevent Al-induced maternal and embryo/fetal toxicity in mice.     

Developmental Toxicity Studies with Atrazine and its Major Metabolites in Rats and Rabbits

Atrazine (ATR), hydroxyatrazine (OH‐ATR), and the three chloro metabolites of ATR (deethylatrazine [DEA], deisopropylatrazine [DIA], diaminochlorotriazine [DACT]) were evaluated for developmental effects in rats and rabbits. Three developmental toxicity studies were conducted on ATR in rats (two studies) and rabbits and a developmental toxicity study was conducted in rats for each of the four ATR metabolites DEA, DIA, DACT, and OH‐ATZ. ATR administration by gavage to pregnant rats and rabbits from implantation (gestation day [GD] 6 in rat, GD 7 in rabbit) through closure of the palate (GD 15 in rat and GD 19 in rabbit) did not statistically significantly alter the incidence of developmental abnormalities or malformations at dose levels up to 100 (rat) or 75 (rabbit) mg/kg bw/day. There were no effects on developmental toxicity parameters for DEA, DIA, DACT, or OH‐ATR at oral dose levels up to 100, 100, 150, or 125 mg/kg bw/day, respectively, with the exception of reductions in fetal body weight by DACT and OH‐ATR in the presence of decreased maternal body weight gain. ATR did not adversely affect developmental end points in a two‐generation study conducted in rats exposed to dose levels up to 500 ppm (38.7 mg/kg/day) in the diet. The 500‐ppm dose level resulted in significantly reduced maternal body weight gain. Overall, data show that neither ATR nor its metabolites statistically significantly affected rat or rabbit embryo‐fetal development even at dose levels producing maternal toxicity.     

Developmental Toxicity of the HMG‐CoA Reductase Inhibitor (PPD10558) in Rats and Rabbits

PPD10558 is an orally active, lipid‐lowering 3–hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor (statin) being developed as a treatment for hypercholesterolemia in patients who have not been able to tolerate statins because of statin‐associated myalgia. We have studied the potential developmental toxicity effects of PPD10558 in pregnant rats and rabbits given daily oral doses during the period of organogenesis. Rats were dosed with 0, 20, 80, or 320 mg/kg/day from Gestation Day (GD) 6 to 17 and rabbits received dose levels of 0, 12.5, 25, or 50 mg/kg/day from GD 6 to 18. Additional groups in both studies served as toxicokinetic animals and received the PPD10558 in the same manner as the main study groups at the same dose levels. Blood samples were collected from toxicokinetic animals at designated time points on GD 6 and 17 in rats and GD 6 and 18 in rabbits. Fetal exposure in rats was assessed on GD 20. Maternal and developmental parameters were evaluated in rats and rabbits on GD 20 and GD 29, respectively. No maternal and developmental toxicity was observed at any of the dose levels used in the rat study. Evidence of fetal exposure was determined in fetal plasma with mean fetal concentrations of PPD10558 and the metabolite (PPD11901) found to be between 1 and 6% of the mean maternal concentrations. In rabbits, marked maternal toxicity including mortality (eight deaths; 1 dose at 25 and 7 at 50 mg/kg/day), abortions (2 at 25 mg/kg/day and 6 at 50 mg/kg/day) and reduction in gestation body weight, gestation body weight changes and decreased food consumption were observed. In addition, fetal body weights of the combined sexes were significantly reduced at 50 mg/kg/day in comparison with the controls. Mean peak exposure (Cmax) and total exposure (AUC(0–24)) of PPD11901 in both rats and rabbits were higher than that of PPD10558 on GD 6 and GD 17 at each of the three dose levels.. Based on the results of these studies, the no observed adverse effect level (NOAEL) for maternal and developmental toxicity in rats was considered to be ≥320 mg/kg/day, the highest dose level used in the study. The NOAEL for maternal and developmental toxicity in rabbits was 12.5 mg/kg/day and 25 mg/kg/day, respectively.     

Developmental toxicity evaluation of emodin in rats and mice

BACKGROUND: Emodin, a widely available herbal remedy, was evaluated for potential effects on pregnancy outcome. METHODS: Emodin was administered in feed to timed-mated Sprague-Dawley (CD) rats (0, 425, 850, and 1700 ppm; gestational day [GD] 6-20), and Swiss Albino (CD-1) mice (0, 600, 2500 or 6000 ppm; GD 6-17). Ingested dose was 0, 31, 57, and approximately 80-144 mg emodin/kg/day (rats) and 0, 94, 391, and 1005 mg emodin/kg/day (mice). Timed-mated animals (23-25/group) were monitored for body weight, feed/water consumption, and clinical signs. At termination (rats: GD 20; mice: GD 17), confirmed pregnant dams (21-25/group) were evaluated for clinical signs: body, liver, kidney, and gravid uterine weights, uterine contents, and number of corpora lutea. Fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations/variations. RESULTS: There were no maternal deaths. In rats, maternal body weight, weight gain during treatment, and corrected weight gain exhibited a decreasing trend. Maternal body weight gain during treatment was significantly reduced at the high dose. In mice, maternal body weight and weight gain was decreased at the high dose. CONCLUSIONS: Prenatal mortality, live litter size, fetal sex ratio, and morphological development were unaffected in both rats and mice. At the high dose, rat average fetal body weight per litter was unaffected, but was significantly reduced in mice. The rat maternal lowest observed adverse effect level (LOAEL) was 1700 ppm; the no observed adverse effect level (NOAEL) was 850 ppm. The rat developmental toxicity NOAEL was > or =1700 ppm. A LOAEL was not established. In mice, the maternal toxicity LOAEL was 6000 ppm and the NOAEL was 2500 ppm. The developmental toxicity LOAEL was 6000 ppm (reduced fetal body weight) and the NOAEL was 2500 ppm.     

Evaluation of developmental toxicity induced by anticholinesterase insecticide,diazinon in female rats

Developmental toxicities, including birth defects, are significant public health problems. This study was planned to assess the cholinergic and developmental potentials of diazinon that is widely used as an organophosphate insecticide. Pregnant female Sprague‐Dawley rats were given diazinon orally at doses of 0, 1.9, 3.8, and 7.6 mg/kg body weight (b.w.)/day on gestation days 6 to 15. Maternal brain acetylcholinesterase activities, measured on gestation day20, were significantly decreased at 3.8 and 7.6 mg/kg b.w./day, but fetal acetylcholinesterase activity was not altered. Maternal toxicities, as evidenced by cholinergic symptoms including diarrhea, tremors, weakness, salivation, and decreased activities, were observed at the 3.8 and 7.6 mg/kg b.w./day dose groups. Net gravid uterine weight was decreased at a dose of 7.6 mg/kg b.w./day. No maternal effects were apparent in the 1.9 mg/kg b.w./day dose group. Maternal toxicity at a dose of 3.8 mg/kg b.w./day did not induce fetotoxicity or teratogeneicity. However, 7.6 mg/kg b.w./day doses significantly resulted in fetal toxicity and malformations in addition to maternal toxicity in animals. In conclusion, teratogenic disorders only outlined by doses that produced marked maternal toxicity. Since the malformations were not morphologically related, they were considered to be secondary to maternal toxicity; hence, the malformations were not related to cholinesterase inhibition. Birth Defects Res (Part B) 92:534–542, 2011. © 2011 Wiley Periodicals, Inc.     

Lack of teratogenicity of trans-2-ene-valproic acid compared to valproic acid in rats

The teratogenicity of trans-2-ene-valproic acid (300 and 400 mg/kg) was compared with that of valproic acid (VPA; 300 mg/kg) and controls (corn oil) administered by gavage to Sprague-Dawley CD rats on embryonic (E) days 7-18. At the 300 mg/kg dose, trans-2-ene-VPA produced no change in maternal weight, number of implantations, proportion of resorptions, proportion of malformations, or fetal weight. By contrast, the same dose of VPA (300 mg/kg) reduced maternal weight during gestation, increased malformations (12.0% vs. 0.7% in controls), and reduced fetal body weight by 25.1%. An even higher dose of trans-2-ene-VPA (400 mg/kg) produced a reduction in maternal body weight during treatment and reduced fetal body weight (by 7.9%), but did not increase resorptions or malformations in the fetuses. On day E18, maternal serum drug concentrations of VPA were higher in the VPA-treated group compared with those of trans-2-ene-VPA in the trans-2-ene-VPA-treated groups at 1 hr posttreatment. At 6 hr posttreatment the reverse was seen. trans-2-ene-VPA may be absorbed more rapidly and distributed differently than VPA. Overall, the data support the view that trans-2-ene-VPA at equal or higher doses than VPA is not teratogenic in rats.     

Developmental toxicity evaluation of Bendectin in CD rats

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).     

Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development

BACKGROUND: A review of the nonsteroidal anti‐inflammatory drug (NSAID) literature suggested occurrences of low‐level incidences of cardiovascular and midline defects in rabbit fetuses exposed in utero. Aspirin (acetylsalicylic acid, ASA) is a widely used NSAID that irreversibly inhibits cyclooxygenases (COXs) 1 and 2. ASA has been studied extensively in rats and has consistently increased low‐incidence cardiovascular malformations and defects in midline closure. The objectives of the current study were to comprehensively define the developmental toxicology profile of ASA in rabbits by using a dosing paradigm encompassing the period of organogenesis and to test the hypothesis that maternal gastrointestinal toxicity after repeated dose administrations hampers the detection of low‐incidence malformations with ASA in rabbits by limiting ASA administration to sensitive windows for cardiovascular development and midline closure. METHODS: ASA was administered to pregnant New Zealand White rabbits from gestation days (GDs) 7 to 19 at dose levels of 125, 250, and 350 mg/kg per day and as single doses of 500, 750, or 1000 mg/kg on GD 9, 10, or 11. Cesarean sections were performed on GD 29, and the fetuses were examined for external, visceral, and skeletal development. RESULTS: In the repeated dose study, maternal toxicity was exhibited in the 250‐ and 350‐mg/kg per day groups by mortality and decreased food consumption and body weight gain. In the single dose studies, maternal toxicity was exhibited at all doses by reductions in body weight gain and food consumption for 3 days after treatment. Fetal body weight was significantly reduced in the repeated dose study at 350 mg/kg per day. Fetal weights were not affected by single doses of ASA on GD 9, 10, or 11. There were no treatment‐related external, visceral, or skeletal malformations associated with ASA administration throughout organogenesis or with single doses administered during critical developmental windows. CONCLUSION: These findings supported previous work demonstrating that ASA is not teratogenic in rabbits, as opposed to rats, even when large doses are administered on single days during specific windows of development. Birth Defects Research (Part B) 68:38–46, 2003. © 2003 Wiley‐Liss, Inc.     

Influence of maternal stress on uranium-induced developmental toxicity in rats

It has been demonstrated that uranium is an embryo/fetal toxicant when given orally or subcutaneously to pregnant mice. On the other hand, maternal stress has been shown to enhance the developmental toxicity of a number of metals. In this study, maternal toxicity and developmental effects of a concurrent exposure to uranyl acetate dihydrate (UAD) and restraint stress were evaluated in rats. Four groups of pregnant animals were given subcutaneous injections of UAD at 0.415 and 0.830 mg/kg/day on Days 6 to 15 of gestation. Animals in two of these groups were also subjected to restraint for 2 hr/day during the same gestational days. Control groups included restrained and unrestrained pregnant rats not exposed to UAD. Cesarean sections were performed on gestation Day 20, and the fetuses were weighed and examined for malformations and variations. Maternal toxicity and embryotoxicity were noted at 0.830 mg/kg/day of UAD, while fetotoxicity was evidenced at 0.415 and 0.830 mg/kg/day of UAD by significant reductions in fetal body weight and increases in the total number of skeletally affected fetuses. No teratogenic effects were noted in any group. Maternal restraint enhanced uranium-induced embryo/fetal toxicity only at 0.830 mg/kg/day, a dose that was also significantly toxic to the dams. As in previous studies with other metals, maternal stress enhances uranium-induced developmental toxicity at uranium doses that are highly toxic to the dams; however, at doses that are less acutely toxic the role of maternal stress would not be significant.     

Developmental toxic effects of antifungal flusilazole administered by gavage to mice

BACKGROUND: The developmental toxicity of flusilazole was studied in CD-1 mice after oral administration. METHODS: Pregnant mice were given flusilazole at doses of 0 (corn oil), 10, 20, and 40 mg/kg/day, by gavage, on gestational days (GD) 6-15. RESULTS: Maternal toxicity, as evidenced by reduction in body weight gain and signs of toxicity, was observed at the middle- and high-dose groups. No significant incidence of resorptions or death was observed in any of dose groups. There was a pronounced reduction in fetal weight, which was significantly lower than control from 20 and 40 mg/kg/day. There was no significant increase in the incidence of fetuses with external or visceral malformations in any of dose groups, but there was a significant increase in the incidence of skeletal malformations was observed at 20 and 40 mg/kg/day. CONCLUSIONS: The results of this study reported marked maternal toxicity, growth retardation, and skeletal abnormalities in the mid- and high-dose groups. It seems likely that marked maternal toxicity contributed to the observed alterations in fetal growth retardation and skeletal development. The no-observed-effect level in the present study for maternal and developmental toxicity was 10 mg/kg/day.     

Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy.

Bisphenol A (BPA) is an essential component of epoxy resins used in the lacquer lining of metal food cans, as a component of polycarbonates, and in dental sealants. The present study was conducted in an attempt to evaluate the adverse effects of the environmental estrogen BPA on initiation and maintenance of pregnancy and embryofetal development after maternal exposure during the entire period of pregnancy in Sprague-Dawley rats. The test chemical was administered by gavage to mated females from days 1 to 20 of gestation (sperm in varginal lavage = day 0) at dose levels of 0, 100, 300, and 1000 mg/kg. All females were subjected to caesarean section on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, significant toxic effects including abnormal clinical signs, decreased maternal body weight and body weight gain, and reduced food consumption were observed in pregnant rats. An increase in pregnancy failure was also found in the successfully mated females. In addition, increased number of embryonal deaths, increased postimplantation loss, reduced litter size and fetal body weight, and decreased number of fetal ossification centers of several skeletal districts were seen. On the contrary, no significant changes induced by BPA were detected in the number of corpora lutea and implantation sites and by fetal morphological examinations. In the 300 mg/kg group, suppressed maternal body weight and body weight gain, decreased food intake and reduced body weight of male fetuses were seen. There were no adverse signs of either maternal toxicity or developmental toxicity in the 100 mg/kg group. It was concluded that BPA administration during the entire period of pregnancy in rats produced pregnancy failure, pre- and postimplantation loss, fetal developmental delay and severe maternal toxicity, but no embryo-fetal dysmorphogenesis at an oral exposure level of 1000 mg/kg.     

Effects of Estrogen Coadministration on Epoxiconazole Toxicity in Rats

Epoxiconazole (EPX; CAS‐No. 133855‐98‐8) is a triazole class–active substance of plant protection products. At a dose level of 50 mg/kg bw/day, it causes a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (gestation day [GD] 7–18 or 21), as reported previously (Taxvig et al., 2007, 2008) and confirmed in these studies. Late fetal resorptions occurred in the presence of significant maternal toxicity such as clear reduction of corrected body weight gain, signs of anemia, and, critically, a marked reduction of maternal estradiol plasma levels. Furthermore, estradiol supplementation at dose levels of 0.5 or 1.0 μg/animal/day of estradiol cyclopentylpropionate abolished the EPX‐mediated late fetal resorptions. No increased incidences of external malformations were found in rats cotreated with 50 mg/kg bw/day EPX and estradiol cyclopentylpropionate, indicating that the occurrence of malformations was not masked by fetal mortality under the study conditions. Overall, the study data indicate that fetal mortality observed in rat studies with EPX is not the result of direct fetal toxicity but occurs indirectly via depletion of maternal estradiol levels. The clarification of the human relevance of the estrogen‐related mechanism behind EPX‐mediated late fetal resorptions in rats warrants further studies. In particular, this should involve investigation of the placenta (Rey Moreno et al., 2013), since it is the materno‐fetal interface and crucial for fetal maintenance. The human relevance is best addressed in a species which is closer to humans with reference to placentation and hormonal regulation of pregnancy, such as the guinea pig (Schneider et al., 2013). Birth Defects Res (Part B) 98:247–259, 2013. © 2013 Wiley Periodicals, Inc.