Maternal and developmental toxicity in mice by aminophenylnorharman,formed from norharman and aniline

9-(4'-Aminophenyl)-9H-pyrido [3,4-b] indole (aminophenylnorharman, APNH) is a novel mutagenic heterocyclic amine, produced by the reaction of norharman with aniline in the presence of S9 mix. In the present study, the maternal and developmental toxicity of APNH were investigated in ICR mice administered oral doses of 0, 0.625, 1.25, 2.5 or 5 mg/kg/day on gestational days (GD) 6 through 15 or 0, 5, 10, or 20 mg/kg on GD 12. Maternal and foetal parameters were evaluated on day 18 of gestation. Foetuses of dams treated on GD 6-15 were examined for external and skeletal malformations and variations, and foetuses of dams treated on GD 12 were inspected for cleft palate. Maternal death occurred when APNH was administered at 5 mg/kg/day on GD 6-15. No significant decrease in body weight gain during the administration period was observed at doses of 2.5 mg/kg/day or less when applied on GD 6-15. Adverse changes in general condition of dams were observed in the groups treated at doses of 2.5 mg/kg/day and above on GD 6-15, whereas no adverse effects on dams were noted even when APNH was applied at a fairly high dose on GD 12. Intracytoplasmic vacuolation in hepatocytes, necrosis of proximal tubular epithelial cells and desquamation of necrotic epithelial cells in the tubular lumen were observed in dams treated with APNH at 2.5 or 5 mg/kg/day on GD 6-15. Increased preimplantation loss was observed at 5 mg/kg/day and post-implantation loss was observed at 2.5 mg/kg/day and above when applied on GD 6-15, or at 20 mg/kg when applied on GD 12. Foetal body weight was decreased by APNH in a dose-dependent manner. The frequency of external malformations (cleft palate) was significantly increased in the group treated with APNH at 2.5 mg/kg/ day on GD 6-15 compared to the controls. However, there were no foetuses with cleft palate even when APNH was given at 20 mg/kg on GD 12. No significant increases in skeletally malformed foetuses were found in any APNH-treated group. The frequency of lumbar ribs was increased dose dependently. This study demonstrated the developmental toxicity of a mutagenic compound, APNH, in mice at maternally toxic doses, and that cleft palate observed in term foetuses resulted from the adverse effect of APNH on the maternal environment during organogenesis. More detailed studies are warranted to assess the possible risks to pregnant women from exposure to APNH.     

Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats.

A thorough review of the literature revealed no published repeated-dose oral developmental toxicity studies of inorganic arsenic in rats. In the present study, which was conducted according to modern regulatory guidelines, arsenic trioxide was administered orally beginning 14 days prior to mating and continuing through mating and gestation until gestational day 19. Exposures began prior to mating in an attempt to achieve a steady state of arsenic in the bloodstream of dams prior to embryo-foetal development. Groups of 25 Crl:CD(SD)BR female rats received doses of 0, 1, 2.5, 5 or 10mg/kg/day by gavage. The selection of these dose levels was based on a preliminary range-finding study, in which excessive post-implantation loss and markedly decreased foetal weight occurred at doses of 15 mg/kg/day and maternal deaths occurred at higher doses. Maternal toxicity in the 10mg/kg/day group was evidenced by decreased food consumption and decreased net body weight gain during gestation, increased liver and kidney weights, and stomach abnormalities (adhesions and eroded areas). Transient decreases in food consumption in the 5mg/kg/day group caused the maternal no-observed-adverse-effect level (NOAEL) to be determined as 2. 5mg/kg/day. Intrauterine parameters were unaffected by arsenic trioxide. No treatment-related foetal malformations were noted in any dose group. Increased skeletal variations at 10mg/kg/day were attributed to reduced foetal weight at that dose level. The developmental NOAEL was thus 5mg/kg/day. Based on this study, orally administered arsenic trioxide cannot be considered to be a selective developmental toxicant (i.e. it is not more toxic to the conceptus than to the maternal organism), nor does it exhibit any propensity to cause neural tube defects, even at maternally toxic dose levels.     

In Utero and Lactational Exposure to Fluoxetine in Wistar Rats: Pregnancy Outcomes and Sexual Development

This study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and oestrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Oestrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine were observed. Finally, pup birthweight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic‐like doses.     

Toxicokinetics of 1,2-diethylbenzene in male Sprague-Dawley rats-part 1: excretion and metabolism of [(14)C]1,2-diethylbenzene.

The excretion and metabolism of neurotoxic 1,2-diethylbenzene (1, 2-DEB) was studied in male Sprague-Dawley rats after i.v. (1 mg/kg) or oral (1 or 100 mg/kg) administration of 1,2-diethyl[U-(14)C]benzene ([(14)C]1,2-DEB). Whatever the treatment, radioactivity was mainly excreted in urine (65-76% of the dose) and to a lower extent in feces (15-23% of the dose), or via exhaled air (3-5% of the dose). However, experiments with rats fitted with a biliary cannula demonstrated that about 52 to 64% of the administered doses (1 or 100 mg/kg) were initially excreted in bile. Biliary metabolites were extensively reabsorbed from the gut and ultimately excreted in urine after several enterohepatic circulations. Insignificant amounts of unchanged 1,2-DEB were recovered in the different excreta (urine, bile, and feces). As reported previously, presence of 1-(2'-ethylphenyl)ethanol (EPE) was confirmed in urine and demonstrated in bile and feces. The two main [(14)C]1,2-DEB metabolites accounted for 57 to 79% of urinary and biliary radioactivity, respectively. Beta-Glucuronidase hydrolysis and electron impact mass spectra results strongly supported their glucuronide structure. Additionally, these two main metabolites were thought to be the glucuronide conjugates of the two potential enantiomers of EPE. The results indicate that the main initial conversion step of the primary metabolic pathway of 1,2-DEB appears to be the hydroxylation of the alpha-carbon atom of the side chain. The presence of two glucuronide conjugates of EPE in the urine in a ratio different from one suggests that the metabolic conversion of 1, 2-DEB is under stereochemical control.     

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.     

Developmental toxicity of benzyl benzoate in rats after maternal exposure throughout pregnancy

The maternal and fetal toxicity of benzyl benzoate, commonly used as antiparasitic insecticide, was evaluated in pregnant rats after a daily oral dose of 25 and 100 mg/kg. Biochemical, histopathological, and morphological examinations were performed. Dams were observed for maternal body weights and food and water consumption and subjected to caesarean section on (GD) 20. Maternal and fetal liver, kidney, heart, brain, and placenta were examined histopathologically under light microscope. Maternal and fetal liver and placenta were stained immunohistochemically for vascular endothelial growth factor (VEGF). Morphometric analysis of fetal body lengths, placental measurements, and fetal skeletal stainings was performed. Statistically significant alterations in biochemical parameters and placental and skeletal measurements were determined in treatment groups. In addition to histopathological changes, considerable differences were observed in the immunolocalization of VEGF in treatment groups. These results demonstrated that benzyl benzoate and its metabolites can transport to the placenta and eventually enter the fetuses. © 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 40–53, 2014.     

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits.

DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).     

Evaluation of the developmental toxicity of formamide in New Zealand white rabbits.

Naturally mated female New Zealand White (NZW) rabbits (24/group) received formamide (35, 70, or 140 mg/kg/day) or vehicle (1 ml/kg deionized/distilled water) by gavage on gestational days (GD) 6 through 29. The study was conducted using a 2-replicate design. Maternal food consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. One and four maternal deaths occurred at the low and high doses, respectively. Abortions or early deliveries were noted in 0, 2, 2, and 8 females in the 0, 35, 70, and 140-mg/kg/day dose groups, respectively. Other clinical signs associated with formamide exposure were minimal: primarily reduced or absent fecal output at the high dose (2-13 animals/day). Also at the high dose, maternal body weight was significantly depressed on GD 21, 24, and 27 (87-90% of the control value); maternal body weight gain was significantly reduced for GD 12 to 15, 18 to 21, and 21 to 24 (treated animals gained less than 1 g, or lost up to 100 g). In addition, maternal body weight gain was reduced at the middle dose for GD 18 to 21. Maternal body weight gain, corrected for gravid uterine weight, was unaffected. Relative maternal food consumption in the high-dose group was 34-59% of control intake from GD 12 through GD 24, but was comparable to controls thereafter. At termination (GD 30), confirmed-pregnant females (9-20 per group) were evaluated for clinical status, liver weights, and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal liver weight (absolute or relative to body weight) was unaffected by treatment, but gravid uterine weight at the high dose was 71% of the control value. A significantly increasing trend was noted for the percent non-live implants per litter. In addition, although not statistically significant from the control group, the values for the percent late fetal deaths per litter and percent non-live implants per litter in the 140-mg/kg/day group were higher than maximum historical values, suggesting an increase in late gestational deaths in the surviving high-dose animals. Formamide decreased the mean number of live fetuses per litter at the high dose to 66% of the control value. Mean fetal body weight per litter for males and the sexes combined was significantly decreased at the high dose; mean female fetal body weight was also decreased, although the difference did not reach statistical significance. There was no effect of treatment on the incidence of external, visceral, or skeletal malformations or variations in animals surviving to scheduled necropsy. In summary, the no-observed-adverse-effect level (NOAEL) for maternal toxicity was 70 mg/kg/day and the lowest-observed-adverse-effect level (LOAEL) was 140 mg/kg/day under the conditions of this study. Similarly, the NOAEL for developmental toxicity was 70 mg/kg/day and the LOAEL was 140 mg/kg/day.     

Developmental toxicity of orally administered thiabendazole in ICR mice.

Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses. To assess whether the effects found in this previous study were attributable to maternal toxicity or TBZ the present study was conducted. TBZ doses of 25, 100 or 200 mg/kg/day were selected based on a preliminary range-finding study in which maternotoxicity was evident at doses of 200 mg/kg/day or above. The compound was administered during gestation days 6-15 as a solution in olive oil. Caesarean sections were completed on gestation day 18 and complete fetal examinations conducted. Decreases in maternal weight gain relative to controls were found at doses of 100 mg/kg/day or above, which paralleled decreases in foetal weights in these same dose groups. However, there were no treatment-related external, visceral or skeletal anomalies in any treatment group. Therefore, TBZ was not teratogenic or selectively foetotoxic in mice, with no-observed-effect levels (NOEL) of 25 and greater than 200 mg/kg/day for maternal and fetal weight effects and teratogenicity, respectively. These results indicate that foetal effects noted in previous studies in mice were probably secondary to severe maternal toxicity.     

Placental transfer of the estrogenic mycotoxin zearalenone in rats.

In order to study the possible placental transfer of the Fusarium mycotoxin zearalenone (ZON), Sprague Dawley rats were treated with a single dose (0.74 mg/kg b.w.) of ZON i.v. on day 12 or day 18 of pregnancy, or intragastrically (i.g.) on day 18 of pregnancy. Samples of placenta, foetus, and maternal liver and spleen were collected for chemical analyses 0.3 h after treatment on day 12, and 0.3, 4, and 24 h after treatment on day 18. Three rats were used for each pregnancy day, administration route, and exposure time. The concentrations of ZON and its metabolites alpha- and beta-zearalenol (-ZOL) were determined quantitatively by high-performance liquid chromatography (HPLC) after incubation with beta-glucuronidase and purification on immunoaffinity columns. Tissue distribution was studied by means of whole body autoradiography at 4 and 24 h after treatment with tritiated ZON (750 microCi/kg b.w; 7.4 mg/kg b.w.) on day 18 of pregnancy. ZON and alpha-ZOL were transferred into the foetus on both gestational days. However, a delay in distribution into the foetus, relative to the maternal tissue, was observed. Beta-ZOL was below the detection limit in the foetus. No specific site of foetal accumulation of ZON or its metabolites was apparent. In the maternal tissues, the highest levels of ZON and of alpha- and beta-ZOL were found in the liver.     

Distribution and Effects of DDT in the Pregnant Rabbit

1. After administration of p, p'-DDT to pregnant rabbits DDT and its metabolites are found in high concn. in both the foetus and the organs of the maternal rabbit which regulate the foetal environment.

2. p.p''-DDT does not rapidly leave the foetal tissue, as whole body levels at day 26 (17 days after DDT dosing) are higher than those in foetal plasma; foetal whole body levels are also higher than those found in placenta or maternal plasma, and half of those of maternal liver.

3. p.p'-DDT treatment of pregnant rabbits at doses of 10 and 50?mg/kg caused an increased incidence of prematurity, an increase in the number of foetal resorptions and a decrease in foetal weight.

4. These doses of DDT did not increase the incidence of chromosomal aberrations in the maternal or foetal tissue and exposure in vitro to levels as high as 100 μg/ml caused no abnormalities.     

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

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

Developmental toxicity of di-isodecyl and di-isononyl phthalates in rats

The developmental toxicity of di-isodecyl phthalate (DIDP; CAS RN 68515-49-1) and di-isononyl phthalate (DINP; CAS RN 68515-48-0) were investigated in Sprague-Dawley rats. DIDP and DINP were administered by gavage to mated rats at doses of 0, 100, 500, and 1000 mg/kg/d on Gestation Days (GD) 6 through 15. Cesarean sections were performed on GD 21 and the fetuses removed for evaluation. Maternal weight gain and food consumption were significantly reduced at 1000 mg/kg/d during the exposure period. No treatment-related effects were noted at cesarean section, nor were there any fetal morphologic observations except for an increased frequency of seventh cervical and rudimentary lumbar ribs at the maternally toxic exposure level of 1000 mg/kg/d. Under these study conditions, mild maternal and developmental effects were observed at 1000 mg/kg/d. Both maternal and developmental NOAELs were therefore established at 500 mg/kg/d. The results indicate that neither DIDP nor DINP is teratogenic or a selective developmental toxicant.     

Teratological evaluations of atrazine technical, a triazine herbicide, in rats and rabbits

Atrazine technical was evaluated for its embryotoxic, fetotoxic, and teratogenic potential in both rats and rabbits. The compound was orally administered at doses of 0, 10, 70, or 700 mg/kg.d to groups of rats on gestational d 6-15, while rabbits were administered doses of 0, 1, 5, or 75 mg/kg.d on gestational d 7-19. Maternal toxicity was observed at doses greater than or equal to 70 mg/kg.d in rats and at doses greater than or equal to 5 mg/kg.d in rabbits. Minor fetal effects, concurrent with maternal toxicity, were observed in rats at doses greater than or equal to 70 mg/kg.d. Among rabbits, fetal effects concurrent with severe maternal toxicity were only observed at the 75 mg/kg.d dose level. There were no adverse maternal or fetal effects in either rats or rabbits at the low dose levels. These findings indicated that pregnant rabbits were more sensitive than pregnant rats to the effects produced by atrazine technical and the compound was not teratogenic at maternally toxic dose levels in either species.     

Developmental Toxicity of 1,2-Dichloropropane (PDC) in Rats and Rabbits Following Oral Gavage

1,2-Dichloropropane (PDC) was evaluated for its potential causeembryonal/fetal toxicity and teratogenicity in pregnant ratsand rabbits. PDC was administered via oral gavage at dose levelsof 0, 10, 30, or 125 mg/kg/day on Days 6 through 15 of gestation(rats) or 0, 15, 50, or 150 mg/kg/day on gestation Days 7 through19 (rabbits). Fetuses were examined on Gestation Day 20 (rats)or Day 28 (rabbits). Maternal toxicity was observed in bothrats and rabbits at the high dose levels. Rats given 125 mg/kg/dayof PDC showed clinical signs of toxicity and decreased bodyweight and body weight gain. Rabbits given 150 mg/kg/day PDCshowed changes in hematologic parameters and decreased bodyweight gain. Although maternal toxicity was apparent, no indicationteratogenicity was observed in rat or rabbit fetuses at anydose level. Significant increases in the incidence of delayedossification of skull bones, considered secondary to decreasedmaternal body weight gain, were observed in rats given 125 mg/kg/dayand rabbits given 150 mg/kg/day. No maternal or developmentaleffects were observed in rats given 10 or 30 mg/kg/day or inrabbits given 15 or 50 mg/kg/day of PDC. Based on the resultsof these studies the maternal and developmental NOELs in ratsand rabbits were 30 and 50 mg/kg/day, respectively.     

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 CI-921, an Anilinoacridine Antitumor Agent

CI-921, an anilinoacridine compound active against leukemicand solid tumors, was evaluated for potential developmentaltoxicity. Intravenous injections of CI-921 in dextrose weregiven to female Sprague-Dawley rats (0.1, 0.5, and 1.0 mg/kg)on Gestation Days (GD) 6–15 and to female New ZealandWhite rabbits (0.1, 1.0 and 2.0 mg/kg) on GD 6–18. Appropriatevehicle and untreated controls were included. Maternal and fetalparameters, including external, visceral, and skeletal malformationsand variations, were assessed. Treatment of rats with 1.0 mg/kgresulted in maternal toxicity, manifested as reduced body weightgain and food consumption during and after treatment. Reducedfetal body weight, an increased incidence of stunted fetuses,malformations of the axial and appendicular skeleton, microphthalmia,and an increased number of anatomical variations (includinganomalies of the axial skeleton and apparent hydronephrosis)also occurred in rats at 1.0 mg/kg. Treatment of rabbits resultedin no apparent maternal toxicity. However, reduced fetal bodyweight, agenesis of the azygous lobe of the lung, and an increasedincidence of variations of the axial skeleton occurred at 2.0mg/kg in rabbits. These results indicate that CI-921, at thehighest dose tested in each species, produced developmentaltoxicity in the presence of maternal toxicity in rats, but inthe absence of maternal toxicity in rabbits.     

Developmental Toxicity Evaluation of Isopropanol by Gavage in Rats and Rabbits

Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosedorally with aqueous isopropanol (IPA; CAS No. 67–63–0)solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on GestationalDays (GD) 6 through 15 at a dosing volume of 5 mI/kg. Artificiallyinseminated New Zealand white rabbits, 15/group, were dosedorally with IPA at 0, 120, 240, or 480 mg/kg/day once dailyon GD 6 through 18 at 2 mI/kg. Maternal body weights, clinicalobservations, and food consumption were re corded throughoutgestation for both species. At scheduled euthanization for bothspecies (GD 20, rats; GD 30, rabbits), fetuses were weighed,sexed, and examined for external, visceral (including craniofacial)and skeletal alterations. For both species, the pregnancy ratewas high and equivalent across all groups; no dams or does aborted,delivered early, or were re moved from study. In rats, two dams(8%) died at 1200 mg/kg/ day and one dam (4%) died at 800 mg/kg/day.Maternal body weights and weight gain were equivalent acrossall groups, ex cept for statistically significantly reducedgestational weight gain (GD 0–20; 89.9% of control value),associated with statisti cally significantly reduced graviduterine weight at 1200 mg/kg/ day (89.2% of control value).There were no treatment-related clinical signs or effects onmaternal food consumption. All gestational parameters evaluatedwere equivalent across groups, including pre- and postimplantationloss, fetal sex ratios, and lit ter size. Twenty-two to 25 litterswere examined per group. Fe tal body weights per litter werestatistically significantly reduced at the two highest doses(97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for allfetuses and males and females separately). No evidence of increasedteratogenicity was observed at any dose tested in rats. In rabbits,four does (26.7%) died at 480 mglkg/day. Maternal body weightswere statistically significantly re duced during treatment (GD6–18) at 480 mg/kg/day (45.4% of control value) with anonsignificant reduction in gestational weight change (GD 0–30;77.3% of control value) at this dose. Profound clinical signsof toxicity and statistically significantly reduced maternalfood consumption were observed at 480 mgI kg/day. All gestationalparameters were equivalent across all doses administered. Thirteento 15 litters were evaluated per group except for the 480 mg/kg/daygroup with 11 litters (due to maternal deaths). There were notreatment-related effects on pre- or postimplantation loss,fetal sex ratio, litter size, or fetal body weight/litter. Moreover,no evidence was found of in creased teratogenicity at any dosetested in rabbits. Therefore, IPA was not teratogenic to CDrats or to NZW rabbits. The NOAELS for both maternal and developmentaltoxicity were 400 mg/kg/day in rats, and were 240 and 480mg/kg/day,respectively, in rabbits.     

Developmental toxicity of acephate by gavage in mice

Acephate (O,S - dimethyl acetyl phosphoramidothioate), an organophosphate insecticide, was evaluated for its potential to produce developmental toxicity in mice after oral administration. Pregnant ICR (CD-1) mice were given sublethal doses of 0 (distilled water), 7, 14, and 28 mg/kg/day acephate by gavage on Gestation Days 6 through 15. Maternal effects in the 28 mg/kg/day dose group included cholinergic signs, decreased body weight at 15 and 18 days of gestation, and decreased absolute and relative brain weight. Placental weight was also decreased and liver weight was increased in the high dose group. Absolute and relative brain weight was decreased in the 14 mg/kg/day group. No maternal effects were apparent in the 7 mg/kg/day dose group. Maternal exposure to acephate during organogenesis significantly affected the number of implantations, number of live fetuses, number of early resorptions, mean fetal weight, and the incidence of external and skeletal malformations in the 28 mg/kg/day dose group. No visceral malformations were observed. On the basis of the present results acephate showed maternal and developmental toxicity at 28 mg/kg/day.     

Prenatal toxicity of Ascaris pepsin inhibitor in mice

The developmental toxicity of pepsin inhibitor isolated from Ascaris suum, a gastrointestinal nematode parasite, was evaluated. An embryo–fetal development study was conducted in BALB/c mice. Groups of 21 mated females were treated by intraperitoneal injection (0.3 ml/30 g body weight) with 0.9% NaCl solution vehicle or isolated Ascaris pepsin inhibitor (API) at dose levels of 50, 100, 150 or 200 mg/kg body weight/day on gestation days (GD) 6–15. Maternal food consumption, body weight, and clinical signs were monitored throughout gestation. Cesarean sections were performed on GD 18 and gravid uterine weight, implantation sites, early and late resorptions, live and dead fetuses were collected. Live fetuses were weighed and examined for external, visceral and skeletal variations and malformations. Maternal body weight gain, gravid uterine weight, food consumption were significantly decreased after injection of higher doses of API (100–200 mg/kg/day). All doses of API exhibited an embryotoxic effect (high rate of intrauterine resorption). The percentage of postimplantation loss in the groups with administered API was higher (over 4–11 times) than that in control group. Fetotoxicity was observed in all treatment groups in a dose-related manner and it was evidenced by increased dead fetuses, decreased fetal weight, increased visceral variations and reduced skeletal ossification. Fetal hydronephrosis and internal hydrocephalus were noted at 150, and 200 mg/kg/day. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 50 mg/kg/day and the low-observed-adverse-effect level (LOAEL) was 100 mg/kg/day under the conditions of this study. However, the developmental toxicity LOAEL was 50 mg/kg/day based on decreased fetal body weight and prenatal mortality.