Developmental Toxicology Studies of Vancomycin Hydrochloride Administered Intravenously to Rats and Rabbits

Pregnant CD rats were given vancomycin intravenously in dosesof 0, 40, 120, or 200 mg/kg on Gestation Days (GD) 6–15;pregnant New Zealand white rabbits were given 0, 40, 80, or120 mg/kg intravenously on GD 6–18. Cesarean sectionswere performed on rats and rabbits on GD 20 and 28, respectively.In rats, maternal toxicity was indicated in the 120- and 200-mg/kgtreatment groups by cortical tubular nephrosis. Maternal bodyweight gain and food consumption and fetal viability, weight,and morphology were not adversely affected by vancomycin. Maternaland developmental no observed adverse effect levels (NOAELs)in the rat were 40 and 200 mg/kg, respectively. In rabbits,maternal toxicity was indicated by cortical tubular nephrosisin the 80- and 120-mg/kg treatment groups; a single death anddepression of body weight gain and food consumption occurredin the 120-mg/kg treatment group. Developmental toxicity wasindicated by depression of fetal weight in the 120-mg/kg treatmentgroup; fetal viability and morphology were not adversely affectedby vancomycin. Maternal and developmental NOAELs in the rabbitwere 40 and 80 mg/kg, respectively. Based on these data, vancomycindid not exhibit selective toxicity toward the developing rator rabbit conceptus.     

Developmental Toxicology Studies of Fluoxetine Hydrochloride Administered Orally to Rats and Rabbits

Pregnant Fischer 344 rats were given fluoxetine orally at doselevels of 0, 2, 5, or 12.5 mg/kg on Gestation Days (GD) 6–15;pregnant Dutch Belted rabbits were given 0, 2.5, 7.5, or 15mg/kg orally on GD 6–18. Cesarean sections were performedon rats and rabbits on GD 20 and 28, respectively. In rats,maternal toxicity was indicated at 12.5 mg/kg by depressionof weight gain and food consumption. Fetal viability, weight,and morphology were not affected at any dose level. Maternaland developmental No Observed Adverse Effect Levels (NOAELs)in the rat were 5 and 12.5 mg/kg, respectively. In rabbits,weight loss occurred at 2.5,7.5, and 15 mg/kg. Food consumptionwas also depressed at 7.5 and 15 mg/kg; abortions and maternalmortality occurred secondarily to anorexia and cachexia at 15mg/kg. Fetal viability, weight, and morphology were not affectedat any dose level. A NOAEL for maternal effects was not establishedin the rabbit; the NOAEL for developmental effects in the rabbitwas 15 mg/kg. Based on these data, fluoxetine did not exhibitany toxicity toward the developing rat or rabbit conceptus atdoses that were maternally toxic.     

Developmental Toxicity of N-Methylformamide Administered by Gavage to CD Rats and New Zealand White Rabbits

N-Methylformamide (NMF) is a metabolite of dimethylformamide(DMF), a solvent with wide applications in the chemical industry.The potential developmental toxicity of NMF was evaluated inCD rats and New Zealand white rabbits. Pregnant rats and rabbitswere dosed once daily by gavage on Gestation Days 6–15and 6–18, respectively. Doses for rats were 0, 1, 5, 10,or 75 mg/kg; doses for rabbits were 0, 5, 10, or 50 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 29, respectively. No treatment-related maternal deathsor clinical signs occurred in either species. Body weight gainand food consumption were depressed in rats given 75 mg/kg andrabbits given 50 mg/kg. Fetal viability was reduced at 75 mg/kgin rats and at 50 mg/kg in rabbits. In rats, a significant increasein the incidence of malformations including cephalocele andstern-oschisis was observed in fetuses from the 75 mg/kg group.In addition, a developmental delay was indicated by reductionof fetal weight and by a significant increase in the occurrenceof incomplete ossification of various skeletal structures. Inthe rabbit, fetal body weight was reduced at 50 mg/kg. Malformationsobserved at 50 mg/kg included gastroschisis, cephalocele, domedhead, flexed paw, and skull and sternum anomalies. The lowest-observed-adverse-effectlevels for maternal and developmental toxicity in the rat andrabbit were 75 and 50 mg/kg, respectively. The no-observed-adverse-effectlevel for maternal and developmental toxicity in the rat andrabbit was 10 mg/kg.     

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.     

RETINYL PALMITATE AS A POSITIVE CONTROL AGENT IN RAT AND RABBIT DEVELOPMENTAL TOXICITY STUDIES

The use of retinyl palmitate (RP) as an oral positive control agent was demonstrated in CD rats and New Zealand White rabbits in 3 developmental toxicity studies in each species. Based on dose range-finding studies, 1000 or 300 mg/ kg day -1 (i.e., 250,000 and 75,000 IU/kg day -1) were administered by oral gavage to rats and rabbits, respectively, on gestation days (GD) 9 and 10. The vehicle control groups received either 1% methylcellulose/0.2% Tween 80 or deionized distilled water from GD 6 to 15 in rats and from GD 6 to 18 in rabbits. Maternal clinical signs, body weights, and food consumption were evaluated. Necropsy and cesarean-section observations were conducted on GD 20 and 29 in rats and rabbits, respectively. All viable fetuses were weighed, sexed, and externally examined. In rats but not rabbits, maternal toxicity was observed as significantly decreased body weights and food consumption, while fetal toxicity occurred as significantly decreased fetal body weights. RP was teratogenic in both rats and rabbits, producing a spectrum of significantly increased external, skeletal, and visceral fetal anomalies in all RP-treated groups. The observed malformations were typical of those produced by vitamin A, i.e., cleft palate, pinna anomalies, and microphthalmia/anophthalmia. These studies demonstrate that RP is a reproducible and cost-effective positive control agent for use in rat and rabbit developmental toxicity studies.     

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.     

Determination of a No-Observed-Effect Level for Developmental Toxicity of Ethylene Glycol Administered by Gavage to CD Rats and CD-1 Mice

Previous studies have indicated that ethylene glycol (EG) isa developmental toxicant in rats and mice primarily when ingested.This study was designed to establish no-observed-effect levels(NOELs) for developmental toxicity of EG administered by gavagein both rodent species. Dams were administered EG on GestationDays 6–15; rats were given 0, 150, 500, 1000, or 2500mg EG/kg/ day; mice were dosed with 0, 50, 150, 500, or 1500mg EG/kg/day. In rat dams given 2500 mg EG/kg/day, water consumptionwas increased during treatment and body weights were reducedthroughout gestation; liver and kidney weights were increasedat euthanization (Gestation Day 21). Relative liver weightswere also increased at 1000 mg/kg/day. Effects observed in ratfetuses at 2500 mg/kg/day included the following hydrocephaly;gastroschisis; umbilical hernia; fused, duplicated, or missingarches, centra, and ribs; poor ossification in thoracic andlumbar regions; and reduced body weights. Reduced body weights,duplicated or missing ribs, centra, and arches, and poor ossificationwere also ob served in rat fetuses at 1000 mg/kg/day. In mice,there was no apparent treatment-related maternal toxicity. Inmouse fetuses (Gestation Day 18), effects were observed at 1500mg/kg/day and included reduced body weights, fused ribs andarches, poor ossification in thoracic and lumbar centra, andincreased occurrence of an extra 14th rib. At 500 mg/kg/day,slight reductions in fetal body weight and increased incidencesof extra ribs were observed. Under conditions of these studies,NOELs for developmental toxicity were 500 mg/kg/day for ratsand 150 mg/kg/day for mice, indicating that mice were more susceptiblethan rats to the teratogenic effects of EG.     

Developmental toxicity of diethanolamine applied cutaneously to CD rats and New Zealand White rabbits

Diethanolamine (DEA) was administered cutaneously to pregnant CD rats and New Zealand White rabbits during the periods of major organogenesis, Gestation Days 6-15 for rats and 6-18 for rabbits. Doses employed were 0, 150, 500, and 1500 mg/kg/day for rats and 0, 35, 100, and 350 mg/kg/day for rabbits. Rat dams exhibited reduced body weight at 1500 mg/kg/day, skin irritation and increased kidney weights at 500 and 1500 mg/kg/day, and a slight microcytic anemia with abnormal red blood cell morphology at all dose levels. Rat fetuses had increased incidences of six skeletal variations at 1500 mg/kg/day. Lower doses were without effect on the fetuses. Rabbit dams administered 350 mg/kg/day exhibited various skin lesions, reduced food consumption, and color changes in the kidneys but no hematological changes. Body weight gain was reduced at >/=100 mg/kg/day. There was no evidence of maternal toxicity at 35 mg/kg/day and no evidence of developmental toxicity in rabbits at any dose level. Developmental toxicity was observed only in the rat and only at doses causing significant maternal toxicity, including hematological effects. Due to a dose discrepancy, the no observable effect level (NOEL) for DEA developmental toxicity in rats was adjusted to 380 mg/kg/day. In rabbits, the embryonal/fetal NOEL was 350 mg/kg/day.     

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 (embryo-fetal toxicity/teratogenicity) toxicity studies of synthetic crystalline lycopene in rats and rabbits.

Synthetic crystalline lycopene is a nutritional supplement to increase dietary intake of lycopene, an antioxidant carotenoid. Its potential oral developmental toxicity was studied in rats and rabbits. Each study included 3 control groups (water and matrix for Lycopene 10 CWD or LycoVit 10%), 3 Lycopene 10 CWD groups [500, 1500 and 3000 (rats)/2000 (rabbits) mg/kg/day] and 1 LycoVit 10% group [3000 mg/kg/day (rats)/2000 (rabbits)]. The high dosages were at maximum achievable concentrations and dosage volumes (15 and 10 ml/kg for rats and rabbits, respectively) of the highly viscous test material suspensions. Dosages were administered on gestation days (GDs) 6 through 19 (rats) or GDs 6 through 28 (rabbits). Endpoints evaluated included viability, body weight, feed consumption, necropsy observations [GD 20 (rats)/GD 29 (rabbits)], uterine contents and fetal viability, gender, body weight and morphology (skeletons double-stained). Feed consumption and weight gain were essentially unaffected in rats and rabbits, despite intubation problems in both species and reduced gastrointestinal motility and mortality in rabbits attributable to the physical properties of the gels. Neither Lycopene 10 CWD nor LycoVit 10% caused direct maternal or developmental toxicity in rats or rabbits at dosages as high as 3000 or 2000 mg/kg/day, respectively.     

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).     

Teratologic Evaluations of N,N-Diethyl-m-toluamide (DEET) in Rats and Rabbits

The potential for DEET to produce developmental toxicity wasevaluated in Charles River CD rats and New Zealand White rabbits.Rats were administered undiluted DEET by gavage on GestationalDays (gd) 6–15 at dosage levels of 0, 125, 250, and 750mg/kg/day. Rabbits were administered undiluted DEET by gavageon gd 6–18 at dosage levels of 0, 30, 100, and 325 mg/kg/day.Group sizes were 25 females per group for rats and 16 femalesper group for rabbits. Control rats and rabbits were ad ministeredcorn oil at the same dosage volumes administered in the high-doseDEET groups. In rats, maternal toxicity in the form of clinicalsigns including two deaths and depressed body weight and foodconsumption was observed at the high-dose level of 750 mg/kg/day.Rat fetal body weights per litter also were reduced at 750 mg/kg/day.In rabbits, maternal toxicity in the form of depressed bodyweight and food consumption was observed at the high-dose levelof 325 mg/kg/day. No maternal toxicity was observed at the low-or mid-dose groups for rats or rabbits. With the exception ofthe reduced fetal weights in rats at 750 mg/kg, there was noevidence of fetal toxicity, no effects on any of the gestationalparameters, nor were there any treat ment-related increasesin external, visceral, or skeletal variations or malformationsin the offspring from the rats and rabbits from these studies.1994 Society of Toxicology.     

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 Evaluation of Sodium Fluoride Administered to Rats and Rabbits in Drinking Water

Sodium fluoride (NaF; Cas No. 7681-49-4) is used in fluoridatingmunicipal water supplies, resulting in chronic exposure of millionsof people worldwide. Because of a lack of pertinent developmentaltoxicity studies in the literature, sodium fluoride was administeredad libitum in deionized/filtered drinking water (to mimic humanexposure) to Sprague-Dawley-derived rats (26/group) on GestationDays (GD) 6 through 15 at levels of 0, 50, 150, or 300 ppm andNew Zealand White rabbits (26/group) on GD 6 through 19 at levelsof 0, 100, 200, or 400 ppm. Higher concentrations via drinkingwater were not practicable due to the poor palatability of sodiumfluoride. Drinking water (vehicle) contained less than 0.6 ppmsodium fluoride (limit of detection) and sodium fluoride contentof the feed was 12.4 ppm fluoride (rats) and 15.6 ppm fluoride(rabbits). Maternal food, water, body weights, and clinicalsigns were recorded at regular intervals throughout these studies.Animals were killed on GD 20 (rats) or 30 (rabbits) and examinedfor implant status, fetal weight, sex, and morphological development.In the high-dose group of both studies there was an initialdecreased maternal body weight gain which recovered over timeand a decreased water consumption—attributed to decreasedpal atability. No clear clinical signs of toxicity were observed.Maternal exposure to sodium fluoride during organogenesis didnot significantly affect the frequency of postimplantation loss,mean fetal body weight/litter, or external, visceral or skeletalmalformations in either the rat or the rabbit. The NOAEL formaternal toxicity was 150 ppm sodium fluoride in drinking water({small tilde}18 mg/kg/day) for rats, and 200 ppm ({small tilde}18mg/kg/day) for rabbits. The NOAEL for developmental toxicitywas 300 ppm sodium fluoride ({small tilde}27 mg/kg/day) forrats and 400 ppm ({small tilde}29 mg/kg/day) for rabbits administeredduring organogenesis in drinking water. The total exposure tofluoride (mg F/kg body weight/day from food and drinking watercombined) in the mid- and high-dose groups for both specieswas >100-fold higher than the range at 0.014–0.08 mgF/kg/day estimated for a 70-kg person from food and fluoridated(1 ppm) drinking water.     

Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits

Exemestane is an orally active, irreversible inactivator of aromatase, structurally related to the natural substrate androstenedione, in clinical use at 25 mg daily for the treatment of advanced breast cancer in postmenopausal women. The reproductive and developmental toxicity of exemestane was assessed in rats and rabbits with oral administration. Pivotal experiments included a fertility study (Segment I), in which female rats received exemestane doses of 4, 20, or 100 mg/kg/day from two weeks premating until GD 20 (cesarean-sectioned dams), or until GD 15 and then from D 1 to D 21 postpartum (dams allowed to deliver), and developmental toxicity studies (Segment II), in which rats and rabbits were treated from GD 6 through GD 17 (rats) or GD 18 (rabbits) at doses of 10, 50, 250, or 810 mg/kg/day and 30, 90, or 270 mg/kg/day, respectively. All rabbits and two-thirds of the rats were cesarean sectioned toward the end of pregnancy to determine litter parameters and examine structural abnormalities in the fetuses; the remaining one-third of the rats was allowed to litter and rear pups to weaning. No pivotal male fertility or peri- and postnatal studies were performed, taking into consideration the therapeutic use. Postnatal effects on the first generation offspring were assessed in both studies in rats, in the portion of dams allowed to deliver. Their F1 offspring were raised to adulthood, when they were evaluated for reproductive performance, and the F1 females were terminated on GD 20. The dosing schedule for the Segment I study in rats, which included a postnatal component, was established to exclude exposure before and during parturition (by withdrawing treatment from GD 16 until the end of parturition). This withdrawal of treatment was put in place because in a preliminary study with treatment including the peripartum period, doses from 5 to 200 mg/kg/day prolonged gestation and interfered with parturition.Overall, studies in rats showed that female fertility was not affected up to 100 mg/kg/day, but doses higher than 4 mg/kg/day, which is approximately the pharmacologically active dose (ED50 = 3.7 mg/kg), prolonged gestation and impaired parturition, leading to maternal deaths in labor and perinatal deaths of offspring. Rats killed on GD 20 showed nondose-related increases in resorptions at doses higher than 10 mg/kg/day, a reduction in fetal body weights at 20 and 100 mg/kg/day (fertility study) and 810 mg/kg/day (developmental toxicity study), and an increase in placental weights at all doses. Female fetuses exposed in utero until GD 20 at 100 mg/kg/day showed an increase in the anogenital distance, very likely related to an increase of the potent androgen DHT as a consequence of aromatase inhibition. Morphologic examinations in fetuses and born pups that were exposed in utero up to the end of the organogenesis period, as well as postnatal investigations on offspring up to adulthood, showed no treatment-related effects. In a developmental toxicity study in rabbits, treatment at 270 mg/kg/day affected maternal food intake and body weight gain, caused abortion or total resorption in about 30% of pregnant females, and reduced body weight and numbers of live fetuses, but did not affect fetal morphology. It was concluded that exemestane did not affect parturition in rats at 4 mg/kg/day or pregnancy in rabbits at 90 mg/kg/day (about 1.5 and 70 times the human dose, respectively, on a mg/m2 basis) and was not teratogenic in rats and rabbits.Exemestane is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women.     

Developmental Toxicity Evaluation of Ethylene Glycol by Gavage in New Zealand White Rabbits

Artificially inseminated New Zealand white (NZW) rabbits wereadministered ethylene glycol (EG) by gavage on Gestational Days(GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day,with 23–24 inseminated animals per group. Clinical signswere recorded and water consumption was measured daily; doeswere weighed on GD 0, 6–19, 25, and 30. At necropsy (GD30), maternal liver, kidney, and gravid uterine weights wererecorded. Histopathologic examination was performed on kidneysfrom 10 does/dose and for all unscheduled deaths. Ovarian corporalutea were counted and uterine implantation sites (total sites,resorptions, dead and live fetuses) were recorded. All livefetuses were weighed, sexed, and examined for external, visceral,and skeletal malformations and variations. EG resulted in profoundmaternal toxicity at 2000 mg/kg/day (42% mortality; three earlydeliveries and one spontaneous abortion) associated with renalpathology and unaccompanied by any other indicators of maternaltoxicity. Renal lesions at 2000 mg/kg/day involved the corticalrenal tubules and included intraluminal oxalate crystals, epithelialnecrosis, and tubular dilatation and degeneration. No dose-relatedmaternal toxicity occurred at 100–1000 mg/kg/day. Therewas no indication of developmental toxicity at any dose tested,including no effects on pre- or postimplantation loss, numberof fetuses, fetal body weight, or sex ratio (% male fetuses)per litter, and no evidence of teratogenicity. The "no observableadverse effect level" (NOAEL) for maternal toxicity was therefore1000 mg/kg/day and the NOAEL for developmental toxicity wasat least 2000 mg/kg/day in this study. The sensitivity of NZWrabbits relative to that of Sprague—Dawley rats and Swissmice for maternal and developmental toxicity from gavage administrationof EG during organogenesis can be determined for maternal toxicity:rabbits>mice>rats, and for developmental toxicity, mice>>rats >> rabbits.     

Comparison of Fetotoxic Effects of a Dermally Applied Complex Organic Mixture in Rats and Mice

A high-boiling (288–454?C), coal-derived complex organicmixture (COM) has been shown to be teratogenic in rats followinginhalation and oral routes of exposure. To determine whethersimilar changes also occur after dermal exposure to this COM,pregnant rats and mice were exposed during periods of organogenesis(Days 11 to 15 of gestation). Shaved backs were painted with0, 500, or 1500 mg/kg of the COM (control, low, or high dose,respectively); the exposed area was not occluded. Maternal weightgain during the gestation period decreased with increasing dosein rats but not in mice. Examination of rat fetuses on Day 20of gestation showed that resorptions had occurred in more than90% of low-and high-dose litters (vs 6% in the control group).In mice, fetal examinations on Day 18 of gestation showed thatresorptions occurred in 71% of litters from both exposure groups(vs 14% in the controls). Fetal measurements indicated thatboth the weight and the length of rat fetuses decreased withincreasing dose, but mouse fetuses were unaffected. Cleft palates,absent in the control groups, were observed in 50 to 55% ofthe high-dose group and 5 to 8% of the low-dose fetuses of bothspecies. Small fetal lungs occurred in nearly 100% of the exposedrat fetuses and in 25% of the high-dose mice; the incidenceof small lungs was 1% in control animals. Other variations observedin exposed groups included edema and reduced ossification inthe rat and renal pelvic cavitation in the mouse. In conclusion,dermal exposure of dams to COM resulted in life-threateningmorphological alterations in fetuses of both species similarto those seen following exposure by Other routes.     

Developmental Toxicity of Dinitroaniline Herbicides in Rats and Rabbits

The potential developmental toxicity of trifluralin was evaluatedin rats and rabbits. Pregnant rats and rabbits were dosed oncedaily by gavage on Gestation Days 6–15 and 6–18,respectively. Doses for rats were 0, 100, 225, 475, or 1000mg/kg; doses for rabbits were 0, 100, 225, or 500 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 28, respectively. In rats, maternal toxicity was indicatedin the 475 and 1000 mg/kg treatment groups by depression ofbody weights and food consumption. Fetal viability and morphologywere not adversely affected at any dose level. Developmentaltoxicity was indicated at the 1000-mg/kg dose level by depressionof fetal weight. The NOAEL for maternal toxicity in the ratwas 225 mg/kg the NOAEL for developmental toxicity in the ratwas 475 mg/kg. In rabbits, maternal toxicity was indicated atthe 225 and 500 mg/kg dose levels by abortions and/or deathsin conjunction with anorexia and cachexia. Developmental toxicitywas indicated at the 500 mg/kg dose level by depressed fetalviability and weight. Fetal morphology was not adversely affectedat any dose level. The NOAELs for maternal and developmentaltoxicity in the rabbit were 100 and 225 mg/kg, respectively.Based on these data, trifluralin did not exhibit selective toxicitytoward the developing conceptus.     

Developmental toxicity studies of the quinolone antibacterial agent irloxacin in rats and rabbits

Embryotoxicity studies on irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS-91524-15-1), a new fluoroquinolone antibacterial agent, were performed in rats and rabbits. Oral administration of irloxacin during the fetal period of organogenesis to pregnant rats and rabbits at dose levels of up to 1000 and 350 mg/kg/d, respectively, elicited no evidence of teratogenicity. During the first days of treatment, transient stasis in body weight increase was observed in rat dams receiving doses of 350 or 1000 mg/kg/d, and reduced food consumption was observed in those receiving 1000 mg/kg/d. Necropsy on day 20 of gestation showed dosage related increase in liver and kidney weights in all rat treated groups. Rabbit dams receiving 350 mg/kg/d showed during the first days of treatment decrease in body weight, and decreased food consumption and faecal output. Also, four females receiving 350 mg/kg/d aborted between days 18 and 20 of gestation. Rat fetuses in the 350 and 1000 mg/kg/d showed decreased body weight, and a decrease in placental weights was observed in the 1000 mg/kg/d group. No retardations or malformations were observed in rat or rabbit fetuses at any tested dose level. For maternal and embryo-fetal effects 100 and 150 mg/kg/d can be considered as the no-effect-level (NOEL) for rats and rabbits, respectively.     

The Developmental Toxicity of Boric Acid in Rabbits

Boric acid (BA), an ingredient of many pharmaceutical, cosmetic,and pesticide products, was previously shown to induce reproductiveand developmental toxicity in laboratory rodents. In this study,BA (0, 62.5, 125, or 250 mg/kg/day, po) was administered onGestational Days (GD) 6–19 to New Zealand White rabbits(18–23 pregnant/group). Maternal body weight, food consumption,and clinical condition were monitored at regular intervals throughoutgestation. At termination (GD 30), the numbers of uterine implantations,resorptions, dead fetuses, and live fetuses were determined.Fetuses were weighed, and live fetuses examined for external,visceral, and skeletal defects. Maternal food intake decreasedduring treatment at 250 mg/kg/day and increased at 125 mg/kg/dayafter treatment. Maternal body weight (GD 9–30), weightgain during treatment, gravid uterine weight, and number ofovarian corpora lutea decreased at 250 mg/kg/day. In contrast,maternal corrected gestational weight gain increased at 125mg/kg/day. Maternal liver weight was not affected. Relative(but not absolute) maternal kidney weight increased at 250 mg/kg/day,and microscopic evaluation revealed no treatment-related renalpathology. At 250 mg/kg/day, prenatal mortality was increased(90% resorptions/litter vs 6% for controls), the proportionof pregnant females with no live fetuses was increased (73%vs 0%), and live litter size was reduced (2.3 fetuses/littervs 8.8). As a result, there were only 14 live fetuses (6 livelitters) available for evaluation in the high-dose group, comparedto 153–175 live fetuses (18–23 live litters) inthe other groups. The percentage malformed fetuses/litter wasincreased at 250 mg/kg/day, primarily due to cardiovasculardefects in 72% of high-dose fetuses vs 3% of controls. The mostprevalent cardiovascular malformation (in terventricular septaldefect) was observed in 57% of high-dose fetuses compared to0.6% among controls. At 250 mg/kg/day, average fetal body weight/litterwas 92% of the average control weight (not statistically significant).In summary, no definitive maternal or developmental toxicitywas observed at 62.5 or 125 mg/kg/day BA. Mild maternal effectsand severe developmental toxicity were observed at 250 mg/kg/day.