Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of Di-n-butyl Phthalate Administered to Pregnant Rats

The developmental toxicity and placental transfer of di-n-butylphthalate(DBP) were evaluated in Sprague-Dawley rats given a single oraldose of DBP on Gestational Day 14. In the developmental toxicitystudy, dams were dosed with 0, 0.5, 1, 1.5, or 2 g DBP/kg andwere necropsied on GD21. Increased incidence of resorptionsand reduced fetal body weight were observed at 1.5 and 2 g/kg.Higher incidences of skeletal variations were found at doses     

Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of N,N-Dimethylformamide Administered to Pregnant Rats

This study evaluates the developmental toxicity and placentaland milk transfer of N,N-dimethylformamide (DMF) in rats. Sprague-Dawleyrats were given 0, 50, 100, 200, and 300 mg DMF/kg/day, by gavage,on Gestational Days (GD) 6 through 20. Maternal toxicity wasindicated by depressions in weight gain and food consumptionat doses 100 mg/kg. Fetal toxicity was indicated by decreasedfetal body weight at doses 100 mg/kg, and by increased incidencesof two skeletal variations (absent or poorly ossified supraoccipitaland sternebrae) at 200 and 300 mg/kg. Thus, the maternal anddevelopmental no-observed-adverse-effect level was 50 mg/kg/day.The time course disposition of [¹⁴C]DMF was examined over a48-hr period in GD12- and GD18-pregnant rats after a singleoral dose of 100 mg [¹⁴C]DMF/kg Peak concentrations of radiocarbonoccurred within 1 hr after dosing. Embryonic (GD 12) and fetal(GD18) tissues accounted for 0.15 and 6% of the administereddose, respectively. Levels of radiocarbon in embryonic and fetaltissues were equal or slightly less than in maternal plasmaup to 8 and 24 hr, respectively, and higher thereafter. HPLCanalysis performed at intervals from 1 to 8 hr on GD12 and 1–24hr on GD18 indicated that unchanged DMF and metabolites werereadily transferred to the embryonic and fetal tissues, wheretheir levels were generally equal to those in maternal plasma.The parent compound accounted for most of the radioactivityuntil 4–8 hr and then decreased. N-Hydroxymethyl-N-methylformamide(HMMF) and N-methylformamide (NMF) were the predominent metabolitesand increased with time. Much lower concentrations were foundfor formamide and N-acetyl-S-(N-methylcarbamoyl)cysteine. Transferof radioactivity into milk was studied in dams given a singleoral administration of 100 mg [¹⁴C]DMF on Lactation Day 14.DMF, HMMF, and NMF were found in the milk at concentrationsequal to those in plasma.     

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 of Bromoxynil in Mice and Rats

Developmental Toxicity of Bromoxynil in Mice and Rats. ROGERS,J. M., FRANCIS, B. M., BARBEE B. D., AND CHERNOFF, N. (1991).Fundam. Appl. Toxicol 17, 442–447. The developmental toxicityof the wide-spectrum herbicide bromoxynil (bromoxynil phenol;3,5-dibromo-4-hydroxyphenyl cyanide) was evaluated in Sprague-Dawleyrats and Swiss-Webster mice, and the developmental toxicityof its octanoate ester (2,6-dibromo-4-cyanophenyl octanoate)was evaluated in Sprague-Dawley rats. Animals were treated fromDay 6 to Day 15 of gestation [presence of sperm or semen plug= 0 of gestation]. The doses administered were as follows: bromoxynilphenol in the mouse, 342, 114, and 38 µmol/kg/day; bromoxynilphenol and bromoxynil octanoate in the rat, 54, 18, and 6 µmol/kg/day.Some animals were killed on selected days during treatment formeasurement of organ weights sensitive to stress. In mice treatedwith bromoxynil phenol, maternal mortality was noted at 114and 342 µmol/kg/day, but surviving females gained weightnormally. Liver to body weight ratios increased with increasingdose, but no consistent effect was seen on adrenal, thymus,or spleen weights. Fetuses of mice treated with the highestdose of bromoxynil phenol were of lower weight and had a higherincidence of supernumerary ribs than controls. In rats, bromoxynilphenol and its octanoate ester at the highest doses used causedno mortality but resulted in only transient decreases in maternalweight gain and significantly increased the liver to body weightratio, but did not significantly alter adrenal, thymus, or spleenweight in the dams. No significant maternal effects were seenat lower doses. The highest doses of both compounds increasedthe incidence of supernumerary ribs in fetuses of treated rats,but did not induce other anomalies. Fetal weight was reducedin rats at the highest dose of bromoxynil octanoate, but noeffects on fetal weight were seen with bromoxynil phenol. Bromoxynilexposure produced a high incidence of supernumerary ribs atmaternally toxic doses in both rats and mice, although no evidenceof maternal stress per se was found. The mechanism and significanceof this effect require further study.     

Developmental Toxicity of Inhaled trans-1,2-Dichloroethylene in the Rat

The developmental toxicity of trans-1,2-dichloroethylene (t-DCE),a component of certain Freon cleaning agents, was examined inpregnant rats. t-DCE was administered by inhalation 6 hr dailyon Days 7–16 of gestation (the day copulation was confirmedwas termed Day 1 of gestation) at exposure levels of 0, 2000,6000, or 12,000 ppm. The offspring were then examined on Day22 of gestation. Overt maternal toxicity was expressed as asignificant reduction in weight gain at 12,000 ppm and in feedconsumption at 6000 and 12,000 ppm. During the exposure period,lacrimation and stained periocular hair, and signs of occularirritation, were observed in all groups. In addition, increasedincidences of alopecia, lethargy, and salivation were observedin the high-dose dams. Significant increases in the mean numberof resorptions per litter were seen in the litters of dams exposedto 6000 and 12,000 ppm of t-DCE; however, these values are withinthe range of historical controls and not considered to be treatmentrelated. The mean combined and female fetal weights were significantlyreduced in the litters of dams exposed to the highest concentration(12,000 ppm) of t-DCE. Marginal effects on feed consumption,unaccompanied by other changes and reflective of the patternseen at higher doses, were seen at 2000 ppm. Thus, marginalmaternal toxicity was seen at 2000 ppm and exposures to 6000ppm t-DCE or higher caused frank maternal toxicity while thefetus was affected only at 12,000 ppm. Therefore, t-DCE is notconsidered to be uniquely toxic to the rat conceptus.     

Developmental Toxicity Evaluation of Acrylamide in Rats and Mice

Developmental Toxicity Evaluation of Acrylamide in Rats andMice. FIELD, E. A., PRICE, C. J., SLEET, R. B., MARR, M. C,MORRISSEY, R. E., AND SCHWETZ, B. A. (1990). Fundam. Appl. Toxicol.14, 502–512. Acrylamide (ACRL), a widely used industrialchemical with neurotoxic effects, was evaluated for developmentaltoxicity. ACRL in distilled water was administered once dailyby gavage on gestational days (gd) 6–17 to mice (0, 3,15, or 45 mg/kg) and on gd 6–20 to rats (0, 2.5, 7.5,or 15 mg/kg). Following termination (gd 17, mice; gd 20, rats)fetuses were examined for external, visceral, and skeletal malformations.Maternal toxicity during treatment was observed at the highestdose as reduced body weight gain in both species and hindlimbsplaying in treated mice only. Weight gain corrected for graviduterine weight was also reduced in rats at 7.5 and 15 mg/kg/day.Embryo/fetal toxicity was not observed in rats, but fetal weightwas reduced in mice administered 45 mg/kg/day. No increase inthe incidence of malformations was observed in either species;however, the incidence of variations (predominately extra rib)increased with dose. In summary, administration of ACRL duringorganogene-sis produced maternal and developmental toxicityat 45 mg/kg/day in mice and maternal, but not developmental,toxicity at doses 7.5 mg/kg/day in rats.     

Developmental Toxicity of Boric Acid in Mice and Rats

Boric acid (BORA), an ingredient of many cosmetics, pharmaceuticals,and pesticides, was tested for developmental toxicity in timed-pregnantSwiss mice and Sprague-Dawley rats (n = 26–28/group).BORA (0, 0.1, 0.2, or 0.4% in feed) was provided throughoutgestation to attain steady-state exposure as early as possibleduring prenatal development. Average doses (mg/kg/day) were248, 452, or 1003 in mice, and 78, 163, or 330 in rats. To limitprenatal mortality, BORA (0.8% or 539 mg/kg/day) was providedto an additional group of rats on Gestational Days (GD) 6 to15 only. On GD 17 (mice) or 20 (rats), fetuses were weighedand examined for malformations (external, visceral, skeletal).Mouse dams exhibited mild renal lesions (0.1%), increased waterintake and relative kidney weight (0.4%), and decreased weightgain (0.4%) during treatment. There was a reduction of fetalbody weight (0.2%) and an increased incidence of resorptionsand malformed fetuses per litter (0.4%). Morphological changesincluded an increased incidence of short rib XIII (a malformation)and a decreased incidence of rudimentary or full rib(s) at lumbarI (an anatomical variation). Maternal rats exhibited increasedliver and kidney weights at 0.2%, altered water and/or foodintake at >0.2%, and decreased weight gain at >0.4%. Averagefetal body weight/litter was reduced at all doses. Prenatalmortality was increased only at 0.8%. The incidence of fetalmalformations was significantly increased at 0.2%. The mostfrequently observed malformations were enlarged lateral ventriclesof the brain and agenesis or shortening of rib XIII. In rats,the no-observable-adverse-effect level (NOAEL) for maternaltoxicity was 78 mg/kg (0.1%), while in mice the low dose of248 mg/kg (0.1%) approached the maternal NOAEL with mild renallesions in only 2 of 10 females. Embryo/fetal toxicity occurredin all groups of rats at 78 mg/kg (0.1%) while the NOAEL fordevelopmental toxicity in mice was 248mg/kg (0.1%). Thus developmentaltoxicity occurred below maternally toxic levels in rats as wellas in the presence of maternal toxicity in mice and rats.     

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 of 1,1,1-Trichloroethane in CD Rats

1,1,1 -Trichloroethane (TCEN), a major industrial and householdsolvent, was evaluated for pre- and postnatal developmentaleffects in SpragueDawley rats. This study was designed to assessthe repeatability of a report (S. C. Dapson, D. E. Hutcheon,and D. Lehr, Teratology 29, 25 A, 1984) that indicated that10 ppm TCEN in drinking water caused cardiac malformations indeveloping rats. In the present study, TCEN (97% pure) was administeredin the drinking water at target concentrations of 3, 10, and30 ppm, using 0.05% Tween 80 as an emulsifying agent Two controlgroups, one receiving deionized/filtered water and the otherreceiving a vehicle control solution containing 0.05% Tween80 and 0.9 ppm 1,4-dioxane, a stabilizing agent found in thebulk chemical, were also included. Male and female breeders(more than 30 per group) were exposed to the control solutionsor test compound for 14 consecutive days prior to cohabitationand for up to 13 days during the cohabitation phase. Sperm-positivefemales (24–29 per group) continued to be exposed to theseformulations during pregnancy and lactation to Postnatal Day(PND) 21. Parental animals exhibited a slight aversion to the30-ppm drinking water during the premating exposure. No significanteffect on reproductive competence of the parental animals orpostnatal growth and development of the offspring to PND 21was noted. A slight increase in mortality from implantationto PND 1, possibly due to high mortality in one litter, wasobserved in the 30-ppm dose group. There was no indication ofan increase in the incidence of cardiac or other malformationsin PND 21 pups. In summary, TCEN administered at 3, 10, and30 ppm in the drinking water had no significant effect on themorphological development of CD rats,     

Developmental Toxicity Study of Glycolic Acid in Rats

ABSTRACT

The developmental toxicity of glycolic acid was assessed in rats by orally administering solutions of the test material in water over days 7-21 of gestation (the day of copulation plug detection was defined as day 1 of gestation). Groups of 25 mated female Crl:CD®BR rats were gavaged at daily dose levels of 0, 75, 150, 300 or 600 mg/kg. The dams were euthanized on day 22 and the offspring were weighed, sexed, and examined for external, visceral, and skeletal alterations. Clear evidence of maternal toxicity was demonstrated at 600 mg/kg; adverse clinical observations were statistically significantly increased (wheezing/lung noise, abnormal gait/staggering, lethargy). in addition, maternal body weights, weight changes, and food consumption were statistically significantly reduced at this dose level. Marginal evidence of maternal toxicity was demonstrated at 300 mg/kg; wheezing/lung noise similar to that seen at 600 mg/kg was observed in 2 of 25 dams. This increase approached statistical significance (p=0.0553). There was marked evidence of developmental toxicity at 600 mg/kg. Mean fetal weight was statistically significantly reduced while the incidences of skeletal (ribs, vertebra, and sternebra) malformations and variations were statistically significantly increased. At 300 mg/kg/day, there was a slight (2 affected fetuses from 2 litters) increase in the incidence of two skeletal malformations: fused ribs and fused vertebra. Although these increases were not statistically significant (p=0.0555), they were consistent with findings seen at 600 mg/kg/day and thus were considered relevant. There was no other evidence of developmental toxicity at 300 mg/kg/day nor was any developmental toxicity seen at 150 or 75 mg/kg/day. Thus, the maternal and developmental no-observed-effect level (NOEL) was considered 150 mg/kg.     

Hydroquinone: A Developmental Toxicity Study in Rats

To determine the potential developmental toxicity of hydroquinone(HQ), pregnant rats (COBS-CD-BR) were given 0, 30, 100, or 300mg/kg HQ by gavage on the 6th through the 15th days of gestation.Maternal effects included a slight, but significant (p 0.05),reduction in body weight gain and feed consumption for the 300mg/kg HQ dams. Reproductive indices, i.e., pregnancy rate, numbersof corpora lutea, implantation sites, viable fetuses, and earlyand late resorptions, fetal sex ratio, pre-and postimplantationlosses, and gravid uterine weights, were not affected by treatmentwith HQ. A slightly reduced (p 0.05) mean fetal body weightseen at the 300 mg/kg dose level was associated with the slightlyreduced body weight gain seen for the dams at this dose level.Gross external, internal soft tissue, and skeletal examinationsof the fetuses revealed no HQ-related malformations. The incidencesof gross external variations (small hematomas) and internalsoft tissue variations (dilated renal pelvis, hydronephrosis,and hydroureter) in the HQ-treated litters were not statisticallydifferent from the control incidences. Skeletal variations (delayedossification of membranous skull bones, hyoid bone, thoraciccentra 1–3, sacral arches 3 and 4, and bilobed thoraciccentra 9–13) were seen with similar frequency in the controland HQ-treated groups. A statistically significant increasein the incidence of total common vertebral variations seen atthe 300 mg/kg HQ dose level was not considered toxicologicallysignificant. The incidences of total skeletal variations werenot statistically different between the control and the HQ-treatedgroups. It is concluded that HQ was not selectively toxic tothe developing rat conceptus and, thus, appears not to havethe properties of a developmental toxicant. The no-observable-effectlevel for both maternal and developmental toxicity was 100 mg/kg,whereas 300 mg/kg was the no-observable-adverse-effect level.     

Reproductive and Developmental Toxicity of N,N-Diethyl-m-toluamide in Rats

N,N-Diethyl-m-toluamide (mDET, DEET) is widely used as a topicalinsect repellent. It is the active ingredient in many consumerformulations, which usually contain 10–25% mDET in analcohol base. More concentrated consumer products are also available,including some that are pure technical grade mDET. Persons livingor employed in mosquito-infested areas may have very high seasonalexposures to mDET. Because contradictory reports had been publishedon the reproductive and developmental toxicity of mDET, a seriesof studies was conducted in male and female Sprague-Dawley rats.All treatments were administered by daily subcutaneous injectionsof undiluted mDET. A dose finding study was done using 12 time-matedfemales per group treated on Gestational Days (GD) 6–15with 0.50, 0.62, 0.78, 0.92, or 1.2 ml mDET /kg/day. No femalessurvived 10 days of mDET dosing with 1.2 ml/kg/day. Deaths occurredin all other groups except the low dose (0.50 ml/kg/ day). Pregnantfemales treated on GD 6–15 with 0 or 0.30 ml/ kg/day wereused for the teratology study. Half of each group was euthanizedon GD 20: the second half was singly housed in nesting boxesand allowed to deliver litters. Live pups were counted and weighedsoon after birth on Postnatal Day (PD) 0 and again on PD 3,9, and 14. Proven fertile males were treated 5 days/week for9 weeks with 0, 0.30, 0.73, 1.15, or 1.80 ml mDET /kg/day fora male dose-finding study. Each group consisted of 20 males.No males survived the 1.80 ml/kg/day. Deaths occurred in allremaining dose groups except the 0.30 ml/kg/ day and controlgroup. Immediately following the final treatment of the maledose study, 11 males were randomly selected from the 0.30 and0.73 ml/kg/day groups. They were cohabited for 7 days with 4females per male during post-treatment Weeks 1 and 2. Half ofthe females were euthanized 12–14 days after the lastday of cohabitation for a dominant lethal study; the remainingfemales were singly housed in nesting boxes and allowed to deliverlitters. Live pups were counted and weighed on PD 0 and 3. Therewas no evidence of reproductive or developmental toxicity inany of these assays, but there were signs of neuro-toxicityin treated adult male and female rats, which may relate to reportsof neurotoxicity in humans heavily exposed to mDET -containinginsect repellents, o 1992 society of Toxicology.     

The Developmental Toxicity of Bisphenol A in Rats and Mice

The Developmental Toxicity of Bisphenol A in Rats and Mice.MORRISSEY, R. E., GEORGE, J. D., PRICE, C. J., TYL, R. W., MARR,M. C., AND KIMMEL, C. A. (1987). Fundam. Appl. Toxicol. 8, 571–582.Bisphenol A (BPA) was evaluated for developmental toxicity inCD rats (0, 160, 320, or 640 mg/kg/day) and CD-1 mice (0, 500,750, 1000, or 1250 mg/kg/day) dosed daily by gastric intubationon Gestational Days 6 through 15. Timed-pregnant dams were sacrificed1 day prior to parturition, the uterine contents were examined,and all fetuses were examined for external, visceral, and skeletalmalformations. In rats, maternal weight gain during gestation,weight gain corrected for gravid uterine weight, and weightgain during treatment were significantly reduced at all BPAdoses. Gravid uterine weight and average fetal body weight perlitter were not affected by BPA. No increase in percentage resorptionsper litter or percentage fetuses malformed per litter was detected.In mice, maternal mortality occurred at all BPA doses, reaching18% at the high dose, which also produced a significant decreasein maternal body weight gain during gestation and treatment.Weight gain corrected for gravid uterine weight was not affectedby BPA. Reductions in gravid uterine weight and average fetalbody weight were observed with the 1250 mg/kg dose of BPA. Relativematernal liver weight was increased at all doses of BPA. Therewas a significant increase in the percentage of resorptionsper litter with 1250 mg BPA/kg/day. Malformation incidence wasnot altered by BPA. Thus, BPA treatment at maternally toxicdose levels during organogenesis produced fetal toxicity inmice but not in rats and did not alter fetal morphologic developmentin either species.     

新橙皮苷对大鼠胚胎-胎仔发育的毒性研究

目的 评价新橙皮苷对大鼠胚胎-胎仔发育的毒性。方法 妊娠大鼠根据妊娠第0天（gestation day 0,GD0）和体质量采用分层随机法分成5组：对照（0.5%羧甲基纤维素钠）组,环磷酰胺（12 mg·kg^-1）组,新橙皮苷低、中、高（0.45,0.9,1.8 g·kg^-1）3个剂量组。妊娠鼠于GD6开始给药至GD15。实验期间,每周至少测定2次体质量和1次摄食量。GD20处死妊娠鼠,对黄体、着床腺、胎仔、胎盘等情况进行检查。结果 试验期间,各组动物临床症状观察均未见明显异常。与对照组相比,新橙皮苷各剂量组动物体质量未见明显改变,环磷酰胺组动物增重减缓;新橙皮苷各剂量组黄体、着床、活胎、吸收胎、死胎计数均未见明显改变,环磷酰胺组子宫重量下降;新橙皮苷高剂量组胎仔身长降低,环磷酰胺组身长、尾长、重量及胎盘重均降低;新橙皮苷各剂量组胎仔外观检查未见给药相关改变,环磷酰胺组主要可见全身浮肿、头、耳、面、肢、指趾等改变。胎仔内脏检查中,新橙皮苷各剂量组分别可见1例脑室改变,中、高剂量组分别可见2例和1例食管扩张;环磷酰胺组可见腭、脑室、食管、睾丸附睾等改变。骨骼检查中,新橙皮苷可延缓顶骨、胸骨的骨化,可能影响下颌骨、颈椎、腰椎、耻骨、枕骨和肋骨的骨化。环磷酰胺12 mg·kg^-1对颅骨、脊椎骨、肋骨、胸骨、掌骨等的骨化均有所影响。结论 新橙皮苷给药后,对母体未产生明显毒性反应,未观察到临床不良反应的剂量水平（NOAEL）为1.8 g·kg^-1;对胚胎-胎仔的发育毒性主要表现为延缓骨骼如顶骨、胸骨等的骨化外,还可能影响脑部和食管的发育,NOAEL<0.45 g·kg^-1。     

Arsine: Absence of Developmental Toxicity in Rats and Mice

Arsine: Absence of Developmental Toxicity in Rats and Mice.MORRISSEY, R. E., FOWLER, B. A., HARRIS, M. W., MOORMAN, M.P., JAMESON, C. W., AND SCHWETZ, B. A. (1990). Fun-dam. Appl.Toxicol. 15, 350–356. Arsine gas is a potent hemolyticagent but the effects of exposure to tolerated concentrationson pregnancy and prenatal development have not been reported.In the present evaluation, groups of bred mice and rats wereexposed to arsine at concentrations of 0.025, 0.5, or 2.5 ppmon Gestation Days (gd) 6 through 15. Animals were killed ongd 17 (mice) or on gd 20 (rats) and endpoints of maternal anddevelopmental toxicity were evaluated. In rats, maternal spleenswere enlarged in the 2.5 ppm group and there was a decreasein packed red cell volume in pregnant rats. Fetuses weighedmore than in the control group but other endpoints of developmentaltoxicity were not affected by arsine exposure. In another experimentinvolving separate groups of rats, the arsenic content of maternalblood and fetal livers increased with increasing atmosphericarsine concentrations, as assessed on gd 20. In mice, maternalspleen size was significantly increased in the 2.5 ppm group.The number of live fetuses, mean fetal body weight, and percentagesof resorptions or malformations per litter were not affectedby arsine exposure. In conclusion, arsine at atmospheric concentrationsthat caused increases in maternal spleen size and measureablelevels of arsenic in maternal blood and fetal livers did notadversely affect endpoints of developmental toxicity     

Developmental Toxicity Evaluation of Inhaled Nitrobenzene in CD Rats

Developmental Toxicity Evaluation of Inhaled Nitrobenzene inCD Rats. TYL, R. W., FRANCE, K. A., FISHER, L. C., DODD, D.E., PRITTS, I. M, LYON, J. P., O'NEAL, F. O., and KIMMERLE,G. (1987). Fundam. Appl. Toxicol. 8, 482–492. PregnantCD (Sprague–Dawley) rats were exposed to nitrobenzenevapor (CAS Registry No. 98-95-3) at 0, 1, 10, and 40 ppm (meananalytical values of 0.0, 1.06, 9.8, and 39.4 ppm, respectively)on gestational days (gd) 6 through 15 for 6 hr/day. At sacrificeon gd 21, fetuses were evaluated for external, visceral, andskeletal malformations and variations. Maternal toxicity wasobserved: weight gain was reduced during exposure (gd 6–9and 6–15) to 40 ppm, with full recovery by gd 21, andabsolute and relative spleen weights were increased at 10 and40 ppm. There was no effect of treatment on maternal liver,kidney, or gravid uterine weights, on pre- or postimplantationloss including resorptions or dead fetuses, on sex ratio oflive fetuses, or on fetal body weights (male, female, or total)per litter. There were also no treatment-related effects onthe incidence of fetal malformations or variations. In summary,during organogenesis in CD rats, there was no developmentaltoxicity (including teratogenicity) associated with exposureto nitrobenzene concentrations that produced some maternal toxicity(10 and 40 ppm) or that produced no observable maternal toxicity(1 ppm).     

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.     

Combined Treatment Potentiates the Developmental Toxicity of Ibuprofen and Acetazolamide in Rats

Aspirin (ASA), an irreversible cyclooxygenase (COX) inhibitor, induces ventricular septal defect (VSD) and diaphragmatic hernia (DH) in rat fetuses when administered on gestation days (GDs) 9–10, a critical period for cardiovascular (CV) and midline development. Evaluation of a spectrum of nonsteroidal antiinflammatory drugs (NSAIDs; reversible COX inhibitors) showed that while some NSAIDs induced VSD in rats, none of the NSAIDs evaluated produced DH. In addition to inhibiting COX, ASA also inhibits carbonic anhydrase. The purpose of this study was to determine whether concurrent inhibition of COX and carbonic anhydrase would produce a teratogenic profile that includes both VSD and DH. To inhibit both COX and carbonic anhydrase, ibuprofen (COX inhibitor) and acetazolamide (carbonic anhydrase inhibitor) were coadministered on GDs 9–10. Groups of 20 female Crl:CD(SD)IGS BR rats were given either 300 mg kg^{? 1} day^{? 1} ibuprofen, 1000 mg kg^{? 1} day^{? 1} acetazolamide, or both (combination of ibuprofen and acetazolamide). Fetuses were evaluated on GD 21 for external and visceral development. Ibuprofen induced VSD in 3.7% of fetuses per litter; no defects in appendicular skeletal development were noted. Acetazolamide induced VSD in 5.9% of the fetuses per litter and appendicular defects in 41% of the fetuses per litter. Coadministration of ibuprofen and acetazolamide produced VSD in 18.7% of the fetuses per litter and appendicular defects in 77% of the fetuses per litter; however, there were no DH. Therefore, while concurrent inhibition of COX and carbonic anhydrase did not produce DH, potentiation was noted for the induction of VSD and appendicular anomalies.     

Evaluation of the Developmental Toxicity of Sodium Nitrite in Long-Evans Rats

Sodium nitrite administered in the drinking water to Long-Evansrats during pregnancy and lactation severely affected erythropoieticdevelopment, growth, and mortality in their offspring. Pregnantrats were maintained throughout gestation on 0.5, 1, 2, or 3g NaNO₂/liter. There were no significant differences betweentreated and control litters at birth. Thereafter, pups of treateddams on 2 and 3 g NaNO₂/liter gained less weight, progressivelybecame severely anemic, and began to die by the third week postpartum.By the second week postpartum, hemoglobin levels, RBC counts,and mean corpuscular volumes of these pups were all drasticallyreduced compared to controls. Blood smears showed marked anisocytosisand hypochromasia. Gross chylous serum lipemia and fatty liverdegeneration were noted. Histopathology demonstrated cytoplasmicvacuolization of centrilobular hepatocytes and decreased hematopoiesisin bone marrow and spleen. Administration of 1 g NaNO₂/literresulted in hematological effects but did not affect growthor mortality. NaNO₂(0.5 g/liter) was at or near the no observedeffect level. Cross-fostering indicated that treatment dunngthe lactational period was more instrumental in producing lesionsthan treatment during the gestational period. The data presentedare consistent with the lactational induction of severe irondeficiency in the neonate.