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 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 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.     

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.     

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     

The Developmental Toxicity of Orally Administered Theophylline in Rats and Mice

The Developmental Toxicity of Orally Administered Theophyllinein Rats and Mice. LIND-STRÖM, P., MORRISSEY, R. E., GEORGE,J. D., PRICE, C. J., MARR, M. C, KJMMEL, C. A., AND SCHWETZ,B. A. (1990). Fundam. Appl. Toxicol. 14, 167–178. Theophylline(THEO), a widely prescribed anti-asthmatic, was evaluated fordevelopmental toxicity. It was administered continuously onGestational Days 6 through 15 to pregnant Sprague-Dawley (CD)rats in the feed (0,0.15,0.30, or 0.40%) and to pregnant Swiss(CD-1) mice in the drinking water (0,0.075, 0.15, or 0.20%).Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day,while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats,maternal weight gain parameters (weight gain during gestationand treatment, as well as corrected weight gain) decreased at0.40%. While food consumption was lower only in the 0.40% treatmentgroup, water consumption was higher in all treated groups. Therewas a dose-related decreasing trend in gravid uterine weight.The number of live fetuses per litter decreased at 0.40% andthe average male and female fetal weight per litter decreasedat 0.30 and 0.40%. There was no increase in malformations. Inmice, maternal corrected body weight and weight gain duringgestation decreased at 0.15 and 0.20%, and weight gain duringtreatment and gravid uterine weight decreased at 0.20%. Waterconsumption was reduced by as much as 30-45% of controls at0.15 and 0.20%, respectively, while food consumption did notchange with THEO treatment There was an increase in percentageresorp-tions per litter and a decrease in the average male andfemale fetal weight per litter at 0.15 and 0.20%. An increasingtrend was noted for percentage malformed fetuses per litter,and percentage litters with externally malformed fetuses wereslightly increased in the mid- and high-dose groups. However,these increases were not statistically significant. In summary,there were developmental effects seen in rats at a dose (0.30%)that did not produce overt maternal toxicity, but the adversedevelopmental effects in mice were observed at doses that causedreduced maternal water consumption and body weight gain. Itis possible that water deprivation contributed to the effectsseen in mice after THEO treatment. For maternal toxicity, noobservable adverse effect levels (NOAELs) were 218 mg/kg forrats and 282 mg/kg for mice. NOAELs for developmental toxicitywere 124 mg/kg for rats and 282 mg/kg for mice. These NOAELsare approximately 10-to 30-fold greater than doses requiredto maintain humans on serum THEO concentrations that are clinicallyuseful.     

The Developmental Toxicity of Orally Administered Oxytetracycline in Rats and Mice

The Developmental Toxicity of Orally Administered Oxytetracyclinein Rats and Mice. MORRISSEY, R.E., TYL, R.W., PRICE, C.J., LEDOUX,T.A., REEL, J.R., PASCHKE, L.L., MARR, M.C, AND KJMMEL, C.A.(1986). Fundam. Appl. Toxicol. 7, 434-443. Timed-pregnant CDrats and CD-1 mice were dosed by gavage with oxytetracyclinehydrochloride (OXT) in corn oil on gestational days (gd) 6-15(0, 1200, 1350, or 1500 mg/kg/day for rats; 0, 1325, 1670, or2100 mg/kg/day for mice). Deaths among treated females occurredin a dose-related manner in all OXT dose groups (2-7%, mice;5-24%, rats), but no maternal deaths occurred in the vehiclecontrol groups. Significant dose-related decreases in maternalweight gain during treatment, as well as for corrected gestationalweight gain (i.e., maternal gestational weight gain minus graviduterine weight), were observed at all doses in rats but notin mice. Gravid uterine weight was reduced in a dose-relatedmanner only in mice, with the high-dose group significantlyreduced compared to the control group. At termination (gd 20,rats; gd 17, mice), the status of uterine implantation siteswas recorded and live fetuses were weighed. Fetuses were examinedfor external, visceral, and skeletal abnormalities. There wereno significant effects of OXT in either species on the incidenceof postimplantation loss (resorptions plus dead fetuses) ormalformations. In both species, there was a significant trendtoward reduced fetal body weight, and each group of rats receivingOXT was significantly reduced compared to the control group.Administration of OXT during organogenesis at doses exceedingthe therapeutic range for humans produced maternal and fetaltoxicity, but did not produce any treatment-related increasein malformations.     

Developmental Toxicity Evaluation of Inhaled Methyl Isobutyl Ketone in Fischer 344 Rats and CD-1 Mice

Developmental Toxicity Evaluation of Inhaled Methyl IsobutylKetone in Fischer 344 Rats and CD-1 Mice. Tyl, R. W., FRANCE,K. A., FISHER, L. C., PRITTS, I. M., TYLER, T. R., PHILLIPS,R. D., and MORAN, E. J. (1987). Fundam. Appl. Toxicol. 8, 310–327.Pregnant Fischer 344 rats and CD-1 mice were exposed to methylisobutyl ketone vapor (CAS No. 108-10-1) by inhalation on GestationalDays 6 through 15 at concentrations of 0, 300, 1000, or 3000ppm (mean analytical values of 0, 305, 1012, and 2997 ppm, respectively).The animals were sacrificed on Gestational Day 21 (rats) or18 (mice), and live fetuses were examined for external, visceral,and skeletal alterations. In rats, exposure to 3000 ppm resultedin maternal toxicity expressed as clinical signs, decreasedbody weight and body weight gain, increased relative kidneyweight, and decreased food consumption, and in fetotoxicityexpressed as reduced fetal body weight per litter and reductionsin skeletal ossification. In mice, exposure to 3000 ppm resultedin maternal toxicity expressed as exposure-related increasesin deaths (12.0%, 3/25 dams), clinical signs, and increasedabsolute and relative liver weight, and in fetotoxicity expressedas increased incidence of dead fetuses, reduced fetal body weightper litter, and reductions in skeletal ossification. No treatment-relatedincreases in embryotoxicity or fetal malformations were seenin either species at any exposure concentration tested. Therewas no evidence of treatment-related maternal, embryo, or fetaltoxicity (including malformations) at 1000 or 300 ppm in eitherSpecies.     

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0,600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widelyused as an industrial solvent) vapors, 6 hr/day, 7 days/week(6–19 days of gestation (DG) for rats; 6–17 DG formice). Body weights of pregnant rats in the 5000 ppm group werereduced at euthanization. There were no effects on the percentageof live rat fetuses/litter or on the fetal sex ratio. Fetalbody weight was significantly reduced for the 5000 ppm group,but the incidence of abnormalities was not increased. Mice inthe 1800 and 5000 ppm groups were sedated during exposure; approximately27% of the mice in the 5000 ppm group died. Mean body and uterineweights of mice were reduced for the 1800 and 5000 ppm groupsat euthanization (18 DG), but adjusted maternal weight gainwas not affected at 1800 ppm. There was a reduction in the percentageof live fetuses/litter for the mice in 1800 and 5000 ppm groups(95% resorptions in the 5000 ppm group). Fetal weight and sexratio in mice were not affected. An increase in the incidenceof reduced sternebral ossifications was correlated to THF concentration,although differences between groups were not statistically significant.There were no increases in the incidences of other malformationsor variations. These results suggest that THF may be embryotoxicin mice, but if the conceptus survives, development as assessedby this experimental design continues in a normal fashion. Theno-observable-adverse-effect level (NOAEL) for maternal toxicitywas 1800 ppm in both rats and mice. The NOAEL for developmentaltoxicity was 1800 ppm in rats and 600 ppm in mice.     

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).     

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.     

Chronic Toxicity and Carcingenic Evaluation of Permethrin in Rats and Mice

Chronic Toxicity and Carcinogenic Evaluation of Permethrin inRats and Mice. Ishmael, )., and LlTCHFiELD, M. H. (1988). Fundam.Appl. Toxicol. 11, 308–322. Groups of Alpk: AP (Wistar-derived)rats were fed diets containing 0, 500, 1000 or 2500 ppm permethrinfor 2 years and Swiss-derived mice were maintained for theirlifetime (80% mortality) on diets containing 0, 250, 1000, or2500 ppm permethrin. Changes of toiucological significance wereconfined to the top dose level of 2500 ppm permethrin in bothspecies. Tremors and hypersensitivity to noise were noted inrats at this dose during the first 2 weeks of study but suchsigns were not seen in mice. Pathological examination of thecentral and peripheral nervous systems did not reveal abnormalitiesattributable to permethrin administration. The effect on miceat 2500 ppm permethrin was shown by decreased body weight gain.Liver hypertrophy, associated with increase in liver weight,microsomal enzyme activity, and proliferation of smooth endoplasmicreticulum occurred in the rat with similar but less marked changesin the mouse. This was considered to be an adaptive responseof no toxicological significance. No evidence of a carcinogeniceffect was seen in the rat study. In the mouse study a slightelevation in benign lung tumor incidence in males only at 2500ppm permethrin was observed but was not considered to representa carcinogenic effect.     

Developmental Toxicity Evaluation of Dietary Di(2-ethylhexyl) phthalate in Fischer 344 Rats and CD-1 Mice

Developmental Toxicity Evaluation of Dietary Di(2-ethylhexyl)phthalatein Fischer 344 Rats and CD-I Mice. TYL, R. W., PRICE, C. J.,MARR, M. C. AND KJMMEL, C. A. (1988). Fundam. Appl. Toxicol.10, 395–412. Di(2-ethylhexyl)phthalate (DEHP), a widelyused plasticizing agent, was evaluated for developmental toxicityin timed-pregnant Fischer 344 rats (22-25 dams/dose) and CD-Imice (24-30 dams/dose). DEHP was administered in the diet ongestational Days (gd) 0 through 20 at 0.0,0.5, 1.0, 1.5, or2.0% (rats) and on gd 0 through 17 at 0.00, 0.025,0.05, 0.10,or 0.15% (mice). At termination (gd 20, rats; gd 17 mice), allfetuses were examined for external, visceral, and skeletal malformationsand variations. In rats, maternal toxicity and reduced fetalbody weight per litter were observed at 1.0, 1.5, and 2.0%.Increased resorptions and decreased number of live fetuses/litterwere observed at 2.0%. Maternal food consumption was reducedand water consumption was increased in all DEHP groups. Thenumber and percentage of fetuses malformed per litter were unaffectedby treatment. In mice, maternal toxicity, increased resorptionsand late fetal deaths, decreased number of live fetuses, andreduced fetal body weight per litter were observed at 0.10 and0.15%. Maternal food and water consumption exhibited a dose-relatedupward trend with food consumption significantly increased at0.15%. The number and percentage of fetuses malformed per litter(open eye, exophthalmia, exen-cephaly, short, constricted, orno tail, major vessel malformations, fused or branched ribs,and fused or misaligned thoracic vertebral centra) were elevatedat 0.05,0.10, and 0.15% DEHP. In conclusion, DEHP was not teratogenicat any dose tested in Fischer 344 rats when administered inthe feed throughout gestation but did produce maternal and otherembryofetal toxicity at 1.0, 1.5, and 2.0%. In contrast, DEHPadministration throughout gestation in CD-I mice resulted inan increased incidence of malformations at doses which producedmaternal and other embryofetal toxicity (0.10 and 0.15%) andat a dose (0.057percnt;) which did not produce significant maternaltoxicity. No treatment-related embryofetal toxicity includingteratogenicity was observed in mice at 0.025% Or in rats at0.5% DEHP.     

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.     

Developmental Toxicity Studies in Mice, Rats, and Rabbits with the Anticonvulsant Gabapentin

The developmental toxicity of the anticonvulsant agent gabapentinwas evaluated in mice, rats, and rabbits treated by gavage throughoutorganogenesis. Mice received 500, 1000, or 3000 mg/kg on gestationdays (GD) 6–15 and rats and rabbits received 60, 300,or 1500 mg/kg on GD 6–15 (rats) or 6–18 (rabbits).Additional groups received an equivalent volume of the vehicle,0.8% methylcellulose, or remained untreated. All dams were observeddaily for clinical signs of toxicity. In mice, body weightsand food consumption were recorded on GD 0, 6, 12, 15, and 18while in rats and rabbits these parameters were evaluated daily.Near term (mouse, GD 18; rat, GD 20; and rabbit, GD 29) eachfemale was euthanatized, necropsies were performed, and litterand fetal data were collected. Live fetuses were examined forexternal, visceral, and skeletal variations and malformations.No adverse maternal or fetal effects were observed in mice orrats given doses up to 1500 or 3000 mg/kg, respectively. Notreatment-related maternal or fetal effects were apparent inrabbits given 60 or 300 mg/kg. At 1500 mg/kg, one rabbit died,four others aborted, and reduced food consumption and body weightgain were observed. No other reproductive, litter, or fetalparameters were affected, except that the incidence of visceralvariations in rat fetuses was slightly but statistically significantlyincreased at 1500 mg/kg due to a slight increase in the incidenceof dilated renal pelvis. This finding was not considered biologicallysignificant because this degree of variability has been seenin this strain of rats. In conclusion, no evidence of teratogenicitywas found for gabapentin at doses up to 3000 mg/kg in the mouseand up to 1500 mg/kg in the rat and rabbit.     

Evaluation of the Developmental Toxicity of Dermally Applied Monoethanolamine in Rats and Rabbits

Pregnant Sprague-Dawley rats and New Zealand White rabbits wereexposed dermally to 0, 10,25, and 75 mg/kg/day of monoethanolamine(MEA) for approximately 6 hr/day on Days 6 through 15 (rats)or 6 through 18 (rabbits) of gestation. A fifth dose group of225 mg MEA/kg/day was evaluated in rats only. Dermal exposureof pregnant rats to 225 mg/kg/day and rabbits to 75 mg/kg/dayresulted in significant increases in the incidence of skin irritation/lesionsand maternal body weight effects. In general, the dermal irritationobserved at the high dose was progressive, beginning with erythemaand leading to necrosis, scabs, and scar formation. Doses of25 mg/kg/day to rabbits produced only minor irritation. Despitematernal effects observed in rats and rabbits, no evidence ofdevelopmental or fetal toxicity was observed at any dose leveltested. Thus, it was concluded that MEA was not developmentallytoxic following dermal application at exposure levels up toand including 225 mg/kg/day for rats and 75 mg/kg/day for rabbits.     

Significance of Supernumerary Ribs in Rodent Developmental Toxicity Studies: Postnatal Persistence in Rats and Mice

Significance of Supernumerary Ribs in Rodent Developmental ToxicityStudies: Postnatal Persistence in Rats and Mice. CHERNOFF, N.,ROGERS, J. M., TURNER, C. I., AND FRANCIS, B. M. (1991). Fundam.Appl Toxicol 17, 448–453. Pregnant Sprague-Dawley ratsand Swiss-Webster mice were gavaged with bromoxynil at 15 and96.4 mg/kg/day, respectively, on Days 6–15 of gestation.The frequency of supernumerary ribs (SNR), which are here definedas any degree of ossification lateral to the first lumbar vertebrae,was determined in fetuses at term and offspring on PostnatalDays 6, 20, and 40. Bromoxynil induced significant increasesin the incidence of SNR in fetuses of both species. In rats,SNR occurred in 62% of treated fetuses as compared to 14% incontrols; in mice these values were 45% and 11%, respectively.The postnatal incidence and persistence of SNR was species dependent.In the rat, postnatal SNR incidence in treated animals did notdiffer significantly from controls. In contrast, in mice thebromoxynil-induced elevated incidence of SNR persisted throughDay 40(42.3% in treated vs 0% in controls). Analysis of SNRwas also done on the basis of their length (greater or lessthan the length of the 13th rib). In the mouse, the incidenceof smaller SNR was much lower on Day 40 as compared to Day 20;in contrast the incidence of larger SNR persisted through Day40. In the rat, the incidence of larger SNR was too small todraw conclusions as to the postnatal fate of these structures.As in the mouse, however, the incidence of smaller SNR was significantlylower by Day 40. The significance of SNR in developmental toxicityremains problematic. The impact of this anomaly on animals isdifficult to assess. While it appears to be a transient effectin rats, detailed examination of the adjacent vertebrae to determinetheir normalcy has not yet been accomplished. While the effectappears to be transient in the rat, data reported here suggestthat this may be a species/strain specific phenomenon ratherthan a general finding.     

Codeine: Developmental Toxicity in Hamsters and Mice

Codeine: Developmental Toxicity in Hamsters and Mice. Williams,J., PRICE, C. J., SLEET, R. B., GEORGE, J. D., MARR, M. C, KIMMEL,C. A., AND MORRISSEY, R. E. (1991). Fundam. Appl. Toxicol. 16,401–413. Timed-pregnant LVG Syrian hamsters and SwissCD-I mice were dosed orally twice daily (b.i.d.) with codeinein water on Gestational Days (gd) 5–13 (0, 10, 50, or150 mg/kg, b.i.d.—hamsters) or 6–15 (0, 37.5, 75,150, or 300 mg/kg, b.i.d.—mice). Dams were necropsiedon gd 14 (hamsters) or 17 (mice), and fetuses were weighed,sexed, and examined for external, visceral, and skeletal malformations.No maternal deaths were observed in hamsters, while 19% of thepregnant mice in the high-dose group died. Maternal weight gain(gestational and treatment periods) and gravid uterine weightswere significantly depressed in hamsters (150 mg/kg, b.i.d.)and in mice (300 mg/kg, b.i.d.). However, the corrected weightgain for both species, although decreased, was not significantlydifferent from that of the controls. In both species, maternalliver weights (relative) were significantly increased in thehigh-dose groups. There were increases in the percentage resorptionsper pregnant dam and in the proportion of litters with 100%resorptions in the high-dose groups of both species. Consideringonly live litters, the number of live fetuses per litter andthe sex ratio were unaffected in both species. Mean fetal bodyweights were also significantly decreased in the 50 and 150mg/kg, b.i.d. (hamsters), and the 150 and 300 mg/kg, b.i.d.(mice), groups. The no-observed-adverse-effect levels (NOAELs)for developmental toxicity were 10 (hamsters) and 75 (mice)mg/kg, b.i.d., whereas the NOAELs for maternal toxicity were50 (hamsters) and 150 (mice) mg/kg, b.i.d. The predominant structuralmalformation in hamsters was meningoencephalocele (high-dosegroup only), affecting 3% of fetuses and 19% of litters (neitherstatistically significant). Codeine did not induce any increasein structural malformations in mice. Thus, codeine produceddevelopmental toxicity (as indicated by decreased fetal bodyweight) at doses below those producing maternal toxicity inboth hamsters and mice. In the hamster, the more sensitive speciesto codeine developmental toxicity, effects were observed ata total daily dose of 100 mg/kg, which is only 11 times themaximum human therapeutic oral dose.