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.     

Developmental Toxicity Evaluation of Inhaled 2-Ethoxyethanol Acetate in Ficher 344 Rats and New Zealand White Rabbits

Developmental Toxicity Evaluation of Inhaled 2–EthoxyethanolAcetate in Fischer 344 Rats and New Zealand White Rabbits. Tyl,R. W., Pritts, I. M, France, K. A., Fisher, L. C, and Tyler,T. R. (1988). Fundam. Appl. Toxicol. 10, 20–39. PregnantFischer 344 rats and New Zealand white rabbits were exposedto 2–ethoxyethanol acetate (EEA; CAS No. 111–15–9)vapor by inhalation on Gestational Days 6 through 15 (rats)or 6 through 18 (rabbits) at concentrations of 0, 50, 100,200,or 300 ppm, 6 hr/day. The animals were terminated on Gesta–tionalDay 21 (rats) or 29 (rabbits) and fetuses were examined forexternal, visceral, and skeletal malformations and variations.In rabbits, exposure to 100–300 ppm resulted in maternaltoxic–ity: decreased weight gain at 100–300 ppm,clinical signs at 200–300 ppm, alterations in hema–tologyat 100–300 ppm, reduced gravid uterine weight at terminationat 200–300 ppm, and elevated absolute liver weight at300 ppm. Developmental toxicity was observed at 100–300ppm: an increased incidence of totally resorbed litters at 200–300ppm, an increase in nonviable fetuses at 300 ppm, and a decreasein viable implants (live fetuses) per litter at 200–300ppm. The incidence of fetal malformations (external, visceral,and skeletal) was increased at 200–300 ppm. The incidenceof total malformations was 100% at 300 ppm and significantlyincreased at 200 ppm. Reduced fetal ossification was observedat 100–300 ppm. In rats, exposure to 100–300 ppmalso resulted in maternal toxicity: reduced weight gain andreduced food consumption at 200–300 ppm and elevated relativeliver weight and alterations in hematology at 100–300ppm. Absolute maternal liver weight was increased at all EEAexposure concentrations; relative liver weight was increasedat 100–300 ppm. Developmental toxicity was observed at100–300 ppm: increased nonviable implantations/litter(300 ppm), reduced fetal body weight/litter (200–300 ppm),and increased incidence of external (300 ppm), visceral, andskeletal (100–300 ppm) variations indicative of toxicity.The incidence of visceral, skeletal, and total malformationswas increased at 200–300 ppm. In conclusion, in both species,inhalation exposure to EEA during organogenesis produced maternaltoxicity at 100–300 ppm and developmental toxicity at100–300 ppm, including teratogenicity at 200–300ppm. At 50 ppm in both species, there was no evidence of maternalor developmental toxicity, including teratogenicity.     

Evaluation of the Developmental Toxicity of {beta}-(3,4-Epoxycyclohexyl) ethytrimethosysilane in Fischer 344 Rats and New Zealand Whit Rabbits

Evaluation of the Developmental Toxicity of ß-(3,4-Epoxycyclohexyl)ethyltrimethoxysilanein Fischer 344 Rats and New Zealand White Rabbits. TYL, R. W.,BALLANTYNE, B., FISHER, L. C, AND FRANCE, K. A. (1988). FundamAppl Toxicol. 10, 439–452. ß-(3,4-epoxycyclohex-yl)ethyltrimethoxysilane(ECEMS, CAS No. 3388-04-3) is mutagenic in vitro and weaklycarcinogenic in mice after dermal application. Timed pregnantFischer 344 rats and New Zealand white rabbits were dosed withECEMS in corn oil by gavage on gestational days (gd) 6 through15 at doses of 0.0,0.25, 1.0, or 2.5 ml ECEMS/kg for rats and0.0,0.05,0.25, or 0.75 ml ECEMS/kg for rabbits. At terminationon gd 21 (rats) or gd 29 (rabbits), live fetuses were examinedfor external, visceral, and skeletal alterations. In rats, maternaltoxicity was observed at 1.0 and 2.5 ml/kg, as evidenced byreduced weight gain and food consumption during treatment, clinicalsigns of toxicity, reduced body weight on gd 21 (corrected forgravid uterine weight), and increased relative liver weight.There were no significant differences among groups on pre- orpostimplantation loss, fetal body weight/litter, or on the incidenceof malformations. Minimal fetal toxicity, dilated lateral cerebralventricles and reduced ossification in the forelimbs, was observedat 2.5 ml/kg. In rabbits, maternal mortality (2/20 does) andslightly (but statistically significantly) elevated maternalrelative kidney weight were observed at 0.75 ml/kg. Clinicalsigns of toxicity were observed at 0.25 and 0.75 ml/kg. Pre-and postimplantation loss, fetal body weight/litter, and theincidence of malformations were all unaffected by treatment.Minimal fetal toxicity, extra (13th) ribs and reduced ossificationin lumbar arch 4, was observed at 0.75 ml/kg ECEMS. Therefore,administration of ECEMS during organogenesis in rats and rabbitsproduced maternal toxicity at 1.0 and 2.5 ml/kg in rats andat 0.25 and 0.75 ml/kg in rabbits. Minimal fetal toxicity wasobserved at 2.5 ml/kg in rats and at 0.75 ml/kg in rabbits.No embryo-toxicity or teratogenicity was observed in eitherspecies at any dosage. The "no observable effect level" (NOEL)for maternal toxicity was 0.25 ml/kg for rats and 0.05 ml/kgfor rabbits; the NOEL for developmental toxicity was 1.0 ml7sol;kgfor rats and 0.25 ml/kg for rabbits.     

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).     

Teratology evaluation of methyl tertiary butyl ether in rats and mice

Mated CD Sprague-Dawley rats and CD-1 mice were exposed during the period of organogenesis to target concentrations of 0, 250, 1000, and 2500 ppm methyl t-butyl ether (MTBE). None of the control or test-group animals died during the treatment or posttreatment periods. Females were sacrificed on d 20 (rats) or d 18 (mice). No adverse effects of treatment were reflected in maternal parameters of body weight, water consumption, or liver weight or in physical examination data for either species. Food consumption fell in the groups of treated rats during d 9-12; similar but nonsignificant effects were observed for mice during d 12-15. In rats, no treatment-related changes were recorded in the uterine implantation data, fetal size parameters, or fetal sex distribution data. Examination of fetuses for external abnormalities, skeletal malformations, or ossification variations did not reveal any changes caused by MTBE exposure. A slight increase in fetal resorptions was observed in the groups of mice exposed to low and high concentrations; this increase was attributed to two females in each group that had an unusually high number of resorptions, rather than to the treatment itself. No significant effects were observed in any groups of treated mice on external and soft-tissue examination or evaluation of skeletal abnormalities or ossification variations. The incidence of fused sternebrae in the high-concentration group increased slightly, which might be attributed to fetotoxicity.     

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropene on Fetal Development in Rats and Rabbits

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropeneon Fetal Development in Rats and Rabbits. HANLEY, T. R., Jr.,JOHN-GREENE, J. A., YOUNG, J. T., CALHOUN, L. L., AND RAO, K.S. (1987). Fundam. Appl. Toxicol. 8, 562–570. 1,3-Dichloropropene(DCP), which has found widespread use as a soil fumigant, wasevaluated for its potential effects on embryonal and fetal developmentin rats and rabbits. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropenefor 6 hr/day during gestation Days 6–15 (rats) or 6–18(rabbits). Exposure-related decreases in maternal weight gainand feed consumption were observed in rats at all treatmentlevels. Decreased weight gain was also observed among rabbitsat 60 and 120 ppm. A slight, but statistically significant,increase in the incidence of delayed ossification of the vertebralcentra in rats exposed in ulero to 120 ppm of DCP was consideredof little toxicologic significance in light of the maternaltoxicity observed at this exposure concentration. No evidenceof a teratogenic or embryotoxic response was observed in eitherspecies at any exposure level tested. Thus, it was concludedthat DCP was not teratogenic at exposure levels up to 120 ppmin either rats or rabbits.     

The developmental toxicity of ethylene glycol in rats and mice

Timed-pregnant CD rats and CD-1 mice were dosed by gavage with ethylene glycol (EG) in distilled water on gestational days (gd) 6 through 15 (0, 1250, 2500, or 5000 mg kg-1 day-1 for rats; and 0, 750, 1500, or 3000 mg kg-1 day-1 for mice). Females were observed daily during treatment, but no maternal deaths or distinctive clinical signs were noted. Dose-related decreases in maternal weight gain during treatment were significant at all doses in rats and at the mid and high doses in mice. Gravid uterine weight was reduced in both species at the mid and high doses, and corrected maternal gestational weight gain showed a significant decreasing trend. At termination (gd 20, rats; gd 17, mice), the status of uterine implantation sites was recorded, and live fetuses were weighed and examined for external, visceral, and skeletal malformations. Dose-related increases in postimplantation loss per litter were observed in both species with the high dose significantly above controls only in rats. Fetal body weight per litter was significantly reduced at the mid and high doses in rats and at all doses in mice. The percentage of malformed live fetuses per litter and/or the percentage of litters with malformed fetuses was significantly elevated in all EG dose groups and greater than 95% of litters were affected at the high dose for each species. A wide variety of malformations were observed; the most common in both species were craniofacial and neural tube closure defects and axial skeletal dysplasia. EG produced severe developmental toxicity in two rodent species at doses that apparently failed to produce any serious maternal effects.     

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.     

Evaluation of the Developmental Toxicity of Ethylene Glycol Monohexyl Ether Vapor in Fischer 344 Rats and New Zealand White Rabbits

Evaluation of the Developmental Toxicity of Ethylene GlycolMonohexyl Ethyl Vapor in Fischer 344 Rats and New Zealand WhiteRabbits. TYL, R. W., BALLANTYNE, B., FRANCE, K. A., FISHER,L. C., KLONNE, D. R., AND PRITTS, I. M. (1989). Fundam Appl.Toxicol. 12, 269-280. Timed pregnant Fischer 344 rats and NewZealand White rabbits were exposed to vapor from ethylene glycolmonohexyl ether (EGHE, CAS No. 112-25-4) for 6 hr/day on gestationaldays (gd) 6 through gd 15 (rats) or gd 6 through gd 18 (rabbits)at analytically measured concentrations (as means ± SD)of 20.8 ± 0.90,41.1 ± 1.77, or 79.2 ± 10.8ppm; control animals were exposed to air alone. Monitors formaternal toxicity were body weight, food and water consumption,clinical signs, and hematology. At sacrifice (gd 2 1 rats, gd29 rabbits) maternal weight, liver weight, and gravid uterineweight were measured. Gestational parameters monitored werenumbers of corpora lutea, preimplantation losses, viable implants,early and late resorptions, and dead fetuses. Live fetuses weresexed, weighed, and examined for external, visceral, and skeletalmalformations and variations. Rabbit maternal toxicity occurredat 79.2 ppm as transient weight gain reduction during the exposureperiod. For maternal rats at 79.2 ppm, there were transientdecrease in body weight and body weight gain during exposure,reduced food consumption, increased water consumption, and excesslacrimation. At 41.1 ppm, maternal body weight gain was reducedduring the exposure period only. There were no treatment- relatedeffects with respect to hematology, necropsy, or gestationalparameters and no significant change in the incidence of malformationsor variations (expressed as total, individual. external, visceral.or skeletal). Thus, exposure of rats and rabbits to EGHE vaporduring the period of organogenesis produced maternal toxicityat near-saturation vapor concentrations (79.2 ppm), but no evidencefor developmental toxicity or teratogenicity. The no-effectvapor concentrations for maternal toxicity were 41.1 ppm forrabbits and 20.8 ppm for rats.     

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.     

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 and reproductive toxicity evaluation of toluene vapor in the rat II. Developmental toxicity

The developmental toxicity of toluene was evaluated via whole body inhalation exposure, in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) from gestation day (GD) 6–15 inclusive, 6 h/day, at concentrations of 0, 250, 750, 1500 and 3000 ppm (0, 938, 2812, 5625 and 11250 mg/m³). Doses were selected from a preliminary study performed over a range of concentrations from 0 to 5000 ppm, in which maternal and fetal toxicity were observed at 2000 ppm and above. This study has been cited in various regulatory documents and is presented here to allow greater accessibility to results and conclusions.

Toluene induced clinical signs in pregnant dams (ataxia, hyper-responsivity, increased water intake, decreased food consumption) at 3000 ppm, ataxia and hyper-responsivity at 1500 ppm, and reduced maternal body weight gain at 1500 during the exposure period only and at 3000 ppm from initiation of exposure to GD20. At Caesarean section on GD20, no adverse effects on implantation, number and viability of fetuses, or fetal sex distribution were observed. Litter weight and mean fetal weight was reduced at 3000 ppm and mean fetal weight was reduced at 1500 ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Mean fetal weight was also reduced at 250 ppm but not at 750 ppm. Extensive statistical analysis of fetal body weight data support the conclusion that there is no toxicologically significant dose-related effect on fetal body weight at or below 750 ppm. Low incidences (≤2.5%) of various malformations occurred in the 250, 1500, and 3000 ppm groups; there was no increase in the incidence of specific or total malformations with increased exposure and thus these were not attributed to toluene.

In this Toluene study, the maternal toxicity NOAEL was 750 ppm with a defined maternal and developmental toxicity LOAEL of 1500 ppm.     

Teratologic Evaluation of Dinitrotoluene in the Fischer 344 Rat

Teratologic Evaluation of Dinitrotoluene in the Fischer 344Rat. PRICE, C. J., TYL, R. W., MARKS, T. A., PASCHKE, L. L.,LEDOUX, T. A., AND REEL, J. R. (1985). Fundam. Appl. Toxicol..5,948-961. Technical grade dinitrotoluene (DNT) was administeredby gavage (po) to timed-pregnant Fischer 344 rats on GestationalDays (gd) 7 through 20. Mortality rates for the DNT (14, 35,37.5, 75, 100, or 150 mg/kg/day) groups were 4.5, 7.7, 0.0,0.0, 4.3, and 46.2% of treated females, respectively. No deathsoccurred in the positive control (hydroxyurea, 200 mg/kg/day)or vehicle control (com oil) groups. At sacrifice on gd 20,the hematological profile for dams in the 100-mg/kg/day groupexhibited characteristic signs of DNT toxicity. Treatment-relatedincreases in maternal relative liver and spleen weight (% bodyweight), and a dose-related decrease in absolute maternal weightgain during gestation (i.e., minus gravid uterine weight) wereobserved across all DNT groups. A notable increase in prenatalmortality occurred at the high dose (16.8% resorptions or latefetal deaths per litter for controls vs 49.6% for DNT), butdid not reach statistical significance. No statistically significanteffects on fetal growth or morphological development as a resultof DNT treatment were observed. Hydroxyurea produced mild hematoxicityin dams and fetuses. Effects of hydroxyurea on fetal growthand morphological development included decreased fetal bodyweight and crown-rump length, and an increased percentage ofmalformed fetuses (30% per litter). In conclusion, DNT was notfound to be teratogenic following oral administration to Fischer344 rats; embryo/fetal toxicity was observed only at a dosewhich also produced 46.2% maternal mortality.     

Developmental Toxicity of Inhaled Methyl Ethyl Ketone in Swiss Mice

Developmental Toxicity of Inhaled Methyl Ethyl Ketone in SwissMice. Schwetz, B. A., Mast, T. J., Weigel, R. J., Dill, J. A.,and Morrissey, R. E. (1991). Fundam. Appl. Toxicol. 16, 742–748.Methyl ethyl ketone (MEK) is a widely used industrial solventto which there is considerable human exposure. To assess thepotential for MEK to cause developmental toxicity in rodents,groups of Swiss (CD-1) mice were exposed to 0, 400, 1000, or3000 ppm MEK vapors 7 hr/day on Days 6–15 of gestation.Groups consisted of about 30 bred females each. Exposure ofpregnant mice to these concentrations of MEK did not resultin overt maternal toxicity although there was a slight, treatment-relatedincrease in relative liver weight which was statistically significantin the 3000 ppm group. Mild developmental toxicity was observedin the 3000 ppm group in the form of a reduction in mean fetalbody weight. This reduction was statistically significant forthe males only, although the relative decrease from the controlvalues was the same for both sexes. There was no increase inthe incidence of resorptions or the number of litters with resorptionsamong mice exposed to MEK. There was no significant increasein the incidence of any single malformation, but several malformationswhich were not observed in the concurrent control group or thecontrols of contemporary studies were present at a low incidence—cleftpalate, fused ribs, missing vertebrae, and syndactyly. Therewas also a significant trend for increased incidence of misalignedsternebrae, a developmental variation. In summary, pregnantSwiss (CD-1) mice were relatively insensitive to the toxic effectsof MEK at the inhaled concentrations used in this study. However,the offspring of the mice exhibited significant signs of developmentaltoxicity at the 3000 ppm exposure level. Neither maternal nordevelopmental toxicity was observed at 1000 ppm MEK or below.     

Reproduction, Growth, and Development of Rats during Chronic Exposure to Multiple Field Strengths of 60-Hz Electric Fields

Reproduction, Growth, and Development of Rats during ChronicExposure to Multiple Field Strengths of 60-Hz Electric Fields.ROMMEREIM, D. N., ROMMEREIM, R. L., SIKOV, M. R., BUSCHBOM,R. L., AND ANDERSON, L. E. (1990). Fundam. Appl. Toxicol. 14,608–621. A study with multiple exposure groups and largegroup sizes was performed to establish whether exposure to 60-Hzelectric fields would result in reproductive and developmentaltoxicity. A response model was developed from previous resultsand tested in groups of rats exposed to electric fields at variousfield strengths. Female rats were mated, and sperm-positiveanimals randomly distributed among four groups: sham-exposedor exposed to 10, 65, or 130 kV/m, 60-Hz vertical electric fields.Animals were exposed for 19 hr/day throughout the experiment.During gestation, exposure to the higher field strengths resultedin slightly depressed weight gains of dams. Offspring were bornin the field and remained with their dams through the sucklingperiod. Numbers of pups per litter and pup mortality did notdiffer among the exposure groups. Dams exposed at 65 kV/m lostslightly more weight through the lactation period than the controlgroup. Male pups exposed to higher field strengths gained slightlyless weight from 4 to 21 days of age than did sham-exposed animals.At weaning, two F₁ females per litter (randomly selected) continuedon the same exposure regimen were mated at 11 weeks of age tounexposed males, and euthanized at 20 days of gestation. Uterinecontents were evaluated, and all live fetuses were weighed andexamined for external, visceral, and skeletal malformations.Fertility and gestational weight gain of F₁ females were notaffected by exposure, nor was prenatal viability or fetal bodyweight. No significant increase in the incidence of litterswith malformations was observed. Although no developmental toxicitywas detected, exposures produced physical changes in the dams,evidenced as a rust-colored deposit on the muzzle and ears (chromodac-ryorrhea)that increased in incidence and severity at 65 and 130 kV/m.Incidence of chromodac-ryorrhea was not significantly differentbetween sham-exposed rats and those exposed at 10 kV/m.     

Teratologic Evaluation of Inhaled Propylene Glycol Monomethyl Ether in Rats and Rabbits

Teratologic Evaluation of Inhaled Propylene Glycol MonomethylEther in Rats and Rabbits. HANLEY, T. R. JR., CALHOUN, L. L.,YANO, B. L, AND RAO, K. S. (1984). Fundam. Appl. Toxicol. 4,784–794. Pregnant Fischer 344 rats and New Zealand Whiterabbits were exposed via inhalation to 0, 500, 1500, or 3000ppm of propylene glycol raonomethji ether (PGME) for 6 hr/dayon Days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation.Initial exposure to 3000 ppm of PGME produced signs of mildcentral nervous system depression which were more pronouncedand of a longer duration in rats than in rabbits. Postexposurerecovery was rapid and accomodation to the test atmosphere developedfollowing subsequent exposures. Rats and rabbits exposed to3000 ppm had decreased weight gains over the exposure periodand rats had decreased food consumption during the first 3 daysof exposure. Fetal examination revealed no embryotoxic or teratogenkeffects among rats or rabbits in any exposure group. Slightfetotoxicity among rats, in the form of delayed sternebral ossification,was observed at 3000 ppm. Thus, it was concluded that PGME wasnot teratogenic at exposure levels up to 3000 ppm.     

Developmental toxicity evaluation of inhaled toluene diisocyanate vapor in CD rats.

Mated female CD (Sprague-Dawley) rats, 25/group, were exposed to toluene diisocyanate (TDI) vapor, for six h/day on gestational days (gd) 6 through 15, at 0.00, 0.02, 0.10, or 0.50 p.p.m.. Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified: resorptions and dead and live fetuses. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm no observed adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm. No treatment-related embryotoxicity or teratogenicity was observed.     

Teratology study in fischer 344 rats exposed to ethylene oxide by inhalation

Pregnant Fischer 344 rats were exposed 6 hr/day to either 100, 33, or 10 ppm of ethylene oxide vapor on Days 6 through 15 of the gestation period. Two separate control groups were maintained under the same conditions but were exposed to room air only. Two other groups of rats were given a known rodent teratogen, aspirin, by gavage; one group was given 500 mg/kg body weight on Day 9 of gestation, and the other was given 625 mg/kg body weight on Day 10 of gestation. No treatment-related effects of ethylene oxide were noted for the following evaluations; maternal survival, litter size, number of implantation and resorption sites, and number of preimplantation losses. Exposure to 100 ppm of ethylene oxide resulted in a significant depression of body weight in the fetuses, but did not result in any abnormal effects of embryonic or fetal lethality, or teratologic effects of the soft tissues or skeleton. Consequently, ethylene oxide was not considered a teratogen by inhalation in the Fischer 344 rat at an exposure concentration of 100 ppm.     

Inhalation Developmental Toxicity Study of Propylene Oxide in Fischer 344 Rats

The developmental toxicity potential of propylene oxide (PO)was evaluated in Fischer 344 rats following inhalation exposure.Four groups of 25 mated female rats were exposed to 0, 100,300, and 500 ppm of PO for 6 hr per day on Gestation Days 6through 15, inclusive. Cesarean sections were performed on allfemales on Gestation Day 20 and the fetuses removed for morphologicalevaluation. Exposure to propylene oxide did not adversely affectsurvival, appearance, or behavior at any of the exposure levelstested. Maternal body weight gain and food consumption werereduced significantly among the females at the 500 ppm levelduring the exposure period. No exposure-related effects werenoted with respect to maternal water consumption, organ weights,cesarean section, or fetal morphological observations with thesole exception of increased frequency of seventh cervical ribsin fetuses at the maternally toxic exposure level of 500 ppm.In summation, the no-observable-adverse-effect level (NOAEL)of propylene oxide. when administered to Fischer 344 rats viawhole-body inhalation exposure, was considered to be 300 ppm.     

Prenatal Toxicity of 2-Methoxypropylacetate-1 in Rats and Rabbits

Prenatal Toxicity of 2-Methoxypropylacetate-l in Rats and Rabbits.MERKLE, J., KLIMISCH, H.-J., and JÄCKH, R. (1987). Fundam.Appl. Toxicol. 8, 71–79. 2-Methoxypropylacetate-1 wasinvestigated in Wistar rats and Himalayan rabbits for embryotoxicpotential. Rats after inhalation exposure to 0, 0.6, 3.0, or14.9 mg/liter (approximately 0, 110, 550, or 2700 ppm, respectively)for 6 hr per day from gestation Days 6 through 15 exhibitedsome degree of maternal toxicity at 2700 and 550 ppm. At 2700ppm an increase of skeletal anomalies of the thoracic vertebraeamong the fetuses was observed and interpreted as an exposure-relatedslight teratogenic effect. In Himalayan rabbits exposed viainhalation to 0,0.2,0.8, or 3.0 mg/liter (approximately 0, 36,145, or 550 ppm, respectively) for 6 hr per day from gestationDays 6 through 18 teratogenicity was much more pronounced: at550 ppm, in the absence of clear maternal toxicity, the fetusesof all litters showed severe malformations. No maternal or fetaleffects were observed at 145 and 36 ppm. Dermal applicationof 1000 and 2000 mg/kg to Himalayan rabbits from gestation Days6 through 18 failed to produce maternal or fetal toxicity.