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.     

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.     

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.     

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 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.     

Reactive oxygen species contribute to lipopolysaccharide-induced teratogenesis in mice.

Lipopolysaccharide (LPS) has been associated with adverse developmental outcome, including embryonic resorption, fetal death and growth retardation, and preterm delivery. In the present study, we showed that an ip injection with LPS daily from gestational day (gd) 8 to gd 12 resulted in the incidence of external malformations. The highest incidence of malformed fetuses was observed in fetuses from dams exposed to 20 microg/kg LPS, in which 34.9% of fetuses per litter were externally malformed. In addition, 17.4% of fetuses per litter in 30 microg/kg group and 12.5% of fetuses per litter in 10 microg/kg group were externally malformed. Importantly, external malformations were also observed in fetuses from dams exposed to only two doses of LPS (20 microg/kg, ip) on gd 8, in which 76.5% (13/17) of litters and 39.1% of fetuses per litter were affected. LPS-induced teratogenicity seemed to be associated with oxidative stress in fetal environment, measured by lipid peroxidation, nitrotyrosine residues, and glutathione (GSH) depletion in maternal liver, embryo, and placenta. alpha-Phenyl-N-t-butylnitrone (PBN, 100 mg/kg, ip), a free radical spin-trapping agent, abolished LPS-induced lipid peroxidation, nitrotyrosine residues, and GSH depletion. Consistent with its antioxidant effects, PBN decreased the incidence of external malformations. Taken together, these results suggest that reactive oxygen species might be, at least partially, involved in LPS-induced teratogenesis.     

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.     

Developmental toxicity study of chlorpyrifos in rats

Chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl)-phosphorothioate) was evaluated for potential developmental toxicity. Groups of 30 bred female Fischer 344 rats were given 0, 5, 15, and 25mg/kg per day by gavage on gestation days 6-15; the fetuses were evaluated on gestation day 21. Clinical signs of toxicity attributed to chlorpyrifos were noted in dams receiving 15 and 25mg/kg per day. Maternal effects in these groups also included depressed body weight and acetylcholinesterase activity. Fetal weight and viability were decreased, and fetal death and early resorption were increased at the 25mg/kg per day maternal dose. Visceral, skeletal, and external variations were also increased in this group. Chlorpyrifos showed fetotoxic and teratogenic effects at a maternal dose of 25mg/kg per day, a dose that also produced maternal toxicity.     

Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats.

Isoeugenol, used as a perfumery and flavoring agent, was evaluated for developmental toxicity. Timed-pregnant CD((R)) outbred albino Sprague-Dawley rats received isoeugenol (250, 500, or 1000 mg/kg/day) or vehicle (5 ml/kg corn oil) by gavage on gestational days (gd) 6 through 19. Maternal food and water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (23-25 per group) were evaluated for gestational outcome. All live fetuses were weighed and examined for external malformations, and approximately 50% were evaluated for visceral or skeletal malformations. There were no treatment-related maternal deaths. Clinical signs associated with isoeugenol exposure included dose-related evidence of sedation and aversion to treatment (rooting behavior) in all isoeugenol groups, as well as an increased incidence of piloerection at >/= 500 mg/kg/day. Maternal body weight, weight gain, and gestational weight gain (corrected for gravid uterine weight) were reduced at all doses in a dose-related manner. Gravid uterine weight was significantly decreased at the mid and high doses, whereas maternal relative liver weight was increased at all three dose levels. During treatment (gd 6 to 20), maternal relative food consumption was significantly decreased at the high dose, and maternal relative water consumption was elevated in the mid- and high-dose groups. Prenatal mortality (resorption or late fetal death) was unaffected. At 1000 mg/kg/day, average fetal body weight/litter was decreased by 7% (male) or 9% (female). Incidences of fetal morphological anomalies were statistically equivalent among groups, except for an increase in the incidence of unossified sternebra(e), a skeletal variation, at the high dose. In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day based primarily on reduced body weight and gestational weight gain (corrected for gravid uterine weight), and the maternal toxicity no observed adverse effect level (NOAEL) was not determined in this study. The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. The developmental toxicity NOAEL was 500 mg/kg/day.     

Teratologic and postnatal evaluation of aniline hydrochloride in the Fischer 344 rat

Timed-pregnant Fischer 344 rats were dosed by gavage with aniline hydrochloride (10, 30, or 100 mg/kg/day), a positive control agent (hydroxyurea, 200 mg/kg/day), or vehicle (distilled water) on gestational days (gd) 7 through 20 or gd 7 through parturition. At termination on gd 20 confirmed-pregnant dams exhibited characteristic signs of aniline HCl toxicity, i.e., methemoglobinemia, increased relative spleen weight, decreased red blood cell (RBC) count, and hematological changes indicative of increased hematopoietic activity. High-dose dams exhibited mild methemoglobinemia, increased relative spleen weight, and increased RBC size at termination on postnatal day (pnd) 30. At termination on gd 20, fetuses from aniline-treated dams exhibited increased relative liver weight and enhanced hematopoietic activity, but no evidence of an embryolethal or teratogenic effect was observed. Postnatal signs of toxicity in litters from aniline-treated dams (i.e., decreased body weight, elevated relative liver weight, and elevated relative spleen weight) were transient, and no evidence of toxicity was observed in pups surviving to pnd 60. Hydroxyurea (200 mg/kg/day) administered by gavage proved to be an excellent positive control for embryotoxicity, maternal toxicity, teratogenicity, and postnatal maturational deficits in the Fischer 344 rat. In conclusion, aniline hydrochloride was not teratogenic to Fischer 344 rats, even at maternally toxic doses; transient signs of toxicity were observed postnatally in the offspring in conjunction with mild, but persistent signs of maternal toxicity through pnd 30.     

Developmental toxicity study of dimethylpiperidone

The potential maternal and developmental toxicity of dimethylpiperidone (DMPD) was assessed in rats. Groups of 25 mated female Crl:CD (SD)IGS BR rats were exposed by inhalation (whole-body exposures) for approximately six hours per day over days 7-21 of gestation (G); day 1G was the day of copulation plug detection. The exposure levels were 0, 52, 260, or 340 (vapor plus aerosol) mg/m3 DMPD. During the in-life portion, body weights, food consumption, and clinical observation data were collected. On day 22G, the dams were euthanized and examined for gross external and internal alterations. The uterine contents were described and the fetuses were weighed and examined for external, visceral, and skeletal alterations. Maternal toxicity was seen at both 260 and 340 mg/m3. At 340 mg/m3, evidence of maternal toxicity included mortality, increased clinical observations, and decreased body weight and food consumption. At 260 mg/m3, maternal toxicity was limited to increased clinical observations and decreased food consumption. Developmental toxicity was also produced at 260 and 340 mg/m3. At 340 mg/m3, evidence of developmental toxicity included decreased fetal weight, increased embryofetal lethality with concomitant reductions in litter size, and increased fetal malformations and variations. At 260 mg/m3, effects in fetuses were limited to slightly decreased fetal weight and increased fetal variations; additionally, one litter from this level consisted entirely of resorptions. There were no compound-related effects in either dams or fetuses at 52 mg/m3. It was, therefore, concluded that DMPD was not selectively toxic to the rat conceptus.     

Developmental toxicity of 2,3,4,7,8-pentachlorodibenzofuran in the Fischer 344 rat

Fischer 344 rats were exposed acutely to 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) during the organogenic period to evaluate its potential as an inducer of teratogenic and embryolethal effects. All dams were treated by gavage with a single dose of 0, 30, 100, or 300 μg 4-PeCDF/kg body wt on gestation Day (gd) 8, 10, or 12. An additional treatment group was included on gd 12 and administered 10 μg 4-PeCDF/kg body wt po. All animals were killed on gd 20 and maternal and fetal toxicities were assessed. Determination of embryotoxicity involved both soft tissue and skeletal examinations. 4-PeCDF induced a dose-related decrease in corrected maternal weight gain following treatment on gd 8 and 10, as well as resulted in a concomitant increase in the liver/body weight ratios, first evident at 30 μg/kg for all 3 days of exposure. The maternal thymus weight decreased relative to body weight compared with those of controls. Embryo-fetal toxicity was evident from the high mortality (>80%) observed at 300 μg/kg for all 3 days of exposure. Mean fetal weight, a sensitive indicator of fetal toxicity, decreased compared to that of controls at 30, 100, and 300 μg/kg following treatment on either gd 8, 10, or 12. 4-PeCDF induced cleft palate in survivors at a dose of 300 μg/kg for all 3 days of exposure. In conclusion, 4-PeCDF is maternally and fetally toxic regardless of the gestation day of exposure, but induced terata only at doses where overt maternal and fetal toxicity were observed, in contrast to previously reported studies in the mice where teratogenic effects were observed at nonfetotoxic dose levels. Thus, the mouse may be a more sensitive model for evaluating specific toxic responses induced prenatally following exposure to the structurally related polyhalogenated aromatic hydrocarbons which include the dioxins, furans, biphenyls, and naphthalenes.     

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.     

Developmental Toxicity of 2,3,4,7,8-Pentachlorodibenzofuran in the Fischer 344 Flat

Developmental Toxicity of 2,3,4,7,8-Pentachlordibenzofuran inthe Fischer 344 Rat. COUTURE, L. A,, HARRIS, M. W., AND BIRNBAUM,L. S. (1989). Fundam Appl Toxicol 12, 358–366. Fischer344 rats were exposed acutely to 2,3,4,7,8-pentachlordibenzofuran(4-PeCDF) during the organogenic period to evaluate its potentialas an inducer of teratogenic and embryolethal effects. All damswere treated by gavage with a single dose of 0, 30, 100, or300 µg 4- PeCDF/kg body wt on gestation Day (gd) 8, 10,or 12. An additional treatment group was included on gd 12 andadministered 10µg 4-PeCDF/kg body wt po. All animals werekilled on gd 20 and maternal and fetal toxicities were assessed.Determination of embryotoxicity involved both soft tissue andskeletal examinations. 4-PeCDF induced a dose-related decreasein corrected maternal weight gain following treatment on gd8 and 10, as well as resulted in a concomitant Increase in theliver/body weight ratios, first evident at 30 µg/kg forall 3 days of exposure. The maternal thymus weight decreasedrelative to body weight compared with those of controls. Embryo-fetaltoxicity was evident from the high mortality (>80%) observedat 300 µg/kg for all 3 days of exposure. Mean fetal weight,a sensitive indicator of fetal toxicity, decreased comparedto that of controls at 30, 100, and 300 µg/kg followingtreatment on either gd 8, 10, or 12. 4- PeCDF induced cleftpalate in survivors at a dose of 300 µg/kg for all 3 daysof exposure. In conclusion, 4-PeCDF is maternally and fetallytoxic regardless of the gestation day of exposure, but inducedterata only at doses where overt maternal and fetal toxicitywere observed, in contrast to previously reported studies inthe mice where teratogenic effects were observed at nonfetotoxicdose levels. Thus, the mouse may be a more sensitive model forevaluating specific toxic responses induced prenatally followingexposure to the structurally related polyhalogenated aromatichydrocarbons which include the dioxins, furans, biphenyls, andnaphthalenes.     

Prenatal toxicity of inhaled polymeric methylenediphenyl diisocyanate (MDI) aerosols in pregnant wistar rats.

Mated Wistar rats, 25/group, were exposed to polymeric methylenediphenyl diisocyanate (MDI) aerosol of respirable size for 6 h/day, on gestational days (gd) 6 through 15, at 0, 1, 4, and 12 mg/m3. Maternal clinical signs, body weights, and feed and water consumption were measured throughout gestation. At scheduled sacrifice on gd 20, maternal body, gravid uterine, liver, and paired lung weights were documented. Corpora lutea were counted, implantation sites were identified: resorptions, dead and live fetuses, and placentas were weighed. All live fetuses were counted, sexed, weighed, and examined for external alterations; approximately 50% of the live fetuses/litter were preserved in Bouin's fixative and examined for visceral alterations, and the remaining live fetuses/ litter were cleared and stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity was observed at 12 mg/m3, including mortality (2 of 24 pregnant), damage to the respiratory tract, reduced body weights and weight gain, reduced liver and increased lung weights, and reduced gravid uterine weight (the last not statistically significantly different from the control value). Developmental toxicity was also observed at 12 mg/m3, including reduced placental and fetal body weights and an increased incidence of fetal skeletal variations and skeletal retardations. There was no evidence of maternal or developmental toxicity at 1 or 4 mg/m3. The no observed adverse effect concentration for maternal and developmental toxicity was therefore 4 mg/m3. There were no treatment-related teratogenic effects at any concentrations evaluated.     

Developmental toxicity evaluation of 1,2,3,4-butanetetracarboxylic acid in Sprague Dawley (CD) rats

1,2,3,4-butanetetracarboxylic acid (BTCA), proposed as a formaldehyde substitute in the treatment of permanent press fabrics, was evaluated for developmental toxicity. Timed-mated CD rats (25 per group) received BTCA 250, 500, or 1000 mg/kg/day or vehicle (deionized/distilled water) by gavage on gestational days (gd) 6 through 19. Maternal feed and water consumption, body weight, and clinical signs were monitored throughout gestation. At termination (gd 20), confirmed-pregnant females (21 to 25 per group) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations. One maternal death, reduced body weight, and reduced weight gain were noted at the high dose; confirmed pregnancy rates were 84 to 100% for each group. There were no treatment-related effects on fetal growth, survival, or morphologic development. The maternal toxicity NOAEL and LOAEL are 500 and 1000 mg/kg/day, respectively. The developmental toxicity NOAEL is > or = 1000 mg/kg/day, and the LOAEL was not established in this study.     

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).     

Reproductive Effects of Theophylline in Mice and Rats

Reproductive Effects of Theophylline in Mice and Rats. MORRISSEY,R. E., COLLINS, J. J., LAMB, J. C, IV, MANUS, A. G., AND GULATI.D. K. (1988). Fundam Appl. Toxtcol. 10, 525–536. Theophyllinewas administered by gavage in 13-week studies to B6C3F, mice(0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150mg/kg/day) with significant reductions in male mouse terminalbody and testicular weights. Male rats also displayed reducedtesticular weight, as well as nonsignificant but dose-relateddecreases in body weight. There was a significant but non-dose-relateddecrease in female mouse body weight. In parallel studies ofB6C3F, mice and F344 rats, theophylline administered in thediet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminalbody weights in male and female mice, but not rats. In rats,cauda epididymis weight was reduced at the high dose comparedto the control group, and there was an increase in abnormalsperm. These studies were followed by continuous breeding reproductiveassays in CD-I mice in which theophylline was administered infeed (0.0, 0.075, 0.15, and 0.30% calculated doses of 0, 125,265, and 530 mg/kg/day, respectively) to breeding pairs for14 weeks. There was a dose-dependent decrease in the numberof live pups produced per litter, a significant decrease inthe number of litters produced per pair (0.30%) and in the adjustedlive pup weight (0.30%), a decrease in the percentage of pupsborn alive (0.15 and 0.30%), and an increase in the number ofdays needed to produce each litter (0.30%). After 19 weeks ofcontinuous treatment at 0.307%, a crossover mating trial indicatedthat females and males were adversely affected by theophylline,as judged by the decreased percentage of pups born alive, thedecreased live pup weight, and the decreased number of livepups per litter relative to matings within the control group,but the effects in females were more extensive. Based on otherstudies, there is a suggestion that the observed changes infertility may be partially attributed to embryotoxicity.     

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

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