Toxicity and Metabolism of Trimethylarsine in Mice and Hamsters

Toxicity and Metabolism of Trimethylaisinc in Mice and Hamsters.YAMAUCHI, H., KAISE, T., TAKAHASHI, K., AND YAMAMURA, Y. (1990).Fundam. Appl. Toxicol. 14, 399–407. Trimethylarsine (TM-As)proved to be an arsenic compound of low toxicity, with a poLD50 of 7870 mg/kg in mice. A single po dose of 10 mg/kg ofTM-As caused no hemolysis, but a single po dose of 750 mg/kginduced mild, transient hemolysis in hamsters. TM-As was veryrapidly eliminated into the urine, with a biological half-lifeof 3.7 hr. TM-As was oxidized In vivo to form trimethylarsineoxide (TMAO) and excreted as such into the urine. TM-As wasnever demethylated In vivo. A mechanism was demonstrated bywhich a part of TM-As was eliminated directly into the expiredair. We drew a conclusion that TM-As is far less toxic thanarsine, most probably due to its In vivo conversion to TMAO.c 1990 Society of Toxicology.     

Cadmium-Induced Ovarian Toxicity in Hamsters, Mice, and Rats

Cadmium-Induced Ovarian Toxicity in Hamsters, Mice, and Rats.REHM, S., AND WAALKES, M.P. (1988). Fundam Appl. Toxicol. 10,635–647. The effects of cadmium on the female genitaltract of Syrian hamsters (CnRGH), of four mouse strains (BALB/cAnNCr,DBA/2NCr, C57BL/ 6NCr, NFS/NCr), and two rat strains (F344/NCrand WF/NCr) were studied by light microscopy after a singlesc injection of cadmium chloride (CdCl₂). Experiments involvedanimals prior to and after sexual maturity, and employed CdCl₂doses ranging from 20 to 47.5 µmol/kg. Animals were examinedat intervals from 24 hr to 8 weeks following treatment. Syrianhamsters were most susceptible to CdCl₂-induced ovarian hemorrhagicnecrosis at all ages tested. Most severe ovarian lesions occurredin immature hamsters, in mature hamsters at high doses, andshortly before ovulation at all doses. The small arteries ofthe developing follicles and interstitial stroma seemed selectivelysusceptible to CdCl₂ toxicity while the corpora lutea, mesothelium,primordial oocytes, and the rete ovarii appeared resistant.Pretreatment with zinc acetate markedly reduced the extent ofovarian lesions in hamsters. Although reduced in weight by 45%,the hamster ovaries recovered morphologically within 2 monthsafter severe acute hemorrhagic necrosis. Uterine and cervicalstromal hemorrhages were seen only in immature hamsters at dosesof 30 µmol CdCl₂/kg. Of the mice, only the DBA/2NCr strainshowed significant CdCl₂-induced ovarian hemorrhages, and thesehemorrhages occurred at doses also producing lethal liver toxicity.Lesions of the uterus were rare. Rats showed dose- and age-dependenttoxicity in the ovaries, uterus, cervix, and liver. CdCl2 exposurein mature rats induced uterine lesions only in F344 rats, whileacute ovarian and hepatic toxicity was less severe in matureanimals of both strains. No lesions were noted after 7 daysin mature WF rats. In both rats and mice, no cycle dependencyof the ovarian lesions was evident.     

Arsine: Absence of Developmental Toxicity in Rats and Mice

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

Developmental Toxicity 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.     

Developmental Toxicity Evaluation of Acrylamide in Rats and Mice

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

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.     

Maternal and Developmental Toxicity of Chronic Aluminum Exposure in Mice

Maternal and Developmental Toxicity of Chronic Aluminum Exposurein Mice. GOLUB, M. S., GERSHWIN, M. E., DONALD, J. M., NEGRI,S., AND KEEN, C. L. (1987). Fundam. Appl. Toxicol. 8, 346–357.The present study demonstrated aluminum-induced neurotoxicityin mouse dams and developmental retardation in their offspringfollowing oral exposure to several dose levels during gestationand lactation. Female mice fed aluminum lactate (AL) at levelsof 500 or 1000 ppm in their diet from Day 0 gestation to Day21 postpartum were compared to mice which received a 100 ppmaluminum diet either ad libitum or pair-fed to the 1000 ppmAL group. Dams receiving the 500 and 1000 ppm AL diets showedsigns of neurotoxicity beginning at Days 12–15 postpartumand showed significant weight loss. Offspring showed dose-dependentdecreases in body weight (F = 6.47, p < 0.001), crown-rumplength (F = 1.11, p < 0.0001), and ponderal index (F = 6.90,p < 0.0002), at birth and preweaning. Absolute and relativeliver and spleen weights were lower in pups from the high ALgroups compared to controls (F = 3.34, p < 0.025 and F =15.54, p < 0.001, respectively). Neurobehavioral developmentwas somewhat delayed in aluminum-treated pups, but not in theirpair-fed controls (F = 5.52, p < 0.005). In addition to showingoral toxicity of excess AL during development dose-dependenttoxic effects of parenteral aluminum exposure were demonstratedin pregnant mice which were injected subcutaneously with aluminumlactate solution at 10, 20, or 40 mg Al/kg body wt on Days 3,5, 7, 9, 12, 13, and 15 of gestation. Maternal spleen and liverweights were significantly increased in aluminum treated animals(p < 0.001 and p < 0.05, respectively). Fetal crown-rumplengths were significantly reduced in the 20 mg/kg aluminumgroup (F = 9.79, p < 0.001).     

Phase-Specific Developmental Toxicity in Mice Following Maternal Methanol Inhalation

Phase-Specific Development Toxicity in Mice Following MaternalMethanol Inhalation. BOLON, B., DORMAN, D. C., JANSZEN, D.,MORGAN, K. T., AND WELSCH, F.(1993). Fundam. Appl. Toxicol.21, 508–516. Methanol is toxic to embryos of mice and rats when inhaled bydams at high concentrations. The present studies examined methanol-induceddevelopmental toxicity following inhalation exposure (6 hr/day)of pregnant CD-1 mice to 5000, 10,000, or 15,000 ppm eitherthroughout organogenesis (GD 6–15), during the periodof neural tube development and closure (GD 7–9), or duringa time of potential neural tube reopening (GD 9–11). Transientneurologic signs and reduced body weights were observed in upto 20% of dams exposed to 15,000 ppm. Examination of near-termfetuses revealed embryotoxicity (increased resorptions, reducedfetal weights, and/or fetal malformations) at 10,000 and 15,000ppm, while 3-day exposures at 5000 ppm yielded no observableadverse effects. Terata included neural and ocular defects,cleft palate, hydronephrosis, deformed tails, and limb (pawand digit) anomalies. Neural tube defects and ocular lesionsoccurred after methanol inhalation between GD 7–9, whilelimb anomalies were induced only during GD 9–11; cleftpalate and hydronephrosis were observed after exposure duringeither period. These findings were consistent with prior reportsthat maternal methanol inhalation at high levels induces developmentaltoxicity in a concentration dependent manner. Furthermore, ourdata indicate that the spectrum of teratogenic effects dependedupon both the timing (i.e., stage of embryonic development)and the number of methanol exposures.     

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.     

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 Diethylene Glycol Dimethyl Ether in Mice

The Developmental Toxicity of Diethylene Glycol Dimethyl Etherin Mice. PRICE, C. J., KIMMEL, C. A., GEORGE, J. D., AND MARR,M. C. (1987). Fundam. Appl. Toxicol. 8, 115–126. Diethyleneglycol dimethyl ether (diEGdiME) is structurally related toseveral compounds which produce reproductive and developmentaltoxicity, including teratogenicity in laboratory animals. Inthe present study, diEGdiME (0, 62.5, 125, 250, or 500 mg/kg/day)was administered by gavage in distilled water to timed-pregnantCD-1 mice during major organogenesis [gestational days (gd)6–15]. Clinical status of treated females was monitoreddaily during treatment and on gd 17. At sacrifice (gd 17), pregnancywas confirmed by uterine examination for 20–24 dams pergroup; each live fetus was examined for external, visceral,and skeletal malformations. No maternal deaths, morbidity, ortreatment-related clinical signs were observed. Reduced maternalweight gain during treatment at 250 mg/kg/day was primarilyattributed to compromised pregnancy status resulting in reducedgravid uterine weight. Maternal weight gain during gestationcorrected for gravid uterine weight, and relative liver weight(% body weight) were not affected. Average fetal body weight/litterwas significantly reduced at 125 mg/kg/day. The percentageof postimplantation loss/litter (5, 8, 7, 12, and 50% for controlthrough high dose) and the percentage of malformed live fetuses/litter(0.4, 0, 2, 24, and 96%) were significantly increased at 250mg/kg/day. Developmental defects involved primarily the neuraltube, limbs and digits, craniofacial structures, abdominal wall,cardiovascular system, urogenital organs, and both the axialand appendicular skeleton. In summary, oral administration ofdiEGdiME during major organogenesis did not produce any distinctivesigns of maternal toxicity, but did produce selective and profoundadverse effects upon fetal growth, viability, and morphologicaldevelopment at 125 mg/kg/day.     

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.     

The Developmental Toxicity of Ethylene Glycol Diethyl Ether in Mice and Rabbits

Timed-pregnant CD-1 outbred Albino Swiss mice and New ZealandWhite rabbits were dosed by gavage with ethylene glycol diethylether (EGdiEE) in distilled water during major organogenesis.Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50,150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19(0, 25, 50, or 100 mg/kg/day). Maternal clinical status wasmonitored daily during treatment. At termination (gd 17, mice;gd 30, rabbits), confirmed-pregnant females (22–24 pergroup, mice; 26–32 per group, rabbits) were evaluatedfor clinical status and gestational outcome; each live fetuswas examined for external, visceral, and skeletal malformations.In mice, no maternal mortality was observed, but maternal bodyweight gain during gestation and treatment, and at terminationwas reduced at 1000 mg/kg/day. The reduction of maternal bodyweight gain during gestation was secondary to embryo/fetal toxicity,i.e., reduced gravid uterine weight as a consequence of decreasedlitter size and fetal weight. The no-observed adverse effectlevel (NOAEL) for developmental toxicity was 50 mg/kg/day. At150 mg/kg/day the number of litters of mice with malformed fetuseswas increased. At 500 mg/kg/day fetal body weight was reduced,and malformation incidence was significantly increased. Exencephalyand fused ribs were observed most often. In rabbits, maternalbody weight was unaffected by treatment even though 6% maternalmortality was observed at 100 mg/kg/day. The developmental NOAELwas 25 mg/kg/day. Malformations were increased at 50 mg/kg/day,short tail, small spleen, fused sternebrae, and fused rib cartilagewere observed most often. In summary, oral administration ofEGdiEE to mice and rabbits during organogenesis produced profoundadverse developmental effects even in the absence of significantmaternal toxicity. Developmental effects in rabbits were morevaried.     

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.     

The Developmental Toxicity of Triethylene Glycol Dimethyl Ether in Mice1

The Developmental Toxicity of Triethylene Glycol Dimethyl Etherin Mice. GEORGE, J. D., PRICE, C. J., KIMMEL, C. A., AND MARR,M. C. (1987). Fundam. Appl. Toxicol. 9, 173–181. Triethyleneglycol dimethyl ether (triEGdiME) is structurally related toseveral compounds which produce reproductive and developmentaltoxicity, including teratogenicity in laboratory animals. Inthe present study, triEGdiME (0, 250, 500, or 1000 mg/kg/day)was administered by gavage to timed-pregnant CD-I mice duringmajor organogenesis (Gestational Days (gd) 6– 15). Maternalclinical status was monitored daily during treatment. At sacrifice(gd 17), confirmed-pregnant females (26–28 per group)were evaluated for clinical Status and gestational outcome;each live fetus was examined for external, visceral, and skeletalmalformations. No maternal death or morbidity was observed.Clinical signs of toxicity including piloerection were minor.Maternal weight gain during treatment, gestation, and maternalweight gain during gestation corrected for gravid uterine weightwere not affected. Gravid uterine weight decreased in a dose-relatedmanner, indicating compromised pregnancy status. Relative maternalliver weight (% body wt) was significantly increased over controlsat doses 500 and 1000 mg/kg/day. Average fetal body weightper litter was significantly reduced at doses 500 mg/kg/day.The percent age malformed live fetuses per litter (0.3, 0, 0.8,and 11.1%) was significantly increased at 1000 mg/kg/day. Majormalformations affected primarily the development of the neuraltube, cranio facial structures, and the axial skeleton. In summary,oral administration of triEGdiME during major organogenesisproduced only marginal signs of altered maternal status, asevidenced by an increase in maternal liver weight, and causedselective adverse effects upon fetal growth and morphologicaldevelopment at doses 500 mg/kg/day.     

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.     

The Effect of Maternal Restraint on Developmental Toxicity of Aluminum in Mice

Both aluminum (Al) and maternal restraint have been reported to cause developmental toxicity in mammals. This study assessed in pregnant mice the potential interaction between Al and maternal restraint. Four groups of plug-positive female mice were given IP injections of AlCl₃ at 37.5 and 75 mg/kg/day on days 6–15 of gestation. Two of these groups were also subjected to restraint for 2 h/day during the same gestational days. Control groups included restrained and unrestrained pregnant mice nonexposed to Al. Cesarean sections were performed on gestation day 18, and the fetuses were weighed and examined for morphological defects. Maternal toxicity was significantly enhanced by restraint at 75 mg AlCl₃/kg/day. No increases in the number of resorptions or dead fetuses per litter were observed following exposure to Al, maternal restraint, or combined Al and restraint. However, a significant decrease in fetal body weight, as well as a significant increase in the number of litters with morphologic defects, was observed in the group exposed to 75 mg AlCl₃/kg/day plus maternal restraint. The current results suggest that maternal restraint could enhance the metal-induced developmental toxicity (reduced fetal body weight, increase in the number of litters with morphologic defects) only at high doses of the metal, which are also toxic to the dam.     

Evaluation of the Developmental Toxicity of Methacrylamide and N,N'-Methylenebisacrylamide in Swiss Mice

Timed-pregnant CD-1 outbred albino Swiss mice received eithermethacrylamlde (MAC; 0, 60, 120, or 180 mg/kg/day) or N,N'-methylenebisacrylamide(BAC; 0, 3, 10, or 30 mg/kg/day) po in distilled water on gestationaldays (GD) 6 through 17. Maternal clinical status was monitoreddaily. At termination (GD 17), confirmed-pregnant females (27–30per group, MAC; 24–25 per group, BAC) were evaluated forclinical status and gestational outcome; live fetuses were examinedfor external, visceral, and skeletal malformations. For MAC,no treatment-related maternal mortality was observed. Maternalbody weight on GD 17, maternal weight gain during treatmentand gestation, and corrected maternal weight gain were reducedat the high dose. Relative maternal food and water intake wasnot adversely affected; neurotoxicity was not observed. Relativematernal liver weight was increased at a 120 mg/kg/day; graviduterine weight was decreased at 180 mg/kg/day. The maternalno-observed adverse effect level (NOAEL) was 60 mg/kg/day. TheNOAEL for developmental toxicity was also 60 mg/kg/day. At 120 mg/kg/day, mean fetal body weight was reduced. At 180 mg/kg/day,increased postimplantation death per litter was observed. Morphologicaldevelopment was not affected. The maternal NOAEL for BAC was10 mg/kg/day. At 30 mg/kg/day, decreased maternal body weighton GD 17, maternal body weight change during treatment and gestation,corrected maternal body weight, and gravid uterine weight wereobserved. Relative maternal liver weight increased at 30 mg/kg/day.The developmental NOAEL was 3 mg/kg/day BAC. Mean fetal bodyweight was reduced at 30 mg/kg/day. At 10 mg/kg/day, an increasedincidence of fetal variations (extra rib) was observed, althoughfetal malformation rate was unaffected. MAC and BAC were notteratogenic to Swiss mice at the doses tested. BAC was morepotent than MAC in causing adverse maternal and developmentaleffects.     

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.