Fetal cartilage malformation by intravenous administration of indium trichloride to pregnant rats

The effects of indium on bone and cartilage development in rat fetuses were examined. Pregnant Sprague Dawley (SD) rats were treated with indium trichloride (0.1, 0.2, or 0.3 mg/kg) by single intravenous administration on Day 10 of gestation, and their fetuses were examined on Day 21. Half of each litter was prepared for skeletal examinations using a skeletal double-staining technique to allow evaluation of cartilage as well as bone. Dose-related increased incidences of external and skeletal fetal malformations occurred at doses of 0.2 mg/kg or more. The incidences of cartilage malformations in the vertebrae, ribs, and forepaw phalanges were significantly increased at 0.3 mg/kg. Malformations of the axial bone were accompanied by cartilage malformations. It was concluded from these results that indium produced cartilage malformations, that were considered to be the underlying cause for the majority of fetal skeletal malformations observed in rats in this study.     

Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats

Ochratoxin A (OTA), a potent in vivo teratogen, has been tested in various laboratory animal species. Present investigation was conducted to determine critical dose and critical time for the developmental toxicity of OTA in pregnant Wistar rats after single oral dose administration. OTA at different graded dose levels (2–4 mg/kg body weight) and at different gestation days (6–15), caused variable developmental defects in developing fetuses. OTA at 2.75 mg/kg body weight, dissolved in 0.1 M sodium bicarbonate (vehicle) and administered by oral intubation as a single dose on one of the gestational days 6–15, caused significant maternal toxicity in the dams and various gross, visceral and skeletal anomalies in the fetuses. The major gross malformations were external hydrocephaly, incomplete closure of skull and omphalocele. Internal hydrocephaly, microphthalmia, enlarged renal pelvis and renal hypoplasia were the main internal soft tissue anomalies. Major skeletal defects were developmental defects in skull bones, sternebrae, vertebrae and ribs. The gestational days 6 and 7 were found to be the most critical for the induction of teratogenicity in rats. Single oral dose of 2.75 mg/kg body weight OTA was found to be the minimum effective teratogenic dose in pregnant Wistar rats.     

Fetal cartilage malformation by intravenous administration of indium trichloride to pregnant rats

The effects of indium on bone and cartilage development in rat fetuses were examined. Pregnant Sprague Dawley (SD) rats were treated with indium trichloride (0.1, 0.2, or 0.3 mg/kg) by single intravenous administration on Day 10 of gestation, and their fetuses were examined on Day 21. Half of each litter was prepared for skeletal examinations using a skeletal double-staining technique to allow evaluation of cartilage as well as bone. Dose-related increased incidences of external and skeletal fetal malformations occurred at doses of 0.2 mg/kg or more. The incidences of cartilage malformations in the vertebrae, ribs, and forepaw phalanges were significantly increased at 0.3 mg/kg. Malformations of the axial bone were accompanied by cartilage malformations. It was concluded from these results that indium produced cartilage malformations, that were considered to be the underlying cause for the majority of fetal skeletal malformations observed in rats in this study.     

Quaternary Silsesquioxane: A Developmental Toxicity Study in Rats

The developmental toxicity of an antimicrobial organosiliconquaternary ammonium chloride (Quaternary Silsesquioxane) wasevaluated in rats. Groups of 25 pregnant CD rats were administered100, 300, or 1000 mg/kg/day of test material by ga-vage as asingle daily dose on Days 6 through 15 of gestation at a volumeof 10 ml/kg. The control group received only corn oil as thevehicle. Cesarean examinations were performed on all femaleson Gestation Day 20 followed by evaluation of the fetuses forteratogenicity. Maternal effects included a slight but statisticallysignificant increase in relative liver weights at the 1000 mg/kg/daydose level. Using these hepatic changes as an adverse effect,the maternal no observable adverse effect level for this studywas identified at 300 mg/kg/day. The number of corpora lutea,implantation sites, viable fetuses, and early and late resorptions,the fetal body weights, the crown-rump length, and the graviduterine and corrected body weights were not affected by theadministration of Quat-Silsesquioxane. The occurrence of externaland internal soft tissue malformations and variations and theincidences of skeletal malformations and variations in the treatedgroups were not significantly different from those in the controlgroup. These results demonstrated that oral administration ofQuat-Silsesquioxane as high as 1000 mg/kg/day did not produceteratogenicity or other indications of developmental toxicityin the rat conceptus.     

The Absence of Teratogenic Hazard Potential of p-phenylenediamine in Sprague-Dawley Rats

The Absence of Teratogenic Hazard Potential of p-phenylenediaminein Sprague-Dawley Rats. Re, Thomas A., Loehr, Richard F., Rodwell,Dean E., D'Aleo, C.J. and Burnett, Clyde M. (1981). Fundam.Appl. Toxicol. 1:421/425. Para-phenylenediamine (PPD) was administeredby gavage to pregnant Sprague-Dawley Rats at dose levels of5, 10, 15, 20, and 30 mg/kg/day on days 6 through 15 of gestation(day 0 = day sperm was found in the vagina). A sham controlgroup and a pair fed control group were studied at the sametime. Pregnant animals were killed on day 20 of gestation and1/3 of the fetuses were examined for visceral malformationsand 2/3 for skeletal malformations and variations. Significantreductions in food consumption and weight gain were noted inthe 30 mg/ kg and pair fed control groups. Two pregnant ratsgiven PPD at 30 mg/kg/ day died but there were no deaths inany other dose groups. Fetal evaluations showed no biologicallyor statistically significant increase in malformations or developmentalvariations in any group. Therefore, although maternal toxicitywas demonstrated at the two highest dose levels, there was noevidence of teratogenic or other embryotoxic effects.     

Teratogenicity and embryotoxicity of titanocene dichloride in mice

The teratogenic and embryotoxic effects of the antitumor agent titanocene dichloride (TDC) were investigated after application of single doses of TDC (30 or 60 mg/kg) to pregnant mice on days 8, 10, 12, 14 or 16 of gestation. The fetuses were removed on day 18 by caesarian section and examined for external, internal and skeletal malformations as well as for toxic phenomena. The most striking result was the occurrence of cleft palate in numerous fetuses (10% of the fetuses, 30 mg/kg; 40-50%, 60 mg/kg) after TDC application on days 10 and 12. Besides the additional appearance of costal malformations in some fetuses, no other malformations were recognizable. On the other hand, the embryotoxic influence of TDC was significant and caused diminution of the number of live fetuses per litter, marked and dose-dependent reduction of mean fetal body weight after TDC application on day 8 through day 16 and distinct retardation of skeletal ossification.     

Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats

Ochratoxin A (OTA), a potent in vivo teratogen, has been tested in various laboratory animal species. Present investigation was conducted to determine critical dose and critical time for the developmental toxicity of OTA in pregnant Wistar rats after single oral dose administration. OTA at different graded dose levels (2–4 mg/kg body weight) and at different gestation days (6–15), caused variable developmental defects in developing fetuses. OTA at 2.75 mg/kg body weight, dissolved in 0.1 M sodium bicarbonate (vehicle) and administered by oral intubation as a single dose on one of the gestational days 6–15, caused significant maternal toxicity in the dams and various gross, visceral and skeletal anomalies in the fetuses. The major gross malformations were external hydrocephaly, incomplete closure of skull and omphalocele. Internal hydrocephaly, microphthalmia, enlarged renal pelvis and renal hypoplasia were the main internal soft tissue anomalies. Major skeletal defects were developmental defects in skull bones, sternebrae, vertebrae and ribs. The gestational days 6 and 7 were found to be the most critical for the induction of teratogenicity in rats. Single oral dose of 2.75 mg/kg body weight OTA was found to be the minimum effective teratogenic dose in pregnant Wistar rats.     

Embryotoxic and teratogenic effects of intraperitoneally administered metavanadate in mice.

Metavanadate was evaluated for developmental toxicity in pregnant Swiss mice. Sodium metavanadate (NaVO3) was administered intraperitoneally on d 6-15 of gestation at doses of 0, 2, 4, or 8 mg/kg/d. On gestation d 18, all live fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal toxicity was observed at 2, 4, and 8 mg/kg/d as evidenced by decreased weight gain during treatment. Increased resorptions and dead fetuses, increased percentage postimplantation loss, and reduced fetal body weight per litter were observed at 4 and 8 mg/kg/d. There were no significant increases in the type or incidence of external and skeletal anomalies, but a significant increase in the incidence of cleft palate was detected at 8 mg/kg/d. The lowest-observed-adverse-effect level (LOAEL) for maternal toxicity was 2 mg NaVO3/kg/d, while 2 mg/kg/d was also the no-observed-adverse-effect level (NOAEL) for significant developmental toxicity.     

Intrauterine growth retardation and lack of teratogenic effects of prenatal exposure to the combination of paracetamol and caffeine in Wistar rats

The effect of the mixture of paracetamol and caffeine on prenatal development in rats was studied. Paracetamol:caffeine was prepared with a 5:1 ratio (w/w) between compounds and administered orally in Tween-80 water suspension once a day to pregnant Wistar rats on gestation days 8 through 14 (plug = day 1). The low dose was similar to the preparation available over-the-counter (OTC), 3.5 mg/kg of paracetamol and 0.7 mg/kg of caffeine. The middle dose was 35.0 and 7.0 mg/kg, and the high dose 350.0 and 70.0 mg/kg for paracetamol and caffeine, respectively. On gestation day 21, fetuses were delivered by laparotomy. Corpora lutea, fetuses, and number of implantation sites were counted. Live fetuses were examined for external, visceral, and skeletal malformations. There was a significant decrease in maternal body weight gain and liver weight in all drug-treated groups and reduced kidney weights in the middle and high dose groups. Dose-dependent effects in the middle and high dose groups on fetal body weight/growth and placental weight were found. In none of the three dose groups was there an increase in external or internal congenital malformations.     

Teratogenic effects of carboplatin, an oncostatic drug, administered during the early organogenetic period in rats

In the preceding study, no teratological effects against rat fetuses were observed when carboplatin, an oncostatic platinum coordination complex, was dosed to their dams from days 7 to 17 of gestation at a dose level of 4 mg/kg/day. However, there are a few reports which show the teratogenic action of carboplatin injected from days 6 to 15 of pregnancy at a dose level of 6 mg/kg/day. In the present study, carboplatin was administered intravenously to pregnant female Crj: CD (Sprague-Dawley) rats from days 6 to 9 or 7 to 10 of gestation at a dose level of 6 mg/kg/day in order to know the teratogenicity of this drug. Carboplatin were highly embryolethal in dams when dosed from days 6 to 9 of gestation, but not in animals when injected from days 7 to 10 of pregnancy. Carboplatin also produced external, internal and skeletal anomalies in fetuses such as gastroschisis, dilatation of cerebral ventricles, cleft sternum, fused ribs, malformed thoracic vertebra when administered from days 6 to 9 of gestation, but not in conceptuses when dosed from days 7 to 10 of pregnancy. However, the delayed ossification which was ascribed to the fetal growth retardation was observed in rats treated with this drug during both administration periods. These results suggest that carboplatin is embryotoxic, inducing intrauterine death and congenital malformations in rats, when injected during the early stages of gestation including day 6 of pregnancy.     

Teratogenicity of 2-Methoxyethanol Applied as a Single Dermal Dose to Rats

Teratogenicity of 2-Methoxyethanol Applied as a Single DermalDose to Rats. FEUSTON, M. H., KERSTETTER, S. L., AND WILSON,P. D. (1990). Fundam. Appl Toxicol. 15, 448–456. 2-Methoxyethanol(2-ME) was applied as a single dermal dose on the backs of collared,pregnant Sprague-Dawley rats on Gestation Days (GD) 10, 11,12, 13, or 14 at doses of 0 and 2000 mg/ kg, and at doses of0, 250, 500, and 1000 mg/kg on GD 12. Except for a transientloss in body weight observed the day after 2-ME administration,no signs of maternal toxicity were observed. On GD 20, damswere necropsied and the fetuses evaluated for normal developmentResorp-tions were significantly (p < 0.05) increased in damsexposed to 2-ME on GD 10. Fetal body weights were reduced atdose levels of 1000 and 2000 mg/kg, but statistically significantdifferences were found only on GD 10 and 12. Significant increasesin external, visceral, and skeletal malformations were observedin fetuses exposed to 2-ME at dose levels of 500 mg/kg or greater.Defects of the cardiovascular and urinary systems were the prominentvisceral malformations observed. Limb defects (especially thosepertaining to the digits) and vertebral column defects (primarilyof the tail) were the most frequently observed skeletal defects.At the 2000 mg/kg dose level, 2-ME was teratogenic regardlessof the GD of administration. Based on the results of this study,the no observed adverse effect level for developmental toxicityfor a single dermal dose of 2-ME applied on GD 12 was determinedto be 250 mg/kg.     

Teratogenicity study of ethylene glycol in rats

Ethylene glycol was administered in the diet to pregnant Fischer 344 rats on days 6 through 15 of gestation. Target dosage levels were 1.0, 0.2, 0.04, and 0.00 g/kg/day. There was no maternal toxicity, embryotoxicity, or increased incidence of malformations in fetuses from doses dams. Positive control dams received 500 mg/kg of hydroxyurea on gestation day 11 and had fetuses with numerous soft tissue and skeletal malformations. Results are interpreted as preliminary indication of lack of teratogenicity of ethylene glycol.     

Effect of acetaldehyde on skeletogenesis in rats

Acetaldehyde (ACH), the metabolite of ethanol was administered to pregnant CF rats intraperitoneally (50 mg/kg) from day 8 through 15 of gestation and fetuses from different mothers were collected from day 16 through 21 of gestation. Fetuses were processed for alizarin skeletal staining. There was significant delay in ossification besides certain skeletal malformations such as wavy ribs. The delay in ossification may be one of the reasons for reduced birth weight and increased postnatal mortality and growth.     

Reproduction and teratology studies with oncolytic agents in the rat and rabbit. II. 5-(3,3-dimethyl-l-triazeno)imidazole-4-carboxamide (DTIC).

Studies were conducted to evaluate the effects of DTIC, a new anticancer drug, on embryonal and fetal development in the rat and rabbit, and on reproduction, perinatal and postnatal behavior, and development in the rat. Twice weekly ip treatment of male rats for 9 weeks with 12.5, 25, or 50 mg/kg did not affect male libido, although females mated to males given 50 mg/kg twice weekly had a higher incidence of resorptions than controls. Intraperitoneal treatment with 7.5, 15, or 30 mg/kg/day for 14 days prior to breeding and through Day 20 of gestation resulted in a higher incidence of resorptions and fewer live fetuses in dams receiving 15 or 30 mg/kg. Doses of 30, 50, or 70 mg/kg given ip on Days 6–15 of gestation resulted in fetal skeletal anomalies, whereas soft tissue anomalies involving the eye, cardiovascular system, and abdominal wall occurred only in fetuses from dams treated with 50 or 70 mg/kg. Treatment from Day 15 of gestation through Day 21 postpartum with 7.5, 15, or 30 mg/kg/day resulted in a dose-dependent adverse effect on neonate survival. In rabbits treated ip on Days 6–18 of gestation at doses of 2.5, 5, or 10 mg/kg/day, DTIC was materno- and fetotoxic and resulted in numerous skeletal abnormalities in fetuses from does treated with 10 mg/kg/day.     

Oral meso-2,3-dimercaptosuccinic acid in pregnant Sprague-Dawley rats: teratogenicity and alterations in mineral metabolism. I. Teratological evaluation

meso-2,3-Dimercaptosuccinic acid (DMSA), an effective antagonist for the treatment of lead, arsenic, mercury, and cadmium poisoning, was evaluated for developmental toxicity in pregnant Sprague-Dawley rats. DMSA was administered by gavage on d 6-15 of gestation at doses of 0, 100, 300, or 1000 mg DMSA/kg/d. At termination on d 20 of gestation, fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal toxicity was observed at all doses, as evidenced by a significant decrease in body weight gain. There were no effects with respect to hematology or clinical chemistry. Increased early resorptions, increased percentage postimplantation loss, and reduced fetal body weight per litter were observed at 100, 300, and 1000 mg/kg/d. Examination of fetuses for gross external abnormalities, visceral and skeletal malformations, or ossification variations revealed that DMSA did not produce teratogenicity at any dosage level. However, significant fetotoxicity was observed at 100, 300, and 1000 mg/kg/d. The no-observable-effect level (NOEL) for maternal and developmental toxicity was less than 100 mg DMSA/kg/d.     

Developmental toxicity of cobalt in the rat

To determine the potential developmental toxicity of cobalt, pregnant Sprague-Dawley rats were given by gavage a daily dose of 0, 25, 50; and 100 mg/kg cobalt(II) chloride on d 6-15 of gestation. Females were sacrificed on d 20. Maternal effects included significant reductions in weight gain and food consumption, particularly at 100 mk/kg.d. Hematocrit, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and reticulocytes were increased significantly in the 100-mg/kg.d group. No treatment-related changes were recorded in the number of corpora lutea, total implants, resorptions, the number of live and dead fetuses, fetal size parameters, or fetal sex distribution data. Increased incidence of stunted fetuses per litter was the only adverse finding at 50 and 100 mg/kg.d group. However, this increase was not statistically significant. Examination of fetuses for gross external abnormalities, skeletal malformations, or ossification variations revealed that cobalt did not produce teratogenicity or significant fetotoxicity in the rat at doses as high as 100 mg/kg.d.     

Teratogenic effects of a lipophilic cationic dye rhodamine 123, alone and in combination with 2-deoxyglucose

An anti-tumor agent, the cationic dye rhodamine 123 (Rh 123), becomes concentrated in mitochondria of certain tissues and inhibits ATP production. Rh 123 was tested for developmental toxicity by i.p. injection into pregnant CD-1 mice daily on gestation days 7-10 (plug = day 1) at doses up to 15 mg/kg/day. Additional mice were given a 500 mg/kg/day dose of 2-deoxy-glucose (2-DOG), an inhibitor of glycolytic ATP generation, alone or with Rh 123. Controls received saline equimolar to the 2-DOG. Prenatal mortality was increased by Rh 123 in combination with 2-DOG, with values of 40%, 43%, or 41% dead or resorbed at Rh 123 doses of 8, 12, or 15 mg/kg/day, respectively. When given alone, neither test agent was associated with a significant increase in prenatal death. Concurrent treatment with Rh 123 and 2-DOG resulted in significant incidences of gross malformations (17% to 20%) and skeletal malformations (9% to 72%). At the two highest Rh 123 doses (12 and 15 mg/kg/day) given with 2-DOG, significant findings included retarded skeletal ossification and variations (up to 83% and 41%, respectively), as well as decreased fetal weight. According to these results, combinations of rhodamine 123 and 2-deoxyglucose administered to the dam during early organogenesis are developmentally toxic to mice.     

Teratogenicity Study of Ethylene Glycol in Rats

ABSTRACT

Ethylene glycol was administered in the diet to pregnant Fischer 344 rats on days 6 through 15 of gestation. Target dosage levels were 1.0, 0.2, 0.04, and 0.00 g/kg/day. There was no maternal toxicity, embryotoxicity, or increased incidence of malformations in fetuses from dosed dams. Positive control dams received 500 mg/kg of hydroxyurea on gestation day 11 and had fetuses with numerous soft tissue and skeletal malformations. Results are interpreted as preliminary indication of lack of teratogenicity of ethylene glycol.     

Toxicological studies on a new cephamycin, MT-141. VIII. Its fertility test in rats

A fertility study of MT-141 was performed in SD rats with the intramuscular (i.m.) injections at the dose levels of 400, 800 and 1,600 mg/kg/day. The male rats were injected with MT-141 for 63 days before mating and during the mating period, while the female rats were injected with MT-141 from the 14th day before mating up to the day 7 of gestation. All pregnant rats were sacrificed on day 20 of gestation followed by external, visceral and skeletal observations of their fetuses. The results are summarized as follows. The suppression of body weight gain was observed in males given above 800 mg/kg/day i.m. and in females of all treated groups during early period of gestation. However, no significant differences were found between treated groups and the control with regard to copulation rate and conception rate. Though no defects were observed for visceral and skeletal specimens in the fetuses of treated groups, MT-141 produced a delayed ossification of forelimbs in the fetuses at the doses above 800 mg/kg/day and of sternebrae at the dose of 1,600 mg/kg/day. It is concluded from the above-mentioned results that the maximal "no 'effective" dose of MT-141 on the fertility is above 1,600 mg/kg/day i.m. in parental rats and less than 800 mg/kg/day i.m. for the fetuses.     

Teratogenic Evaluation of Tributyltin Chloride in Rats Following Oral Exposure

ABSTRACT

The teratogenicity of tri-n-butyltin chloride (TBTC1) was examined in Wistar rats. The pregnant rats were administered orally 25, 15, 9, 5 and 0(Control) mg of TBTCl/kg of body weight/day from day 7 to 15 of pregnancy. Maternal toxicity, as evidenced by both of decreased body weight gain and food consumption was observed at 25, 15 and 9 mg/kg/day dose group. However, only in the 25 mg/kg/day dose group some clinical signs of toxicity (sedation, diarrhoea and salivation) were observed and 70 percent of the dams were dead. In the 25 mg/kg/day dose group, all fetuses were dead. Statistically significant reductions in the female fetal body weight were observed in 9 and 5 mg/kg/day dose groups. In all groups treated with TBTC1 except the 25 mg/kg/day dose group, no significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the TBTC1-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any of the dose levels. However, several types of skeletal and internal variations including delayed ossifications were observed in some groups treated with TBTC1, but the incidences were not significantly different from controls. Also, two fetuses with dilatation of the renal pelvis were found in 9 and 5 mg/kg/day dose group. Statistically significant increases of placental weight in all TBTC1-treated groups were observed when compared to that of control group. In conclusion, TBTC1 administered orally to Wistar rats during days 7–15 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity and induced a marked increase in placental weight.