A study on the effect of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic, on reproduction. III. Its effects on perinatal and postnatal rats

This paper describes effects of (2"R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) on perinatal and postnatal rats. The drug was administered intravenously to female rats at 0.01, 0.03 or 0.1 mg/kg daily from day 17 of pregnancy to 21 days after delivery. Results were described below. At any dose levels tested, THP did not affect the body weight gain, food and water consumption by pregnant rats, and length of gestation period or delivery rate. However, at the highest dose level, THP decreased spleen weight. THP, at any dose levels, did not have toxic effect on development, physiological functions, behavior, mating, fertility or pregnancy of the first generation offspring (F1). At the highest dose of 0.1 mg/kg, however, THP produced delayed ossification of sacrococcygeal vertebra in the second generation fetuses (F2). The results suggest that the maximum "no effect" dose of THP to pregnant rats and offsprings is 0.03 mg/kg/day intravenously.     

A study on the effect of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic, on reproduction. I. Its effect on the fertility of rats

The effect of a new antitumor antibiotic on the fertility was studied using SD rats. (2"R)-4'-O-Tetrahydropyranyladriamycin (THP) was administered to each rat at 0.01, 0.03 or 0.1 mg/kg daily. Males were given the drug intravenously for 63 days prior to mating and during the mating period; females were given the drug intravenously from 14 days prior to mating until day 7 of pregnancy. All the pregnant rats were sacrificed on day 20 of pregnancy, followed by external, visceral and skeletal observations of their fetuses. Results were summarized as follows. THP, at 0.1 mg/kg, suppressed body weight gain in females during the late period of pregnancy but did not affect body weight gain in males. THP, at 0.1 mg/kg, increased the numbers of dead fetuses and of resorptions. It caused no external, visceral or skeletal anomalies at any dose levels. The results suggest that, in rats, the maximum "no effect" dose of THP is 0.03 mg/kg/day intravenously regarding fertility and fetal development.     

Effect of isepamicin (HAPA-B) on reproduction. II. Teratological study in rats (intramuscular administration)

Teratological study of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was performed in Jcl: Wistar rat. The drug was given intramuscularly to dams at doses of 25, 100 and 200 mg/kg from day 7 to 17 after mating. The influence on dams, their fetuses and offspring was studied. A decrease in food intake and a development of pale color of the kidney of dams at a dose level of 200 mg/kg were observed in the prenatal study. The HAPA-B did not show any influence on prenatal development of fetuses. In the postnatal study, no effect of HAPA-B on parturition and lactation of dams was seen except that a discoloration of the kidney was observed at autopsy. However, some differences were observed between the control and treatment groups in postnatal development, behavior and reproduction performance of offspring. Dose-response effects of HAPA-B on offspring were not observed in the postnatal study. No effect dose levels of HAPA-B established in this study on rat fetuses and offspring were 200 mg/kg and 100 mg/kg on pregnant rat, respectively.     

Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits

Exemestane is an orally active, irreversible inactivator of aromatase, structurally related to the natural substrate androstenedione, in clinical use at 25 mg daily for the treatment of advanced breast cancer in postmenopausal women. The reproductive and developmental toxicity of exemestane was assessed in rats and rabbits with oral administration. Pivotal experiments included a fertility study (Segment I), in which female rats received exemestane doses of 4, 20, or 100 mg/kg/day from two weeks premating until GD 20 (cesarean-sectioned dams), or until GD 15 and then from D 1 to D 21 postpartum (dams allowed to deliver), and developmental toxicity studies (Segment II), in which rats and rabbits were treated from GD 6 through GD 17 (rats) or GD 18 (rabbits) at doses of 10, 50, 250, or 810 mg/kg/day and 30, 90, or 270 mg/kg/day, respectively. All rabbits and two-thirds of the rats were cesarean sectioned toward the end of pregnancy to determine litter parameters and examine structural abnormalities in the fetuses; the remaining one-third of the rats was allowed to litter and rear pups to weaning. No pivotal male fertility or peri- and postnatal studies were performed, taking into consideration the therapeutic use. Postnatal effects on the first generation offspring were assessed in both studies in rats, in the portion of dams allowed to deliver. Their F1 offspring were raised to adulthood, when they were evaluated for reproductive performance, and the F1 females were terminated on GD 20. The dosing schedule for the Segment I study in rats, which included a postnatal component, was established to exclude exposure before and during parturition (by withdrawing treatment from GD 16 until the end of parturition). This withdrawal of treatment was put in place because in a preliminary study with treatment including the peripartum period, doses from 5 to 200 mg/kg/day prolonged gestation and interfered with parturition.Overall, studies in rats showed that female fertility was not affected up to 100 mg/kg/day, but doses higher than 4 mg/kg/day, which is approximately the pharmacologically active dose (ED50 = 3.7 mg/kg), prolonged gestation and impaired parturition, leading to maternal deaths in labor and perinatal deaths of offspring. Rats killed on GD 20 showed nondose-related increases in resorptions at doses higher than 10 mg/kg/day, a reduction in fetal body weights at 20 and 100 mg/kg/day (fertility study) and 810 mg/kg/day (developmental toxicity study), and an increase in placental weights at all doses. Female fetuses exposed in utero until GD 20 at 100 mg/kg/day showed an increase in the anogenital distance, very likely related to an increase of the potent androgen DHT as a consequence of aromatase inhibition. Morphologic examinations in fetuses and born pups that were exposed in utero up to the end of the organogenesis period, as well as postnatal investigations on offspring up to adulthood, showed no treatment-related effects. In a developmental toxicity study in rabbits, treatment at 270 mg/kg/day affected maternal food intake and body weight gain, caused abortion or total resorption in about 30% of pregnant females, and reduced body weight and numbers of live fetuses, but did not affect fetal morphology. It was concluded that exemestane did not affect parturition in rats at 4 mg/kg/day or pregnancy in rabbits at 90 mg/kg/day (about 1.5 and 70 times the human dose, respectively, on a mg/m2 basis) and was not teratogenic in rats and rabbits.Exemestane is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women.     

Oral dosage study of miporamicin administered during the period of fetal organogenesis in rats

Experiments were conducted to assess the effects of miporamicin (MPM) on prenatal and postnatal development of fetuses and offsprings of rats receiving the compound at oral dosages of 40, 200, or 1,000 mg/kg/day during the organogenesis stage of gestation. The drug treatment had no appreciable effect on maternal body weight during pregnancy or lactation period. The rats showed decreased food intake and increased water intake during gestation period in the groups given greater than or equal to 200 mg/kg/day, and increased food and water intakes during lactation period in the group given 1,000 mg/kg/day. There was no macroscopic evidence of changes indicative of any effect of the treatment in the viscera of rat dams at terminal necropsy. Observation of the fetuses did not reveal any effect of the treatment with MPM with respect to the number of implantations, the number of living fetuses, the death rate of fetuses or incidence of external, visceral, or skeletal anomalies. Male fetal weights were low in the groups given greater than or equal to 200 mg/kg/day. Observation of the offspring post partum failed to disclose any abnormalities indicative of adverse effects of the treatment with respect to birth index, viability index, weaning index, postnatal external differentiation, body weight changes, external morphology, skeleton, viscera, organ weight, functional and behavioral tests, emotion, learning ability, or reproductive performance, or in respect of prenatal development of their fetuses (F2). It is concluded from the results that no effect dose levels of MPM was 40 mg/kg/day in rat dams, 40 mg/kg/day also for their fetuses, and 1,000 mg/kg/day for postnatal development of the offspring under the experimental conditions described.     

Peri- and postnatal developmental toxicity of the fluoroquinolone antibacterial DW-116 in rats.

DW-116 is a fluoroquinolone antibacterial developed by Dong-Wha Pharmaceutical Industry Co. The aim of this study is to determine the potential adverse effects of this chemical on pregnancy, delivery and lactation of dams and on peri- and postnatal development of F1 offspring. The test chemical was orally administered to pregnant rats from day 16 of pregnancy, through parturition and throughout the period of lactation up to weaning (postnatal day 21) at dose levels of 0, 10, 50, or 250 mg/kg/day. The progeny were examined at birth and subsequently to weaning. Mortality, body weight change, physical signs of postnatal development (pinna detachment, incisor eruption, fur development, eye opening, testis descent and vaginal opening) and behavioral function (righting reflex, negative geotaxis, grip-strength, pupillary reflex, acoustic startle response, rotating rod test, open field test and water-filled T-maze test) were evaluated. When the exposed offspring reached maturity (11 weeks old) their reproductive capacity was assessed. Maternal toxicity was observed only in the highest dose group and was limited to decreased food consumption during the late stage of pregnancy. However, this change was not observed during the lactation period. There were no adverse effects on mortality, clinical signs, body weight, necropsy findings, organ weight of dams in any treatment group. No adverse effects on the offspring were seen with the low and middle doses tested, but the highest dose increased postnatal mortality. The number of stillborn was also increased at the highest dose but the difference was not statistically significant. Meanwhile, no treatment-related effects were observed in clinical sign, developmental and behavioral landmarks and necropsy findings at any dose levels tested. There were no treatment-related effects on the mating of the F1 generation and resulting F2 offspring. The results of this study indicate that the peri- and postnatal administration of DW-116 to female rats results in an increase in postnatal mortality at a minimally maternotoxic dose, i.e., 250 mg/kg/day. Under the experimental conditions, the no-observed-adverse-effect level for peri- and postnatal developmental toxicity was considered to be 50 mg/kg/day.     

Reproductive and developmental toxicity studies of S-1090, cefmatilen hydrochloride hydrate (4)--A study on oral administration during the perinatal and lactation periods in rats

Cefmatilen hydrochloride hydrate (S-1090) was administered daily by gavage to female rats at doses of 100, 300 or 1000 mg potency/kg/day from Day 17 of pregnancy to Day 20 of lactation to assess its effects on pregnant/lactating females and on development of the offspring. In dams, loose feces/reddish brown feces, increased cecum weight, decreased weights of the heart, spleen and submaxillary gland in all the S-1090 dosing groups and a decreased weight of the thymus in the 1000 mg potency/kg dosing group were observed. However, no effects on parturition and lactation were observed in any of the dosing groups. In F1 offspring, although increased cecum weight was found at weaning in all the S-1090 dosing groups, no abnormalities in viability, physical development, sensory functions/reflexes, behavior and reproductive function were observed. No adverse effects were observed in F2 fetuses and offspring. On the basis of these results, the no observed adverse effect levels of S-1090 are estimated to be less than 100 mg potency/kg/day for maternal general toxicity, and 1000 mg potency/kg/day for maternal reproductive toxicity and for developmental and reproductive toxicity in offspring under the conditions of the present study.     

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.     

Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. II: Perinatal and postnatal exposure

Pergolide mesylate is a dopamine agonist and, therefore, reduces prolactin secretion. In Experiment I, pregnant mice were given oral doses of 0, 0.1, 0.3, 1.0 or 3.0 mg/kg/day pergolide on GD 15 through PD 10 or 20 to identify a tolerated dose which would not markedly reduce offspring survival during late gestational and lactational exposure. Offspring survival was not affected at any dose, but dose-related decreases in progeny body weights occurred at weaning. On PD 10, suckling-induced increases in maternal serum prolactin concentrations did not occur in dams treated with 3.0 mg/kg/day. In Experiment II, pregnant mice were given oral doses of 0, 0.002, 0.1 or 3.0 mg/kg/day pergolide on GD 15 through PD 20. Dams were allowed to deliver and maintain their offspring throughout a 21-day lactation period. Growth and behavioral performance of one F1 male and one F1 female per litter were monitored, followed by a reproduction trial and terminal organ weight measurements. There were no treatment-related effects on maternal body weights, food consumption, or terminal organ weights and pathology. Three dams showed overt signs of mammary inflammation and lactational insufficiency and mean progeny survival was decreased slightly in the 3.0 mg/kg/day group. There were no adverse effects on growth, development or reproductive performance in the F1 treatment-derived generation. Neonatal negative geotaxis, 1-h activity levels at 30 and 60 days of age, auditory startle habituation at 55 days of age, and two-way active avoidance performance at 65 days of age were not affected significantly by treatment. Thus doses of pergolide that did not inhibit lactation completely in the F0 dams were found to have no enduring effects on offspring development.     

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.     

Teratological assessment of the antiprotozoal, diminazene diaceturate, in rats

Diminazene diaceturate was dissolved in deionized water and administered to pregnant rats by oral gavage once daily on days 8-15 of pregnancy at dose levels of 0, 100, 250, 500 and 1000 mg/kg. On day 21 of pregnancy, the dams were killed and the number of implants, resorptions and live fetuses counted. All fetuses were examined by routine teratological method. A significant increase in fetal resorptions and decrease in fetal body weights were found at the 1000 mg/kg dose. No significant increase in the incidence of anomalous fetuses was observed in external, skeletal and internal examinations even at the maternally toxic dose of 1000 mg/kg. Thus, these data indicate that diminazene diaceturate is not teratogenic in rats.     

Susceptible period for the teratogenicity of di-n-butyltin dichloride in rats.

Pregnant rats were given di-n-butyltin dichloride (DBT) by gastric intubation at a dose of 20 mg/kg on days 7-9, 10-12 or 13-15 of pregnancy or at a dose of 20 or 40 mg/kg on day 6, 7, 8 or 9 of pregnancy. While treatment with DBT on days 7-9 was significantly and highly teratogenic, no evidence of teratogenicity was detected when DBT was given on days 10-12 or 13-15. Treatment on day 7 or 8 with both doses of DBT, but neither on day 6 or 9, resulted in an increased incidence of fetuses with malformations. The highest incidence of malformed fetuses occurred after treatment on day 8. The incidence of malformed fetuses was proportional to the dose of DBT. Anomaly of tail, anal atresia, club foot, omphalocele, deformity of the vertebral column, defect of the ribs and anophthalmia or microphthalmia were predominantly observed. It could be concluded that, following maternal exposure to DBT in rats, developing offspring are not susceptible to teratogenic effects of DBT on day 6 and that day 7 is the earliest susceptible period, day 8 is the highest susceptible period and day 9 is no longer a susceptible period for teratogenesis of DBT.     

Reproductive toxic effects of Tityus serrulatus scorpion venom in rats

Tityus serrulatus is the most venomous scorpion in Brazil. Little is known about the effect of maternal exposure to the venom on fetal development. We investigated the effect of low to moderate doses of the venom (0.3 or 1.0 mg/kg s.c. on either day 5 or day 10 of gestation) on pregnant rats and on their offspring. For dams, we observed their body weight gain and reproductive parameters. For the offspring, we observed their body weight and weight of internal organs and the number of live and dead fetuses, and we investigated whether the venom caused external, visceral, skeletal or histopathological alterations in the offspring. The offspring were examined on gestational day 21. Injection of the venom on gestational day 5 did not change the reproductive parameters of the dams, their weight or fetuses' weight. Rats that received the high dose of the venom (1.0 mg/kg) on gestational day 10 had heavier placentas and heavier fetuses with heavier lungs. Injections on day 10 of gestation did not alter the reproductive parameters of the dams nor their weight gain at either dose. The venom did not cause malformations of the fetal skeleton or viscera and did not delay fetal development with either dose. In conclusion, subcutaneous administration of 0.3 or 1.0 mg/kg T. serrulatus venom to pregnant Wistar rats at either day 5 or day 10 of gestation did not cause maternal or clear fetal toxicity. Subtle increases in placental weight and fetal body and lung weights observed following treatment with 1.0 mg/kg on day 10 of gestation were not associated with histopathological findings. Whether these observations represent a reaction to treatment and, if so, the underlying mechanisms and their toxicological impact remain to be examined further in future studies.     

Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study.

Testosterone plays a major role in male sexual development. Exposure of females to testosterone in utero can induce masculine characteristics such as anovulation, increased anogenital distance (AGD), absence of nipples, retention of male-like tissues, and agenesis of the lower vagina. In addition, high levels of androgens during fetal development can lead to toxic effects such as reduced litter size and viability. The study of the effects of testosterone administration during sexual differentiation provides a foundation for understanding the effects of environmental androgens on fetuses, a sensitive subpopulation. In the current study, we investigated the ability of a range of concentrations of testosterone propionate (TP) administered prenatally to masculinize female and alter male offspring, and measured maternal and fetal T levels. Pregnant Sprague-Dawley rats were dosed by sc injection on gestational day (GD) 14-19 (GD 1= day of plug) with either corn oil (vehicle; 0.1 ml/rat) or with 0.1 ml of TP solution at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml. Parturition was delayed at 2, 5, and 10 mg TP, litter size was reduced at 5 and 10 mg TP, and pup weight was significantly reduced in both sexes at 0.5 mg TP and higher doses. Viability of offspring was unaffected at any dosage level. Androgenic effects seen at 0.5 mg TP in females included increased AGD at weaning and adulthood, reduced number of areolas and nipples, cleft phallus, small vaginal orifice, and presence of prostate tissue. This dose of TP elevated maternal T levels 10x but had no effect on fetal T levels. At 1 mg TP and above, female AGD on postnatal day (PND) 2 (or postcoital day 24 [gestation length = 22(1/2)]) was increased; areolas and nipples were virtually eliminated; levator ani muscle, bulbourethral glands, and seminal vesicles (2 mg TP and above) were present; none of the females developed a vaginal orifice and many females in the 1 and 2 mg TP dose groups developed a greatly distended, fluid-filled uterus after puberty. Maternal T levels at 1 mg TP were elevated 30x, and female fetal T levels showed an 80% increase. Male offspring displayed a reduced AGD and body weight on PND 2 at 0.5 mg TP and higher doses. These effects were not evident by weaning and male offspring displayed no malformations. We conclude that gestational administration of 0.5 and 1 mg TP masculinizes female offspring without greatly affecting pup viability or pregnancy of the dam. This study provides a useful model for in utero testing of environmental androgens for their potential to induce developmental abnormalities.     

Reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone,a new anticonvulsant and hypnotic drug,in mice. Fertility and peri- and post-natal studies

The reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone (EPBL, CAS 53380-21-5), a new anticonvulsant and hypnotic drug, was investigated by performing fertility and peri- and post-natal studies in mice. In both studies, EPBL was administered by gavage at 0, 50, 10, or 200 mg/kg doses. The first study found parent toxicity as measured by reduced body weight at the higher dose. At the same dose, the number of live fetuses was decreased. However, neither male or female fertility nor the reproductive performance of mice were affected. The results of the second study showed that the only negative effects were a depression of maternal weight gain and a decrease in body weight of the litter at birth which was 200 mg/kg. A reduction in the survival rate was also seen. There was no evidence that treatment of F0 females from day 15 of pregnancy to day 21 post-partum affected either the reproductive capacity of the F1 offspring or the development of F2 progenies. The non observed effects levels (NOEL) for both studies can be estimated at 100 mg/kg.     

Prenatal developmental toxicity study of ethyl tertiary-butyl ether in rabbits

Ethyl tertiary-butyl ether (ETBE) is commonly used as an oxygenated gasoline additive. In this study, the prenatal developmental toxicity of ETBE was determined in rabbits. New Zealand white rabbits were given ETBE by gavage at 100, 300, or 1,000 mg/kg/day on gestational days (GDs) 6-27, and the pregnancy outcome was determined on GD 28. Neither death nor abortion occurred in the pregnant rabbits at any dose. Slightly and significantly suppressed maternal body-weight gain and transiently decreased maternal food consumption were found at 1,000 mg/kg/day during the administration period. At this dose, no changes in clinical or macroscopic finding were noted in dams. No treatment-related changes were observed in any dam treated at 300 mg/kg/day or less. There was no significant effect of ETBE on the numbers of corpora lutea, implantations, live fetuses, resorptions and dead fetuses, incidences of pre- and postimplantation loss, viability of fetuses, fetal body weight, sex ratio of fetuses, or weights of gravid uteri. No significant difference was detected in the incidences of fetuses with malformations or variations between the ETBE-treated and control groups. Also, no adverse effects on the progress of ossification were noted in fetuses of dams given ETBE. Based on these findings, it is concluded that the no observed adverse effect levels of ETBE were 300 mg/kg/day for dams and 1,000 mg/kg/day for fetuses in rabbits.     

Teratology study of Tween 60 in rats

The teratogenicity of Tween 60 was studied in Wistar rats. Pregnant rats were given Tween 60 at a dose of 0, 0.1, 1.0 or 10% in the diet from day 7 to day 14 of pregnancy. Daily intakes of Tween 60 were 99 mg/kg for the 0.1% group, 960 mg/kg for the 1.0% group and 7693 mg/kg for the 10% group. No change induced by Tween 60 was detected in the number, sex ratio and body weight of live fetuses. External, skeletal and internal examinations of the fetuses revealed no evidence of teratogenesis. It could be concluded that Tween 60 has no harmful effects on the prenatal development of the rat offspring at doses employed in the present study.     

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.     

Effects on growth of rat offspring born from dams treated subcutaneously with a surfactant, polyoxyethylene(10)nonylphenyl ether(NP-10), during lactational period

A surfactant NP-10 was administered subcutaneously to Jcl:Wistar female rats at dose levels of 5, 20 and 80 mg/kg/day from date of birth to day 21 after birth of F1 offspring to assess its effects on the growth, behavior and functions of the offspring. For F0 dams, scab formation and loss of hair at the test substance administration site were observed in all treatment groups and induration of the skin at the test substance administration site in the 20 and 80 mg/kg groups in general condition and necropsy findings at the end of the dosing period. In necropsy findings, in addition to these changes, hemorrhage and whitish change of the subcutis at the test substance administration site were seen in all treatment groups, adhesion to the somatic muscles and granulation of the subcutis at the test substance administration site in the 20 and 80 mg/kg groups, and swelling of the spleen and adrenals in the 80 mg/kg group. Reduction or a tendency for reduction in food consumption was also detected from the initial day of dosing (day 0) to day 17 after birth F1 offspring in the 80 mg/kg group. Body weight or the findings on the day after birth and day of weaning failed to reveal any evidence of an effect that could be ascribed to the test substance. In F1 born offspring, a decrease or tendency for decrease in body weight was observed from day 7 after birth in both sexes and for females during the gestation period in the 80 mg/kg group. However, body weight gains based on the weights at 4 weeks after birth or on day 0 of gestation in the 80 mg/kg group failed to reveal any difference from that in the control group. The observation on the day of birth and during the period of lactation, physical development test, reflex test, general condition, open-field test, water-maze test, reproductive ability test, observations at cesarean section, necropsy findings, organ weights, histopathological findings of females or males that did not achieve successful gestation, skeletal examination, and the observations at cesarean section and external examination of F2 fetuses failed to reveal any evidence that could be ascribed to the test substance. These results indicate that NP-10 had no effect on the behavior or functions of the offspring, although it affected the growth of the offspring born, under the conditions of this study. The non-effective dose level is considered to be 20 mg/kg for general toxicity of the dams and for their offspring.     

The effects of perinatal exposure to nicotine on plasma LH levels in prepubertal rats

Adult female rats were chronically treated with nicotine administered via the drinking water during pregnancy and/or lactation. The approximate doses of nicotine consumed per day were 2.4 mg/kg and 4.5 mg/kg of body weight. The pups were weaned at 20 days of age. The pups were killed by decapitation on postnatal days 20, 30, or 40 and plasma from heparinized trunk blood was assayed for luteinizing hormone (LH). At 30 days of age untreated male and female offspring had the highest levels of plasma LH compared to 20 and 40 days of age. This level was not affected by any subsequent dose or treatment. Prepubertal females exposed to nicotine during pregnancy failed to exhibit the pattern of LH levels seen in control animals, whereas those exposed during lactation or throughout the perinatal period showed a distinctive pattern of plasma LH. Chronic exposure of female offspring to the low dose of nicotine during lactation tended to increase plasma LH levels at 20 and 40 days. Female offspring exposed to nicotine during pregnancy or to the low dose during lactation showed significant deficits in body weight at 40 days of age which appeared to correlate with a delay in vaginal opening. The results suggest that perinatal exposure to maternally administered nicotine may disrupt normal patterns of LH release in the offspring of both sexes and alter sexual development in female offspring.