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PubMed1996

[Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (I)--Fertility study in rats by oral administration].

S-1 is a newly developed antineoplastic agent consisting of the mixture of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. As part of a reproductive and developmental toxicity study of S-1, a fertility study was carried out in Sprague-Dawley rats. Twenty-four male rats were administered S-1 orally starting at 64 days before mating and 24 female rats were administered S-1 orally from 15 days before mating to day 7 of pregnancy at doses of 0, 1, 4, or 7 mg/kg/day (as a dose of FT) in order to investigate the effect of S-1 on the reproductive ability and development of embryos and fetuses. There were no dose-related changes in clinical signs. Body weight gains and food consumption were decreased and were associated with the decreased weights of thymus, testis and epididymis in male rats receiving S-1 at the 7 mg/kg/day group. In females, the only organ affected was the kidney at 7 mg/kg/day. There were no dose-related changes in copulation, fertility, pre-implantation loss and implantation. Decreases in live fetal body weight and retardation of fetal ossification were observed in the 7 mg/kg/day group. There were no dose-related changes in post-implantation loss, and no fetal malformations were observed. The results suggest that the non-observed effects dose level of S-1 for general toxicity in male and female rats in 4 mg/kg/day, for reproductive toxicity in adults is more than 7 mg/kg/day, and for developmental toxicity in utero is 4 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1994

The developmental toxicity of boric acid in mice, rats, and rabbits.

Boric acid (BA) is a naturally occurring agent used in manufacturing processes and numerous consumer products. Because of the potential for both industrial and consumer exposure to boron-containing compounds, and the lack of developmental toxicity data, the National Toxicology Program evaluated the potential for boric acid to cause developmental toxicity in pregnant Swiss (CD-1) mice, Sprague-Dawley rats (n = 26-28/group), and New Zealand rabbits (n = 18-23/group). BA was provided in the feed to mice and rats at 0, 0.1, 0.2, or 0.4% throughout gestation to attain steady-state exposure as early as possible during development. Average doses (mg/kg/day) were 248, 452, or 1003 for mice, and 78, 163, or 330 in rats. A separate group of rats received 0.8% BA in the feed, or 539 mg/kg/day only on gestation days (gd) 6 to 15. Rabbits were given BA (0, 62.5, 125, or 250 mg/kg) by gavage administration on gd 6 to 19. Maternal body weight, food and/or water consumption and signs of toxicity were monitored at regular intervals. At termination, gd 17 (mice), 20 (rats), or 30 (rabbits), the uterus was examined to determine the number of resorptions, dead, or live fetuses. Fetuses were weighed and live fetuses were examined for external, visceral, and skeletal defects. Mouse dams exhibited mild renal lesions (> or = 248 mg/kg/day BA), increased water intake and relative kidney weight (1003 mg/kg/day BA), and decreased weight gain during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1994

Developmental toxicity of cesium in the mouse.

1. Maternal intake of 1 mEq CsCl in drinking water at conception until weaning the offspring mice resulted in certain maternal mediated neonatal and developmental toxicity. 2. Initial reduction in body and brain weights were determined in male offspring due to maternal exposure to Cs salt before they attained the control levels. 3. Offspring from both sexes showed increased spleen weight from control as a consequence of maternal exposure to Cs. This may precipitate delayed immunotoxicity. 4. Maternal Cs exposure did not alter litter size or specific activities of offspring heart lactate dehydrogenase isoenzymes from respective controls. 5. Maternal exposure to Cs altered specific activities of offspring liver alcohol- and aldehyde dehydrogenase during development compared to controls. 6. The results indicate neonatal and developmental toxicity of Cs as a function of maternal intake of CsCl during pregnancy and breast feeding.

Alcohol Dehydrogenase↗
PubMed1992

The developmental toxicity of diethylene and triethylene glycol dimethyl ethers in rabbits.

Diethylene glycol dimethyl ether (diEGdiME) and triethylene glycol dimethyl ether (triEGdiME), widely used organic solvents, are structurally related to several compounds that produce reproductive and developmental toxicity, including teratogenicity in laboratory animals. In the present studies, diEGdiME (0, 25, 50, 100, or 175 mg/kg/day) or triEGdiME (0, 75, 125, 175, or 250 mg/kg/day) were administered by gavage in distilled water to timed-pregnant New Zealand white rabbits (15-25 dams/group) during major organogenesis [Gestational Days (gd) 6-19]. Treated females were euthanized on gd 30, uterine contents were examined, and live fetuses were examined for morphological alterations. In the diEGdiMe study, evidence of maternal toxicity, per se, was observed only at 175 mg/kg/day with 15% mortality among treated females compared to 4% among controls. No significant maternal toxicity was observed in the 25 mg/kg/day group, and only minimal maternal toxicity (decreased maternal weight gain during treatment) was observed at 50 and 100 mg/kg/day compared to the vehicle control group. The no-observed-adverse-effect level for developmental toxicity in rabbits for diEGdiME was 50 mg/kg/day. The incidences of prenatal mortality and malformed live fetuses were significantly above controls at 100 and 175 mg/kg/day. Malformations observed most frequently included fusion of ribs to each other and hydronephrosis; clubbing of the limbs without underlying bone deformities, a variation, was also observed. In the triEGdiME study, clinical signs of toxicity were minimal and there was no increased maternal mortality. Maternal body weight and gravid uterine weight were significantly reduced at 250 mg/kg/day, whereas maternal weight gain during treatment was significantly depressed at doses of 175 mg/kg/day and above.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Vitamin E supplementation in phenytoin induced developmental toxicity in rats: postnatal study.

OBJECTIVES: The aim of this study was to test the effect of supranutritional dosage of the natural antioxidant vitamin E (VitE) on phenytoin (PHT) induced developmental toxicity and possible long-term effects in rat offspring. METHODS: PHT (150 mg/kg) was administered by oral gavage daily from day 7 to 18 of gestation and VitE prior to PHT orally on the same days. RESULTS: PHT administration alone resulted in decreased survival rate and lower body weight of pups on day 21 post partum (PP). Moreover, PHT slightly changed somatic growth and pups failed to present dynamic air righting on days 15-20 PP. VitE supplementation did not alleviate these changes but rather induced persisting body weight reduction on the days 21 PP and 100 PP. We observed also decreased brain wet weight in the PHT and VitE + PHT groups compared to controls. CONCLUSIONS: We concluded that prenatal supplementation with 500 mg/kg of VitE did not ameliorate the developmental toxicity of PHT and failed to protect postnatal development of rat offspring. Further, in the group supplemented with VitE, the occurrence of persistent body weight gain depression up to adulthood indicates its possible interference with somatic growth regulation.

Animals↗
PubMedDate not supplied

Vanadium: a review of the reproductive and developmental toxicity.

While the essentiality of vanadium for living organisms has yet to be established with certainty, vanadium has become an increasingly important environmental metal. Moreover, in recent years pharmacological interest in vanadium has also increased because of the hypothetical utilization of oral vanadium as an alternative therapy to parenteral insulin in diabetic patients. Adverse effects of vanadium depend on the circulating levels of this element. Among those effects, it is now well established that vanadate (V+5) and vanadyl (V+4) may be reproductive and developmental toxicants in mammals. Decreased fertility, embryolethality, fetotoxicity, and teratogenicity have been reported to occur in rats, mice, and hamsters following vanadium exposure. The reproductive vanadium toxicity, the maternal and embryo/fetal toxicity of this trace element, the perinatal and postnatal effects of vanadium, as well as the prevention by chelating agents of vanadium-induced developmental toxicity are reviewed here. The developmental effects of vanadium in pregnant diabetic rats are also summarized.

Animals↗
PubMed2000

Comparative developmental toxicity study of indium in rats and mice.

The developmental toxicity of indium was examined in both rats and mice using comparable experimental protocols. Pregnant rats received a single intravenous administration of indium trichloride (InCl(3)) at 0.4 mg In/kg, on day 9, 10, or 11 of pregnancy and their fetuses were examined on day 20. Pregnant mice were treated in the same manner at 0.8 or 1.6 mg In/kg on day 7, 8, or 9 of pregnancy and their fetuses were examined on day 18. In rats, indium caused fetal weight decrease and fetal gross malformations, such as brachyury, kinked tail, cleft palate, and oligodactyly, most severely by the administration on day 10. In mice, however, indium did not cause fetal gross malformations, although it caused fetal weight decrease at 0.8 mg In/kg or more and fetal death at 1.6 mg In/kg, most severely by the administration on day 8. It was concluded from these results that rats and mice were susceptible to the embryotoxicity of indium at similar developmental stages in the early organogenetic period, but mice were less susceptible to the teratogenicity of indium than rats in terms of gross malformation. Toxicokinetic factors may be involved in this different susceptibility. Teratogenesis Carcinog. Mutagen. 20:219-227, 2000.

Abnormalities, Drug-Induced↗
PubMed1986

Health assessment of exposure to developmental toxicants.

The U.S. EPA has taken an important step in developing these guidelines, the first of their kind. They more precisely delineate the hazard identification process and the factors important in supporting risk decisions for developmental toxicants than does any other document. Unfortunately, however, more precise estimates of risk are hampered by our lack of understanding of a number of factors, including the biological mechanisms underlying developmental toxicity, intra/interspecies differences, the influence of maternal effects on the dose-response curve, the likelihood of thresholds for certain of these end points, and the appropriate quantitative models for dose-response data and for low-dose extrapolation. To this extent, the Agency is supporting and conducting a number of investigations which will hopefully further our knowledge and improve our ability to assess risks for the developing human. The guidelines will be updated as such information becomes available.

Animals↗
PubMed1993

Phase-specific developmental toxicity in mice following maternal methanol inhalation.

Methanol is toxic to embryos of mice and rats when inhaled by dams at high concentrations. The present studies examined methanol-induced developmental toxicity following inhalation exposure (6 hr/day) of pregnant CD-1 mice to 5000, 10,000 or 15,000 ppm either throughout organogenesis (GD 6-15), during the period of neural tube development and closure (GD 7-9), or during a time of potential neural tube reopening (GD 9-11). Transient neurologic signs and reduced body weights were observed in up to 20% of dams exposed to 15,000 ppm. Examination of near-term fetuses revealed embryotoxicity (increased resorptions, reduced fetal weights, and/or fetal malformations) at 10,000 and 15,000 ppm, while 3-day exposures at 5000 ppm yielded no observable adverse effects. Terata included neural and ocular defects, cleft palate, hydronephrosis, deformed tails, and limb (paw and digit) anomalies. Neural tube defects and ocular lesions occurred after methanol inhalation between GD 7-9, while limb anomalies were induced only during GD 9-11; cleft palate and hydronephrosis were observed after exposure during either period. These findings were consistent with prior reports that maternal methanol inhalation at high levels induces developmental toxicity in a concentration-dependent manner. Furthermore, our data indicate that the spectrum of teratogenic effects depended upon both the timing (i.e., stage of embryonic development) and the number of methanol exposures.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat.

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.

Abnormalities, Drug-Induced↗
PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (2). Teratogenicity study in rats by oral administration].

A study of teratogenicity and developmental toxicity of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats. Female rats were given NS-21 orally at dose levels of 0 (control), 2, 25 and 300 mg/kg from day 7 to day 17 of pregnancy. Twenty-two female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the remaining pregnant rats (twenty-three per dose level) were allowed to deliver naturally for postnatal examination of their offspring. At the 300 mg/kg dosage level, rales, partially closed eyes and reduced activity were observed in pregnant rats. Decreases in body weight gain, food consumption and water consumption were observed in the dams at the 300 mg/kg dosage level. Fetal body weights were decreased at the 300 mg/kg dosage level. The drug never altered the numbers of corpora lutea and implantations, fetal mortality, the number of live fetuses, sex ratio, placental weight, and external, visceral and skeletal development of fetuses. NS-21 did not affect the delivery of dams, the number of live newborns, birth index, body weight or survival index. Nor did NS-21 have any adverse effect on the postnatal development of the offspring, including physical and functional development, emotionality, motor activity, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity in mother animals. 300 mg/kg for reproductive function in mother animal and 25 mg/kg for developmental toxicity.

Administration, Oral↗
PubMed2006

Developmental toxic effects of chronic exposure to high doses of iodine in the mouse.

Chronic exposure to high doses of iodine induces thyroid dysfunction, but effects of chronic exposure to high amounts of iodine on pregnancy and fetal outcome are uncertain. In the present study, Balb/C mice were given different doses of iodine at the levels of 0 (sterile water), 1,500, 3,000, 6,000, 12,000 and 24,000 micro g/L in drinking water for 4 months, then were mated and the developmental toxicity and teratogenicity were evaluated. An obvious colloid goiter was observed, and serum total thyroxine (TT4) levels increased and serum total triiodothyronine (TT3) levels decreased significantly in dams when iodine dose reached 3,000 micro g/L. Maternal effect was evident by the reduction of average daily food consumption in higher doses of iodine groups. Embryotoxicity and teratogenicity were mainly indicated by the reduced body weight in female fetuses, the decreased number of live fetuses, and the increased incidence of resorptions, and especially skeletal variations. These results suggest that exposure to maternally toxic doses of iodine may have a potential developmental toxic effect.

Animals↗
PubMed1992

Developmental toxicity evaluation of inhaled citral in Sprague-Dawley rats.

Citral is a commonly used fragrance and flavour ingredient that has demonstrated a potential for teratogenicity in chick embryo screening studies. To investigate potential mammalian developmental toxicity, pregnant Sprague-Dawley rats were exposed to citral by inhalation for 6 hr/day on gestation days 6-15 at mean concentrations of 0, 10 or 34 ppm as vapour, or 68 ppm as an aerosol/vapour mixture. Dams were killed on gestation day 20 and the foetuses were removed and evaluated for gross, visceral and skeletal malformations. Exposure to 68 ppm was maternally toxic, with reduced body-weight gains, ocular opacity, breathing difficulty, nasal discharge and salivation noted in the dams. No maternal toxicity was seen at the lower vapour exposure levels. The number of corpora lutea, implantations, resorptions, foetal viability, litter size, and sex ratio were not adversely affected by citral at any exposure level tested, and no exposure-related malformations were observed. At a maternally toxic exposure level, a slight reduction in mean foetal body weight and a slight increase in the incidence of hypoplastic bones were noted. Results of this study indicate that citral does not produce developmental toxicity in the rat when administered by inhalation at concentrations up to a maternally toxic exposure level.

Abnormalities, Drug-Induced↗
PubMed1992

Developmental toxicity of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). I. Multireplicated dose-response studies in four inbred strains and one outbred stock of mice.

A large-scaled multireplicated developmental toxicity study was conducted in various strains/stocks of mice with the herbicide, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), by gavage on Gestational Days 6 through 14. The most important attributes of the study design were replicated test groups, a minimum of four dose levels per replicate, use of multiple stocks/strains of animals to obtain an estimate of the range in sensitivities due to genotype, complete pathological evaluation of maternal animals, and histopathological as well as teratological evaluation of the fetuses. Developmental toxicity was observed at doses below those producing discernible or measurable maternal toxicity. Regression and/or probit analyses were conducted to determine whether a dose-response relationship existed. Reduced fetal weight and increased incidence of cleft palate and embryolethality were the most significant prenatal effects of 2,4,5-T exposure observed in this study. Each strain/stock exhibited a dose-related decrease in fetal weight with the CD-1 mice having the steepest slope and the A/J mice having the shallowest slope. There was a striking similarity among the slopes of the dose-response curves for the various strains/stocks. The mean incidence of embryolethality in the A/J strain was significantly greater than that of the other strains or stocks. There was substantial variation among replicates within strains. The use of the replicated study design was logistically necessary due to the magnitude of the study and it also served to increase the statistical power of the study.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1987

Teratogenicity and developmental toxicity of valproic acid in rats.

The teratogenicity and developmental toxicity of valproic acid (VPA) was investigated in Sprague-Dawley CD rats at doses of 0, 150, 200, 300, 400, and 600 mg/kg administered by gavage on days 7-18 of gestation. The VPA-600 dose was maternally toxic, causing death in two of four dams. This dose produced 100% embryonic resorption. The VPA-400 dose was maternally toxic in as much as maternal weight gain was reduced, but no deaths occurred. At this dose five of fifteen litters were completely resorbed, and 52% of all embryos were resorbed. Among survivors, 49% were malformed (68% having skeletal defects and 41% visceral defects). Fetal weight was reduced by 43% in this group. Most of the defects were ectrodactyly, hydronephrosis, cardiovascular defects, hypoplastic bladder, rib and vertebral defects, and other defects of the limbs and tail. The VPA-300 dose (nine litters) produced fewer defects, larger fetuses, and no increase in resorptions. The defects at this dose were primarily cariovascular, rib, and vertebral. The VPA-200 dose (12 litters) produced no reduction in fetal weight, no increase in resorptions, and few defects. The defects noted were hydronephrosis, cardiovascular abnormalities, and rib defects, primarily wavy ribs. Additional litters were prepared using doses of 150 and 200 mg/kg and were allowed to deliver and grow until 70 days. These doses produced no reduction in maternal weight gain, no reduction in litter size, birth weight, or sex ratio of the offspring. These doses produced no reduction in offspring weight to day 70, no increase in mortality, and only rare cases (two offspring of each dose) of tail defects.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1992

The developmental toxicity of 2-ethylhexanoic acid in Wistar rats.

The developmental toxicity of 2-ethylhexanoic acid (2-EHA), a wood preservative and a mammalian metabolite of di-(2-ethylhexyl) phthalate was examined in Wistar rats (20-21 pregnant females/dose). Mated animals were exposed to 2-EHA in their drinking water at doses of 100, 300, or 600 mg/kg/day on Days 6-19 of gestation. Control animals received vehicle water. The fetuses were examined (on Gestational Day 20) for external, visceral, and skeletal malformations and variations. 2-EHA was marginally toxic to the dams at 600 mg/kg, but not at lower doses, since the mean near term body weight was reduced by 11%. This dose level was also slightly fetotoxic as indicated by a 5 to 8% decrease in the mean fetal body weight both in males and females. No treatment-related effects were observed in the number of implantations or live fetuses. At doses of 100 mg/kg and above, 2-EHA caused skeletal malformations (clubfoot, absence of fibula, polydactyly), while the development of visceral tissues was less affected. The number of affected fetuses increased in a dose-dependent way (4.9, 8.9, and 15.3% of treated offspring at 100, 300, and 600 mg/kg/day, respectively, vs 2.4% control). These results indicate that 2-EHA is teratogenic in rats already at doses which are not yet maternally toxic. The skeleton appears to be the main target of 2-EHA in developing rats.

Abnormalities, Drug-Induced↗
PubMed1990

Developmental toxicity potential of grayanotoxin I in mice and chicks.

Developmental toxicity potential of grayanotoxin I (GTX I), a toxic diterpenoid contained in plants of the family Ericaceae, with sodium ionophore activity, was studied in mice and chicks. In mice, intraperitoneal injections of 1.5 mg GTX I/kg body weight of mouse for three consecutive days during the organogenetic period caused some dams to die, but neither embryotoxicity nor teratogenicity was detected. In chicks, a single injection of 0.1-1.0 microgram GTX I per egg into the extraembryonic coelom on day 1.5 or 2 of incubation, or into the amnionic cavity on day 3 or 4 of incubation induced neither embryotoxic nor teratogenic signs, but 10 micrograms GTX I per egg showed lethal effects when applied on each of those days.

Animals↗
PubMed2000

[Studies on the mechanisms of developmental toxicity of alcohol].

OBJECTIVE: To study the mechanisms of developmental toxicity in animals induced by ethyl alcohol. METHOD: Rat embryos of 9.5 days of gestation were exposed to different doses of ethyl alcohol in vitro. Postimplantation whole embryo culture and fluorescence polarization technique were used to investigate the effects of alcohol on embryo development and visceral yolk sac (VYS) membrane lipid fluidity. RESULT: 400 mg alcoho/L caused no significant differences to embryo development, organ morphological scores, polarization (Pr value) and lipid fluidity unit (LFU), as compared with the non-alcohol treated controls. 1,000 mg alcohol/L led to the decrease of scores of brain, VYS circle, neurotube, head length and heart, as well as DNA and Pr value; whereas LFU values were increased significantly. Above 2,000 mg alcohol/L, all indexes were decreased except LFU of VYS cell membrane. Alcohol significantly elevated lipid fluidity of VYS cell membrane. CONCLUSIONS: Alcohol causes development toxicity and teratogenisis in rats. Brain and VYS are the targets of alcohol effect. Its development toxicity is related with lipid fluidity and the VYS membrane damage.

Abnormalities, Multiple↗