Effects of thalidomide on developmental, peri- and postnatal function in female New Zealand white rabbits and offspring.

The present study determined effects of thalidomide on three successive generations of New Zealand White rabbits after oral dosing to F0 maternal rabbits during the later third of gestation (post major organogenesis) and lactation. One hundred and twenty four time-mated F0 rabbits (31/dose) were gavaged with 0, 30, 150, or 500 mg/kg thalidomide from gestation day 18 (DG 18) to lactation day 28 (DP or day postpartum 28) for approximately 42 days. At 6 months, 12 F1 males and 12 F1 females were randomly paired within each dose group and mated. Reproductive evaluation and/or gross necropsy of the thoracic, abdominal, and pelvic viscera was performed on day 29 postpartum (DP 29) for F0 rabbits, on DP 49 for F1 pups not selected for continued evaluation, after completion of mating for F1 rabbits, and on DG 29 for F1 rabbits on continued evaluation of F2 litter. There was no thalidomide-related mortality in F0 and F1 rabbits. One F0 doe at 30 and 150 mg/kg and 2 at 500 mg/kg aborted. Maternal F0 rabbits had reductions in feed consumption but not body weight gain during the gestation and lactation periods for 150 and 500 mg/kg. The numbers of does with stillborn and all pups dying from DP 1-4 was increased at 150 and 500 mg/kg. Mean number of liveborn (litter size) and percentage of live pups were decreased at 500 mg/kg. A significantly increased number of pups died at 150 and 500 mg/kg, resulting in a reduced viability index and decreased litter size. There were some F1 male and female body weight reductions at 150 and 500 mg/kg postweaning with no change in feed consumption. F1 Caesarean-sectioning and litter observations were normal. Fertility of F1 offspring was not affected by maternal doses of thalidomide, but the pregnancy index may have been reduced by the 500 mg/kg maternal thalidomide dose. There was an apparent dose-related increase in splayed limbs in F1 pups. Splaying has been reported in New Zealand White rabbits and may be a recessive trait. The splay could be caused by the nerve and muscle fiber degeneration and skeletal muscle atrophy observed in some pups. It could also be due to the decrease in litter size, resulting in fewer pups per litter for nursing, leading to rapid weight gain and a failure of the pups to support this weight. No F2 fetal gross external alterations were observed. In summary, pregnant rabbits orally dosed with up to 500 mg/kg thalidomide from gestation day 18 to lactation day 28 had increased abortion, changes in some natural delivery and litter parameters, and limb splay in some F1 pups. No gross external changes were observed in F1 and F2 pups.     

Oral developmental toxicity study of methylsulfonylmethane in rats.

Methylsulfonylmethane (MSM) is a metabolite of dimethyl sulfoxide, and occurs naturally at low levels in many foods. MSM has received wide attention as a dietary supplement to promote joint health. The objective of these studies was to determine the developmental toxicity potential of MSM when administered orally to pregnant rats during the period of major organogenesis and histogenesis. In a preliminary dose-finding study, distilled MSM microprill (i.e., microspherical pellets of MSM) was administered by oral gavage at dose levels of 0 (vehicle control), 50, 250, 500, and 1000 mg/kg/day to 8-9 sperm-positive female Sprague-Dawley rats/group/day on gestation days 6-20. No evidence of maternal or fetal toxicity was observed. For the definitive developmental study, four groups of 24-25 timed-bred primiparous female rats were administered 0, 50, 500, or 1000 mg MSM/kg/day via gavage on gestation days 6-20. Maternal feed consumption, body weight, body weight gain, uterus weight and corrected body weight/body weight gain were unaffected by treatment. No evidence of maternal toxicity, and no significant differences in litter viability, litter size, or litter body weight were detected. Fetal evaluations failed to show any biologically significant increase in the incidence of anomalies in the MSM treated groups, and no malformations were seen in any of the fetuses. No evidence of fetal mortality, alterations to growth, or structural alterations were observed in the fetuses of dams administered 50-1000 mg/kg/day. Therefore, under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 1000 mg/kg/day.     

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

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

Vitamin A acetate: a behavioral teratology study in rats

We evaluated the effects of maternal administration of vitamin A acetate on pup development and behavior. Vitamin A acetate was administered by oral gavage to pregnant rats (N = 10/treatment) on gestation days 6-19 at doses of 25,000, 50,000 or 100,000 I.U./kg/day. Male and female pups from dams that received 100,000 I.U./kg/day showed a significantly reduced live birth index but few external abnormalities. Twenty-four and 48 hour survival indices were also significantly reduced. The mean pup body weight gain at 100,000 I.U./kg/day was significantly reduced at days 1-3, 3-7 and 21-42. Pinna detachment and eye opening were significantly delayed in all male pups and in female pups from the 50,000 and 100,000 I.U./kg/day groups. Incisor eruption was significantly delayed in male and female pups from the 25,000 and 50,000 I.U./kg/day groups. The following showed no treatment effects: dam mean weight change, length of gestation, total litter size, surface righting, cliff avoidance, negative geotaxis, swimming development, open field activity and discriminatory learning.     

Effects of the serotonin antagonist amesergide on reproduction in female rats

Amesergide, a serotonin (5-HT₂) antagonist intended to treat depression, was administered orally to female CD rats (20/group) at doses of 0, 3, 10, or 30 mg/kg to evaluate effects of mating, fertility, litter size, live birth index (100 × total liveborn progeny/litter size), progeny survival, and weight gain of each litter. The treatment period extended from two weeks prior to mating through postpartum day 21 to cover possible effects of estrons cycle, mating, gestation, and postpartum events. Twenty additional female rats were given 30 mg/kg through gestation day 18, after which they received the acacia vehicle (recovery group). All females were allowed to deliver naturally and rear their progeny. On postpartum day 8, progeny in the control, 30 mg/kg and 30 mg/kg recovery groups were removed from dams for 4 h. Progeny were weighed as litters, returned to the dams for a 1-h nursing period, and then weighed again to provide an indication of milk intake. Mating and fertility, using the present study design, were not affected by treatment with amesergide. No effects were observed on litter size, live birth index, or progeny survival. In contrast, treatment with amesergide throughout gestation and lactation produced a significant dose-related depression in progeny body weight gains. However, when treatment was discontinued after day 18 of gestation (30 mg/kg recovery group), progeny body weight gains did not differ from those of the control group. When weight gain of progeny following 1 h of nursing on postpartum day 8 was examined, the offspring of the 30 mg/kg group in which treatment was continued through lactation, exhibited a significantly lower weight gain than did those from controls or the 30 mg/kg recovery group. This difference occurred in the absence of an observable change in nursing behavior amoung treatment groups. In conclusion, treatment of maternal animals with amesergide produced a reduction in progeny body weight gains. This effect was only apparent when treatment of the females continued through lactation and appeared to be due, at least in part, to a reduction in milk consumption by the progeny suggesting an alteration in milk production of the females.     

Effects of deoxynivalenol (DON, vomitoxin) on in utero development in rats.

Deoxynivalenol (DON, vomitoxin), is one of the most common contaminants of cereal grains world-wide. The effects of DON on fetal development were assessed in Charles River Sprague-Dawley rats. Pregnant female rats were gavaged once daily with DON at doses of 0, 0.5, 1, 2.5, or 5 mg/kg body weight on gestation days (GD) 6-19. At cesarean section on GD 20, reproductive and developmental parameters were measured. All females survived to cesarean section. DON caused a dose-related increase in excessive salivation by the pregnant females, a reaction probably linked to the lack of emetic reflex in rats. At 5 mg/kg, feed consumption and mean body weight gain were significantly decreased throughout gestation, mean weight gain (carcass weight), and gravid uterine weight were significantly reduced, 52% of litters (12/23) were totally resorbed, the average number of early and late deaths per litter was significantly increased, average fetal body weight and crown-rump length were significantly decreased, the incidence of runts was significantly increased, and the ossification of fetal sternebrae, centra, dorsal arches, vertebrae, metatarsals, and metacarpals was significantly decreased. At 2.5 mg/kg, DON significantly decreased average fetal body weight, crown-rump length, and vertebral ossification. These effects may be secondary to maternal toxicity and the reduced size of the fetuses. The incidence of misaligned and fused sternebrae was significantly increased at 5.0 mg/kg. No adverse developmental effects were observed at 0.5 and 1.0 mg/kg. Dose-related increases in maternal liver weight-to-body weight ratios were observed in all treated groups (significant at 1, 2.5, and 5 mg/kg). The weight changes were correlated with dose-related cytoplasmic alterations of hepatocytes. The NOEL for maternal toxicity for this study is 0.5 mg/kg based on the dose-related increase in liver-body weight ratio at 1 mg/kg. The NOEL for fetal toxicity is 1 mg/kg based on the general reduction in fetal development at 2.5 and 5 mg/kg. DON is considered a teratogen at 5 mg/kg day in Sprague-Dawley rats based on the anomalous development of the sternebrae.     

Vitamin A Acetate : A Behavioral Teratology Study In Rats

ABSTRACT

We evaluated the effects of maternal administration of vitamin A acetate on pup development and behavior. Vitamin A acetate was administered by oral gavage to pregnant rats (N = 10/treatment) on gestation days 6–19 at doses of 25,000, 50,000 or 100,000 I.U./kg/day. Male and female pups from dams that received 100,000 I.U./kg/day showed a significantly reduced live birth index but few external abnormalities. Twenty-four and 48 hour survival indices were also significantly reduced. The mean pup body weight gain at 100,000 I.U./kg/day was significantly reduced at days 1–3, 3–7 and 21–42. Pinna detachment and eye opening were significantly delayed in all male pups and in female pups from the 50,000 and 100,000 I.U./kg/day groups. Incisor eruption was significantly delayed in male and female pups from the 25,000 and 50,000 I.U./kg/day groups. The following showed no treatment effects: dam mean weight change, length of gestation, total litter size, surface righting, cliff avoidance, negative geotaxis, swimming development, open field activity and discriminatory learning.     

Evaluation of the developmental toxicity of formamide in New Zealand white rabbits.

Naturally mated female New Zealand White (NZW) rabbits (24/group) received formamide (35, 70, or 140 mg/kg/day) or vehicle (1 ml/kg deionized/distilled water) by gavage on gestational days (GD) 6 through 29. The study was conducted using a 2-replicate design. Maternal food consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. One and four maternal deaths occurred at the low and high doses, respectively. Abortions or early deliveries were noted in 0, 2, 2, and 8 females in the 0, 35, 70, and 140-mg/kg/day dose groups, respectively. Other clinical signs associated with formamide exposure were minimal: primarily reduced or absent fecal output at the high dose (2-13 animals/day). Also at the high dose, maternal body weight was significantly depressed on GD 21, 24, and 27 (87-90% of the control value); maternal body weight gain was significantly reduced for GD 12 to 15, 18 to 21, and 21 to 24 (treated animals gained less than 1 g, or lost up to 100 g). In addition, maternal body weight gain was reduced at the middle dose for GD 18 to 21. Maternal body weight gain, corrected for gravid uterine weight, was unaffected. Relative maternal food consumption in the high-dose group was 34-59% of control intake from GD 12 through GD 24, but was comparable to controls thereafter. At termination (GD 30), confirmed-pregnant females (9-20 per group) were evaluated for clinical status, liver weights, and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal liver weight (absolute or relative to body weight) was unaffected by treatment, but gravid uterine weight at the high dose was 71% of the control value. A significantly increasing trend was noted for the percent non-live implants per litter. In addition, although not statistically significant from the control group, the values for the percent late fetal deaths per litter and percent non-live implants per litter in the 140-mg/kg/day group were higher than maximum historical values, suggesting an increase in late gestational deaths in the surviving high-dose animals. Formamide decreased the mean number of live fetuses per litter at the high dose to 66% of the control value. Mean fetal body weight per litter for males and the sexes combined was significantly decreased at the high dose; mean female fetal body weight was also decreased, although the difference did not reach statistical significance. There was no effect of treatment on the incidence of external, visceral, or skeletal malformations or variations in animals surviving to scheduled necropsy. In summary, the no-observed-adverse-effect level (NOAEL) for maternal toxicity was 70 mg/kg/day and the lowest-observed-adverse-effect level (LOAEL) was 140 mg/kg/day under the conditions of this study. Similarly, the NOAEL for developmental toxicity was 70 mg/kg/day and the LOAEL was 140 mg/kg/day.     

The Developmental Toxicity of Boric Acid in Rabbits

Boric acid (BA), an ingredient of many pharmaceutical, cosmetic,and pesticide products, was previously shown to induce reproductiveand developmental toxicity in laboratory rodents. In this study,BA (0, 62.5, 125, or 250 mg/kg/day, po) was administered onGestational Days (GD) 6–19 to New Zealand White rabbits(18–23 pregnant/group). Maternal body weight, food consumption,and clinical condition were monitored at regular intervals throughoutgestation. At termination (GD 30), the numbers of uterine implantations,resorptions, dead fetuses, and live fetuses were determined.Fetuses were weighed, and live fetuses examined for external,visceral, and skeletal defects. Maternal food intake decreasedduring treatment at 250 mg/kg/day and increased at 125 mg/kg/dayafter treatment. Maternal body weight (GD 9–30), weightgain during treatment, gravid uterine weight, and number ofovarian corpora lutea decreased at 250 mg/kg/day. In contrast,maternal corrected gestational weight gain increased at 125mg/kg/day. Maternal liver weight was not affected. Relative(but not absolute) maternal kidney weight increased at 250 mg/kg/day,and microscopic evaluation revealed no treatment-related renalpathology. At 250 mg/kg/day, prenatal mortality was increased(90% resorptions/litter vs 6% for controls), the proportionof pregnant females with no live fetuses was increased (73%vs 0%), and live litter size was reduced (2.3 fetuses/littervs 8.8). As a result, there were only 14 live fetuses (6 livelitters) available for evaluation in the high-dose group, comparedto 153–175 live fetuses (18–23 live litters) inthe other groups. The percentage malformed fetuses/litter wasincreased at 250 mg/kg/day, primarily due to cardiovasculardefects in 72% of high-dose fetuses vs 3% of controls. The mostprevalent cardiovascular malformation (in terventricular septaldefect) was observed in 57% of high-dose fetuses compared to0.6% among controls. At 250 mg/kg/day, average fetal body weight/litterwas 92% of the average control weight (not statistically significant).In summary, no definitive maternal or developmental toxicitywas observed at 62.5 or 125 mg/kg/day BA. Mild maternal effectsand severe developmental toxicity were observed at 250 mg/kg/day.     

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.     

Evaluation of the Pre-, Peri-, and Postnatal Toxicity of Monoethanolamine in Rats Following Repeated Oral Administration during Organogenesis

Pregnant Wistar rats (40/group) were administered monoethanolamine(MEA) as an aqueous solution by gavage at dose levels of 0,40, 120, and 450 mg/kg/day on days 6 through 15 of gestation.On day 20 of gestation, 25 dams/group were euthanized and thefetuses were delivered by cesarean section, weighed, sexed,and examined for external, visceral, and skeletal alterations.The remaining dams (15/group) were allowed to litter and reartheir pups to day 21 postpartum. The dams and pups were theneuthanized and examined for gross pathologic changes. Gavageadministration of 450 mg MEA/kg/day to pregnant rats resultedin maternal toxicity as evidenced by statistically significant( = 0.05) decreases in feed consumption on gestation days 6–8and 17–20 and on postpartum days 0–4. Additionally,statistically significant decreases in mean maternal body weightswere observed on gestation days 15, 17, and 20 and on lactationdays 0, 4, 7, and 21. Body weight gains of the 450 mg/kg/daydams were also significantly decreased (13% relative to controls)on gestation days 15–20. There was no evidence of maternaltoxicity at 40 or 120 mg/kg/day of MEA. Despite the maternaleffects observed at 450 mg/kg/day, no significant fetal effectswere observed at this or any dose level tested, nor were thereany indications of a treatment-related effect on postnatal growthor on the viability of offspring. Thus, it was concluded thatMEA was not developmentally toxic to Wistar rats following repeatedoral administration, even at maternally toxic dose levels ashigh as 450 mg/kg/day.     

Developmental Toxicity Study of Clarified Slurry Oil (CSO) in the Rat

Pregnant CD rats were exposed dermally to 0.05, 1, 10, 50, and250 mg/kg/day of Clarified Slurry Oil (CSO) on Days 0–19of gestation to determine its potential developmental toxicity.Untreated and vehicle controls were included in the study. Day20 of gestation Caesarean-derived fetuses were examined forgross, external, and visceral or skeletal alterations. Dosagesof 1 mg/kg/day and higher significantly decreased maternal bodyweight, body weight gain, feed consumption, gravid uterine weight,and live litter size and significantly increased resorptionrate. These dosages also significantly reduced fetal weightsand retarded development of the brain, kidney, thoracic andcaudal vertebrae, metacarpals, and hindpaw phalanges in dosagegroups with live fetuses (high dosage group dams resorbed allconceptuses). The 50- and 250-mg/kg/day dosage group dams hadonly placentas and/or dark red viscous fluid in the uterus orvagina and significant body weight loss (associated with resorption).The highest dosage also caused emaciation, slight dehydration,and swollen dark anogenital areas. These results indicate thatCSO produces adverse developmental effects at maternally toxicdosages. The maternal and developmental NOAELs (no observedadverse effect levels) were 0.05 mg/kg/day. In a second study,groups of 10 mated female rats were exposed to "pulse" exposuresand dosages of 1, 50, or 250 mg/kg/day of CSO applied dermallyfor 2- or 3-day intervals that spanned the gestation period.All dosages reduced maternal feed consumption and body weightgain during the treatment period. Dosages of 50 and 250 mg/kg/dayalso produced early resorptions when administered on Days 6through 8 and 9 through 11 of gestation. However, no increasein fetal alterations occurred, indicating that the effects onembryo–fetal development were due to early death and notto the death of malformed conceptuses.     

Impaired performance on odor-aversion testing following prenatal aspartame exposure in the guinea pig

Pregnant guinea pigs were administered aspartame (500 mg/kg) in sesame oil by gavage or sesame oil alone between the day of conception and parturition. A nontreated control group was also maintained. There were no statistically significant effects of the treatment on maternal weight gain, litter size, or birth weight of the pups. Newborn pups were weighed daily and on day 15 were injected with either LiCl or saline and placed in a cage with vanilla odor for 30 min. Twenty-four hr later the pups were permitted to choose between vanilla and lemon odors in a preference test. While both the vehicle-treated control and nontreated control groups injected with LiCl showed a conditioned aversion to vanilla, the aspartame-treated pups injected with LiCl did not. These data indicate that aspartame exposure at 500 mg/kg throughout gestation disrupts odor-associative learning in 15-day-old guinea pigs.     

Developmental toxic effect after subcutaneous injections of methadone in Charles River CD-1 mice

Four groups of Charles River CD-1 pregnant mouse dams were dosed subcutaneously daily with 5, 10, 20, and 28 mg/kg of methadone during day 6 to 15 of gestation. Prenatal and postnatal studies were conducted in the offspring and mouse dams. Caesarean sections were performed on some of the females from each group on day 19 of gestation and fetuses evaluated by routine teratologic methods. All females remaining were allowed to deliver, and several postnatal signs were recorded from the pups during the lactation period. Maternal mean body weight gains and food consumption were reduced. No apparent alteration in the food efficiency index was detected, thus maternal malnutrition may not have been a factor in producing adverse effects on offspring. The incidence of external and visceral malformations was neither dose-related nor significantly different from those of the controls. However, administration of methadone decreased ossification of the digits, sternum, and skull of the offspring. Adverse effects of methadone on reproduction were apparent at doses of 20 mg/kg/day and above, and characterized by an increase in resorptions and a decrease in the number of live fetuses per litter. Methadone was found not to be teratogenic to the CD-1 mice. However, adverse effects on intrauterine growth, fetal ossification, neonatal growth, development, and survival rate were seen among weaned pups.     

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.     

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

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

Developmental toxicity studies in rats and rabbits with 3,5,6-trichloro-2-pyridinol, the major metabolite of chlorpyrifos.

3,5,6-Trichloro-2-pyridinol (TCP), the primary metabolite of chlorpyrifos and chlorpyrifos-methyl, was evaluated for potential developmental toxicity. Groups of 32-34 bred female Fischer 344 rats were given 0, 50, 100, or 150 mg TCP/kg/day by gavage on gestation days 6-15; the fetuses were evaluated on gestation day 21. Similarly, groups of 16 inseminated female New Zealand White rabbits were given 0, 25, 100, or 250 mg TCP/kg/day by gavage on gestation days 7-19, and fetuses were evaluated on gestation day 28. No clinical signs of toxicity attributed to TCP were noted in either species. In rats, at 150 mg/kg/day, maternal effects included slight decreases in feed consumption, significantly depressed body weight gain (25% relative to controls) resulting in significantly lower maternal terminal body weights, and increased relative liver weight. At 100 mg/kg/day, maternal body weight gain in rats was depressed approximately 22%. Among rabbits, maternal effects were limited to the group given 250 mg/kg/day, which lost an average of approximately 70 g during the treatment period (vs. 140 g in the controls). There were no effects on fetal weight or viability, nor were there significant increases in any fetal alteration in either species. A slightly higher (not statistically significant) than usual incidence of central nervous system anomalies occurred in rabbits, but these anomalies were found in both treated and control groups in this study as well as contemporaneous studies of unrelated compounds. This, and the fact that these anomalies were not seen with the parent compound, chlorpyrifos, suggest that their origin was spontaneous. Thus, TCP was not considered fetotoxic or teratogenic in either rats or rabbits, even at dose levels that produced maternal toxicity.     

Prenatal oral (gavage) developmental toxicity study of decabromodiphenyl oxide in rats

Decabromodiphenyl oxide (DBDPO) is a highly effective flame retardant that is primarily used in electrical and electronic equipment with a secondary, but important, application in upholstery textiles. DBDPO, the second largest volume brominated flame retardant in use today, has undergone a wide range of toxicology tests in mammalian species with the results indicating a no-adverse-effect level of approximately 1000 mg/kg/day in oral repeated-dose studies. An oral prenatal developmental toxicity study of the commercial DBDPO product (97% purity) was performed under current EPA OPPTS and OECD guidelines. Female Sprague-Dawley rats (25 mated females/group) received 0,100, 300 or 1000 mg DBPDO/kg/ day via gavage in corn oil during gestation days 0 through 19. All females survived until scheduled sacrifice. No clinical signs of toxicity were observed. Pregnancy rates in the control and treated groups ranged from 96% to 100% and provided 23 or more litters in each group for evaluation on gestation day 20. No effect of treatment was seen in maternal gestational parameters (body weight, body weight gain, and food consumption), uterine implantation data, liver weight, or necropsy findings. Likewise, no effect of treatment was seen in fetal body weights, fetal sex distribution, or during the fetal external, visceral, or skeletal examinations. The NOEL (no-observable-effect level) for maternal and developmental toxicity was 1000 mg DBPDO/kg/day, the highest dose level administered on gestation days 0 to 19.     

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.     

Skin absorption of hexafluoroacetone: teratogenic and lethal effects in the rat fetus.

Hexafluoroacetone trihydrate (HFA) was applied to the skin of pregnant rats from Day 6 through 16 of gestation. All rats were killed on Day 21 with uterine weights, fetal survival, number of resorptions, live fetal weights plus crown-rump lengths, and gross abnormalities by external examination determined at necropsy. The fetuses were processed for examination of visceral/neural anomalies and skeletal abnormalities. In a range-finding study, doses were from 2.3 to 90 mg/kg/day. At 90 mg/kg/day signs of maternal toxicity were observed. At 40 mg/kg/day and above, all but one of 36 fetuses were resorbed. At all doses nonlethal to fetuses, teratogenic effects were suggested. Based on maternal toxicity and embryolethality observed in the range-finding study, doses of either 1, 5, or 25 mg/kg/day were used in the main study. Fetal toxicity, measured by number of resorptions and live fetuses per litter, was evident at 25 mg/kg/day. At 5 and 25 mg/kg/day the mean fetal weights and crown-rump lengths were significantly lower than those of the controls and maternal weight gain was adversely affected. Teratogenic effects consisting of gross external, internal soft-tissue, and skeletal abnormalities were observed at 5 and 25 mg/kg/day. At 1 mg/kg/day a possible treatment-related increase in fetal gross external and internal soft-tissue abnormalities was observed.