PHENYLSILSESQUIOXANE FLUID: DEVELOPMENTAL TOXICITY STUDIES IN RATS AND RABBITS FOLLOWING ORAL ADMINISTRATION

Phenylsilsesquioxane fluid (PSF) is used widely in the personal care industry and is a common component of skin and oral care products. The potential developmental toxicity of PSF was evaluated in rats and rabbits. Groups of 25 sperm-positive Sprague-Dawley rats (Taconic Farms) and 15 sperm-positive New Zealand White rabbits (HRP) were administered dose levels of 50, 500, or 1000 mg/kg PSF in corn oil. Vehicle control groups of equal size were administered corn oil alone. Rats were dosed daily (5 ml/kg) on gestation d 6?15 and sacrificed on gestation d 20, while rabbits were dosed daily (1.5 ml/kg) on gestation d 6?18 and sacrificed on gestation d 29. The fetuses were removed by cesarean section and examined for gross external, visceral, cephalic, and skeletal anomalies. No treatment-related clinical signs of toxicity were observed. No marked effects upon maternal food consumption, body weight, body weight gain, or uterus or liver weight were detected. Fetal viability and body weight, as well as developmental endpoints, were unaffected by treatment. Accordingly, exposure of pregnant rats or rabbits to 50, 500, or 1000 mg/kg of PSF during the period of major organogenesis did not result in any biologically significant adverse or teratogenic effects in the dams or fetuses.     

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.     

Reproductive toxicity studies in rats with rimexolone, a corticoid ophthalmic suspension.

Rimexolone is a potent anti-inflammatory corticosteroid with a lower potential for elevating intraocular pressure, relative to other ophthalmic steroids, and is indicated for postsurgical inflammation and uveitis. Fertility and peri/postnatal toxicities were evaluated at oral gavage doses of 50, 150 or 500 mg/kg, and developmental toxicity at 100, 500, or 1000 mg/kg. In the fertility study, male rats were treated daily beginning 4 weeks prior to mating and females were treated daily beginning 2 weeks prior to mating, and through gestation day 6. Females were necropsied on gestation day 15 and males were necropsied after 10 weeks of exposure. In males, dose-related reductions in mean body weights, body weight gains, and food consumption occurred in all groups. In the 500 mg/kg females, mean body weights were reduced during gestation, and there was an increase in early resorptions and concomitant decrease in viable fetuses at this level. There were no effects on copulation or fertility indices, or on the number of corpora lutea and implantation sites. The no-observed-effect level (NOEL) for fertility and reproductive effects was 150 mg/kg. In the developmental toxicity study, female rats were treated daily from gestation days 6 through 17, necropsied on gestation day 20 and fetuses were evaluated. Maternal toxicity occurred at 500 and 1000 mg/kg as indicated by reduced maternal body weights and body weight gains. However, there was no indication of a developmental effect on fetuses due to rimexolone. The NOEL was 1000 mg/kg for the developing fetuses. In the peri/postnatal toxicity study, female rats were treated daily from gestation day 6 through lactation day 20 and necropsied. F1 developmental and behavioral parameters were evaluated. Selected F1 animals were mated at 12 weeks, allowed to deliver, and necropsied on lactation day 21. At 500 mg/kg, F0 maternal body weights were reduced during gestation and lactation, and F1 pup weights were reduced during lactation and the growth phase. There were no effects on the F1 fertility or reproductive capabilities, or on F2 developmental parameters. The NOEL for the F0 females and F1 offspring was 150 mg/kg. Together, these studies indicate that, unlike some corticosteroids, rimexolone does not produce developmental or reproductive toxicity in rats.     

Teratogenesis study of o-toluenediamine in rats and rabbits

o-Toluenediamine in corn oil was administered po to Sprague-Dawley rats at dosages of 10, 30, 100, or 300 mg/kg body wt/day during Days 6 through 15 of gestation. All animals were killed on Day 20 of gestation. A similar study was conducted with Dutch-Belted rabbits dosed po daily at 3, 10, 30, or 100 mg of o-toluenediamine/kg body wt/day from Days 6 through 18 of gestation. Rabbits were killed on Day 29 of gestation. Maternal toxicity was indicated at 300 mg/kg in rats and 100 mg/kg in rabbits by reduced body weight gain during gestation. Fetal body weight was reduced at the highest dosage in both rats and rabbits. In addition, at the high dosage, an increase in the number of resorption sites in rabbits were noted. Skeletal examination of rats showed increased incidence of missing sternebrae at 300 mg/kg and incompletely ossified vertebrae at 100 and 300 mg/kg in comparison to control fetuses. The effects on the fetus could be the result of maternal toxicity. There was no evidence of teratogenic effects or effects on the dams at dosages through 30 mg/kg body wt.     

Determination of a No-Observed-Effect Level for Developmental Toxicity of Ethylene Glycol Administered by Gavage to CD Rats and CD-1 Mice

Previous studies have indicated that ethylene glycol (EG) isa developmental toxicant in rats and mice primarily when ingested.This study was designed to establish no-observed-effect levels(NOELs) for developmental toxicity of EG administered by gavagein both rodent species. Dams were administered EG on GestationDays 6–15; rats were given 0, 150, 500, 1000, or 2500mg EG/kg/ day; mice were dosed with 0, 50, 150, 500, or 1500mg EG/kg/day. In rat dams given 2500 mg EG/kg/day, water consumptionwas increased during treatment and body weights were reducedthroughout gestation; liver and kidney weights were increasedat euthanization (Gestation Day 21). Relative liver weightswere also increased at 1000 mg/kg/day. Effects observed in ratfetuses at 2500 mg/kg/day included the following hydrocephaly;gastroschisis; umbilical hernia; fused, duplicated, or missingarches, centra, and ribs; poor ossification in thoracic andlumbar regions; and reduced body weights. Reduced body weights,duplicated or missing ribs, centra, and arches, and poor ossificationwere also ob served in rat fetuses at 1000 mg/kg/day. In mice,there was no apparent treatment-related maternal toxicity. Inmouse fetuses (Gestation Day 18), effects were observed at 1500mg/kg/day and included reduced body weights, fused ribs andarches, poor ossification in thoracic and lumbar centra, andincreased occurrence of an extra 14th rib. At 500 mg/kg/day,slight reductions in fetal body weight and increased incidencesof extra ribs were observed. Under conditions of these studies,NOELs for developmental toxicity were 500 mg/kg/day for ratsand 150 mg/kg/day for mice, indicating that mice were more susceptiblethan rats to the teratogenic effects of EG.     

Biodisposition of dibromoacetic acid (DBA) and bromodichloromethane (BDCM) administered to rats and rabbits in drinking water during range-finding reproduction and developmental toxicity studies

Dibromoacetic acid (DBA) and bromodichloromethane (BDCM), by-products of chlorine disinfection of water, were provided in drinking water in range-finding reproductive/developmental toxicity studies (rats) and a developmental toxicity study (BDCM) in rabbits. Studies included absorption and biodisposition of DBA and BDCM, including passage into placentas, amniotic fluid, fetuses (rats and rabbits), or milk (rats). The DBA and BDCM range-finding reproductive/developmental toxicity studies each included 50 Sprague-Dawley rats/sex/group. DBA (0, 125, 250, 500, or 1000 ppm) or BDCM (0, 50, 150, 450, or 1350 ppm) was provided in drinking water 14 days premating through gestation and lactation (63 to 70 days). The developmental toxicity range-finding study included 25 time-mated New Zealand white rabbits/group given 0, 50, 150, 450, or 1350 ppm BDCM in drinking water on gestation days (GDs) 6 through 29. Satellite groups (6 male, 17 female rats/group/study and 4 rabbits/group) were used for bioanalytical sampling. Rats and rabbits had exposure-related reduced water consumption caused by apparent taste aversion to DBA or BDCM, especially in the parental animals at the two highest exposure levels (500 and 1000 ppm DBA; 450 and 1350 ppm BDCM). Female rats consumed slightly higher mg/kg/day doses of DBA than male rats, especially during gestation and lactation; weanling rats consumed the highest mg/kg/day doses. DBA produced detectable and quantifiable concentrations in plasma, placentas, amniotic fluid, and milk. Plasma samples confirmed that rats drink predominately during the dark; this drinking pattern, not accumulation, produced detectable plasma concentrations for 18 to 24 hours/day. No quantifiable concentrations of BDCM occurred in plasma, placentas, amniotic fluid, or milk, suggesting that BDCM is rapidly degraded or metabolized in vivo. DBA (500 and 1000 ppm, rats) and BDCM (450 and 1350 ppm, rats and rabbits) produced secondary toxicity in the parental generation by reducing water consumption, which caused severe exposure-related apparent dehydration, reduced feed intake and weight gain. Reproductive and developmental parameters were essentially unaffected (mating possibly reduced [DBA at 1000 ppm]; exposure-related decreases in body weights of pups secondary to reduced water and feed consumption [DBA at 250, 500, and 1000 ppm; BDCM at 150, 450, and 1350 ppm]). No effects on development of rabbit fetuses occurred at BDCM concentrations as high as 1350 ppm. Results from these preliminary studies, in which DBA and BDCM were provided in the drinking water at concentrations thousands of times higher than those to which humans are exposed, suggest that neither DBA nor BDCM are reproductive/developmental risks for humans.     

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

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

Evaluation of the teratogenic potential of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat and rabbit

To assess its teratogenic potential, advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate) was administered to mated rats (22/group) in the diet at 0, 5000, 15,000, and 50,000 ppm (providing approximately 465, 1418, and 4828 mg/kg body weight/day), and to mated rabbits (24/group) via oral gavage at 0, 500, 1000, and 2000 mg/kg body weight/day throughout gestation. Shortly before delivery (rats: day 20; rabbits: day 29), animals were killed and subjected to a detailed necropsy. Fetuses were examined for external, visceral, and skeletal alterations. Atypical coloration of the feces and cage liners seen with test diets in both rats and rabbits was attributed to excretion of test material/metabolites in the feces and urine. Advantame had no adverse effect on rat offspring survival or development. The no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity in rats was 50,000 ppm, the highest dietary concentration tested. Due to adverse effects associated with reduced food intake and fecal output, approximately 20% of mated rabbits receiving 200 0mg/kg body weight/day and 1 animal at 1000 mg/kg body weight/day had to be terminated before scheduled necropsy. A NOAEL of 500 mg/kg body weight/day was established for maternal toxicity in rabbits. No teratogenic effects were observed in any animals, and based on a slightly increased incidence of fetal deaths at 2000 mg/kg body weight/day, a finding that was considered to be indirectly related to advantame treatment, 1000 mg/kg body weight/day was considered the NOAEL for developmental toxicity.     

Developmental toxicity studies of caprolactam in the rat and rabbit

Caprolactam was evaluated for developmental toxicity potential in both rats and rabbits by the oral route. In rats dosed on days 6-15 of gestation with 100, 500 or 1000 mg/kg/day of caprolactam, the maternal survival rate was significantly lower in the high-dose group and implantation efficiencies were slightly lower in the 100 and 1000 mg/groups (but not the 500 mg/kg) than in the control. The incidence of fetal death was comparable for all groups, and the incidence of fetal viability was considerably lower in the high-dose group (but not the mid or low) than in the control group. Visceral anomalies and one visceral variant were observed in one 100 mg/kg and one 500 mg/kg pup, respectively. The anomalies included exencephaly, an incomplete left eyelid, microphthalmia (right), and a protruding tongue. No skeletal anomalies were observed. It was concluded that caprolactam at levels up to at least 500 mg/kg of body weight produced no teratogenic effects in the Fischer 344 rats. In rabbits receiving 50, 150 or 250 mg/kg caprolactam on days 6-28 of gestation, the pregnancy rate in all groups was at least 80%. The numbers of corpora lutea, live and dead fetuses, resorptions, the sex ratio and the pre- and post-implantation losses were not significantly different among the test and control groups. The incidence of major malformations and of minor skeletal anomalies was unaffected by treatment with caprolactam. Maternal weights were depressed in the group receiving 250 mg/kg. Treatment of a separate group with a positive control substance (6-aminonicotinamide) resulted in significantly (P less than 0.001) increased incidences of major malformations, minor visceral anomalies and minor skeletal anomalies. Maternal toxicity in terms of mortality was observed in pregnant rabbits treated with caprolactam at a dose of 250 mg/kg/day. Fetotoxicity was evidenced by lower fetal weights at the 150 and 250 mg/kg/day levels, and an increased incidence of thirteenth ribs was observed at the 250 mg/kg/day dose level. Neither embryotoxicity nor teratogenicity occurred at any dose level.     

Developmental Toxicity of Dinitroaniline Herbicides in Rats and Rabbits

The potential developmental toxicity of trifluralin was evaluatedin rats and rabbits. Pregnant rats and rabbits were dosed oncedaily by gavage on Gestation Days 6–15 and 6–18,respectively. Doses for rats were 0, 100, 225, 475, or 1000mg/kg; doses for rabbits were 0, 100, 225, or 500 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 28, respectively. In rats, maternal toxicity was indicatedin the 475 and 1000 mg/kg treatment groups by depression ofbody weights and food consumption. Fetal viability and morphologywere not adversely affected at any dose level. Developmentaltoxicity was indicated at the 1000-mg/kg dose level by depressionof fetal weight. The NOAEL for maternal toxicity in the ratwas 225 mg/kg the NOAEL for developmental toxicity in the ratwas 475 mg/kg. In rabbits, maternal toxicity was indicated atthe 225 and 500 mg/kg dose levels by abortions and/or deathsin conjunction with anorexia and cachexia. Developmental toxicitywas indicated at the 500 mg/kg dose level by depressed fetalviability and weight. Fetal morphology was not adversely affectedat any dose level. The NOAELs for maternal and developmentaltoxicity in the rabbit were 100 and 225 mg/kg, respectively.Based on these data, trifluralin did not exhibit selective toxicitytoward the developing conceptus.     

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.     

Subchronic, reproductive, and developmental toxicity of a fluorotelomer-based urethane polymeric product

A commercial fluorotelomer-based urethane polymeric dispersion, consisting of polymer, surfactant, and water, was evaluated in subchronic, reproduction, and developmental toxicity studies. The dispersion was administered daily by gavage to rats at dosages of 0, 50, 250, or 1000 mg polymer/kg/day or with 70 mg/kg/day of the sulfonate surfactant. Dose levels of 0, 50, 250, or 1000 mg polymer/kg/day were also used for the reproductive and developmental studies. Nasal olfactory epithelial degeneration and necrosis occurred in all dose groups in the 90-day study. Nasal adhesions were observed only in rats administered surfactant alone. Liver-enzyme alterations at 250 and 1000 mg/kg were considered to be potentially adverse effects. The subchronic no-observed-adverse-effects level (NOAEL) was 50 mg/kg. For the reproduction study, rats were dosed for 10 weeks prior to cohabitation and throughout mating, gestation, and lactation. There were no effects on reproductive function in males or females at any dosage. Thyroid weight was decreased in the 250 and 1000 mg/kg day F(1) groups unaccompanied by microscopic effects. In the developmental toxicity study, female rats were dosed from gestation days 6-20; there was no test-substance-related embryolethality, nor was there any dose-related increase in either fetal malformations. Fetal weight was minimally decreased at 1000 mg/kg/day in the presence of slight maternal toxicity; the NOAEL for developmental parameters was 250 mg/kg/day. The polymeric product was not a specific developmental or reproductive toxin.     

Subchronic,Reproductive, and Developmental Toxicity of a Fluorotelomer-Based Urethane Polymeric Product

A commercial fluorotelomer-based urethane polymeric dispersion, consisting of polymer, surfactant, and water, was evaluated in subchronic, reproduction, and developmental toxicity studies. The dispersion was administered daily by gavage to rats at dosages of 0, 50, 250, or 1000 mg polymer/kg/day or with 70 mg/kg/day of the sulfonate surfactant. Dose levels of 0, 50, 250, or 1000 mg polymer/kg/day were also used for the reproductive and developmental studies. Nasal olfactory epithelial degeneration and necrosis occurred in all dose groups in the 90-day study. Nasal adhesions were observed only in rats administered surfactant alone. Liver-enzyme alterations at 250 and 1000 mg/kg were considered to be potentially adverse effects. The subchronic no-observed-adverse-effects level (NOAEL) was 50 mg/kg. For the reproduction study, rats were dosed for 10 weeks prior to cohabitation and throughout mating, gestation, and lactation. There were no effects on reproductive function in males or females at any dosage. Thyroid weight was decreased in the 250 and 1000 mg/kg day F₁ groups unaccompanied by microscopic effects. In the developmental toxicity study, female rats were dosed from gestation days 6–20; there was no test-substance-related embryolethality, nor was there any dose-related increase in either fetal malformations. Fetal weight was minimally decreased at 1000 mg/kg/day in the presence of slight maternal toxicity; the NOAEL for developmental parameters was 250 mg/kg/day. The polymeric product was not a specific developmental or reproductive toxin.     

Developmental toxicity studies of the quinolone antibacterial agent irloxacin in rats and rabbits

Embryotoxicity studies on irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone-3-carboxylic acid, CAS-91524-15-1), a new fluoroquinolone antibacterial agent, were performed in rats and rabbits. Oral administration of irloxacin during the fetal period of organogenesis to pregnant rats and rabbits at dose levels of up to 1000 and 350 mg/kg/d, respectively, elicited no evidence of teratogenicity. During the first days of treatment, transient stasis in body weight increase was observed in rat dams receiving doses of 350 or 1000 mg/kg/d, and reduced food consumption was observed in those receiving 1000 mg/kg/d. Necropsy on day 20 of gestation showed dosage related increase in liver and kidney weights in all rat treated groups. Rabbit dams receiving 350 mg/kg/d showed during the first days of treatment decrease in body weight, and decreased food consumption and faecal output. Also, four females receiving 350 mg/kg/d aborted between days 18 and 20 of gestation. Rat fetuses in the 350 and 1000 mg/kg/d showed decreased body weight, and a decrease in placental weights was observed in the 1000 mg/kg/d group. No retardations or malformations were observed in rat or rabbit fetuses at any tested dose level. For maternal and embryo-fetal effects 100 and 150 mg/kg/d can be considered as the no-effect-level (NOEL) for rats and rabbits, respectively.     

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.     

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.     

Developmental toxicity studies of methyl ethyl ketoxime (MEKO) in rats and rabbits

The developmental toxicity of methyl ethyl ketoxime (MEKO), an industrial antioxidant used primarily as an antiskinning agent in alkyd paint, was investigated in rats and rabbits. Following preliminary dose range finding studies, groups of 25 pregnant rats or 18 pregnant rabbits were dosed by gavage with aqueous solutions of MEKO at 0, 60, 200, or 600 mg/kg (rats) or 0, 8, 14, 24, or 40 mg/kg (rabbits) on gestation days 6-15 or 6-18, respectively. In rats, dose-dependent clinical signs of maternal toxicity including reduced body weight gains were noted at 200 and 600 mg/kg. At 60 mg/kg and above enlarged spleens were observed at necropsy. The preliminary study found methemoglobin formation and reticulocytosis indicative of anemia at these dose levels. No treatment-related gestational effects, malformations or developmental variations were observed in the rats. In rabbits, 3 females aborted and 8 females were found dead at 40 mg/kg between gestation days 11 and 24. Clinical signs of maternal toxicity were present in surviving doses at this dose level. Body weight gains were reduced at 24 and 40 mg/kg. The preliminary study indicated maternal hematological effects in the rabbits similar to the rats at dose levels as low as 10 mg/kg. MEKO was not considered to have produced any treatment-related gestational effects, malformations or developmental variations in the rabbit at dose levels at or below 24 mg/kg. Because of excessive maternal mortality and abortions at the 40 mg/kg dose level, only 6 rabbits produced litters. The severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity at 40 mg/kg. Nonetheless, MEKO did not appear to be teratogenic to the rabbit at this dose level.     

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

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

Developmental Toxicity of 1,2-Dichloropropane (PDC) in Rats and Rabbits Following Oral Gavage

1,2-Dichloropropane (PDC) was evaluated for its potential causeembryonal/fetal toxicity and teratogenicity in pregnant ratsand rabbits. PDC was administered via oral gavage at dose levelsof 0, 10, 30, or 125 mg/kg/day on Days 6 through 15 of gestation(rats) or 0, 15, 50, or 150 mg/kg/day on gestation Days 7 through19 (rabbits). Fetuses were examined on Gestation Day 20 (rats)or Day 28 (rabbits). Maternal toxicity was observed in bothrats and rabbits at the high dose levels. Rats given 125 mg/kg/dayof PDC showed clinical signs of toxicity and decreased bodyweight and body weight gain. Rabbits given 150 mg/kg/day PDCshowed changes in hematologic parameters and decreased bodyweight gain. Although maternal toxicity was apparent, no indicationteratogenicity was observed in rat or rabbit fetuses at anydose level. Significant increases in the incidence of delayedossification of skull bones, considered secondary to decreasedmaternal body weight gain, were observed in rats given 125 mg/kg/dayand rabbits given 150 mg/kg/day. No maternal or developmentaleffects were observed in rats given 10 or 30 mg/kg/day or inrabbits given 15 or 50 mg/kg/day of PDC. Based on the resultsof these studies the maternal and developmental NOELs in ratsand rabbits were 30 and 50 mg/kg/day, respectively.     

Examination of the reproductive effects of tricresyl phosphate administered to Long-Evans rats

Tricresyl phosphate (TCP) is used commercially as a plasticizer and a flame retardant. The reproductive effects of TCP (less than 9.0% TOCP) were examined. Male Long-Evans rats received 0, 100, or 200 mg/kg and females received 0, 200, or 400 mg/gk TCP in corn oil by gavage. The 100 mg/kg TCP males were mated with 200 mg/kg TCP females, and 200 mg/kg TCP males were bred with 400 mg/kg TCP females. Males were dosed for 56 days and females for 14 days prior to breeding and throughout the 10-day breeding period. Following breeding, the males were necropsied and evaluated for sperm parameters and reproductive tract histopathology. Females were dosed throughout gestation and lactation. Pups and adult females were necropsied on postnatal day 21. Sperm concentration, motility, and progressive movement were decreased for 200 mg/kg dose group males. A dose-dependent increase in abnormal sperm morphology was observed for males in both TCP dose groups. The percent of sperm-positive females per group was unchanged, but the number of females delivering live young was severely decreased by TCP exposure. Litter size and pup viability were decreased in the 400 mg/kg dose group. Pup body weight and developmental landmarks were unaffected by TCP exposure. Histopathologic changes were observed in the testes and epididymides of male rats and in the ovaries of female rats exposed to TCP.