RESUMEN
Adult male and female CD rats (F0) were dosed with glutaraldehyde (GA; CAS number 111-30-8) in drinking water at concentrations of 0 (controls), 50, 250, or 1000 ppm for a 10-wk prebreed period and through mating, gestation, and lactation. Resultant F1 offspring, selected to be parents of the next generation, were continued on the same regime from prebreed through lactation. Twenty-eight parental animals per sex per generation for each dose group were evaluated for clinical signs, body weight (absolute and gain), and water and food consumption. The offspring were evaluated for survival and body weight to weaning. Necropsy and light microscopic examination of removed tissues were conducted in all F0 and F1 parents and in 10 offspring/sex/group/generation. Average daily consumptions of GA (as mean +/- SD) for the low, intermediate, and high concentrations were respectively 4.25 +/- 0.87, 17.50 +/- 4.16, and 69.07 +/- 14.58 mg/kg/d for F0 parental males, and 6.68 +/- 0.78, 28.28 +/- 4.09, and 98.37 +/- 11.71 mg/kg/d for F0 parental females. The corresponding values for the F1 parents were 4.53 +/- 1.02, 21.95 +/- 4.88, and 71.08 +/- 16.21 mg/kg/d for males and 6.72 +/- 0.84, 29.57 +/- 5.41, and 99.56 +/- 16.72 mg/kg/d for females. There were no effects on parental fertility and mating performance or on pup viability and litter size in any generation. No apparent treatment-related histopathology was seen in parents or offspring. Parental body weights and body weight gains were significantly reduced at 1000 ppm at a few isolated time periods, particularly during prebreed. Food consumption was significantly reduced at 1000 ppm for F0 and F1 parents during the prebreed and gestation periods, and at 250 ppm for F0 males during prebreed and gestation and F1 females during gestation and lactation. Water consumption by the F0 and F1 parents of the 250 at 1000 ppm groups was reduced throughout the prebreed period. At 1000 ppm, average litter weights were reduced over lactation d 21-28 for the F1 and F2 offspring. The no-observed-effect level (NOEL) for adult toxicity was 50 ppm and for offspring 250 ppm. There were no indications of reproductive toxicity, and the NOEL for this study was therefore > 1000 ppm.
Asunto(s)
Glutaral/toxicidad , Reproducción/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Crecimiento/efectos de los fármacos , Lactancia/efectos de los fármacos , Masculino , Exposición Materna/efectos adversos , Exposición Paterna/efectos adversos , Embarazo , Ratas , Conducta Sexual Animal/efectos de los fármacosRESUMEN
Diethanolamine (DEA) was administered cutaneously to pregnant CD rats and New Zealand White rabbits during the periods of major organogenesis, Gestation Days 6-15 for rats and 6-18 for rabbits. Doses employed were 0, 150, 500, and 1500 mg/kg/day for rats and 0, 35, 100, and 350 mg/kg/day for rabbits. Rat dams exhibited reduced body weight at 1500 mg/kg/day, skin irritation and increased kidney weights at 500 and 1500 mg/kg/day, and a slight microcytic anemia with abnormal red blood cell morphology at all dose levels. Rat fetuses had increased incidences of six skeletal variations at 1500 mg/kg/day. Lower doses were without effect on the fetuses. Rabbit dams administered 350 mg/kg/day exhibited various skin lesions, reduced food consumption, and color changes in the kidneys but no hematological changes. Body weight gain was reduced at >/=100 mg/kg/day. There was no evidence of maternal toxicity at 35 mg/kg/day and no evidence of developmental toxicity in rabbits at any dose level. Developmental toxicity was observed only in the rat and only at doses causing significant maternal toxicity, including hematological effects. Due to a dose discrepancy, the no observable effect level (NOEL) for DEA developmental toxicity in rats was adjusted to 380 mg/kg/day. In rabbits, the embryonal/fetal NOEL was 350 mg/kg/day.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Etanolaminas/toxicidad , Administración Cutánea , Animales , Peso Corporal/efectos de los fármacos , Dermatitis Irritante/etiología , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Edad Gestacional , Masculino , Embarazo , Conejos , Ratas , Piel/efectos de los fármacosRESUMEN
Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.
Asunto(s)
Reproducción/efectos de los fármacos , Teratógenos/toxicidad , 2,4-Diisocianato de Tolueno/toxicidad , Administración por Inhalación , Animales , Cámaras de Exposición Atmosférica , Peso Corporal/efectos de los fármacos , Femenino , Peso Fetal/efectos de los fármacos , Lactancia/efectos de los fármacos , Tamaño de la Camada/efectos de los fármacos , Masculino , Exposición Profesional/efectos adversos , Embarazo , Ratas , Ratas Sprague-Dawley , Rinitis/inducido químicamente , Razón de Masculinidad , 2,4-Diisocianato de Tolueno/administración & dosificación , Aumento de Peso/efectos de los fármacosRESUMEN
In range-finding and definitive developmental toxicity studies, timed pregnant New Zealand White rabbits were exposed to acrylic acid (CAS No. 79-10-7) vapour for 13 consecutive days during pregnancy. In the range-finding study, eight pregnant does/group were exposed to 30, 60, 125 or 250 ppm acrylic acid vapour on gestation days (gd) 10-22 of pregnancy. Monitors of toxicity included body weight measurements, daily food consumption measurements and clinical observations. Three of the eight does/group were killed on the day following the last exposure (gd 23), and the remaining does were killed and autopsied on gd 29. At autopsy, special attention was given to gross observation of maternal nasal turbinates, and nasal turbinates from all does were evaluated histologically. No evaluation of foetuses was performed in the range-finding study. In the definitive study, 16 does/group were exposed to concentrations of 25, 75 or 225 ppm acrylic acid vapour from gd 6 to 18, the major period of organogenesis. Monitors of maternal toxicity included clinical observations and measurements of body weight and daily food consumption measurements. Does were killed and autopsied on gd 29. Maternal liver and kidney weights were measured and external, visceral and skeletal evaluations of foetuses were conducted. Maternal nasal turbinates were not evaluated histologically in the definitive study. Effects in does from both studies included consistent concentration-related reductions in food consumption and body weight gains throughout the exposure period at concentrations of acrylic acid vapour above 60 ppm. Characteristic clinical signs of sensory irritation, including perinasal and perioral wetness and severe nasal congestion, were noted in does from both studies at or above vapour concentrations of 75 ppm. Gross observation of nasal turbinates immediately following exposures in the range-finding study indicated colour changes in the nasal turbinates of does in the 60 and 250 ppm groups. Colour changes in the nasal turbinates were noted in one doe from the 250 ppm exposure group killed on gd 29. Pertinent autopsy findings in the does from the definitive study included ulceration of the nasal turbinates of a single doe in the 225 ppm group. Histological evaluation of turbinates from does killed the day following exposures in the range-finding study revealed lesions in the nasal epithelium in all acrylic acid-exposed groups. The severity of the lesions was concentration related. Microscopic evaluation of turbinates from does killed on gd 29 showed the presence of nasal lesions in the 60, 125 and 250 ppm groups. However, the nasal tissues had recovered considerably during the post-exposure interval. Despite the severe effects on the nasal mucosa of does in both studies, there was no evidence of developmental toxicity including teratogenicity at any exposure concentration used in the definitive study.
Asunto(s)
Anomalías Inducidas por Medicamentos , Acrilatos/toxicidad , Feto/efectos de los fármacos , Acrilatos/administración & dosificación , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Embarazo , ConejosRESUMEN
Pregnant CD-1 mice (30 per group) and female New Zealand White rabbits (15 per group) were exposed by inhalation to 0, 1000, 4000 and 8000 ppm methyl tertiary-butyl ether (MTBE) vapor for 6 h a day during gestational days (GD) 6-15 and 6-18, respectively. Maternal body weights, clinical observations and food consumption were recorded throughout gestation for both species. At scheduled euthanization (GD 18 for mice and GD 29 for rabbits), fetuses were weighed, sexed and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no pregnant animals died or aborted. There were no does that delivered early, but there were three mouse dams in the control group and two dams in the 4000 ppm group that delivered early and were removed from the study. In mice, maternal body weights, body weight gain, corrected maternal gestational weight change and food consumption were significantly reduced in mice at 8000 ppm. Hypoactivity and ataxia were observed in dams exposed to 4000 and 8000 ppm. Gestational parameters affected at 8000 ppm included post-implantation loss (due to increased late resorptions and dead fetuses) and altered sex ratio (decreased males); fetal body weights per litter were reduced at 4000 and 8000 ppm. There was a significantly increased incidence of cleft palate at 8000 ppm; this resulted in increased incidences of pooled external and visceral malformations and of total malformations at this exposure concentration. There were also treatment-related increases in the incidence of individual skeletal variations at 4000 and 8000 ppm. In rabbits, maternal weight gain and food consumption were significantly reduced at 4000 and 8000 ppm. Relative liver weights were also reduced at 8000 ppm. All gestational parameters were equivalent across all groups, including pre- and post-implantation loss, fetal sex ratios, litter size and fetal weights/litter. There was no evidence of treatment-related teratogenicity observed at any dose tested in rabbits. The no-observed-effect levels (NOELs) for maternal and developmental toxicity were both 1000 ppm in mice and 1000 ppm and at least 8000 ppm, respectively, in rabbits.
Asunto(s)
Anomalías Múltiples/inducido químicamente , Contaminantes Atmosféricos/toxicidad , Feto/efectos de los fármacos , Éteres Metílicos/toxicidad , Administración por Inhalación , Animales , Cámaras de Exposición Atmosférica , Relación Dosis-Respuesta a Droga , Femenino , Reabsorción del Feto/inducido químicamente , Masculino , Ratones , Embarazo , ConejosRESUMEN
A two-generation reproductive toxicity study of methyl tertiary-butyl ether (MTBE) was conducted in Sprague-Dawley rats. Twenty-five rats of each sex (F0) were exposed by inhalation to 0, 400, 3000 or 8000 ppm MTBE vapor, 6 h a day for 10 weeks prior to mating. Parental animals were then mated within groups for up to 3 weeks. Parental females were exposed during mating, gestation and lactation (starting on day 5); parental males were exposed during mating through delivery of their last litter sired. The F1 adults were selected from the F1 litters and were exposed beginning on postnatal day 28 for at least 8 weeks before mating to produce F2 litters. During exposures to 3000 and 8000 ppm MTBE, group observations included hypoactivity and lack of startle reflex in parental animals from both generations. Parental animals at 8000 ppm were also ataxic. During the pre-mating period, body weights of the 8000 ppm males from both generations and the F1 females were significantly reduced compared to control animals. Transient body weight reduction was also observed in the 3000 ppm F1 males and females during the pre-mating period. Lactational body weights were increased in the 8000 ppm females from both generations. In the F1 generation, increased liver weights were noted in the 3000 and 8000 ppm animals for both sexes, although histopathological examination revealed no treatment-related effects. There were no treatment-related reproductive effects noted in any of the parameters measured in this study. Offspring survival was equivalent among treated and control groups from both generations, and there were no remarkable post-mortem findings. There was, however, a significant increase in dead F2 pups in the 8000 ppm group on postnatal day 4. The F1 litters at 3000 and 8000 ppm had lowered body weights from postnatal days 14-21 and 14-28, respectively. The F2 generation of pups at 3000 and 8000 ppm also exhibited lowered body weights from postnatal days 14-28 and 7-28, respectively. Body weight gains in both the F1 and F2 litters were also reduced for the corresponding time intervals. Thus, exposure to MTBE vapor produced no reproductive toxicity to two generations of Sprague-Dawley rats even in the presence of parental toxicity at 3000 and 8000 ppm. Postnatal toxicity was observed in the offspring of both generations, but only in the presence of maternal toxicity. The no-observed-effect level (NOEL) for both parental and postnatal toxicity is 400 ppm, and the NOEL for reproductive toxicity is at least 8000 ppm.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Éteres Metílicos/toxicidad , Reproducción/efectos de los fármacos , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Muerte Fetal/inducido químicamente , Feto/efectos de los fármacos , Tamaño de la Camada/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Pregnant Sprague-Dawley rats and New Zealand White rabbits were exposed dermally to 0, 10, 25, and 75 mg/kg/day of monoethanolamine (MEA) for approximately 6 hr/day on Days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation. A fifth dose group of 225 mg MEA/kg/day was evaluated in rats only. Dermal exposure of pregnant rats to 225 mg/kg/day and rabbits to 75 mg/kg/day resulted in significant increases in the incidence of skin irritation/lesions and maternal body weight effects. In general, the dermal irritation observed at the high dose was progressive, beginning with erythema and leading to necrosis, scabs, and scar formation. Doses of 25 mg/kg/day to rabbits produced only minor irritation. Despite maternal effects observed in rats and rabbits, no evidence of developmental or fetal toxicity was observed at any dose level tested. Thus, it was concluded that MEA was not developmentally toxic following dermal application at exposure levels up to and including 225 mg/kg/day for rats and 75 mg/kg/day for rabbits.
Asunto(s)
Desarrollo Embrionario y Fetal/efectos de los fármacos , Etanolaminas/toxicidad , Teratógenos/toxicidad , Anomalías Inducidas por Medicamentos/patología , Administración Tópica , Animales , Etanolamina , Etanolaminas/administración & dosificación , Femenino , Irritantes/toxicidad , Masculino , Embarazo , Conejos , Ratas , Piel/patología , Aumento de Peso/efectos de los fármacosRESUMEN
Previous studies have indicated that ethylene glycol (EG) is a 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 gavage in both rodent species. Dams were administered EG on Gestation Days 6-15; rats were given 0, 150, 500, 1000, or 2500 mg EG/kg/day; mice were dosed with 0, 50, 150, 500, or 1500 mg EG/kg/day. In rat dams given 2500 mg EG/kg/day, water consumption was increased during treatment and body weights were reduced throughout gestation; liver and kidney weights were increased at euthanization (Gestation Day 21). Relative liver weights were also increased at 1000 mg/kg/day. Effects observed in rat fetuses at 2500 mg/kg/day included the following: hydrocephaly; gastroschisis; umbilical hernia; fused, duplicated, or missing arches, centra, and ribs; poor ossification in thoracic and lumbar regions; and reduced body weights. Reduced body weights, duplicated or missing ribs, centra, and arches, and poor ossification were also observed in rat fetuses at 1000 mg/kg/day. In mice, there was no apparent treatment-related maternal toxicity. In mouse fetuses (Gestation Day 18), effects were observed at 1500 mg/kg/day and included reduced body weights, fused ribs and arches, poor ossification in thoracic and lumbar centra, and increased occurrence of an extra 14th rib. At 500 mg/kg/day, slight reductions in fetal body weight and increased incidences of extra ribs were observed. Under conditions of these studies, NOELs for developmental toxicity were 500 mg/kg/day for rats and 150 mg/kg/day for mice, indicating that mice were more susceptible than rats to the teratogenic effects of EG.
Asunto(s)
Anomalías Inducidas por Medicamentos , Glicoles de Etileno/toxicidad , Feto/efectos de los fármacos , Teratógenos/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Glicol de Etileno , Glicoles de Etileno/administración & dosificación , Glicoles de Etileno/metabolismo , Femenino , Masculino , Ratones , Nivel sin Efectos Adversos Observados , Embarazo , Ratas , Reproducción/efectos de los fármacosRESUMEN
The potential for DEET to produce developmental toxicity was evaluated in Charles River CD rats and New Zealand White rabbits. Rats were administered undiluted DEET by gavage on Gestational Days (gd) 6-15 at dosage levels of 0, 125, 250, and 750 mg/kg/day. Rabbits were administered undiluted DEET by gavage on gd 6-18 at dosage levels of 0, 30, 100, and 325 mg/kg/day. Group sizes were 25 females per group for rats and 16 females per group for rabbits. Control rats and rabbits were administered corn oil at the same dosage volumes administered in the high-dose DEET groups. In rats, maternal toxicity in the form of clinical signs including two deaths and depressed body weight and food consumption was observed at the high-dose level of 750 mg/kg/day. Rat fetal body weights per litter also were reduced at 750 mg/kg/day. In rabbits, maternal toxicity in the form of depressed body weight and food consumption was observed at the high-dose level of 325 mg/kg/day. No maternal toxicity was observed at the low- or mid-dose groups for rats or rabbits. With the exception of the reduced fetal weights in rats at 750 mg/kg, there was no evidence of fetal toxicity, no effects on any of the gestational parameters, nor were there any treatment-related increases in external, visceral, or skeletal variations or malformations in the offspring from the rats and rabbits from these studies.
Asunto(s)
DEET/toxicidad , Teratógenos/toxicidad , Animales , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Reabsorción del Feto/inducido químicamente , Embarazo , Conejos , Ratas , Ratas Endogámicas , Razón de Masculinidad , Teratología/métodos , Aumento de Peso/efectos de los fármacosRESUMEN
Sister-chromatid exchange (SCE) induction and cell cycle kinetics alterations by ethyl carbamate in bone marrow of non-gravid murine Swiss Webster, ICR/Jcl, and C57Bl/6J dams were evaluated, and data from non-gravid females were compared with those previously reported for pregnant dams of the same strains. In addition, lung adenoma induction by ethyl carbamate in gravid Swiss Webster dams, their offspring, and in non-pregnant Swiss Webster females was also determined. Relative cytogenetic and tumor responses in non-gravid and gravid Swiss Webster females and their offspring were compared. In contrast to the increased sensitivity reported for gravid Swiss Webster dams versus ICR/Jcl and C57Bl/6J dams, SCE responses to 1.1, 2.2, or 3.3 mmol/kg of ethyl carbamate in non-gravid females were approximately equivalent among strains. In Swiss Webster and C57Bl/6J (but not ICR/Jcl) strains, SCE responses in non-gravid females at 2.2 and 3.3 were significantly lower than those of their pregnant counterparts. Tumor induction by 3.3 mmol/kg ethyl carbamate paralleled relative SCE induction with Swiss Webster dams, demonstrating a 5-fold increase in the number of tumors relative to their offspring and a 4-fold enhancement of tumor induction relative to their non-pregnant counterparts.
Asunto(s)
Adenoma/inducido químicamente , Neoplasias Pulmonares/inducido químicamente , Preñez/efectos de los fármacos , Intercambio de Cromátides Hermanas/efectos de los fármacos , Uretano/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Muerte Celular , Femenino , Intercambio Materno-Fetal , Ratones , Ratones Endogámicos , EmbarazoRESUMEN
Murine susceptibility to ethyl carbamate-induced carcinogenesis is strain dependent. In vivo sister chromatid exchange (SCE) responses to ethyl carbamate were evaluated in bone marrow cells of gravid adenoma-susceptible (ICR/Jcl), and resistant (C57Bl/6J) and (DBA/2J) murine dams, as well as in liver cells of their respective ICR/Jcl, C57Bl/6J X DBA/2J (BDF1), and DBA/2J X C57Bl/6J (BDF), fetuses following a single intravenous injection of 1.1, 2.2, or 3.3 mmol/kg of ethyl carbamate on gestation day 13/14. Bone marrow tissues of C57Bl/6J and DBA/2J, but not ICR/Jcl dams, demonstrated greater sensitivity to SCE induction than liver cells of their respective fetuses. Furthermore, relative SCE responses in bone marrow among dams indicated greater sensitivity of the more tumor-susceptible ICR/Jcl and C57Bl/6J strains to SCE induction by ethyl carbamate relative to the more tumor-resistant DBA/2J strain. In addition, concurrent alterations (stimulation or inhibition) of bone marrow cell cycle kinetics by ethyl carbamate were consistent with hormone-related, strain-dependent hematopoietic stress during pregnancy.
Asunto(s)
Feto/efectos de los fármacos , Preñez/genética , Intercambio de Cromátides Hermanas/efectos de los fármacos , Uretano/farmacología , Animales , Médula Ósea/fisiología , Ciclo Celular/efectos de los fármacos , Femenino , Inmunidad Innata , Hígado , Masculino , Ratones , Ratones Endogámicos , Neoplasias/genética , Neoplasias/inmunología , Embarazo , Preñez/efectos de los fármacosRESUMEN
Gravid Swiss Webster dams were injected via tail vein with a single (1.1, 2.2, or 3.3 mmol/kg) dose of ethyl carbamate (urethane) on days 13-17 of pregnancy. Relative sister chromatid exchange (SCE) responses in maternal bone marrow vs. individual fetal liver cells were assessed. In addition, in order to evaluate the significance of intralitter variability in fetal SCE responses, SCE in combined ("pooled") fetal liver tissue preparations were measured and compared with average individual responses. In contrast to maternal responses, average fetal SCE responses to ethyl carbamate varied with gestational age. In addition, significant variation was observed among individual littermate responses at all dose levels. Nonetheless, fetal SCE responses determined from "pooled" tissue preparations provided a valid estimate of average litter responses. Regardless of the method of SCE evaluation in fetal tissue or gestational age, maternal bone marrow exhibited greater sensitivity than fetal liver to SCE induction by ethyl carbamate.