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Biomedical subjects

M C Marr

Publications and source records attributed to M C Marr.

At least 37 records · Page 2Linked to original sources
PubMed1993

Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits.

Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice >> rats >> rabbits.

Animals↗
PubMed1992

Developmental stages of the CD (Sprague-Dawley) rat skeleton after maternal exposure to ethylene glycol.

Ethylene glycol (EG), a chemical which causes skeletal malformations in rats, was administered by gavage to sperm positive CD rats on gestational days (gd) 6 through 15 at doses of 0 or 2,500 mg/kg/day to assess its effects on the pre- and postnatal skeletal development. Dams and fetuses/pups were killed on gd 18, 20, postnatal day (pnd) 1, 4, 14, 21, or 63, and offspring were double-stained for examination of skeletal malformations and degree of ossification of rapidly developing skeletal districts. No difference in gestational day of delivery between controls and the EG-treated dams was seen. Fetal weights per litter were significantly decreased with EG treatment in both the gd 18 and 20 groups. Pup body weight on pnd 1 was significantly below controls; however, EG had no effect on pup body weight on pnd 4-63. The percentage of fetuses/pups with skeletal malformations per litter was significantly increased after EG exposure for all time points except at pnd 63, with a predominance of axial skeletal defects. The percentages of total ossification, of sternabrae ossified, and of vertebral centra ossified were significantly reduced in the EG groups on gd 20 and on pnd 1-21, but not on gd 18 or on pnd 63. When the ossification data were subjected to statistical analysis with fetal/pup weights as a covariate, the values for EG-exposed pups on gd 20 were not statistically significantly different from the control values. The reduced ossification values for EG-exposed pups on pnd 1-21 retained statistical significance even after covariate analysis. There was no effect of dose or body weight on ossification of fore- or hindlimb digits. In conclusion, the differences in incidence of skeletal alterations observed prenatally and through pnd 21 were not evident by pnd 63, suggesting that perinatal skeletal abnormalities may not always be permanent.

Animals↗
PubMed1992

The developmental toxicity of ethylene glycol diethyl ether in mice and rabbits.

Timed-pregnant CD-1 outbred Albino Swiss mice and New Zealand White rabbits were dosed by gavage with ethylene glycol diethyl ether (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 was monitored daily during treatment. At termination (gd 17, mice; gd 30, rabbits), confirmed-pregnant females (22-24 per group, mice; 26-32 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed, but maternal body weight gain during gestation and treatment, and at termination was reduced at 1000 mg/kg/day. The reduction of maternal body weight gain during gestation was secondary to embryo/fetal toxicity, i.e., reduced gravid uterine weight as a consequence of decreased litter size and fetal weight. The no-observed adverse effect level (NOAEL) for developmental toxicity was 50 mg/kg/day. At greater than or equal to 150 mg/kg/day the number of litters of mice with malformed fetuses was increased. At greater than or equal to 500 mg/kg/day fetal body weight was reduced, and malformation incidence was significantly increased. Exencephaly and fused ribs were observed most often. In rabbits, maternal body weight was unaffected by treatment even though 6% maternal mortality was observed at 100 mg/kg/day. The developmental NOAEL was 25 mg/kg/day. Malformations were increased at greater than or equal to 50 mg/kg/day; short tail, small spleen, fused sternebrae, and fused rib cartilage were observed most often. In summary, oral administration of EGdiEE to mice and rabbits during organogenesis produced profound adverse developmental effects even in the absence of significant maternal toxicity. Developmental effects in rabbits were more varied.

Abnormalities, Drug-Induced↗
PubMed1992

Developmental toxicity of boric acid in mice and rats.

Boric acid (BORA), an ingredient of many cosmetics, pharmaceuticals, and pesticides, was tested for developmental toxicity in timed-pregnant Swiss mice and Sprague-Dawley rats (n = 26-28/group). BORA (0, 0.1, 0.2, or 0.4% in feed) was provided throughout gestation to attain steady-state exposure as early as possible during prenatal development. Average doses (mg/kg/day) were 248, 452, or 1003 in mice, and 78, 163, or 330 in rats. To limit prenatal mortality, BORA (0.8% or 539 mg/kg/day) was provided to an additional group of rats on Gestational Days (GD) 6 to 15 only. On GD 17 (mice) or 20 (rats), fetuses were weighed and examined for malformations (external, visceral, skeletal). Mouse dams exhibited mild renal lesions (greater than or equal to 0.1%), increased water intake and relative kidney weight (0.4%), and decreased weight gain (0.4%) during treatment. There was a reduction of fetal body weight (greater than or equal to 0.2%) and an increased incidence of resorptions and malformed fetuses per litter (0.4%). Morphological changes included an increased incidence of short rib XIII (a malformation) and a decreased incidence of rudimentary or full rib(s) at lumbar I (an anatomical variation). Maternal rats exhibited increased liver and kidney weights at greater than or equal to 0.2%, altered water and/or food intake at greater than 0.2%, and decreased weight gain at greater than 0.4%. Average fetal body weight/litter was reduced at all doses. Prenatal mortality was increased only at 0.8%. The incidence of fetal malformations was significantly increased at greater than or equal to 0.2%. The most frequently observed malformations were enlarged lateral ventricles of the brain and agenesis or shortening of rib XIII. In rats, the no-observable-adverse-effect level (NOAEL) for maternal toxicity was 78 mg/kg (0.1%), while in mice the low dose of 248 mg/kg (0.1%) approached the maternal NOAEL with mild renal lesions in only 2 of 10 females. Embryo/fetal toxicity occurred in all groups of rats at greater than or equal to 78 mg/kg (greater than or equal to 0.1%) while the NOAEL for developmental toxicity in mice was 248 mg/kg (0.1%). Thus developmental toxicity occurred below maternally toxic levels in rats as well as in the presence of maternal toxicity in mice and rats.

Abnormalities, Drug-Induced↗
PubMed1992

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

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

Animals↗
PubMed1991

Codeine: developmental toxicity in hamsters and mice.

Timed-pregnant LVG Syrian hamsters and Swiss CD-1 mice were dosed orally twice daily (b.i.d.) with codeine in water on Gestational Days (gd) 5-13 (0, 10, 50, or 150 mg/kg, b.i.d.--hamsters) or 6-15 (0, 37.5, 75, 150, or 300 mg/kg, b.i.d.--mice). Dams were necropsied on gd 14 (hamsters) or 17 (mice), and fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations. No maternal deaths were observed in hamsters, while 19% of the pregnant mice in the high-dose group died. Maternal weight gain (gestational and treatment periods) and gravid uterine weights were significantly depressed in hamsters (150 mg/kg, b.i.d.) and in mice (300 mg/kg, b.i.d.). However, the corrected weight gain for both species, although decreased, was not significantly different from that of the controls. In both species, maternal liver weights (relative) were significantly increased in the high-dose groups. There were increases in the percentage resorptions per pregnant dam and in the proportion of litters with 100% resorptions in the high-dose groups of both species. Considering only live litters, the number of live fetuses per litter and the sex ratio were unaffected in both species. Mean fetal body weights were also significantly decreased in the 50 and 150 mg/kg, b.i.d. (hamsters), and the 150 and 300 mg/kg, b.i.d. (mice), groups. The no-observed-adverse-effect levels (NOAELs) for developmental toxicity were 10 (hamsters) and 75 (mice) mg/kg, b.i.d., whereas the NOAELs for maternal toxicity were 50 (hamsters) and 150 (mice) mg/kg, b.i.d. The predominant structural malformation in hamsters was meningoencephalocele (high-dose group only), affecting 3% of fetuses and 19% of litters (neither statistically significant). Codeine did not induce any increase in structural malformations in mice. Thus, codeine produced developmental toxicity (as indicated by decreased fetal body weight) at doses below those producing maternal toxicity in both hamsters and mice. In the hamster, the more sensitive species to codeine developmental toxicity, effects were observed at a total daily dose of 100 mg/kg, which is only 11 times the maximum human therapeutic oral dose.

Abnormalities, Drug-Induced↗
PubMed1990

Developmental toxicity evaluation of acrylamide in rats and mice.

Acrylamide (ACRL), a widely used industrial chemical with neurotoxic effects, was evaluated for developmental toxicity. ACRL in distilled water was administered once daily by gavage on gestational days (gd) 6-17 to mice (0, 3, 15, or 45 mg/kg) and on gd 6-20 to rats (0, 2.5, 7.5, or 15 mg/kg). Following termination (gd 17, mice; gd 20, rats) fetuses were examined for external, visceral, and skeletal malformations. Maternal toxicity during treatment was observed at the highest dose as reduced body weight gain in both species and hindlimb splaying in treated mice only. Weight gain corrected for gravid uterine weight was also reduced in rats at 7.5 and 15 mg/kg/day. Embryo/fetal toxicity was not observed in rats, but fetal weight was reduced in mice administered 45 mg/kg/day. No increase in the incidence of malformations was observed in either species; however, the incidence of variations (predominately extra rib) increased with dose. In summary, administration of ACRL during organogenesis produced maternal and developmental toxicity at 45 mg/kg/day in mice and maternal, but not developmental, toxicity at doses greater than or equal to 7.5 mg/kg/day in rats.

Acrylamide↗
PubMed1990

The developmental toxicity of orally administered theophylline in rats and mice.

Theophylline (THEO), a widely prescribed anti-asthmatic, was evaluated for developmental toxicity. It was administered continuously on Gestational Days 6 through 15 to pregnant Sprague-Dawley (CD) rats in the feed (0, 0.15, 0.30, or 0.40%) and to pregnant Swiss (CD-1) mice in the drinking water (0, 0.075, 0.15, or 0.20%). Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day, while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats, maternal weight gain parameters (weight gain during gestation and treatment, as well as corrected weight gain) decreased at 0.40%. While food consumption was lower only in the 0.40% treatment group, water consumption was higher in all treated groups. There was a dose-related decreasing trend in gravid uterine weight. The number of live fetuses per litter decreased at 0.40% and the average male and female fetal weight per litter decreased at 0.30 and 0.40%. There was no increase in malformations. In mice, maternal corrected body weight and weight gain during gestation decreased at 0.15 and 0.20%, and weight gain during treatment and gravid uterine weight decreased at 0.20%. Water consumption was reduced by as much as 30-45% of controls at 0.15 and 0.20%, respectively, while food consumption did not change with THEO treatment. There was an increase in percentage resorptions per litter and a decrease in the average male and female fetal weight per litter at 0.15 and 0.20%. An increasing trend was noted for percentage malformed fetuses per litter, and percentage litters with externally malformed fetuses were slightly increased in the mid- and high-dose groups. However, these increases were not statistically significant. In summary, there were developmental effects seen in rats at a dose (0.30%) that did not produce overt maternal toxicity, but the adverse developmental effects in mice were observed at doses that caused reduced maternal water consumption and body weight gain. It is possible that water deprivation contributed to the effects seen in mice after THEO treatment. For maternal toxicity, no observable adverse effect levels (NOAELs) were 218 mg/kg for rats and 282 mg/kg for mice. NOAELs for developmental toxicity were 124 mg/kg for rats and 282 mg/kg for mice. These NOAELs are approximately 10- to 30-fold greater than doses required to maintain humans on serum THEO concentrations that are clinically useful.

Abnormalities, Drug-Induced↗
PubMed1989

Developmental toxicity of 1,1,1-trichloroethane in CD rats.

1,1,1-Trichloroethane (TCEN), a major industrial and household solvent, was evaluated for pre- and postnatal developmental effects in Sprague-Dawley rats. This study was designed to assess the repeatability of a report (S.C. Dapson, D.E. Hutcheon, and D. Lehr, Teratology 29, 25A, 1984) that indicated that 10 ppm TCEN in drinking water caused cardiac malformations in developing rats. In the present study, TCEN (97% pure) was administered in the drinking water at target concentrations of 3, 10, and 30 ppm, using 0.05% Tween 80 as an emulsifying agent. Two control groups, one receiving deionized/filtered water and the other receiving a vehicle control solution containing 0.05% Tween 80 and 0.9 ppm 1,4-dioxane, a stabilizing agent found in the bulk chemical, were also included. Male and female breeders (more than 30 per group) were exposed to the control solutions or test compound for 14 consecutive days prior to cohabitation and for up to 13 days during the cohabitation phase. Sperm-positive females (24-29 per group) continued to be exposed to these formulations during pregnancy and lactation to Postnatal Day (PND) 21. Parental animals exhibited a slight aversion to the 30-ppm drinking water during the premating exposure. No significant effect on reproductive competence of the parental animals or postnatal growth and development of the offspring to PND 21 was noted. A slight increase in mortality from implantation to PND 1, possibly due to high mortality in one litter, was observed in the 30-ppm dose group. There was no indication of an increase in the incidence of cardiac or other malformations in PND 21 pups. In summary, TCEN administered at 3, 10, and 30 ppm in the drinking water had no significant effect on the morphological development of CD rats.

Animals↗
PubMed1988

Developmental toxicity evaluation of Bendectin in CD rats.

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).

Abnormalities, Drug-Induced↗
PubMed1988

Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice.

Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizing agent, was evaluated for developmental toxicity in timed-pregnant Fischer 344 rats (22-25 dams/dose) and CD-1 mice (24-30 dams/dose). DEHP was administered in the diet on gestational Days (gd) 0 through 20 at 0.0, 0.5, 1.0, 1.5, or 2.0% (rats) and on gd 0 through 17 at 0.00, 0.025, 0.05, 0.10, or 0.15% (mice). At termination (gd 20, rats; gd 17 mice), all fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal toxicity and reduced fetal body weight per litter were observed at 1.0, 1.5, and 2.0%. Increased resorptions and decreased number of live fetuses/litter were observed at 2.0%. Maternal food consumption was reduced and water consumption was increased in all DEHP groups. The number and percentage of fetuses malformed per litter were unaffected by treatment. In mice, maternal toxicity, increased resorptions and late fetal deaths, decreased number of live fetuses, and reduced fetal body weight per litter were observed at 0.10 and 0.15%. Maternal food and water consumption exhibited a dose-related upward trend with food consumption significantly increased at 0.15%. The number and percentage of fetuses malformed per litter (open eye, exophthalmia, exencephaly, short, constricted, or no tail, major vessel malformations, fused or branched ribs, and fused or misaligned thoracic vertebral centra) were elevated at 0.05, 0.10, and 0.15% DEHP. In conclusion, DEHP was not teratogenic at any dose tested in Fischer 344 rats when administered in the feed throughout gestation but did produce maternal and other embryofetal toxicity at 1.0, 1.5, and 2.0%. In contrast, DEHP administration throughout gestation in CD-1 mice resulted in an increased incidence of malformations at doses which produced maternal and other embryofetal toxicity (0.10 and 0.15%) and at a dose (0.05%) which did not produce significant maternal toxicity. No treatment-related embryofetal toxicity including teratogenicity was observed in mice at 0.025% or in rats at 0.5% DEHP.

Animals↗
PubMed1987

The developmental toxicity of diethylene glycol dimethyl ether in mice.

Diethylene glycol dimethyl ether (diEGdiME) is structurally related to several compounds which produce reproductive and developmental toxicity, including teratogenicity in laboratory animals. In the present study, diEGdiME (0, 62.5, 125, 250, or 500 mg/kg/day) was administered by gavage in distilled water to timed-pregnant CD-1 mice during major organogenesis [gestational days (gd) 6-15]. Clinical status of treated females was monitored daily during treatment and on gd 17. At sacrifice (gd 17), pregnancy was confirmed by uterine examination for 20-24 dams per group; each live fetus was examined for external, visceral, and skeletal malformations. No maternal deaths, morbidity, or treatment-related clinical signs were observed. Reduced maternal weight gain during treatment at greater than or equal to 250 mg/kg/day was primarily attributed to compromised pregnancy status resulting in reduced gravid uterine weight. Maternal weight gain during gestation corrected for gravid uterine weight, and relative liver weight (% body weight) were not affected. Average fetal body weight/litter was significantly reduced at greater than or equal to 125 mg/kg/day. The percentage of postimplantation loss/litter (5, 8, 7, 12, and 50% for control through high dose) and the percentage of malformed live fetuses/litter (0.4, 0, 2, 24, and 96%) were significantly increased at greater than or equal to 250 mg/kg/day. Developmental defects involved primarily the neural tube, limbs and digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs, and both the axial and appendicular skeleton. In summary, oral administration of diEGdiME during major organogenesis did not produce any distinctive signs of maternal toxicity, but did produce selective and profound adverse effects upon fetal growth, viability, and morphological development at greater than or equal to 125 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1987

The developmental toxicity of bisphenol A in rats and mice.

Bisphenol A (BPA) was evaluated for developmental toxicity in CD 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 intubation on Gestational Days 6 through 15. Timed-pregnant dams were sacrificed 1 day prior to parturition, the uterine contents were examined, and all fetuses were examined for external, visceral, and skeletal malformations. In rats, maternal weight gain during gestation, weight gain corrected for gravid uterine weight, and weight gain during treatment were significantly reduced at all BPA doses. Gravid uterine weight and average fetal body weight per litter were not affected by BPA. No increase in percentage resorptions per litter or percentage fetuses malformed per litter was detected. In mice, maternal mortality occurred at all BPA doses, reaching 18% at the high dose, which also produced a significant decrease in maternal body weight gain during gestation and treatment. Weight gain corrected for gravid uterine weight was not affected by BPA. Reductions in gravid uterine weight and average fetal body weight were observed with the 1250 mg/kg dose of BPA. Relative maternal liver weight was increased at all doses of BPA. There was a significant increase in the percentage of resorptions per litter with 1250 mg BPA/kg/day. Malformation incidence was not altered by BPA. Thus, BPA treatment at maternally toxic dose levels during organogenesis produced fetal toxicity in mice but not in rats and did not alter fetal morphologic development in either species.

Animals↗
PubMed1987

The developmental toxicity of triethylene glycol dimethyl ether in mice.

Triethylene glycol dimethyl ether (triEGdiME) is structurally related to several compounds which produce reproductive and developmental toxicity, including teratogenicity in laboratory animals. In the present study, triEGdiME (0, 250, 500, or 1000 mg/kg/day) was administered by gavage to timed-pregnant CD-1 mice during major organogenesis (Gestational Days (gd) 6-15). Maternal clinical 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 skeletal malformations. No maternal death or morbidity was observed. Clinical signs of toxicity including piloerection were minor. Maternal weight gain during treatment, gestation, and maternal weight gain during gestation corrected for gravid uterine weight were not affected. Gravid uterine weight decreased in a dose-related manner, indicating compromised pregnancy status. Relative maternal liver weight (% body wt) was significantly increased over controls at doses greater than or equal to 500 and 1000 mg/kg/day. Average fetal body weight per litter was significantly reduced at doses greater than or equal to 500 mg/kg/day. The percentage malformed live fetuses per litter (0.3, 0, 0.8, and 11.1%) was significantly increased at 1000 mg/kg/day. Major malformations affected primarily the development of the neural tube, craniofacial structures, and the axial skeleton. In summary, oral administration of triEGdiME during major organogenesis produced only marginal signs of altered maternal status, as evidenced by an increase in maternal liver weight, and caused selective adverse effects upon fetal growth and morphological development at doses greater than or equal to 500 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1986

The developmental toxicity of orally administered oxytetracycline in rats and mice.

Timed-pregnant CD rats and CD-1 mice were dosed by gavage with oxytetracycline hydrochloride (OXT) in corn oil on gestational days (gd) 6-15 (0, 1200, 1350, or 1500 mg/kg/day for rats; 0, 1325, 1670, or 2100 mg/kg/day for mice). Deaths among treated females occurred in a dose-related manner in all OXT dose groups (2-7%, mice; 5-24%, rats), but no maternal deaths occurred in the vehicle control groups. Significant dose-related decreases in maternal weight gain during treatment, as well as for corrected gestational weight gain (i.e., maternal gestational weight gain minus gravid uterine weight), were observed at all doses in rats but not in mice. Gravid uterine weight was reduced in a dose-related manner only in mice, with the high-dose group significantly reduced compared to the control group. At termination (gd 20, rats; gd 17, mice), the status of uterine implantation sites was recorded and live fetuses were weighed. Fetuses were examined for external, visceral, and skeletal abnormalities. There were no significant effects of OXT in either species on the incidence of postimplantation loss (resorptions plus dead fetuses) or malformations. In both species, there was a significant trend toward reduced fetal body weight, and each group of rats receiving OXT was significantly reduced compared to the control group. Administration of OXT during organogenesis at doses exceeding the therapeutic range for humans produced maternal and fetal toxicity, but did not produce any treatment-related increase in malformations.

Animals↗
PubMed1985

The developmental toxicity of ethylene glycol in rats and mice.

Timed-pregnant CD rats and CD-1 mice were dosed by gavage with ethylene glycol (EG) in distilled water on gestational days (gd) 6 through 15 (0, 1250, 2500, or 5000 mg kg-1 day-1 for rats; and 0, 750, 1500, or 3000 mg kg-1 day-1 for mice). Females were observed daily during treatment, but no maternal deaths or distinctive clinical signs were noted. Dose-related decreases in maternal weight gain during treatment were significant at all doses in rats and at the mid and high doses in mice. Gravid uterine weight was reduced in both species at the mid and high doses, and corrected maternal gestational weight gain showed a significant decreasing trend. At termination (gd 20, rats; gd 17, mice), the status of uterine implantation sites was recorded, and live fetuses were weighed and examined for external, visceral, and skeletal malformations. Dose-related increases in postimplantation loss per litter were observed in both species with the high dose significantly above controls only in rats. Fetal body weight per litter was significantly reduced at the mid and high doses in rats and at all doses in mice. The percentage of malformed live fetuses per litter and/or the percentage of litters with malformed fetuses was significantly elevated in all EG dose groups and greater than 95% of litters were affected at the high dose for each species. A wide variety of malformations were observed; the most common in both species were craniofacial and neural tube closure defects and axial skeletal dysplasia. EG produced severe developmental toxicity in two rodent species at doses that apparently failed to produce any serious maternal effects.

Animals↗
PubMedDate not supplied

Two-generation reproductive toxicity study of inhaled tertiary amyl methyl ether (TAME) vapor in CD rats.

Under Office of Prevention, Pesticides and Toxic Substances draft guidelines, CD weanling F0 rats (30 of each gender per group) inhaled tertiary amyl methyl ether vapor at 0, 250, 1500 or 3000 ppm 5 days a week and 6 h a day for 10 weeks, with vaginal cytology evaluated for weeks 8-10. The F0 animals then produced F1 offspring, with exposure 7 days a week from mating through to lactation. During the F1 prebreed exposure period, vaginal patency, preputial separation (PPS) and vaginal cytology were evaluated. The F1 animals were mated, with F2 anogenital distance measured on postnatal day zero. At F2 weaning 30 of each gender per group were selected for postwean retention, with no exposures, through vaginal patency and PPS. Body weights, feed consumption and clinical signs were recorded throughout the study. Adult F0 and F1 systemic toxicity was present at 1500 and 3000 ppm. Minor adult male reproductive toxicity was present at 3000 ppm. There were no adult effects on vaginal cyclicity, estrous cycle length, mating, fertility, pregnancy, gestational length or ovarian and uterine weights. There were no treatment-related gross or histopathologic findings in parental male or female systemic or reproductive organs. The F1 and F2 offspring toxicity was present at 1500 and 3000 ppm. The no-observable-adverse-effect level for adult systemic and offspring toxicity was 250 ppm and 1500 ppm for male reproductive toxicity (females at >3000 ppm).

Air Pollutants↗