Effects of triethylenetetramine upon the metabolism and toxicity of 63NiCl2 in rats

Triethylenetetramine (TETA, 0.75 mmol/kg, im) was administered to Fischer rats immediately prior to ⁶³NiCl₂ (0.068 or 0.10 mmol/kg, ip or im) to determine (a) effects of TETA upon ⁶³Ni-kinetics, and (b) antidotal effects of TETA upon Ni-induced nephrotoxicity and hyperglycemia. TETA markedly reduced plasma ⁶³Ni concentrations and greatly increased urine ⁶³Ni excretion during 6 hr after injection of ⁶³NiCl₂, compared to values in control rats that received only ⁶³NiCl₂. In rats killed 6 hr after injections of TETA and ⁶³NiCl₂, ⁶³Ni concentrations in liver, kidney, spleen, lung, and heart averaged 3.4, 0.72, 0.27, 0.22, and 0.12 times corresponding ⁶³Ni concentrations in organs from control rats that received only ⁶³NiCl₂. The results supported the hypothesis that combined administration of TETA and ⁶³NiCl₂ resulted in partition of the body pool of ⁶³Ni between two major ⁶³Ni-components: (a) ⁶³Ni-TETA complex, and (b) nonchelated-⁶³Ni, and that each ⁶³Ni-component was eliminated from plasma according to its respective clearance. The renal clearance of ⁶³Ni-TETA complex was estimated to be >20 times that of nonchelated-⁶³Ni. Administration of TETA substantially reduced Ni-induced proteinuria and aminoaciduria. TETA did not prevent Ni-induced hyperglycemia and hyperglucagonemia, but TETA did partially inhibit Ni-induced hyperinsulinemia.     

Placental transfer and body distribution of nickel chloride in pregnant mice

Placental transfer and body distribution of NiCl₂ were studied in pregnant mice (ICR strain, 12–14 weeks old). A single injection of NiCl₂ (4.6 mg/kg as Ni ip) was administered on the 16th day of gestation. Animals were killed at intervals of 2, 4, 6, 8, 10, 24, 30, and 48 hr after the injection and tissues were obtained for measurement of nickel concentration. Concentration of nickel in blood and placentas were found to be at maximum level (19.8 and 3.9 μg/g) 2 hr after injection, and those in liver, spleens, and kidneys reached maximum levels of 4.9, 1.3, and 56.2 μg/g, respectively, 4 hr after injection. Maximum concentration in fetal tissues (1.1 μg/g) was reached 8 hr after injection, and a slight gradual decrease was observed during 24 hr. Thereafter, there was a rapid decrease. The relative concentrations of Ni in blood, organs, and tissues of pregnant mice at 24 hr after injection were found in order from highest to lowest concentration: Kidneys > blood > placentas > fetuses ? liver > spleen. It is estimated that the Ni will be excreted in about 42 to 84 hr after injection from the calculated biological half-times.     

Aminoaciduria and proteinuria in rats after a single intraperitoneal injection of Ni(II).

Proteinuria was found in Fischer female rats after a single ip injection of NiCl₂ in dosages from 34 to 85 μmol/kg (2–5 mg Ni/kg). Generalized α-aminoaciduria was found after a single ip injection of NiCl₂ in dosages of 68 and 85 μmol/kg (4 and 5 mg Ni/kg). Amino acids in plasma were normal or slightly diminished from 1 to 48 hr after injection of Ni(II). Electron microscopy of kidneys of five rats at 48 hr after Ni(II) (68 μmol/kg) consistently revealed fusion of foot processes of glomerular epithelial cells. Focal tubular necrosis was present in the kidney of one of these rats. This study demonstrates that toxic nephrophathy with aminoaciduria and proteinuria develops in rats after ip Ni(II). Amino acid and protein excretions consistently returned to normal by Day 5.     

The toxic effects of nickel chloride on liver,erythropoiesis, and development in Wistar albino preimplanted rats can be reversed with selenium pretreatment

The exposure to nickel chloride (NiCl₂) can cause hematotoxicity and hepatotoxicity and canaffect development. The present study pertains to the protective effect of selenium (Se) against NiCl₂‐induced toxicity in preimplanted Wistar albino rats. The subcutaneous (s.c.) administration of 25 or 50 mg/kg of NiCl₂ to Wistar albino rats on day 3 of gestation induced an immediate and significant decrease in maternal body weight and anemia 2 days after treatment. In addition, an increase in plasma aspartate aminotransferase (AST) was observed. These effects were maintained on day 20 of gestation. Moreover, a significant increase in plasma alanine aminotransferase (ALT) levels was observed with the administration of 25 mg/kg of NiCl₂. Conversely, administration of 50 mg/kg of NiCl₂ by s.c. injection increased erythropoiesis at day 20 of gestation and decreased platelets counts. In addition, administration of 100 mg/kg of NiCl₂ markedly reduced the maternal body weight and number of live fetuses and increased fetal loss, predominantly at the end of the experimental period. All dose levels of NiCl₂ caused an alteration in the hepatic histoarchitecture. When 0.3‐mg/kg Se was injected s.c. with 100‐mg/kg NiCl₂, the levels of plasma AST and ALT and the structure of the liver were restored. Administration of 20 mg/L/day of NiCl₂ in the drinking water significantly reduced the maternal body weight at day five of gestation as well as erythropoiesis during the exposure period. The present study suggests that Se can counteract the nocuous effect of nickel on the liver; however this antioxidant did not prevent alterations in development and erythropoiesis. © 2011 Wiley Periodicals, Inc. Environ Toxicol 2013.     

Nadolol: placental transfer and excretion in the milk of rats.

The transfer of radioactivity from maternal blood to the fetuses of pregnant rats was studied after they had been dosed orally with 100 mg/kg of [¹⁴C]nadolol (2,3-cis-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol) on Days 12, 15, and 18 of gestation. On Day 12 of gestation, during the time of organogenesis, radioactivity crossed the placental barrier to the fetuses; however, the extent of this transfer was significantly reduced on Days 15 and 18 of gestation. The excretion of radioactivity was studied in the milk of lactating rats that had been given oral 100-mg/kg doses of [¹⁴C]nadolol. Twelve or 30 hr after the dams had been dosed, radioactivity was presentin greater concentrations in milk than it was in either blood or plasma. The amount of radioactivity found in the pups that had been allowed to suckle during the intervals of 0 to 6 and 12 to 24 hr after the dams had been dosed was, for both intervals, an average of 0.041% of the dose.     

A study of teratological effects of intravenous, subcutaneous, and intragastric administration of delta9-tetrahydrocannabinol in mice.

Delta-9-tetrahydrocannabinol (Δ⁹-THC) has been recognized to be the principal psychoactive component of cannabis. Pregnant Swiss Webster mice were given single treatments of Δ⁹-THC at doses ranging from 3.0 to 400 mg/kg by the iv, sc, and po routes on gestational Days 7 to 11. Untreated and vehicle-injected controls were used for each series. All fetuses were examined on Day 18 of gestation. Significant fetal growth retardation was induced by several dose levels. No malformations were found after single iv doses of 10 and 20 mg/kg of Δ⁹-THC. Subcutaneous injections of 6.25 mg/kg of Δ⁹-THC produced few abnormal fetuses (3.9%). However, a high po dose of 400 mg/kg given on Day 9 was teratogenic; 12.1% of the live fetuses were malformed. Fetuses from DBA mice given single po doses of Δ⁹-THC on Days 8, 9, or 10 of pregnancy also had a significantly increased incidence of gross external abnormalities as compared to corresponding controls; 23% of the fetuses from dams given 200 mg/kg of Δ⁹-THC on gestational Day 10 were abnormal. Skeletal anomalies were also induced in fetuses from dams treated with 200 mg/kg of Δ⁹-THC on Day 10 by gastric intubation. These results are considered in relation to previous reports of a complete lack of teratogenic activity of multiple exposure to Δ⁹-THC and a highly significant teratogenicity of crude extracts of cannabis in experimental animals.     

Protective effect of Dunaliella sp., lipid extract rich in polyunsaturated fatty acids,on hepatic and renal toxicity induced by nickel in rats

Aims: The present study was undertaken to investigate the protective effect of lipid extract of Dunaliella sp. (LE) rich in polyunsaturated fatty acids (PUFA), against oxidative stress induced by nickel in experimental rats.

Methods: Our investigation evaluated the antioxidant activity of LE using both DPPH and NBT assays. Twenty female albino Wistar rats, randomly allocated into four experimental groups, namely (C): control, (Ni_t): nickel-treated rats with 5?mg/kg/d of NiCl₂ during 30 days, (LE_a): lipid extract-administered rats with 5 mg/kg BW/d during 30 days and (Ni_t?+_?LE_a): rats treated with Ni and LE-administered during 30 days.

Results: The in vitro antioxidant activity demonstrated that LE presents an important antioxidant potential. In vivo, the (Ni_t?+_?LE_a) cotreatment decreased the level of malondialdehyde and restored the antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase) in livers and kidneys in comparison with those treated with Ni only. LE administration to rats treated with Ni also ameliorated biochemical and histological parameters as compared to only Ni-treated group. LE of Dunaliella sp., rich in polyunsaturated fatty acids showed a significant hepato- and reno-protective effect against metal-induced toxicity.

Conclusion: LE of Dunaliella sp., rich in PUFA has been proven to be effective in protection against Ni-induced toxicity.     

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.     

Dopamine and interscapular fat hemorrhage in the rat pup

Female Sprague-Dawley rats were given dopamine during gestation. Several hours after birth, interscapular adipose tissue hemorrhages appeared in some of the offspring of dopamine-treated rats. Dopamine (10 mg/kg/day ip) administered during Days 1–7, 8–14, and 15–21 of gestation caused hemorrhages in 14.8, 6.2, and 0.0% of the offspring, respectively. Only 1.9 and 1.6% of 21-day fetuses from rats given either dopamine (10 mg/kg/day ip) or saline, respectively, during Days 1–7 of gestation had hemorrhages in the interscapular fat. During Days 1–7 of gestation, dopamine (10 mg/kg/day) given intramuscularly produced hemorrhages in only 3.0% of the offspring; intraperitoneal administration led to 14.8% hemorrhage. Female rats were given a single dose of 2.0 μCi of [¹⁴C]dopamine (10 mg/kg ip) on Day 7 of gestation and sacrificed after birth. No radioactivity was detected in the interscapular fat, liver, kidney, or brain of the newborn pups. Only the maternal adrenal gland and kidney contained measurable radioactivity (0.011 and 0.006% of the dose per gram of tissue). Moreover, rats given 0.5 μCi of [¹⁴C]dopamine (10 mg/kg im) on Day 3 of gestation excreted 99.9% of the radioactivity in their urine within 4 days. Neither vaginal norepinephrine content nor adrenal tyrosine hydroxylase activity in 21-day pregnant rats was altered by dopamine treatment during Days 1–7 of gestation. Thus, neither exogenous dopamine nor endogenous catecholamines appear to be the final mediator of the hemorrhagic mechanism.     

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

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

Reproduction and teratology studies with oncolytic agents in the rat and rabbit. II. 5-(3,3-dimethyl-l-triazeno)imidazole-4-carboxamide (DTIC).

Studies were conducted to evaluate the effects of DTIC, a new anticancer drug, on embryonal and fetal development in the rat and rabbit, and on reproduction, perinatal and postnatal behavior, and development in the rat. Twice weekly ip treatment of male rats for 9 weeks with 12.5, 25, or 50 mg/kg did not affect male libido, although females mated to males given 50 mg/kg twice weekly had a higher incidence of resorptions than controls. Intraperitoneal treatment with 7.5, 15, or 30 mg/kg/day for 14 days prior to breeding and through Day 20 of gestation resulted in a higher incidence of resorptions and fewer live fetuses in dams receiving 15 or 30 mg/kg. Doses of 30, 50, or 70 mg/kg given ip on Days 6–15 of gestation resulted in fetal skeletal anomalies, whereas soft tissue anomalies involving the eye, cardiovascular system, and abdominal wall occurred only in fetuses from dams treated with 50 or 70 mg/kg. Treatment from Day 15 of gestation through Day 21 postpartum with 7.5, 15, or 30 mg/kg/day resulted in a dose-dependent adverse effect on neonate survival. In rabbits treated ip on Days 6–18 of gestation at doses of 2.5, 5, or 10 mg/kg/day, DTIC was materno- and fetotoxic and resulted in numerous skeletal abnormalities in fetuses from does treated with 10 mg/kg/day.     

Binding of 63Ni by Cellular Constituents in Some Tissues of Mice after the Administration of 63NiCl2 and 63Ni(CO)4

Abstract One and 24 hours after the administration of ⁶³NiCl₂ and ⁶³Ni(CO)₄ to mice ⁶³Ni was present in association with both particulate and soluble cellular constituents in the lung, liver and kidney. After disruption of the cellular organells by sonication, a considerable part of the ⁶³Ni was still bound to the cellular fragments. Sephadex G-75 chromatography of the cytosol of the lung showed that the largest proportion of ⁶³Ni was eluted in the void volume and a smaller proportion was present in the salt volume. In the kidney, the proportions were reversed. Twentyfour hours after the injection of ⁶³NiCl₂ an intermediate ⁶³Ni-containing peak, with an estimated molecular weight of about 30,000, was found in the lung and the kidney. In the liver of ⁶³NiCl₂-injected mice, most of the nickel was recovered in the void volume, a lesser amount in the salt volume. There was no evidence that ⁶³Ni was bound to metallothionein (induced by Cd-pretreatment) or to superoxide dismutase in the studied tissues. Pretreatments with non-labelled NiCl₂ did not alter the elution profiles. In serum, most ⁶³Ni was present in association with albumin. Gel-chromatograms of red blood-cell hemolysates from ⁶³Ni(CO)₄-injected mice showed ⁶³Ni at an elution volume corresponding to hemoglobin, but ⁶³Ni-binding ligands with higher and lower molecular weights were also present.     

Chronic toxicity, teratologic, and reproduction studies with hair dyes.

Administration of paraquat to mice, 1.67 and 3.35 mg/kg ip or 20 mg/kg po, daily on Days 8–16 of gestation induced no significant teratogenic effects, although a slight increase in nonossification of sternabrae was observed. Radioactivity reaching the mouse embryo after ip or po administration of [¹⁴C]paraquat on Day 11 of gestation was low. The fetal toxicity of diquat in rats, as measured by the number of dead and resorbing fetuses, was greater than that caused by paraquat after 15 mg/kg iv doses on various days of gestation, which correlated with higher fetal concentrations of [14C]diquat compared to [¹⁴C]paraquat. In perinatal organ distribution studies, more radioactivity from [¹⁴C]paraquat was retained in lung tissue of postnatal mice and rats than that in liver and kidney tissue. In prenatal studies, however, [¹⁴C]paraquat was retained in lung tissue of fetal rats after maternal administration of paraquat on Day 21 of gestation but not in lung tissue of fetal mice after maternal paraquat on Day 16 of gestation. This may be indicative of prenatal development of binding sites or of an active transport process for the uptake of paraquat into the lung or that elevated oxygen tensions in postnatal lungs contributes to paraquat retention in lung tissue.     

Comparison of protein, RNA, and DNA binding and cell-cycle-specific growth inhibitory effects of nickel compounds in cultured cells

Crystalline NiS particles are potent inducers of morphological transformation and are actively phagocytosed by cells. Water-soluble nickel compounds are less potent, possibly because the total amount of nickel that enters cells is less, and its subcellular distribution differs in a number of ways from that following the entry of NiS in the form of an internalized particle. To further study this problem, we have examined the binding of ⁶³Ni to DNA, RNA, and protein isolated from cultured Chinese hamster ovary cells treated with either crystalline ⁶³NiS or ⁶³NiCl₂. Treatment of cultured cells with ⁶³NiS at 10 μg/ml for 3 days resulted in binding of nickel to DNA, RNA, or protein in the range of 1 μg of nickel bound per milligram macromolecule. However, similar treatment of cells with ⁶³NiCl₂ at 10 μg/ml for 1 to 5 days resulted in approximately one to several orders of magnitude less nickel bound to DNA, RNA, and protein. In the case of ⁶³NiCl₂ treatment, cellular proteins contained about 100 times more ⁶³Ni bound than the respective RNA or DNA fractions. However, the protein fraction obtained from cells treated with crystalline NiS contained about 15 times more nickel bound than the same fraction isolated from cells that were similarly treated with ⁶³NiCl₂. RNA or DNA had 300 to 2000 times more bound nickel following crystalline NiS treatment compared to cells treated similarly with NiCl₂. In contrast to the selective binding of ⁶³NiCl₂ to protein, cultured cells treated with crystalline ⁶³NiS had equivalent levels of nickel associated with RNA, DNA, and protein. Since the interaction of ⁶³Ni with these macromolecules following crystalline ⁶³NiS treatment was not due to the binding of the actual particles, the dissolution of intracellular ⁶³NiS particles probably plays an important role in governing the distribution of ⁶³Ni ions available for binding. The greater intracellular macromolecular binding of ⁶³Ni resulting from treatment of cells with ⁶³NiS compared to cultures similarly exposed to ⁶³NiCl₂ paralleled the more potent effects of crystalline NiS in slowing and arresting cell proliferation. Crystalline NiS caused pronounced cell cycle specific blockage at a considerably lower concentration than was required for NiCl₂ to similarly arrest cell growth. Flow cytometry analysis showed that both compounds selectively blocked cell cycle progression in S phase (DNA synthetic stage). These results are suggestive of a common mechanism and site of toxicity inherent to both compounds and related to the cell growth phase during which DNA is replicated.     

Disposition of NICKEL-63 in the rat

The urinary and faecal excretion of nickel-63 (⁶³Ni) and the distribution of ⁶³Ni in kidneys, liver, heart and blood serum after an i.p. injection of radiolabelied nickel chloride (⁶³NiCl₂) have been investigated. Most of ⁶³Ni was excreted via urine within 24 h. The daily faecal excretion, though very low, was consistent up to 6 days. The uptake of ⁶³Ni was highest in kidneys and the order was kidneys 0 serum > heart > liver, 24 h after ⁶³NiCl₂ injection. However, ⁶³Ni was eliminated rapidly from the body and there was almost no radioactivity 6 days post administration.     

Calcium homeostasis in pregnant rats treated with ethylene glycol monomethyl ether (EGME)

The industrial solvent ethylene glycol monomethyl ether (EGME) is a known teratogen that has been reported to alter calcium metabolism in guinea pigs during chronic exposure. Because of the tremendous demand of reproduction on maternal calcium stores, the effects of EGME on calcium and vitamin D metabolism during gestation were examined. Timed pregnant rats were treated by gavage with 0, 50, or 100 mg/kg EGME in 10 ml/kg distilled water on Days 9-15 of gestation (sperm = Day 1) and examined on Days 16 and 21. Virgin rats were treated for 7 days with 0 or 100 mg/kg EGME and examined 5 days later. EGME exposure did not affect body or kidney weight in virgin or pregnant rats, but liver weight was reduced in near-term pregnant rats treated with 100 mg/kg EGME. EGME (50 mg/kg) reduced litter size and fetal body weight and caused a significant number of live fetuses to have visceral abnormalities. EGME (100 mg/kg) caused all fetuses to be resorbed. In nonpregnant rats, 100 mg/kg did not affect serum 1,25-dihydroxyvitamin D (1,25(OH)2D3), 25-hydroxyvitamin D, ionic calcium, total calcium, or parathyroid hormone. EGME appeared to have a dose-dependent effect on calcium and vitamin D metabolism during gestation. On Day 21 of gestation, total calcium and ionic calcium were increased and 1,25(OH)2D3 was reduced in rats treated with EGME compared with nontreated controls. However, significant alterations in calcium homeostasis were evident only in dams that completely resorbed their litters. The changes in calcium and vitamin D metabolism during gestation appear to be secondary to the EGME-induced loss of litters.     

Effects of diethyldithiocarbamate and penicillamine on the tissue distribution of 63NiCl2 in mice

The effects of sodium diethyldithiocarbamate and DL-penicillamine on the fate of ⁶³Ni²⁺ in mice injected with ⁶³NiCl₂ were studied by whole body autoradiography and liquid scintillation counting. Sodium diethyldithiocarbamate caused a retention and redistribution of ⁶³Ni²⁺ in the tissues. DL-penicillamine decreased the ⁶³Ni²⁺-concentration in the tissues. The nickel-diethyldithiocarbamate complex is lipophilic, whereas the nickel-DL-penicillamine complex is hydrophilic, and these differenes in chemical properties may determine the different effects which these chelating agents have on the fate of Ni²⁺.     

Vomitoxin (4-deoxynivalenol): effects on reproduction of mice and rats

Weanling male and female mice (F_o) were fed daily diets containing 4-deoxynivalenol (DON) at concentrations that resulted in a dose of 0 or 2.0 mg/kg body wt in Experiment I and 0, 0.375, 0.75, or 1.5 mg/kg body wt in Experiment II. The test diets were continuously fed to the F_o parents and their progeny for the entire duration of these two experiments, which were similar in design. After 30 days of dietary feeding, the mice were allowed to mate within experimental groups for a maximum of three 5-day trials. Females found to have mated successfully were allowed to litter normally. The F_1a progeny from 10 dams of each control and 1.5-mg DON/kg groups were cross-fostered at birth, whereas all of the remaining F_1a progeny were reared by their natural dams. The progeny were examined until 21 days of age and discarded. The F_o mice were rebred. The females bred to produce the F_1b litters were killed on Day 19 of gestation and their fetuses were examined for gross, visceral, and skeletal malformations. Reductions were observed in feed and water intakes and body weight of F_o male and female mice, the number of live pups and postnatal survivors, postnatal body weight of F_1a progeny, number of live fetuses, and mean fetal weight of F_1b fetuses. No adverse effects on fertility of F₀ male and female mice and no major malformations in F_1b fetuses were found. Cross-fostering offspring between control dams and 1.5-mg DON/kg-treated dams revealed that both postnatal survival and body weight were adversely affected by prenatal exposure as well as by a combined pre- and postnatal exposure. Male and female Sprague-Dawley rats were fed diets containing DON so as to deliver daily doses of 0.25, 0.5, or 1.0 mg/kg body wt. After 6 weeks of feeding, the rats were bred within groups and the males were then discarded. The mated females, maintained on their respective diets for the entire period of pregnancy, were killed on the last day of pregnancy and fetuses evaluated for effects on prenatal development. Except for dilation of renal pelvis and urinary bladder, the significance of which remains undetermined, no other adverse effect was observed.     

Teratogenicity Study of Ethylene Glycol in Rats

ABSTRACT

Ethylene glycol was administered in the diet to pregnant Fischer 344 rats on days 6 through 15 of gestation. Target dosage levels were 1.0, 0.2, 0.04, and 0.00 g/kg/day. There was no maternal toxicity, embryotoxicity, or increased incidence of malformations in fetuses from dosed dams. Positive control dams received 500 mg/kg of hydroxyurea on gestation day 11 and had fetuses with numerous soft tissue and skeletal malformations. Results are interpreted as preliminary indication of lack of teratogenicity of ethylene glycol.     

Comparison of Fetotoxic Effects of a Dermally Applied Complex Organic Mixture in Rats and Mice

A high-boiling (288–454?C), coal-derived complex organicmixture (COM) has been shown to be teratogenic in rats followinginhalation and oral routes of exposure. To determine whethersimilar changes also occur after dermal exposure to this COM,pregnant rats and mice were exposed during periods of organogenesis(Days 11 to 15 of gestation). Shaved backs were painted with0, 500, or 1500 mg/kg of the COM (control, low, or high dose,respectively); the exposed area was not occluded. Maternal weightgain during the gestation period decreased with increasing dosein rats but not in mice. Examination of rat fetuses on Day 20of gestation showed that resorptions had occurred in more than90% of low-and high-dose litters (vs 6% in the control group).In mice, fetal examinations on Day 18 of gestation showed thatresorptions occurred in 71% of litters from both exposure groups(vs 14% in the controls). Fetal measurements indicated thatboth the weight and the length of rat fetuses decreased withincreasing dose, but mouse fetuses were unaffected. Cleft palates,absent in the control groups, were observed in 50 to 55% ofthe high-dose group and 5 to 8% of the low-dose fetuses of bothspecies. Small fetal lungs occurred in nearly 100% of the exposedrat fetuses and in 25% of the high-dose mice; the incidenceof small lungs was 1% in control animals. Other variations observedin exposed groups included edema and reduced ossification inthe rat and renal pelvic cavitation in the mouse. In conclusion,dermal exposure of dams to COM resulted in life-threateningmorphological alterations in fetuses of both species similarto those seen following exposure by Other routes.