Evaluation of the teratogenic potential of the dopamine agonist bromocryptine in rats

Single subcutaneous injections of bromocryptine (BCR; 2 mg/kg) to rats on days 5, 7 or 10 of gestation caused a lowering of the serum prolactin (PRL) concentration and, on days up to and including day 8 of gestation, abortion of entire litters. Coincident with the end of the PRL-dependent phase of gestation (approximately day 9), BCR was no longer abortifacient, allowing higher doses of the drug to be administered from this time without the risk of abortion. Treatment at 50 or 100 mg/kg from day 10 to 16 of pregnancy, despite affecting the dams (increased water consumption), had no adverse effects on pregnancy or fetal development.     

Evaluation of the teratogenic potential of the rubber accelerator dibenzthiazyl disulphide in rats

The teratogenic potential of dibenzthiazyl disulphide (MBTS) was studied in Wistar rats. Pregnant rats were given MBTS at a dosage of 0, 0.04, 0.2 or 1% in the diet from day 0 to day 20 of pregnancy. Daily intakes of MBTS were 26 mg kg-1 for the 0.04% group, 127 mg kg-1 for the 0.2% group and 596 mg kg-1 for the 1% group. Maternal body weight gain during day 0 to day 14 of pregnancy in the 1% group was significantly lowered, but no significant changes induced by MBTS were observed in any other maternal parameters, such as food consumption and clinical sign of toxicity. There were no significant compound-related effects on the incidences of pre- and postimplantation losses and the number, sex ratio and body weight of live fetuses. Morphological examinations of the fetuses revealed no evidence of teratogenesis. In the postnatal development of the offspring from the dams given MBTS, a high survival rate and good growth of the offspring were seen. It could be concluded that MBTS possesses no adverse effects on the pre- and postnatal development of the offspring in rats at the doses employed in the present study.     

Evaluation of the teratogenic potential of the plasticizer butyl benzyl phthalate in rats

The teratogenicity of butyl benzyl phthalate (BBP) was studied in Wistar rats. Pregnant rats were given BBP at a dosage of 0, 0.25, 0.5, 1.0 or 2.0% in the diet from day 0 to day 20 of pregnancy. Daily intakes of BBP were 185 mg kg-1 for the 0.25% group, 375 mg kg-1 for the 0.5% group, 654 mg kg-1 for the 1.0% group and 974 mg kg-1 for the 2.0% group. Adjusted maternal body weight gain (body weight gain excluding the gravid uterus) during pregnancy in the 1.0 and 2.0% groups was significantly lowered. Food consumption during pregnancy in the 0.25 and 0.5% groups did not differ from that in the control group. No death was noted in the pregnant females of any group. There was no significant compound-related effects on the incidence of preimplantation loss. All dams given 2.0% BBP exhibited complete resorption of all the implanted embryos. Morphological examinations of the fetuses revealed no evidence of teratogenesis. It could be concluded that the no-observable-effect-levels (NOEL) in rats were 0.5 and 1.0% BBP in the diet for maternal and embryofetal toxicity, respectively.     

Inhalation toxicology of sodium sulfite aerosols in rats

Rats were exposed to well-characterized aerosols of sodium sulfite, at levels ranging from 0.1 to about 15 mg/m³ and particle sizes of about 1 μm (mass median aerodynamic diameter). The responses of rats to breathing these aerosols for 3 days were evaluated by measurements of glycoprotein secretion rates by cultured tracheal explants from these rats, by measurement of protein, DNA, and RNA levels of lung homogenates prepared from these rats, and by quantitation of wet to dry weight ratios of right apical lung lobes from these rats. Increased rates of glycoprotein secretion were observed for tracheae from rats exposed to 5 or to 15 mg/m³ of Na₂SO₃ aerosol, and increased wet to dry weight ratios of right apical lobes were also observed after exposure to these levels, as well as after exposure to 1 mg/m³ of Na₂SO₃ aerosol. Control experiments involving exposure to a sulfate (Na₂SO₄) aerosol at 15 mg/m³ indicated that the observed effects were indeed due to exposure to the sulfite moiety. Exposure to aerosols of sodium hydroxymethane sulfonate (the product of addition of formaldehyde to sodium sulfite) aerosols (5 mg/m³) elicited less response in these assays than did exposure to sodium sulfite aerosol at the same concentration. We conclude that exposure of rats to well-characterized 1-μm aerosols of sodium sulfite at concentrations equivalent to amounts of SO₂ of about 0.2 – 2.7 ppm results in responses of the rats that may be conveniently evaluated when sensitive enough toxicological indexes are quantitated.     

Evaluation of the teratogenic potential of the rubber accelerator N-cyclohexyl-2-benzothiazylsulfenamide in rats

The teratogenicity of N-cyclohexyl-2-benzothiazylsulfenamide (CBS) was studied in Wistar rats. Pregnant rats were given CBS at a dosage of 0.001, 0.01, 0.1 or 0.5% in the diet from Day 0 to Day 20 of pregnancy. Daily intakes of CBS were 0.7 mg kg-1 for the 0.001% group, 7.1 mg kg-1 for the 0.01% group, 69.6 mg kg-1 for the 0.1% group and 288.8 mg kg-1 for the 0.5% group. Maternal body weight gain during pregnancy in the 0.1 and 0.5% groups was significantly lowered. Food consumption during pregnancy in the CBS-treated groups, except for the 0.5% group, did not differ from that in the control group. Neither death nor clinical signs of toxicity were noted in the pregnant females of any group. Lowered weight in fetuses and the placentae were observed in the 0.5% group. There were no significant compound-related effects on the incidences of pre- and post-implantation losses and the number and ratio of live fetuses. Morphological examinations of the fetuses revealed no evidence of teratogenesis. It could be concluded that CBS possesses no adverse effects on the prenatal development of the offspring in rats at doses employed in the present study.     

The teratogenic potential of the herbicide glyphosate-Roundup in Wistar rats

The aim of this study was to assess the teratogenicity of the herbicide glyphosate-Roundup (as commercialized in Brazil) to Wistar rats. Dams were treated orally with water or 500, 750 or 1000 mg/kg glyphosate from day 6 to 15 of pregnancy. Cesarean sections were performed on day 21 of pregnancy, and number of corpora lutea, implantation sites, living and dead fetuses, and resorptions were recorded. Weight and gender of the fetuses were determined, and fetuses were examined for external malformations and skeletal alterations. The organs of the dams were removed and weighed. Results showed a 50%, mortality rate for dams treated with 1000 mg/kg glyphosate. Skeletal alterations were observed in 15.4, 33.1, 42.0 and 57.3% of fetuses from the control, 500, 750 and 1000 mg/kg glyphosate groups, respectively. We may conclude that glyphosate-Roundup is toxic to the dams and induces developmental retardation of the fetal skeleton.     

Evaluation of the teratogenic potential of phosphamidon in mice by gavage

Phosphamidon, an organophosphate pesticide, is an established cholinesterase inhibitor. Alteration of tissue and plasma cholinesterase activity at a critical developmental period may influence cellular division and growth sufficiently to produce anatomically or functionally abnormal tissue or organ. The present study was, therefore, undertaken to evaluate the teratogenic potential of phosphamidon in pregnant Swiss albino mice, when administered at different gestational days during the period of organogenesis. The animals were sacrificed on day 18 of gestation for routine teratological examinations. It was observed that phosphamidon was more embryotoxic than teratogenic. Maximum effects were observed when administered on day 7 and day 13. Treatment on day 10 produced little effects. Repeated exposure during the organogenetic phase also produced significant adverse effects. This possibly indicates that phosphamidon is more embryotoxic during the post-implantation period (day 7) and during late organogenesis (day 13) as compared to the early organogenesis period (day 10).     

Evaluation of the teratogenic potential of the oxidative dye N-phenyl-para-phenylenediamine

The oxidative dye N-phenyl-para-phenylenediamine was evaluated for teratogenic potential. The dye was administered by gavage to pregnant Sprague-Dawley rats at dose levels of 50, 100, and 200 mg/kg on gestation days six through fifteen. No signs of toxicity were observed during the treatment period. A significant reduction in mean maternal weight gain was noted during treatment at the high dose level of 200 mg/kg. The test material did not produce embryotoxic nor fetal toxic effects at dose levels utilized. Evaluation of fetal external, visceral, and skeletal anomalies revealed no statistically significant differences between dye treated and control groups. Oral exposure of dams to the positive control, Vitamin A, resulted in a significant increase in the number of litters with fetuses having external, visceral, and skeletal anomalies.     

A study of the potential teratogenic effects of pentachloronitrobenzene in rats.

Pregnant Charles River CD strain albino rats received daily oral doses of 8, 20, 50, or 125 mg pentachloronitrobenzene (PCNB)/kg on Days 6–15 of gestation. Three control groups were also used: a negative control group which received no treatment, a vehicle control group receiving corn oil, and a positive control group which received chlorcyclizine HCL. Treatment with PCNB had no apparent effect on reproductive parameters such as the number and position of implantations, incidence of dead and/or resorbed fetuses, viable litter size, fetal sex ratios, and birth weights. Detailed gross, visceral, and skeletal examinations were performed on fetuses removed from dams on Day 20 of gestation. The number and type of external, soft tissue and skeletal malformations and variations detected in PCNB groups did not differ significantly from those found in negative and vehicle controls. Under the conditions of the present study, PCNB when administered in daily oral doses of up to 125 mg/kg during the period of differentiation and organogenesis, is not embryolethal nor teratogenic in the rat.     

Evaluation of the teratogenic potential and reproductive toxicity of coal-derived naphtha

Liquids which are derived from coal liquefaction processes and boil above approximately 250 degrees C have induced terata in rats. However, few studies have addressed the teratogenic potential of coal liquids which boil below 250 degrees C. The present studies evaluated the reproductive and teratogenic potential of EDS hydrotreated naphtha, a refined coal liquid boiling below 177 degrees C. These studies were conducted by inhalation exposures with Sprague-Dawley rats at target vapor concentrations of 0.2, 1.0, and 5.0 g/m3. The first study assessed teratogenesis. There was no evidence that inhalation exposures for 6 hr per day between Days 6 and 19 of gestation induced maternal toxicity, fetal toxicity, or malformation. In a second study, rats were exposed for 6 hr per day, 5 days per week for 13 weeks, and then mated to assess reproductive toxicity. There was little evidence that inhalation exposure to EDS hydrotreated naphtha adversely affected reproductive performance or fetal development in Sprague-Dawley rats. A low incidence of malformations was observed in treated groups, but these malformations were probably not treatment related.     

Anti-candida activity of sodium sulfite

The growth of Candida albicans in RPMI1640 medium was inhibited by sodium sulfite between pH 3-6. Under the condition of pH 7, growth of C. albicans was not inhibited by sodium sulfite. Under an acidic pH condition, sodium sulfite had a candidacidal effect and the activity was expressed within 150 min. The concentration of ATP in C. albicans was decreased by sodium sulfite. Ethanol production by C. albicans was inhibited by sodium sulfite at pH 5. These results indicated that the candidacidal effect of sodium sulfite under acidic conditions was caused by interruption of alcohol fermentation and aerobic respiration.     

An experimental evaluation of possible teratogenic potential in Boerhaavia diffusa in Albino rats.

The present study was undertaken to evaluate any possibility of teratogenic effects in Boerhaavia diffusa (Punarnava), a widely used herbal medicine for renal and urinary tract diseases by Ayurvedic physicians in India. The ethanolic extract of Boerhaavia diffusa (BDE) was administered daily in a dose of 250 mg/kg, body weight p.o., to pregnant albino female rats during the entire period of gestation. BDE was found to be devoid of any teratogenic effect as litter size and survival rate of foetuses were the same as for the normal control group and no foetal anomaly could be detected.     

The teratogenic potential in rats and rabbits of D & C Yellow No. 8

The teratogenic potential of D & C Yellow No. 8, sodium fluorescein (C.I. No. 45350, CAS No. 518-47-8) was determined in rats and rabbits. An aqueous solution of the dye was administered by gavage to groups of 25 Charles River Sprague-Dawley rats at doses of 100, 500 and 1500 mg/kg on days 6-19 of gestation and to groups of 14 Dutch Belted rabbits at doses of 30, 100 and 250 mg/kg on days 6-27 of gestation. These doses did not result in evidence of maternal toxicity or adverse effects on foetal development.     

Final report on the safety assessment of sodium sulfite, potassium sulfite, ammonium sulfite, sodium bisulfite, ammonium bisulfite, sodium metabisulfite and potassium metabisulfite

Sodium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Potassium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite are inorganic salts that function as reducing agents in cosmetic formulations. All except Sodium Metabisulfite also function as hair-waving/straightening agents. In addition, Sodium Sulfite, Potassium Sulfite, Sodium Bisulfite, and Sodium Metabisulfite function as antioxidants. Although Ammonium Sulfite is not in current use, the others are widely used in hair care products. Sulfites that enter mammals via ingestion, inhalation, or injection are metabolized by sulfite oxidase to sulfate. In oral-dose animal toxicity studies, hyperplastic changes in the gastric mucosa were the most common findings at high doses. Ammonium Sulfite aerosol had an acute LC(50) of >400 mg/m(3) in guinea pigs. A single exposure to low concentrations of a Sodium Sulfite fine aerosol produced dose-related changes in the lung capacity parameters of guinea pigs. A 3-day exposure of rats to a Sodium Sulfite fine aerosol produced mild pulmonary edema and irritation of the tracheal epithelium. Severe epithelial changes were observed in dogs exposed for 290 days to 1 mg/m(3) of a Sodium Metabisulfite fine aerosol. These fine aerosols contained fine respirable particle sizes that are not found in cosmetic aerosols or pump sprays. None of the cosmetic product types, however, in which these ingredients are used are aerosolized. Sodium Bisulfite (tested at 38%) and Sodium Metabisulfite (undiluted) were not irritants to rabbits following occlusive exposures. Sodium Metabisulfite (tested at 50%) was irritating to guinea pigs following repeated exposure. In rats, Sodium Sulfite heptahydrate at large doses (up to 3.3 g/kg) produced fetal toxicity but not teratogenicity. Sodium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite were not teratogenic for mice, rats, hamsters, or rabbits at doses up to 160 mg/kg. Generally, Sodium Sulfite, Sodium Metabisulfite, and Potassium Metabisulfite were negative in mutagenicity studies. Sodium Bisulfite produced both positive and negative results. Clinical oral and ocular-exposure studies reported no adverse effects. Sodium Sulfite was not irritating or sensitizing in clinical tests. These ingredients, however, may produce positive reactions in dermatologic patients under patch test. In evaluating the positive genotoxicity data found with Sodium Bisulfite, the equilibrium chemistry of sulfurous acid, sulfur dioxide, bisulfite, sulfite, and metabisulfite was considered. This information, however, suggests that some bisulfite may have been present in genotoxicity tests involving the other ingredients and vice versa. On that basis, the genotoxicity data did not give a clear, consistent picture. In cosmetics, however, the bisulfite form is used at very low concentrations (0.03% to 0.7%) in most products except wave sets. In wave sets, the pH ranges from 8 to 9 where the sulfite form would predominate. Skin penetration would be low due to the highly charged nature of these particles and any sulfite that did penetrate would be converted to sulfate by the enzyme sulfate oxidase. As used in cosmetics, therefore, these ingredients would not present a genotoxicity risk. The Cosmetic Ingredient Review Expert Panel concluded that Sodium Sulfite, Potassium Sulfite, Ammonium Sulfite, Sodium Bisulfite, Ammonium Bisulfite, Sodium Metabisulfite, and Potassium Metabisulfite are safe as used in cosmetic formulations.     

Evaluation of the teratogenic potential of cocoa powder and theobromine in New Zealand White rabbits

Studies were conducted to determine the teratogenic potential of theobromine (TBR) and cocoa powder (CP) in rabbits. TBR was given either by gavage at dose levels of 0, 25, 75, 125 or 200 mg/kg body weight/day or administered in the diet at 0, 0.0625, 0.125 or 0.1875% (approximately 0, 21, 41 or 63 mg/kg/day, respectively). CP was given at 2.5, 5.0 or 7.5% of the diet (approximately 25, 50 or 75 mg methylxanthines/kg body weight/day). The duration of exposure was from days 6 to 29 of gestation. Significant maternal mortality (40%) and reduced food consumption were observed at 200 mg TBR/kg/day. Mean foetal weights were similar to those of the control group at 25 or 75 mg TBR/kg/day, but decreases in foetal body weight and increases in various malformations and developmental variations were observed in groups given 125 or 200 mg/kg/day. Insufficient litters were available for examination in the 200-mg/kg/day dose group because of maternal toxicity/lethality (repetitive exposure by gavage to 200 mg TBR/kg approached the maternal LD50). In the dietary CP studies, three does died and three aborted, but these deaths and abortions were not treatment related. No maternal deaths occurred during dietary TBR exposure. Maternal weight gain and food consumption, and the mean number of corpora lutea were unaffected by either dietary CP or TBR. Neither foetotoxicity nor teratogenicity was associated with dietary ingestion of CP or TBR. The foetuses exposed to 0.125% or 0.1875% TBR had a significantly higher incidence of incompletely ossified or absent sternebrae, whereas exposure to 0.1875% or 7.5% CP resulted in corresponding effects on metacarpal bones, indicating a delay in osteogenesis. The predominant compound found in serum after TBR ingestion was unchanged TBR, and there was no evidence of bioaccumulation of TBR in serum during gestation. The highest levels of CP or TBR used in these studies was 38 times greater than the maximum consumption level reported for humans in marketing surveys, and corresponds to a consumption of greater than 7.5 lb milk chocolate/day.     

A study of the teratogenic potential of caffeine given by oral intubation to rats

A study was made to resolve questions about the fetotoxic and teratogenic potential of the alkaloid caffeine, 1,3,7-trimethylxanthine. Caffeine in aqueous solution was orally intubated to Osborne-Mendel rats as dose levels of 6, 12, 40, 80, or 125 mg/kg during Days 0–19 of gestation; 61 rats were randomly assigned to each dose level. Concurrent control rats were intubated with distilled water on the same days. Six females died at the highest caffeine dose level. The experimental animals gained less weight during gestation than did the controls. Food consumption decreased primarily during the first week of gestation. Two litters were totally resorbed at 80 mg/kg and four litters at 125 mg/kg. Resorptions increased at the dose levels 80 and 125 mg/kg. These were significant decreases in fetal weight and crown-rump lengths in both males and females at 80 and 125 mg/kg, and in female weight and crownrump length at 40 mg/kg. Ectrodactyly was seen only at the dose levels 80 and 125 mg/kg, along with assorted skeletal ossification problems such as misshapen centra, missing centra, reduced dorsal arch, reduced pubis, missing hind phalanges, reduced metacarpals, and reduced metatarsals. In addition, delayed ossification of the sternebrae was seen at all dose levels. No soft tissue variations appeared related to caffeine intake.     

Reduction of teratogenic effects of ethylenethiourea in rats by interaction with sodium nitrite in vivo

Nitrites are present in a wide variety of foods and their daily intake in man has been estimated at 1·5 mg. Ethylenethiourea (ETU), a major food contaminant resulting from degradation of ethylenebisdithiocarbamate fungicides, is a potent rat teratogen. The co-administration of ETU (60 or 40 mg/kg) and NaNO₂ (80 mg/kg) to rats by gavage on day 15 of gestation resulted in a higher survival of progeny than occurred with the corresponding dose of ETU alone. In a second study, ETU (60 mg/kg) and NaNO₂ (80, 100 or 120 mg/kg) were administered, either individually or in combination, as a single dose on day 13 of gestation. Administered alone, NaNO₂ did not produce any teratogenic response in full-term foetuses, whereas ETU produced a high incidence of various anomalies. However, the combined dosing resulted in the elimination of almost all the anomalies. The reducing effect of NaNO₂ on ETU-induced malformations was reversed when the animals were pretreated with 200 mg ascorbic acid/kg or 360 mg sodium ascorbate/kg. Since both of these are well-known inhibitors of N-nitrosation reactions, it was presumed that the simultaneous oral dosing of ETU and NaNO₂ resulted in the formation of N-nitrosoethylenethiourea.     

Evaluation of potential antidotes for sodium fluoroacetate in mice

Pathogenesis in fluoroacetate poisoning is multifactorial. Biochemically it is characterized by lethal synthesis of fluorocitrate, causing hypocalcemia, and energy deficiency through blockade of the TCA cycle. Calcium gluconate (CaG) was chosen to antagonize hypocalcemia, while sodium alpha kelogluterate (NaKG) and sodium succinate (NaSuc) were selected as potential antidotes to revive the TCA cycle. Effectiveness of each of these antidotes individually and in certain combinations was tested in mice exposed to lethal doses (15 mg/kg ip) of sodium fluoroacetate (NaFAC). Antidotal treatments were administered at 15 min, 4 h, 10 h, 24 h, and 36 h after NaFAC. All 3 of the antidotes alone, as well as a combination of CaG with NaKG, were ineffective in reducing mortality in mice after NaFAC. On the other hand, a combination of CaG (130 mg/kg) with NaSuc (240 mg/kg) was effective if the 2 solutions were either injected at separate sites or mixed in the same syringe just prior to injection. Similar solutions, if mixed for 24 h or longer before administrations, were ineffective. Increasing the dose of NaSuc to 360 or 480 mg/kg with CaG (130 mg/kg) was unrewarding. These results indicate that CaG in combination with 240 mg NaSuc/kg offer a promising therapy modality in NaFAC intoxication. Additional studies involving biochemical parameters and other species are needed to confirm the efficacy and mechanism(s) of action of this combination.     

Effect of sulfite on cognitive function in normal and sulfite oxidase deficient rats

Sulfites, which are commonly used as preservatives, are continuously formed in the body during metabolism of sulfur-containing amino acids. Sulfite is oxidized to sulfate ion by sulfite oxidase (SOX, EC. 1.8.3.1). The aim of this study was to investigate the possible toxic effects of sulfite on neurons by measuring active avoidance learning in normal and SOX-deficient rats. For this purpose, male albino rats used in this study were divided into eight groups such as control group (C), sulfite group (25 mg/kg) (S), vitamin E group (50 mg/kg) (E), sulfite (25 mg/kg)+vitamin E group (50 mg/kg) (SE), SOX-deficient group (D), deficient+vitamin E group (50 mg/kg) (DE), deficient+sulfite group (25 mg/kg) (DS) and deficient+sulfite (25 mg/kg)+vitamin E group (50 mg/kg) (DSE). Sulfite-induced impairment of active avoidance learning in SOX-deficient rats but not in normal rats. Sulfite had no effect on hippocampus TBARS levels in SOX normal groups. In SOX-deficient rats, TBARS levels were found to be significantly increased with sulfite exposure. Vitamin E reversed the observed detrimental effects of sulfite in the SOX-deficient rats on their hippocampal TBARS but not on their active avoidance learning. In conclusion, sulfite has neurotoxic effects in sulfite oxidase deficient rats, but this effect may not depend on oxidative stress.     

Neurobehavioral teratogenic effects of thalidomide in rats.

Thalidomide-induced embryopathy has been known for four decades, however, the drug has been reintroduced for human use in a number of countries, including the United States. In utero thalidomide exposure in humans is associated with central nervous system (CNS) effects in addition to the well-known limb, ear and other malformations. Despite knowledge of these CNS effects, not a single experimental study could be found that examined thalidomide for possible developmental neurobehavioral effects. In the present experiment, gravid Sprague-Dawley rats were treated with either thalidomide (100 mg/kg by gavage) or vehicle (propylene glycol) on embryonic days E7-18 and allowed to deliver and raise their own offspring. The offspring were evaluated in a series of neurobehavioral tests (reflexes, locomotor activity, startle reactivity and learning in the Morris and Cincinnati water mazes). There was a small reduction in maternal weight among thalidomide-treated dams during midgestation. Thalidomide offspring showed increased preweaning mortality and male-specific, late onset reduction in growth that persisted until the end of the study. Male thalidomide offspring showed significant increases in errors and latency in the multiple-T Cincinnati water maze. Although rats are refractory to thalidomide-induced teratogenesis, the present results suggest that thalidomide selectively impairs offspring survival and growth and at least one type of learning among male offspring.