Developmental toxicity of homobrassinolide in Wistar rats

Brassinosteroids (BRs) are close analogues of animal cholesterol. Brassinosteroids have shown their great value as yield promoters of a variety of plants. In view of its steroidal moiety and recent use in agriculture in many countries, the teratogenic potential of homobrassinolide (HBR) was evaluated in Wistar rats. Homobrassinolide was administered by oral gavage at doses 0, 100, and 1000 mg/kg body weight in water during gestation days (GD) 6 to 15 in groups of 20 mated females. Maternal and embryo-fetal toxicity was analyzed by studying the effects such as clinical signs, mortality/morbidity, abortions, body weight, feed consumption, and pregnancy data, gravid uterine weights, implantation losses, litter size, external, visceral, and skeletal malformations. No treatment-related effect was observed on any of the maternal/fetal end points in any dose group. From the results, it can be concluded that HBR is nonteratogenic at doses as high as up to 1000 mg/kg body weight in Wistar rats.     

Reproductive toxicity of ofloxacin

The reproductive toxicity of (+/-)-9-fluoro-2, 3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylic acid (ofloxacin, Tarivid), a new antibacterial agent, was investigated in rats and rabbits after oral administration. Neither the male or female fertility nor the reproductive performance of the rats was affected by doses of up to 360 mg/kg. Ofloxacin elicited no evidence of teratogenicity when administered orally during the period of organogenesis to pregnant rats at doses of up to 810 mg/kg, or to pregnant rabbits at doses of up to 160 mg/kg. However, the female rats receiving 810 mg/kg showed salivation, dirty hair coats, soft stools, and decreases of body weight and food intake. The fetuses in the higher dose groups exhibited decreased body weight and retardation of ossification, and those in the highest dose group showed increased mortality and skeletal variations (cervical ribs, shortened 13th ribs). Further investigation of the fetal skeleton revealed that the critical period of the occurrence of skeletal variations was on days 9 and 10 of gestation. The occurrence of cervical ribs and shortened 13th ribs was not an indicator of teratogenicity when ofloxacin was administered at doses of up to 1600 mg/kg during the critical period. Moreover, the shortening of the 13th ribs was the only type of retardation of ossification degree. Decreases of maternal body weight and food intake, and increased mortality of fetuses were observed in rabbits at a dose of 160 mg/kg. In a perinatal and postnatal toxicity study in rats using doses of up to 360 mg/kg, no adverse effects were observed.     

Evaluation of the developmental toxicity of artemether during different phases of rat pregnancy

The present investigation was performed to examine the effect of artemether on rat pregnancy and embryonic/fetal development during different phases of pregnancy. Artemether was administered orally to Wistar rats at doses 3.5 and 7 mg/kg during blastogenesis, organogenesis and fetal period. When administered during blastogenesis, the preimplantation loss, number of implantations, resorptions, living fetuses, external and skeletal examination did not differ from those of control, however the higher dose induced reduction in fetal body weight and caused pre-term delivery in 3 of 10 pregnant rats. During organogenesis complete fetal resorption was observed in all dams treated with the higher dose, while in the lower dose 32% of implants were resorbed and live fetuses showed decreased fetal weight with low incidence of skeletal retardation. Artemether did not adversely affect prenatal development in rats treated during the fetal period although the higher dose level induced reduction in fetal body weight. In conclusion, no evidence of maternal toxicity, artemether was embryolethal at 3.5 and 7 mg/kg when dosed during organogenesis, the surviving fetuses showed fetal growth retardation without incidence of malformations, treatment during blastogenesis and fetal period had no lethal or teratogenic effect although the mean fetal body weight was significantly lower than control.     

A study on the effect of (2"R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic, on reproduction. I. Its effect on the fertility of rats

The effect of a new antitumor antibiotic on the fertility was studied using SD rats. (2"R)-4'-O-Tetrahydropyranyladriamycin (THP) was administered to each rat at 0.01, 0.03 or 0.1 mg/kg daily. Males were given the drug intravenously for 63 days prior to mating and during the mating period; females were given the drug intravenously from 14 days prior to mating until day 7 of pregnancy. All the pregnant rats were sacrificed on day 20 of pregnancy, followed by external, visceral and skeletal observations of their fetuses. Results were summarized as follows. THP, at 0.1 mg/kg, suppressed body weight gain in females during the late period of pregnancy but did not affect body weight gain in males. THP, at 0.1 mg/kg, increased the numbers of dead fetuses and of resorptions. It caused no external, visceral or skeletal anomalies at any dose levels. The results suggest that, in rats, the maximum "no effect" dose of THP is 0.03 mg/kg/day intravenously regarding fertility and fetal development.     

Maternal hepatic and embryonic effects of 1,2,3,4-tetrachlorobenzene in the rat

To assess possible maternal hepatic and reproductive effects of this uncharged, low molecular weight, lipophilic chlorinated benzene 0, 100, 300 and 1000 mg/kg/day of 1,2,3,4-tetrachlorobenzene (TCB) was orally administered to pregnant rats on days 9-13 of gestation and the animals were killed on day 14 of pregnancy. Phenobarbital and beta-naphthoflavone were administered to other pregnant rats as positive hepatic controls. Maternal mortality (7/19 rats) was increased and body weight gain was greatly decreased in the 1000 mg/kg/day TCB group. Liver to body weight ratio and hepatic microsomal protein content were unaffected by any TCB treatment. On day 14 maternal NADPH-cytochrome c reductase activity was increased at 1000 mg/kg/day, while the maternal hepatic microsomal cytochrome P-450 content was significantly induced by both 300 and 1000 mg/kg/day of TCB. Microsomal N-demethylation of aminopyrine was increased from 2.6 to 4.0 and 4.5 nmol/mg protein/min at doses of 300 and 1000 mg/kg TCB, respectively. However, maternal hepatic microsomal ethoxyresorufin O-deethylase activity was not consistently increased by TCB. Hepatic glutathione S-transferase activity towards 1,2-dichloro-4-nitrobenzene was increased only by the 1000 mg/kg/day TCB treatment. The rate of microsomal p-nitrophenol and phenolphthalein glucuronidation was increased by TCB administration. Embryonic growth was adversely affected by TCB treatment. Yolk sac diameter, embryonic crown-rump length, and head length were all decreased by treatment with 300 mg/kg/day TCB. This TCB treatment did not significantly elevate the number of dead or abnormal embryos.     

Toxicity evaluation of a beta-galactosidase preparation produced by Penicillium multicolor

Tilactase is a beta-galactosidase enzyme preparation having lactase activity produced from the fungus Penicillium multicolor. The safety of tilactase was investigated in rats, dogs, and rabbits. Adult and juvenile rats administered 0, 500, 1000, or 4000 mg/kg bw/day of the enzyme preparation by gavage for 35 days, and dogs administered 0, 200, 500, or 1000 mg/kg bw/day in capsules for 30 days, exhibited no significant dose-related changes in body weights, feed consumption, organ weights, urinalysis, hematological profiles, clinical chemistry, or histopathological profiles. Rats receiving the same doses for 6 months also exhibited no dose-related effects, except for a small increase in the weight of the large intestine, an effect considered to be a physiological reaction to passage of a large amount of a non-absorbable substance. The no-observable-adverse-effect level (NOAEL) was 4000 mg/kg bw/day for rats and 1000 mg/kg bw/day for dogs. In three separate studies to examine reproductive and developmental toxicity, rats received 0, 250, 1000 or 4000 mg/kg bw/day by gavage up to the 7th day of pregnancy, during days 7-17 of pregnancy, and from day 17 of pregnancy to 21 days after delivery. There were no treatment-related effects on the dams, gestation period, numbers of implantations, parturition rates, sex ratios, or survival of offspring in any of the studies. No treatment-related external, internal, or skeletal abnormalities were observed in fetuses from any of the three studies. The NOAEL was 4000 mg/kg bw/day. In addition to the three rat studies, rabbits received 0, 250, 500, or 1000 mg/kg bw/day by gavage from the 6th to 18th day of pregnancy. No treatment-related changes were observed in the dams, or fertility indices; nor were there any treatment-related fetal abnormalities. The NOAEL was 1000 mg/kg bw/day. When viable P. multicolor spores were injected into the tail veins of mice, no deaths occured, no fungal cells were observed in various organs, and histopathology showed only focal necrosis in the liver of some of the animals, including the controls. Similar effects were observed when spores were administered to mice in a single dose by gavage. The particular strain of P. multicolor used to prepare tilactase is not pathogenic.     

Reproduction/developmental toxicity screening test in rats with orally-administered 1-hexene

This study was conducted to provide screening information concerning the potential systemic, reproductive and developmental toxicity of 1-hexene when administered orally, by gavage, to male and female rats using a modified OECD 421 protocol. 1-Hexene was administered at doses of 100, 500, and 1000 mg/kg/day in corn oil; the control group received the vehicle at an equivalent volume. The males were treated for 28 days prior to mating and until euthanasia (44 days of dosing). The females were treated for 14 days prior to mating and during mating, gestation, and lactation until euthanasia (41-55 total days of dosing). Females were allowed to deliver and rear their offspring until lactation day 4. The parental rats were subject to a gross and microscopic examination. Viability and development of the pups were followed through lactation day 4. There was no mortality, and there were no clinical signs of toxicity or differences in body weights, weight gain, feed consumption or organ weights. Copulation and fertility indices, precoital intervals, gestation lengths and pregnancy rates were comparable among the groups, and no signs of prolonged delivery or unusual nesting behaviors were noted. Pup viability, body weights, external observations and necropsy data were comparable among the groups. Pitted kidneys were observed at necropsy for two parental males in the 500 mg/kg/day group and three males in the 1000 mg/kg/day group. Microscopic changes in the kidneys of some male rats from the 100, 500, and 1000 mg/kg/day groups consisted of dose-related accumulations of hyaline droplets in the epithelial cells of the proximal convoluted tubules of the kidneys. In summary, the only treatment-related effect noted in this study was hydrocarbon nephropathy in male rats, which is not considered relevant for human health. The NOAEL for systemic and reproductive toxicity was 1000 mg/kg/day, excluding the finding of male rat hydrocarbon nephropathy.     

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

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

Teratological assessment of the antiprotozoal, diminazene diaceturate, in rats

Diminazene diaceturate was dissolved in deionized water and administered to pregnant rats by oral gavage once daily on days 8-15 of pregnancy at dose levels of 0, 100, 250, 500 and 1000 mg/kg. On day 21 of pregnancy, the dams were killed and the number of implants, resorptions and live fetuses counted. All fetuses were examined by routine teratological method. A significant increase in fetal resorptions and decrease in fetal body weights were found at the 1000 mg/kg dose. No significant increase in the incidence of anomalous fetuses was observed in external, skeletal and internal examinations even at the maternally toxic dose of 1000 mg/kg. Thus, these data indicate that diminazene diaceturate is not teratogenic in rats.     

Teratogenic assessment of carbadox in rats

Carbadox was administered by gavage once daily to pregnant rats at doses of 0 (control), 10, 25, 50 or 100 mg/kg on days 8 through 15 of pregnancy. The dams were killed on day 21 and the number of implantation sites, resorptions and live fetuses were counted. A significant dose-related decrease in maternal body weight gains during treatment (days 8 through 15 of pregnancy) occurred at doses of 10 mg/kg and above. There was a dose-related decrease in fetal body weights which was statistically significant at 25 mg/kg and above. This compound showed not only embryolethal but teratogenic effect. Resorption rates were 81.8% at 100 mg/kg, occurring complete resorptions in five dams, compared with 3.4% resorption rate in the control. In fetal examinations, a significant increase in the incidence of external, skeletal and internal malformations occurred at 100 mg/kg, where the surviving fetuses born to dams with 40-93% resorptions had any malformations, short tail; kinky tail; brachygnathia or ectrodactyly.     

REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS WITH ORALLY-ADMINISTERED 1-HEXENE

This study was conducted to provide screening information concerning the potential systemic, reproductive and developmental toxicity of 1-hexene when administered orally, by gavage, to male and female rats using a modified OECD 421 protocol. 1-Hexene was administered at doses of 100, 500, and 1000 mg/kg/day in corn oil; the control group received the vehicle at an equivalent volume. The males were treated for 28 days prior to mating and until euthanasia (44 days of dosing). The females were treated for 14 days prior to mating and during mating, gestation, and lactation until euthanasia (41–55 total days of dosing). Females were allowed to deliver and rear their offspring until lactation day 4. The parental rats were subject to a gross and microscopic examination. Viability and development of the pups were followed through lactation day 4. There was no mortality, and there were no clinical signs of toxicity or differences in body weights, weight gain, feed consumption or organ weights. Copulation and fertility indices, precoital intervals, gestation lengths and pregnancy rates were comparable among the groups, and no signs of prolonged delivery or unusual nesting behaviors were noted. Pup viability, body weights, external observations and necropsy data were comparable among the groups. Pitted kidneys were observed at necropsy for two parental males in the 500 mg/kg/day group and three males in the 1000 mg/kg/day group. Microscopic changes in the kidneys of some male rats from the 100, 500, and 1000 mg/kg/day groups consisted of dose-related accumulations of hyaline droplets in the epithelial cells of the proximal convoluted tubules of the kidneys. In summary, the only treatment-related effect noted in this study was hydrocarbon nephropathy in male rats, which is not considered relevant for human health. The NOAEL for systemic and reproductive toxicity was 1000 mg/kg/day, excluding the finding of male rat hydrocarbon nephropathy.     

Evaluation of the developmental toxicity of linalool in rats

The developmental toxicity of linalool, a widely used fragrance ingredient, was evaluated in presumed pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 250, 500, or 1000 mg/kg/day linalool were administered by gavage on gestational days 7 to 17. The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. There were no maternal deaths, clinical signs, or gross lesions that were considered related to linalool. During the dosage period, mean relative feed consumption was significantly reduced by 7% and mean body weight gains were reduced by 11% at 1000 mg/kg/day. During the postdosage period, feed consumption values at 1000 mg/kg/day were significantly higher than vehicle control values, which corresponded to the increase in body weight gains during this period. Caesarean section and litter parameters, as well as fetal alterations, were not affected by linalool at any of the three dosages tested. On the basis of these data, the maternal no observed adverse effect level (NOAEL) of linalool is 500 mg/kg/day, whereas the developmental NOAEL is > or = 1000 mg/kg/day. It is concluded that linalool is not a developmental toxicant in rats at maternal doses of up to 1000 mg/kg/day.     

Discriminative stimulus effects of self-administered ethanol

The conditions under which a drug is administered often alter the behavioral effects of that drug. The present study examined the effect of changes in response dependence on the discriminative stimulus effects of ethanol. Six Long-Evans rats were trained to discriminate 1000 mg/kg, interperitoneal (i.p.) ethanol from saline. A dose-effect curve was then obtained using i.p. doses of 100, 320, 560, 1000, 1320 and 1560 mg/kg ethanol. Ethanol doses of 1000 mg/kg and greater produced more than 80% ethanol-lever selection. The rats were then trained to orally self-administer 10% weight/volume ethanol and tested to determine if self-administered oral ethanol would substitute for experimenter administered i.p. ethanol. A mean self-administered ethanol intake of 1114 mg/kg (+/-156 mg/kg) produced 83% ethanol-lever responding. Restricted access to 560 mg/kg of self-administered ethanol resulted in 33% i.p. ethanol-lever responding. Doses of 100 and 320 mg/kg ethanol did not substitute for i.p. ethanol. These data show that orally self-administered ethanol can produce discriminative stimulus effects that are similar to i.p. experimenter-administered ethanol and that orally self-administered ethanol produces centrally-mediated discriminative stimulus effects.     

Oral developmental toxicity study of methylsulfonylmethane in rats.

Methylsulfonylmethane (MSM) is a metabolite of dimethyl sulfoxide, and occurs naturally at low levels in many foods. MSM has received wide attention as a dietary supplement to promote joint health. The objective of these studies was to determine the developmental toxicity potential of MSM when administered orally to pregnant rats during the period of major organogenesis and histogenesis. In a preliminary dose-finding study, distilled MSM microprill (i.e., microspherical pellets of MSM) was administered by oral gavage at dose levels of 0 (vehicle control), 50, 250, 500, and 1000 mg/kg/day to 8-9 sperm-positive female Sprague-Dawley rats/group/day on gestation days 6-20. No evidence of maternal or fetal toxicity was observed. For the definitive developmental study, four groups of 24-25 timed-bred primiparous female rats were administered 0, 50, 500, or 1000 mg MSM/kg/day via gavage on gestation days 6-20. Maternal feed consumption, body weight, body weight gain, uterus weight and corrected body weight/body weight gain were unaffected by treatment. No evidence of maternal toxicity, and no significant differences in litter viability, litter size, or litter body weight were detected. Fetal evaluations failed to show any biologically significant increase in the incidence of anomalies in the MSM treated groups, and no malformations were seen in any of the fetuses. No evidence of fetal mortality, alterations to growth, or structural alterations were observed in the fetuses of dams administered 50-1000 mg/kg/day. Therefore, under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 1000 mg/kg/day.     

Effects of prenatal exposure to the environmental pollutant 2-bromopropane on embryo-fetal development in rats

2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered subcutaneously to pregnant rats at dose levels of 0, 250, 500, and 1000 mg/kg per day. All dams were subjected to caesarean section on GD 20 and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, maternal toxicity included an increase in the incidence of abnormal clinical signs, a suppression in the body weight and body weight gain, and a decrease in the food intake. Developmental toxicity included an increase in the fetal deaths, a decrease in the litter size, and a reduction in the fetal body weight. In addition, an increase in the incidence of fetal external, visceral, and skeletal abnormalities was seen. In the 500 mg/kg group, minimal developmental toxicity including decreased fetal body weight and increased fetal ossification delay was observed. There were no adverse effects on either pregnant dams or embryo-fetal development in the 250 mg/kg group. These findings suggest that a 14-day subcutaneous dose of 2-BP is embryotoxic and teratogenic at a maternally toxic dose (i.e., 1000 mg/kg per day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 500 mg/kg per day) in Sprague-Dawley rats. In the present experimental conditions, the no-observed-adverse-effect level (NOAEL) of 2-BP is considered to be 500 mg/kg per day for dams and 250 mg/kg per day for embryo-fetal development.     

Teratogenic evaluation of tributyltin chloride in rats following oral exposure

The teratogenicity of tri-n-butyltin chloride (TBTC1) was examined in Wistar rats. The pregnant rats were administered orally 25, 15, 9, 5 and 0(Control) mg of TBTC1/kg of body weight/day from day 7 to 15 of pregnancy. Maternal toxicity, as evidenced by both of decreased body weight gain and food consumption was observed at 25, 15 and 9 mg/kg/day dose group. However, only in the 25 mg/kg/day dose group some clinical signs of toxicity (sedation, diarrhoea and salivation) were observed and 70 percent of the dams were dead. In the 25 mg/kg/day dose group, all fetuses were dead. Statistically significant reductions in the female fetal body weight were observed in 9 and 5 mg/kg/day dose groups. In all groups treated with TBTC1 except the 25 mg/kg/day dose group, no significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the TBTC1-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any of the dose levels. However, several types of skeletal and internal variations including delayed ossifications were observed in some groups treated with TBTC1, but the incidences were not significantly different from controls. Also, two fetuses with dilatation of the renal pelvis were found in 9 and 5 mg/kg/day dose group. Statistically significant increases of placental weight in all TBTC1-treated groups were observed when compared to that of control group. In conclusion, TBTC1 administered orally to Wistar rats during days 7-15 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity and induced a marked increase in placental weight.     

Developmental toxic effects of diisobutyl phthalate, the methyl-branched analogue of di-n-butyl phthalate, administered by gavage to rats

The developmental toxicity of diisobutyl phthalate (DIBP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given DIBP at doses of 0 (olive oil), 250, 500, 750, and 1000 mg/kg/day, by gavage (5 ml/kg), on gestational days (GD) 6 through 20. Maternal toxicity, as evidenced by reduction in body weight gain, was observed at the beginning of treatment (GD 6-9), at 500 mg/kg and higher doses. The incidence of resorptions was significantly increased at 750 mg/kg, and reached 60% at 1000 mg/kg. There was a dose-related decrease in fetal weight, which was significantly lower than control from 500 mg/kg. A significant increase in the incidence of fetuses with visceral and skeletal malformations was seen at 750 and 1000 mg/kg. In particular, fused sternebrae occurred at a significantly higher frequency. Two skeletal variations were increased at 750 and 1000 mg/kg: retarded ossification of vertebrae, and predominantly, supernumerary ribs. The incidence of male fetuses with undescended testes was also significantly elevated at the two highest doses. In conclusion, DIBP administered by gavage is embryotoxic and teratogenic, and affects the developing male reproductive tract, at maternal toxic doses.     

Reproductive and developmental toxicity studies of S-1090, cefmatilen hydrochloride hydrate (1)--A study on oral administration prior to and in the early stages of pregnancy in rats

Cefmatilen hydrochloride hydrate (S-1090) was administered daily by gavage to rats at doses of 100, 300 or 1000 mg potency/kg/day prior to and in the early stage of pregnancy to assess its adverse effects on parental reproductive ability and embryo-fetal development. Loose and/or reddish brown feces were observed in both males and females of all the S-1090 dosing groups, and abdominal distention was also observed in males throughout the dosing period. No drug-related deaths occurred in either males or females. In males, body weight and food consumption were increased at a dose of 1000 mg potency/kg/day throughout the dosing period. In females, body weight gain was restrained during late pregnancy, and food consumption was decreased transiently following the initiation of dosing, and then remained high on the day before parturition in all the S-1090 dosing groups. Necropsy of male and female rats revealed an increase in the cecum weight. The reproductive ability of males and females was normal in all the S-1090 dosing groups. No effects of S-1090 were observed in the implantation ratio, embryo-fetal viability, fetal body weight, and incidence of external, skeletal and visceral anomalies. Based on these results, the no observed adverse effect levels of S-1090 are estimated to be less than 100 mg potency/kg/day for parental general toxicity, 1000 mg potency/kg/day for reproductive toxicity, and 1000 mg potency/kg/day for developmental toxicity in embryo-fetuses under the conditions of the present study.     

A teratology study on vomitoxin (4-deoxynivalenol) in rabbits

Diets containing 4-deoxynivalenol (vomitoxin) of greater than 98% purity were fed to rabbits on days 0-30 of gestation. The dietary concentrations of 4-deoxynivalenol were 0, 0.00075, 0.0015, 0.003, 0.006, 0.012 and 0.024% and the daily intakes of deoxynivalenol were 0, 0.3, 0.6, 1.0, 1.6, 2.0 and 1.8 mg/kg body weight/day, respectively. A pair-fed group was given a feed intake equivalent to that in the 1.6-mg/kg group. The only significant effects that were observed in foetuses examined at day 30 of gestation occurred only at doses that caused reductions in both the body weight and feed intake of does. The foetal effects consisted of a 100% incidence of resorption in the 1.8- and 2.0-mg/kg groups and decreased mean foetal weight in the 1.0- and 1.6-mg/kg and pair-fed groups. The doses that did not appear to be maternotoxic (0.6 and 0.3 mg/kg) did not show any adverse effects in foetuses at term. Vomitoxin given in the diet during pregnancy failed to show any evidence of teratogenic potential in rabbits.     

Teratogenicity and embryotoxicity study of carmine of cochineal in the rat

Groups of 30 mated female rats were given daily doses of 0, 200, 500 or 1000 mg carmine/kg body weight by oral intubation throughout pregnancy. A group of 17 similar animals was given a solution of chlorides to provide an intake of sodium, potassium and ammonium equal to that resulting from the highest dose level of carmine. There were no effects of carmine treatment on body weights, pregnancy rates, pre-implantation losses, the average numbers of live young, litter weights or foetal weights. The group given the highest dose of carmine and the cation control had increased numbers of implantations and post-implantation losses. The latter was considered to be due to an inability to maintain the increased numbers of implantations rather than to an embryotoxic effect. The foetuses showed no malformations and those from the carmine-treated rats tended to have a slightly more advanced degree of ossification of certain skeletal elements than foetuses of the control animals. On the basis of the results obtained it is considered that there were no untoward effects on embryo development in rats given oral doses of up to 1000 mg carmine/kg body weight/day throughout pregnancy.