Pre-clinical toxicity studies on the new nitroimidazole 1-methylsulphonyl-3-(1-methyl-5-nitroimidazole-2-yl)-2- imidazolidinone

Administration of 1-methylsulphonyl-3-(1-methyl-5-nitro-2-imidazole-yl)-2-imidazolidinone (Go 10213) at a dose of 5000 mg/kg to rat, mouse, guinea pig and rabbit and 3000 mg/kg to dog did not induce any toxic symptoms or mortality. Repeated daily gavaging with doses ranging from 50-3000 mg/kg/day were tolerated by rats for 2 weeks. No mortality was noticed in treated animals. Reduction in weight gain was observed in male rats on 2000 mg/kg per day and females on 1000 mg/kg per day. No toxic changes were noticed in dogs treated with 200 mg/kg per day for 2 weeks. One monkey treated with 75 mg/kg per day for 4 weeks tolerated the compound without exhibiting any toxic effects. No drug induced alterations were noticed in rats gavaged with 60 and 200 mg/kg per day for 4 weeks. Rats treated with a daily dose of 600 mg/kg showed reduction in body weight gain and atrophy of testes and these changes were reversible after stopping of medication. Dogs medicated with 30 and 100 mg/kg per day tolerated the drug for 4 weeks. Except slight ataxia in a few dogs treated with 100 mg/kg per day, no other drug induced toxic effects were noticed. Neurological symptoms were noticed in all dogs on high dose of 200 mg/kg. Three animals out of six were sacrificed in extremis in this dose. After discontinuation of Go 10213 all dogs on 100 and 200 mg/kg per day recovered normal gait in about a week. No definitive drug induced changes were noticed in laboratory investigations, gross and histopathological examinations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reproductive, teratogenic, perinatal and postnatal studies with cyclazocine.

Cyclazocine, a mixed narcotic agonist-antagonist, was evaluated for teratogenic effects in rats and rabbits and for effects on reproductive performance, perinatal and postnatal development in rats. To evaluate teratogenic effects, Charles River albino rats were treated orally from days 6 through 15 of gestation with 3, 10, or 30 mg/kg/day of cyclazocine; New Zealand rabbits were dosed orally from days 6 through 18 of gestation with 1, 3, or 10 mg/kg/day. Rats and rabbits were sacrificed on day 20 or day 29 of gestation, respectively. Numbers of implantation sites, resorption sites, corpora lutea, and viable fetuses, as well as external, internal, and skeletal abnormalities were similar in test and control groups. No dose-related, external, internal or skeletal abnormalities were found in the offspring of either species. To evaluate effects on fertility and general reproductive performance, male or female rats were dosed orally for either 63 or 14 days, respectively, prior to mating with 3, 10, or 30 mg/kg/day. Dosing continued until day 14 of gestation for one-half of the females or after weaning for the other half. Control and treated groups displayed comparable food consumption values, behavior, mating, and fertility indices. To evaluate perinatal and postnatal effects, pregnant female rats were treated from day 15 of gestation throughout lactation. No untoward, drug-related effects were observed in any of the groups. Moreover, when the pups of the high-dose drug group were cross-fostered with control pups, no noticeable drug-related effects were apparent.     

Toxicological studies on a new cephamycin, MT-141. VIII. Its fertility test in rats

A fertility study of MT-141 was performed in SD rats with the intramuscular (i.m.) injections at the dose levels of 400, 800 and 1,600 mg/kg/day. The male rats were injected with MT-141 for 63 days before mating and during the mating period, while the female rats were injected with MT-141 from the 14th day before mating up to the day 7 of gestation. All pregnant rats were sacrificed on day 20 of gestation followed by external, visceral and skeletal observations of their fetuses. The results are summarized as follows. The suppression of body weight gain was observed in males given above 800 mg/kg/day i.m. and in females of all treated groups during early period of gestation. However, no significant differences were found between treated groups and the control with regard to copulation rate and conception rate. Though no defects were observed for visceral and skeletal specimens in the fetuses of treated groups, MT-141 produced a delayed ossification of forelimbs in the fetuses at the doses above 800 mg/kg/day and of sternebrae at the dose of 1,600 mg/kg/day. It is concluded from the above-mentioned results that the maximal "no 'effective" dose of MT-141 on the fertility is above 1,600 mg/kg/day i.m. in parental rats and less than 800 mg/kg/day i.m. for the fetuses.     

Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde

Male and female Fischer 344 rats and B6C3F1 mice were treated daily (5 days/wk) with benzaldehyde by gavage either in 12 doses of 0 (vehicle control), 100 (rats only), 200, 400, 800, 1600 or (for mice only) 3200 mg/kg body weight/day (followed by 2 days' observation without treatment), or for 90 days in doses of 0, 50, 100, 200, 400 or 800 mg/kg/day (rats) or 0, 75, 150, 300, 600 or 1200 mg/kg/day (mice). In the acute studies, benzaldehyde induced deaths and decreased body-weight gain in both sexes of rats given 800 or 1600 mg/kg/day and caused deaths in both sexes of mice given 1600 or 3200 mg/kg/day. In the 90-day studies, deaths occurred in both sexes of rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Body-weight gain was depressed in male rats on 800 mg/kg/day, in male mice on 600 mg/kg/day and in female mice on 1200 mg/kg/day. Necrotic and degenerative lesions were seen in the cerebellar and hippocampal regions of the brain in both sexes of rats given 800 mg/kg/day, but not in mice. Renal tubular necrosis occurred in male and female rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Mild epithelial hyperplasia or hyperkeratosis of the forestomach was seen in male and female rats on 800 mg/kg/day. In this limited study, the no-observed-toxic-effect doses of benzaldehyde administered by gavage were 400 mg/kg/day in male and female rats, 300 mg/kg/day in male mice and 600-1200 mg/kg/day in female mice.     

Effects of in utero and lactational exposure to flutamide in SD rats: comparison of the effects of administration periods

Pregnant CD(SD) IGS rats were given flutamide (FLUT) orally at doses of 0.4, 2, or 10 mg/kg/day from gestational day 6 to postnatal day (PND) 20, and the effects of FLUT exposure on male offspring were examined 10 weeks after birth, and compared to the effects in offspring treated after weaning and in offspring untreated after weaning. Although the body weight of the dams treated with FLUT remained normal, two dams in the 10 mg/kg/day group were killed because of abnormal parturition periods and loss of all the pups. The number of stillborns and dead newborns at birth was significantly higher in the 10 mg/kg/day group than in the control groups. No abnormalities in the reproductive parameters of the other dams treated with FLUT were detected. The body weights of the male offspring in each group remained normal from birth until the end of the study. The ano-genital distance was significantly shortened in 2 and 10 mg/kg/day groups. Changes in the organ weights and gross findings were detected in the 2 and/or 10 mg/kg/day groups with or without the continuous administration of FLUT after weaning; these changes were more appreciable in groups treated with FLUT after weaning than in groups untreated after weaning. The prolongation of preputial separation was observed in the 0.4 and 2 mg/kg/day groups treated with FLUT after weaning, but this change was not detected in the same dose groups untreated after weaning. The testosterone levels were higher in the 10 mg/kg/day group treated with FLUT after weaning. The present data demonstrated that the endocrine-mediated effects on rats were more appreciable in offspring treated with FLUT after weaning than in offspring untreated after weaning.     

Di(2-ethylhexyl) adipate (DEHA) induced developmental toxicity but not antiandrogenic effects in pre- and postnatally exposed Wistar rats

Di(2-ethylhexyl) adipate (DEHA) has replaced the phthalates in thin plasticized polyvinyl chloride films used for food packaging, mainly because some phthalates induce testis toxicity and antiandrogenic effects. A dose-range finding study followed by a dose-response/effect study in Wistar rats investigated whether pre- and postnatal DEHA doses of 0, 800, or 1200mg/kg/day body weight and doses of 0, 200, 400, or 800mg/kg/day (main study) elicited developmental toxicity including antiandrogenic effects. In the main study, DEHA induced a prolonged gestation period (800mg/kg/day) and a dose-related increase in postnatal death (400 and 800mg/kg/day). DEHA also induced a permanent decrease in offspring body weight (800mg/kg/day). No antiandrogenic endpoints were affected. We conclude that DEHA induced developmental toxicity and the NOAEL is 200mg/kg. DEHA did not induce antiandrogenic effects similar to those of di(2-ethylhexyl) phthalate even though the chemical structures have similarities and the two chemicals have a common metabolite.     

Reproductive and repeated dose toxicity of cyclododecatriene (CDDT) in rats following oral (gavage) treatment

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD (SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1-2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.     

REPRODUCTIVE AND REPEATED DOSE TOXICITY OF CYCLODODECATRIENE (CDDT) IN RATS FOLLOWING ORAL (GAVAGE) TREATMENT

ABSTRACT

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD®(SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1–2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.     

Toxicological studies on a new cephamycin, MT-141. X. Its perinatal and postnatal test in rats

A perinatal and postnatal study of MT-141 was performed in SD rats. The dams were administered intramuscularly (i.m.) with MT-141 at the dose levels of 400, 800 and 1,600 mg/kg/day from the day 17 of gestation until the day 21 post delivery. The results are summarized as follows. No significant adverse effects of MT-141 were observed on the body weight gain, food consumption and water intake in dams of all groups treated with the drug during the perinatal and postnatal period. MT-141 did not change parameters of reproductive study in birth, development, physiological function and behavior of F1 rat. This compound had no effect on the fertility in F1 rats and also did not caused significant defects in the external appearance, viscera and skeleton of fetuses from dams (F1). It is concluded from these results that the maximal "no effective" dose of MT-141 is above 1,600 mg/kg/day i.m. for dams and the offsprings.     

Dermal toxicity of a high-boiling (bp 250-450 degrees C) coal liquefaction product in the rat--II

Coal liquefaction products have been considered as an alternate source of energy to replace conventional crude oil. The present study was designed to investigate the dermal toxicity of a heavy fraction of coal liquefaction product (CLP, bp 250-450 degrees C) in the rat. Groups of 10 male and 10 female Sprague-Dawley rats (180-200 g) were treated dermally with CLP at dose levels of 100, 200, 400, or 800 mg/kg body weight.d for 6 wk. The controls were treated with 0.4 ml/kg of normal saline, while the positive control group received 400 mg/kg diesel fuel. Growth suppression was observed in all CLP-treated groups of males; in the females this effect occurred in the two highest dose groups. Diesel fuel at 400 mg/kg also caused growth suppression of a similar magnitude to that of CLP in male rats. Male animals treated with high doses of CLP or diesel fuel had severe skin lesions. Increased liver weights were observed in the diesel fuel-treated as well as all CLP-treated groups of females. The kidney weights of females treated with 400 mg/kg and 800 mg/kg CLP were also higher than control values. Decreased red cell count, hemoglobin, and hematocrit volume occurred in some CLP and diesel fuel groups of both sexes. There was mild bone marrow hyperplasia in rats of both sexes treated with CLP or diesel fuel. Mild histological changes were observed in the thyroid, liver, bone marrow, and skin of rats of both sexes treated with CLP and diesel fuel. Based on the data presented, dermal application of CLP produced systemic toxicity at the dose levels studied, and CLP and diesel fuel possess toxic effects of similar nature and magnitude.     

Reproductive and developmental toxicity screening test of tetrahydrofurfuryl alcohol in rats

Twelve male and female rats per group were given tetrahydrofurfuryl alcohol (THFA) by gavage at 0, 15, 50, 150 or 500 mg/kg/day. Males were dosed for 47 days, beginning 14 days before mating, and females were dosed for 42–52 days beginning 14 days before mating to day 4 of lactation throughout the mating and gestation period. Changes in locomotor activity, inhibition of body weight gain, and/or histopathological changes in the thymus, spleen, testes and/or epididymides were observed in males and females at 150 mg/kg and above. No effects of THFA were found on the copulation index, fertility index, or the number of corpora lutea and implantations in pregnant females. At 500 mg/kg, no pregnant females delivered any pups. At 150 mg/kg, gestation length was prolonged, and the total number of pups born and the number of live pups on postnatal days 0 and 4 was markedly decreased. No effects of THFA were found on the sex ratio and body weight of live pups, or the incidence of pups with malformations or variations. Based on these findings, the NOAELs for parental and reproductive/developmental toxicity of THFA were concluded to be 50 mg/kg/day in rats.     

Effect of fosmocyin-Na on reproductive performance of rats and rabbits. I. Teratogenicity test (author's transl)]

The teratogenicity study of fosfomycin-Na (FOM-Na) was undertaken in Wistar rats and New Zealand white rabbits. Rats were treated intraperitoneally at dose levels of 125, 250, 750 and 1,500 mg/kg/day from day 7 to day 17 of gestation, and rabbits were treated intravenously at dose levels of 80, 100, 200, 400 and 800 mg/kg/day from day 6 to day 18 of gestation. In the case of rats, two-thirds of pregnant mothers in each group was sacrificed on day 20 of gestation and then their fetuses were examined for external, visceral and skeletal observation. The remaining mothers were allowed to deliver naturally, and then their offsprings were examined for postnatal development. In the case of rabbits, all pregnant mothers were sacrificed on day 29 of gestation and their fetuses were examined. Body weight of rat mothers during gestation were decreased and 4 mothers were dead until day 20 of gestation in the maximum dose. In this dose, foetal toxicity was recognized too. However, external, visceral and skeletal anomalies related with FOM-Na treatment were not observed in all groups. No effect on development of offsprings was observed. No effect of treatment of FOM-Na to rabbits was found except foetal body weight was slightly decreased in the maximum dose.     

Developmental Toxicity Evaluation of Isopropanol by Gavage in Rats and Rabbits

Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosedorally with aqueous isopropanol (IPA; CAS No. 67–63–0)solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on GestationalDays (GD) 6 through 15 at a dosing volume of 5 mI/kg. Artificiallyinseminated New Zealand white rabbits, 15/group, were dosedorally with IPA at 0, 120, 240, or 480 mg/kg/day once dailyon GD 6 through 18 at 2 mI/kg. Maternal body weights, clinicalobservations, and food consumption were re corded throughoutgestation for both species. At scheduled euthanization for bothspecies (GD 20, rats; GD 30, rabbits), fetuses were weighed,sexed, and examined for external, visceral (including craniofacial)and skeletal alterations. For both species, the pregnancy ratewas high and equivalent across all groups; no dams or does aborted,delivered early, or were re moved from study. In rats, two dams(8%) died at 1200 mg/kg/ day and one dam (4%) died at 800 mg/kg/day.Maternal body weights and weight gain were equivalent acrossall groups, ex cept for statistically significantly reducedgestational weight gain (GD 0–20; 89.9% of control value),associated with statisti cally significantly reduced graviduterine weight at 1200 mg/kg/ day (89.2% of control value).There were no treatment-related clinical signs or effects onmaternal food consumption. All gestational parameters evaluatedwere equivalent across groups, including pre- and postimplantationloss, fetal sex ratios, and lit ter size. Twenty-two to 25 litterswere examined per group. Fe tal body weights per litter werestatistically significantly reduced at the two highest doses(97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for allfetuses and males and females separately). No evidence of increasedteratogenicity was observed at any dose tested in rats. In rabbits,four does (26.7%) died at 480 mglkg/day. Maternal body weightswere statistically significantly re duced during treatment (GD6–18) at 480 mg/kg/day (45.4% of control value) with anonsignificant reduction in gestational weight change (GD 0–30;77.3% of control value) at this dose. Profound clinical signsof toxicity and statistically significantly reduced maternalfood consumption were observed at 480 mgI kg/day. All gestationalparameters were equivalent across all doses administered. Thirteento 15 litters were evaluated per group except for the 480 mg/kg/daygroup with 11 litters (due to maternal deaths). There were notreatment-related effects on pre- or postimplantation loss,fetal sex ratio, litter size, or fetal body weight/litter. Moreover,no evidence was found of in creased teratogenicity at any dosetested in rabbits. Therefore, IPA was not teratogenic to CDrats or to NZW rabbits. The NOAELS for both maternal and developmentaltoxicity were 400 mg/kg/day in rats, and were 240 and 480mg/kg/day,respectively, in rabbits.     

Teratological study of 4-ethoxy-2-methyl 5-morpholino-3(2H)-pyridazinone (M73101) in mice and rats (author's transl)]

M73101 was given orally to pregnant mice (0, 100, 400 and 800 mg/kg/day) and rats (0, 100, 300 and 600mg/kg/day) during the major organogenesis to assess the influences of prenatal and postnatal development of progeny. There were no apparent effects of M73101 on litter size, fetal mortality or sex ratio in both species, although slight decrease in body weight occurred in fetuses of mice and rats exposed to the largest dose. No external, internal or skeletal malformations attributable to M73101 were observed in mouse and rat fetuses. No apparent influences of M73101 on postnatal development of mouse or rat offspring were seen.     

Effects of D-004, a lipid extract from the royal palm (Roystonea regia) fruits, tamsulosin and their combined use on urodynamic changes induced with phenylephrine in rats

5-alpha-Reductase inhibitors, alpha1-adrenoreceptors blockers and herbal drugs, like lipid extracts from saw palmetto fruits, are used to treat benign prostatic hyperplasia (BPH). D-004, a lipid extract from the Royal palm fruits, prevented prostate hyperplasia (PH) induced with testosterone and the atypical PH induced with phenylephrine (PHE) in the rat, its effect in this last model being comparable to that of saw palmetto, but lesser than that of tamsulosin (CAS 106133-20-4). It was investigated whether single doses of D-004, tamsulosin and their combined therapy can prevent urodynamic changes induced with PHE in the rat. Firstly, the effects of PHE on rat volume voided per micturition (VM) were explored in rats that were distributed in three groups: a negative control and two groups injected s. c. with PHE (5 and 10 mg/kg, respectively). In the other two experiments, rats were distributed in four groups: a negative control and three groups injected with PHE (a positive control and two groups treated with either tamsulosin 0.05 and 0.1 mg/kg, or D-004 400 and 800 mg/kg. In another experiment, the effects of the combined therapy were assessed using four groups: a negative control, a positive control and three groups treated orally with tamsulosin 0.05 mg/kg, D-004 400 mg/kg or D-004 400 mg/kg + tamsulosin 0.05 mg/kg, respectively. Sixty min later, all rats (except negative controls) were injected s. c. with PHE (5 mg/kg), and all (including the negative controls) received a fluid-loading dose. Thirty min later, they were placed in metabolic cages and theVM was measured for 1 h. The VM was significantly reduced with PHE (5 and 10 mg/kg), the high dose producing anuria in 50% of the rats. The reduction of VM was significantly and dose-dependently prevented with tamsulosin (0.05 and 0.1 mg/kg) (42.9% and 60.3%, respectively) and with D-004 (400 and 800 mg/kg) (25.2% and 43.1%, respectively). The inhibition reached (70.9%) with the combined therapy was greater than that reached with each monotherapy and also greater than the sum (56.8%) of the inhibitions reached with tamsulosin (35%) or D-004 (21.8%) alone. In conclusion, tamsulosin (0.05 and 0.1 mg/kg) and D-004 (400-800 mg/kg) dose-dependently inhibited the VM reduction induced with PHE, their combined therapy producing the greater effects.     

Multigeneration study of FD & C Blue No. 2 in rats

In a three-generation reproduction study, groups of ten male and 20 female Charles River CD rats were fed FD & C Blue No. 2 at dietary levels providing intakes of 0.0, 2.5, 25, 75 and 250 mg/kg body weight/day. Slightly bluish-coloured fur was noted in rats at the 250-mg/kg/day dose level and bluish-green-coloured faeces were produced by rats in the 75- and 250-mg/kg/day groups. The gestation, viability and lactation indices of all litters were comparable for the control and treated groups. The fertility indices for female rats in the 2.5- and 25-mg/kg/day groups were significantly lower than those for control females in the case of the F2 litters. However, there was no reduction in the female fertility indices for the F2 litters at the two higher dosage levels, nor for the F1 and F3 litters at any dosage level. Although fertility indices were reduced for some groups of male rats in the F2b and F2c litters, these changes were not considered to be compound-related. Examination of the ovaries and uteri of all dams killed on day 19 of gestation of the F2c and F3c litters revealed no gross anatomical abnormalities. No unusual changes were observed in the stillborn pups or in pups dying during the study. There were no compound-related gross or microscopic pathological lesions in any of the F1 or F3a rats that were killed and necropsied, and no compound-related organ-weight variations were recorded in the F1 parental rats.     

Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.

Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.     

Toxicological studies of a new cephamycin, MT-141. III. Its chronic toxicity in rats

The chronic toxicity of MT-141 was studied in male and female Wistar rats with 182-time intramuscular injections of 50, 100, 200, 400, 800 and 1,600 mg/kg/day and the following results were obtained. MT-141 at all dosage levels caused no lethal effect on rats. However, it induced local inflammatory changes at the site of injection, such as hemorrhage, infiltration of round cells and fibrosis particularly at high doses. MT-141 at a high dose of 1,600 mg/kg/day decreased the gain of body weights in male rats but not in female rats. MT-141 increased the water intake in male and female rats from 8th day till last day after treatments with the doses more than 800 mg/kg/day. This compound also softened the feces and distended the cecum. MT-141 at the highest dosage level of 1,600 mg/kg/day increased the weight of kidney in male and female rats. Electron-microscopic findings revealed dissociation of basal infolding and dilatation of endoplasmic reticulum in renal epithelial cells of rats treated with the doses more than 800 mg/kg/day. These results suggest that MT-141 may induce renal toxicity in rats at these doses. The administration of MT-141 changed some toxicological parameters in gross and histopathological examinations and analyses of blood, serum and urine. However, the changes were accidental, independent on the dose and within physiological variations. It is concluded from above-mentioned results that the maximal "no effective" dose of MT-141 is 400 mg/kg/day in male and female rats.     

Toxicological studies of a new cephamycin, MT-141. II. Its subacute toxicity in rats

In this subacute study, male and female rats were administered with 100, 200, 400, 800 and 1,600 mg/kg/day of MT-141 through an intramuscular (i.m.) route or with 50, 100, 200, 400 and 800 mg/kg/day through an intravenous (i.v.) route for 30 days. MT-141 did not cause lethal effect on male and female rats even at the high dosage of 1,600 mg/kg/day i.m. (approx. one-6th of LD50) and 800 mg/kg/day i.v. (approx. one-8th of LD50). Histopathological findings revealed that MT-141 induced slight local irritation at the sites of i.m. and i.v. injection. Only at a high dose of 1,600 mg/kg/day i.m., MT-141 reduced significantly the gain of body weight in male rats, which was closely related to the decrease of food intake. A slight decrease in serum Cr. and Glc. was observed in male rats at the doses more than 200 mg/kg/day i.m. and a slight decrease of liver weight at the doses more than 800 mg/kg/day i.m., while a slight increase of serum CPK, GOT, A1-P and LDH was perceived at the doses more than 800 mg/kg/day i.m. The distention of cecum was induced by the doses more than 400 mg/kg/day i.m. but histopathological findings revealed no abnormality in the cecum. These results suggest that MT-141 at the dosage level of 1,600 mg/kg/day i.m. causes nonspecific slight toxicity based on the disturbance of nourishment in male rats. In female rats given 100 to 1,600 mg/kg/day i.m., MT-141 at the high doses induced a slight increase of serum GOT, LDH and CPK and distention of the cecum. It is assumed from these results that MT-141 at the dosage level of 1,600 mg/kg/day causes nonspecific slight toxicity in female rats. In male rats given 50 to 800 mg/kg/day through an i.v. route, the level of serum Glc. and Cr. and the liver weight slightly decreased at the doses more than 200 mg/kg/day i.v. The cecum distended at the doses more than 100 mg/kg/day i.v. The dose of 800 mg/kg/day i.v. increased the activity of LDH and CPK in the serum. In female rats, MT-141 raised slightly the level of serum GOT, A1-P, LDH and CPK even at the doses more than 400 mg/kg/day i.v., reduced the liver weight at the dose of 800 mg/kg/day i.v. and distended the cecum at the all doses. These results suggest that MT-141 at the dosage level of 800 mg/kg/day i.v. induces nonspecific slight toxicity in male and female rats.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of perinatal exposure to aspartame on rat pups

Possible effects of perinatal exposure to L-aspartyl-L-phenylalanine methyl ester (aspartame) on rat pups were investigated. Adult female rats, and later their pups, were exposed, via their drinking water, to aspartame (0.007%, 0.036%, 0.18% or 0.9% w/v) or phenylalanine (0.45% w/v) for 12 days prior to conception until the pups were 38 days old. Control rats were given plain water. The adults exposed to aspartame consumed an average of 14, 68, 347 and 1614 mg/kg/day of aspartame and those exposed to phenylalanine consumed an average of 835 mg/kg/day of phenylalanine. After weaning the pups given aspartame consumed an average of 32, 154, 836, and 3566 mg/kg/day of aspartame and those given phenylalanine consumed an average of 1795 mg/kg/day of phenylalanine. No effect of aspartame or phenylalanine was detected on either two measures of morphological development (i.e., latencies to pinnae detachment and eye opening) or two tests of reflex development (i.e., latencies for surface righting at 7 days of age and negative geotaxis at 8 days of age). All groups were similar in spatial memory as assessed with two different mazes with pups 30-36 days old. The number of arms before reentry in an 8-arm radial-arm maze and the acquisition curves from a milk maze did not differ between groups. Furthermore, the latencies of mothers to retrieve their litters was also unaffected by the aspartame and phenylalanine. These results indicate that perinatal exposure to aspartame, when voluntarily consumed by mothers (14-1614 mg/kg/day) and later directly by the rat pups (32 to 3566 mg/kg/day) does not affect reflex development, morphological development or spatial memory.