Combined repeated dose and reproductive/developmental toxicity screening test of the nitrophenolic herbicide dinoseb, 2-sec-butyl-4,6-dinitrophenol, in rats

In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, Crj:CD(SD)IGS rats were dosed with dinoseb, 2-sec-butyl-4,6-dinitrophenol, by gavage at 0 (vehicle), 0.78, 2.33, or 7.0 mg/kg bw/day. Six males per group were dosed for a total of 42 days beginning 14 days before mating. Twelve females per group were dosed for a total of 44-48 days beginning 14 days before mating to day 6 of lactation throughout the mating and gestation period. Recovery groups of six males per group and nonpregnant six females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in males of any dose group or in females of the recovery groups. At 7.0 mg/kg bw/day, eight females died and two animals were moribund during late pregnancy, and a significant decrease in body weight gain was found in both sexes. Hematocrit was significantly higher at 0.78 mg/kg bw/day and above in the main group males at the end of administration period. Reduction in extramedullary hematopoiesis in the spleen was significant at 2.33 mg/kg bw/day in the main group females. Sperm analysis revealed a decrease in sperm motility and an increase in the rates of abnormal sperm, abnormal tail, and abnormal head at 7.0 mg/kg bw/day. A number of dams delivered their pups and of dams with live pups at delivery was significantly lowered in the 7.0 mg/kg bw/day group. Based on these findings, the LOAEL for males and NOAEL for females were 0.78 mg/kg bw/day, and the NOAEL for reproductive/developmental toxicity was considered to be 2.33 mg/kg bw/day.     

Reproductive and developmental toxicity screening study of 2,4-dinitrophenol in rats

Rats were treated by gavage once daily with 2,4-dinitrophenol (DNP) at 0 (control), 3, 10, or 30 mg/kg bw. Males were dosed for 46 days, beginning 14 days before mating, and females were dosed for 40-47 days, from 14 days before mating to day 3 of lactation. No deaths were observed in males and females of any group. A significant decrease in body weight gain and significant increase in liver weight were found in males and females at 30 mg/kg bw/day. The number of live pups on postnatal days (PNDs) 0 and 4, live birth index, and body weight of live male and female pups on PNDs 0 and 1 were significantly lowered at 30 mg/kg bw/day. External and internal examinations of pups revealed no increased incidence of malformations in DNP-treated groups. On the basis of these findings, we concluded that DNP has general and reproductive/developmental toxicity, but not teratogenicity, under the present conditions. The NOAEL of DNP is considered to be 10 mg/kg bw/day in rats.     

Reproductive and Developmental Toxicity Screening Study of 4-Aminophenol in Rats

Twelve male and female rats per group were given 4-aminophenol (PAP) by gavage at 0, 20, 100, or 500 mg/kg/day. Males were dosed for a total of 49 days, beginning 14 days before mating. Females were dosed for a total of 40–60 days, from 14 days before mating to Day 3 of lactation throughout the mating and gestation periods. Four males and 2 females died at 500 mg/kg/day, and all surviving males and females showed brown urine at 100 mg/kg/day and above. Body-weight gain was lower in males and females at 500 mg/kg/day, and food consumption was decreased in males at 500 mg/kg/day and in females at 100 and 500 mg/kg/day. Absolute and relative weights of the testes and epididymides were decreased at 500 mg/kg/day. Histopathological examinations revealed decreased spermatocyte and spermatid levels in the testis, debris of germ cell in the epididymis lumen, basophilic tubules in the kidney, and deposits of hemosiderin in the red pulp and extramedullary hematopoiesis in the spleen in males at 500 mg/kg/day. Longer gestation period, decreased delivery index, and lower body weight of pups on postnatal day (PND) 0 and increased number of stillborns at 500 mg/kg/day were also observed. At this dose, the viability of pups on PND 4 was decreased markedly. No adverse effects on reproduction or development were detected at 20 and 100 mg/kg/day. These findings indicate that PAP is general and reproductive/developmental toxic, but is unlikely to be teratogenic, in rats.     

Reproductive and developmental toxicity screening test of 3-cyanopyridine in rats

Crl:CD(SD)rats were given 3-cyanopyridine by gavage at 0, 5, 30 or 180 mg/kg/day. Males were dosed for 42 days beginning 14 days before mating, and females for 40–53 days beginning 14 days before mating to day 3 of lactation, including throughout the mating and gestation periods. General toxicity, mainly liver damage, was observed in males at ≥30 mg/kg/day and in females at ≥5 mg/kg/day. Sertoli cell vacuolation was observed at 180 mg/kg/day, and spermatocyte damages were observed at ≥30 mg/kg/day. Effects on estrous cycles, corpora lutea and implantations, and unsuccessfully mated females, despite additional mating, were observed at 180 mg/kg/day. Delayed initiation of delivery, dystocia, and deaths or moribundities of pregnant females were observed at 180 mg/kg/day, and only two pregnant rats delivered live pups at that dose. The NOAEL for reproductive/developmental toxicity was concluded to be 30 mg/kg/day.     

Screening Study for Repeated Dose and Reproductive/Developmental Toxicity of Rubber Accelerator,N,N-Dicyclohexyl-2-benzothiazolesulfenamide,in Rats

A screening study for a vulcanization accelerator N,N-dicyclohexyl-2-benzothiazolesulfenamide (DCBS) was performed in rats. Rats were given DCBS by gavage daily at 0, 6, 25, 100, or 400 mg/kg. Males were dosed for a total of 44 days beginning 14 days before mating. Females were dosed for a total of 40–51 days beginning 14 days before mating to day 3 of lactation. Toxicologic changes were significantly noted only at 400 mg/kg. Three females died. An increased incidence of females showing decreased locomotor activity, soil of the lower abdominal fur, and reddish tears was observed. A lowered body weight was found in males and females. Increased urinary ketones and serum inorganic phosphorus and decreased serum glutamate pyruvate transaminase in males were found. Increased absolute and relative weights of the kidneys in males and decreased absolute weight of the thymus in both sexes were noted. Significant fatty degeneration of the renal tubular epithelia, vacuolation of the adrenocortical cells, and atrophy of the spleen were observed in females. Significant decreases in the gestation index, numbers of corpura lutea, implantations, pups born and pups born alive, live birth index, and viability index were detected. It is concluded that the No Observed Adverse Effect Levels (NOAELs) for repeat dose and reproductive/developmental toxicity are 100 mg kg^?1 day^?1 in this screening study.     

Combined repeated dose and reproductive/developmental toxicities of copper monochloride in rats

This study investigated the combined repeated dose and reproductive/developmental toxicity of copper monochloride in rats. The test substance was administered once daily by gavage at 0, 1.3, 5, 20, or 80 mg/kg/day. Male rats were dosed for a total of 30 days beginning 14 days before mating. Female rats were dosed from 2 weeks before mating to day 3 of lactation throughout the mating and gestation period. At 80 mg/kg/day, deaths were observed in 3 out of 12 females. There was a dose-dependent increase in the incidence of clinical signs and a reduction in the food consumption. Hematological and serum biochemical investigations revealed a decrease in the red blood cell, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin (MCH), and serum total protein levels and an increase in the white blood cell and platelets in males, and a decrease in the MCH and an increase in the platelets in females. Histopathological examination showed an increased incidence of squamous cell hyperplasia of the stomach in both genders as well as increased hematopoiesis of the femur in males. There was an increase in the number of icteric and runt pups at birth. At 20 mg/kg/day, there was an increase in the incidence of clinical signs and squamous cell hyperplasia of the stomach in both genders. At 5 mg/kg/day, an increase in the incidence of squamous cell hyperplasia of the stomach was observed in females. There were no adverse effects in the lowest group in both genders. Based on these findings, the no-observed-adverse-effect levels of copper monochloride were concluded to be 5 mg/kg/day in male rats and 1.3 mg/kg/day in female rats for general toxicity and 20 mg/kg/day for reproductive/developmental toxicity.     

Reproductive and developmental toxicity screening study of 4-aminophenol in rats

Twelve male and female rats per group were given 4-aminophenol (PAP) by gavage at 0, 20, 100, or 500 mg/kg/day. Males were dosed for a total of 49 days, beginning 14 days before mating. Females were dosed for a total of 40-60 days, from 14 days before mating to Day 3 of lactation throughout the mating and gestation periods. Four males and 2 females died at 500 mg/kg/day, and all surviving males and females showed brown urine at 100 mg/kg/day and above. Body-weight gain was lower in males and females at 500 mg/kg/day, and food consumption was decreased in males at 500 mg/kg/day and in females at 100 and 500 mg/kg/day. Absolute and relative weights of the testes and epididymides were decreased at 500 mg/kg/day. Histopathological examinations revealed decreased spermatocyte and spermatid levels in the testis, debris of germ cell in the epididymis lumen, basophilic tubules in the kidney, and deposits of hemosiderin in the red pulp and extramedullary hematopoiesis in the spleen in males at 500 mg/kg/day. Longer gestation period, decreased delivery index, and lower body weight of pups on postnatal day (PND) 0 and increased number of stillborns at 500 mg/kg/day were also observed. At this dose, the viability of pups on PND 4 was decreased markedly. No adverse effects on reproduction or development were detected at 20 and 100 mg/kg/day. These findings indicate that PAP is general and reproductive/developmental toxic, but is unlikely to be teratogenic, in rats.     

Screening study for repeated dose and reproductive/developmental toxicity of rubber accelerator, N,N-dicyclohexyl-2-benzothiazolesulfenamide, in rats

A screening study for a vulcanization accelerator N,N-dicyclohexyl-2-benzothiazole-sulfenamide (DCBS) was performed in rats. Rats were given DCBS by gavage daily at 0, 6, 25, 100, or 400 mg/kg. Males were dosed for a total of 44 days beginning 14 days before mating. Females were dosed for a total of 40-51 days beginning 14 days before mating to day 3 of lactation. Toxicologic changes were significantly noted only at 400 mg/kg. Three females died. An increased incidence of females showing decreased locomotor activity, soil of the lower abdominal fur, and reddish tears was observed. A lowered body weight was found in males and females. Increased urinary ketones and serum inorganic phosphorus and decreased serum glutamate pyruvate transaminase in males were found. Increased absolute and relative weights of the kidneys in males and decreased absolute weight of the thymus in both sexes were noted. Significant fatty degeneration of the renal tubular epithelia, vacuolation of the adrenocortical cells, and atrophy of the spleen were observed in females. Significant decreases in the gestation index, numbers of corpura lutea, implantations, pups born and pups born alive, live birth index, and viability index were detected. It is concluded that the No Observed Adverse Effect Levels (NOAELs) for repeat dose and reproductive/developmental toxicity are 100 mg kg-1 day-1 in this screening study.     

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.     

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.     

Repeated dose and reproductive/developmental toxicity of perfluorooctadecanoic acid in rats

Male and female rats were given perfluorooctadecanoic acid (PFOdA) by gavage at 40, 200 or 1,000 mg/kg/day, and each female was mated with a male in the same dose group after 14-day administration. Males were dosed for 42 days and females were dosed throughout the gestation period until day 5 of lactation. One female given 1,000 mg/kg/day was euthanized on day 18 of gestation due to a moribund condition; however, no other treatment-related clinical signs of toxicity were observed. Body weights fell at 1,000 mg/kg/day from day 28 through the administration period in males and throughout gestation and lactation in females. Red blood cell count, hemoglobin level and hematocrit were decreased at 200 and 1,000 mg/kg/day in males and activated partial thromboplastin time was prolonged at 1,000 mg/kg/ day in females. Histopathological examination revealed hepatic changes, such as centrilobular hypertrophy and necrosis, in males given 200 and 1,000 mg/kg/day and in females given 1,000 mg/kg/day. Pancreatic zymogen granule was decreased in both sexes at 1,000 mg/kg/day. As for reproductive and developmental toxicity, there were decreases in the number of corpora lutea, implantation, total number of pups born and the number of live pups on postnatal days 0 and 4 at 1,000 mg/kg/day. At this dose, birth weights of pups were decreased and postnatal body weight gain was inhibited. Based on these findings, the NOAEL of PFOdA was considered to be 40 mg/kg/day for repeated dose toxicity and 200 mg/kg/day for reproductive/developmental toxicity.     

Reproductive and developmental toxicity screening test of basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats

Twelve male and female rats per group were exposed to the rubber accelerator 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 8, 20 or 50 mg/kg bw/day. Males were dosed for a total of 49 days beginning 14 days before mating. Females were dosed for a total of 40-49 days beginning 14 days before mating to day 3 of lactation throughout the mating and gestation period. At 50 mg/kg bw/day, deaths were observed in two males and three females. Lowered body weight gain and food consumption were noted in males at 50 mg/kg bw/day and females at 20 and 50 mg/kg bw/day. Mydriasis, decreased locomotor activity, bradypnea, prone position, tremor and/or salivation were observed in males and females at 20 and 50 mg/kg bw/day. No effects of DTG were found on the estrous cyclicity, precoital interval, copulation, fertility and gestational indices, numbers of corpora lutea and implantations, or gestation length. A significant decrease in the number, body weight and viability of offspring and increase in the incidence of fetuses with external malformations were found at 50 mg/kg bw/day. Oligodactyly, anal atresia and tail anomalies were observed. These data suggest that DTG may be teratogenic. The NOAELs of DTG for general and developmental toxicity in rats are 8 and 20 mg/kg bw/day, respectively.     

Effects of thalidomide on developmental, peri- and postnatal function in female New Zealand white rabbits and offspring.

The present study determined effects of thalidomide on three successive generations of New Zealand White rabbits after oral dosing to F0 maternal rabbits during the later third of gestation (post major organogenesis) and lactation. One hundred and twenty four time-mated F0 rabbits (31/dose) were gavaged with 0, 30, 150, or 500 mg/kg thalidomide from gestation day 18 (DG 18) to lactation day 28 (DP or day postpartum 28) for approximately 42 days. At 6 months, 12 F1 males and 12 F1 females were randomly paired within each dose group and mated. Reproductive evaluation and/or gross necropsy of the thoracic, abdominal, and pelvic viscera was performed on day 29 postpartum (DP 29) for F0 rabbits, on DP 49 for F1 pups not selected for continued evaluation, after completion of mating for F1 rabbits, and on DG 29 for F1 rabbits on continued evaluation of F2 litter. There was no thalidomide-related mortality in F0 and F1 rabbits. One F0 doe at 30 and 150 mg/kg and 2 at 500 mg/kg aborted. Maternal F0 rabbits had reductions in feed consumption but not body weight gain during the gestation and lactation periods for 150 and 500 mg/kg. The numbers of does with stillborn and all pups dying from DP 1-4 was increased at 150 and 500 mg/kg. Mean number of liveborn (litter size) and percentage of live pups were decreased at 500 mg/kg. A significantly increased number of pups died at 150 and 500 mg/kg, resulting in a reduced viability index and decreased litter size. There were some F1 male and female body weight reductions at 150 and 500 mg/kg postweaning with no change in feed consumption. F1 Caesarean-sectioning and litter observations were normal. Fertility of F1 offspring was not affected by maternal doses of thalidomide, but the pregnancy index may have been reduced by the 500 mg/kg maternal thalidomide dose. There was an apparent dose-related increase in splayed limbs in F1 pups. Splaying has been reported in New Zealand White rabbits and may be a recessive trait. The splay could be caused by the nerve and muscle fiber degeneration and skeletal muscle atrophy observed in some pups. It could also be due to the decrease in litter size, resulting in fewer pups per litter for nursing, leading to rapid weight gain and a failure of the pups to support this weight. No F2 fetal gross external alterations were observed. In summary, pregnant rabbits orally dosed with up to 500 mg/kg thalidomide from gestation day 18 to lactation day 28 had increased abortion, changes in some natural delivery and litter parameters, and limb splay in some F1 pups. No gross external changes were observed in F1 and F2 pups.     

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.     

Prenatal toxicity of Ascaris pepsin inhibitor in mice

The developmental toxicity of pepsin inhibitor isolated from Ascaris suum, a gastrointestinal nematode parasite, was evaluated. An embryo–fetal development study was conducted in BALB/c mice. Groups of 21 mated females were treated by intraperitoneal injection (0.3 ml/30 g body weight) with 0.9% NaCl solution vehicle or isolated Ascaris pepsin inhibitor (API) at dose levels of 50, 100, 150 or 200 mg/kg body weight/day on gestation days (GD) 6–15. Maternal food consumption, body weight, and clinical signs were monitored throughout gestation. Cesarean sections were performed on GD 18 and gravid uterine weight, implantation sites, early and late resorptions, live and dead fetuses were collected. Live fetuses were weighed and examined for external, visceral and skeletal variations and malformations. Maternal body weight gain, gravid uterine weight, food consumption were significantly decreased after injection of higher doses of API (100–200 mg/kg/day). All doses of API exhibited an embryotoxic effect (high rate of intrauterine resorption). The percentage of postimplantation loss in the groups with administered API was higher (over 4–11 times) than that in control group. Fetotoxicity was observed in all treatment groups in a dose-related manner and it was evidenced by increased dead fetuses, decreased fetal weight, increased visceral variations and reduced skeletal ossification. Fetal hydronephrosis and internal hydrocephalus were noted at 150, and 200 mg/kg/day. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 50 mg/kg/day and the low-observed-adverse-effect level (LOAEL) was 100 mg/kg/day under the conditions of this study. However, the developmental toxicity LOAEL was 50 mg/kg/day based on decreased fetal body weight and prenatal mortality.     

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.     

紫杉醇对大鼠的一般生殖毒性作用

紫杉醇是一种抗肿瘤新药，对大鼠的一般生殖毒性实验结果表明，给药剂量在１．０ｍｇ／ｋｇ时雄鼠和雌鼠摄食量减少，体重增长下降，雌鼠肾上腺及卵巢重量减轻，雄鼠的生育率和雌鼠受孕率下降，但对交配率无明显影响；母鼠剖检时发现黄体数、着床数及活胎数减少，着床痕数增加。未见致畸胎作用。对活胎体重、身长和尾长无明显影响。     

Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats

Perfluorooctanesulfonate (PFOS) is a persistent acid found widely distributed in wildlife and humans. To understand the potential reproductive and developmental effects of PFOS, a two-generation reproduction study was conducted in rats. Male and female rats were dosed via oral gavage at dose levels of 0, 0.1, 0.4, 1.6, and 3.2 mg/(kg day) for 6 weeks prior to mating, during mating, and, for females, through gestation and lactation, across two generations. Due to substantial F1 neonatal toxicity observed in the 1.6 and 3.2 mg/(kg day) groups, continuation into the second generation was limited to F1 pups from the 0, 0.1, and 0.4 mg/(kg day) groups. No adverse effects were observed in F0 females or their fetuses upon caesarean sectioning at gestation day 10. Statistically significant reductions in body-weight gain and feed consumption were observed in F0 generation males and females at dose levels of 0.4 mg/(kg day) and higher, but not in F1 adults. PFOS did not affect reproductive performance (mating, estrous cycling, and fertility); however, reproductive outcome, as demonstrated by decreased length of gestation, number of implantation sites, and increased numbers of dams with stillborn pups or with all pups dying on lactation days 1-4, was affected at 3.2 mg/(kg day) in F0 dams. These effects were not observed in F1 dams at the highest dose tested, 0.4 mg/(kg day). Neonatal toxicity in F1 pups, as demonstrated by reduced survival and body-weight gain through the end of lactation, occurred at a maternal dose of 1.6 mg/(kg day) and higher while not at dose levels of 0.1 or 0.4 mg/(kg day) or in F2 pups at the 0.1 or 0.4 mg/(kg day) dose levels tested. In addition to these adverse effects, slight yet statistically significant developmental delays occurred at 0.4 (eye opening) and 1.6 mg/(kg day) (eye opening, air righting, surface righting, and pinna unfolding) in F1 pups. Based on these data, the NOAELs were as follows: reproductive function: F0> or =3.2 and F1> or =0.4 mg/(kg day); reproductive outcome: F0=1.6 and F1> or =0.4 mg/(kg day); overall parental effects: F0=0.1 and F1> or =0.4 mg/(kg day); offspring effects: F0=0.4 and F1> or =0.4 mg/(kg day). To distinguish between maternal and pup influences contributing to the perinatal mortality observed in the two-generation study, a follow-up cross-foster study was performed. Results of this study indicated that in utero exposure to PFOS causally contributed to post-natal pup mortality, and that pre-natal and post-natal exposure to PFOS was additive with respect to the toxic effects observed in pups.     

Developmental toxicity of perfluorooctane sulfonate (PFOS) is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPARα) in the mouse

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of perfluorinated compounds. Both are environmentally persistent and found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in laboratory rodents. Exposure to these chemicals in utero delays development and reduces postnatal survival and growth. Exposure to PFOS on the last 4 days of gestation in the rat is sufficient to reduce neonatal survival. PFOS and PFOA are weak agonists of peroxisome proliferator activated receptor-alpha (PPARα). The reduced postnatal survival of neonatal mice exposed to PFOA was recently shown to depend on expression of PPARα. This study used PPARα knockout (KO) and 129S1/SvlmJ wild type (WT) mice to determine if PPARα expression is required for the developmental toxicity of PFOS. After mating overnight, the next day was designated gestation day (GD) 0. WT females were weighed and dosed orally from GD15 to 18 with 0.5% Tween-20, 4.5, 6.5, 8.5, or 10.5 mg PFOS/kg/day. KO females were dosed with 0.5% Tween-20, 8.5 or 10.5 mg PFOS/kg/day. Dams and pups were observed daily and pups were weighed on postnatal day (PND) 1 and PND15. Eye opening was recorded from PND12 to 15. Dams and pups were killed on PND15, body and liver weights recorded, and serum collected. PFOS did not affect maternal weight gain or body or liver weights of the dams on PND15. Neonatal survival (PND1–15) was significantly reduced by PFOS in both WT and KO litters at all doses. WT and KO pup birth weight and weight gain from PND1 to 15 were not significantly affected by PFOS exposure. Relative liver weight of WT and KO pups was significantly increased by the 10.5 mg/kg dose. Eye opening of PFOS-exposed pups was slightly delayed in WT and KO on PND13 or 14, respectively. Because results in WT and KO were comparable, it is concluded that PFOS-induced neonatal lethality and delayed eye opening are not dependent on activation of PPARα.     

Developmental and reproductive toxicity evaluation of toluene vapor in the rat. I. Reproductive toxicity

The reproductive toxicity of toluene was evaluated in a 2-generation test in which male and female Sprague–Dawley rats, parental (F0) and first generation (F1), were exposed to toluene via whole body inhalation, 6 h/day, 7 days/week for 80 days premating and 15 days of mating at concentrations of 0, 100, 500 and 2000 ppm (0, 375, 1875 and 7500 mg/m³). Toluene was administered at 2000 ppm to both sexes, or to females or males only to be mated with untreated partners. Pregnant females at all dose levels were exposed from gestation day (GD) 1–20 and lactation day (LD) 5–21. At LD5, females were removed from their litters for daily exposure and returned when 6 h of exposure was completed. F1 pups selected to produce the F2 generation were treated for 80 days beginning immediately after weaning (LD21) and initially mated at a minimum of 100 days of age. F2 pups were not exposed to toluene by inhalation.

Toluene exposure did not induce adverse effects on fertility, reproductive performance, or maternal/pup behaviors during the lactation period in males and females of the parental or first generation, but did inhibit growth in F1 and F2 offspring in the 2000 ppm (both sexes treated) and 2000 ppm (females only treated) groups. Caesarean section of selected 2000 ppm (both sexes treated) dams at GD20 showed reduced fetal body weight and skeletal variations. Exposure to toluene caused decreased pup weights throughout lactation in F1 and F2 2000 ppm (both sexes treated), and 2000 ppm (females only treated) groups. Exposure at 2000 ppm to male parents only did not induce similar weight inhibition in offspring. The toluene offspring NOAEL is 500 ppm in groups in which maternal animals were exposed, and 2000 ppm for male only treated groups.