Developmental toxicity of flucytosine following administration to pregnant rats at a specific time point of organogenesis.

To investigate the abnormalities that are specific to administration of flucytosine at one time point during embryonic organogenesis, flucytosine was administered orally to pregnant Sprague Dawley (SD) rats in a single dose on day 11 of pregnancy at 25 or 35 mg/kg. Fetuses on day 20 of pregnancy were externally, viscerally, and skeletally examined. Maternal body weight gain and food consumption were suppressed the day after administration of a 35 mg/kg. Fetal examinations revealed various alterations in both dose groups: externally preaxial polydactyly in the hind limb; skeletally fused lumbar centrum, absent sacral centrum, supernumerary sacral vertebra, and absent ribs. Our findings indicated that specific types of external and skeletal anomalies were induced following flucytosine administration on day 11 of pregnancy.

Historical control data on developmental toxicity studies in rats.

Historical control data from prenatal developmental toxicity studies in rats have been used to evaluate whether toxicology outcomes were induced by exposure to a chemical or were within the range of spontaneous variation. These data are also important for monitoring animal characteristics. As a follow-up to historical control data from 1998 to 2010, this study analyzed control data from prenatal developmental studies performed in rats from 2011 to 2015. Data were collected from studies performed by 24 Japanese laboratories, including 15 pharmaceutical and chemical companies and nine contract research organizations, in Sprague-Dawley and two-sub-strains of Wistar Hannover rats. The data included maternal reproductive findings at terminal cesarean section and fetal findings, including incidences of spontaneous external, visceral, and skeletal anomalies. No noticeable differences in maternal reproductive data were observed among laboratories. The inter-laboratory variations in the incidences of fetal anomalies seemed to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, as well as to differences in terminology of fetal alterations. These historical control data may be helpful for adequate interpretation of experimental results and for evaluating the reproductive and developmental toxicities of various chemicals.

Evaluation of reproductive and developmental toxicity of the rubber accelerator N,N-dicyclohexyl-2-benzothiazolesulfenamide in rats.

Male and female Crl:CD(SD) rats were fed a diet containing the rubber accelerator N,N-dicyclohexyl-2-benzothiazolesulfenamide (DCBS) at 0, 1500, 3000, 6000 or 10,000 p.p.m. (0, 83, 172, 343 or 551 mg/kg bw/day in males and 0, 126, 264, 476 or 707 mg/kg bw/day in females) for a total of 57 days beginning 16 days before mating in males, and a total of 61-65 days from 16 days before mating to day 21 of lactation in females. Body weight gains and food consumption were reduced in males at 6000 p.p.m. and higher and in females at 3000 p.p.m. and higher. The weights of the spleen at 6000 and 10,000 p.p.m. and of the thymus at 10,000 p.p.m. were decreased in females. No changes in estrous cyclicity, copulation index, fertility index, gestation index, delivery index, precoital interval or gestation length were observed at any dose of DCBS. Numbers of implantations at 6000 and 10,000 p.p.m. and pups delivered at 10,000 p.p.m. were reduced. There were no changes in the sex ratio or viability of pups. The body weights of male and female pups were lowered at 6000 p.p.m. and higher. Decreased weight of the spleen in weanlings was also observed in males at 1500 p.p.m. and higher and in females at 3000 p.p.m. and higher. The data indicate that DCBS possesses adverse effects on reproduction and development in rats.

A two-generation reproductive toxicity study of diethyl phthalate (DEP) in rats.

A two-generation reproductive toxicity study was performed to evaluate the effects of diethyl phthalate on parental reproductive performance, including features of the endocrine system and development and growth of offspring at dietary dose levels of 0, 600, 3000 and 15000 ppm. In F0 and F1 parents, no treatment-related adverse effects were observed in clinical findings, body weights, food consumption, reproductive parameters, and gross or histopathological findings in any treated group. Increased liver weights and enhanced activities of metabolic enzymes were observed in F0 males at 15000 ppm. F0 males also exhibited an increase in the content of CYP3A2, a cytochrome P450 isozyme, at 15000 ppm, and a decrease in the levels of serum testosterone at 3000 and 15000 ppm, suggesting sex steroid metabolism might be changed. However, these were not considered adverse effects because the degree of change was too slight to affect the reproductive capability to produce progeny. Body weight gains before weaning were inhibited in F1 and F2 pups and vaginal opening was slightly delayed in F1 females at 15000 ppm. No changes were observed in the reproductive performance. Therefore, the no-observed-adverse-effect level (NOAEL) from this study is considered to be 15000 ppm for parental animals, and 3000 ppm for development and growth of the pups.

Historical control data on developmental toxicity studies in rodents.

Historical control data on rodent developmental toxicity studies, performed between 1994 and 2010, were obtained from 19 laboratories in Japan, including 10 pharmaceutical and chemical companies and nine contract research organizations. Rats, mice, and hamsters were used for developmental toxicity studies. Data included maternal reproductive findings at terminal cesarean sections and fetal findings including the spontaneous incidences of external, visceral, and skeletal anomalies. No noticeable differences were observed in maternal reproductive data between laboratories. Inter-laboratory variations in the incidences of fetuses with anomalies appeared to be due to differences in the selection of observation parameters, observation criteria, classification of the findings, and terminology of fetal alterations. Historical control data are useful for the appropriate interpretation of experimental results and evaluation of the effects of chemical on reproductive and developmental toxicities.

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.

Historical control data on prenatal developmental toxicity studies in rabbits.

Historical control data on rabbit prenatal developmental toxicity studies, performed between 1994-2010, were obtained from 20 laboratories, including 11 pharmaceutical and chemical companies and nine contract laboratories, in Japan. In this paper, data were incorporated from a laboratory if the information was based on 10 studies or more. Japanese White rabbits and New Zealand White rabbits were used for prenatal developmental toxicity studies. The data included maternal reproductive findings at terminal cesarean sections and fetal findings including spontaneous incidences of morphological alterations. No noticeable differences between strains or laboratories were observed in the maternal reproductive and fetal developmental data. The inter-laboratory variations in the incidences of fetal external, visceral, and skeletal alterations seem to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, and terminology of fetal alterations.

A one-generation reproductive toxicity study of ethyl tertiary butyl ether in rats.

A one-generation reproductive toxicity study was conducted to evaluate the effects of ethyl tertiary butyl ether (ETBE), a bio-fuel, on reproduction of parental rats, as well as development and growth of their offspring at dose levels of 0, 100, 300 and 1000 mg/kg-d by gavage. No treatment-related changes were observed in either F0 parents or their F1 offspring in the 100 and 300 mg/kg groups in any parameters examined. Some parental animals in the 1000 mg/kg group exhibited transient salivation, possibly a reflex to a bitter taste of ETBE, immediately after dosing, although their body weights, food consumption, reproductive parameters, and gross pathological findings were not affected. Their absolute and relative liver weights increased significantly in the 1000 mg/kg group, suggesting enhanced activities of metabolic enzymes. Pup viability was slightly reduced during the early lactation period in the 1000 mg/kg group. These results lead to the conclusion that the no-observed-adverse-effect-level (NOAEL) of ETBE on both parental rats and their offspring is 300 mg/kg-d under the current study condition.

Syndactyly lethal: new mutation with multiple malformations occurring in Sprague Dawley rats.

We previously found newborns exhibiting syndactyly of both fore- and hindlimbs in a litter from a pair of Sprague Dawley rats. Continuous breeding of the parental animals yielded pups with the same anomaly in following litters, suggesting that the syndactyly was genetic in origin. In the present study, as all the syndactylous pups died on postnatal day 0, we conducted genetic analyses using 30 phenotypically normal female progeny and the sire. The females were subjected to caesarean section on day 20 of gestation and the fetuses were examined for the phenotypes. The results of the mating experiments suggest that the mutant phenotype is caused by a single autosomal recessive gene at a homozygous condition. As homozygous mutants are lethal at the neonatal stage, the mutant gene was named syndactyly lethal, gene symbol syl. The mutant rats have multiple abnormalities, such as syndactyly, micrognathia, fused/absent/small lung lobes, absent kidney and ureter, small spleen, small uterus, fused phalanges, sternoschisis, absent/detached rib, and splitting/fused/absent/small thoracic vertebra, some of which must be the cause of death on postnatal day 0. This mutant is considered to be useful for investigating the mechanisms and/or pathogenesis of syndactyly, as well as the accompanying malformations.