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 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.     

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.     

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.     

Reproductive and developmental toxicity studies of pyridostigmine bromide in rats

These studies were performed to evaluate the reproductive and developmental toxicity of pyridostigmine bromide (PB) in rats. Separate male and female fertility/reproductive performance studies, a perinatal/postnatal study and a teratology study were conducted. Dose levels were sufficient to result in overt cholinergic tremors at the high dose in each study. PB did not affect male or female fertility/reproductive performance. Pups born to treated dams did show slight, transient decreases in body weight gain, apparently secondary to the nursing behavior of dams demonstrating overt tremors. PB did not result in an increase in visceral or skeletal malformations. A slight increase in delayed ossification and early resorption were seen at the highest dose tested and were considered secondary to maternal stress/toxicity.     

Comparative toxicity study of 3-aminophenol in newborn and young rats

Repeated dose toxicity of 3-aminophenol was examined on oral administration to newborn and young rats, and susceptibility was analyzed in terms of the no observed adverse effect level (NOAEL) and the unequivocally toxic level. In the 18-day newborn rat study, starting at day 4 after birth, tremors and depression of body weight gain were observed, as well as hypertrophy of thyroid follicular epithelial cells and increases of relative liver and kidney weights at 240 mg/kg. Increase of relative liver weights in males and decrease of blood sugar in females without any histopathological changes at 80 mg/kg were not considered to be adverse effects. No chemical-related changes were observed at 24 mg/kg. Abnormalities of external development and reflex ontogeny in the newborn were not observed. In the 28-day study, starting at 5 weeks of age, depression of body weight gain, tremors, anemia, and liver, kidney and thyroid toxicity were observed at 720 mg/kg. Although slight pigmentation in the renal proximal tubular epithelium was observed in females at 240 mg/kg, this was not considered to be an adverse effect because of the lack of changes in related toxicological parameters. It was concluded that the NOAEL is 80 mg/kg/day in newborn rats and 240 mg/kg/day in young rats, with unequivocally toxic levels of 240 mg/kg/day and 720 mg/kg/day, respectively. Based on these two endpoints, the susceptibility of newborn rats to the chemical was approx. 3 times higher than that of young rats, consistent with our previous results for 4-nitrophenol and 2,4-dinitrophenol.     

Pyruvate reduces 4-aminophenol in vitro toxicity

Pyruvate has been observed to reduce the nephrotoxicity of some agents by maintaining glutathione status and preventing lipid peroxidation. This study examined the mechanism for pyruvate protection of p-aminophenol (PAP) nephrotoxicity. Renal cortical slices from male Fischer 344 rats were incubated for 30-120 min with 0, 0.1, 0.25 or 0.5 mM PAP in oxygenated Krebs buffer containing 0 or 10 mM pyruvate or glucose (1.28 or 5.5 mM). LDH leakage was increased above control by 0.25 and 0.5 mM PAP beginning at 60 min and by 0.1 mM PAP at 120 min. Pyruvate prevented an increase in LDH leakage at 60- and 120-min exposure to 0.1 and 0.25 mM PAP. Pyruvate also prevented a decline in ATP levels. Glucose (1.28 and 5.5 mM) provided less protection than pyruvate from PAP toxicity. Total glutathione levels were diminished by 0.1 and 0.25 mM PAP within 60 and 30 min, respectively. Pyruvate prevented the decline in glutathione by 0.1 mM PAP at both time periods and at 30 min for 0.25 mM PAP. Pyruvate reduced the magnitude of glutathione depletion by 0.25 mM PAP following a 60-min incubation. Glutathione disulfide (GSSG) levels in renal slices were increased at 60 min by exposure to 0.25 mM PAP, while pyruvate prevented increased GSSG levels by PAP. Pyruvate also reduced the extent of 4-hydroxynonenal (4-HNE)-adducted proteins present after a 90-min incubation with PAP. These results indicate that pyruvate provided protection for PAP toxicity by providing an energy substrate and reducing oxidative stress.     

Reproductive and developmental toxicity of inhaled 2,3-dichloro-1,3-butadiene in rats

Inhalation developmental and reproductive toxicity studies were conducted with 2,3-dichloro-1,3-butadiene (DCBD), a monomer used in the production of synthetic rubber. In the reproductive toxicity study, Crl:CD^®(SD)IGS BR rats (24/sex/group) were exposed whole body by inhalation to 0, 1, 5, or 50 ppm DCBD (6 h/day) for approximately 10–11 weeks total, through premating (8 weeks; 5 days/week), cohabitation of mating pairs (up to 2 weeks, 7 days/week), post-cohabitation for males (7 days) and from conception to implantation (gestation days 0–7 [GD 0–7]), followed by a recovery period (GD 8–21) for presumed pregnant females. Estrous cyclicity was evaluated during premating (last 3 weeks) and cohabitation. Reproductive organs and potential target organs, sperm parameters, and GD 21 fetuses (viability, weight, external alterations) were evaluated. In the developmental study, pregnant Crl:CD^®(SD)IGS BR rats (22/group) were exposed whole body by inhalation to 0, 1, 10, or 50 ppm DCBD (6 h/day) on GD 6–20; dams were necropsied on GD 21 (gross post-mortem only) and fetuses were evaluated (viability, weight, and external, visceral and skeletal exams). During the in-life portion of the studies, body weight, food consumption, and clinical observation data were collected. At 50 ppm, gasping and labored breathing occurred in both studies during the first few exposures; body weight and food consumption parameters were affected in parental animals from both studies, but were more severely affected in the developmental study. Fetal weight was decreased in the developmental study at 50 ppm. Degeneration of the nasal olfactory epithelium was observed in the reproduction study at 50 ppm. There were no effects on reproductive function, embryo–fetal viability, or increases in fetal structural alterations in either study. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity was 50 ppm. The NOAEL for systemic toxicity in the reproduction study was 5 ppm based on adverse effects on body weight and food consumption parameters and nasal olfactory epithelial toxicity at 50 ppm in parental rats. The NOAEL for maternal and developmental toxicity was 10 ppm based on reduced maternal weight gain and food consumption and reduced fetal weight at 50 ppm in the developmental toxicity study.     

Reproductive and developmental toxicity study of T-3762 in rats administered intravenously during the period of organogenesis

A teratogenicity study of T-3762, an injectable new quinolone antibacterial agent, was conducted in Sprague-Dawley rats to determine the effects on dams and next generations. T-3762 was administered intravenously to pregnant rats at the dose levels of 26, 78 and 156 mg/kg/day from day 7 to day 17 of gestation, during the organogenesis. 1. In the dams, there were no effects on general condition, food intake, water intake and body weight in the T-3762 treated groups. There were no abnormal findings on the autopsy at the end of gestation and lactation periods in the T-3762 treated groups. 2. In the fetuses, there were no effects on the number of dead and live fetuses, sex ratio and body weight in the T-3762 treated groups. No external, visceral and skeletal abnormalities attributed to T-3762 were observed. 3. In the offspring, there were no effects on birth rate, viability, differentiation of external development, body weight, sensory function, emotionality, learning ability and reproductive performance in the T-3762 treated groups. From these results, no-toxic dose levels of T-3762 are considered to be 156 mg/kg for the general toxicity and the reproductive toxicity of parents and for the development of next generation, respectively.     

Combined repeated-dose and reproductive/developmental toxicity screening test of 1-tert-butoxy-4-chlorobenzene in rats

We have carried out animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade, and Industry of Japan. Here, we tested 1-tert-butoxy-4-chlorobenzene in a combined repeat-dose and developmental and reproductive toxicity test. The test chemical was administered daily by gavage to 9-week-old Crl:CD (SD) rats at doses of 0, 20, 100, and 500 mg/kg/d. Males were treated for 42 d beginning 14 d before mating. Females were treated from 14 d before mating to day 4 of lactation. Decreased spontaneous locomotion, decreased respiratory rate, and incomplete eyelid opening were observed at 500?mg/kg/d (both sexes), but resolved within 30?min of administration, suggesting central nervous system depression. No notable changes were observed in body weight, food consumption, functional battery tests, or blood test. Increased liver weight with centrilobular or diffuse hepatocyte hypertrophy was observed at 100 and 500?mg/kg/d (both sexes). There were no biochemical or histopathological changes related to hepatotoxicity. Increased kidney weight with basophilic tubules, tubule dilatation, and increased hyaline droplets were observed in males dosed at 100 and 500?mg/kg/d. Immunohistochemical staining indicated α_2u-globulin nephropathy, a male rat-specific toxicity. Although kidney weight was also increased in females dosed at 500?mg/kg/d, it was not considered to be an adverse effect because there were no histopathological changes. Pup weights on postnatal day 0 were decreased at 500?mg/kg/d and still decreased on postnatal day 4. Our data indicated the no-observed-adverse-effect-level for repeated-dose and reproductive/developmental toxicity for 1-tert-butoxy-4-chlorobenzene was 100?mg/kg/d.     

Combined repeated dose and reproductive/developmental toxicity screening test of 4-methoxy-2-nitroaniline in rats

4-Methoxy-2-nitroaniline (4M2NA) is widely used as an intermediate for the synthesis of dyes, pigments and other chemical compounds. Since 4M2NA has amino-group and nitro-group on the benzene ring, it was expected that it induced obvious hemolytic anemia. We conducted a combined repeated dose and reproductive/developmental toxicity screening test according to Organisation for Economic Co-operation and Development (OECD) Test Guideline No. 422 (OECD TG 422) to enrich the toxic information and ensure the safety of 4M2NA. 4M2NA was administered to Crl:CD(SD) male and female rats by gavage at 0, 12.5, 75 or 450?mg/kg/day for 42 to maximum of 54 days through pre-mating, mating, pregnancy and lactation periods. An extramedullary hematopoiesis and congestion in spleen, and higher reticulocyte ratio were noted in only females at 450?mg/kg/day without decreased anemic parameters in the hematological examination. Hypertrophy of centrilobular hepatocytes in both sexes was observed with increased relative liver weight at 450?mg/kg/day. Furthermore, the diffuse follicular cell hypertrophy of the thyroid was observed in females at 450?mg/kg/day. No abnormalities were detected in the reproductive indices of copulation, delivery or fetal viability. We concluded the no-observed-adverse-effect level (NOAEL) for repeated-dose toxicity was 75?mg/kg/day based on the trace evidences of hemolytic anemia, and the NOAEL for reproductive/developmental toxicity as 450?mg/kg/day based on no toxicological concerns for reproductive endpoints. The hemolytic anemia was much milder than expected. Thus, we discussed the reason of this much less hemolytic effect from the point of view of the structural characteristics of 4M2NA.     

Maternal and developmental toxicity study of sodium azide in rats

Sodium azide (NaN(3)) is being proposed for use as an active ingredient to control a broad spectrum of soil borne pathogens including insects, weeds, nematodes, fungi, and bacteria. The purpose of this study was to determine the maternal and developmental toxicity of NaN(3) in rats. Sperm-positive Sprague-Dawley rats were treated with NaN(3) via oral gavage once daily from Gestation Day (GD) 6 through 19 at respective dose levels of 0, 1, 5, and 17.5mg/kg/day. From GD 10-12, the high-dose was reduced to 10mg/kg/day due to maternal mortality. Cesarean section was performed on GD 20 and implantation and resorptions sites, live and dead fetuses were counted. Fetuses were weighed, sexed externally and processed for gross external, visceral and skeletal examinations. A high rate of maternal mortality; reduced gestation body weight, gestation body weight changes and food consumption; decreased corrected body weight and corrected weight gain were observed at 17.5/10mg/kg/day. Fetal weight was also reduced at 17.5/10mg/kg/day. There were no maternal deaths, clinical signs or body weight effects that were considered related to NaN(3) at 1 and 5mg/kg/day. No increase in the incidence of malformations and variations were observed at any of the doses evaluated. Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) and the Lowest Observed Adverse Effect Level (LOAEL) for maternal and developmental toxicity of NaN(3) in rats were considered to be 5 and 17.5/10mg/kg/day, respectively.     

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.     

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.     

Reproductive and developmental toxicity of ethylene glycol in the mouse

The effects of ethylene glycol on reproduction of CD-1 mice were tested in a protocol which permitted continuous breeding during a specified interval. The dosage amounts of 0, 0.25, 0.5, or 1% ethylene glycol by continuous administration in drinking water for male and female mice were selected from the general toxic responses observed in a 14-day pilot study. After the first week of administration, begun at 11 weeks of age, the animals were housed one male and one female per cage for 14 weeks during which time any offspring were examined, sexed, weighted, and killed to allow continuous mating of the first generation. At the end of the 14-week cohabitation period, the males and females were separated and any litters delivered after that time were kept until weaning. Those second-generation animals were mated at about 70 days of age. Slight, but statistically significant, decreases were found in the numbers of litters per fertile pair and live pups per litter in the 1% dose group and live pup weight at the 1% dose groups compared to control F0 mice. Facial anomalies were noted in a number of offspring of high-dose-treated mice and an examination for skeletal defects demonstrated a pattern including reduction in the size of bones in the skull, fused ribs, and abnormally shaped sternebrae and vertebrae in the high-dose-treated, but not the untreated, mice. Neither the 0.25 nor 0.5% dose groups were significantly affected. No clinical signs of toxicity or significant adverse effects on body weight or water consumption were seen at the doses used, but two deaths occurred at the 0.5% quantity which may have been related to oxalate crystal deposition in the kidney.     

Reproductive and developmental toxicity of hydrofluorocarbons used as refrigerants

The present paper summarizes data on the reproductive and developmental toxicity of hydrofluorocarbons (HFCs), including pentafluoroethane (HFC-125), 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1-trifluoroethane (HFC-143a), 1,1-difluoroethane (HFC-152a), difluoromethane (HFC-32) and 1,1,1,3,3-pentafluoropropane (HFC-245fa), used as refrigerants, published in openly available scientific literature. No developmental toxicity of HFC-125 was found even at 50,000 ppm in rats or rabbits. Although HFC-134a exhibited no dominant lethal effect or reproductive toxicity in rats, it caused low body weight in pre- and postnatal offspring and slightly retarded skeletal ossification in fetuses at 50,000 ppm in rats. No maternal or developmental toxicity was noted after exposure to HFC-143a even at 40,000 ppm in rats or rabbits or HFC-152a even at 50,000 ppm in rats. HFC-32 is slightly maternally and developmentally toxic at 50,000 ppm in rats, but not in rabbits. HFC-245fa caused decreases in maternal body weight and food consumption at 10,000 and 50,000 ppm and fetal weight at 50 000 ppm. No evidence of teratogenicity for these HFCs was noted in rats or rabbits. There is limited information about the reproductive toxicity of these HFCs. Animal studies remain necessary for risk assessments of chemicals because it is difficult to find alternative methods to determine the toxic effects of chemicals. It is required to reduce emissions of organic vapors containing HFCs to reduce the risk of exposure.     

Evaluation of OECD screening tests 421 (reproduction/developmental toxicity screening test) and 422 (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test)

The Advisory Committee on Existing Chemicals (BUA) of the Federal Republic of Germany convened a panel with expertise in reproductive and developmental toxicology to evaluate the OECD Screening Tests 421 (Reproduction/Developmental Toxicity Screening Test) and 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) with respect to their ability to unmask any potential toxic effects on reproduction. The original assignment for that panel was to "validate" those screening tests. However, the panel members recognized beforehand that this was actually an impossible task because of lack of a sufficient database. Only five chemicals with known reproductive toxicity had been examined following the OECD Screening Test Guidelines 421 or 422. A comparison of these test results with those of the definitive OECD Test Guidelines 414, 415, 416, or additional investigations could, therefore, only have been made with this very limited number of chemicals that had also undergone evaluation by one of the test guidelines cited. In each case biological properties relevant to reproductive toxicity were also indicated by the OECD Screening Tests 421 or 422. This communication reviews the main differences in study design of OECD Screening Test Guidelines 421 and 422 compared to those definitive test guidelines of similar study design for reproduction or developmental toxicity (especially with the one-generation study, OECD Test Guideline 415). The very limited possibilities of detecting late postnatal and postlactational manifestations are emphasized, as is the low statistical power of the OECD Screening Tests 421 and 422. Furthermore, the very limited ability to unmask teratogenicity is delineated. The outcome of screening tests was evaluated based on the results of 57 studies conducted according to the OECD Test Guideline 421 or 422. The test results were categorized according to the incidence of toxic effects on reproduction in the parent animals or their offspring and related to general toxic effects. Based on the ranking of these results, recommendations regarding setting rational priorities for further evaluations of existing chemicals' reproductive hazards are made. In general, the reviewer panel supports the OECD position that the screening tests are useful for initial hazard assessment and can contribute to the decision-making process on setting priorities for further test requirements. The panel also agrees with the OECD statement that the OECD Screening Tests 421 and 422 are neither an alternative to definitive tests (i.e., OECD Test Guidelines 414, 415, and 416) nor are they intended as their replacement.     

Reproductive and developmental toxicity of arsenic in rodents: a review

Arsenic is a recognized reproductive toxicant in humans and induces malformations, especially neural tube defects, in laboratory animals. Early studies showed that murine malformations occurred only when a high dose of inorganic arsenic was given by intravenous or intraperitoneal injection in early gestation. Oral gavage of inorganic arsenic at maternally toxic doses caused reduced fetal body weight and increased resorptions. Recently, arsenic reproductive and developmental toxicity has been studied in situations more similar to human exposures and using broader endpoints, such as behavioral changes and gene expression. For the general population, exposure to arsenic is mostly oral, particularly via drinking water, repeated and prolonged over time. In mice and rats, methylated or inorganic arsenic via drinking water or by repeated oral gavage induced male and female reproductive and developmental toxicities. Furthermore, at nonmaternally toxic levels, inorganic arsenic given to pregnant dams via drinking water affected fetal brain development and postnatal behaviors. However, arsenic given by repeated oral gavage to pregnant mice and rats was not morphologically teratogenic. In this review of arsenic reproductive and developmental toxicity in rats and mice, the authors summarize recent in vivo studies and discuss possible underlying mechanisms. The influences of folate, selenium, zinc, and arsenic methylation on arsenic reproductive and developmental toxicity are also discussed.     

Oral toxicity study of 2-pentenenitrile in rats with reproductive toxicity screening test

A combined repeated-dose toxicity study with reproduction was conducted with 2-pentenenitrile (2-PN). Rats (10/sex per dose level) were dosed with 2-PN once daily by gavage at dose levels of either 0, 1, 3, or 10 mg kg(-1) day(-1) for 28 days, prior to and during cohabitation, and through day 3 of lactation. General clinical observations were recorded daily; body weights were recorded weekly. A neurobehavioral evaluation consisting of a functional observational battery and motor activity was conducted in all parental rats (10/sex per group). Clinical pathology parameters (hematology, clinical chemistry, coagulation) were measured in parental rats. Pup weights and clinical signs were recorded at birth and on lactation day 4. Parental rats were given a gross pathological examination, organ weights were obtained, and histological examination was conducted for the control and 10 mg kg(-1) day(-1) groups. No effects were seen with regard to mortality, clinical signs, functional observational battery and motor activity, hematology, or organ weights. Females receiving 10 mg/kg and males from all dose groups showed lower body weight gains and feed efficiency. Increased albumin concentrations were seen in both sexes given 10 mg/kg. Females in the 10 mg/kg group showed degeneration of the olfactory mucosa. No effects on the numbers of pups born, number surviving to lactation day 4, pup weight, and no gross anatomical development changes were observed. Under the conditions of this study, the no-observed-effect level (NOEL) for systemic toxicity in rats was 3 mg kg(-1) day(-1), based on degeneration of olfactory mucosa in females at 10 mg kg(-1) day(-1). The NOEL for reproductive and neurobehavioral toxicity in rats and for toxicity to offspring was 10 mg kg(-1) day(-1), the highest dose level tested.