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PubMed1984

Toxicologic, pathologic, and immunotoxic effects of 2,4-dichlorophenol in rats.

2,4-Dichlorophenol (DCP) is a drinking and waste-water contaminant formed by the spontaneous reaction of chlorine with phenols following chlorination of water for disinfection and deodorization. Rats were exposed to 0, 3, 30, or 300 ppm DCP in drinking water either in utero or for 12 wk postnatally following in utero exposure. Toxicity to DCP was assessed by organ and body weight changes, histopathology, and effects on reproduction and immunocompetence. Reproductive parameters measured included conception, litter size, pup birth weight, number stillborn, survival to weaning, and weaning weight. Immune parameters assessed were humoral immunity (antibody production) by an indirect enzyme-linked immunosorbent assay (ELISA), cell-mediated immunity by a delayed-type hypersensitivity response, and macrophage function by phagocytosis of radiolabeled blood cells. Rats that received the combined in utero and postnatal treatment with 300 ppm DCP had significantly increased liver and spleen weights, enhanced humoral immune responsiveness, and depressed cell-mediated immunity. Histopathologic changes were unremarkable in DCP-exposed rats, even in the presence of increased liver and spleen weights. The 6-wk-old progeny of DCP-treated dams had normal immune functions and showed no signs of DCP toxicity, other than increased spleen weights in the 300-ppm exposure group. The results indicate that (1) the immune system may be a sensitive target for chlorinated phenolic compounds, (2) DCP may exert different effects on separate major immune responses, and (3) unlike some other chlorinated phenols, DCP does not appear to alter reproductive performance in rats.

Animals↗

PubMed1991

Selection of food allotment for New Zealand white rabbits in developmental toxicity studies.

In three initial studies, female rabbits were fed 125, 150, or 230 g of Purina Certified Rabbit Chow No. 5322 ("regular" chow) per day or 150 g/day of Purina Certified High Fiber Rabbit Chow ("high fiber" chow) for at least 5 weeks prior to artificial insemination and until Day 28 of gestation when fetuses were removed and examined. Animals allotted 230 g/day of regular chow ate approximately 180 g/day and gained more weight than the 150 g/day group until Day 14 of gestation after which food consumption declined and body weight decreased. Animals fed 150 g/day regular chow ate all food provided until after Day 22 of gestation when food consumption decreased dramatically in some animals. Animals in the 125 g/day regular chow and 150 g/day high fiber chow groups ate essentially all food provided throughout gestation. Ad lib feeding in the 230 g/day groups was associated with adverse reproductive consequences consisting of decreased numbers of implants and live fetuses and decreased fetal weight. In one study involving 3 groups fed 125 and 150 g/day regular chow and 150 g/day high fiber chow, reproductive parameters were similar in all 3 groups. However, fetal weight in the 150 g/day regular chow group was 50% more variable than the other groups in association with more variable maternal body weight change late in gestation in that group. In subsequent studies using 125 g/day, there has consistently been fewer animals going off feed late in gestation and a decrease in fetal weight variance of approximately 60% compared to previously when the standard daily allotment was 150 g/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Toxicological studies on debitterized Neem oil (Azadirachta indica).

Azadirachta indica, popularly known as 'Neem' in India, is widely grown all over the tropics. The seed contains 45% oil and is a minor oil of considerable potential. Neem oil is bitter and inedible. Recently, a method has been developed to completely remove the bitter and odoriferous principles and leave a bitterless, odourless and colourless oil. The nutritional and chemical evaluation of debitterized neem oil (NO) was reported earlier (C. Rukmini, Food Chemistry 1987, 26, 119). We report here a three-generation study, carried out according to WHO/FDA protocol in groups of 15 male and 15 female rats fed a diet containing 10% NO or groundnut oil (GNO). Reproductive toxicology was monitored for three generations. The results obtained in both the matings in all the three generations did not show any adverse effects on the reproductive parameters studied in rats fed NO and were similar to those observed in rats fed GNO. The mean organ weights and the histopathological evaluation of all the organs were similar to those of the control (GNO-fed) rats. A mutagenicity test of NO was also found to be negative in Ames test as reported earlier (K. Polasa and C. Rukmini, Food and Chemical Toxicology 1987, 25, 763). These studies indicate that NO devoid of all the bitter and odoriferous principles, may be recommended as safe for consumption by humans.

Animals↗

PubMed1992

Reproductive effects of placing micro-implants of melatonin in the mediobasal hypothalamus and preoptic area in rams.

The reproductive effects of placing micro-implants of melatonin in the mediobasal hypothalamus (MBH) and preoptic area (POA) were monitored in Soay rams. Groups of animals were initially conditioned to alternating 16 weekly periods of long days (16 h light: 8 h darkness; 16L:8D) and short days (8L:16D) for at least 9 months to entrain the seasonal reproductive cycle. All experiments were then initiated at 10 weeks under long days when the animals were sexually inactive. In experiment 1, rams were exposed to short days for 14 weeks or maintained on long days to illustrate the photoperiodically induced re-activation and regression of the reproductive axis. In experiments 2-4, rams received micro-implants of melatonin in the MBH or POA, or received control treatments (sham-operated or no surgery) for 12-14 weeks while maintained on long days (total of 12 animals/treatment). The melatonin implants consisted of 22-gauge stainless-steel cannulae with melatonin fused inside the tip and were placed bilaterally in the brain. Incubation of the implants in Tricine-buffered saline (pH 8.0) at 37 degrees C showed that the release rate of melatonin was relatively constant after an initial peak in week 1 (means +/- S.E.M.: 3.42 +/- 0.43 micrograms/24 h). Rams with melatonin implants placed in the MBH, but not in the POA, showed a consistently earlier re-activation of the reproductive axis compared with the control animals in all three experiments (12/12 for MBH vs 2/12 for POA). The mean time to maximum testicular diameter was 12.2 +/- 0.9, 21.6 +/- 1.8 and 22.3 +/- 1.2 weeks for the MBH, POA and combined control groups respectively (MBH vs control, P less than 0.01; analysis of variance). The premature growth of the testes in the MBH group was associated with an earlier increase in the blood plasma concentrations of FSH and testosterone, and the appearance of the sexual skin coloration. Removal of the implants resulted in a decline in all reproductive parameters. The melatonin treatments did not cause a detectable increase in the peripheral concentrations of melatonin, or affect the diurnal rhythm in melatonin which reflected the long-day photoperiod. When implants containing 125I-labelled melatonin were introduced into the brain the associated radioactivity was localized to within 1 mm of the implants. The overall results demonstrate that the constant administration of melatonin into the MBH blocks the effect of the endogenous long-day melatonin signal and induces gonadal redevelopment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1993

A two-generation reproduction study with hydroquinone in rats.

The effects of hydroquinone (HQ) on reproductive performance and fertility were assessed in a two-generation study with CD Sprague-Dawley rats (one litter per generation). HQ was administered in an aqueous solution by gavage at doses of 0, 15, 50, and 150 mg/kg/day. F0 and F1 parental animals were dosed daily for at least 10 weeks prior to cohabitation, during cohabitation, and until scheduled termination. At all dose levels tested, no adverse effects were observed on feed consumption, survival, or reproductive parameters for the F0 or F1 parental animals. Mild, transient tremors were observed shortly after dosing at 150 mg/kg/day in several F0 and F1 parental animals and in a single F0 male at 50 mg/kg/day. These tremors occurred infrequently and were considered to be due to an acute stimulatory effect of HQ on the nervous system. Body weights for F0 and F1 parental females were similar between all dose groups throughout the study. Body weights for F0 parental males were also comparable to those of control throughout the study. Statistically significant differences in body weights were noted for the F1 parental males in the 50 and 150 mg/kg/day dose groups at several intervals during the premating, mating, and postmating periods. No treatment-related effects on pup weight, sex distribution, or survival were noted for pups of either generation. Upon postmortem examination, no treatment-related gross lesions were observed in either the F0 or F1 parental animals or their weanlings. Histopathologic examination of reproductive tissues and pituitary glands from high-dose F0 and F1 parental animals did not reveal any changes related to treatment with HQ.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Studies on reproductive toxicity of iloprost in rats, rabbits and monkeys.

A reproduction toxicological test program was performed with the carbaprostacyclin derivative iloprost, an analogue to the endogenous prostacyclin PGI2, in order to detect possible effects on fertility and reproductive performance, on preimplantational, embryonal and fetal development, on delivery as well as on lactation and postpartum development. While in humans iloprost is administered as an i.v. infusion for 6 h/day, it was administered i.v. to rats, rabbits and monkeys by continuous infusion with a subcutaneously implanted pump. No influence on mating or reproductive parameters was found after treatment of male or female rats during the premating phase up to day 7 post coitum (p.c.). Embryonal and fetal development were not remarkably impaired in rabbits or monkeys after treatment throughout the period of organogenesis. The only remarkable observations in the embryotoxicity and peri-/postnatal studies in the rat were defects on the digits (reductions of phalangeal structures) in single individuals. These malformations were interpreted as resulting from a compound-related hypotonia with subsequent change in the regional blood flow and the consequence of temporary impairments of placental blood supply leading to hypoxia in the affected structures.

Animals↗

PubMed1985

The effect of repeated mating at short intervals on reproductive performance of gilts.

Three trials involving 87 gilts were completed to investigate the role of additional sexual stimulation on various reproductive parameters. Forty-five gilts were mated twice at 12-h intervals at second pubertal estrus with intact boars beginning 12 h after detection of sexual receptivity (control group). Forty-two gilts were exposed to a vasectomized boar 15 min following each fertile mating to provide additional copulatory stimulus (treatment group). This additional exposure improved (P less than .01) conception rate (100 vs 84%). No statistical differences were observed in number of corpora lutea (CL), number of viable embryos (VE) or number of total embryos (TE) at d 30. These results suggest that additional mating stimuli may have a beneficial effect on conception rate. While the use of additional males resulted in more pregnant females, it likely did not have an effect on litter size.

Animals↗

PubMed1990

Reproductive toxicity of a single dose of 1,3-dinitrobenzene in two ages of young adult male rats.

These studies evaluated the reproductive response and the possible influence of testicular maturation on the reproductive parameters, in male rats treated with 1,3-dinitrobenzene (m-DNB). Young adult male rats (75 or 105 days of age) were given a single oral dose of 0, 8, 16, 24, 32, or 48 mg/kg of m-DNB and killed at 14 days post-treatment. Mortality and neurotoxicity were observed at 48 mg/kg, but only in the older animals. Epididymis weight, testicular sperm head counts, cauda sperm reserves, and sperm morphology were affected at 16 and 24 mg/kg and higher in the older and younger animals, respectively. Testis weight and sperm motility were affected at 24 mg/kg and higher in both age groups. Histologic changes included maturation depletion of mid and late spermatids at 16 mg/kg and higher, atrophy of a few to many seminiferous tubules at 24 mg/kg and higher, and immature germ cells in the epididymis. The movement and/or mixing of luminal elements in the epididymis appeared to be influenced by severe testicular effects. In separate groups given only the 48 mg/kg dosage, fertilizing ability was lost by 5-6 weeks post-treatment and several animals failed to recover in 5 months. In the breeder males, minimal to extensive degrees of seminiferous tubule atrophy and sloughed germ cells in the epididymis were still present after 175 days. The studies indicated that the lowest dosage to produce reproductive changes was 16 mg/kg with a no-effect level of 8 mg/kg. A few animals suffered protracted or permanent reproductive damage. Since the older animals were more susceptible to both the general and the reproductive toxicity of m-DNB, the less severe reproductive changes in the younger animals cannot be attributed solely to maturational differences in the testis.

Aging↗

PubMed1981

Effects of room temperature on reproduction, body and organ weights, food and water intake, and hematology in rats.

Two generations of rats were raised at animal room temperature ranging from 12 to 32 degrees C at steps of 2 degrees C. The body weight of rats born in 22 degrees C environment and exposed to each temperature did not significantly differ within the range of 16-28 degrees C. The delivery rate, litter size, and weaning rate decreased at 30 degrees C and 32 degrees C, and only the weaning rate had a tendency to decrease at 12 degrees C. No significant difference was demonstrated within the 14-28 degrees C range for any reproduction parameter observed. The body weight of sucklings did not differ at birth within the 12-32 degrees C range; and at 3 weeks of age, there were no differences within the range of 18-28 degrees C. The body weight gain in both sexes after weaning was generally small when the temperature was below 18 degrees C or above 30 degrees C. There were no significant differences in food intake within the 20-26 degrees C range, in water intake within the 12-26 degrees C range, in hematological and serum biochemical values within the 20-26 degrees C range, and in organ weights within the 18-28 degrees C range. Therefore, the range of 20-26 degrees C (68-78 degrees F) was the optimum temperature range in rat rooms.

Animals↗

PubMed1985

[Demography and reproduction of Macaca sylvanus in different habitats in Algeria].

Usually described as a cedar forest monkey, the Barbary macaque in effect has colonized a great variety of habitat types. At the moment, it is not known to what extent these different habitats are suitable for the species' survival. We tried to answer this question by comparing the demography of three monkey troops: one lives in a deciduous oak forest; the second lives in an nondeciduous cedar-green oak forest while the third is found on rocky ridges of mountains without any arborescent vegetation. In the three sites, there is a true seasonal breeding season with most births taking place in April to May and most matings occurring in November to December. Details are given on reproduction parameters (sexual activity of females; fertility rates; young survival...). Monkeys densities are higher in cedar forest than in deciduous forest. The smallest density is found on mountain ridges. Forest troops are more numerous, highly stable; their growth rate is better and the population is relatively young. The situation is slightly better still in the cedar forest than in the oak forest with a sex ratio more in favor of females and a better survival of the young. The troop of the mountain ridges is an unstable group ranging from 10 to 25 individuals; the population is aging, with a low birth rate and more male infants surviving compared with females. Demographic differences between sites are discussed according to climate, food availability and human influences (tree-clearing and overgrazing). Conclusions are drawn from this situation, for species conservation.

Algeria↗

PubMedDate not supplied

The selective estrogen receptor modulator, raloxifene: reproductive assessments following preimplantation exposure in mated female rats.

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed for postmenopausal osteoporosis. As part of an integrated reproductive toxicity assessment, two studies were conducted in which raloxifene was administered orally to CD rats during Gestation Days (GD) 0 through 5. In each study, animals received daily raloxifene doses of 0, 0.1, 1, or 10 mg/kg. In Study 1, GD 20 evaluations of maternal reproductive parameters identified dose-related increases in pre- and postimplantation loss, reductions in the numbers of corpora lutea and live conceptuses, and reduced fetal weight. The low fetal weights were consistent with an extent of morphologic development that corresponded to developmental ages up to 8 d younger than GD 20. Study 2 characterized the potential impact of this disrupted and apparently delayed implantation on gestation length, parturition, and progeny viability. Dams were allowed to deliver and rear their offspring through Postpartum Day 21. Gestation lengths were extended up to 1 week, and litter sizes were reduced in a dose-dependent manner. Nevertheless, parturition occurred normally and pup morphology, survival, and physical and behavioral development were unaffected.

Animals↗

PubMed1982

[Effect of dietetic and ethological factors on reproduction in cows].

The application of dietetic and ethologic factors on three cow farms led to the improvement of the reproduction parameters. Basic dietetic factors were the correction of the energy--protein ratio, and the percent of the crude protein in the diet. In so far as the ethologic factors were concerned greatest attention was paid to the organization of work on the farms, the strict observance of the daily regime, and the principle of the herd hierarchy. The "independence period", i.e. the period between the time of calving and the time of the following first estrus dropped by 16, 8 and 10 days, respectively. The conception rate at first insemination rose by 25, 25 and 14.9 per cent, and the impregnation rate up to the 60th day--by 9, 13 and 3 per cent, respectively. Milk productivity increased by 1000 1 for the first two farms and by 300 1 for the third one. The number of calves obtained per 100 cows rose by 13, 14 and 2, respectively.

Animal Feed↗

PubMed1997

Oestrus, ovulation and peri-ovulatory hormone profiles in tethered and loose-housed sows.

Multiparous sows that had been tethered during lactation were put in two different housing conditions after weaning (Day 0); the sows were either tethered by neck chain, or individually housed in a pen of approximately 6 m2. After two months, ten tethered and eleven loose housed sows were used to assess stress and reproductive parameters. Stereotypic behaviour after the afternoon feeding was assessed from Day 18 onwards; at Day 53 stereotypic behaviour tended to occur during a higher percentage of time in the tethered sows (P = 0.11) and at Day 66, the differences were significant (tethered, 78 +/- 5 vs. loose-housed, 40 +/- 10% of time (mean +/- sem); P = 0.03). At Day 35 and 55, cortisol profiles after afternoon feeding were similar for the two groups of sows (P > 0.10). Around oestrus (approximately Day 64), the profiles of oestradiol-17 beta, luteinizing hormone and progesterone were measured and proved to be similar for both treatment groups (P > 0.10). The duration of oestrus was shorter in the tethered sows (42 +/- 4 vs. 63 +/- 2 h; P < 0.001) and, consequently, the timing of ovulation during oestrus (h after onset of oestrus) was advanced in the tethered sows (28 +/- 2 vs. 41 +/- 2; P < 0.001). The duration of ovulation did not differ (tethered, 2.9 +/- 0.5 vs. loose-housed, 2.1 +/- 0.2 h; P = 0.16). The sows were sacrificed at Day 5 after ovulation; ovulation rate, fertilization rate, embryo development and embryo diversity were similar for the two groups, as were adrenal weight and size of adrenal cortex. Duration of oestrus and the levels of stereotypies at Day 60 tended to be negatively related in the tethered sows (P = 0.07), but not in the loose-housed sows (P = 0.65). In conclusion, sows that had been tethered during pregnancy and lactation, and were housed loose or were tethered again at weaning within two months differed both in stereotypic behaviour and in duration of oestrus, without apparent effects on reproductive hormones.

Adrenal Glands↗

PubMed1997

Standard values for reproductive and clinical chemistry parameters of Japanese quail.

Historical control data of Japanese quail collected from reproduction studies conducted at the Federal Institute for Health Protection of Consumers and Veterinary Medicine between 1988 and 1994 are presented in this paper. Reproductive and clinical chemistry data from control animals of 10 ecotoxicological studies are summarized and discussed to develop a normal data base of this species. The data obtained were compared to the control reproductive parameters of bob-white quail and mallard ducks available in the literature. For a long time these two species have been most used in avian reproductive toxicology studies. In summary, the data obtained indicate that Japanese quail appears to be more appropriate to be used for the determination of reproductive effects of pesticides on birds.

Animals↗

PubMed1985

Effects of cimetidine, nitrite, cimetidine plus nitrite, and nitrosocimetidine on tumors in mice following transplacental plus chronic lifetime exposure.

Cimetidine (CM), a drug widely prescribed for ulcers, readily undergoes nitrosation to form nitrosocimetidine (NCM), a genotoxic agent. In a test of the chronic effects of NCM in mice, (C57BL/6 X BALB/c)F1 mice were exposed chronically to NCM (113 or 1130 ppm) in the drinking water from preconception through prenatal and neonatal development and adult life. Each group consisted of 40 to 80 mice of each sex, and median survival time was 27 months. Other groups were given CM alone or in combination with NaNO2 (184 or 1840 ppm), or NaNO2 alone. None of the chemical treatments had large effects on reproductive parameters, survival, or incidence of nonneoplastic lesions. CM treatment was associated with a small but significant increase in incidence of lymphomas in females, 41 of 59 (69%), compared with 31 of 66 controls (47%, P = 0.01). No females receiving either dose of NCM developed mammary carcinomas (0 of 91), compared with an incidence of four of 66 controls (6%, P = 0.03). Males given the high-dose combination of CM and NaNO2 showed a higher incidence of lung tumor bearers than controls (71 of 79 versus 30 of 52, P less than 0.01) and also experienced a significant, dose-dependent increase in numbers of large lung tumors (greater than 1 cm in diameter), lung carcinoma, and metastatic lung tumors. Females given the higher dose of NCM had significantly greater incidence of mice with large lung tumors than controls (nine of 41 versus three of 66, P = 0.009). The possibility of carcinogenicity of cimetidine, nitrosocimetidine, and cimetidine plus nitrite is discussed.

Animals↗

PubMed1990

Effect of aluminum on performance and mineral metabolism in young chicks and laying hens.

This study was performed to determine the long-term effects of dietary aluminum on egg production and reproductive parameters in the mature laying hen and on growth rate and feed efficiency in young chicks. The diets used in these studies were adequate in phosphorus and other essential nutrients. Aluminum added to constitute 0.30% of the diet severely depressed growth and reduced feed efficiency, bone ash and plasma phosphorus in male Ross x Leghorn chicks. At the same time, 0.15% added aluminum mildly depressed growth, feed efficiency and bone ash but had no effect on plasma phosphorus levels. The reduction in bone ash was relatively mild, and no clinical signs of rickets were observed. In laying hens, diets containing 0.15% added aluminum did not affect egg production, but 0.30% added aluminum reduced production significantly. Long-term exposure to aluminum increased percent shell in both groups receiving aluminum, whereas egg weight remained similar to that in controls. There were no changes in hatchability or bone ash associated with dietary aluminum. Although dietary aluminum influenced bone aluminum content, egg aluminum content was not affected. These studies indicate that dietary aluminum interferes with systems in addition to phosphorus metabolism.

Aluminum↗

PubMed1992

Effects of methoxychlor treatment of pregnant mice on female offspring of the treated and subsequent pregnancies.

This study was designed to assess whether exposure to the estrogenic pesticide methoxychlor (MXC) during pregnancy would affect reproductive parameters not only in female offspring exposed prenatally, but also in those of a subsequent litter. Mice were exposed via oral gavage to 7.5, 5.0, or 2.5 mg technical grade MXC (50%) or 0.025 mg estradiol-17 beta (E-17 beta) from days 6 to 15 of pregnancy. Following delivery, female offspring (F1a) were cross-fostered and sacrificed at 8 weeks of age. Mothers exposed during their first pregnancy were allowed to mate again and their second set of offspring (F1b) were similarly evaluated to detect any latent effects from the initial exposure. Mice exposed to 7.5 mg MXC were unable to carry their litters to term. Results revealed a significant increase in the length of gestation of mice exposed to both E-17 beta and 5.0 mg MXC. A larger percentage of atretic follicles appeared in the ovaries of F1a females exposed prenatally to 5.0 mg MXC when compared to controls. Females from the F1b litter displayed a significant advance in time of vaginal opening, an apparent residual effect of MXC from a mother exposed during a previous pregnancy.

Abnormalities, Drug-Induced↗

PubMed1996

Nonclinical toxicology studies with zidovudine: reproductive toxicity studies in rats and rabbits.

Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague-Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6-18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose, Cmax values in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a peri- and postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.

Animals↗