Systemic and Developmental Toxicity of Dermally Applied Syntower Bottoms in Rats

Syntower bottoms (STB) was evaluated for subchronic and developmentaltoxicity. In the subchronic study, undiluted STB was appliedon the shaved backs of male and female rats at dose levels of0, 8, 30, 125, and 500 mg/kg for 13 weeks, 5 days per week.Exposure sites were not covered. In the developmental toxicitystudy, STB was similarly applied, but to pregnant rats at doselevels of 0, 8, 30, and 125 mg/kg on Gestation Days 0—19.In addition, 4 mg/kg was dosed as 8 mg/kg every other day, startingon Gestation Day 0, and 500 mg/kg was dosed on Gestation Days10—12. Evidence of toxicity observed in the subchronicstudy included death, decreased body weights, aberrant serumchemistry and hematology values, altered organ weights, andhistopathologic changes in a variety of organs. A no observedadverse effect level for systemic toxicity could not be established.Evidence of maternal toxicity was observed at all exposure levelsin the development study. Regardless of the length of the exposureperiod, STB was toxic to the developing conceptus. Evidenceof developmental toxicity observed included increased resorptionswith a concomitant decrease in litter size and reduced fetalbody weights. Cleft palate was observed in fetuses exposed inutero to STB during Gestation Days 10—12 at 500 mg/kg.No evidence of teratogenicity was observed when the exposureperiod was throughout gestation. Ossification delays were observedin fetuses exposed in utero to STB at doses in excess of 4 mg/kg.A no observed adverse effect level for maternal and developmentaltoxicity could not be established.     

Experimental Studies on Reproduction with the Lipid-Regulating Agent Gemfibrozil

Experimental Studies on Reproduction with the Lipid-RegulatingAgent Gemfibrozil. FITZGERALD, J. E., PETRERE, J. A., AND DELA IGLESIA, F. A. (1987). Fundam. Appl. Toxicol. 8, 454–464.Gemfibrozil, a new lipid-regulating agent, was evaluated inrats and rabbits for effects on various phases of the reproductionprocess. In teratology studies groups of pregnant rats and rabbitsreceived gemfibrozil at doses up to 200 mg/kg during organogenesis(rat, Days 6–15; rabbit, days 6–18). For peri- andpostnatal studies, groups of pregnant rats were given 92 or3 31 mg/kg from Day 15 of gestation through weaning. In fertilitystudies groups of sexually mature male rats were given 93 or326 mg/kg of gemfibrozil for 61 days and females were given94 or 318 mg/kg for 15 days prior to mating within treatmentgroups. Drug administration continued in females through gestationand weaning of the F₁ offspring. In subsequent fertility experiments,treated male rats were mated with untreated females and treatedfemales were cohabitated with untreated males. Gemfibrozil didnot elicit a teratogenic response in either rats or rabbitsup to doses that resulted in maternal toxicity. Reduced pupweights during the neonatal and weaning periods in the femalefertility study as well as in the perinatal–postnatalstudy were the only apparent drug effect. Treatment of femalerats prior to mating had no significant effects on general reproductiveparameters. Male rats given doses of about 300 mg/kg/day showedinconsistent and equivocal lower rates of fertility relativeto the concurrent controls. No adverse effects were seen inthe reproductive performance of offspring of gemfibrozil-treatedmale rats.     

Postnatal Survival in Wistar Rats following Oral Dosage with Zidovudine on Gestation Day 10

Postnatal Survival in Wistar Rats following Oral Dosage withZidovudine on Gestation Day 10. GREENE, J. A., AYERS, K. M.,DE MIRANDA, P., AND TUCKER, W. E., JR. (1990). Fundam. Appl.Toxicol. 15, 201–206. Groups of 20 female Wistar ratsfrom Charles River Breeding Laboratories (Kingston, NY) weregiven three oral doses of 100 mg zidovudine/kg at 5-hr intervalson Gestation Day 10 (total dose = 300 mg/kg). Control rats receivedthree oral doses of the vehicle, distilled water. This designapproximated that of an earlier study that reported 38% postnatalmortality among the offspring of Wistar rats given zidovudine.In the study reported here, no adverse effects were noted onmaternal body weight, food consumption, reproductive capacity,or hematology. Similarly, no effects on growth or survival ofthe offspring were noted. Hematology and clinical chemistryvalues were comparable between offspring of treated and controldams, and no treatment-related gross or histopathologic lesionswere noted in the weanling rats. The mean concentration of zidovudinein embryonal homogenates, collected 30 min after administrationof the third dose to the dam on Gestation Day 10, was 21.1 µg/gtissue. This value is approximately one-third of the mean drugplasma concentration (62.6 µg/ml) measured in the thmsat the same time point. The dramatic difference in results inthe two studies may be related to differences in Wistar ratsfrom two different sources or to other unknown factors associatedwith the design and conduct of the studies. The results of thecurrent study were consistent with other preclinical studieson the reproductive toxicity of zidovudine in rats and rabbits.     

Developmental Toxicity of Dinitroaniline Herbicides in Rats and Rabbits

The potential developmental toxicity of trifluralin was evaluatedin rats and rabbits. Pregnant rats and rabbits were dosed oncedaily by gavage on Gestation Days 6–15 and 6–18,respectively. Doses for rats were 0, 100, 225, 475, or 1000mg/kg; doses for rabbits were 0, 100, 225, or 500 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 28, respectively. In rats, maternal toxicity was indicatedin the 475 and 1000 mg/kg treatment groups by depression ofbody weights and food consumption. Fetal viability and morphologywere not adversely affected at any dose level. Developmentaltoxicity was indicated at the 1000-mg/kg dose level by depressionof fetal weight. The NOAEL for maternal toxicity in the ratwas 225 mg/kg the NOAEL for developmental toxicity in the ratwas 475 mg/kg. In rabbits, maternal toxicity was indicated atthe 225 and 500 mg/kg dose levels by abortions and/or deathsin conjunction with anorexia and cachexia. Developmental toxicitywas indicated at the 500 mg/kg dose level by depressed fetalviability and weight. Fetal morphology was not adversely affectedat any dose level. The NOAELs for maternal and developmentaltoxicity in the rabbit were 100 and 225 mg/kg, respectively.Based on these data, trifluralin did not exhibit selective toxicitytoward the developing conceptus.     

Nonclinical Toxicology Studies with Zidovudine: Reproductive Toxicity Studies in Rats and Rabbits

Zidovudine (ZDV) was evaluated for adverse effects on reproductionand fetal development in animal test species. Standard preclinicaltests for reproduction and fertility, developmental toxicity,and postnatal toxicity were conducted in CD (Sprague-Dawley)rats and a developmental toxicity study was conducted in NewZealand white rabbits. In an additional study, reproductiveoutcome was characterized in female rats given ZDV before, during,or after mating and drug levels in the plasma and milk of lactatingrats were determined. Finally, drug exposure data includingobserved peak plasma concentrations (C_max) and area under theconcentration-time curve (AUC) were evaluated for pregnant ratsand rabbits. In a reproduction/fertility study in CD rats, toxicityto the early rat embryo, manifested as an increase in earlyresorptions and a decrease in litter size, was noted followingdosage 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 thetime of mating, male rats had been dosed for 85 days, and femaleshad been dosed for 26 days. To further evaluate the effectsof ZDV on reproduction, dosing of male rats was continued to149 days when they were mated a second time to virgin, untreatedfemales. All reproductive parameters were normal in the untreatedfemales from this second mating, indicating that the embryotoxiceffect of the drug was not likely mediated by a genotoxic orother effect in the male. A separate study in female CD ratsgiven 225 mg/kg bid for various periods pre- or postconceptionsuggests that the toxic effect of ZDV is primarily to the earlyrodent embryo. Early embryo death did not occur in rats or rabbitsin standard developmental (teratology) studies; however, pregnantNew Zealand white rabbits given 250 mg/kg bid during gestationDays 6–18 showed reduced weight gain, anemia, and an increasein late fetal deaths. No other evidence of developmental toxicitywas noted in either species, and ZDV was not teratogenic inrats or rabbits given up to 250 mg/kg bid during the periodof major organogenesis. At this dose, C_max, values in rats andrabbits were approximately 234 and 150 times higher, respectively,than the mean steady-state serum concentration in adults followingchronic oral administration of 250 mg every 4 hr. In both thereproduction/fertility study and a periand postnatal study inrats, liveborn offspring showed no adverse effects on survival,growth, or developmental measurements.     

The Effect of Piroctone Olamine on Reproduction of Male and Female Rats

The purpose of this study was to determine the effect of piroctoneolamine, an antidandruff active, on reproductive performance,fertility, parturition, and neonatal viability and growth. Piroctoneolamine was administered orally by gavage to three groups of35 male Sprague-Dawley rats each beginning 64 days prior tomating and continuing until euthanized and to three groups of35 female Sprague-Dawley rats each beginning 14 days prior tomating and continuing until euthanized. Animals in the treatedgroups received piroctone olamine in a combination of 1.0% methylcelluloseand polyethylene glycol 400 as a single daily dose at levelsof 0, 10, 100, and 250 mg/kg/day, at a volume of 2.5 ml/kg.The control group received the vehicle only. Ten randomly selectedfemales/group were mated and underwent a uterine examinationon Gestation Day 13; the remaining females were allowed to deliver.Because earlier studies reported hematological effects, bloodsamples were collected from all parental animals during acclimationand prior to euthanasia for hematological and blood chemistry(Gestation Day 13 females) characterization. The parental animalswere necropsied and tissues were grossly examined. Systemiceffects induced by the test article were seen at the mid- andhigh-dose levels but only among the male rats. These effectswere reduced body weight and decreased liver weights. Hematologicalfindings representative of anemia occurred at the high-doselevel, as did rales in several animals. Offspring growth wasinhibited for the high-dose group as evidenced by significantlyreduced mean weight values throughout lactation. The remainingparameters assessed, including mating ability and reproductiveperformance, were not affected by treatment at any dosage leveltested. In summary, the no observable effect level of piroctoneolamine with respect to systemic toxicity was considered tobe 10 mg/kg/day. Neonatal growth was not affected at 100 mg/kg/dayor less, and the no observable effect level with respect toreproductive parameters, including fertility, was 250 mg/kg/day.     

Reproductive Toxicological Evaluation of Omadine MDS

Reproductive Toxicological Evaluation of Omadine MDS. JOHNSON,D. E., SCHARDEIN, J. L, MITOMA, C., AND WEDIG, J. H. (1984).Fundam. Appl. Toxicol. 4, 81–90. Reproductive toxicologystudies with Omadine MDS were conducted using rats and rabbits,and plasma levels of the metabolite, 2-methylsulfonylpyridine(2-MSP), were assayed. In phase I (treated males, untreatedfemales) of the fertility study, the no-effect level, for oraldosing, was 3.0 mg/kg; 7.5 mg/kg caused a decrease in male weightgain. In phase II (treated females, untreated males), the no-effectoral dose level was 1.0 mg/kg. At 3.0 mg/kg, decreases wereseen in maternal body weight gain, the fertility index, andin total implantations and viable embryos at the 13-day uterineexamination. Severe maternal toxicity including impaired motorfunction of limbs, decrease in weight gain, and mortality occurredat 7.5 mg/kg. In the perinatal/postnatal study, the no-effectlevel was 3.0 mg/kg. At 7.5 mg/kg, mortality was high, witha majority of animals dying during mid lactation. In the ratteratology study, the high dosage level, 30 mg/kg, dermallyadministered on Gestation Days 6 through 15 caused slight maternaltoxicity, whereas 10 mg/kg produced none. These dosage levelscorresponded to peak plasma levels on Gestation Day 10 of 470and 1950 ng/ml 2-MSP at the 10- and 30-mg/kg dosage levels,respectively. In the rabbit, 5 mg/kg topically applied on GestationDays 6 through 18 produced slight maternal toxicity while 1.5mg/kg produced no maternal effects. The plasma levels of 2-MSPpeaked on Days 12 and 15 of gestation. At 1.5 mg/kg these levelswere 155 and 148 ng/ml; at 5.0 mg/kg, levels were 513 and 573ng/ml. There was no teratogenic response seen in either species.     

Relationship between acrylamide reproductive and neurotoxicity in male rats

To determine whether there is a relationship between the reproductive and neurotoxic effects of acrylamide monomer (AM), the first week of the study design of Sublet et al. ?14 was duplicated: Long-Evans male rats were gavaged with AM in water, 25/group, at 0, 5, 15, 30, 45, or 60 mg/kg/day for 5 days (days 1 through 5). On Day 8, males were paired overnight with untreated virgin females (1 : 1) in proestrus/estrus. On day 9, males were evaluated for forelimb and hindlimb grip strength. Five males/group were perfusion fixed, 20/group were used for andrologic assessment, and all were necropsied. Perfusion-fixed sciatic nerves were examined histologically. Sperm-positive females were examined for preimplantation and postimplantation loss at midpregnancy. At 15 to 60 mg/kg/day, males exhibited significantly reduced weight gain, reduced mating, fertility, and pregnancy indices by trend analysis (significant at 60 mg/kg/d by pairwise comparison), and increased postimplantation loss and dominant lethal factor, F(L)%, at 45 and 60 mg/kg/day. At 60 mg/kg/day, the sperm beat cross frequency was increased, with no significant effects on epididymal sperm motility or concentration, and hindlimb grip strength was decreased, with no pathologic lesions in sciatic nerves. Therefore, epididymal sperm, mating, and neurotoxic effects were observed at AM doses that also resulted in increased postimplantation loss, possibly by different mechanisms.     

Pre- and Postnatal Toxicity of the HMG-CoA Reductase Inhibitor Atorvastatin in Rats

Atorvastatin is a potent inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoAto mevalonate and constitutes the rate-limiting step in thebiosynthesis of cholesterol. Steroid hormones derived from cholesterol,as well as mevalonate and its isoprenoid derivatives, provideimportant contributions to the maternal animal during pregnancyand lactation, as well as to the growth and development of theoffspring; these contributions may potentially be influencedby inhibition of HMG-CoA reductase. To investigate the effectsof atorvastatin on various aspects of reproduction and development,female Sprague-Dawley rats received 0, 20, 100, or 225 mg/kgdaily by gavage from gestation day 7 through lactation day 20.Maternal toxicity, characterized by morbidity/mortality (13%),reduced body weight gain and food consumption, and pathologiclesions in the nonglandular mucosa of the stomach, occurredat 225 mg/kg. Offspring survival at birth and during the neonatalperiod at 225 mg/kg was reduced relative to control by up to45%, and 28% of litters had no viable offspring by 10 days postpartum.Additional effects on offspring included reduced body weightduring the neonatal and maturation periods (100, 225 mg/kg),delayed appearance of pinnae detachment and incisor eruption(225 mg/kg), impaired rotorod performance (females only; 100,225 mg/kg), reduced acoustic startle responding (males only;20, 100, 225 mg/kg), and transient effects on shuttle avoidance(females only; 225 mg/kg). No treatment-related effects wereobserved on offspring reproduction. In a separate experiment,a single dose of 10 mg/kg atorvastatin administered to femaleWistar rats on gestation day 19 or lactation day 13 providedevidence of placental transfer and excretion into the milk.Results of this study indicate that pre- and postnatal administrationof atorvastatin to female rats produces developmental toxicityin their offspring via in utero and/or lactational exposure,and in the presence or absence of maternal toxicity.     

Evaluation of Teratogenic Potential of N-Formylpiperidine in Rats

Evaluation of Teratogenic Potential of N-Formylpiperidine inRats. NAIR, R. S., ALVAREZ, L., AND JOHANNSEN, F. R. (1992).Fundam. Appl. Toxicol. 18, 96–101. The teratogenic potential of a versatile solvent, N-formylpiperidine(NFP), was evaluated in the rat. Three groups of 25 mated femaleSprague-Dawley rats were given 110, 220, or 440 mg/kg/day NFPin distilled water by gavage on Days 6 through 20 of gestation.A control group of 25 animals received distilled water on acomparable regimen. Maternal animals were observed daily forsigns of toxicity; body weights and food consumption were measuredat regular intervals throughout the study. All animals wereeuthanized on Gestation Day 21 and the fetuses examined forcleft palate and external abnormalities. One-half of the fetusesin each litter were examined for visceral anomalies while theremaining fetuses were examined for skeletal malformations afterappropriate staining. One female in the high dosage group diedon Gestation Day 12. Clinical signs of toxicity, observed in6 females in the high dosage group, included tremors, convulsivemovements, and an apparent weakness of the legs. Maternal toxicity,in terms of significantly decreased body weight and food consumption,was observed in the mid and high dosage groups. Food consumptionwas also significantly depressed for the first 4 days of dosingin the low dosage group. There was a significant increase innumber of resorptions in the high dosage group when comparedto controls. No effects were observed on other reproductiveparameters. Mean fetal body weight was significantly lower inthe high dosage group when compared to controls. While the incidenceof fetal malformations on a litter basis was higher in the highdosage group, this change was not statistically significant.The incidence of ossification variations was also higher inthe high dosage group. Thus, a dosage of 440 mg/kg NFP producedmaternal toxicity, embryolethality, fetal growth retardation,and an increased number of malformations. Maternal body weightswere depressed at 220 mg/kg but no embryo- or fetotoxicity wasobserved at or below 220 mg/kg NFP. The number and type of fetalmalformations in the 110 and 220 mg/kg dosage groups were alsocomparable to controls. In conclusion, NFP produced fetal effectsonly at 440 mg/kg, a dosage which resulted in marked toxicityto the dams.     

Evaluation of the Teratogenic Effects of Tri-ortho-cresyl Phosphate in the Long-Evans Hooded Rat

Evaluation of the Teratogenic Effects of Tn-ortho-ciesyl Phosphatein the Long–Evans Hooded Rat. TOCCO, D. R., RANDALL, J.L., YORK, R. G., and SMITH, M. K. (1987). Fundam. Appl. Toxicol.8, 291–297. The developmental toxicity of tri-ortho-cresylphosphate (TOCP) was evaluated in Long–Evans rats. Pregnantrats were treated with 87.5, 175, and 350 mg/kg/day TOCP throughoutorganogenesis from gestation Days 6 through 18 (Day of sperm= Day 0). The highest dose tested (350 mg/kg) was lethal in28% of the dams; no maternal deaths or toxicity were observedin the 87.5 or 175 mg/kg dose groups. There were no significantdifferences noted among the experimental and control groupsfor preimplantation loss or resorption. Fetal weights for bothsexes in the TOCP groups were significantly greater than inthe control group; however, no difference among the TOCP groupswas observed. Malformation rates were too low to warrant statisticalanalysis. Numerous soft tissue and skeletal variations wereobserved in both control and TOCP-treated groups; there wereno significant differences in the frequency of variations amongthe dose groups. The results of this study indicate that TOCPis not teratogenic in the Long–Evans rat.     

Developmental Toxicity of N-Methylformamide Administered by Gavage to CD Rats and New Zealand White Rabbits

N-Methylformamide (NMF) is a metabolite of dimethylformamide(DMF), a solvent with wide applications in the chemical industry.The potential developmental toxicity of NMF was evaluated inCD rats and New Zealand white rabbits. Pregnant rats and rabbitswere dosed once daily by gavage on Gestation Days 6–15and 6–18, respectively. Doses for rats were 0, 1, 5, 10,or 75 mg/kg; doses for rabbits were 0, 5, 10, or 50 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 29, respectively. No treatment-related maternal deathsor clinical signs occurred in either species. Body weight gainand food consumption were depressed in rats given 75 mg/kg andrabbits given 50 mg/kg. Fetal viability was reduced at 75 mg/kgin rats and at 50 mg/kg in rabbits. In rats, a significant increasein the incidence of malformations including cephalocele andstern-oschisis was observed in fetuses from the 75 mg/kg group.In addition, a developmental delay was indicated by reductionof fetal weight and by a significant increase in the occurrenceof incomplete ossification of various skeletal structures. Inthe rabbit, fetal body weight was reduced at 50 mg/kg. Malformationsobserved at 50 mg/kg included gastroschisis, cephalocele, domedhead, flexed paw, and skull and sternum anomalies. The lowest-observed-adverse-effectlevels for maternal and developmental toxicity in the rat andrabbit were 75 and 50 mg/kg, respectively. The no-observed-adverse-effectlevel for maternal and developmental toxicity in the rat andrabbit was 10 mg/kg.     

Reproductive and Developmental Toxicity Studies of a Linear Alkylbenzene Mixture in Rats

Alkylate 215, a mixture of linear decyl- to tridecylbenzenes,is an intermediate in the manufacture of detergent sulfonates.A two-generation reproduction study and a developmental toxicitystudy were conducted using single daily doses given by gastricintubation in a corn oil vehicle. In the reproduction study,groups of 30 rats/sex/group were given doses of 0, 5, 50, or500 mg/kg/day. F₀ animals received a 10-week premating treatmentperiod and were then mated to produce a single litter; F₁ adultswere selected from the F₁ litters. F₁ animals were dosed for11 weeks before mating to produce a single litter. Adults andweaned pups received a gross postmortem examination. Histopathologystudies were conducted on reproductive tissues, tissues withgross lesions, and the pituitary gland taken from each adultin the control and high dose groups. In the developmental toxicitystudy, groups of 24 mated female rats were given 0, 125, 500,or 2000 mg/kg/day on Days 6 through 15 of gestation. Dams wereterminated on gestation Day 20 and fetuses were examined forexternal, soft tissue, and skeletal defects. Results of thereproduction study were as follows. At 50 mg/kg/day, pup weightswere decreased at Day 7 in the F₁ litter. At 500 mg/kg/day,decreases were found in the F₁ females in premating and earlylactation weight gains; in both generations in premating weightgains in males and in weight gains during gestation in females;and in litter size, pup viability at birth, Day 0–4 sur vival, and pup weights on Days 14 and 21. The NOAEL for reproductiveeffects was 5 mg/kg/day. The developmental toxicity study foundeffects on several parameters. The only effect noted at 125mg/kg/day was a slight decrease in maternal weight gain. Maternalweight gains were depressed to a greater extent at 500 and 2000mg/kg/day. Ossification variations and delayed ossificationwere increased significantly at 2000 mg/kg/day and were abovecontrol levels at 500 mg/kg/day. The NOAEL for developmentaltoxicity was 125 mg/kg/day. Alkylate 215 did not have any unusualor selective reproductive or developmental toxicity.     

Effects of Ethylene Glycol Monomethyl Ether (EGME) on Mating Performance and Epididymal Sperm Parameters in F344 Rats

Effects of Ethylene Glycol Monomethyl Ether (EGME) on MatingPerformance and Epididymal Sperm Parameters in F344 Rats. CHAPIN,R. E., DUTTON, S. L., ROSS, M. D., and LAMB, J. C, IV. (1985).Fundam. Appl. Toxicol. 5, 182–189. Previous histologicstudies on the effects of EGME identified dividing spermatocytesas a primary target cell type in the testis. The following studieswere undertaken to assess possible effects of EGME on late-stageand epididymal spermatids, and spermatogonia. Adult male F344rats (n = 20/group) of proven fertility were dosed po with 0,50, 100, or 200 mg EGME/kg/day for 5 days. Each male was thenmated with two females/week for 8 weeks. Females were sacrificedca. 2 weeks after removal from the male, and number of liveand dead fetuses, resorption sites, and corpora lutea were noted.Additional males were treated similarly, sacrificed at weeklyintervals, and measures of epididymal sperm count, motility,and morphology were made. The fertility of males treated with200 mg EGME/kg declined at Week 4, and remained low for therest of the study. There was a modest but significant increasein the number of resorption sites at Weeks 5 and 6 in the highdose group. There was a decrease in the number of Utters siredat Week 5 after dosing in the 100-mg EGME/kg group. There weretime- and dose-related decreases in sperm concentration andmotility, primarily in the 100- and 200-mg/kg groups, as wellas concurrent elevations in the number of abnormal sperm formsin the epididymis. These studies show that EGME is a very weakinducer of dominant–lethal mutations, and produces previouslyundescribed effects on late-stage spermatids and spermatogonia.     

Effects of 2-Ethylhexanoic Acid on Reproduction and Postnatal Development in Wistar Rats

Reproductive toxicity of 2-ethylhexanoic acid (2-EHA) was studiedin Wistar rats. The animals (24 animals per sex per group) weregiven 2-EHA as a sodium salt in drinking water at daily dosesof 100, 300, or 600 mg/kg. Control animals received plain water.Male rats were exposed to 2-EHA for 10 weeks and females for2 weeks prior to mating, both sexes during the mating periodand females during the entire gestation and lactation period.2-EHA caused a slight but dose-dependent decrease in fertility;time to mating increased at 300 and 600 mg/kg and even totalinfertility ensued. 2-EHA slightly decreased sperm quality inmales. The spermatozoa were significantly less motile at 100and 600 mg/kg and abnormal sperm occurred more frequently atthe two highest dose levels. The average litter size was reducedby 16% in the dose group receiving 600 mg/kg. The birth weightsof the pups were unaffected but the body weight gain was transientlyslower during lactation at 600 mg/kg. Several pups appearedabnormal (kinky tail, lethargic, slightly paralyzed legs) andthe physical development assessed by several landmarks (openingof eyes, eruption of teeth, hair growth) and reflexes (gripreflex, cliff avoidance) was delayed at 300 and 600 mg/kg. Inanother experiment, a single dose of 600 mg/kg 2-EHA was givento pregnant females by gavage on Gestational Day 4, 5, 6, or7 and the number of implantations were counted on GestationalDay 10. Administration on Day 6 decreased the number of implantationsand caused resorptions. In conclusion, 2-ethylhexanoic acidcaused impaired fertility in Wistar rats and delayed postnataldevelopment of pups. The reduced fertility might result fromdisturbed implantation in uterus and the retarded developmentof pups from teratogenicity and pre- and postnatal toxic effectsof 2-EHA.     

Evaluation of the intramuscular administration of Cervarix™ vaccine on fertility,pre- and post-natal development in rats

Cervarix? is a prophylactic human papillomavirus (HPV)-16/18 vaccine for the prevention of cervical cancer. It contains GSK Biologicals’ proprietary Adjuvant System AS04. The objective of this study was to investigate the effects of Cervarix? and of AS04 on female fertility and pre- and post-natal development in Sprague Dawley rats. Female rats were injected with vaccine, AS04, or saline 30 days before mating and on Gestation Days 6, 8, 11 and 15. Each dose of vaccine was one-fifth the human dose volume. Treatment of rats with vaccine or AS04 was not associated with any systemic toxicity and had no impact on female fertility. There were no adverse effects on pre- or post-natal development of litters from treated rats, as judged by fetal evaluation at Gestation Day 20, and growth and survival of pups to postnatal Day 25. These results support the use of the vaccine in the targeted human population.     

A 40-week male fertility study of the anticancer agent sulofenur (LY186641) administered orally to rats.

Sulofenur was evaluated for fertility effects on rats. Five-week old male rats (20/group) received 0, 5, 30, or 60 mg Sulofenur/kg/day for 14 weeks. Fertility was evaluated five times. Treated males were mated with untreated females at 10 weeks. Half the males from each group were necropsied after the 14-week treatment period and the remainder were mated four additional times during a 26-week posttreatment period. Following each mating, females were killed on gestation-day 20 and examined for evidence of pregnancy. Six weeks after mating trial 5, the remaining males were necropsied. Testes and epididymides were collected, weighed, and examined microscopically. All rats mated in each mating trial, and all control and low-dose animals were fertile. A significant reduction in fertility occurred in the middle- and high-dose males. This was consistent with testicular hypospermatogenesis in these groups. Fertility recovered in the high-dose group following cessation of treatment, but remained reduced in the middle-dose group. Preimplantation and postimplantation loss in mating trial 1 were higher in the middle- and high-dose groups. Abnormal fetuses were present in the high-dose group in mating trial 3, but not in mating trials 4 or 5. In conclusion, male rats given doses of 30 and 60 mg/kg/day of Sulofenur showed hypospermatogenesis and decreased fertility. Spermatogenesis and fertility recovered in the high-dose group. A dose of 5 mg/kg/day did not produce any effect on testes or fertility.     

Evaluation of the Developmental and Reproductive Toxicity of Chlorpyrifos in the Rat

Chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl)-phosphorothioate),an organophosphate insecticide, was evaluated for its potentialto produce developmental and reproductive toxicity in rats followingoral exposure. Pregnant Fischer 344 rats were given doses of0 (corn oil vehicle), 0.1, 3.0, or 15 mg chlorpyrifos/kg/day,by gavage, on Gestation Days 6 through 15. Maternal effectsnoted at the two higher dose levels included decreased cholinesteraselevels at 3.0 mg/kg/day and cholinergic signs (excessive salivationand tremors), decreased cholinesterase levels, and decreasedbody weight gain at 15 mg/kg/day. No maternal effects were apparentat 0.1 mg/kg/day. Although maternal toxicity was observed atthese two higher exposure levels, no developmental effects werenoted at any dose. In a two-generation reproduction study, Sprague-Dawleyrats were maintained on diets supplying 0, 0.1, 1.0, or 5.0mg chlorpyrifos/kg/day. Parental effects included decreasedplasma, and erythrocyte cholinesterase at 1.0 mg/kg/day, anddecreased plasma, erythrocyte, and brain cholinesterase andhistopathologic alterations of the adrenal zona fasciculataat 5.0 mg/kg/day. The histopathologic alterations of the adrenalwere characterized as very slight to slight vacuolation (consistentwith fatty change) in males, and very slight vacuolation and/oraltered tinctorial properties in females. No effects on thereproductive or fertility indices or on the histopathology ofreproductive tissues were observed at any dose level, and noneonatal effects were observed at 0.1 or 1.0 mg/kg/ day in theF1 or F2 litters. Parental toxicity at the high dose was accompaniedby decreased pup body weight and increased pup mortality inthe F1 litters only. These data show that oral administrationof chlorpyrifos to rats at parentally toxic dose levels wasnot embryolethal, embryo/fetotoxic, or teratogenic and did notadversely affect fertility or the function or structure of thereproductive organs. Although effects on neonatal growth andsurvival were observed at a maternally toxic dose level in onegeneration, this effect was not observed in the subsequent generationand, therefore, may not have been related to treatment.     

Teratogenic Response of Dimethylacetamide in Rats

Pregnant CD rats (25/group) were used to determine the teratogenicpotential of dimethylacetamide (DMAC). DMAC was administeredin deionized water once a day by gavage on Days 6 through 19of gestation at dosages of 0, 65, 160, and 400 mg/kg/day. Cesareansections were performed on all females on Gestation Day 20.No treatment-related effects were observed in survival, appearance,or behavior at necropsy. Mean maternal body weight gain wasreduced significantly only at the 400 mg/kg/day level. Fetotoxicitymanifested by increased postimplantation loss was seen at the400 mg/kg/day level while reduction in mean fetal body weightswas noted at the 160 and 400 mg/kg/day test levels. Developmentalvariations (reduced ossification and unossified skeletal variations)wereincreased at the 400 mg/kg/day test level and corresponded tothe reduced fetal body weights which were observed. Treatment-relatedmalformations of the heart, major vessels and oral cavity, andanasarca were seen at the 400 mg/kg/day DMAC level. No teratogeniceffect of DMAC treatment was observed at or below dosage levelsof 160 mg/kg/day     

Reproductive capability of male rats and mice treated with methyl mercury

Male Wistar rats were administered single daily doses of 0, 1, 2.5 and 5 mg Hg²⁺ (as methyl mercuric chloride)/kg po for 7 consecutive days. After dosing was discontinued, 14 sequential mating trials were conducted, each trial consisting of individual males being caged with 2 untreated virgin females for 5 days. A dose-related reduction in mean litter size per pregnancy attributable to preimplantation losses occurred at all doses during days 5–20 of post-treatment. In a long-term experiment, male rats were dosed po daily throughout a maximum of 21 mating trials, each of 5 days duration. From 30 days onward at 1 mg/kg/day and from 90 days onward at 0.5 mg/kg/day, a reduction in average litter size due to preimplantation losses was noted. Such an effect was not observed at 0.1 mg/kg/day. Male rats dosed for 7 days had a dose-related reduction in incidence of fertile matings. This effect was not apparent during chronic treatment. Male mice administered daily doses po of up to 5 mg Hg²⁺/kg for 5 or 7 consecutive days and then sequentially mated for 5–7 trials produced no postimplantation losses or reduction of fertility. There was an indication of slight reduction in average number of viable embryos possibly resulting from preimplantation loss.