Selective Developmental Toxicant Research Articles

Gamma secretase inhibition: Effects on fertility and embryo-fetal development in rats

Avagacestat inhibits γ-secretase, a protease that cleaves the amyloid precursor protein (APP) to produce amyloid beta (Aβ). Aβ plaques, a predominant lesion in Alzheimer's patient's brain, is considered a mechanism driving neurodegeneration. As part of the nonclinical reproductive safety assessment, avagacestat effects on fertility and early embryonic development and embryo-fetal development were evaluated in rats. In the embryo-fetal development study, avagacestat was a selective developmental toxicant with dose-related increased fetal mortality, decreased fetal growth, and increased fetal malformations and variations (primarily affecting the axial and appendicular skeletal system) at ≥3 mg/kg/day. In the female fertility and early embryonic development study, avagacestat-related reductions in female fecundity at ≥5 mg/kg/day were attributed to impaired ovarian follicular development that was reflected in dose-dependent reductions in implantation sites, litter size, and gravid uterine weights. In the male fertility and early embryonic development study, avagacestat-related effects on reproduction could not be fully assessed because of low systemic exposures achieved due to extensive metabolism and clearance of the drug. The results obtained in these studies were consistent with pharmacologically mediated inhibition of γ-secretase and resulting inhibition of Notch processing and signaling that are key for embryonic development and ovary folliculogenesis. These findings are not considered a risk for late-onset AD where the patient population is ≥65 years old most with women who are post-menopausal. However, for treatment of early onset AD with a younger patient population, there are risks for reproductive or developmental toxicities with treatment with gamma secretase inhibitors like avagacestat.

The impact of dasatinib on pregnancy outcomes.

Prolonged survival in patients with chronic myeloid leukemia treated with BCR-ABL1-targeted tyrosine kinase inhibitors allows consideration of parenthood for patients on chronic therapy, but there are limited data about the effects of dasatinib on pregnancy. Pregnancy-related outcomes in dasatinib-treated patients or their partners reported to Bristol-Myers Squibb from clinical trials or healthcare providers through December 2013 were reviewed. Outcomes were available in 46/78 dasatinib-treated women (59%) and 33/69 partners of dasatinib-treated men (48%). Fifteen women (33%) delivered a normal infant; 18 (39%) and 8 (17%) had an elective or spontaneous abortion; and 5 (11%) had an abnormal pregnancy. There were 7 reports of fetal/infant abnormalities (encephalocele, renal tract abnormalities, and hydrops fetalis). Thirty of 33 (91%) infants fathered by dasatinib-treated men were reported normal at birth. Also, animal studies evaluated the impact of dasatinib on fertility, embryo-fetal toxicity, and development, suggesting that dasatinib may be a selective developmental toxicant. The outcomes of most pregnancies conceived by men treated with dasatinib were normal, but due to the small number of cases, further monitoring is required. Significant effects on pregnancy outcomes in women treated with dasatinib were found, supporting current recommendations that women avoid becoming pregnant during dasatinib treatment and be informed of fetal risks.

Dose–Response Effects of Diphenylhydantoin on Pregnant Dams and Embryo‐Fetal Development in Rats

Despite the widespread use of diphenylhydantoin (DPH), there is a lack of reliable information on the teratogenic effects, correlation with maternal and developmental toxicity, and dose-response relationship of DPH. This study investigated the dose-response effects of DPH on pregnant dams and embryo-fetal development as well as the relationship between maternal and developmental toxicity. DPH was orally administered to pregnant rats from gestational days 6 through 15 at 0, 50, 150, and 300 mg/kg/day. At 300 mg/kg, maternal toxicity including increased clinical signs, suppressed body weight, decreased food intake, and increased weights of adrenal glands, liver, kidneys, and brain were observed in dams. Developmental toxicity, including a decrease in fetal and placental weights, increased incidence of morphological alterations, and a delay in fetal ossification delay also occurred. At 150 mg/kg, maternal toxicity manifested as an increased incidence of clinical signs, reduced body weight gain and food intake, and increased weights of adrenal glands and brain. Only minimal developmental toxicity, including decreased placental weight and an increased incidence of visceral and skeletal variations, was observed. No treatment-related maternal or developmental effects were observed at 50 mg/kg. These results show that DPH is minimally embryotoxic at a minimal maternotoxic dose (150 mg/kg/day) but is embryotoxic and teratogenic at an overt maternotoxic dose (300 mg/kg/day). Under these experimental conditions, the no-observed-adverse-effect level of DPH for pregnant dams and embryo-fetal development is considered to be 50 mg/kg/day. These data indicate that DPH is not a selective developmental toxicant in the rat.

Influence of Maternal Toxicity on the Outcome of Developmental Toxicity Studies

The relevance of fetal abnormalities noted at maternally toxic doses is a long-standing issue regarding the interpretation of findings of segment II studies. A number of diseases and conditions during pregnancy are known to adversely affect embryo/fetal development, and along this line many scientists believe that any marked disturbance of maternal homeostasis produced by chemical exposure may eventually produce a teratogenic effect. Although there is little doubt that developmental toxicity may be maternally mediated, the notion that, in principle, any maternal toxicity leads to birth defects is disputed. When embryotoxicity is noted only within the maternally toxic dose range, it is not possible to ascertain whether it is in fact maternally mediated or not (i.e., embryo development may have been impaired by a direct action of the chemical at doses that also adversely affect the mother; in these circumstances it would still be a selective developmental toxicant). However, currently, a chemical is not regarded as a “developmental toxicant” (or “teratogenic agent”) if embryotoxicity is apparent only at doses that are also toxic to the mother. In the European Union, developmental hazard identification exerts a strong influence on the classification and labeling of chemicals. In Brazil, registration of any pesticide that proved to be teratogenic in animal studies is strictly forbidden by law (Pesticide Law, Federal Law 7.802, 1989). Therefore, interpretation of findings from developmental toxicity studies in light of maternal toxicity is particularly relevant to regulatory agencies, and becomes even more important when labeling or cutoff decision-making criteria are adopted regarding teratogenicity.

Evaluation of the Developmental Toxicity of Dihydromyrcenol in Rats

Dihydromyrcenol, a widely used fragrance ingredient, was evaluated for developmental toxicity in pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 250, 500, or 1000 mg/kg/d in corn oil were administered on gestational days 7 to 17. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Fetuses were weighed and examined for sex, gross external changes, and soft tissue or skeletal alterations. All rats survived until scheduled termination. No clinical signs were attributed to dihydromyrcenol. There were no gross tissue changes at necropsy. The 1000-mg/kg/d dosage group had reduced mean maternal body weight gains of 5% compared with controls, whereas absolute and relative feed consumption were significantly reduced during the dosage period. This threshold systemic maternal toxicity was associated with threshold developmental toxicity in the 1000-mg/kg/d dosage group. Fetal effects included a minimal approximately 3% reduction in fetal body weight; reversible variations in ossification, including retarded ossification of the metatarsal bones in the hindpaws; and an increase in supernumerary thoracic ribs with associated increases or decreases in thoracic and lumbar vertebrae, respectively. Based on these data, maternal and developmental no observable effect levels of 500 mg/kg/d and maternal and developmental no observable adverse effect levels of 1000 mg/kg/d were established for dihydromyrcenol. It was concluded that dihydromyrcenol is not a selective developmental toxicant in rats under the conditions of this study and that a margin of safety of 25 000 exists between reversible developmental delays in rats and the estimated daily human exposure level of 0.02 mg/kg/d.

Alternative experimental approaches for interpreting skeletal findings in safety studies

Standard evaluations for characterizing selective developmental toxicity are traditionally undertaken in vivo. These studies incur significant cost in animal use, labor and compound, ultimately limiting the selection of compounds that can be evaluated in vivo. Such limitations hinder the ability to address questions regarding whether teratogenic outcome was caused by intended pharmacology or attributed to off-target effects associated with the structure of the small molecule. Ascertaining a better understanding of the published literature can enhance interpretation of existing in vivo datasets and hypotheses regarding critical windows of sensitivity and underlying mechanisms of teratogenicity. Thoughtful execution of investigative in vivo and in vitro studies can test and further define the underlying mechanism of teratogenicity. Skeletal variations and malformations are frequently encountered in in vivo studies and can be difficult to interpret in context of defining hazard assessment and mechanisms of abnormal development. This commentary reviews how investigative approaches can be integrated to better understand teratogenic mechanism as it pertains compounds that produce skeletal abnormalities. Approaches are discussed in context of how they could be used to study a compound that has been found to produce fused and wavy ribs in rat fetuses. An investigative approach is described that utilizes three strategies: 1) maximizing the data available from in vivo studies; 2) performing critical window studies in vivo; and 3) performing mechanism of action evaluations using gene expression studies and developmental model systems.

Nonclinical Safety Evaluation of Muraglitazar, a Novel PPARα/γ Agonist

The toxicity of muraglitazar, an oxybenzylglycine, nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; reproductive and developmental toxicity studies in rats and rabbits; and studies to investigate species-specific findings. Pharmacologically mediated changes, similar to those observed with other PPARgamma agonists, were observed following chronic administration and included subcutaneous edema, hematologic/hematopoietic and serum chemistry alterations, and morphologic findings in the heart and adipose tissue in rats and monkeys. In dogs, a species highly sensitive to PPARgamma agonists, muraglitazar caused pronounced species-specific clinical toxicity and degenerative changes in the brain, spinal cord, and testes at high doses and exposures. Muraglitazar was nongenotoxic in the standard battery of genotoxicity studies. Gallbladder adenomas in male mice and adipocyte neoplasms in male and female rats were seen at suprapharmacologic exposures, whereas urinary bladder tumors occurred in male rats at lower exposures. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Muraglitazar had no effects on reproductive function in male and female rats at high systemic exposures, was not teratogenic in rats or rabbits, and demonstrated no selective developmental toxicity. Overall, there were no nonclinical findings that precluded the safe administration of muraglitazar to humans.

Developmental toxic effects of ethylbenzene or toluene alone and in combination with butyl acetate in rats after inhalation exposure

First, the developmental toxic potential of n-butyl acetate (BA) was examined in Sprague-Dawley rats following whole body inhalation exposure, 6 h day(-1), from day 6 to 20 of gestation, at concentrations of 0, 500, 1000, 2000 and 3000 ppm. Maternal toxicity was evidenced by significant decreases in body weight gain at 2000 and 3000 ppm, and by reduced food consumption at 1000 ppm and higher concentrations. The effects on prenatal development were limited to a significant decrease in fetal weight at 3000 ppm. Thus, inhaled BA was not a selective developmental toxicant. In the second part of this study, the developmental toxic effects of simultaneous exposures to ethylbenzene (EB) and BA, or to toluene (TOL) and BA were evaluated. Pregnant rats were administered EB (0, 250 or 1000 ppm) and BA (0, 500 or 1500 ppm), or TOL (0, 500 or 1500 ppm) and BA (0, 500, 1500 ppm), separately and in combinations, using a 2 x 2 factorial design. The maternal weight gain was reduced after exposure to 1000 ppm EB, to 1500 ppm BA, or to 1500 ppm TOL, either alone or in binary combinations. A significant reduction of fetal weight was associated with exposure to 1000 ppm EB alone, to either mixtures of EB with BA, or to 1500 ppm TOL alone or combined with BA at either concentration. No embryolethal or teratogenic effects were observed whatever the exposure. There was no evidence of interaction between EB and BA or between TOL and BA in causing maternal or developmental effects.

Trichloroethylene and dichloroethylene: A critical review of teratogenicity

Trichloroethylene (TCE) and dichloroethylene (DCE) are high-volume industrial chemicals frequently found as contaminants in public drinking water supplies. The developmental toxicity of both chemicals has been evaluated in laboratory and epidemiologic studies. It has been suggested that TCE and DCE are specific cardiac teratogens and that drinking water contaminated with them increases the risk of congenital heart defects in exposed human populations. In contrast, other laboratory and epidemiologic studies do not find an increase in developmental effects, either in general or specifically affecting the heart. This laboratory and epidemiologic base was reviewed to evaluate the strengths and weaknesses of the conflicting published reports. We conclude that the weight of experimental and epidemiologic evidence does not support the hypothesis that TCE or DCE is a selective developmental toxicant in general or a cardiac teratogen specifically.

Evaluation of the Developmental Toxicity of 8-2 Telomer B Alcohol

The potential maternal and developmental toxicity of 8-2 Telomer B Alcohol was assessed in rats. Groups of 22 time-mated female Crl:CD (SD)IGS BR rats were administered oral gavage doses as suspensions of 8-2 Telomer B Alcohol in aqueous 0.5% methylcellulose from day 6 through 20 of gestation (G) at daily doses of either 0, 50, 200, or 500 mg/kg. Under the conditions of this study, adverse maternal toxicity was produced at 500 mg kg− 1 day− 1 and consisted of maternal mortality, decreased body weights and body weight gains, and increased clinical observations of toxicity. One litter at 500 mg kg− 1 day− 1 consisted of one early resorption and was believed to be secondary to overt maternal toxicity, although single conceptus litters occur historically in this strain of rats. Developmental toxicity at 500 mg kg− 1 day− 1 consisted of increased fetal skeletal variations (delayed pelvic bone ossification and wavy ribs). At 200 and 500 mg kg− 1 day− 1, there were transient reductions in maternal feed consumption. In addition, there were slight increases in the incidence of delayed fetal skull bone ossification at 200 and 500 mg kg− 1 day− 1. The no-observed-adverse-effect level (NOAEL), defined as the highest dose at which adverse effects attributable to the test substance were not detected, for both maternal and developmental toxicity, is considered to be 200 mg kg− 1 day− 1. Thus, 8-2 Telomer B Alcohol is not considered to be a selective developmental toxicant in rats. The transient and quantitative nature of the observations in the 200 mg/kg group supports the conclusion that these findings were not adverse.

Oral (drinking water) developmental toxicity study of ammonium perchlorate in Sprague-Dawley rats.

A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.1, 1.0, and 30.0 mg/kg-day beginning 14 days before cohabitation and continuing through sacrifice. Twenty-four rats/group were cesarean-sectioned on day of gestation (DG) 21 and fetuses examined for visceral and skeletal alterations. An additional 16 litters/group were sacrificed on DG 21 for maternal and fetal serum TSH, T(3), and T(4) (thyroid-stimulating hormone, triiodothyronine, and thyroxine) levels and thyroid histopathology. Clinical and necropsy observations, body weights, feed and water consumption, and cesarean-sectioning parameters were comparable among the groups with only delays in ossification observed in the 30 mg/kg-day group. Maternal thyroid weights were increased in the 30.0 mg/kg-day group. Decreased colloid was present in male and female fetal thyroids in the 1.0 and 30.0 mg/kg-day groups. Maternal TSH was increased and T(4) was decreased at all levels, and T(3) was reduced at 30.0 mg/kg-day. Fetal TSH was increased at 1.0 and 30.0 mg/kg-day, T(4) was reduced at 30.0 mg/kg-day, and T(3) was decreased at all levels. The maternal no-observable-adverse-effect level (NOAEL) was 1.0 mg/kg-day; exposures of 30.0 mg/kg-day increased absolute and relative maternal thyroid weights and histopathology findings. The developmental NOAEL was 1.0 mg/kg-day; developmental delays in ossification occurred in the 30.0 mg/kg-day group. The colloid depletion in the thyroids and increased TSH and decreased T(3) and T(4) levels at lower exposures were considered adaptive and not adverse. No adverse effects on development at occurred levels that did not cause maternal toxicity. AP is not a selective developmental toxicant.

Evaluation of the Potential Developmental Toxicity of Cyclododecatriene (CDDT)

The potential maternal and developmental toxicity of cyclododecatriene (CDDT) was assessed in rats. Groups of 22 time-mated female Crl:CD® (SD) BR rats were exposed by inhalation (whole-body, 6 h/day) to either 0 (control), 10, 25, or 67 ppm CDDT over days 6–20 of gestation (days 6–20 G); the day of copulation plug detection was designated day 0 G. The dams were euthanized on day 21 G, and their abdominal and thoracic viscera were examined grossly. The fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations. Evidence of maternal toxicity was seen at 25 and 67 ppm. There were compound-related reductions in maternal body weight and food consumption parameters as well as increased occurrences of wet and stained fur at these exposure levels. Developmental toxicity evident as reduced mean fetal weight and delayed skeletal ossification was seen only at 67 ppm. There was no evidence of either maternal or developmental toxicity at 10 ppm. Thus, the no-observed-effect level (NOEL) for maternal toxicity was 10 ppm, and the NOEL for developmental toxicity was 25 ppm. Because developmental toxicity was observed only after exposures that also produced signs of maternal toxicity, CDDT was not considered to be a selective developmental toxicant in the rat.

Developmental toxicity evaluation of the new fluoroquinolone antibacterial DW-116 in rats

We have recently reported that the fluoroquinolone antibacterial DW-116 induces a significant developmental toxicity in rat. The present study was conducted to better understand the teratogenic effects of DW-116 at several developmental toxic doses in rats. DW-116 was orally administered to pregnant rats from gestational day (GD) 6 through 16 at dose levels of 0, 320, 400, and 500 mg/kg/day. All dams were subjected to caesarean section on GD 20 and their fetuses were examined for external, visceral, and skeletal abnormalities. At above 400 mg/kg, severe decreases in maternal body weight gain, food consumption, litter size, fetal weight and placental weight, and severe increases in resorption rate and fetal morphological alterations were observed. At 320 mg/kg, mild decreases in maternal body weight gain, food consumption, fetal weight and placental weight, and mild increases in fetal variations and retardations were observed. These results suggest that DW-116 is embryotoxic at above 320 mg/kg/day and is embryolethal and teratogenic at above 400 mg/kg in pregnant rats and that DW-116 is a selective developmental toxicant in rat conceptuses.

A study of the developmental toxicity potential of pentachlorophenol in the rat.

Pentachlorophenol (penta, CAS #87-86-5) is primarily used as a wood preservative. As part of the USEPA pesticide reregistration process, the developmental toxicity (embryo-fetal toxicity and teratogenic potential) of commercially available penta was studied following oral gavage to presumed pregnant female Sprague-Dawley rats (Crl:CD BR VAF/Plus Subdivision F, 83-3). Both study design and penta purity met the requirements of the USEPA. Doses of 0 (corn oil), 10, 30, and 80 mg/kg/day were administered to the rats at concentrations of 0, 2, 6, and 16 mg/ml, respectively from day 6 to day 15 of presumed gestation. The dosage volume was 5 ml/kg, adjusted on each day of dosage based on individual body weights recorded immediately before intubation. The rats were sacrificed on day 20 of presumed gestation and necropsied. The number of corpora lutea in each ovary was recorded. The uterus was examined for pregnancy, number and distribution of implantations, early and late resorptions and live and dead fetuses. Each fetus was weighed, sexed, and examined for gross external, soft tissue and skeletal alterations. The no-observable-adverse-effect-level (NOAEL) for maternal toxicity in rats was determined to be 30 mg/kg/day of penta. The developmental NOAEL for penta in rats was also found to be 30 mg/kg/day. The lowest-observable-adverse-effect-level (LOAEL) for penta developmental toxicity (80 mg/kg/day) was associated with increased resorptions, reduced live litter size and fetal body weights, and caused increased malformations and variations. These NOAELs, derived using USEPA approved study designs, are higher than those previously reported using penta that is no longer commercially available in studies with non-approved experimental designs. Penta should not be identified as a selective developmental toxicant in the rat because adverse effects on development of rat conceptuses occurred only at maternally toxic dosages.

EVALUATION OF THE POTENTIAL DEVELOPMENTAL TOXICITY OF 3-AMINOPENTANENITRILE (3-APN) IN THE RAT

The potential developmental toxicity of 3-aminopentanenitrile (3-APN) was assessed in rats. Groups of 25 time-mated female Crl:CD®(SD)IGS BR rats were orally gavaged at daily dose levels of 0, 5, 30, 100 or 300 mg/kg over days 6–20 of gestation (days 6–20G); the day of copulation plug detection was designated day 0G. The dams were euthanized on day 21G and their abdominal and thoracic viscera were examined grossly. The fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations. Evidence of maternal and developmental toxicity was seen at 100 and 300 mg/kg. Regarding maternal toxicity, there were compound-related, statistically significant reductions in maternal body weight and food consumption at 100 and 300 mg/kg. The incidence of alopecia was significantly increased at these levels as well. Regarding developmental toxicity, mean fetal weight was slightly but significantly reduced at 100 and 300 mg/kg. In addition, at 300 mg/kg, there were significant increases in several skeletal variations (wavy ribs and skull, rib, and vertebral ossification delays) consistent with developmental delay. There was no evidence of either maternal or developmental toxicity at 5 or 30 mg/kg. Thus, the maternal and developmental no-observed-effect level (NOEL) was 30 mg/kg. Because developmental toxicity was observed only after administration of doses that also produced signs of maternal toxicity, 3-APN is not considered to be a selective developmental toxicant in the rat.

Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats

A thorough review of the literature revealed no published repeated-dose oral developmental toxicity studies of inorganic arsenic in rats. In the present study, which was conducted according to modern regulatory guidelines, arsenic trioxide was administered orally beginning 14 days prior to mating and continuing through mating and gestation until gestational day 19. Exposures began prior to mating in an attempt to achieve a steady state of arsenic in the bloodstream of dams prior to embryo-foetal development. Groups of 25 Crl:CD ®(SD)BR female rats received doses of 0, 1, 2.5, 5 or 10 mg/kg/day by gavage. The selection of these dose levels was based on a preliminary range-finding study, in which excessive post-implantation loss and markedly decreased foetal weight occurred at doses of 15 mg/kg/day and maternal deaths occurred at higher doses. Maternal toxicity in the 10 mg/kg/day group was evidenced by decreased food consumption and decreased net body weight gain during gestation, increased liver and kidney weights, and stomach abnormalities (adhesions and eroded areas). Transient decreases in food consumption in the 5 mg/kg/day group caused the maternal no-observed-adverse-effect level (NOAEL) to be determined as 2.5 mg/kg/day. Intrauterine parameters were unaffected by arsenic trioxide. No treatment-related foetal malformations were noted in any dose group. Increased skeletal variations at 10 mg/kg/day were attributed to reduced foetal weight at that dose level. The developmental NOAEL was thus 5 mg/kg/day. Based on this study, orally administered arsenic trioxide cannot be considered to be a selective developmental toxicant (i.e. it is not more toxic to the conceptus than to the maternal organism), nor does it exhibit any propensity to cause neural tube defects, even at maternally toxic dose levels.

Developmental toxicity assessment of C8 iso acid in CD rats: relevance to embryotoxic aliphatic carboxylic acids.

Cekanoic C8 acid (CAS RN 25103-52-0) is a complex isomeric substance containing several aliphatic carboxylic acids, primarily dimethyl hexanoic acid. Because Cekanoic C8 acid is a structural isomer of octanoic acid, its potential for developmental toxicity was investigated in CD (Sprague-Dawley) rats. Cekanoic C8 acid was administered by oral gavage to 25 confirmed-mated females at doses of 0, 200, 400, and 800 mg/kg/day on gestation days (GD) 6-15, based on a range-finding experiment. Maternal body weights, food consumption, and clinical observations were recorded throughout gestation. On GD 21, cesarean sections were performed and the uterine contents removed and subjected to conventional teratological evaluation. At 800 mg/kg/day, maternal body weight gain and food consumption were reduced during the exposure period, and clinical signs were evident. There were no significant differences in fetal weight, malformation incidence, or fetal viability in any of the experimental groups. There was a statistically significant increase in the incidence of total variations in the 800-mg/kg/day group, which was within the historical control range of this laboratory and not considered biologically significant. These results indicate that, unlike related compounds, Cekanoic C8 acid was not teratogenic or a selective developmental toxicant in rats. This is the first report of a dimethyl substituted aliphatic acid being evaluated for developmental toxicity in a definitive study. The results are consistent with a structure-teratogenicity relationship for aliphatic acids, indicating that side-chain branching larger than a methyl group is required to elicit teratogenic effects. This study established a maternal no-observable-adverse-effect level (NOAEL) for Cekanoic C8 acid at 400 mg/kg/day and a developmental NOAEL at 800 mg/kg/day.

Developmental toxicity of di-isodecyl and di-isononyl phthalates in rats

The developmental toxicity of di-isodecyl phthalate (DIDP; CAS RN 68515-49-1) and di-isononyl phthalate (DINP; CAS RN 68515-48-0) were investigated in Sprague–Dawley rats. DIDP and DINP were administered by gavage to mated rats at doses of 0, 100, 500, and 1000 mg/kg/d on Gestation Days (GD) 6 through 15. Cesarean sections were performed on GD 21 and the fetuses removed for evaluation. Maternal weight gain and food consumption were significantly reduced at 1000 mg/kg/d during the exposure period. No treatment-related effects were noted at cesarean section, nor were there any fetal morphologic observations except for an increased frequency of seventh cervical and rudimentary lumbar ribs at the maternally toxic exposure level of 1000 mg/kg/d. Under these study conditions, mild maternal and developmental effects were observed at 1000 mg/kg/d. Both maternal and developmental NOAELs were therefore established at 500 mg/kg/d. The results indicate that neither DIDP nor DINP is teratogenic or a selective developmental toxicant.

DEVELOPMENTAL TOXICITY EVALUATION OF A SCRUBBING SOLUTION USED IN PETROLEUM REFINERIES

The developmental toxicity potential of a scrubbing solution used extensively in petroleum refineries to remove CO2 from hydrogen gas streams was evaluated via inhalation. Pregnant female CD (Sprague-Dawley) rats were exposed to aerosols of a "used" scrubbing solution at 0.05, 0.1, 0.2, or 0.3 mg/l for 6 h/d on d 6-19 of pregnancy. Control animals were exposed to filtered air under the same exposure conditions. Dams were sacrificed on d 20 of pregnancy and a laparohysterectomy was performed. The mass median aerodynamic diameter of the aerosol revealed that all particles ranged from 1.6 to 2.8 mum, with geometric standard deviations between 2.0 and 2.3 mum. The overall pregnancy rate was high (>95% ) and equivalent across all groups. All pregnant dams had live litters, and 22-24 litters were examined in each group. Treatment-related clinical signs consisted of rales, observed at all exposure levels, and gasping noted only at the 0.3 mg/l exposure level. The occurrence of rales was presumably a localized effect on the respiratory tract and likely due to the irritating properties of the scrubbing solution. Maternal toxicity was exhibited in the 0.3 mg/l group, including reduced body weight, weight gain, and food consumption and one possible treatment-related death on gestation d 17. At scheduled necropsy, there were no treatment-related gross pathological observations and no statistically significant reproductive and developmental effects. The incidences of fetuses with skeletal variations involving the sternum were clustered in two litters at the highest exposure level with atypically low term fetal body weights. Under the conditions of this investigation, potassium carbonate scrubbing solution is not a selective developmental toxicant.

Lack of selective developmental toxicity in rats treated with cekanoic C8 acid

Lack of selective developmental toxicity in rats treated with cekanoic C8 acid