[show abstract][hide abstract] ABSTRACT: Effects of common anaesthetics such as ether, methoxyflurane, isoflurane, carbon dioxide (at 100%, 80% or 60% admixed with O(2)) on toxicity and clinical pathology parameters in rats were investigated. Ether, methoxyflurane and 100% CO(2) induced toxicity in some animals. Erythrocyte, haemoglobin and haematocrit were reduced in females by 100% CO(2), methoxyflurane and isoflurane. Glucose was increased by 60% CO(2), 80% CO(2), ether, isoflurane and methoxyflurane in males. Chloride was reduced by isoflurane and all CO(2) concentrations in females. Serum proteins were reduced by isoflurane and methoxyflurane. Sodium, inorganic phosphate, calcium and magnesium were reduced by methoxyflurane and isoflurane, but increased by all CO(2) concentrations. Potassium was reduced by ether, methoxyflurane or isoflurane. Triiodothyronine and thyroxine were reduced by all anaesthetics. Prolactin was reduced by methoxyflurane, but raised by ether and isoflurane. Erythrocyte cholinesterase (E-ChE) activity is markedly reduced (20-40%) after anaesthesia with all CO(2) concentrations in both sexes. E-ChE was unaffected by ether, methoxyflurane, or isoflurane. Serum and brain cholinesterase activities were not affected. E-ChE inhibition correlated with decreased blood pH, suggesting that this was caused by acidosis. This is of practical relevance in the risk assessment of cholinesterase inhibitors. Conclusions: Clinical pathology data were affected by all anaesthetics. CO(2)/O(2) (80%/20%) and isoflurane are the most suitable anaesthetics. If E-ChE activity is to be determined, isoflurane is the anaesthetic of choice.
Food and Chemical Toxicology 10/2007; 45(9):1709-18. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Wistar rats continuously received octyl methoxycinnamate (OMC) in the diet through two successive generations at nominal doses of 0, 150, 450 or 1000 mg/kg bw/day. OMC had no adverse effects on estrous cycles, mating behavior, conception, parturition, lactation and weaning, sperm and follicle parameters, macropathology and histopathology of the sexual organs. 1000 mg/kg bw/day reduced parental food consumption and body weight (-14% to -16% in males, -4% to -5% females), increased liver weight, produced hepatic cytoplasmic eosinophilia and erosion/ulceration of glandular stomach mucosa. and led to a slightly decreased implantation rate in the top dose F0 and F1 dams. The high dose F1 and F2 pups had reduced lactation weight gain and organ weights and delayed sexual maturation landmarks. There was no evidence of a selective influence of the test compound on pups' sexual landmarks. The NOAEL (no observed adverse effect level) is 450 mg/kg bw/day for fertility and reproductive performance, for systemic parental and developmental toxicity.
Food and Chemical Toxicology 08/2005; 43(7):1083-92. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Synthetic crystalline lycopene is a nutritional supplement to increase dietary intake of lycopene, an antioxidant carotenoid. Its potential oral developmental toxicity was studied in rats and rabbits. Each study included 3 control groups (water and matrix for Lycopene 10 CWD or LycoVit 10%), 3 Lycopene 10 CWD groups [500, 1500 and 3000 (rats)/2000 (rabbits) mg/kg/day] and 1 LycoVit 10% group [3000 mg/kg/day (rats)/2000 (rabbits)]. The high dosages were at maximum achievable concentrations and dosage volumes (15 and 10 ml/kg for rats and rabbits, respectively) of the highly viscous test material suspensions. Dosages were administered on gestation days (GDs) 6 through 19 (rats) or GDs 6 through 28 (rabbits). Endpoints evaluated included viability, body weight, feed consumption, necropsy observations [GD 20 (rats)/GD 29 (rabbits)], uterine contents and fetal viability, gender, body weight and morphology (skeletons double-stained). Feed consumption and weight gain were essentially unaffected in rats and rabbits, despite intubation problems in both species and reduced gastrointestinal motility and mortality in rabbits attributable to the physical properties of the gels. Neither Lycopene 10 CWD nor LycoVit 10% caused direct maternal or developmental toxicity in rats or rabbits at dosages as high as 3000 or 2000 mg/kg/day, respectively.
Food and Chemical Toxicology 07/2003; 41(6):773-83. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pregnant Wistar rats were administered 0, 100, 400 or 1000 mg mono-n-butylamine hydrochloride/kg body weight/day by gavage on days 6 through 15 post coitum (sperm-positive=day 0), or inhaled mono-n-butylamine 0, 17, 50 or 152 ppm (whole-body exposure), 6 h/day on days 6 through 19 post coitum. Oral n-butylamine HCl 1000 mg/kg reduced maternal feed consumption, increased early post-implantation losses (embryonic resorptions), reduced fetal and placental weight, and retarded skeletal development (incomplete skull and sternebral ossification), and produced malformations (filiform/kinked tail, enlarged cardiac ventricular chamber(s), malpositioned heart, aortic arch atresia, diaphragmatic hernia); 100 mg/kg was the no-observed-adverse effect level (NOAEL) for prenatal developmental toxicity; 400 mg/kg, the maternal no-effect level, produced only malformations (aortic arch atresia, malpositioned heart, diaphragmatic hernia). Inhaled n-butylamine produced concentration-dependent nasal epithelial hyperplasia and squamous metaplasia, inflammation and necrosis; the maternal NOAEL was less than 17 ppm. There were no treatment-related signs of embryo/fetotoxicity, particularly, no effects on fetal morphology. The developmental NOAEL was 152 ppm. The neutralization of n-butylamine by hydrochloride converts it from a strong alkali causing tissue burns into a weak acid/base which is fetotoxic. Possible mechanisms of fetotoxicity are free radical production, metabolic acidosis, and lysosomotrophy.
Food and Chemical Toxicology 01/2003; 40(12):1833-42. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: In a two-generation reproduction toxicity study, 25 male and 25 female Wistar rats per dose group and generation were exposed continuously to tetrahydrofuran in the drinking water for at least 70 days prior to and during mating, gestation, parturition and lactation to weaning, at concentrations of 0, 1000, 3000 or 9000 ppm (approximately 100, 300 and 700 mg/kg/day in males and females premating, 100, 300 and 800 mg/kg/day in females during gestation, and 200, 500 and 1300 mg/kg/day in females during lactation) through two successive generations. In both generations and sexes, water consumption was dose-relatedly reduced at all doses; food consumption and body weight were reduced at 9000 ppm. Necropsy kidney weights were increased in 9000 ppm F0 males. Pup body weight gain during lactation was reduced in both generations (F1 and F2 pups) and eye opening delayed in the first generation (F1 pups) at 9000 ppm; there were no treatment-related malformations. The NOAEL of tetrahydrofuran in drinking water is 9000 ppm for parental fertility and reproductive performance, and 3000 ppm for systemic parental and developmental toxicity.
Food and Chemical Toxicology 11/2002; 40(10):1515-23. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: (1) Dimethylacetamide was tested for developmental toxicity after inhalation exposure of pregnant Himalayan rabbits. Fifteen female rabbits per main group were exposed to dimethylacetamide vapours at concentrations of 0, 0.2, 0.7 or 2.0 mg/l (equivalent to 0, 57, 199.5 or 570 ppm) and five female rabbits per satellite group to 0 or 2.0 mg/l 6 h/day from day 7 post-insemination (p.i.) to day 19 p.i. All animals were observed until day 29 p.i. (2) No signs of maternal toxicity were seen in the does of the main groups (body weight and gross pathology) or in the does of the satellite groups (body weight, blood chemistry, histopathological findings of the liver). (3) Fetotoxic effects were caused at a concentration of 0.7 mg/l (e.g., increased skeletal variations) and 2.0 mg/l (e.g., significantly decreased fetal and placental weights, increase in soft tissue and skeletal variations). At 2.0 mg/l, there were also signs of a weak teratogenic effect expressed as a marginal, statistically not significant increase in soft tissue malformations (regarding the heart and great vessels). No compound-related effects were observed in the fetuses after exposure to 0.2 mg/l. (4) The highest concentration tested under these conditions (2.0 mg/l) was found to be a no-observable-adverse-effect-level (NOAEL) for the maternal Himalayan rabbit, whereas 0.2 mg/l was defined as the NOAEL for the developing organism.
Human & Experimental Toxicology 01/2001; 19(12):676-83. · 1.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: The reproductive effects of the administration of 4-chloro-2-methylphenoxyacetic acid (MCPA) to rats were evaluated through two generations, from prior to mating, throughout mating, to gestation and lactation. MCPA was administered in the diet at doses of 0, 50, 150, or 450 ppm to 25 male and female immature rats (F0 parents) for 10 weeks. F0 parents were then mated to produce a first litter (F1a), retained only until weaning, and were subsequently remated to produce a second litter, F1b. Groups of male and female F1b animals were then dosed as were their parents for 10 weeks postweaning, and the breeding was repeated to produce F2a and F2b animals. The study concluded with the F2b weanlings. MCPA was administered continuously throughout the study. Only minimal, non-treatment-related observations were noted, which included rhinorrhea (in both treated and control animals in the F0 generation) and malocclusion and alopecia (in both the F0 and F1b generations). There were no consistent dose-related effects on reproductive function for parental animals of either sex in either generation. Statistically significant differences were noted in body weights and body weight gains in the 450-ppm dose group for both male and female pups in F2a and F2b. There were no treatment-related macroscopic or microscopic observations noted for any animal in this study. The no-observable-effect level (NOEL) for reproductive function in rats administered MCPA continuously for two successive generations was determined to be 450 ppm (approximately 22 mg/kg/day). The NOEL for general systemic toxicity, based on body weight effects in adult animals in the F1b generation was 150 ppm. The NOEL for effects on the offspring of the F1b generation, manifested as reduced pup weights and pup weight gains was also 150 ppm (approximately 8 mg/kg/day). Based upon the results of this study, MCPA, administered for two generations to Crl:CD(SD)BR Albino rats, is considered not to be a reproductive toxicant.
International Journal of Toxicology 01/2001; 20(1):29-38. · 1.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vinclozolin administered to pregnant Wistar and Long-Evans rats from day 14 postcoitum to day 3 postpartum at 200 mg/kg body wt/day was maternally toxic (reduced food consumption and body weight gain) and increased perinatal mortality; major adverse effects on sex-specific organs in male offspring were seen (reduced anogenital distance and index; persistence of nipples/areolas into adulthood; hypospadic penis; penile hypoplasia or development of a vaginal pouch; transient paraphimosis; hypoplasia and chronic inflammation of epididymides, prostate, seminal vesicles, and coagulating glands; and also testicular tubular atrophy and chronic inflammation of the urinary bladder in some Long-Evans) with isolated inflammation-related deaths due to pyelonephritis. At 12 mg/kg, prevalence of female areola/nipple anlagen in immature (preweaning) male offspring was increased in both strains; these persisted to adulthood in a few treated Long-Evans but not Wistar offspring. Adult Long-Evans but not Wistar at this dose also had hypoplasia of prostate, seminal vesicles, and coagulating glands, and a minority had testicular tubular atrophy. The no-observed-adverse-effect levels (NOAEL) were 12 and 6 mg/kg body wt in Wistar and Long-Evans rats, respectively, in these studies. The data suggest that both the Long-Evans and the Wistar rats are comparably sensitive to the antiandrogenic effects of vinclozolin. At dose levels below the NOAEL (1 and 3 mg/kg, respectively), there were no indications of any test-substance-related effects.
Regulatory Toxicology and Pharmacology 09/2000; 32(1):42-50. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mated Wistar rats, 25/group, were exposed to polymeric methylenediphenyl diisocyanate (MDI) aerosol of respirable size for 6 h/day, on gestational days (gd) 6 through 15, at 0, 1, 4, and 12 mg/m3. Maternal clinical signs, body weights, and feed and water consumption were measured throughout gestation. At scheduled sacrifice on gd 20, maternal body, gravid uterine, liver, and paired lung weights were documented. Corpora lutea were counted, implantation sites were identified: resorptions, dead and live fetuses, and placentas were weighed. All live fetuses were counted, sexed, weighed, and examined for external alterations; approximately 50% of the live fetuses/litter were preserved in Bouin's fixative and examined for visceral alterations, and the remaining live fetuses/ litter were cleared and stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity was observed at 12 mg/m3, including mortality (2 of 24 pregnant), damage to the respiratory tract, reduced body weights and weight gain, reduced liver and increased lung weights, and reduced gravid uterine weight (the last not statistically significantly different from the control value). Developmental toxicity was also observed at 12 mg/m3, including reduced placental and fetal body weights and an increased incidence of fetal skeletal variations and skeletal retardations. There was no evidence of maternal or developmental toxicity at 1 or 4 mg/m3. The no observed adverse effect concentration for maternal and developmental toxicity was therefore 4 mg/m3. There were no treatment-related teratogenic effects at any concentrations evaluated.
[show abstract][hide abstract] ABSTRACT: The Styrene Steering Committee (SSC) of the European Chemical Industry Council (CEFIC) sponsored this work to address any concern that styrene dimers and trimers that might migrate from polystyrene containers into food could possess some estrogenic activity and thus possibly affect human health. All phases of the study were conducted in conformance with GLP regulations and without knowledge of the oligomer migrates tested. All activities were managed and audited under a third-party contract between the SSC and Argus International. Low and high doses of the styrene oligomer migrates of 23 polystyrene samples [i.e. 9 general purpose polystyrenes (GPPS), 8 high impact polystyrenes (HIPS) and 6 expandable polystyrenes (EPS)] were tested for estrogenicity in an in vivo uterotrophic assay (immature female rat model). This model is considered to be the "gold standard" for use in screening for estrogenic effects because it evaluates both direct and indirect potential effects. The two concentrations of migrates of each of the 23 polystyrenes tested were selected to simulate daily human consumption of a low and high amount of food. Representative dimer and trimer concentrations were obtained in conformance with EEC Council Directives and calculated to be at levels simulating human consumption of 0.5 or 5 kg of food for the GPPS and the HIPS samples and of 0.5 or 3.15 kg of food for the EPS samples, respectively. The study was conducted in a series of three blocks. Each block included concurrent untreated control (negative control), vehicle control (25% ethanol, 20 ml/kg/day) and positive control (diethylstilbestrol-dipropionate, DES-DP, 5 micrograms/kg/day) groups, and low and high doses of each of 7 (1 block) or 8 (2 blocks) polystyrene oligomer migrates. Each group in each block consisted of 10 immature Wistar (Chbb: THOM-SPF) female rats. Beginning when the rats were 22 +/- 1 days of age, each rat was appropriately handled (untreated control group) or administered twice daily oral (gavage) dosages of the vehicle, positive control agent or one of the two doses of the migrates of each polystyrene for 4 consecutive days and then sacrificed at 26 +/- 1 days of age. The uterus of each rat was weighed, and the uterine weight was compared with the terminal body weight. The positive control agent (DES-DP, 5 micrograms/kg/day) significantly increased both absolute and relative (to terminal body weight) uterine weights, as compared to the untreated and vehicle control group values in each block, demonstrating sensitivity and response of the animals to an estrogenic agent. None of the 23 polystyrene oligomer migrates tested at low and high doses demonstrated biologically important or statistically significant differences from the untreated or vehicle control group values for absolute or relative (to body weight) uterine weights. Based on these data, it is concluded that low and high doses of the 23 polystyrene oligomer migrates tested did not induce an estrogenic response.
Drug and Chemical Toxicology 02/1998; 21 Suppl 1:1-30. · 1.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inclusion of biological outlier values was found to bias the results of rat uterotrophic assays towards false negatives, i.e., not identify uterotrophic effects in treated populations. The present investigation was conducted to identify the background variability in the rat uterotrophic assay and to evaluate the need to exclude biological outlier values in untreated control groups. The Styrene Steering Committee (SSC) of the European Chemical Industry Council (CEFIC) co-sponsored this work with Argus Research Laboratories (Argus). The rat uterotrophic response assay originally was used as a pharmacology screen to identify estrogenic agents. Classically, 5 to 10 immature female rats (18 to 22 days of age) are administered an agent for three or four days. At sacrifice on the following day (21 to 26 days of age), the uterus is removed, weighed and a uterine weight/terminal body weight ratio calculated. This in vivo assay has been adapted for use in identifying the potential estrogenicity of chemicals, generally using 10 immature female rats per group, more closely controlling the ages, and adding one or more positive control groups to demonstrate sensitivity and response of the test system. Statistically significant increases in the positive control group means for absolute and relative uterine weights, as compared with the untreated (or vehicle-treated) means, is generally interpreted as identifying a sensitive test system. The untreated (and/or vehicle-treated) control group is then compared with the various test groups, and statistically significant increases in the mean absolute and relative uterine weights are identified as evidence of estrogenicity of the agent. Although not fully described previously, the inherent biological variability existing in both untreated and treated animals, can confound interpretation of the data, especially when numbers are relatively small. Our laboratories have identified that under controlled GLP-compliant conditions, some Wistar rats [randomly assigned (weight-ordered) to groups of ten at 22 +/- 1 days of age, and sacrificed when 26 +/- 1 days of age] in untreated control groups have high relative uterine weights that skew data distributions such that statistically significant differences are not present between untreated control and positive control groups. Based on these observations, further evaluations of untreated control and positive control (DES-DP, 2.5 micrograms/kg, b.i.d.) populations of three rat strains [Wistar--Chbb:THOM-SPF, Wistar--Crl:(WI)BR and Sprague-Dawley--Crl:CD(SD)IBS BR VAF/Plus "International Genetic Standard"] were made to define when such normal findings should be considered biological outliers, and whether outlier values should be excluded from analyses. Our data indicate that body weight is not always predictive of uterine weight, that relative uterine weight outlier values occur in each of these rat strains, and that statistically significant differences exist between groups of untreated control animals when outlier values are included in analyses. Of 98, 60 and 60 untreated control rats in the three respective strains, 11 (11.2%), 16 (26.7%) and 15 (25.0%) had relative uterine weights > or = 0.150%, and 5 (5.1%), 4 (6.7%) and 9 (15.0%) of these rats had relative uterine weights > or = 0.200%, values within the positive control range. All positive control rats attained relative uterine weights > or = 0.100%. Of 50, 60 and 60 positive control rats in the three respective rat strains, 27 (54%), 47 (78.3%) and 36 (60%) had relative uterine weights > or = 0.200%, 9 (18%), 2 (3.3%) and 7 (11.7%) had relative uterine weights > or = 0.300% and 5 (10%), 1 (1.7%) and 3 (5%) had relative uterine weights > or = 0.400%. The incidences of relative uterine weights > or = 0.300% in the positive control group may indicate the presence of high responders. Histological evaluations of uteri of positive control rats and untreated control rats with relative uterine weights > or = 0.
Drug and Chemical Toxicology 02/1998; 21 Suppl 1:51-100. · 1.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: In a two-generation reproduction toxicity study, groups of 25 male and 25 female Wistar rats (for both F0 and F1 generations) received acrylic acid (AA) in the drinking water at concentrations of 0 (control), 500, 2500 and 5000 ppm for at least 70 days prior to mating, through mating, gestation, lactation and to weaning. The study continued through to weaning of the F2 offspring at 21 days of age. Achieved intakes of AA for the F0 and F1 parents during premating ranged from 46 (500 ppm) to 502 (5000 ppm) mg/kg/day. AA had no adverse effects on fertility and reproductive performance of the parent rats at doses up to 5000 ppm. General systemic toxicity was apparent with reduced body weights, food and water consumption in F0 parents at 5000 ppm and in F1 parents at 2500 and 5000 ppm; the only treatment-related pathological finding was a minimal hyperkeratosis of the limiting ridge of the forestomach with a minimal oedema of the submucosa of the glandular stomach in both parental generations at 5000 ppm. Dose-related signs of developmental toxicity were detected in F1 and F2 pups at 2500 and 5000 ppm in the form of retarded growth and some delay in the eye/auditory canal opening in F2 pups, but there was no evidence that AA had an adverse influence on pup morphology. Thus, the no-observed-adverse-effect level (NOAEL) is 5000 ppm for fertility and reproductive performance of the parents, 2500 ppm (F0 parents) or 500 ppm (F1 parents) for general systemic toxicity and 500 ppm for developmental toxicity.
Food and Chemical Toxicology 10/1997; 35(9):859-68. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Developmental toxicity of 2-butin-1,4-diol was determined in groups of 18-22 pregnant Wistar rats at dose levels of 10, 40 and 80 mg/kg bw/day administered by gavage from days 6 to 15 pc. At 80 mg/kg bw/day food consumption and maternal body weight were reduced and one dam died during the treatment period. At this dose level the incidence of affected fetuses per litter with accessory 14th ribs was increased. This variation is assessed as an embryotoxic effect resulting from non-specific stress on the dams. No teratogenic effects were caused by 2-butin-1,4-diol. The NOAEL on the maternal and the developing organism was 40 mg/kg bw/day.
[show abstract][hide abstract] ABSTRACT: Developmental toxicity of isobutylidenediurea (IBDU) was determined by oral administration to Wistar rats. The substance was administered as an aqueous suspension to 22-24 pregnant rats per group by gavage in daily doses of 100, 400 and 1000 mg/kg body weight from day 6 post-coitum (p.c.) to day 15 p.c. The control group received the vehicle only (0.5% aqueous carboxymethyl cellulose solution). There were no substance-related effects in the dams concerning food consumption, body weight, body weight gain, uterine weights and clinical or autopsy observations even at the highest dose of 1000 mg/kg body weight/day. The reproduction data revealed no biologically relevant differences between the control and treated groups. The incidence and type of the foetal external, soft tissue and skeletal findings, which were classified as malformations, variations and/or retardations observed in the treated foetuses were similar to the concurrent and/or historical control data. Thus, under the conditions of this study, no signs of maternal toxicity or embryo/foetotoxicity were induced by IBDU and the no-observable-adverse-effect level on the maternal and developing organism was 1000 mg/kg body weight/day.
Food and Chemical Toxicology 08/1997; 35(7):677-81. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: One straight-chain alcohol (n-octanol) and five branched-chain alcohols [2-ethylhexanol (2-EH), isodecanol, two types of isononanol and a C7-9-11 alcohol] were investigated for developmental effects in Wistar rats at equimolar dose levels (0, 1, 5 and 10 mmol/kg by gavage from gestation day 6 to 15; 10 animals per group). n-Octanol and both isononanols were also investigated in a supplementary experiment at 7.5 mmol/kg/day. Pronounced maternal but no developmental toxicity was achieved with n-octanol. C7-9-11 alcohol, which is a mixture of isomers mostly of a low degree of branching (alpha-methyl), showed no adverse effects at any dose levels. The two types of isononanols (typical mixtures of two different sets of isomers originating from two different production routes) exhibited a marked degree of maternal and foetal toxicity at 7.5 and 10 mmol/kg and slight foetal effects at 5 mmol/kg. Because of maternal toxicity in the top dose, a statistically significant increase in malformations was obtained only in the dose window of 7.5 mmol/kg in the supplementary experiment. Isodecanol (a mixture of different isomers) elicited maternal toxicity at 10 mmol/kg and caused a low incidence of retardations and rare malformations at that dose level. Some maternal signs but no foetal effects were observed at 5 mmol/kg. 2-EH showed strong maternal and also foetal toxicity at 10 mmol/kg and slight maternal and foetal toxicity at 5 mmol/kg. The differential responses to the test materials indicate that, at present, within this chemical class of alcohols, the potential for developmental toxicity has to be investigated case by case for each individual structure.
Food and Chemical Toxicology 06/1997; 35(5):489-500. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several phthalate esters with alcohol moieties ranging from C5-C10 chains were investigated for prenatal toxicity in 10 rats per group after gavage administration of 0, 40, 200 and 1000 mg/kg/day from gestation day 6 to 15. At 1000 mg/kg di(2-ethylhexyl) phthalate showed clear foetotoxicity, embryolethality and teratogenicity. No significant effects were recorded at 40 and 200 mg/kg. Di-711-phthalate, a phthalic ester with linear components and a predominantly alpha-methyl branching type, and di-isopentylphthalate showed a very similar spectrum of effects. Interestingly, the alcohol moiety of di-711-phthalate, 711-alcohol was developmentally inactive in a previous experiment. Di-iso-decylphthalate and three types of di-iso-nonylphthalate showed foetal effects of borderline significance at 1000 mg/kg/day.
Food and Chemical Toxicology 06/1997; 35(5):501-12. · 3.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: 2-Ethylhexanol (2EH) is a weak nongenotoxic hepatic peroxisome proliferator in the rat. It is a high-volume chemical intermediate in the preparation of the plasticizers bis-(2-ethylhexyl) adipate (DEHA), bis-(2-ethylhexyl) phthalate (DEHP), and tris-(2-ethylhexyl) phosphate (TEHP), which are weak hepatocellular tumorigens in female mice. In consequence, the oncogenic potential of 2EH was evaluated in male (M) and female (F) rats and mice (50 animals/sex/group). Oral gavage doses of 2EH in 0.005% aqueous Cremophor EL (polyoxyl-35 castor oil) were given five times a week to rats: 0 (water), 0 (vehicle), 50, 150, and 500 mg/kg for 24 months, and to mice: 0 (water), 0 (vehicle), 50, 200, and 750 mg/kg for 18 months. Statistical comparisons of data were made between vehicle controls and treatment groups. There were no differences of biological significance between data from vehicle and water control groups. In rats, there were no dose-related changes at 50 mg/kg. There was reduced body weight gain at 150 mg/kg (M, 16; F, 12%) and 500 mg/kg (M, 33; F, 31%) and an increased incidence of lethargy and unkemptness. There were dose-related increases in relative liver, stomach, brain, kidney, and testis weights at sacrifice. Female rat mortality was markedly increased at 500 mg/kg. There was marked aspiration-induced bronchopneumonia in rats at 500 mg/kg; hematologic, gross, and microscopic changes, including tumors, were otherwise comparable among all rat groups. In mice at 50 and 200 mg/kg there were no dose-related changes and essentially no time-dependent or time-independent adverse trends in liver tumor incidence at the 5% significance level. At 750 mg/kg mouse body weight gain was reduced (M, 26; F, 24%), and mortality increased (M and F, 30%) versus vehicle controls. At 750 mg/kg there was a slight increase in nonneoplastic focal hyperplasia in the forestomach of mice (M 5/50, F 4/50) versus vehicle controls (M 1/50, F 1/50). There were increases in mouse relative liver (F, 21%) and stomach (M, 13%; F, 19%) weights at 750 mg/kg. There was a 12% incidence of hepatic basophilic foci and an 18% incidence of hepatocellular carcinomas in male mice at 750 mg/kg, not statistically significant compared with either control by Fisher's exact test. There was a 12% incidence of hepatic basophilic foci and a 10% incidence of hepatocellular carcinomas in female mice at 750 mg/kg, statistically significant (p < 0.05) compared with vehicle but not with water controls by Fisher's exact test. There were no metastases. Time-dependent and -independent statistical analyses showed an adverse trend in the incidence of hepatocellular carcinomas in male and female mice, correlated with toxicity (expressed as mortality) at 750 mg/kg. The time-adjusted incidence of hepatocellular carcinomas in male mice (18.8%) was within the historical normal range at the testing facility (0-22%), but that in females (13.1%) lay outside the normal range (0-2%). Under the conditions of these studies 2EH was not oncogenic in rats, but there were weak adverse trends in hepatocellular carcinoma incidence in mice at high dose levels which may have been associated with toxicity. The major effects of chronic dosing were mortality in female rats at 500 mg/kg and in male and female mice at 750 mg/kg, accompanied by reductions in body weight gain in rats at 150 and 500 mg/kg and in mice at 750 mg/kg. Direct comparison of any tumorogenic effects of 2EH given alone to female mice with those due to 2EH formed in vivo from DEHA, DEHP, or TEHP is limited by the high mortality caused by 2ER in female mice at equivalent doses of 2EH. While 2EH may be a contributing factor in the hepatocellular carcinogenesis in female mice associated with the chronic administration of DEHA and DEHP, it is unlikely to be the entire proximate carcinogen.
Fundamental and Applied Toxicology 06/1996; 31(1):29-41.
[show abstract][hide abstract] ABSTRACT: Diethylene glycol was tested for prenatal toxicity after oral administration (gavage) to pregnant Himalayan rabbits. The substance was administered to 15 female rabbits per group by stomach tube in daily doses of 100, 400, or 1000 mg/kg body wt from Day 7 postinsemination (p.i.) through Day 19 p.i. The control group received the vehicle only (twice distilled water). There were no compound-related effects on the dams concerning food consumption, body weight, body weight gain, or clinical or necropsy observations even at the highest dose of 1000 mg/kg body wt/day. All data obtained on gestational parameters also revealed no biologically relevant differences between the control and treated groups. The fetal external, soft tissue, and skeletal findings, which were classified as malformations, variations, and/or retardations, were seen in the treated fetuses at a frequency similar to the corresponding and/or historical controls. Thus, under the conditions of this study, no signs of maternal toxicity or embryo-/fetotoxicity were induced by diethylene glycol. Therefore, a no-observable-adverse-effect level for diethylene glycol of > 1000 mg/kg body wt/day was established for both the maternal and the developing Himalayan rabbit.
Fundamental and Applied Toxicology 11/1995; 28(1):27-33.
[show abstract][hide abstract] ABSTRACT: 3-Methyl-1-butanol (MEB) and 2-methyl-1-propanol (MEP) were tested for their prenatal inhalation toxicity in pregnant Wistar rats or Himalayan rabbits. Twenty-five female rats and 15 female rabbits per group were exposed to MEB and MEP vapors at concentrations of 10, 2.5, or 0.5 mg/liter, 6 hr/day. The rats were exposed on Days 6-15 postcoitum (pc) and the rabbits were exposed on Days 7-19 postinsemination (pi). Control groups were exposed to clean air. The body weights of the animals of either species were determined several times throughout the studies. All rats and all rabbits were killed on Day 20 pc and Day 29 pi, respectively. The fetuses were removed from the uterus and examined for compound-related effects. The high concentration of 10 mg/liter caused a slight retardation of body weight gain in the dams of either species exposed to MEB and in the dams of rabbits exposed to MEP during the first days of the exposure period. Eye irritation was observed only in the MEB-treated rabbits during the period of exposure to 10 mg/liter. The fetuses of either species exhibited no signs of embryo-/fetotoxicity or teratogenic effects caused by MEP or MEB. Under the experimental conditions, 2.5 mg/liter was found to be a no-observable-adverse-effect level (NOAEL) for the dams of either species exposed to MEB and for the does exposed to MEP, whereas 10 mg/liter MEP was the NOAEL for the maternal rats. For both substances 10 mg/liter was defined as the NOAEL for the conceptuses of either species.
Fundamental and Applied Toxicology 09/1995; 27(1):77-89.