Investigations on the subchronic toxicity of 2-methoxypropanol-1(acetate) in rats.

Wistar rats were exposed to 2-methoxypropylacetate-1 (2-MPAc-1) vapours in concentrations of 0, 110, 560 and 2800 ppm for (equiv. to 0; 0.6; 3.0 and 14.9 mg/L) for 4 weeks in chambers (6 hours/day; 5 days/week; five male and five female animals per group). The top concentration was equivalent to a 95% vapour saturation at 20 degrees C and the animals reacted to this with a moderate respiratory irritation during the 6 hours exposure times; at 560 ppm these effects were only slight. The top dose was also associated with a significantly reduced body weight development and some hematologic and biochemical alterations of little specificity. The most prominent effect was thymic atrophy. No effects were noted on the testes or on the cellularity in blood or bone marrow. 560 ppm were without systemic effects. Furthermore, 2-methoxypropanol-1 (2-MP-1), 2-MPAc-1 and 2-ethoxyethanol (EE) were administered in parallel by gavage to groups of five male Wistar rats daily for 10 days at near equimolar dose levels (1800, 2600 and 1800 mg/kg per day, respectively). At the end of the administration period the testes were investigated. There was a pronounced testicular atrophy in animals exposed to EE, whereas no adverse effects were observed with 2-MP-1 and 2-MPAc-1. The results of these studies indicate that 2-MP-1 and 2-MPAc-1 which previously had been shown to exert pronounced prenatal toxicity in rabbits and weak prenatal effects in rats are devoid of other forms of systemic toxicity in rats that are typically observed with ethoxyethanol and methoxyethanol.

Aniline: early indicators of toxicity in male rats and their relevance to spleen carcinogenicity.

Early indicators of aniline hydrochloride (AH) toxicity were investigated in male Fisher 344 rats for 1 or 4 weeks at dietary dose levels of 10, 30 or 100 mg/kg body weight (bw)/day (actual intake at least 6, 17 and 57 mg/kg). The doses were based on earlier studies that had shown spleen toxicity and carcinogenicity in male rats at 100 mg/kg/day but not at 10 mg/kg/day. In the present study a dose-related formation of haemoglobin adducts and Heinz bodies was found from 10 and 30 mg/kg bw/ day, respectively, onwards. Signs of anaemia (decreased red blood cell counts and increased reticulocytes) were recorded from 30 mg/kg onwards. At 100 mg/kg, an overt haemolytic anaemia was associated with increases in serum transferrin concentration and total iron binding capacity in the blood reflecting major perturbations in iron metabolism. At this dose there was an increase in peripheral neutrophil leucocytosis in the blood, indicating an inflammatory process in the spleen. Histopathologic evaluation showed a focal perisplenitis and haemosiderin deposition in sinusoidal Kupffer cells of the liver at 100 mg/kg. These results corroborate the contention that carcinogenic doses of aniline cause early effects on haematological parameters, inflammatory reaction in the spleen and perturbations in iron metabolism as a result of haemolytic anaemia. Accordingly, the carcinogenicity of aniline may be linked to definable threshold-related processes.

Biomonitoring of aromatic amines VI: determination of hemoglobin adducts after feeding aniline hydrochloride in the diet of rats for 4 weeks.

The assessment of the carcinogenic properties of aniline is still controversial. Aniline has, if at all, genotoxic properties but is also acutely toxic and it has been proposed that the hematotoxic effects are responsible for the formation of hemangiosarcomas and fibrosarcomas in the spleen of male rats. As part of a bigger project in which the pathology of male Fischer F344 rats was studied after feeding 10, 30, or 100 mg/kg body weight aniline hydrochloride for 1 and 4 weeks in the diet, the aniline-hemoglobin (Hb) adducts were determined as a biochemical effect marker during those periods. An improved method for the work-up procedure and the adduct analysis was developed for this purpose. The Hb adduct levels increased proportionately with dose after 1 week, which indicates that metabolic activation was not saturated. After 4 weeks of feeding, the adduct levels increased less than proportionately, which suggests that a saturation process is involved. Since it is unlikely that metabolic activation was saturated, the results could be explained by a more rapid clearance of stressed erythrocytes at the carcinogenic dose level. The latter interpretation is supported by other observations which indicate that erythrocytes are damaged dose dependently. A no-observed-effect level (NOEL) has not been reached but could be close to the low dose of 10 mg/kg body weight per day. The Hb adduct formation at the low dose, however, indicates that this should not be considered a no-effect level (NEL). The results support the conclusion that hemolytic anemia is an essential prerequisite for aniline toxicity and tumor development, but they do not fully explain the tissue specificity.

NTA and Fe(III)NTA: differential patterns of renal toxicity in subchronic studies.

Differential patterns in terms of nephropathology and 8-hydroxyguanine formation in the course of oral 28-day studies were observed with nitrilotriacetic acid (NTA) and FeNTA. FeNTA, but not NTA, caused enhanced 8-hydroxyguanine formation in kidney DNA after oral and intraperitoneal administration. Enhanced lipid peroxidation in the kidney homogenate was observed with FeNTA as well as with NTA. For NTA, the low dose (9 mg/kg per day) was without adverse effect. The kidney toxicity of oral FeNTA (50, 200, and 1000 mg/kg per day) was only mild, 50 mg/kg per day; however, it still led to an increased 8-hydroxyguanine content. The relevance of Iron(III) (Fe(III)) or Fe(III)NTA formation as a relevant mediator of NTA-related toxicity was excluded on the basis of these data. Also, a thermodynamic consideration presented here, supports the view that zinc (Zn), and not Fe, is likely to mediate the tubular cell cytotoxicity of NTA.

Effects of ethylene glycol and metabolites on in vitro development of rat embryos during organogenesis.

The aim of this study was to investigate in vitro the relative impact of ethylene glycol, a major industrial chemical, and its individual metabolites on the embryonic development of rats. Rat whole embryos were exposed for 48 h (day 9.5-11.5 of gestation) to ethylene glycol (EG) and its metabolites glycolaldehyde (GAl), glycolic acid (GA), glyoxylic acid (GXA), glyoxale (GXAl) and oxalic acid (OXA) at increasing concentrations. Embryotoxic concentrations were achieved within the following range: ethylene glycol (100-200 mM), glycolic acid (3 mM), glyoxal (6 mM), oxalic acid (1-3 mM), glyoxylic acid (0.3-1 mM), glycolaldehyde (0.1-0.2 mM). The pattern of dysmorphogenesis with all compounds including EG showed a general embryotoxicity with diffusely distributed cell necroses with no specific target tissues selectively affected. The results obtained in this study emphasize the hypothesis that the metabolites and not ethylene glycol itself are responsible for the embryotoxicity of ethylene glycol in rats.

Uterotrophic assay of two concentrations of migrates from each of 23 polystyrenes administered orally (by gavage) to immature female Wistar rats.

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.

Different patterns of kidney toxicity after subacute administration of Na-nitrilotriacetic acid and Fe-nitrilotriacetic acid to Wistar rats.

Na-nitrilotriacetic acid (Na3NTA) and Fe-nitrilotriacetic acid (FeNTA) have both been described to cause tumors in the urinary tract of rodents. However, these effects were observed using different modes of administration at extremely different dose levels and explained by different mechanisms. Whereas FeNTA causes an iron overload of cells and is genotoxic in various assays, Na3NTA is predominantly bound to zinc in vivo and thereby causes cytotoxic effects in the urinary tract. In contrast to FeNTA, Na3NTA requires high dose levels to produce tumors. The aim of this study was to compare the effects of Na3NTA and FeNTA on cellular proliferation, histopathology, lipid peroxidation, and 8-OH-2'-deoxyguanosine levels in the kidneys as well as on the urinary excretion of Ca, Fe, and Zn. For evaluation of DNA synthesis both compounds were administered for 1 or 4 weeks to 14-week-old male Wistar rats at a tumor causing dose, Na3NTA via the diet at 150 ppm and 20,000 ppm (approximately 9 and approximately 1000 mg/kg/day) and FeNTA i.p. at 25 mg/kg/day. An osmotic minipump, containing 20 mg/ml BrdU, was implanted subcutaneously 7 days before necropsy. Na3NTA showed nearly no effect on DNA replication after 1 week but a strong reaction after 4 weeks. The increase was 10- to 18-fold in different renal compartments. The enhancement of proliferation in the proximal tubules was nearly twice that in the distal tubules. In contrast, FeNTA caused DNA replication during the first week, and this was restricted to the proximal tubules. After 4 weeks there was an 18-fold increase in the outer stripe and no effect in the inner stripe of the outer medulla. The data presented give evidence to the assumption that both substances increase cell proliferation as a compensatory mechanism, causing different pattern of tubular proliferation in terms of time course and affected cell types. Both Na3NTA at 20,000 ppm and FeNTA led to increased lipid peroxidation, whereas increased levels of 8-OH-2'-deoxyguanosine were observed only after treatment with FeNTA. Urinary excretion of Zn was increased 30-fold after administration of 20,000 ppm Na3NTA but only 2-fold after administration of FeNTA. Urinary excretion of Ca and Fe remained unchanged after treatment with either Na3NTA and FeNTA. These results show that the Na3NTA-related proliferative effects are not mediated by an internal formation of FeNTA.

Potency of monomethyl-, dimethylformamide and some of their metabolites to induce abnormal development in a limb Bud organ culture.

DMF, NMF and their major metabolites were investigated for their developmental toxicity in the mouse limb bud assay. We found that neither DMF, NMF nor the predominant urinary metabolite HMFF exhibited developmental activity. In contrast, all metabolites resulting from the glutathione binding pathway, SMG, SMC and AMCC showed potent developmental activity. Under the chosen exposure conditions, the developmental toxicity of DMF in different species appears to be related to the magnitude of glutathione binding. The results further show the value of using an in vitro system which is incapable of metabolic transformation of exogenous compounds for the identification of ultimate teratogenic species.

Differential prenatal toxicity of one straight-chain and five branched-chain primary alcohols in rats.

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.

Differential prenatal toxicity of branched phthalate esters in rats.

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.

Investigation of the prenatal toxicity of orally administered diethylene glycol in rabbits.

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.

Prenatal toxicity of inhalation exposure to 2-methoxypropanol-1 in rabbits.

2-Methoxypropanol-1 was investigated for prenatal toxicity in Himalayan rabbits after inhalation exposure to 0, 145, 225, 350, and 545 ppm for 6 hr per day from Gestation Day 6 through 18. Maternally toxic effects were found with decreased body weights from Day 12 of gestation through the end of the study at 545 ppm. A dose-dependent increase of resorptions, fetal malformations, and variations was observed at 225, 350, and 545 ppm, whereas 145 ppm was devoid of exposure-related effects. The malformation rate at 545 ppm was 100%. The types of malformations mainly consisted of absent phalanges and absent or rudimentary metatarsal bones, malformed ribs, and a unique enlargement of sternebrae. The effects are very similar to those previously found with 2-methoxypropyl-acetate-1. The results of this study may have implications for the quantitative estimation of risks associated with 2-methoxy-propanol-1 impurities in the widely used isomer 1-methoxypropanol-2 which itself does not show developmental toxicity.

Evaluation of the genotoxicity of 4-diethylamino-4'-nitroazobenzene and seven analogues.

A series of eight nitroaromatic azo compounds based on 4-diethylamino-4'-nitroazobenzene has been examined for genotoxic activity in a collaborative study conducted under the auspices of the Ecological and Toxicological Association of Dyes and Organic Pigments Manufacturers (ETAD). The evaluation has been conducted in two parts, firstly an examination in vitro to assess any intrinsic genotoxic activity of the compound. The chemicals were examined in the Salmonella assay in a standard plate incorporation protocol in both the presence and absence of S9 and in a minimum of the four tester strains recommended in the OECD guideline for this assay, i.e. TA1535, TA1537, TA98 and TA100. All of the compounds were mutagenic in one or more of the Salmonella tester strains, and all were positive in TA98 with S9. A considerable range of potency was seen in this assay. The chemicals were further examined in vitro for mammalian cell gene mutation at either the HGPRT or TK locus in a standard (CHO, V79 or L5178Y) cell system. Only one of the chemicals was mutagenic and only with S9. This chemical also showed the most potent response in the Salmonella assay. The second part of the study was an examination in vivo to see whether any genotoxic activity was expressed in the whole animal. The in vivo rat liver DNA repair (unscheduled DNA synthesis; UDS) assay was chosen as being the most likely to be sensitive to aromatic nitroazo compounds. All of the materials were negative when tested alongside a structurally related positive control. The chemicals were also examined in the mouse bone marrow micronucleus assay in order to provide a second in vivo assessment.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of mutagenicity testing with Salmonella typhimurium TA102 in three different laboratories.

Thirty compounds of various chemical classes were investigated for mutagenicity in a collaborative study (three laboratories) using Salmonella typhimurium TA102. With five compounds, hydrazine sulfate, phenylhydrazine, hydralazine, glutardialdehyde, and glyoxal, mutagenicity was detected by all laboratories. Formaldehyde was assessed as weakly mutagenic in only one of three laboratories. The remaining 24 agents were uniformly described as non-genotoxic in TA102. In spite of the overall good qualitative agreement in the mutagenicity results between the three laboratories, some quantitative discrepancies occurred in the dose response of the mutagenic compounds. Varying inter- and intralaboratory differences in the spontaneous rate of revertants were obtained. The usefulness of the tester strain TA102 in routine mutagenicity testing is discussed.

Di-(2-ethylhexyl) phthalate: a short-term repeated inhalation toxicity study including fertility assessment.

In a study of the 28-day inhalation toxicity of di-(2-ethylhexyl) phthalate (DEHP) aerosols, 9-wk-old Wistar rats, 27 males (mean weight 226 g) and 17 females (mean weight 155 g) per group, were exposed in head-nose inhalation systems to DEHP aerosols of respirable particle size (mass median aerodynamic diameter < or = 1.2 microns) or air (controls). Exposure for 6 hr per day, 5 days per wk for 4 wk to target concentrations of 0, 0.01, 0.05 and 1.0 mg/litre gave estimated doses of 230, 11 and 2.3 mg/kg/day for the males, and 360, 18 and 3.6 mg/kg/day for females, on the assumption of 100% deposition and absorption. Clinical investigation and blood chemistry parameters did not reveal any treatment-related effects. At the end of exposure a statistically significant (16%) increase in relative lung weights, accompanied by increased foam-cell proliferation and thickening of the alveolar septi, was found in the males of the highest dose group. Absolute liver weights were significantly (8.75%) increased in females and relative liver weights were increased in both sexes in the highest dose group, but there were no corresponding histological effects. All these effects were reversed during the 8-wk post-exposure period. No testicular toxicity was observed histologically and no impact on mating performance and male fertility was detected after two matings of treated males with untreated females, 2 and 6 wk after the end of exposure. Electron microscopic examination of liver samples from two male and two female rats per group at the end of exposure and after the 8-wk post-exposure period did not reveal clear substructural changes that could be attributed to exposure or to peroxisome proliferation. The no-observed-effect level for all exposure-related findings was 0.05 mg/litre under the conditions used.

Collaborative study of mutagenicity with Salmonella typhimurium TA102.

Thirty compounds of various chemical classes were investigated for mutagenicity in a collaborative study (3 laboratories) using Salmonella typhimurium TA102. With 5 compounds, namely hydrazine sulfate, phenylhydrazine, hydralazine, glutardialdehyde and glyoxal, mutagenicity was detected by all laboratories. Formaldehyde was assessed as weakly mutagenic in only 1 of 3 laboratories. The remaining 24 agents were uniformly described as non-genotoxic in TA102. In spite of the overall good qualitative agreement in the mutagenicity results between the 3 laboratories some quantitative discrepancies occurred in the dose response of the mutagenic compounds. Varying inter- and intra-laboratory differences in the spontaneous rate of revertants were obtained. The usefulness of the tester strain TA102 in routine mutagenicity testing is discussed.

Studies on the prenatal toxicity of N,N-dimethylformamide in mice, rats and rabbits.

Prenatal toxicity studies with N,N-dimethylformamide (DMF) in rabbits, rats and mice were carried out using the oral (gavage), dermal, inhalation and ip injection routes of administration. Administration of DMF by gavage led to an increase in malformations in rats and mice in the absence of overt maternal toxicity. The lowest-observable-effect level was 182 mg/kg body weight/day in mice and 166 mg/kg body weight/day in rats. After dermal administration a dose-dependent incidence of teratogenicity was observed in rats at 94-944 mg/kg/body weight/day in the absence of overt maternal toxicity. In rabbits dermal administration led to a steeper increase in the dose-response relationship and at 400 mg/kg body weight/day to a clear teratogenic effect in the presence of slight maternal toxicity. The 200 mg/kg body weight/day dose appeared to be the no-adverse-effect level. Inhalation in rats caused foetotoxicity and embryolethality at 287 ppm. A clear teratogenic effect was shown in rabbits at 450 ppm and a marginal effect at 150 ppm. The no-effect level for does and foetuses was 50 ppm. Ip injection in mice caused clear teratogenicity at 944 mg/kg body weight/day and slight embryotoxicity at 378 mg/kg body weight/day. The rabbit appears to be more sensitive than the rat to DMF-related prenatal toxicity and should, therefore, be used as the basis for the evaluation of teratogenic risk in humans.

Examination of potential mechanisms of carcinogenicity of 1,4-dioxane in rat nasal epithelial cells and hepatocytes.

Several long-term studies with 1,4-dioxane (dioxane) have shown it to induce liver tumors in mice, and nasal and liver tumors in rats when administered in amounts from 0.5 to 1.8% in the drinking water (Argus et al. 1965; Kociba et al. 1974; National Cancer Institute, 1978). In order to examine potential mechanisms of action, chemically-induced DNA repair (as an indicator of DNA reactivity) and cell proliferation (as an indicator of promotional activity) were examined in nasal turbinate epithelial cells and hepatocytes of male Fischer-344 rats treated with dioxane. Neither dioxane nor 1,4-dioxane-2-one, one of the proposed metabolites, exhibited activity in the in vitro primary rat hepatocyte DNA repair assay, even from cells that had been isolated from animals given either 1 or 2% dioxane in the drinking water for 1 week to induce enzymes that might be responsible for producing genotoxic metabolites. No activity was seen in the in vivo hepatocyte DNA repair assay in animals given a single dose of up to 1000 mg/kg dioxane or up to 2% dioxane in the drinking water for 1 week. Treatment of rats with 1.0% dioxane in the drinking water for 5 days yielded no increase in liver/body weight nor induction of palmitoyl CoA oxidase, indicating that dioxane does not fit into the class of peroxisomal proliferating carcinogens. The percentage of cells in DNA synthesis phase (S-phase) was determined by administration of 3H-thymidine and subsequent quantitative histoautoradiography. The hepatic labeling index (LI) did not increase at either 24 or 48 h following a single dose of 1000 mg/kg dioxane.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental toxicity in rats after inhalation exposure of di-2-ethylhexylphthalate (DEHP).

Di-2-ethylhexylphthalate (DEHP) was investigated in Wistar rats for developmental toxicity after head-nose exposure to aerosol concentrations of 0, 0.01, 0.05 and 0.3 mg/l for 6 h per day from gestation day 6 through 15. A range finding study revealed peroxisome proliferation in the liver of the dams throughout exposure levels of 0.2, 0.5 and 1.0 mg/l with an increasing trend. 0.3 mg/l was therefore regarded as an exposure level leading to peroxisome proliferation as a marker for maternal effects. All concentrations were tolerated without clinical signs of maternal toxicity. The fetuses of 20 animals per exposure group were investigated for structural defects. Five additional animals per group were allowed to litter and the offsprings were raised and observed for postnatal signs of toxicity. No significant developmental toxicity or changes in the postnatal physical development were observed. DEHP is assumed not to exhibit developmental toxicity under the experimental conditions employed.

Prenatal toxicity of 2-methoxypropylacetate-1 in rats and rabbits.

2-Methoxypropylacetate-1 was investigated in Wistar rats and Himalayan rabbits for embryotoxic potential. Rats after inhalation exposure to 0, 0.6, 3.0, or 14.9 mg/liter (approximately 0, 110, 550, or 2700 ppm, respectively) for 6 hr per day from gestation Days 6 through 15 exhibited some degree of maternal toxicity at 2700 and 550 ppm. At 2700 ppm an increase of skeletal anomalies of the thoracic vertebrae among the fetuses was observed and interpreted as an exposure-related slight teratogenic effect. In Himalayan rabbits exposed via inhalation to 0, 0.2, 0.8, or 3.0 mg/liter (approximately 0, 36, 145, or 550 ppm, respectively) for 6 hr per day from gestation Days 6 through 18 teratogenicity was much more pronounced: at 550 ppm, in the absence of clear maternal toxicity, the fetuses of all litters showed severe malformations. No maternal or fetal effects were observed at 145 and 36 ppm. Dermal application of 1000 and 2000 mg/kg to Himalayan rabbits from gestation Days 6 through 18 failed to produce maternal or fetal toxicity.