Developmental toxicity of oral and inhaled vinyl acetate in the rat.

Vinyl acetate (VA) is used almost exclusively as an industrial chemical in polymerization, copolymerization, or as a chemical intermediate. The present studies were undertaken as part of a collaborative effort by the VA producers of Western Europe, Japan, and the United States to provide animal toxicology data for risk assessment. To assess the potential of VA causing developmental toxicity in rodents, groups of 23 or 24 Crl:CD(SD)BR rats were given 0, 200, 1000, or 5000 ppm VA in drinking water or exposed 6 hr/day to 0, 50, 200, or 1000 ppm VA vapors on Days 6-15 of gestation (both routes approximately 0, 25, 100, or 500 mg/kg/day). Administration of VA in the drinking water produced no evidence of maternal or developmental toxicity. A significantly lowered water intake was observed in dams from the 5000 ppm VA group and probably reflected unpalatability of the VA water solution at the highest dose level. In the inhalation study, maternal toxicity was evident by a marked reduction in weight gain of dams exposed to 1000 but not 200 or 50 ppm VA. Fetal toxicity was evident by a statistically significant decrease in mean fetal weight and mean crown-rump length in fetuses from the 1000-ppm VA group. In addition, there was a statistically significant increase in the incidence of minor skeletal alterations in fetuses from dams exposed to 1000 ppm VA. Delayed ossification was the main skeletal alteration. In summary, pregnant rats were relatively insensitive to the effects of VA administered in the drinking water at a concentration level as high as 5000 ppm. However, VA did adversely affect both the dam and the conceptus at an inhaled concentration of 1000 ppm, but not at lower exposure levels. These results indicate that VA is not uniquely toxic to the conceptus. The no-observed-effect level for the dam and conceptus under these experimental conditions was greater than 5000 ppm for the drinking water study and was 200 ppm for the inhalation study.

A two-generation reproduction study in rats receiving drinking water containing vinyl acetate.

Vinyl acetate (VA) is a commonly used chemical in polymerization and copolymerization processes and as a chemical intermediate. As part of a collaborative effort between VA producers of the United States and British Petroleum, the present study was carried out to provide a base set of data for risk assessment. Groups of male and female Crl:CD(SD)BR rats were given 0, 200, 1000, or 5000 ppm VA via the drinking water over two generations. In addition, a cross-mating trial of control and 5000-ppm male and female rats was conducted in the F1 generation to investigate the slightly decreased litter production in the high-dose group. No treatment-related mortality was observed in any of the groups. Water consumption was significantly reduced in the 5000-ppm groups in both generations and in the 1000-ppm F1 female rats. The body weights of the F0 and F1 male rats and the F1 female rats in the 5000-ppm group tended to be slightly lower than those of the control group. Body weight gain was significantly decreased during lactation in the F0 females at 5000 ppm and in the F1 females at 1000 and 5000 ppm. Pup weights in the F1 generation, but not in the F2 generation, were significantly lower than those of the control on lactation Day 21. The number of litters produced in the F1 generation in the 5000-ppm group was slightly lower than that of the control group and was attributed to lower fertility. Fewer pups were produced when control females were mated with the 5000-ppm males; however, the decrease was due to poor mating performance rather than decreased fertility. No decrease was apparent when the 5000-ppm females were mated with the control group males. Under the conditions of this study, the no-observed adverse effort level was considered to be 1000 ppm.

Chronic toxicity and oncogenicity study with vinyl acetate in the rat: in utero exposure in drinking water.

The purpose of this study was to evaluate vinyl acetate for potential chronic toxicity and oncogenicity when given to rats in drinking water from the time of gestation. Target concentrations were 0, 200, 1000, and 5000 ppm (v/v). Drinking water solutions were prepared daily and analyzed at approximately 4-week intervals. F0 rats were given solutions of vinyl acetate for 10 weeks and then mated. Offspring (F1 rats) were culled to equal group sizes of 60 main study rats and 30 rats for satellite groups. F1 rats were treated for up to 104 weeks with interim kills of satellite groups at 52 and 78 weeks. Body weights and clinical signs of toxicity were monitored in F0 and F1 rats. Food and water consumption were measured in F1 rats. At Weeks 52 and 78 of the test, clinical pathology and urine analysis examinations were conducted on 10 rats per group from satellite animals. A complete gross and histopathological examination of F1 rats was conducted at the interim kills and on main study rats at Week 104. Average vinyl acetate consumption over the course of the study in male rats of the 200, 1000, and 5000 ppm groups was 10, 47, and 202 mg/kg/day, respectively. Female rats consumed an average of 16, 76, and 302 mg/kg/day, respectively. Compound-related effects observed during the study included a concentration-related decrease in water consumption among rats of the 1000 and 5000 ppm groups and a decrease in food consumption among rats of the 5000 ppm groups. Concurrent body weight decrement was observed only in the 5000 ppm groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse.

Vinyl acetate was evaluated for chronic toxicity and oncogenicity in male and female rats and mice in a 104-week study. Target concentrations were 0, 50, 200, and 600 ppm. The study included interim terminations at approximately 53 and 83 weeks and a group whose exposure was terminated at 70 weeks and allowed a 15-week recovery period. Over the course of the exposures, body weight gain was consistently depressed in all 600 ppm groups and in the 200 ppm mice. Except for female rats of the 600 ppm exposure group, recovery animals showed significant improvements in weight gain relative to controls. There were no changes in hematological parameters of either species that could be unequivocally related to treatment. The only effect noted on clinical chemical parameters during the study were decreases in blood glucose in the 600 ppm females. There were no adverse effects on survival in either species. Increases in lung weight were noted in rats and mice primarily in the 600 ppm groups. These changes were associated with bronchial exfoliation, macrophage accumulation, and fibrous plaques and buds extending into the airway lumen, and bronchial/bronchiolar epithelial disorganization. The most significant histopathological changes were noted in the nasal cavity. In the olfactory epithelium of both rats and mice, the main nonneoplastic changes included epithelial atrophy, regenerative effects (squamous metaplasia and respiratory metaplasia of olfactory epithelium), basal cell hyperplasia, and epithelial nest-like infolds. No nonneoplastic changes were observed in the respiratory epithelium of rats, while squamous metaplasia at the naso/maxilloturbinate region was prevalent in mice. Nonneoplastic changes were similar in the recovery groups. Oncogenic responses to vinyl acetate exposure were mainly confined to the nasal cavity in rats and included endo- and exophytic papillomas, squamous cell carcinoma, carcinoma in situ in olfactory regions, and endophytic papilloma in respiratory regions. Squamous cell carcinomas were also found either in areas normally covered by cuboidal epithelium or areas of unknown origin. One squamous cell carcinoma was found in the larynx of a rat of the 600 ppm groups. One squamous cell carcinoma was found in the lung of a mouse of the 600 ppm group.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicokinetics of [14C]hexafluoroacetone in the rat.

The disposition and metabolism of [14C]hexafluoroacetone (HFA) were studied in the rat as part of an investigation of the mechanism of HFA-induced testicular atrophy. After sc injection of 13 mg/kg [14C]HFA, radioactivity was eliminated in a biphasic manner from the blood; the half-life of the initial phase was 22.6 hr and that of the elimination phase 75.1 hr. Following injection of 130 mg/kg [14C]HFA, the elimination of radioactivity was initially zero order, but with time it became first order and biphasic with half-lives of the initial and terminal elimination phases being 23.0 and 59.9 hr, respectively. The primary route of elimination was via the urine and all of the [14C]HFA was excreted unmetabolized. [14C]HFA was uniformly distributed throughout the major organs of the body with the exception of the liver which contained disproportionately higher levels of [14C]HFA. The hepatic binding of [14C]HFA was noncovalent and capacity limited. Notably, the testes, the target organ of HFA-induced toxicity, did not exhibit any unusual accumulation or retention of [14C]HFA.

In vivo formation of nitrosocarbamates in the stomach of rats and guinea pigs.

The N-nitrosocarbamates are potent mutagens and carcinogens, and have been synthesized under acid conditions that prevail in the human stomach. However, it has never been documented that nitrosocarbamates are actually formed in vivo in the stomach of any mammalian species. Using 14C-labeled carbaryl and carbofuran, attempts were made to isolate the nitroso derivatives from the stomach contents of rats and guinea pigs treated orally with the carbamate and sodium nitrite. Only trace quantities of nitrocarbamate were recovered from the rat stomach, whereas 0.5 to 2.0% of the carbamate doses were isolated as the nitroso derivative from the contents of the guinea pig stomach. The rather low apparent yields resulted in part from the instability of the nitrosocarbamates and from absorption of the carbamate and/or nitrosocarbamate from the stomach. Higher rates of synthesis were indicated by incubating the carbamates with sodium nitrite in the presence of the stomach contents at 37 degrees C for 15 min. About 30% nitrosation occurred with the guinea pig and about 0.5% with the rat. The difference was attributed to the pH of the gastric contents. For the rat, the pH ranged from 3 to 5; gastric contents of the guinea pig had a pH between 1 and 2. Since the pH of the human stomach is also in the pH 1-2 range, it is likely that nitrosation of carbamates in humans would be very similar to that in the guinea pig.