Toxicity report series最新文献

Toxicology studies of cobalt sulfate heptahydrate (99%percnt; pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to a cobalt sulfate heptahydrate aerosol 6 hours per day, 5 days per week, for 16 days or 13 weeks. In 16-day studies, all rats and mice exposed at the top concentration of 200 mg cobalt sulfate/m3 died (5 animals per group); partial survival was seen in the 50 mg/m(3) exposure groups. Degeneration of the olfactory epithelium and necrotizing inflammation occurred in the nose of all rats and mice that died and in animals exposed to 50 mg/m(3). Necrotizing inflammation was observed in the larynx and trachea of rats and mice at concentrations as low as 5 mg/m(3), and a similar lesion was present in the bronchi at exposure concentrations of 50 mg/m(3) or higher. Regenerative and inflammatory lesions, including peribronchial and septal fibrosis in the lung, were found in rats and mice exposed to 50 mg/m(3). In 13-week studies, all rats, all female mice, and all but 2 male mice exposed at the top concentration survived to the end of the studies (target exposure concentrations of 0, 0.3, 1, 3, 10, and 30 mg/m(3), 10 animals per group). Rats and mice exposed to 30 mg/m(3) lost weight during the first exposure week and then gained weight at the same rate as controls. Lung weights were increased over those of controls in rats exposed at concentrations as low as 1 mg/m(3) and in mice exposed to 10 mg/m(3) or more. Polycythemia was observed in rats exposed to cobalt sulfate but not in mice. Sperm motility was decreased in mice exposed at 3 mg/m(3) or at higher concentrations (lower concentrations were not evaluated), and increased numbers of abnormal sperm were found in mice exposed to 30 mg/m(3). Testis and epididymal weights were decreased in mice exposed to 30 mg/m(3). Cobalt content in the urine of rats increased with increasing atmospheric cobalt exposure. Lesions seen in the respiratory tract in 13-week studies in rats and mice included degeneration of the olfactory epithelium, squamous metaplasia of the respiratory epithelium, and inflammation in the nose; inflammation, necrosis, squamous metaplasia, ulcers (rats), and inflammatory polyps (rats) of the larynx; squamous metaplasia of the trachea (mice); and histiocytic infiltrates, bronchiolar regeneration, peribronchiolar and septal fibrosis, and epithelial hyperplasia in the alveoli of the lung. The most sensitive tissue was the larynx, with squamous metaplasia observed in rats and mice at the lowest exposure concentration of 0.3 mg/m(3). Thus, a no-observed-adverse-effect level was not reached in these studies. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

Thirteen-week inhalation toxicity studies of n-hexane were conducted with B6C3F1 mice of each sex exposed to 0, 500, 1,000, 4,000, or 10,000 ppm, 6 hours per day, 5 days per week or to 1,000 ppm, 22 hours per day (referred to as 1,000c), 5 days per week. All mice lived to the end of the studies. The final mean body weights of mice exposed to 1,000c ppm or 10,000 ppm were 10% or 17% lower than that of the controls for males and 0% or 6% lower for females. Hematologic analyses were performed on whole blood samples collected at the end of the 13-week exposure. Segmented neutrophils were significantly increased in male mice exposed to 10,000 ppm. A battery of behavioral measurements was conducted on mice, and the only parameter affected was locomotor activity, which was decreased in female mice at 1,000c ppm and 10,000 ppm. The test battery performed included forelimb and hind limb grip strength, motor activity and exploratory behavior, acoustic startle response, foot splay, and analgesia response. Compound-related lesions of the nasal turbinates were seen in all groups of exposed mice except males exposed to 500 or 4,000 ppm. At the 10,000-ppm concentration, nasal lesions included inflammatory, erosive, and regenerative lesions of the olfactory and respiratory epithelium; luminal exudation and metaplastic lesions of the olfactory epithelium; and fibrosis of the submucosa. Lymphoid hyperplasia of the mandibular lymph nodes and neutrophilic hyperplasia of the bone marrow were also seen. At lower concentrations, lesions were not present in all mice and were limited to minimal regeneration or metaplasia of the olfactory epithelium. A few paranodal swellings in the teased fibers of the tibial nerve were observed in 3/4 males and 3/4 females exposed to 10,000 ppm, 3/4 males and 3/4 females exposed to 1,000c ppm, and 0/4 male and 0/4 female controls; the severity of the lesions was minimal. Neither segmental demyelination nor distal axonal degeneration was seen. Exposure of mice to n-hexane at concentrations up to 10,000 ppm resulted in only minimal toxicity. Paranodal swellings seen in nerves at 1,000c ppm and at 10,000 ppm were considered to be minimal nerve damage that would not result in paralysis. Exposure- related lesions of the nasal cavity occurred after n-hexane exposure, but minimal or no effects were seen at 1,000 ppm or below. Synonyms: Hexyl hydride. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

Two-week and 13-week toxicity studies of hexachloro-1,3-butadiene incorporated in the diet were conducted in B6C3F1 mice. Groups of five mice of each sex received diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm hexachloro-1,3-butadiene for 15 days. Toxic responses in the 2-week studies, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough hair coats, light sensitivity, and/or in coordination), deaths (all mice in the two highest dose groups died by day 7), body and organ weight depression, and gross and histopathologic changes. The most prevalent microscopic lesion, seen in all hexachloro-1,3-butadiene-dosed mice, was renal tubular cell necrosis and/or regeneration. Regeneration was seen in lower dose groups. In addition to kidney lesions, histopathologic changes were also seen in the liver (hepatocyte necrosis, cytoplasmic vacuolization), lymphoid tissues (lymph node necrosis, depletion), and testis (seminiferous tubule giant cells) of mice in the two highest dose groups which died during the first week of the studies. Thirteen-week studies were conducted in which groups of 10 mice per sex received 0,1, 3,10, 30, or 100 ppm hexachloro-1,3-butadiene in feed (corresponding to doses of 0, 0.1, 0.4, 1.5, 4.9, or 16.8 mg/kg per day for males and 0.2, 0.5, 1.8, 4.5, or 19.2 mg/kg per day for females). No compound-related clinical signs or deaths were observed. Compared with controls, body weight gain was reduced in males receiving 30 and 100 ppm (-49% and -56%, respectively) and females receiving 100 ppm (-47%). Kidney weights were reduced in the males receiving 30 and 100 ppm and females receiving 100 ppm. A compound-related increase in tubular cell regeneration in the renal cortex occurred in male and female mice. This lesion, characterized by a diffuse increase in basophilia of the tubular epithelial cytoplasm and an increase in the number of nuclei, increased in severity with increased dose. The motility of sperm from dosed mice was lower, though not dose related, than that from controls. Female mice were more susceptible to the toxicity of hexachloro-1,3-butadiene than male mice. Based on the histopathologic evaluations, the no-observed-adverse-effect level appeared to be 10 ppm for the male mice in this 13-week study; no such level was identified for the female mice. Synonyms: HCBD; hexachlorobutadiene; 1,1,2,3,4,4-hexachloro-1,3- butadiene; perchlorobutadiene; C 46; Dolen-Pur, (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

Toxicity studies were conducted by administering D&C Yellow No. 11 (approximately 99%percnt; pure) in feed at dietary concentrations of up to 50,000 ppm to groups of F344/N rats and B6C3F1 mice of each sex for 14 days or 13 weeks. A separate study was conducted to determine the effects of feeding diets containing D&C Yellow No. 11 to female rats during a reproductive cycle and to their offspring. Although the estimated intake of D&C Yellow No. 11 by mice was more than twice that by rats, the results of the 14-day and 13- week studies were similar for both rats and mice. In both species, D&C Yellow No. 11 caused no deaths (5 animals per group in the 14- day studies and 10 per group in the 13-week studies) but did reduce body weight gain slightly in rats of each sex exposed to 17,000 or 50,000 ppm. Liver weights were increased in dosed rats and mice. There was minimal-to-mild degeneration of the periportal portion of the liver lobules of rats at dietary concentrations of 1,700 ppm and higher and of mice at 5,000 ppm and higher. A dose- related yellow-brown pigment was observed in hepatocytes, Kupffer cells, and biliary epithelium of the liver of each sex and species and in the tubular epithelium of the kidney of rats of each sex. Hepatocellular degeneration progressed slightly in severity with increased time of exposure (i.e., 14 days to 13 weeks) in rats but not in mice. The number and size of hyaline droplets in the tubular epithelium of the cortex and outer medulla of the kidney were increased in all dosed groups of male rats. In a perinatal toxicity study, body weight gain of rat dams given diets containing as much as 50,000 ppm D&C Yellow No. 11 for 4 weeks before mating to unexposed males was similar to that of controls at the time of mating but was lower at parturition and weaning. However, fertility, gestation length, litter size, and pup birth weights were unaffected by exposure. At weaning, body weights of pups from all dosed dams (5,000, 17,000, and 50,000 ppm) were lower than weights of pups from the controls. After exposure to DC Yellow No. 11 for 4 weeks through the milk and to feed containing the same dietary concentrations that the dams received, weights of the 5,000-ppm pups were similar to those of the controls, but weights of the 17,000- and 50,000-ppm dose groups remained depressed. Microscopic evaluation showed lesions in the pups in all dosed groups; these lesions were similar to those described in the liver and kidney of rats in the 14-day and 13-week studies, including the male rat kidney cytoplasmic alterations. The results of these studies indicate that compound-related effects occurred at all dietary concentrations of DC Yellow No. 11; i.e., liver weights were increased in dosed rats and mice, and there was an increase in the number and size of hyaline droplets in all dosed groups of male rats. Synonyms: 2-(2-quinolyl)-1,3-indanedione; Arlosol Yellow S; Chinoline Yellow D soluble in spirits; Chinoline ZSS; CI 47000;

Thirteen-week studies were conducted to investigate potential differences in rat strain susceptibility to 1,2-dichloroethane toxicity. F344/N rats, Sprague Dawley rats, Osborne-Mendel rats, and B6C3F1 mice (10 animals of each sex) were exposed to 1,2- dichloroethane in drinking water at 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm for 13 weeks. In addition, Groups of 10 F344/N rats of each sex were administered 1,2-dichloroethane in corn oil by gavage to compare toxicity resulting from bolus administration with that of continuous exposure in drinking water. Gavage doses of 1,2-dichloroethane were within the range of daily doses resulting from exposure in drinking water. No compound-related deaths occurred in any of the rat strains exposed to 1,2-dichloroethane in drinking water. Weight gain depression was common in each sex of all three rat strains in the 4,000 and 8,000-ppm groups throughout the studies. Water consumption was decreased by 50%-60% with increasing dose for all exposed male and female rats regardless of strain. Kidney and liver weights were increased in dosed rats of all three strains. No chemical-related lesions were observed except for a dose- related incidence of renal tubular regeneration in female F344/N rats. Nine of 10 female mice exposed to 8,000 ppm 1,2-dichloroethane in drinking water died before the end of the study. Mean body weights of males at 500 ppm or more and females at 1,000 ppm or more were lower than those of controls throughout most of the studies. Kidney weights were significantly increased for dosed males and females. Renal tubular cell regeneration was seen in males at 8,000 ppm; at 4,000 ppm, minimal regeneration was present in 8/10 male mice. All male F344/N rats that received 240 or 480 mg/kg and 9/10 females that received 300 mg/kg 1,2-dichloroethane by gavage died before the end of the studies. Mean body weights of the highest dose males and females were lower than those of vehicle controls throughout the studies. Liver and kidney weights were increased for dosed males and females; however, no compound-related lesions were observed. Necrosis of the cerebellum, hyperplasia, inflammation, and mineralization of the forestomach, and necrosis of the thymus were seen in animals that died or were killed in moribund condition. Rat strain differences in susceptibility to 1,2-dichloroethane toxicity were not apparent at the drinking water concentrations used in these studies; only female F344/N rats exhibited mild chemical related renal lesions. Male B6C3FI mice appeared to be more susceptible than rats to toxicity of 1,2-dichloroethane administered in drinking water; renal tubule regeneration was observed in male mice in the 4,000- and 8,000-ppm groups. The higher toxicity in mice was likely due to higher water consumption, resulting in up to tenfold higher doses to mice than to rats. 1,2-Dichloroethane administered in drinking water resulted in less toxicity to F344/N rats than administration of similar dos

Toxicity studies were conducted by administering acetone (greater than 99%percnt; pure) in drinking water to groups of F344/N rats and B6C3F1 mice of each sex for 14 days or 13 weeks. Fourteen-Day Studies: All rats and mice receiving concentrations as high as 100,000 ppm acetone in drinking water lived to the end of the 14-day studies. The mean body weights of male rats receiving 50,000 or 100,000 ppm and female rats given 100,000 ppm were lower than those of controls. Body weights of all groups of mice were similar. Kidney and liver weight to body weight ratios for exposed rats and mice were greater than those for controls. Histopathologic changes were not seen in these organs in rats or in the kidney in mice. Centrilobular hepatocellular hypertrophy was noted in male and female mice receiving 20,000 and 50,000 ppm acetone, respectively. Thirteen-Week Studies: All rats lived to the end of the 13-week studies (drinking water concentrations as high as 50,000 ppm). The final mean body weights of rats receiving 50,000 ppm were 19%percnt; lower than that of controls for males and 7%percnt; lower for females. Water consumption by all rats that received 50,000 ppm acetone and females that received 20,000 ppm or more was notably lower than that by controls. Liver and kidney weight to body weight ratios were increased for male and female rats receiving 20,000 ppm or greater. Caudal and right epididymal weights and sperm motility were decreased for male rats given 50,000 ppm, and the percentage of abnormal sperm was increased. Leukocytosis and thrombocytopenia were observed at 20,000 ppm and above (males and females), and reticulocytopenia and erythrocytopenia were seen at 5,000 ppm and above (males). These changes, in addition to increase in erythrocyte size (MCV), are consistent with macrocytic anemia. Splenic pigmentation (hemosiderosis) noted in dosed male rats was apparently related to these changes. The increased incidence and severity of nephropathy observed in dosed male rats were considered the most prominent chemically related findings in this study. All mice lived to the end of the 13-week studies (drinking water concentrations up to 20,000 ppm for males and up to 50,000 ppm for females). The final mean body weights of dosed and control mice were similar. Water consumption by female mice that received 50,000 ppm acetone was notably lower than that by controls. The absolute liver weight and the liver weight to body weight ratio were significantly increased for females receiving 50,000 ppm, and the absolute spleen weight and the spleen weight to body weight ratio were significantly decreased. Results from the hematologic analyses did not show any biologically significant effects. Centrilobular hepatocellular hypertrophy of minimal severity was seen in 2110 female mice receiving 50,000 ppm. No compound-related lesions were found in male mice. In summary, the results from these studies show that acetone is mildly toxic to rats and mice when a

Toxicology studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to 1,2,4,5-tetrachlorobenzene (greater than 99%percnt; pure) at various concentrations in formulated diets for 14 days or 13 weeks. Dietary concentrations were 0, 30, 100, 300, 1,000, or 3,000 ppm 1,2,4,5-tetrachlorobenzene in the 14 day studies. All rats survived to the end of the studies, but all mice in the 3,000-ppm groups died (five animals per group). Histologically, exposed male rats had an accumulation of abnormal hyaline droplets in the renal cortical epithelium. Significant histologic lesions were not seen in female rats or in mice of either sex. Dietary concentrations were 0, 30, 100, 300, 1,000, or 2,000 ppm 1,2,4,5-tetrachlorobenzene in the 13-week studies (10 animals per group). All rats survived to the end of the studies; two female mice in the 2,000-ppm group were killed in a moribund condition. Body weight gains in the higher dose groups of rats and mice were less than those of controls. In exposed male rats, lesions included renal cortical tubular epithelial hyaline droplet formation, cortical tubular regeneration, and medullary granular casts and mineralization. This spectrum of renal lesions in male rats is consistent with the entity described as "hydrocarbon or hyaline droplet nephropathy." In some exposed female rats (30- to 2,000-ppm groups), there was renal cortical tubular cell regeneration plus accumulation of an unidentified yellow-brown pigment in the renal cortical epithelium. Centrilobular hepatocellular hypertrophy was observed in the livers of exposed male and female rats. In mice, minimal-to-mild centrilobular hepatocellular hypertrophy was present in males in the 1,000 and 2,000-ppm groups and in females in the 2,000-ppm group. Minimal-to-mild individual hepatocyte degeneration occurred in mice of each sex in the 2,000-ppm groups. Increased serum sorbitol dehydrogenase and alanine aminotransferase activity was observed in the two highest dose groups of male and female mice and indicated hepatocellular injury. Thyroid follicular cell hypertrophy was present in male rats in the 300- to 2,000-ppm groups and in female rats in the 100- to 2,000-ppm groups. Decreased free thyroxin and total thyroxin concentrations in male rats in the 300- to 2,000 ppm groups and female rats in the 30- to 2,000-ppm groups indicated a primary hypothyroid state. Hematologic findings for rats that received 1,000 or 2,000 ppm included significantly decreased hematocrit values, hemoglobin concentration, and erythrocyte counts for males and decreased mean cell volume for females; for mice, decreased hemoglobin concentrations, mean corpuscular hemoglobin, hematocrit, and mean cell volume were observed in males in the 2,000-ppm group and in females in the 1,000- and 2,000-ppm groups. These findings suggest a poorly regenerative anemia in both species. The no-observed-effect level (NOEL) for histologic lesions was 30 ppm for male and female rats