UMLS:C0023380 - FACTA Search

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Query: UMLS:C0023380 (lethargy)
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Each morning for a month female subjects placed either 5 alpha-androst-16-en-3 alpha-ol, a putative human pheromone, or a placebo on the upper lip. Each evening the subjects rated on five scales their moods during that day. In the middle of their monthly cycle those females exposed to androstenol rather than a control tended to rate their moods as submissive rather than aggressive. The compound did not significantly influence ratings of being happy/depressed; lethargic/lively; sexy/unsexy; irritable/good-tempered. The results are discussed in terms of the possible increased olfactory sensitivity of the human female to androstenol in the middle of her monthly cycle.
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PMID:The influence of androstenol - a putative human pheromone - on mood throughout the menstrual cycle. 689 8

Fischer 344 rats (250-300 g) were exposed to the resulting aerosols from the pyrolysis of Spectrex Fire Extinguishant (SFE) Formulation A, a pyrotechnically generated aerosol fire suppressant, at a loading equivalent of 50 or 80 g m(-3) air for 15 or 60 min. Exposures were conducted in a 700-1 whole-body inhalation chamber under static conditions. The chamber atmosphere was analyzed for mass aerosol concentration and size distribution. Clinical observations were taken throughout the exposure. Animals were euthanized at 1 h, 6 h, 24 h, 7 days or 14 days post-exposure and underwent histopathological examination, enzyme analyses and wet/dry lung weight determination. No deaths occurred during the study. Animals exhibited signs of dyspnea, coughing, lack of coordination and lethargy during each exposure. These signs became more pronounced as the load and exposure length increased. No lesions were noted in the trachea, lung, heart or abdominal organs upon gross examination. A reversible pulmonary edema and olfactory necrosis were observed only in those animals exposed to an SFE loading equivalent to 80 g m(-3) for 60 min. Protein concentrations increased in the bronchoalveolar lavage but no changes in enzyme levels were observed. There was no significant difference between the control groups and the exposure groups for wet/dry lung weight determination.
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PMID:Evaluation of the respiratory tract after acute exposure to a pyrotechnically generated aerosol fire suppressant. 918 52

Cyclododecatriene (CDDT, CAS No. 4904-61-4) was tested for its inhalation toxicity in rats following repeated exposures. Male rats were exposed nose-only to CDDT for 6 hr/day, 5 days/wk for a total of 9 exposures over 2 weeks. Particular attention was paid to neurotoxicologic endpoints. Concentrations of 0 (control), 5, 50, and 260 ppm were studied. The 260 ppm chamber contained both vapor and aerosol while the 5 and 50 ppm chambers were vapor only. Four groups of 10 rats each were used to measure standard clinical signs and growth, clinical pathology (including hematology, biochemistries, and urine analysis), and tissue pathology. Another 4 groups of similar size were used for neurotoxicity testing. In the standard toxicity groups, 1/2 of the rats were sacrificed 1 day following the 9th exposure; the other half underwent a 2-week recovery period prior to being sacrificed (recovery group). During the exposures rats inhaling 260 ppm had a diminished or absent response to an alerting stimulus. Irregular respiration and lethargy were observed in these rats immediately following exposure. These signs were rapidly reversible and were not seen prior to the subsequent exposure. Body weights in rats exposed to either 50 or 260 ppm were significantly lower than the corresponding controls. No compound-related clinical pathology changes were seen in any of the test groups and tissue pathology effects only occurred in the nasal tissue. In rats exposed to 260 ppm, minimal degeneration/necrosis of nasal olfactory epithelium was observed in rats examined immediately following the exposure period. This change was not seen in the recovery rats. Functional observational battery (FOB) assessments and motor activity (MA) evaluations conducted after the 4th and 9th exposures on rats from all test groups, and specific neuropathologic evaluation on perfused brain, spinal cord, and skeletal muscle from rats exposed to 260 ppm failed to demonstrate any specific neurotoxicity. Outward signs of sedation were seen at the top level tested. Under the conditions of this test, the no-observed-adverse-effect level (NOAEL) was determined to be 5 ppm based upon a reduced rate of body weight gain in the 50 ppm group. No specific neurotoxicity was detected and the histopathologic response was limited to reversible changes in the nasal epithelia in rats exposed to 260 ppm.
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PMID:Inhalation toxicity of cyclododecatriene in rats. 1044 57

Mature female natural dark mink (Mustela vison) were fed 0.0006 (control), 0.016, 0.053, 0.180, or 1.40 ppb 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 131-132 d to ascertain the chronic toxic effects of TCDD in mink, including reproduction. Consumption of the 1.4 ppb TCDD diet resulted in lethargy, bloody stools, and 16.7% mortality. Final mink body weights were inversely proportional to the dietary TCDD concentrations. Due to subnormal mink breeding, definitive effects of TCDD on mink reproductive performance were not ascertained; however, there were significant dose-dependent decreases in kit (young mink) birth weight and survival from birth to 3 w of age in the groups that had reproduction. There were also significant differences in adult minkwhite blood cell counts, plasma total solids, serum iron, phosphorus, albumin, total protein, total CO2, cholesterol, osmolality, and anion gap concentrations, and alanine aminotransaminase activity between the various dietary groups. During the latter stages alopecia and thickened, deformed, and elongated toenails were observed in the adult mink fed 1.4 ppb TCDD. At termination the mink fed 1.4 ppb TCDD had ascites, gastric ulcers, intestinal hemorrhages, depletion of adipose tissue, and mottled and/or discolored livers, spleens, and kidneys. Focal lymphocytic meningitis in region of the olfactory bulb was present in 42% of the mink fed 1.4 ppb TCDD. These results confirmed the high sensitivity of mink to TCDD and revealed a toenail abnormality not previously reported for mink fed TCDD.
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PMID:Chronic toxicity of dietary 2,3,7,8-tetrachlorodibenzo-p-dioxin to mink. 1138 52

Methacrylonitrile is an aliphatic nitrile used extensively in the preparation of homo- and copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, esters, and other nitriles. This aliphatic nitrile is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer. Methacrylonitrile was nominated for toxicity and carcinogenicity testing by the National Cancer Institute due to its high production volume and extensive use, the lack of chronic or carcinogenicity data, and its structural resemblance to the known rat carcinogen acrylonitrile. The current 13-week studies were conducted as part of an overall effort by the NTP to assess the toxicity and carcinogenicity of methacrylonitrile. During the 13-week studies, groups of 20 male and 20 female F344/N rats were administered 0, 7.5, 15, 30, 60, or 120 mg methacrylonitrile/kg body weight in deionized, purified water by gavage. Groups of 20 male and 20 female B6C3F1 mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg/kg methacrylonitrile. Ten male and ten female rats and mice from each group were evaluated on day 32. The results of these studies clearly revealed that male rats are more sensitive than females to methacrylonitrile treatment. In the rat study, 19 males and one female administered 120 mg/kg and two males administered 60 mg/kg died during the first week of the study. Males in the 60 mg/kg group at the 32-day interim evaluation and at 13 weeks and females in the 120 mg/kg group at 13 weeks had significantly lower final mean body weights and body weight gains than did the vehicle controls; the surviving male in the 120 mg/kg group also weighed less than the controls at the 32-day interim evaluation. Clinical findings of toxicity were dose dependent and included lethargy, lacrimation, tremors, convulsions, ataxia, and abnormal breathing. There was hematologic evidence indicating that administration of methacrylonitrile induced minimal, normocytic, normochromic anemia. At the 32-day interim evaluation, a minimal dose-related anemia was evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts in male and female rats. The anemia ameliorated by week 13. Administration of methacrylonitrile resulted in dose-related increases in serum thiocyanate and blood cyanide concentrations of male and female rats. These changes were expected and would be consistent with the in vivo metabolism of methacrylonitrile to cyanide. Blood cyanide concentrations were generally higher in males than in females, which may explain the higher sensitivity of males to the lethal effect of methacrylonitrile. There was also biochemical evidence of increased hepatocellular leakage and/or altered function in dosed male rats, suggesting that the liver may be a target organ for toxic effects of methacrylonitrile. Minimal, but significant, decreases in absolute right kidney and thymus weights (32-day interim evaluation) and increases in liver and stomach weights (week 13) occurred in male rats that received 60 mg/kg compared to the vehicle controls. In female rats, stomach weights of the 60 and 120 mg/kg groups were significantly greater and thymus weights of the 120 mg/kg group were significantly less than those of the controls on day 32 and at week 13; liver weights were also significantly greater in females in the 120 mg/kg group than in the vehicle controls on day 32. Male and female rats administered 60 mg/kg and females administered 120 mg/kg had significantly greater incidences of metaplasia of the nasal olfactory epithelium on day 32 and at the end of the study than did the vehicle controls; incidences of olfactory epithelial necrosis were also significantly greater in females in the 60 and 120 mg/kg groups than in the vehicle controls on day 32. Incidence and/or severity increased with increasing dose in females; however, the mortality in male rats administered 120 mg/kg made it difficult to assess the dose-response relationship in males. The no-observed-adverse-effect level for the nasal cavity of rats was 30 mg/kg. Female rats administered 60 or 120 mg/kg methacrylonitrile had significantly longer estrous cycles than did the vehicle controls. Females in the 60 mg/kg group spent more time in diestrus than the vehicle controls. One male and one female mouse in the 12 mg/kg groups died early. Methacrylonitrile administration caused no significant differences in final mean body weights or body weight gains. Clinical findings included lethargy, tremors, ataxia, convulsions, and abnormal breathing. At the 32-day interim evaluation, stomach weights of males administered 3 mg/kg or greater were significantly greater and thymus weights of males in the 12 mg/kg group were significantly less than those of the vehicle controls. At week 13, however, the stomach weights of only males in the 12 mg/kg group were increased relative to the vehicle controls. No treatment-related histopathologic lesions occurred in mice. Methacrylonitrile did not induce mutations in any of several strains of Salmonella typhimurium, with or without S9 activation, and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster fed methacrylonitrile during the larval stage. Results of in vivo bone marrow micronucleus tests with methacrylonitrile in male rats and mice were also negative. In summary, gavage administration of methacrylonitrile to rats and mice resulted in dose-dependent lethargy, tremors, lacrimation, convulsions, and abnormal breathing. However, these effects were more pronounced in rats than mice; these differences may be attributed to the higher doses of methacrylonitrile administered to rats. Body weight gain and survival data of rats demonstrated that males are more sensitive to methacrylonitrile dosing than females. There is an apparent correlation between blood cyanide concentrations and survival rates, with males having greater cyanide concentrations and lower survival rates than female rats administered methacrylonitrile. Microscopically, the only target of methacrylonitrile toxicity was the olfactory epithelium of the nasal cavity. Necrotic and metaplastic effects were induced in male and female rats that received 60 or 120 mg/kg per day. No similar lesions were observed in mice administered methacrylonitrile. The no-observed-adverse-effect level for olfactory epithelial lesions in male and female rats administered methacrylonitrile for 13 weeks was 30 mg/kg per day. No clear chemical-related effects were observed in male or female mice administered methacrylonitrile for 13 weeks by gavage at doses up to 12 mg/kg per day.
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PMID:NTP technical report on the toxicity studies of methacrylonitrile (CAS No. 126-98-7). Administered by gavage to F344/N rats and B6C3F1 mice. 1180 6

2-Butoxyethanol is a member of a family of ethylene glycol monoalkyl ethers. It is used extensively as a solvent in surface coatings such as lacquers, enamels, varnishes, and latex paint; in paint thinners, paint stripping formulations, and inks; and in degreasers and industrial and household cleaners. 2-Butoxyethanol was nominated for study because of its widespread use in industrial and consumer applications, the potential for exposure to workers and the general population, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to 2-butoxyethanol (greater than 99% pure) by inhalation (primary route of human exposure) for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and the bone marrow of male F344/N rats and B6C3F1 mice. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours per day, 5 days per week for 14 weeks. One female rat in the 250 ppm group was killed moribund during week 8; four females in the 500 ppm group were killed moribund during week 1 and one during week 5. Final mean body weights of females exposed to 500 ppm were significantly less than those of the chamber controls. Clinical findings included abnormal breathing, pallor, red urine stains, nasal and eye discharge, lethargy, and increased salivation and/or lacrimation. Due to vascular thrombosis and infarction in the tail vertebrae of 500 ppm female rats, the tails became necrotic and either sloughed off or were chewed off. The primary effect on the hematopoietic system was an anemia characterized as macrocytic, normochromic, and regenerative in males exposed to 125 ppm or greater and, to a greater extent, in all exposed groups of females. Compared to the chamber controls, kidney weights of males exposed to 500 ppm and females exposed to 125 ppm or greater and liver weights of males exposed to 250 or 500 ppm and females exposed to 125 ppm or greater were significantly increased, and thymus weights of females exposed to 500 ppm were significantly less. In female rats killed moribund, there was considerable histologic evidence of thrombosis in tissues and organs including the nasal cavity, incisors, liver, lung, and heart. In addition to thrombosis, infarction occurred in the vertebrae of the tail resulting in necrosis and loss of the distal portion of the tail. There were also inflammation, necrosis, and ulceration of the forestomach; necrosis and centrilobular degeneration of the liver; renal tubule degeneration; and atrophy of the spleen and thymus. Exposure-related increases in the incidences of Kupffer cell pigmentation, forestomach inflammation and epithelial hyperplasia, bone marrow hyperplasia, splenic hematopoietic cell proliferation, and renal tubule pigmentation were observed in male and/or female rats surviving to the end of the study. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours per day, 5 days per week for 14 weeks. Two male and two female mice exposed to 500 ppm died and two males and two females were killed moribund during the first 2 weeks of the study. Final mean body weights of 125, 250, and 500 ppm male mice were significantly less than those of the chamber controls. Clinical findings were observed only in 500 ppm males and females that died or were killed moribund and included abnormal breathing, red urine stains, and lethargy. Hematologic evaluation indicated an anemia that was characterized as normocytic, normochromic, and regenerative in mice exposed to 62.5 ppm or greater; the anemia was more pronounced in females. Liver weights of males exposed to 500 ppm were significantly greater than the chamber controls. In mice either dying early or killed moribund, there were inflammation, necrosis, and ulceration of the forestomach; mediastinal pleura and peritoneal inflammationmmation associated with the forestomach lesions; liver necrosis; renal tubule degeneration; atrophy of the spleen, thymus, and mandibular and mesenteric lymph nodes; and degeneration of the testis. Exposure-related increases in the incidences of hematopoietic cell proliferation and hemosiderin pigmentation of the spleen, Kupffer cell hemosiderin pigmentation of the liver, inflammation and epithelial hyperplasia of the forestomach, and renal tubule hemosiderin pigmentation occurred in male and/or female mice surviving to the end of the study. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 31.2, 62.5, or 125 ppm, 6 hours per day, 5 days per week for 104 weeks. For hematology and bone marrow analyses, additional groups of 27 male and 27 female rats were exposed to 0, 62.5, or 125 ppm for evaluation at 3, 6, and 12 months and nine male and nine female rats were exposed to 31.2 ppm for evaluation at 3 (hematology only) and 6 months. Survival and Body Weights: Survival of exposed male and female rats was similar to the chamber control groups. The mean body weights of females exposed to 125 ppm were generally less than the chamber control group. Hematology and Bone Marrow Cellularity: The most consistent exposure-related effect on the hematopoietic system was an exposure concentration-related mild macrocytic, normochromic, regenerative anemia present at 3, 6, and 12 months, with females more affected than males. Significant increases in bone marrow cellularity and decreases in the myeloid/erythroid ratio relative to the chamber controls were observed at all time points in females exposed to 125 ppm, and a decrease in the myeloid/erythroid ratio was observed in males exposed to 125 ppm at 12 months. Pathology Findings: The incidence of benign or malignant pheochromocytoma (combined) of the adrenal medulla in females exposed to 125 ppm was not significantly increased compared to the chamber controls but exceeded the historical control range. Exposure-related increases in the incidences of hyaline degeneration of the olfactory epithelium and Kupffer cell pigmentation of the liver were observed in male and female rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 62.5, 125, or 250 ppm, 6 hours per day, 5 days per week for 104 weeks. For hematology and bone marrow analyses, additional groups of 30 male and 30 female mice were exposed to 0, 62.5, 125, or 250 ppm for evaluation at 3, 6, and 12 months. Survival and Body Weights: Survival of male mice exposed to 125 or 250 ppm was significantly less than that of the chamber control group. The mean body weights of exposed males were generally less than those of the chamber control group during the last 6 months of the study. The mean body weights of exposed female mice were less than those of the chamber control group; the reductions were greater and occurred earlier than those observed in males. Hematology: The most consistent exposure-related effect on the hematopoietic system was an exposure concentration-related minimal normocytic, normochromic, regenerative anemia present at 3, 6, and 12 months, with females affected slightly more than males. Pathology Findings: In females exposed to 250 ppm, incidences of forestomach squamous cell papilloma and squamous cell papilloma or carcinoma (combined) were significantly increased relative to the chamber controls, and these incidences exceeded the ranges in historical chamber controls. In 2-butoxyethanol exposed males, there were possible exposure-related increases in the incidences of squamous cell papilloma of the forestomach, although the increases were not significant and the incidences were within the historical control range for chamber controls. Accompanying these neoplasms in females and, to a lesser extent, in males were exposure-related increases in the incidences of ulcer and epithelial hyperplasia of the forestomach. In male mice exposed to 250 ppm, the incidence of hemangiosarcoma of the liver was significantly increased relative to chamber controls and exceeded the range in historical controls; in addition, there were possible exposure-related increases in the incidence of hepatocellular carcinoma. Incidences of hemosiderin pigmentation in the Kupffer cells were significantly increased in 125 and 250 ppm males and all exposed groups of females. The incidences of splenic hematopoietic cell proliferation and hemosiderin pigmentation were generally increased in males and females, and the incidences of bone marrow hyperplasia were increased in males. The incidences of hyaline degeneration of the olfactory and respiratory epithelia of the nose were increased in female mice. GENETIC TOXICOLOGY: 2-Butoxyethanol did not induce mutations in any of the S. typhimurium strains tested, with or without induced hamster or rat liver S9. 2-Butoxyethanol induced cycle delay but did not induce either sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells with or without S9. 2-Butoxyethanol did not induce micronuclei in bone marrow cells of male rats or mice administered the chemical by intraperitoneal injection three times at 24-hour intervals. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of 2-butoxyethanol in male F344/N rats exposed to 31.2, 62.5, or 125 ppm. There was equivocal evidence of carcinogenic activity of 2-butoxyethanol in female F344/N rats based on the increased combined incidences of benign or malignant pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence of carcinogenic activity of 2-butoxyethanol in male B6C3F1 mice based on increased incidences of hemangiosarcoma of the liver. A marginal increase in the incidences of forestomach squamous cell papilloma and an increase in the incidences of hepatocellular carcinoma may have been exposure related. There was some evidence of carcinogenic activity of 2-butoxyethanol in female B6C3F1 mice based on increased incidences of fore stomach squamous cell papilloma or carcinoma (mainly papilloma). Increased incidences of forestomach neoplasms in male and female mice occurred in groups in which ulceration and hyperplasia were also present. Exposure to 2-butoxyethanol caused a mild regenerative anemia and effects secondary to the anemia. Synonyms: 2-Butoxy-1-ethanol; m-butyl ether; butyl glycol; ethylene glycol monobutyl ether Trade name: Butyl Cellosolve
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PMID:NTP Toxicology and Carcinogenesis Studies 2-Butoxyethanol (CAS NO. 111-76-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 79

Nickel sulfate hexahydrate is used in nickel plating, as a mordant in dyeing and printing textiles, as a blackening agent for zinc and brass, and in the manufacture of organic nickel salts. Nickel sulfate hexahydrate was nominated by the National Cancer Institute to the NTP as part of a class study of nickel compounds for which there was little information on the toxic and carcinogenic effects of inhalation exposure. Male and female F344/N rats and B6C3F1 mice were exposed to nickel sulfate hexahydrate (greater than 98% pure) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in L5178Y mouse lymphoma cells. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel sulfate hexahydrate/m(3) (equivalent to 0, 0.7, 1.4, 3.1, 6.1, or 12.2 mg nickel/m(3)). Rats were exposed on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of four or five male and female F344/N rats were exposed to 0, 3.5, 15, or 30 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, two 60 mg/m(3) males, one 30 mg/m(3) female, and all 60 mg/m(3)females died before the end of the study. Final mean body weights of all exposed groups of males and females were significantly lower than those of the controls, as were mean body weight gains of male rats. Clinical findings included increased rates of respiration and reduced activity levels in rats in all exposure groups, except those exposed to 3.5 mg/m(3). Absolute lung weights of 60 mg/m(3) males and of all exposed groups of females were significantly greater than those of the controls, as were the relative lung weights of all exposed groups of males and females. Inflammation (including degeneration and necrosis of the bronchiolar epithelium) occurred in the lungs of all exposed groups of males and females. Atrophy of the olfactory epithelium occurred in the nasal passages of all exposed groups of males (except 60 mg/m(3)) and in 15, 30, and 60 mg/m(3) females. Lymphoid hyperplasia in the bronchial or mediastinal lymph nodes was observed in 30 mg/m(3) males and in 60 mg/m(3) males and females. The concentration of nickel in the lungs of all exposed groups of males and females was greater than in control animals. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel sulfate hexahydrate/m(3). Mice were exposed on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of five male and five female B6C3F1 mice were exposed to 0 or 3.5 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. All core study mice exposed to 7 mg/m(3) or greater died before the end of the study; all control and 3.5 mg/m(3)mice survived to the end of the study. Final mean body weights and weight gains of 7, 15, 30, and 60 mg/m(3)males and females were significantly less than those of the controls, and clinical findings in these groups included emaciation, lethargy, and rapid respiration rates. Absolute and relative lung weights of male and female mice exposed to 7 mg/m(3) or greater were significantly greater than those of the controls. Only tissues from mice exposed to 0, 3.5, or 7 mg/m(3) were examined histopathologically. Inflammation occurred in the lungs of 3.5 and 7 mg/m(3) males and females; necrosis of the alveolar and bronchiolar epithelium was a component of the inflammation in 7 mg/m(3)males and females. In addition, atrophy of the olfactory epithelium of the nasal passages was observed in 3.5 mg/m(3) males and females. Nickel concentrations in the lungs of mice exposed to 3.5 mg/m(3) were greater than those in the controls. 13-WEEK STUDY IN RATS: Groups of ten male and ten female F344/N rats were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulfate hexahydrate (equivalent to 0, 0.03, 0.06, 0.11, 0.22, or 0.44 mg nickel/m(3)), 5 days per week for 13 weeks. Additional groups of six male and six female F344/N rats were exposed to 0, 0.12, 0.5, or 2 mg nic mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, one 2 mg/m(3)male rat died before the end of the study; all other males and all females survived until the end of the study. Final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no significant clinical findings noted during the study. Exposure-related increases in neutrophil and lymphocyte numbers occurred and were most pronounced in female rats. With the exception of 0.12 mg/m(3)rats, absolute and relative lung weights of all exposed groups were generally significantly greater than those of the controls. Exposure-related increases in the incidence and severity of inflammatory lesions (alveolar macrophages, chronic inflammation, and interstitial infiltration) occurred in the lungs of all exposed groups of males and females. Lymphoid hyperplasia of the bronchial and/or mediastinal lymph nodes occurred in males exposed to 0.5 mg/m(3)or greater. Atrophy of the olfactory epithelium occurred in males and females exposed to 0.5, 1, and 2 mg/m(3)and in 0.25 mg/m(3)females. The concentration of nickel in the lungs of 0.5 and 2 mg/m(3) rats was greater than that in the lungs of control animals at 4, 9, and 13 weeks for males and at 13 weeks for females. 13-WEEK STUDY IN MICE: Groups of ten male and ten female B6C3F1 mice were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulfate hexahydrate, 5 days per week for 13 weeks. Additional groups of up to five or six male and female B6C3F1 mice were exposed to 0, 0.12, 0.5, or 2 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, four control males, three control females, and one 0.12 mg/m(3)male died before the end of the study; the deaths were not considered to be chemical related, and all other mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no chemical-related clinical findings. Hematology changes similar to those reported in female rats occurred in female mice, but the mice were minimally affected. The absolute and relative lung weights of 1 mg/m(3)males and 2 mg/m(3)males and females were significantly greater than those of the controls. Increased numbers of alveolar macrophages occurred in all males and females exposed to 0.5 mg/m(3)or greater. Chronic active inflammation and fibrosis occurred in 1 and 2 mg/m(3)males and females. Lymphoid hyperplasia of the bronchial lymph node and atrophy of the olfactory epithelium in the nasal passages were observed in 2 mg/m(3)males and females. Nickel concentration in the lung of 2 mg/m(3)females was significantly greater than in control animals. 2-YEAR STUDY IN RATS: Groups of 63 to 65 male and 63 to 64 female rats were exposed to nickel sulfate hexahydrate by inhalation at concentrations of 0, 0.12, 0.25, or 0.5 mg/m(3) (equivalent to 0, 0.03, 0.06, or 0.11 mg nickel/m(3)). Animals were exposed for 6 hours plus T90 (8 minutes) 5 days per week for 104 weeks. Five male and five female rats from each group were evaluated at 7 months for histopathology; an additional seven males and seven females from each group were evaluated at 7 months for nickel tissue burden in the lung and kidney; and five males and five females from each group were evaluated at 15 months for alterations in hematology, nickel tissue burden in the lung and kidney, and histopathology. Survival, Body Weights, Clinical Findings, and Hematology The survival rates of all exposed groups of males and females were similar to those of the controls. Mean body weights of 0.5 mg/m(3)female rats were slightly lower (6&percnt; to 9&percnt;) than those of the controls throughout the second year of the study; final mean body weights of all exposed groups of males and 0.12 and 0.25 mg/m(3)females were similar to those of the controls. There were no clinical findings or hematology differences that were considered to be related to nickel sulfate hexahydrate administration. Pathology Findings No exposure-related neoplasms occurred in male or female rats exposed by inhalation to nickel sulfate hexahydrate for 2 years. Increased incidences of inflammatory lung lesions were generally observed in all exposed groups of male and female rats at the end of the study. The incidences of chronic active inflammation, macrophage hyperplasia, alveolar proteinosis, and fibrosis were markedly increased in male and female rats exposed to 0.25 or 0.5 mg/m(3). Increased incidences of lymphoid hyperplasia in the bronchial lymph nodes occurred in 0.5 mg/m(3)male and female rats at the end of the 2-year study. The incidences of atrophy of the olfactory epithelium in 0.5 mg/m(3)males and females were significantly greater than those in controls at the end of the study. Tissue Burden Analyses Lung nickel burdens in exposed male and female rats were greater than those in the controls at the 7- and 15-month interim evaluations, and lung nickel burdens values increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 80 male and 80 female mice were exposed to nickel sulfate hexahydrate by inhalation at concentrations of 0, 0.25, 0.5, or 1 mg/m(3) (equivalent to 0, 0.06, 0.11, or 0.22 mg nickel/m(3)). Animals were exposed for 6 hours plus T90 (8 minutes) 5 days per week for 104 weeks. Five male and five female mice from each group were evaluated at 7 months for histopathology; five males and five females from each group were evaluated at 7 months for nickel tissue burden in the lung and kidney; five males and five females from each group were evaluated at 15 months for alterations in hematology and histopathology; and five males and five females from each group were evaluated at 15 months for nickel tissue burden in the lung and kidney. Survival, Body Weights, Clinical Findings, and Hematology The survival rates of all exposed groups of males and females were similar to those of the controls. The mean body weights of 1 mg/m(3)males and of all exposed groups of females were lower than those of the controls during the second year of the study. There were no clinical findings or hematology differences considered to be related to chemical exposure. Pathology Findings Inflammatory lesions of the lung generally occurred in all exposed groups of male and female mice at the end of the 2-year study. These lesions included macrophage hyperplasia, chronic active inflammation, bronchialization (alveolar epithelial hyperplasia), alveolar proteinosis, and infiltrating cells in the interstitium. Incidences of macrophage hyperplasia and/or lymphoid hyperplasia occurred in the bronchial lymph nodes of most of the 1 mg/m(3)males and females and in some 0.5 mg/m(3)females at the end of the 2-year study. Atrophy of the olfactory epithelium was observed in 0.5 and 1 mg/m(3)males and in all exposed groups of females at the end of the 2-year study. Tissue Burden Analyses At the 7- and 15-month interim evaluations, lung nickel burden parameters measured in control and exposed groups were below the limit of detection. Absolute lung weights of 0.5 and 1 mg/m(3)lung burden study females were significantly greater than those of the controls at 15 months. GENETIC TOXICOLOGY: Nickel sulfate hexahydrate (500 to 800 g/mL) was tested for induction of trifluorothymidine resistance in L5178Y mouse lymphoma cells. A positive response was observed in the absence of S9. The test was not performed with S9. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female F344/N rats exposed to 0.12, 0.25, or 0.5 mg/m(3) (0.03, 0.06, or 0.11 mg nickel/m(3)). There was no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female B6C3F1 mice exposed to 0.25, 0.5, or 1 mg/ m3 (0.06, 0.11, or 0.22 mg nickel/m(3)). Exposure of rats to nickel sulfate hexahydrate by inhalation for 2 years resulted in increased incidences of chronic active inflammation, macrophage hyperplasia, alveolar proteinosis, and fibrosis of the lung; lymphoid hyperplasia of the bronchial lymph node; and atrophy of the olfactory epithelium. Exposure of mice to nickel sulfate hexahydrate by inhalation for 2 years resulted in increased incidences of chronic active inflammation, bronchialization (alveolar epithelial hyperplasia), macrophage hyperplasia, interstitial infiltration, and alveolar proteinosis of the lung; lymphoid and macrophage hyperplasia of the bronchial lymph node; and atrophy of the olfactory epithelium. Synonyms: Blue salt; hexahydrate, nickel (2+) salt; nickel monosulfate hexahydrate; nickel (2+) sulfate hexahydrate; nickel (II) sulfate hexahydrate; nickel sulphate hexahydrate; nickelous sulfate hexahydrate; nickelous sulphate hexahydrate; single nickel salt, sulfuric acid
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PMID:NTP Toxicology and Carcinogenesis Studies of Nickel Sulfate Hexahydrate (CAS No. 10101-97-0) in F344 Rats and B6C3F1 Mice (Inhalation Studies). 1258 12

Isobutyl nitrite is used to a limited extent as an intermediate in the syntheses of aliphatic nitrites. It is also an ingredient of various incenses or room odorizers and is used as a euphoric. The chemical has also been used as a jet propellant and in the preparation of fuels. Isobutyl nitrite was nominated by the Consumer Product Safety Commission to the NTP for toxicology and carcinogenicity studies because of its possible contribution to the high incidence of Kaposi's sarcoma among male homosexual acquired immune deficiency syndrome patients and because of the lack of available data on the potential carcinogenicity of isobutyl nitrite. Male and female F344/N rats and B6C3F1 mice were exposed to isobutyl nitrite (purity of 93% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All males and females exposed to 600 or 800 ppm and one 400 ppm female died on the first day of the study. Final mean body weights and mean body weight gains of 400 ppm males and females were significantly lower than those of the controls. Clinical findings observed in 400 ppm males and females included ocular discharge, lethargy, hunched posture, and rough coats. Absolute and relative lung weights of all exposed groups of males and of 200 and 400 ppm females were less than those of the controls. Chemical-related hyperplasia of the bronchial epithelium was observed in 200 and 400 ppm males and females and hyperplasia of the nasal turbinate epithelium was observed in rats exposed to 400 ppm or less. Hemosiderin pigmentation was observed in the spleen of 200 and 400 ppm males and females and bone marrow hematopoietic hyperplasia was observed in rats exposed to 400 ppm or less. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. Three males and four females exposed to 800 ppm died before the end of the study. Final mean body weights and mean body weight gains of 600 and 800 ppm males and females were significantly lower than those of the controls. Mice exposed to 400 ppm or greater were lethargic and exhibited hunched posture and rough coats. Absolute and relative lung weights of 600 and 800 ppm males and the relative lung weight of 600 ppm females were significantly greater than those of the controls. Chemical-related hyperplasia of the bronchiolar epithelium was observed in all exposed groups of males and females. Lymphocytic atrophy of the spleen and thymus was observed in males and females exposed to 400 ppm or greater. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. All rats survived to the end of the study. Final mean body weights and mean body weight gains of 300 ppm males and females were significantly lower than those of the controls, as was the mean body weight gain of 150 ppm females. Clinical findings observed during the study included ruffled fur in 300 ppm males and females, hypoactivity in 300 ppm males, and hyperactivity in 150 and 300 ppm females. A very mild chemical-related methemoglobinemia and anemia occurred in male and female rats in the 75, 150, and 300 ppm groups. Hematopoietic hyperplasia occurred in the bone marrow of all exposed groups of males and females and was considered to be a secondary response to the anemia and methed methemoglobinemia. There was minimal hemosiderin pigment accumulation in the spleens of males and females exposed to 75 ppm or greater, mild to moderate epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males and females, and minimal hyperplasia occurred in 150 ppm males and females. Hyperplasia of the bronchial epithelium was observed in 300 ppm males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. There were no chemical-related deaths. Final mean body weights and mean body weight gains of 150 and 300 ppm females were significantly less than those of the controls. Final mean body weights and mean body weight gains of exposed groups of males were similar to those of the controls. There were no chemical-related clinical findings. A very mild chemical-related methemoglobinemia occurred in male and female mice in the 150 and 300 ppm groups. A very mild anemia occurred in the 300 ppm groups. In the lung, increased incidences of mild to moderate hyperplasia of the bronchiolar epithelium occurred in males and females exposed to 300 ppm. Minimal hyperplasia occurred in males exposed to 75 ppm or greater and in females exposed to 150 ppm. Minimal epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males. Increased hematopoiesis of the spleen, secondary to the hematotoxicity, occurred in males exposed to 75 ppm or greater and in females exposed to 150 or 300 ppm. Increased hemosiderosis of the spleen occurred in males exposed to 300 ppm and in females exposed to 75 ppm or greater. 2-YEAR STUDY IN RATS: Based on the low final mean body weights, anemia, and the mild to moderate nasal mucosal lesions and the hyperplastic bronchial lesions observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in rats were 37.5, 75, and 150 ppm. Groups of 56 male and 56 female rats were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. Ten male and 10 female rats from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, Hematology, and Clinical Chemistry: Survival rates of exposed groups of rats were greater than those of the controls, and the survival rates of 75 and 150 ppm males were significantly greater than that of the control. Mean body weights of 150 ppm males and females were 3&percnt; to 11&percnt; lower than those of the controls throughout the course of the study. There were no clinical findings considered to be related to isobutyl nitrite exposure. A very mild methemoglobinemia and anemia occurred in male and female rats exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms in 75 ppm males and in 150 ppm males and females were significantly greater than those in the controls. The incidence of alveolar/bronchiolar carcinoma was significantly greater in 150 ppm male rats than that in the controls. The incidences of alveolar epithelial hyperplasia were also increased in 75 and 150 ppm males and in all exposed groups of females. The incidences of mononuclear cell leukemia in exposed groups of males and females were significantly less than those in the controls. 2-YEAR STUDY IN MICE: Based on the low final mean body weight of 300 ppm females and the mild to moderate bronchiolar hyperplasia observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in mice were 37.5, 75, and 150 ppm. Groups of 60 male and 60 female mice were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. As many as 10 male and 10 female mice from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, and Hematology and Clinical Chemistry: Survival rates of exposed groups of males were similar to those of the controls. Survival rates of exposed groups of females were greater than those of the controls, and the survival rate in 37.5 ppm females was significantly greater than that of the controls. Mean body weights of exposed groups of males and of 37.5 and 75 ppm females were similar to those of the controls throughout the study. Mean body weights of 150 ppm females were lower than those of the controls from week 20 until the end of the study. There were no biologically significant clinical findings noted in the 2-year study in mice. A very mild methemoglobinemia and anemia occurred in male and female mice exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms were significantly greater than those in the controls in 75 ppm males and in 150 ppm males and females. Incidences of alveolar epithelial hyperplasia were significantly increased in 75 and 150 ppm male and female mice. Thyroid gland follicular cell adenoma occurred with a significant positive trend in male mice; the incidences of thyroid gland follicular cell hyperplasia were increased in all exposed groups of males, and the incidences in males exposed to 37.5 or 150 ppm were significantly greater than those in the controls. Incidences of serous exudate and olfactory epithelium atrophy in the nose of 150 ppm females were significantly greater than those in the controls. Incidences of minimal to mild hemosiderin pigment in the spleen of 75 and 150 ppm male mice were significantly greater than those in the controls. GENETIC TOXICOLOGY: Isobutyl nitrite was found to be mutagenic in vitro and in vivo. It induced base-pair substitution mutations in Salmonella typhimurim strains TA100 and TA1535 and sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. Positive responses in the S. typhimurium tests required S9 activation, but isobutyl nitrite induced chromosomal effects in cultured Chinese hamster ovary cells with and without S9. In vivo, no induction of sex-linked recessive lethal mutations was noted in the germ cells of male Drosophila melanogaster exposed to isobutyl nitrite via feeding or injection. However, significant increases in micronucleated normochromatic erythrocytes were observed in the peripheral blood of male and female mice treated with isobutyl nitrite for 90 days by inhalation. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of isobutyl nitrite in male and female F344/N rats based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of isobutyl nitrite in male and female B6C3F1 mice based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) in males and females. The increased incidence of thyroid gland follicular cell adenoma in male mice may have been related to isobutyl nitrite exposure. Exposure of rats and mice to isobutyl nitrite by inhalation for 2 years resulted in increased incidences of alveolar epithelial hyperplasia (male and female rats and mice), thyroid gland follicular cell hyperplasia and splenic hemosiderin pigmentation (male mice), and serous exudate and atrophy of the olfactory epithelium of the nose (female mice). Exposure of rats to isobutyl nitrite by inhalation for 2 years resulted in decreased incidences of mononuclear cell leukemia in males and females.
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PMID:NTP Toxicology and Carcinogenesis Studies of Isobutyl Nitrite (CAS No. 542-56-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies). 1259 27

Butanal oxime is used as a volatile antiskinning agent in paints, inks, and similar products. Butanal oxime was chosen for toxicology testing as a representative of the aldoxime class. Male and female F344/N rats and B6C3F1 mice received butanal oxime (99 percent pure) in drinking water for 15 days or by gavage in 0.5 percent methylcellulose for 14 weeks. Animals were evaluated for clinical pathology, reproductive system effects, and histopathology. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. In the 15-day studies, groups of five male and five female rats and mice received 0, 312, 625, 1,250, 2,500, or 5,000 ppm butanal oxime in drinking water, resulting in average daily doses of approximately 40, 70, or 100 mg butanal oxime/kg body weight to male and female rats; 45, 90, 130, 200, or 300 mg/kg to male mice; and 45, 85, 100, 130, or 170 mg/kg to female mice. Due to body weight loss and lack of water consumption, all male and female rats receiving 2,500 or 5,000 ppm were removed from the study on day 9; average daily doses were not calculated for these groups. All other rats and mice survived until the end of the studies. Mean body weights of 1,250 ppm male and female rats and 2,500 and 5,000 ppm male and female mice were significantly less than those of the controls. Male mice receiving 5,000 ppm and females receiving 2,500 or 5,000 ppm lost weight during the study. Water consumption by rats and mice receiving 1,250 ppm or greater was less than that by the controls. Thinness in 2,500 and 5,000 ppm rats and mice was the only clinical finding of toxicity. Spleen weights were significantly decreased in 2,500 and 5,000 ppm female mice. No chemical-related lesions were observed grossly; histologic examinations were not performed. In the 14-week studies, groups of 10 male and 10 female rats and mice received butanal oxime by gavage at doses of 0, 25, 50, 100, 200, or 600 mg/kg, 5 days per week for 14 weeks. All 600 mg/kg rats died or were killed moribund during the first week of the study; in the 600 mg/kg mouse groups, seven males and nine females died, were killed moribund, or were killed accidentally before the end of the study. Mean body weights of 100 and 200 mg/kg male rats, 600 mg/kg male mice, and female mice administered 50 mg/kg or greater were less than those of the controls. Clinical findings of toxicity in 600 mg/kg rats included loss of coordination, wobbly gait, shaking, blinking, constant grooming and scratching of the face, head weaving, burying of the face in bedding, lethargy, and prostration; in 600 mg/kg mice, clinical findings included ataxia, loss of balance after rearing, squinting, and burying of the face in the bedding. Hematology results of the 14-week gavage studies indicate that butanal oxime induces a methemoglobinemia and a responsive anemia in rats and mice. Spleen weights of 100 and 200 mg/kg male rats, female rats administered 50 mg/kg or greater, and 200 and 600 mg/kg male mice were increased, as were the liver weights of 200 mg/kg female rats and mice. In animals that died early due to butanal oxime administration, hepatocellular necrosis was the primary pathologic finding. Degeneration of the nasal olfactory epithelium was observed in dosed rats and mice that died early as well as in animals that survived to the end of the studies. Additional chemical-related nasal findings were respiratory epithelial changes in male rats and suppurative exudate in male and female mice. Increased incidences and/or severities of splenic hematopoietic cell proliferation and pigmentation (hemosiderin) as well as bone marrow hyperplasia were also observed in dosed groups, particularly in the 200 and 600 mg/kg groups, and were indicative of erythrocyte damage. Butanal oxime (3 to 10,000 ug/plate) was mutagenic in S. typhimurium strain TA1535 in the presence of 5 percent or 10 percent rat liver S9; an equivocal response was seen in TA100 with 30 percent rat S9, and no mutagenic activity was seen in TA98, with or without rat or hamster liver S9. Butanal oxime induced chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. Significant increases in the frequencies of micronucleated normochromatic erythrocytes were observed in vivo in peripheral blood of male and female mice administered 25 to 600 mg/kg butanal oxime for 14 weeks by gavage. Synonyms: Butanaloxime; butylaldoxime; butyraldehyde oxime; n-butyraldehyde oxime; butyraldoxime; n-butyraldoxime Trade names: Exkin 1, Exkin No. 1 Anti-Skinning Agent, Skino #1, Troykyd Anti-Skin BTO
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PMID:NTP technical report on the toxicity studies of Butanal oxime (CAS No. 110-69-0) administered in drinking water and by gavage to F344/N rats and B6C3F1 mice. 1501 36

2,4-Decadienal is used as a synthetic flavoring and fragrance material and has been evaluated as a corrosion inhibitor for steel in oil field operations. 2,4-Decadienal was nominated by the National Cancer Institute for toxicity testing because the dienaldehydes occur naturally in a variety of foods and food components, are used as food additive/flavoring agents, and the potential for human exposure is high. In the toxicity studies, male and female F344/N rats and B6C3F1 mice received 2,4-decadienal (at least 93% pure) in corn oil by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. In the 2-week studies, groups of five male and five female rats and mice received 2,4-decadienal in corn oil by gavage at doses of 0, 45, 133, 400, 1,200, or 3,600 mg 2,4-decadienal/kg body weight 5 days per week for 16 days. All animals in the 3,600 mg/kg groups were found dead or sacrificed moribund by day 3 (rats) or day 9 (mice). One 133 mg/kg female rat was found dead on day 8, and one male and one female mouse in the 1,200 mg/kg groups were found dead on days 12 and 16, respectively. At 1,200 mg/kg, treatment-related ulceration of the forestomach was observed in male and female rats and mice. Focal necrosis of the forestomach occurred in a 1,200 mg/kg female mouse. Mean body weights of all 1,200 mg/kg groups were less than those of the vehicle controls, and 1,200 mg/kg female mice lost weight during the study. Diarrhea, lethargy, abnormal breathing (rats), and thinness (mice) occurred in the 1,200 and 3,600 mg/kg groups. Gross lesions seen at necropsy included ulcerations of the forestomach in 1,200 mg/kg rats and 1,200 and 3,600 mg/kg mice. Adhesions involving the stomach and other abdominal organs were also seen in 1,200 and 3,600 mg/kg mice. In the 3-month studies, groups of 10 male and 10 female rats and mice received 2,4-decadienal in corn oil by gavage at doses of 0, 50, 100, 200, 400, or 800 mg 2,4-decadienal/kg 5 days per week for 14 weeks. No chemical-related deaths occurred. Mean body weights of 400 mg/kg male rats and 800 mg/kg male and female rats and male mice were significantly less than those of the vehicle controls. Dosed male and female rats were lethargic after week 7; the severity of the lethargy was dose related. There were changes in the leukon of dosed rats compared to vehicle control rats characterized by decreased leukocyte, lymphocyte, and eosinophil counts and increased neutrophil counts. Spleen weights of 800 mg/kg female rats and thymus weights of 400 and 800 mg/kg female rats were significantly less than those of the vehicle controls. Thymus, spleen, testis, cauda epididymis, and epididymis weights of 800 mg/kg male rats were less than those of the vehicle controls. The incidences of epithelial hyperplasia of the forestomach were significantly greater in 400 and 800 mg/kg male and female rats, 200, 400, and 800 mg/kg male mice, and 800 mg/kg female mice than in the vehicle controls. Incidences of epithelial degeneration of the forestomach were significantly increased in 800 mg/kg rats and the incidence of chronic active inflammation of the forestomach was significantly increased in 800 mg/kg female rats. Incidences of exudate and olfactory epithelial atrophy of the nose were significantly increased in 800 mg/kg male rats, and incidences of olfactory epithelial necrosis occurred in 200 mg/kg or greater mice. Olfactory epithelial hydropic degeneration occurred in a single female mouse from the 100 mg/kg group. 2,4-Decadienal was not mutagenic in any of several strains of S. typhimurium tested with and without liver S9 activation enzymes. Acute bone marrow micronucleus tests in laboratory rodents administered 2,4-decadienal by intraperitoneal injection yielded mixed results. In male rats, a single injection of 2,4-decadienal gave a positive response, but no confirmatory trial was conducted. In male mice, a standard three-injection bone marrow micronucleus experiment yielded negative results but a 48-hour bone marrow analysis after a single dose of 600 mg/kg revealed a small but statistically significant increase in micronucleated polychromatic erythrocytes. Analysis of peripheral blood erythrocytes in these same mice also showed a dose-related increase in micronucleated polychromatic cells, but the increase was insufficient for a positive call and the results of the acute micronucleus assays in mice were judged to be equivocal overall. No increase in the frequency of micronucleated normochromatic erythrocytes was seen in peripheral blood of male or female mice administered 2,4-decadienal by gavage for 3 months. In summary, 2,4-decadienal administration caused decreased body weights and increased incidences of forestomach lesions in the 3-month studies in rats and mice. In addition, treatment-related lesions of the olfactory epithelium were observed in male rats and male and female mice. The no-observed-adverse-effect level was determined to be 100 mg/kg in rats and mice. 2,4-Decadienal was not mutagenic in vitro or in vivo. Synonyms: 2,4-De; deca-2,4-dienal; trans,trans-2,4-decadienal; trans,trans-2,4-decadien-1-al; heptenyl acrolein; RIFM#77-102.
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PMID:NTP toxicity studies of toxicity studies of 2,4-decadienal (CAS No. 25152-84-5) administered by gavage to F344/N Rats and B6C3F1 mice. 2144 2

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