UMLS:C0023380 - FACTA Search

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Query: UMLS:C0023380 (lethargy)
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Juliflorine (CAS 76202-00-1), an antibacterial and antidermatophytic alkaloid, was studied for its toxicity in mice, rabbits, chicks, chick embryos and vero cell line. In mice LD50 was determined as 17.46 mg/kg; in rabbits 33.11 mg/kg; in chicks 24.104 mg/kg; and in chick embryos 18.284 mg/kg. In rabbits the subsequent injection of non-lethal doses (10 mg/kg) through the same route induced swelling, induration, inflammation and tissue degeneration (around injected area) with sterile abcess. Topically 1% juliflorine in polyethylene glycol-400 was found non-toxic but higher concentrations (less than or equal to 2.5%) produced irritation and inflammation; the severity of reaction was dose dependent. In vero cell-line juliflorine was found toxic at greater than or equal to 5 micrograms/ml. Injected animals showed lethargy, prostration and weakness (dose dependent) but recovered after some days, while newly hatched chicks, from injected eggs with higher dose, did not survive after 48 to 72 h. Internal organs (liver, kidney, brain, etc.) of dead, sick and healthy animals were examined and found normal.
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PMID:Toxicological studies of the antimicrobial alkaloid juliflorine. 204 77

Experiments were conducted to study the acute inhalation toxicity of T-2 mycotoxin in both young adult and mature mice. For a 10-min aerosol exposure, the 24-hr LC50 of T-2 mycotoxin in young adult mice was 0.08 +/- 0.04 mg T-2/liter air and that for mature mice was 0.325 +/- 0.1 mg T-2/liter air. Deaths among mice exposed to the higher aerosol concentrations used in this study (i.e., 1.5 to 2.4 mg T-2/liter air) occurred in less than 5 hr. General clinical symptoms in these animals immediately postexposure were tremors, lethargy, stilted gait, and, in some animals, prostration. In experiments separate from the concentration-response studies, total deposition of T-2 aerosol and selective retention of T-2 in the respiratory tract and nasal turbinates were determined analytically from 3H-labeled T-2. When total deposition of T-2 was quantitated, there was excellent agreement between that amount of T-2 deposited and that amount of T-2 predicted from calculations based on aerosol size and animal minute volume. Based on the aerosol deposition data, the LD50 values of T-2 mycotoxins was 0.24 mg/kg for young adult mice and 0.94 mg/kg for mature mice. For mice, inhalation of T-2 mycotoxin is at least 10 times more toxic than systemic administration (LD50 approximately 4.5 mg/kg) and at least 20 times more toxic than dermal administration (LD50 greater than 10 mg/kg).
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PMID:Acute inhalation toxicity of T-2 mycotoxin in mice. 355 34

Two thousand Panama X Rambouillet ewes from a flock of 2,200 developed signs of acute toxicosis after being moved to a field that had been sprayed 16 hours earlier with elemental sulfur. Acute signs were lethargy, abdominal discomfort, and prostration. Two hundred six (10%) of the affected ewes died within 24 hours. Polioencephalomalacia that was unresponsive to thiamine treatment developed in another 40 (2%) of the ewes; 28 (70%) of the ewes with polioencephalomalacia recovered. Sulfur is converted to hydrogen sulfide in the rumen. Signs of sulfur toxicosis are a result of absorption of hydrogen sulfide and interaction with the cytochrome system and hemoglobin. Sulfide is detoxified in the RBC and by the liver.
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PMID:Elemental sulfur toxicosis in a flock of sheep. 862 20

BACKGROUND Salicylates continue to be marketed and to be used in developing countries as over-the-counter (OTC) antipyretics in children, whereas in developed countries they are no longer used in children because of safety concerns. The presenting signs of salicylate poisoning, especially chronic (repeated administration of therapeutic or excessive doses for longer than 12 h), can include metabolic acidosis, hypoglycaemia, lethargy, and coma and fits. These signs are also common in severe malaria in African children. Admission of two probable cases of chronic salicylate poisoning prompted us to look for other cases among children presenting to our hospital in Kenya, apparently with severe malaria. METHODS All children admitted to Kilifi District Hospital between July and September, 1994, who had a positive blood film for Plasmodium falciparum, and one or more of coma, prostration, or respiratory distress were eligible. As well as routine tests for malaria and routine biochemistry, salicylate concentrations were measured. Management of children (aged 6 months to 10 years) in the community was assessed by a cross-sectional survey of 463 households and by interviews with mothers 2 days after they had bought OTC drugs for a child with fever. FINDINGS Data were available for 143 of 154 children with initial primary diagnoses of severe malaria. 129 (90 percent) had detectable (>l mg/dL) salicylate. Six of these had salicylate concentrations of 20 mg/dL or higher. All six had neurological impairment and metabolic acidosis and four were, or became, hypoglycaemic. OTC drugs were the first-line treatment in 188 (74 percent) of 254 fever episodes during the 2 weeks before the cross-sectional survey. Of 250 mothers who bought drugs for a febrile child, 236 (94 percent) bought a preparation containing salicylates and 50 (21 percent) gave a dose higher than the manufacturer's recommended maximum. INTERPRETATION These cases suggest that in some children salicylate poisoning may cause or contribute to the development of metabolic acidosis and hypoglycaemia, complications of severe malaria associated with high mortality.
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PMID:Chronic salicylate poisoning and severe malaria. 865 7

[carisoprodol structure: see text] Carisoprodol is a widely used skeletal muscle relaxant and analgesic and is available as a prescription drug. Comparative studies were conducted to determine the toxicity of carisoprodol administered in corn oil and in 0.5% methylcellulose by gavage. Carisoprodol plasma concentrations of rats and mice were measured at the end of the 13-week studies; single-dose plasma carisoprodol analyses were also performed. Genetic toxicity studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and peripheral blood erythrocytes of mice. Groups of 10 male and 10 female F344/N rats received 0, 100, 200, 400, 800, or 1,600 mg carisoprodol per kilogram body weight in corn oil by gavage or 0, 100, 200, 400, or 800 mg/kg carisoprodol in 0.5% methylcellulose by gavage for 13 weeks. Groups of 10 male and 10 female B6C3F1 mice received 0, 75, 150, 300, 600, or 1,200 mg/kg carisoprodol in corn oil by gavage or 0, 600, 1,200, or 1,600 mg/kg carisoprodol in 0.5% methylcellulose by gavage for 13 weeks. Among rats that received carisoprodol in corn oil, survival was similar to that of the vehicle controls. Survival of rats administered carisoprodol in 0.5% methylcellulose was also similar to that of the vehicle controls after adjustment for deaths (two males and one female in the 800 mg/kg group and two females in the 400 mg/kg group). The final mean body weight gain of males administered 1,600 mg/kg carisoprodol in corn oil was significantly less than that of the vehicle controls; the final mean body weights and body weight gains of female rats in the 800 and 1,600 mg/kg groups were significantly greater. In the carisoprodol in 0.5% methylcellulose study, males in the 200 mg/kg group and females in the 100 and 800 mg/kg groups had significantly greater mean body weights and body weight gains than did the vehicle controls. Clinical findings in rats administered carisoprodol in corn oil or in 0.5% methylcellulose included lethargy, ataxia, diarrhea, and prostration; the incidences were dose-related, and females were more sensitive than males to the effects of carisoprodol. In the carisoprodol in corn oil study, differences in hematology and clinical chemistry parameters occurred with no consistent patterns. The effects of carisoprodol in 0.5% methylcellulose on hematology and clinical chemistry parameters were not studied. In the corn oil study, the kidney and liver weights of male and female rats administered 200 mg/kg carisoprodol or greater were generally significantly greater than those of the vehicle controls. In the 0.5% methylcellulose study, liver weights were significantly greater in male rats administered 400 or 800 mg/kg and in female rats administered 800 mg/kg carisoprodol compared to the vehicle controls; however, a consistent effect on the kidney weights was not observed. Nephropathy was observed in male rats administered 400 mg/kg carisoprodol or greater in corn oil; the livers of four males in the 1,600 mg/kg group had centrilobular hypertrophy of hepatocytes. No lesions were observed histopathologically in female rats administered carisoprodol in corn oil. In the carisoprodol in 0.5% methylcellulose study, the severity of nephropathy in males administered 200 mg/kg or greater was enhanced, and the incidence of nephropathy in female rats in the 800 mg/kg group was slightly greater than that in the vehicle controls. Plasma carisoprodol concentrations at the end of 13 weeks generally increased with increasing dose in rats administered carisoprodol in corn oil or in 0.5% methylcellulose. The plasma carisoprodol concentrations in rats administered a single gavage dose of carisoprodol in corn oil also increased with increasing dose. In the carisoprodol in corn oil mouse study, two females each in the vehicle control and 75 mg/kg groups and one female each in the 150 and 600 mg/kg groups were accidentally killed; all males survived to the end of the study. One male and one female administered 1,600 mg/kg carisoprodol in 0.5% methylcellulose died; seven mice were accidentally killed. The mean body weights and body weight gains of mice administered carisoprodol in corn oil were generally similar to those of the vehicle controls. The final mean body weights and body weight gains of all groups of males and females administered carisoprodol in 0.5% methylcellulose were significantly less. Clinical findings in the carisoprodol in corn oil study included lethargy, ataxia, tremors, and prostration in male and female mice. Ataxia, lethargy, convulsions, and prostration were observed in all dosed groups of males and females administered carisoprodol in 0.5% methylcellulose. In the carisoprodol in corn oil study, liver weights were significantly greater in males administered 300 mg/kg or greater and in females administered 150 mg/kg or greater than in the vehicle controls. In the carisoprodol in corn oil study, no gross or microscopic lesions were considered related to carisoprodol administration. Minimal to mild centrilobular hypertrophy was observed in the liver of all dosed groups of males and in females in the 1,200 and 1,600 mg/kg groups in the carisoprodol in 0.5% methylcellulose study. The testis weights of males administered 1,200 mg/kg carisoprodol in corn oil were significantly less than those of the vehicle controls; the sperm motility of males in this group was also significantly less than that of the vehicle controls. There were no significant differences in vaginal cytology parameters between dosed and vehicle control females. At the end of the carisoprodol in corn oil study, the concentration of carisoprodol was above the limit of detection in the plasma of only one male mouse each in the 300 and 1,200 mg/kg groups and in four females in the 1,200 mg/kg group. In mice administered a single gavage dose of carisoprodol in corn oil, plasma concentrations increased with increasing dose; peak plasma concentrations occurred at 20 to 120 minutes in males and 60 to 120 minutes in females. In the carisoprodol in 0.5% methylcellulose study, plasma carisoprodol concentrations of female, but not male, mice increased with increasing dose; peak plasma carisoprodol concentrations occurred at 30 minutes postdosing in all groups of males and females. Results of proportionality and bioavailability studies indicated that single gavage doses of 200 to 800 mg/kg carisoprodol in 0.5% methylcellulose in rats or 300 to 1,200 mg/kg in mice were dose proportional; absolute bioavailability values increased with increasing dose, ranging from 15% to 32% for rats and from 18% to 38% for mice. For rats, the bioavailability of carisoprodol in 0.5% methylcellulose was approximately fivefold that of carisoprodol in corn oil; the Cmax values of the dose in 0.5% methylcellulose were approximately threefold those of the dose in corn oil. For mice, no significant difference was observed in the bioavailability of carisoprodol between the vehicles; however, the Cmax values of the dose in 0.5% methylcellulose were 1.5 to 1.75 times those of the dose in corn oil. Carisoprodol was not mutagenic in any of four strains of Salmonella typhimurium, with or without S9 metabolic activation. It did induce mutations in L5178Y mouse lymphoma cells in the absence of S9; with S9, no mutagenic activity was noted in this assay. Results of the sister chromatid exchange test with carisoprodol in cultured Chinese hamster ovary cells were considered equivocal with and without S9. Chromosomal aberrations in cultured Chinese hamster ovary cells were clearly increased by carisoprodol treatment, particularly in the presence of S9. No significant increases in the frequency of micronucleated erythrocytes were observed in peripheral blood samples from male and female mice administered carisoprodol by gavage for 13 weeks. In conclusion, carisoprodol induced ataxia and prostration in rats and mice, increases in liver weights in rats and mice, and nephropathy in male rats. The bioavailability of carisoprodol in 5% methylcellulose was greater than in corn oil. The no-observed-adverse-effect (NOAEL) level of carisoprodol administered in corn oil or in 0.5% methylcellulose was determined to be 100 mg/kg, compared to the clinical dose of 20 mg/kg per day for adults and 5 to 7.5 mg/kg per day for children.
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PMID:NTP toxicity studies of carisoprodol (CAS No. 78-44-4) administered by Gavage to F344/N rats and B6C3F1 mice. 1198 79

The technical grade of xylenes (mixed) (hereafter termed xylenes) contains the three isomeric forms and ethylbenzene (percentage composition shown above). The annual production for 1985 was approximately 7.4 x 108 gallons. Xylenes is used as a solvent and a cleaning agent and as a degreaser and is a constituent of aviation and automobile fuels. Xylenes is also used in the production of benzoic acid, phthalate anhydride, and isophthalic and terephthalic acids as well as their dimethyl esters. Toxicology and carcinogenesis studies of xylenes were conducted in laboratory animals because a large number of workers are exposed and because the long- term effects of exposure to xylenes were not known. Exposure for the present studies was by gavage in corn oil. In single-administration studies, groups of five F344/N rats and B6C3F1 mice of each sex received 500, 1,000, 2,000, 4,000, or 6,000 mg/kg. Administration of xylenes caused deaths at 6,000 mg/kg in rats and mice of each sex and at 4,000 mg/kg in male rats. In rats, clinical signs observed within 24 hours of dosing at 4,000 mg/kg included prostration, muscular incoordination, and loss of hind limb movement; these effects continued through the second week of observation. Tremors, prone position, and slowed breathing were recorded for mice on day 3, but all mice appeared normal by the end of the 2- week observation period. In 14- day studies, groups of five rats of each sex were administered 0, 125, 250, 500, 1,000, or 2,000 mg/kg, and groups of five mice of each sex received 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. Chemical- related mortality occurred only at 2,000 mg/kg in rats and at 4,000 mg/kg in mice. Rats and mice exhibited shallow breathing and prostration within 48 hours following dosing at 2,000 mg/kg. These signs persisted until day 12 for rats, but no clinical signs were noted during the second week for mice. In 13- week studies, groups of 10 rats of each sex received 0, 62.5, 125, 250, 500, or 1,000 mg/kg, and groups of 10 mice of each sex received 0, 125, 250, 500, 1,000, or 2,000 mg/kg. No deaths or clinical signs of toxicity were recorded in rats. However, high dose male rats gained 15% less weight and females 8% less weight than did the vehicle controls. Two female mice died at the 2,000 mg/kg dose. Lethargy, short and shallow breathing, unsteadiness, tremors, and paresis were observed for both sexes in the 2,000 mg/kg group within 5- 10 minutes after dosing and lasted for 15- 60 minutes. Two- year toxicology and carcinogenesis studies were conducted by administering 0, 250, or 500 mg/kg xylenes in corn oil by gavage to groups of 50 F344/N rats of each sex, 5 days per week for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg xylenes on the same schedule. Although the mortality was dose related in male rats (final survival: vehicle control, 36/50; low dose, 26/50; high dose, 20/50), many of the early deaths in the dosed males were gavage related. Body weights of the high dose male rats were 5%- 8% lower than those of the vehicle controls after week 59. The mean body weights of low dose and vehicle control male rats and those of dosed and vehicle control female rats were comparable. Survival rates of female rats and both sexes of dosed mice were not significantly different from those of the vehicle controls. The mean weights of dosed male and female mice were comparable to those of the vehicle controls. Hyperactivity lasting 5- 30 minutes was observed in high dose mice after dosing, beginning after week 4 and continuing through week 103. At no site was the incidence of nonneoplastic or neoplastic lesions in dosed rats or mice of either sex considered to be related to the administration of xylenes. Neither xylenes nor any of its components (o- xylene, m-xylene, p- xylene, or ethylbenzene) were mutagenic when tested with or without metabolic activation in Salmonella typhimurium strains TA100, TA1535, TA97, or TA98 with the preincubation protocol. In addition, ethylbenzene was tested in cytogenetic assays using cultured Cetic assays using cultured Chinese hamster ovary cells both with and without metabolic activation; neither sister- chromatid exchanges nor chromosomal aberrations were induced by ethylbenzene. An audit of the experimental data was conducted for the 2-year studies of xylenes. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of xylenes (mixed) for male or female F344/N rats given 250 or 500 mg/kg or for male or female B6C3F1 mice given 500 or 1,000 mg/kg.
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PMID:NTP Toxicology and Carcinogenesis Studies of Xylenes (Mixed) (60% m-Xylene, 14% p-Xylene, 9% o-Xylene, and 17% Ethylbenzene) (CAS No. 1330-20-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 97

Toxicology and carcinogenesis studies of technical-grade 2-mercaptobenzothiazole (96%-97% pure), a rubber accelerant and preservative, were conducted by administering the chemical by gavage in a corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. 2-Mercaptobenzothiazole was nominated for study by the National Institute of Environmental Health Sciences and the National Institute for Occupational Safety and Health. Sixteen-Day and Thirteen-Week Studies: In 16-day studies, mean body weight gains of rats receiving 2,500 mg/kg were 6-7 g lower than those of vehicle controls; 4/5 male and 5/5 female mice dosed with 3,000 mg/kg and 4/5 female mice dosed with 1,500 mg/kg died; lethargy and prostration occurred in most of these animals after gavage. Based on these results, doses were selected for both species in the 13-week studies were 0, 94 (mice only), 188, 375, 750, and 1,500 mg/kg. In the 13-week studies, no chemical-related deaths occurred in rats, but body weight gains in males dosed with 1,500 mg/kg and in females dosed with 750 or 1,500 mg/kg were lower than those in the vehicle control groups. Hepatomegaly occurred at the two highest doses in males and at all doses in females; however, no microscopic pathologic changes were noted in any tissue. More than half the mice dosed with 1,500 mg/kg died, but no compound-related body weight changes occurred. Clinical signs in mice were dose related and included lethargy in animals dosed with 375 mg/kg and lacrimation, salivation, and clonic seizure in some dosed with 750 or 1,500 mg/kg. No association between these clinical signs of toxicity and gross or microscopic pathologic effects were observed. Doses selected for the 2-year studies were 0, 375, and 750 mg/kg for male rats and for mice of each sex and 0, 188, or 375 mg/kg for female rats. Body weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered 2-mercaptobenzothiazole in corn oil by gavage 5 days per week for 103 weeks. Administration of 2-mercaptobenzothiazole resulted in decreased survival in dosed male rats (vehicle control, 42/50; low dose, 22/50; high dose, 20/50) and in the high dose group of female mice (37/50; 39/50; 22/50) but not in female rats (28/50; 31/50; 25/50) or in male mice (38/50; 33/50; 30/50). No effect on body weight gain in dosed rats was observed; in dosed mice, minor reductions occurred between weeks 3 and 64, withrecovery thereafter. Postgavage lethargy and prostration occurred frequently in dosed rats and mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The severity of nephropathy was increased in dosed male rats. Ulcers and inflammation of the forestomach were prevalent in dosed rats, as were increased incidences of epithelial hyperplasia and hyperkeratosis in male rats, but no neoplasms of the forestomach were observed. There were no increases of nonneoplastic lesions in mice which were considered to be compound related. The incidences of a variety of tumors were increased in rats dosed with 2-mercaptobenzothiazole; some of the increased incidences were not dose related. In low dose male rats, increased incidences (P<0.01) were observed for mononuclear cell leukemia (7/50; 16/50; 3/50) and pancreatic acinar cell adenomas (2/50; 13/50; 6/49). Increased tumor incidences with dose-related trends (P<0.05) included pituitary gland adenomas in females (15/49; 24/50; 25/50), preputial gland adenomas or carcinomas (combined) in males (1/50; 6/50; 5/50), adrenal gland pheochromocytomas or malignant pheochromocytomas (combined) in males (18/50; 27/50; 24/49), and pheochromocytomas in females (1/50; 5/50; 6/50). These tumors were observed at significantly greater incidences (P</=0.05) in the high dose groups than in the vehicle controls. An increased incidence (P=0.028) of hepatocellular adenomas or carcinomas (combined) was observed only in low dose female mice (4/50; 12/49; 4/50). No significant increases in tumor incidences were seen in male mice. Genetic Toxicology: 2-Mercaptobenzothgy: 2-Mercaptobenzothiazole was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. In the presence of rat liver S9, 2-mercaptobenzothiazole increased the frequency of chromosomal aberrations and sister chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells, as well as mutations at the TK locus of mouse L5178Y lymphoma cells. Audit: The data, documents, and pathology materials from the 2-year studies of 2-mercaptobenzothiazole were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 2-mercaptobenzothiazole for male F344/N rats, indicated by increased incidences of mononuclear cell leukemia, pancreatic acinar cell adenomas, adrenal gland pheochromocytomas, and preputial gland adenomas or carcinomas (combined). There was some evidence of carcinogenic activity for female F344/N rats, indicated by increased incidences of adrenal gland pheochromocytomas and pituitary gland adenomas. There was no evidence of carcinogenic activity of 2-mercaptobenzothiazole for maleB6C3F1 mice dosed with 375 or 750 mg/kg. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice, indicated by increased incidences of hepatocellular adenomas or carcinomas (combined). Synonyms and Trade Names: Captax; Dermacid; Mertax; Thiotax; 2(3H)-benzothiazolethione; 2-benzothiazolyl mercaptan
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PMID:NTP Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 4

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

1,1-Difluoroethane (DFE) is a halogenated hydrocarbon used as a propellant in products designed for dusting electronic equipment and air brush painting. When abused, inhaled DFE produces intoxication and loss of muscular coordination. To investigate DFE toxicokinetics, groups (n = 3) of Sprague-Dawley rats were exposed to 30 s of 20 L/min DFE. The experimental model was designed to mimic exposure during abuse, a protocol which has not been conducted. Tissue collection (blood, brain, heart, liver, and kidney) occurred at 0, 10, 20, 30, 45, 60, 120, 240, 480, and 900 s. Average peak DFE levels were blood 352, brain 519, heart 338, liver 187, and kidney 364 mg/L or mg/kg. The total percent uptake of the administered dose was 4.0%. Uptake into individual compartments was 2.72, 0.38, 0.15, 0.41, and 0.32% for blood, brain, heart, liver, and kidney, respectively. All animals showed signs of intoxication within 20 s manifested as lethargy, prostration and loss of righting reflex. Marked intoxication continued for about 4 min when DFE averaged 21 mg/L in blood and 17 mg/kg in brain. Between 4 and 8 min, animals continued to show signs of sedation as evidenced by reduced aggression and excitement during handling. No discernable intoxication was evident after 8 min and blood and brain levels had fallen to 10 and 6 mg/L or kg, respectively. Plots of concentration (log) versus time were consistent with a two compartment model. Initial distribution was rapid with average half life (t((1/2))) during the alpha phase of 9 s for blood, 18 s for brain and 27 s in cardiac tissue. During beta slope elimination average t((1/2)) was 86 s in blood, 110 s in brain and 168 s in heart. Late elimination half lives were longer with blood gamma = 240 s, brain gamma = 340 s, and heart gamma = 231 s. Following acute exposure the Vd = 0.06 L, beta = 0.48 min(-1), AUC = 409.8 mg.min L(-1), and CL from blood was 0.03 L min(-1). The calculated toxicokinetic data may underestimate these parameters if DFE is abused chronically due to continued uptake into lowly perfused tissues with repeated dosing.
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PMID:Uptake and distribution of the abused inhalant 1,1-difluoroethane in the rat. 2082 75

In an effort to develop a sustainable platform for manufacturing protein-based vaccine candidates, we expressed a triple mutant of staphylococcal enterotoxin B carrying the L45R, Y89A, and Y94A modifications in transgenic soybean seeds (soy-mSEB). Soy-mSEB possessed no detectable superantigen activity in vitro. We found that this soybean-derived, nontoxic mutant of SEB could be stably expressed, stored in seeds for extended periods at room temperature without degradation, and easily purified from contaminating soy proteins. Vaccination of pigs with purified soy-mSEB, or the identical triple mutant expressed in Escherichia coli (E. coli-mSEB), resulted in high antibody titers against the native toxin in immunized animals. In fact, titers were indistinguishable regardless of the immunogen used, demonstrating the equivalence of soy-mSEB and E. coli-mSEB vaccinations. Antisera from either immunized group were able to block native SEB superantigen activity in an in vitro neutralization assay. Similar results were obtained when immunized animals were challenged with a sublethal dose of native toxin. Significant reductions in toxin-induced serum cytokine levels were observed in soy-mSEB- and E. coli-mSEB-immunized pigs compared to control animals. The reductions in SEB-induced cytokine responses were similar regardless of the immunogen used for vaccination. Surprisingly, however, some clinical symptoms, such as prostration, lethargy, emesis, and/or diarrhea, were still observed in all immunized animals. These studies demonstrate the potential for soybean-derived proteins as a platform technology for sustainable vaccine manufacturing and the usefulness of a sublethal challenge model in pigs for evaluating the efficacy of potential SEB vaccine candidates.
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PMID:Sublethal staphylococcal enterotoxin B challenge model in pigs to evaluate protection following immunization with a soybean-derived vaccine. 2311 2

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