Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroquinone is used an antioxidant in the rubber industry and as a developing agent in photography. It is also an intermediate in the manufacture of rubber and food antioxidants and monomer inhibitors. Hydroquinone and products containing hydroquinone are used as depigmenting agents to lighten skin. NTP Toxicology and Carcinogenesis studies were conducted by administering hydroquinone (greater than 99% pure) in corn oil or water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Additionally, genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Preliminary 3-day dermal studies were conducted with rats and mice using sufficient hydroquinone in 95% ethanol to crystallize on the skin (4 or 40 mg per animal); conjugated metabolites of hydroquinone were detected in the urine. Fourteen-day dermal studies were conducted at doses up to 3,840 mg/kg for rats and 4,800 mg/kg for mice. No toxic effects were seen in the 3- or 14-day dermal studies. Therefore, in further evaluations of hydroquinone, the gavage route of administration was used. Results of Fourteen-Day and Thirteen-Week Studies: Fourteen-day gavage studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1,000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg. All rats receiving 1,000 mg/kg and 1/5 male and 4/5 female rats receiving 500 mg/kg died before the end of the 14 days. Compound-related clinical signs in rats included tremors lasting up to 30 minutes after each dosing at 500 and 1,000 mg/kg. In the 14-day gavage studies with mice, 4/5 male mice and 5/5 female mice receiving 500 mg/kg and 3/5 males receiving 250 mg/kg died before the end of the studies. Tremors followed by convulsions were seen at 250 and 500 mg/kg. In the 13-week studies, doses for rats and mice ranged from 25 to 400 mg/kg. All rats receiving 400 mg/kg and 3/10 female rats receiving 200 mg/kg died before the end of the studies. The mean body weight at necropsy of male rats administered 100 or 200 mg/kg was about 8%-9% lower than that of vehicle controls. Mean body weights of vehicle control and dosed female rats at necropsy were similar. Tremors and convulsions were observed after dosing in most rats receiving 400 mg/kg and in several female rats receiving 200 mg/kg. Inflammation and/or epithelial hyperplasia (acanthosis) of the forestomach were seen in 4/10 male rats and 1/10 female rats receiving 200 mg/kg. Toxic nephropathy, characterized by tubular cell degeneration in the renal cortex, was seen in 7/10 male and 6/10 female rats receiving 200 mg/kg and in 1/10 females receiving 100 mg/kg. In the 13-week studies in mice, 8/10 males and 8/10 females receiving 400 mg/kg and 2/10 male mice receiving 200 mg/kg died early. Mean body weights of dosed and vehicle control mice at necropsy were similar. Liver weight to body weight ratios for dosed male mice were significantly greater than for vehicle controls. Ulceration, inflammation, or epithelial hyperplasia of the forestomach was found in 3/10 male and 2/10 female mice receiving 400 mg/kg and 1/10 females receiving 200 mg/kg. Based on these collective results, 2-year studies were conducted by administering 0, 25, or 50 mg/kg hydroquinone in deionized water by gavage to groups of 65 rats of each sex, 5 days per week. Groups of 65 mice of each sex were administered 0, 50, or 100 mg/kg on the same schedule. Ten rats and 10 mice from each group were killed after 15 months for an interim evaluation. Observations at Fifteen Months: In the rats killed at 15 months, the relative kidney weight for high dose male rats was greater than that for vehicle controls. The hematocrit value, hemoglobin concentration, and erythrocyte count for high dose female rats were decreased. Compound-related increased severity of nephropathy was observed in male rats. In mice killed at 15 months, the relative liver weights for high dose male and female mice were signif and female mice were significantly greater than those for vehicle controls. Lesions seen in the liver of male mice included increased syncytial cells and diffuse cytomegaly. Body Weights, Organ Weights, and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 5%-13% lower than those of vehicle controls after week 73, and those of low dose male rats were 5%-9% lower than those of vehicle controls after week 89. Mean body weights of dosed female rats were similar to those of vehicle controls throughout the study. The relative kidney and liver weights for high dose male rats were higher than those for vehicle controls. Mean body weights of high dose male mice were 5%-8% lower than those of vehicle controls after week 93, and those of high dose female mice were 5%-14% lower after week 20. Relative liver weights were increased for dosed male and high dose female mice. No significant differences in survival were observed between any groups of rats or mice of either sex after 2 years (male rats: vehicle control, 27/55; low dose, 18/55; high dose, 18/55; female rats: 40/55; 27/55; 32/55; male mice: 33/55; 37/54; 36/55; female mice: 37/55; 39/55; 36/55). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nearly all male rats and most female rats in all vehicle control and dosed groups had nephropathy. The severity of this disease was judged to be greater in high dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts, changes observed with advanced renal disease, were increased in male rats. Renal tubular hyperplasia was seen in 2 high dose male rats, and renal tubular adenomas were seen in 4/55 low dose and 8/55 high dose male rats; none was seen in vehicle controls. Mononuclear cell leukemia in female rats occurred with a positive trend, and the incidences in the dosed groups were greater than that in the vehicle controls (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). The historical incidence of leukemia in water gavage vehicle control female F344/N rats is 25% ± 15% and in untreated controls is 19% ± 7%. Compound-related lesions observed in the liver of high dose male mice included anisokaryosis (0/55; 2/54; 12/55), syncytial alteration (5/55; 3/54; 25/55), and basophilic foci (2/55; 5/54; 11/55). The incidences of hepatocellular adenomas were increased in dosed male mice (9/55; 21/54; 20/55), but these increases were offset by decreases in the incidences of hepatocellular carcinomas (13/55; 11/54; 7/55). The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice (male: 5/55; 15/53; 19/54; female: 13/55; 47/55; 45/55). Follicular cell adenomas were seen in 2/55 vehicle control, 1/53 low dose, and 2/54 high dose male mice and in 3/55 vehicle control, 5/55 low dose, and 6/55 high dose female mice, a follicular cell carcinoma was seen in a seventh high dose female mouse. The highest observed incidence of follicular cell adenomas or carcinomas(combined) in historical water gavage vehicle control female B6C3F1 mice is 3/48 (6%). Genetic Toxicology: Hydroquinone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It induced trifluorothymidine (Tft) resistance in mouse L5178Y/TK lymphoma cells in the presence or absence of metabolic activation. An equivocal response was obtained in tests for induction of sex-linked recessive lethal mutations in Drosophila administered hydroquinone by feeding. Hydroquinone induced sister chromatid exchanges (SCEs) in CHO cells both with or without exogenous metabolic activation and caused chromosomal aberrations in the presence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of hydroquinone for male F344/N rats, as shown by marked increases in tubular cell adenomas of the kidney. There was some evidence of carcinogenic activity of hydroquinone for female F344/N rats, as shown by increases in mononuclear cell leukemia. There was no evidence of carcinogenic activity of hydroquinone for male B6C3F1 mice administered 50 or 100 mg/kg in water by gavage. There was some evidence of carcinogenic activity of hydroquinone for female B6C3F1 mice, as shown by increases in hepatocellular neoplasms, mainly adenomas. Administration of hydroquinone was associated with thyroid follicular cell hyperplasia in both male and female mice and anisokaryosis, multinucleated hepatocytes, and basophilic foci of the liver in male mice. Synonyms: 1,4-benzenediol; p-benzenediol; benzohydroquinone; benzoquinol; 1,4-dihydroxybenzene; p-dihydroxybenzene; p-dioxobenzene; p-dioxybenzene; hydroquinol; hydroquinole; a-hydroquinone; p-hydroquinone; p-hydroxyphenol; quinol; b-quinol
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PMID:NTP Toxicology and Carcinogenesis Studies of Hydroquinone (CAS No. 123-31-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 38

Toxicology and carcinogenesis studies of n-butyl chloride (greater than 99.5% pure), a solvent as well as an alkylating agent, were conducted by exposing groups of F344/N rats and B6C3F1 mice to n-butyl chloride in corn oil by gavage for 14 days, 13 weeks, and 2 years. In the 14-day studies, no compound-related gross pathologic effects were observed in groups of five male or female rats or mice administered doses of up to 3,000 mg/kg body weight. However, deaths occurred in the groups administered 750, 1,500, or 3,000 mg/kg. Tremors and convulsions following gavage administration were observed. In the 13-week studies, groups of 10 male and 10 female rats were administered up to 500 mg/kg n-butyl chloride, and similar groups of mice received up to 1,000 mg/kg, Three of 10 male rats in the 500 mg/kg dose group and one female mouse in the 120 mg/kg dose group died before the end of the studies. Mild to moderate extramedullary hematopoiesis was observed in 3/10 male rats receiving 500 mg/kg. Mean body weights of male and female rats receiving 250 or 500 mg/kg were lower than those of the vehicle controls. Convulsions were observed in male and female rats receiving 250 mg/kg or higher and in 2/10 female mice receiving 1,000 mg/kg. Based on these results, 2-year toxicology and carcinogenesis studies of n-butyl chloride were conducted by administering doses of 0, 60, or 120 mg/kg in corn oil by gavage to groups of 50 male and 50 female rats and doses of 0, 500, or 1,000 mg/kg to groups of 50 male and 50 female mice. In the 2-year studies, survival relative to that of vehicle controls was significantly lower in high dose male rats (40/50 vs 17/50) and high dose female rats (35/50 vs 11/50) and in male mice receiving 1,000 mg/kg (33/50 vs 10/50). Due to excessive mortality in the 1,000 mg/kg female mice, the group was terminated in the 45th week and a second series of 2-year studies in mice of each sex was started at concentrations of 0 and 250 mg/kg. Male mice in the 1,000 mg/kg group had 10% lower mean body weights than the vehicle control group. No adverse effects on survival or body weights in other dosed groups of rats and mice were observed. Convulsions were observed before or after gavage administration on several occasions during the rat studies. These observations were noted primarily in the high dose groups (male: vehicle control, 1/50; low dose, 3/50; high dose, 27/50; female: vehicle control, 0/50; low dose, 7/50; high dose, 45/50). Hemorrhage of the brain and alveoli were observed primarily in high dose male and female rats dying from convulsions. Lymphoid depletion of the spleen and splenic hemosiderosis were also observed inthese animals. In mice, convulsions were observed only in the first studies (in the high dose female mice that were terminated early and in 6/50 high dose male mice). Pheochromocytomas of the adrenal gland occurred at marginally increased incidence in low dose female rats (1/50; 6/50; 1/49). Hyperplasia was observed in 3/50 vehicle controls, 7/50 low dose females, and 4/49 high dose females. The incidence of pheochromocytomas was low, not dose related, and not seen in males, and thus it was not considered to be compound related. Cytoplasmic vacuolization of the adrenal cortex occurred at increased incidences in males (5/50; 10/50; 20/50) but not in female rats. Nephropathy of the kidney occurred at increased incidences in female rats (13/50; 25/50; 20/50) but not in male rats. Additional nonneoplastic lesions such as congestion, inflammation, or nephrosis were not present to any degree in either vehicle control or dosed female rats. An increased incidence of alveolar/bronchiolar adenomas or carcinomas (combined) was observed in the 500 mg/kg group of female mice (3/50 vs 9/50), but little effect was seen in the 250 mg/kg group (6/50 vs 8/50). The incidences of adenomas or carcinomas (combined) in dosed female mice were not significantly different from that in the pooled vehicle control group from the first and second studies (pooled controls, 9/100; 250 mg/kg, 8/50; 500 mg/kg, 9/50). The lack o0). The lack of hyperplasia in female mice and the negative trend in male mice suggest that these marginal effects were probably not related to the administration of n-butyl chloride. An increased incidence of hepatocellular adenomas or carcinomas (combined) was observed in the 500 mg/kg dose group of female mice (3/50 vs 8/50) but not in the 250 mg/kg dose group (9/50 vs 7/50). An increased incidence of hemangiosarcomas was observed in male mice in the first study (1/50; 3/50; 4/50) but not in the second study (4/50 vs 2/50). Neither of these marginal effects was regarded as compound related. n-Butyl chloride was not mutagenic in Salmonella typhimurium strains TA98, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat liver S9 or in the presence of male Syrian hamster liver S9. n-Butyl chloride was mutagenic in the mouse lymphoma L5178Y/TK± assay in the absence of Aroclor-induced male rat liver S9 and was not tested in the presence of S9. n-Butyl chloride did not induce sister-chromatid exchanges or chromosomal aberrations in Chinesehamster ovary cells in the presence or absence of Aroclor-induced male rat liver S9. An audit of the experimental data was conducted for the 2-year studies of n-butyl chloride. 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 n-butyl chloride for male and female F344/N rats at daily doses of 60 or 120mg/kg, for male B6C3F1 mice at doses of 250, 500, or 1,000 mg/kg, or for female B6C3F1 mice at doses of 250 or 500 mg/kg. Chemical-induced toxicity in high dose rats (primarily females) reduced the sensitivity of the study for determining carcinogenicity. Synonyms: 1-chlorobutane; butyl chloride; n-propylcarbinyl chloride
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PMID:NTP Toxicology and Carcinogenesis Studies of n-Butyl Chloride (CAS No. 109-69-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 17