Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of acute aflatoxicosis on sperm maturation in the rat were evaluated using sperm GOT, GPT and LDH activities as indices. The levels of these enzymes in sperm undergoing maturation were stable like the sperm populations in the testis and epididymis. Acute aflatoxicosis enhanced corpus epididymal sperm transaminase but not sperm transit.
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PMID:Sperm maturation and storage in the male rat after acute treatment with aflatoxin B1. 393 3

Hamster sperm collected from the cauda epididymis were washed and the pellet diluted in a medium containing Triton x 100 (Sigma, Saint Louis, MO, USA) to dissolve the cell membrane and then reactivated with various concentrations of ATP (0-3 mM). Spermatozoal axonemes were initially immotile but the maximal percentage motility was obtained almost immediately following addition of 1 mM ATP. A stepwise increase in the concentration of ATP caused a 5-min delay in development of maximal reactivation and a change in the beating pattern as indicated by a decrease in the percentage of reactivating sperm. Under the same experimental condition GPT, UTP, CTP, and AMP failed to initiate the axonemal motility. In demembranated sperm reactivated by ADP, however, the beat frequency was lower compared with that reactivated by ATP. Pretreatment of the sperm with the mitochondrial phosphorylation blockers oligomycin and 2'4'-DNP (dinitrophenol) failed to inhibit the axonemal movement, although the presence of the dynein ATPase inhibitor, vanadate, was able to inhibit the reactivation. These results suggest that the exogenous ATP, but not the mitochondrial ATP, is responsible for axonemal motility.
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PMID:Specificity of ATP for the initiation of flagellar motility of hamster sperm. 827 42

Adult male rats were injected sc with cadmium chloride (CdCl(2)) in a single dose of 7 mg/kg body wt. Twenty-four hours postinjection, exposure to CdCl(2) increased the hemoglobin absorbance of the testes from 0.36 +/- 0.01 to 2.46 +/- 0.02. Pretreatment of rats with chlorpromazine (CPZ) 3 mg/kg ip either for 1 or 2 days before exposure to CdCl(2) significantly (p < 0.05) reduced the testicular damage and the hemoglobin absorbance decreased to 1.03 +/- 0.02 and 0.92 +/- 0.04, respectively. After CdCl(2) injection there was a progressive increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. CdCl(2) injection induced hemorrhage and a diffuse area of coagulative necrosis in liver. Pretreatment with CPZ partially protected liver from the effect of CdCl(2). Two months postinjection, exposure to CdCl(2) significantly decreased the weights of testes, epididymis, and accessory sex organs. Furthermore, CdCl(2) induced a highly significant (p < 0.01) decrease in sperm cell concentration and the percentage of mobile cells. Moreover CdCl(2) induced degenerative changes in testes, epididymis, and seminal vesicles. Pretreatment with CPZ partially protected these organs from the toxic effects of CdCl(2). It could be concluded that chlorpromazine partially antagonized the toxic effects of cadmium on liver, testes, and other male reproductive organs of rats.
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PMID:The antagonistic effect of chlorpromazine on cadmium toxicity. 1055 21

In male albino mice, the petroleum ether extract of the leaves of Mentha arvensis L., at the doses 10 and 20 mg/mouse per day for 20, 40 and 60 days, when administered orally, showed a dose and duration dependent reduction in the number of offspring of the treated male mated with normal females. Negative fertility was observed in both dose regimens after 60 days of treatment. The body weight and libido of the treated ammals remain unaffected. However, a significant decrease in the weight of the testis, epididymis, cauda epididymal sperm count, motility, viability and normal morphology of the spermatozoa was observed. The levels of serum protein, bilirubin, GOT, GPT and acid phosphatase, blood urea and haematological indices were unaltered throughout the course of investigation. All the altered parameters were reversible following withdrawal of treatment. The results suggest that the petroleum ether extract of the leaves of M. arvensis possess reversible antifertility property without adverse toxicity in male mice.
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PMID:Antifertility investigation and toxicological screening of the petroleum ether extract of the leaves of Mentha arvensis L. in male albino mice. 1128 36

Gallium arsenide is used primarily to make light- emitting diodes, lasers, laser windows, and photodetectors and in the photoelectronic transmission of data through optical fibers. Gallium arsenide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to gallium arsenide particles (greater than 98% pure; mass median aerodynamic diameter = 0.8 to 1.0 &mgr;m) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed to gallium arsenide for 14 weeks. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived to the end of the study. The final mean body weights of all exposed groups of males and females were similar to those of the chamber controls. Compared to chamber controls, the liver and lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased; the thymus weights of all exposed groups of males were decreased. Gallium arsenide particles were visible in the alveolar spaces and, to a lesser extent, within alveolar macrophages of exposed rats. Moderate proteinosis (surfactant mixed with small amounts of fibrin) and minimal histiocytic cellular infiltrate were observed in the alveoli of exposed males and females. Epithelial hyperplasia and squamous metaplasia of the larynx were observed primarily in males exposed to 150 mg/m(3). 16-DAY STUDY IN MICE: Groups of five male and four or five female mice were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. The final mean body weights were similar among exposed and chamber control groups. Compared to chamber controls, the lung weights of males and females exposed to 10 mg/m(3) or greater were increased. Gallium ar senide particles were visible in alveolar spaces and macrophages in some mice exposed to 150 mg/m(3). Moderate proteinosis, mild epithelial hyperplasia, and histiocytic infiltration of the lung were observed in males and females exposed to 10 mg/m(3) or greater. In the larynx, mild squamous metaplasia was seen in mice exposed to 10 mg/m(3) or greater, and mild chronic inflammation occurred in mice exposed to 75 or 150 mg/m(3). 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. All rats survived until the end of the study. The final mean body weight and body weight gain of males exposed to 75 mg/m(3) were significantly less than those of the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in exposed groups of rats. There were also increases in platelet and neutrophil counts, a transient decrease in leukocyte counts, and increases in the serum activities of alanine aminotransferase and sorbitol dehydrogenase. These changes were of greater magnitude in male rats. The lung weights of all exposed groups of rats were increased, while testis, cauda epididymis, and epididymis weights of males exposed to 37 or 75 mg/m(3) were generally less than those of chamber controls. Total spermatid heads and spermatid counts were significantly decreased in males exposed to 75 mg/m(3), while epididymal spermatozoa motility was significantly reduced in males ees exposed to 10 mg/m(3) or greater. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of exposed rats. Minimal to marked proteinosis and minimal histiocytic cellular infiltration of the alveoli were observed in all exposed groups; minimal squamous metaplasia in the larynx and lymphoid cell hyperplasia of the mediastinal lymph node were observed in some males and females exposed to 37 or 75 mg/m(3). Exposure-related increases in the incidences of plasma cell hyperplasia of the mandibular lymph node, testicular atrophy, epididymal hypospermia, bone marrow hyperplasia (males), and hemosiderosis in the liver were observed in the 37 and 75 mg/m(3) groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. One female mouse exposed to 75 mg/m(3) died before the end of the study. Final mean body weights and body weight gains of males in the 75 mg/m(3) group were signifi cantly less than the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide affected the circulating erythroid mass and induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in male and female mice. There were also increases in platelet and neutrophil counts. Compared to the chamber controls, the lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased. Testis, cauda epididymis, and epididymis weights, total spermatid heads, spermatid counts, and concentration and motility of epididymal spermatozoa were generally decreased. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of mice exposed to 1 mg/m(3) or greater. Mild to marked proteinosis, histiocytic infiltration, and epithelial hyperplasia were observed in the alveoli of males and females exposed to 1 mg/m(3) or greater. Minimal to mild suppurative inflammation and granuloma in the lung and squamous metaplasia in the larynx were present in males and females exposed to 10 mg/m(3) or greater. Min imal hyperplasia was observed in the tracheobronchial lymph node of males exposed to 10 mg/m(3) or greater and females exposed to 37 or 75 mg/m(3). Exposure- related increases in the incidences of testicular atrophy, epididymal hypospermia, hematopoietic cell proliferation of the spleen, and hemosiderosis of the liver and spleen were observed in groups of male and female mice exposed to 10 mg/m(3) or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.01, 0.1, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights: Survival of exposed male and female rats was similar to the chamber controls. Mean body weights of males exposed to 1.0 mg/m(3) were generally less than those of the chamber controls throughout the study; females exposed to 1.0 mg/m(3) had slightly lower mean body weights during the second year. Pathology Findings: Compared to the chamber controls, the incidences of alveolar/bronchiolar neoplasms were significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control ranges. Exposure-related nonneoplastic lesions in the lungs of male and female rats included atypical hyperplasia, alveolar epithelial hyperplasia, chronic active inflammation, proteinosis, and alveolar epithelial metaplasia. In the larynx of males exposed to 1.0 mg/m(3), the incidences of hyperplasia, chronic active inflammation, squamous metaplasia, and hyperplasia of the epiglottis were significantly increased. The incidences of benign pheochromocytoma of the adrenal medulla occurred with a positive trend in female rats, and the incidence was significantly increased in the 1.0 mg/m(3) group and exceeded the historical control range. The incidence of mononuclear cell leukemia was significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control range. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 0.5, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 (males) or 106 (females) weeks. Survival and Body Weights: Survival of male and female mice was similar to the chamber controls. Mean body weights of exposed groups of males were similar to those of the chamber controls throughout the study; mean body weights of exposed groups of females were greater than those of the chamber controls from week 13 until the end of the study. Pathology Findings: Exposure-related nonneoplastic lesions in the lung of all groups of exposed mice included suppurative focal inflammation, chronic focal inflammation, histiocyte cellular infiltration, alveolar epithelial hyperplasia, and proteinosis. Increased incidences of minimal lymphoid hyperplasia of the tracheobronchial lymph node occurred in mice exposed to 1.0 mg/m(3) and in 0.5 mg/m(3)mg/m(3) males. GENETIC TOXICOLOGY: Gallium arsenide was not mutagenic in several strains of Salmonella typhimurium, with or without S9 metabolic activation enzymes, and no increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to gallium arsenide by inhalation for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of gallium arsenide in male F344/N rats exposed to 0.01, 0.1, or 1.0 mg/m(3). There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of benign and malignant neoplasms in the lung. Increased incidences of benign neoplasms of the adrenal medulla and increased incidences of mononuclear cell leukemia were also considered to be exposure related. There was no evidence of carcinogenic activity in male or female B6C3F1 mice exposed to 0.1, 0.5, or 1.0 mg/m(3). Exposure to gallium arsenide caused a spectrum of nonneoplastic lesions in the lung of rats and mice, the larynx of male rats and hyperplasia of the tracheobronchial lymph node in mice. Synonym: Gallium monoarsenide.
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PMID:NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1256 48

Methyleugenol is used as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish, and ice cream. It is also used as a fragrance in perfumes, creams, lotions, detergents, and soaps. Methyleugenol has also been used as an insect attractant in eradication programs and as an anesthetic in rodents. Methyleugenol was nominated for testing because of its widespread use and because of its structural resemblance to safrole, a known carcinogen, and isosafrole and estragole. Male and female F344/N rats and B6C3F1 mice received methyleugenol (approximately 99% pure) in 0.5% methylcellulose by gavage for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 9 or 10 male and 10 female F344/N rats were administered 0, 10, 30, 100, 300, or 1,000 mg methyleugenol/kg body weight in 0.5% methylcellulose by gavage 5 days per week for 14 weeks. A water control group of 10 male and 10 female rats received deionized water by gavage. All rats survived until the end of the study. The final mean body weights of 300 and 1,000 mg/kg males and of all dosed groups of females were significantly less than those of the vehicle controls. Erythrocyte microcytosis was demonstrated by decreased mean cell volumes in 300 mg/kg males and 1,000 mg/kg males and females. There was evidence of a thrombocytosis at all time points, demonstrated by increased platelet counts in the 100 mg/kg or greater groups. The serum activities of alanine aminotransferase and sorbitol dehydrogenase were increased in the 100 mg/kg or greater rats at various time points, suggesting hepatocellular injury. Additionally, bile acid concentrations were generally increased in the 300 and 1,000 mg/kg groups at all time points, consistent with cholestasis or altered hepatic function. A hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations, occurred in rats in the 300 and 1,000 mg/kg groups at all time points. Liver weights of 100, 300, and 1,000 mg/kg males and 300 and 1,000 mg/kg females and testis weights of 1,000 mg/kg males were significantly increased. Increased incidences of liver lesions occurred in 300 and 1,000 mg/kg males and females and hepatocellular adenoma occurred in one 1,000 mg/kg male. The incidences of atrophy and chronic inflammation of the mucosa of the glandular stomach were significantly increased in rats administered 300 or 1,000 mg/kg. Increased incidences of adrenal gland cortical hypertrophy and/or cytoplasmic alteration in the submandibular gland occurred in the 100 mg/kg or greater groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice received methyleugenol in 0.5% methylcellulose by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg, 5 days per week for 14 weeks. A water control group of 10 male and 10 female mice received deionized water by gavage. All but one male and all females receiving 1,000 mg/kg died before the end of the study. The mean body weight gains of mice in the 300 mg/kg groups were significantly less than those of the vehicle controls. The only clinical finding was toxicity manifested as generalized morbidity in mice administered 1,000 mg/kg. Liver weights of 30, 100, and 300 mg/kg males and of 300 mg/kg females were significantly increased. Male mice administered 10 or 30 mg/kg had significantly lower cauda epididymis, epididymis, and testis weights; males receiving 100 mg/kg had significantly lower spermatozoal concentrations. Increased incidences of liver lesions occurred in 1,000 mg/kg males and 300 and 1,000 mg/kg females. The incidences of lesions of the glandular stomach were increased in one or more groups administered 30 mg/kg or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats received methyleugenol in 0.5% methylcellulose by gavage at doses of 37, 75, or 150 mg/kg, 5 days per week for 105 weeks; groups of 60 male and 60 female rats received the 0.5% me60 female rats received the 0.5&percnt; methylcellulose vehicle only. Stop-exposure groups of 60 male and 60 female rats received 300 mg/kg in 0.5&percnt; methylcellulose by gavage for 52 weeks followed by just the 0.5&percnt; methylcellulose vehicle for the remaining 53 weeks of the study. Special study groups of 10 male and 10 female rats administered 36, 75, 150, or 300 mg/kg were designated for toxicokinetic studies. Survival and Body Weights: All 150 and 300 mg/kg males died before the end of the study, and survival of 150 mg/kg females was slightly less than that of the vehicle controls. Mean body weights of all dosed groups of rats were less than those of the vehicle controls throughout most of the 2-year study. Pathology Findings: Chemical-related liver neoplasms occurred in all dosed groups of rats and included hepatocellular adenoma, hepatocellular carcinoma, hepatocholangioma, and hepatocholangiocarcinoma; at 2 years, there were positive trends in the incidences of hepatocellular adenoma, carcinoma, and adenoma or carcinoma (combined) in core study rats and in the numbers of rats with multiple liver neoplasms. Nonneoplastic lesions included eosinophilic and mixed cell foci, hepatocellular hypertrophy, oval cell hyperplasia, cystic degeneration, and bile duct hyperplasia (females); the incidences of these lesions in dosed groups of male and female rats were increased at 6 months, 12 months, and/or 2 years. Chemical-related neoplasms and nonneoplastic lesions of the glandular stomach included benign and malignant neuroendocrine tumors in the 150 and 300 mg/kg groups and females in the 75 mg/kg group. In all dosed groups of rats at all time points, the incidences of mucosal atrophy were significantly greater than in the vehicle controls. Neuroendocrine cell hyperplasia was observed in females at 6 months and males and females at 12 months and at 2 years. In core study female rats, there was a positive trend in the incidences of squamous cell papilloma or carcinoma (combined) of the forestomach, and the incidence in the 150 mg/kg group exceeded the historical control range. The incidences of renal tubule proliferative lesions in male rats were suggestive of a neoplastic effect in the kidney. Therefore, additional step sections of the kidneys of male rats were prepared. The incidences of renal tubule hyperplasia and adenoma in the extended evaluation and the combined incidences of standard and step sections in the 75, 150, and 300 mg/kg groups were greater than those in the vehicle controls. The incidences of nephropathy were increased in all dosed groups of females, and the increase was significant in the 300 mg/kg group. In dosed groups of male rats, there was a positive trend in the incidences of malignant mesothelioma, and the incidences were significantly greater in 150 and 300 mg/kg males than in the vehicle controls. The incidences of mammary gland fibroadenoma in 75 and 150 mg/kg males were significantly increased. The incidences of fibroma of the subcutaneous tissue in 37 and 75 mg/kg males and the combined incidences of fibroma or fibrosarcoma in 37, 75, and 150 mg/kg males were significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice received methyleugenol in 0.5&percnt; methylcellulose by gavage at doses of 0, 37, 75, or 150 mg/kg for 105 weeks. Special study groups of 10 male and 10 female mice administered 37, 75, or 150 mg/kg were designated for toxicokinetic studies. Survival and Body Weights: Survival of all dosed groups of male mice was similar to that of the vehicle controls. Survival of dosed groups of females was significantly less. Mean body weights of dosed mice were generally less than those of the vehicle controls throughout the studies. Pathology Findings: Chemical-related increases in the incidences of liver neoplasms and nonneoplastic lesions in mice included hepatocellular adenoma and carcinoma, hepatoblastoma, hepatocholangiocarcinoma, eosinophilic foci, oval cell hyperplasia, bile duct hyperplasia, hemosiderin pigmentation, chronic active inflammation, and hematopoietic cell proliferation. In all dosed groups ofmales and females, the incidences of hepatocellular neoplasms and the multiplicity of neoplasms were generally greater than in the vehicle controls. The incidences of hepatoblastoma were significantly increased in all dosed groups of females and slightly increased in 150 mg/kg males. Hepatocholangiocarcinoma was observed in 150 mg/kg females. The incidences of eosinophilic foci, oval cell hyperplasia, portal hypertrophy, hepatocyte necrosis, hematopoietic cell proliferation, bile duct hyperplasia, and hemosiderin pigmentation were significantly increased in two or more dosed groups of male and/or female mice. The incidences of glandular ectasia, mucosal atrophy, chronic active inflammation, epithelial hyperplasia, and neuroendocrine cell hyperplasia of the glandular stomach were increased in one or more dosed groups of male and female mice. In addition, malignant neuroendocrine tumors were observed in the glandular stomach of two 150 mg/kg male mice; one male in this group had a carcinoma. TOXICOKINETIC STUDIES: Methyleugenol is rapidly absorbed following oral administration to rats and mice. The kinetic data are consistent with rapid clearance from the blood, metabolism in the liver, and excretion of the parent and various metabolites in the urine. GENETIC TOXICOLOGY: Methyleugenol was not mutagenic in S. typhimurium strain TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). In cytogenetic tests with cultured Chinese hamster ovary cells, methyleugenol induced sister chromatid exchanges in the presence of S9, but no induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells following exposure to methyleugenol, with or without S9. In vivo, no increase in the frequency of micronucleated normochromatic erythrocytes was seen in male or female mice administered methyleugenol by gavage for 14 weeks. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL: A physiologically based pharmacokinetic (PBPK) model resulting from intravenous and oral exposure was created to characterize tissue concentrations of methyleugenol in rats and mice. Data used to create the model were obtained from the literature or from current studies. The primary conclusions that can be reached from the PBPK model are: 1) absorption of oral doses of methyleugenol in rats and mice is rapid and complete, 2) distribution of methyleugenol to tissues is not hampered by capillary permeability, and 3) metabolism of methyleugenol is saturable and must have some extrahepatic component in the mouse. Model-based plasma methyleugenol concentrations were not found to be good dosimeters for evaluating neoplasm dose-response data. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of methyleugenol in male and female F344/N rats based on the increased incidences of liver neoplasms and neuroendocrine tumors of the glandular stomach in male and female rats and the increased incidences of kidney neoplasms, malignant mesothelioma, mammary gland fibroadenoma, and subcutaneous fibroma and fibroma or fibrosarcoma (combined) in male rats. A marginal increase in the incidence of squamous cell neoplasms of the forestomach may have been related to methyleugenol administration in female rats. There was clear evidence of carcinogenic activity of methyleugenol in male and female B6C3F1 mice based on the increased incidences of liver neoplasms. Neuroendocrine tumors of the glandular stomach in male mice were also considered related to methyleugenol administration. In male and female rats and mice, methyleugenol administration caused significant increases in nonneoplastic lesions of the liver and glandular stomach. Synonyms: 1-Allyl-1,2-dimethoxybenzene; 4-allylveratrole; 4-allyl-1,2-dimethoxy-benzene; 1,2-dimethoxy-4-allylbenzene; 3,4-dimethoxyallylbenzene; ENT 21040; 1-(3,4-dimethoxyphenyl)-2-propene; eugenol methyl ether; 1,3,4-eugenol methyl ether; veratrole methyl ether.
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PMID:NTP Toxicology and Carcinogenesis Studies of Methyleugenol (CAS NO. 93-15-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1256 49

Oxymetholone is a synthetic anabolic steroid used to treat a variety of conditions, including hypogonadism and delayed puberty. It is also used to correct hereditary angioneurotic edema, manage carcinoma of the breast, promote a positive nitrogen balance following injury or surgery, and stimulate erythropoiesis. Considerable amounts of androgens are consumed by athletes in attempts to improve athletic performance. The National Institute of Environmental Health Sciences and the National Cancer Institute nominated oxymetholone for study based on its extensive illicit pharmaceutical use and the limited evidence that it is a potential human carcinogen. Male and female F344/N rats received oxymetholone (greater than 99% pure) in 0.5% methylcellulose by gavage for 16 days, 14 weeks, or 2 years, and male and female B6C3F1 mice received oxymetholone in 0.5% methylcellulose by gavage for 16 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 160, 315, 625, 1,250, or 2,500 mg oxymetholone/kg body weight in 0.5% methylcellulose by gavage for 16 days. All male rats survived to the end of the study; one 2,500 mg/kg female died on day 14. The mean body weights of all dosed groups of males were significantly less than those of the vehicle controls, while those of 160 and 315 mg/kg females were significantly greater. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were administered 0, 320, 630, 1,250, 2,500, or 5,000 mg/kg in 0.5% methylcellulose by gavage for 16 days. All mice survived to the end of the study. The final mean body weights of all dosed groups of females were greater than those of the vehicle controls. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 80, 160, 315, 625, or 1,250 mg/kg in 0.5% methylcellulose by gavage for 14 weeks. One male rat each in the 625 and 1,250 mg/kg groups died before the end of the study. The mean body weights of males administered 160 mg/kg or greater were significantly less than those of the vehicle controls; in contrast, the mean body weights of all dosed groups of females were significantly greater. A dose-related erythrocytosis, evidenced by increases in erythrocyte counts, total hemoglobin concentrations, and hematocrit values, occurred in dosed groups of rats at week 14. A dose-related hypocholesterolemia occurred at all time points in all dosed groups of rats. Dose- and time-related decreases in 5 -nucleotidase activity occurred in treated rats. There was a transient, treatment-related increase in the activity of alanine aminotransferase in males and females. For male rats administered oxymetholone, cauda epididymis, epididymis, and testis weights and spermatid counts and total spermatid heads per testis were significantly less than those of the vehicle controls, and total spermatid heads per gram testis were significantly greater. Female rats in the 80 mg/kg group spent more time in diestrus and less time in estrus than did the vehicle controls. Kidney weights of males and females and liver and uterus weights of females were increased compared to vehicle controls in rats that received 315 mg/kg or greater; thymus weights of males and females and sartorius muscle and testis weights of males were less. Compared to the vehicle controls, rats that received 160 mg/kg or greater had increased incidences of nonneoplastic lesions of the kidney and mammary gland, and the incidences of hydrometra of the uterus and dysgenesis of the ovary were increased in dosed groups of females. Female rats administered 315 mg/kg or greater had increased incidences of cytoplasmic vacuolization of the adrenal gland and myocardial degeneration of the heart. The severities of these lesions generally increased with increasing dose. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 0, 160, 320, 630, 1,250, or 2,500 mg/kged 0, 160, 320, 630, 1,250, or 2,500 mg/kg in 0.5&percnt; methylcellulose by gavage for 14 weeks. All mice administered oxymetholone survived until the end of the study. The mean body weights of all dosed groups were similar to those of the vehicle controls. The percentages of motile sperm in 1,250 and 2,500 mg/kg males were significantly less than those of the vehicle controls. The estrous cycle lengths of 630, 1,250, and 2,500 mg/kg females were significantly longer, and females in the 1,250 and 2,500 mg/kg groups spent more time in diestrus and less time in estrus. Kidney and liver weights of males and females were greater and thymus weights of females were less than those of the vehicle controls. All dosed females had hyperplasia of the clitoral gland, metaplasia of the parietal layer epithelium of the Bowman's capsule in the kidney, and cytoplasmic alteration of the submandibular gland; these lesions were not observed in the vehicle control group. The incidences of hypoplasia of the ovary in 320 mg/kg or greater females and of parotid gland atrophy in 1,250 and 2,500 mg/kg females were increased. The results of the 14-week oral gavage studies were generally similar in rats and mice, but rats were much more sensitive to oxymetholone. Because it was not likely that a long-term mouse study would provide significant additional toxicity information, the NTP decided to conduct a 2-year study in rats only. 2-YEAR STUDY IN RATS: Groups of 90 male F344/N rats were administered 0, 3, 30, or 150 mg/kg in 0.5&percnt; methylcellulose by gavage, and 90 female F344/N rats were administered 0, 3, 30, or 100 mg/kg in 0.5&percnt; methylcellulose by gavage for up to 104 weeks, with 9 or 10 rats per group evaluated at 3, 6, 12, or 18 months. Survival and Body Weights: Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of the 30 mg/kg male group were generally within 10&percnt; of those of the vehicle controls, but those of the 150 mg/kg group were markedly decreased. Mean body weights of 3 and 30 mg/kg females were generally greater than those of the vehicle controls throughout the study. Determinations of Oxymetholone in Plasma: The concentrations of oxymetholone in plasma of male and female rats receiving 3 mg/kg for 6, 12, or 18 months were generally below the limits of quantification; therefore, all plasma concentrations in the 3 mg/kg group are considered to be estimates (Table 8). The plasma concentrations at 30 mg/kg were approximately one order of magnitude greater than those of the estimates for males and females receiving 3 mg/kg. There were no dose-related differences in plasma concentrations in female rats receiving 30 or 100 mg/kg, but plasma concentrations in males were significantly elevated in the 150 mg/kg group. It was concluded that oxymetholone kinetics was saturated at 30 mg/kg in female but not male rats. Pathology Findings: A wide spectrum of neoplasms and nonneoplastic lesions was seen in rats administered oxymetholone for 2 years. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in 100 mg/kg females as were the incidences of basophilic and clear cell foci in 150 mg/kg males and 100 mg/kg females compared to vehicle controls. The incidences of alveolar/bronchiolar adenoma and adenoma or carcinoma (combined) were significantly increased in 30 mg/kg females. The incidences of mineralization in the lung of 150 mg/kg males and 30 and 100 mg/kg females were significantly increased. The incidence of keratoacanthoma was increased in 30 mg/kg females, and the combined incidence of squamous cell papilloma, keratoacanthoma, basal cell adenoma, squamous cell carcinoma, or carcinoma of the sweat gland was significantly increased in 100 mg/kg females. The incidences of subcutaneous tissue fibroma and fibroma or fibrosarcoma (combined) were significantly increased in 3 mg/kg males. At 2 years, the incidences of benign pheochromocytoma and benign or malignant pheochromocytoma (combined) of the adrenal gland in 150 mg/kg males and medullary hyperplasia in 100 mg/kg females were significantly increased. The incidences of cytoplasmic vacuolization of adrenal cortical cells were significantly increased in 30 and 150 mg/kg males at 18 months and 2 years and in 100 mg/kg females beginning at 12 months and in 30 mg/kg females at 2 years. The incidences of renal tubule adenoma in 3 and 150 mg/kg males were slightly increased. An extended evaluation of the kidney was conducted, and additional incidences of renal tubule adenoma were observed in step sections in vehicle control and dosed male rats. The combined single- and step-section incidence of renal tubule adenoma was significantly increased in 3 mg/kg males. The incidences of nephropathy were significantly increased in 30 and 150 mg/kg males at 2 years and in 100 mg/kg females beginning at 3 months. The severities of nephropathy were significantly increased in dosed groups of males at 2 years and in 100 mg/kg females at 18 months and 2 years. The incidences of mineralization of the kidney were significantly increased in 150 mg/kg males at all time points. The incidences of ovarian dysgenesis were significantly increased in 100 mg/kg females beginning at 3 months and in 30 mg/kg females beginning at 6 months, and severities increased with increasing dose. The incidences of chronic myocardial degeneration (cardiomyopathy) were significantly increased in 100 mg/kg females at 6 months and 2 years and the severity was increased at 2 years. The incidences of lobular hyperplasia were increased in 150 mg/kg males at 18 months and 2 years and in 30 and 100 mg/kg females at all time points. The incidences of seminiferous tubule degeneration were significantly increased in 30 and 150 mg/kg males at 2 years, and the incidences of mineralization of the testis were increased in 150 mg/kg males at 12 months and in 30 mg/kg males at 18 months and at 2 years. Decreased incidences of neoplasms occurred in male and female rats. The incidence of uterine stromal polyp or stromal sarcoma (combined) was significantly decreased in 100 mg/kg females at 2 years. The incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) were significantly decreased in all dosed groups of females. The incidences of pituitary gland pars distalis adenoma were significantly decreased in 30 and 100 mg/kg females at 2 years. The incidences of testicular interstitial cell adenoma were significantly decreased in 30 and 150 mg/kg males at 18 months and in all dosed groups at 12 months and 2 years. The incidences of mononuclear cell leukemia were significantly decreased in 30 and 150 mg/kg males and 100 mg/kg females at 2 years. GENETIC TOXICOLOGY: Oxymetholone was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535, with or without S9 metabolic activation. It did not induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9, and no increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood samples from male or female mice treated for 14 weeks with oxymetholone. CONCLUSIONS: Under the conditions of this 2-year gavage study, there was equivocal evidence of carcinogenic activity of oxymetholone in male F344/N rats based on increased incidences of subcutaneous tissue fibromas and fibromas or fibrosarcomas (combined) of the skin, variably increased incidences of benign and benign or malignant pheochromocytomas (combined) of the adrenal gland, and increased incidences of renal tubule adenomas. There was clear evidence of carcinogenic activity of oxymetholone in female F344/N rats based on increased incidences of hepatocellular neoplasms. Increased incidences of alveolar/bronchiolar neoplasms and skin neoplasms in female rats were also related to oxymetholone administration. Decreased incidences of alveolar/bronchiolar neoplasms and testicular interstitial cell adenomas in males; uterine stromal polyps or stromal sarcomas (combined), mammary gland neoplasms, and pituitary gland pars distalis adenomas in females; and mononuclear cell leukemia in males and females were related to oxymetholone administration. In addition, gavage administration of oxymetholone to male and female F344/N rats resulted in a spectrum of nonneoplastic effects frequently reported with administration of synthetic anabolic androgens. Synonyms: Adroidin; anadroyd; anasteron; anasteronal; anasterone; androstan-3-one, androstano[2,3-c]1,2,5-oxadiazol-17-ol, 17-methyl-, (5-a,17-b)-; becorel; 4,5-dihydro-2-hydroxymethylene-17-a-methyltestosterone; dynasten; HMD; 17b-hydroxy-2- (hydroxymethyl)-17-methyl-5-a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-(5-a,17-b)-; 17-hydroxy- 2-(hydroxymethylene)-17-methyl-5-a-17-b-androst-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-a-methyl-5-a-androstan-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-methyl-5a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-5-a-17- b-androstan-3-one; 17b-hydroxy-2-hydroxymethylene-17a-methyl-3-androstanone; 2-hydroxymethylene-17-a-methyl-5- a-androstan-17-b-ol-3-one; 2-hydroxymethylene-17a-methyl dihydrotestosterone; 2-hydroxymethylene-17-a-methyl-17-b- hydroxy-3-androstanone; methabol; 17a-methyl-2-hydroxymethylene-17-hydroxy-5-a-androstan-3-one; oximetholonum; oximetolona; oxitosona-50; oxymethenolone; roboral; zenalosyn Trade names: Adroyd; Anadrol; Anapolon; Anapolon 50; Nastenon; Pardroyd; Pavisoid; Plenastril; Protanabol; Synasteron
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PMID:NTP Toxicology and Carcinogenesis Studies of Oxymetholone (CAS NO. 434-07-1) in F344/N Rats and Toxicology Studies of Oxymetholone in B6C3F1 Mice (Gavage Studies). 1257 78

[molecular structure: see text] p-tert-Butylcatechol is used as an antioxidant, stabilizer, and polymerization inhibitor for styrene, butadiene, neoprene, and other olefins and reactive monomers. p-tert-Butylcatechol was nominated by the National Cancer Institute and the U.S. Food and Drug Administration for testing based on reports of its increasing levels of production and use and to compare the toxicity of p-tert-butylcatechol with that of similar antioxidants, butylated hydroxyanisole and butylated hydroxytoluene, which are added to food. Male and female F344/N rats and B6C3F1 mice were exposed to p-tert-butylcatechol (greater than 99% pure) in feed for 15 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, rat bone marrow cells, and mouse peripheral blood erythrocytes. In the 15-day studies, groups of five male and five female rats and mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 290 to 2,470 mg p-tert-butylcatechol/kg body weight to rats and 590 to 8,200 mg/kg to mice). All animals in the 50,000 ppm groups were killed moribund on day 8 (rats) or by day 7 (mice). Mean body weights of all groups of rats exposed to 6,250 ppm or greater were significantly less than those of the controls. Mean body weights of male mice exposed to 12,500 or 25,000 ppm and of 25,000 ppm female mice were significantly less than those of the controls. Female rats, male and female mice in the 25,000 ppm groups, and 12,500 ppm male mice lost weight during the studies. Feed consumption by exposed rats generally decreased with increasing exposure concentration; feed consumption by exposed mice was similar to that by the controls. Thymus weights of 25,000 ppm rats and mice were significantly less than those of the controls. Gross findings noted at necropsy included thin carcasses for three male and all female rats in the 12,500 ppm groups and all male and female rats and mice in the 25,000 and 50,000 ppm groups. No exposure-related lesions were observed microscopically. In the 14-week studies, groups of 10 male and 10 female rats and mice were fed diets containing 0, 781, 1,562, 3,125, 6,250, or 12,500 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 70 to 1,030 mg/kg to rats and 135 to 2,815 mg/kg to mice). All animals survived to the end of the studies. Mean body weights of male rats exposed to 1,562 ppm or greater, female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm were significantly less than those of the controls. Feed consumption by male and female rats in the 6,250 and 12,500 ppm groups at week 1 and the 12,500 ppm groups at week 14 was less than that by the controls; feed consumption by exposed and control mice was similar. An erythrocytosis, indicated by increased hematocrit values, hemoglobin concentrations, and erythrocyte counts, was observed in 6,250 and 12,500 ppm rats on day 4 and in 12,500 ppm rats on day 22. At these time points, a transient hepatic effect was demonstrated by increases in alanine aminotransferase activities and bile salt concentrations in exposed rats. In 12,500 ppm male rats, absolute left cauda epididymis, epididymis, and testis weights were decreased by 15%, 10%, and 9%, respectively, compared to the controls. The number of spermatid heads per testis and epididymal sperm motility of male rats in the 12,500 ppm group were significantly less than those of the controls. The numbers of cycling female rats and females with regular estrous cycles were decreased in the 6,250 and 12,500 ppm groups. Exposed groups of females had significantly fewer estrous cycles than did the controls. Estrous cycle length increased with increasing exposure concentration; female rats in the 6,250 and 12,500 ppm groups had significantly longer cycles and spent more time in diestrus and less time in proestrus, estrus, and metestrus than did the controls. Female mice in the 12,500 ppm group had a significantly longer estrous cycle than did the controls. The incidences of hyperkeratosis of the forestomach epithelium were significantly increased in male and female rats in all exposed groups and in 12,500 ppm female mice. The incidences of hyperplasia of the forestomach epithelium were significantly increased in male and female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm. The severities of the forestomach lesions were minimal to moderate in male rats and minimal to mild in female rats and in mice. All male rats exposed to 6,250 or 12,500 ppm had minimal cytoplasmic alteration in the liver. The absorption, distribution, metabolism, and excretion of p-tert-butylcatechol following intravenous injection, gavage dosing, or dermal application were determined in male F344/N rats and B6C3F1 mice. The absorption of [(14)C]-p-tert-butylcatechol following gavage dosing or dermal application was high. The percent absorption following dermal application increased with increasing dose. Peak concentrations of [(14)C]-p-tert-butylcatechol equivalents in plasma were reached 1 hour after gavage dosing (200 mg/kg) and 2 hours after dermal application (60 mg/kg); no parent compound was detected in the plasma extracts. Regardless of route of administration, p-tert-butylcatechol derived radioactivity was readily excreted in the urine and was markedly nonpersistent in the tissues. p-tert- Butylcatechol was excreted as p-tert-butylcatechol sulfate and other polar metabolites that included predominately sulfate conjugates; it was not excreted as the parent compound. One metabolite was determined to be an O-methyl- ON-sulfate of p-tert-butylcatechol. p-tert-Butylcatechol (10 to 1,000 microg/plate) was not mutagenic in any of several strains of S. typhimurium with or without rat or hamster liver S9. Bone marrow micronucleus tests in which 125 to 500 mg/kg p-tert-butylcatechol was administered three times by intraperitoneal injection to male rats gave negative results. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in the peripheral blood of male or female mice administered p-tert-butylcatechol in feed for 14 weeks. No significant alteration in the percentage of polychromatic erythrocytes in mouse bone marrow was observed. In summary, the primary toxicity of p-tert-butylcatechol was to the forestomach of rats and mice. In the 14-week study in rats, forestomach toxicity was observed at all exposure concentrations, and the no-observed-adverse-effect level (NOAEL) was not reached for this effect. In the 14-week study in mice, the NOAEL for forestomach toxicity was 1,562 ppm.
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PMID:NTP technical report on the toxicity studies of p-tert-butylcatechol (CAS No. 98-29-3) administered in feed to F344/N rats and B6C3F1 mice. 1259 14

Toxicological effect of 3-chloro-1,2-propanediol on rats were studied to provide scientific basis for assessing the effect of Chloropropanols on human health. 170 SD rats were divided randomly into 8 groups and the dose of 0, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 16.0 mg/kg 3-chloro-1,2-propanediol were given to rats for 90 days by gavages per day, respectively. The weight and food efficiency, hematology and clinical chemistry, NAG, GGT and total protein in urine, sperm number, sperm survive rate and sperm aberration rate, the LDH and LDH-X activity in testis, rate of organ/weight and histopathological analysis were measured. The results showed that different dose of 3-chloro-1,2-propanediol did not has adverse effect on body weight, food efficiency, Hb, red cell, white cell, serum AST, ALT, creatine, ALP, LDH, total protein and albumin, urine GGT and total protein, LDH activity in testis. At the dose of 4.0, 8.0 and 16.0 mg/kg group, the activity of NAG in urine and the rate of kidney/weight was significantly increased compared with negative control groups; the pathological changes in kidney were observed in the same groups, and the sperm number was also significantly decreased. At the dose of 8.0 and 16.0 mg/kg group, sperm survive rate and the X-LDH activity were significantly decreased and pathological changes were also observed in testis and caudal epididymis. It was concluded that the activity of NAG in urine and sperm number is the sensitive biological effective marker. Because urine is a kind of convenient available biological material, NAG activity in urine is a good biological effective marker for assessing effect of Chloropropanols on health. If the NAG activity can be used as sensitive marker for assessment on human health need to be tested further in human study.
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PMID:[Study on the toxicological effect of chloropropanols on rats]. 1453 99

[Structure-see text] 2-Methylimidazole and 4-methylimidazole are intermediate/starting materials or components in the manufacture of pharmaceuticals, photographic and photothermographic chemicals, dyes and pigments, agricultural chemicals, and rubber; these chemicals have been identified as undesirable by-products in several foods and have been detected in mainstream and sidestream tobacco smoke. The National Cancer Institute nominated 2- and 4-methylimidazole as candidates for toxicity and carcinogenicity studies. Toxicity studies were carried out in male and female F344/N rats and B6C3F1 mice. Animals were exposed to 2- or 4-methylimidazole in feed for 15 days or 14 weeks; clinical pathology studies were conducted in the 14-week studies on days 8, 29, and 86 and at week 14. Genetic toxicity studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. Groups of five male and five female rats and mice were fed diets containing 0, 1,200, 3,300, or 10,000 ppm 2-methylimidazole (equivalent to average daily doses of approximately 115, 290, or 770 mg 2-methylimidazole/ kg body weight to rats; 220, 640, or 2,100 mg/kg to male mice; 300, 800, or 2,400 to female mice) for 15 days. Groups of five male and five female rats and mice were fed diets containing 0, 300, 800, or 2,500 ppm 4-methylimidazole (equivalent to average daily doses of approximately 30, 80, or 220 mg/kg for rats and 65, 170, or 500 mg/kg for mice) for 15 days. In the 15-day 2-methylimidazole studies, all animals survived to the end of the studies. The mean body weights of 10,000 ppm male rats and female mice were significantly less than those of the controls. Feed consumption by 10,000 ppm male and female rats was reduced. Enlarged thyroid glands were observed in 3,300 and 10,000 ppm male and female rats. The incidences of diffuse hyperplasia of follicular cells of the thyroid gland in 3,300 and 10,000 ppm male and female rats and pars distalis hypertrophy of the pituitary gland in 3,300 and 10,000 ppm males and 10,000 ppm females were increased compared to the controls. In all exposed groups of male and female mice, the incidences and severities of follicular cell hypertrophy of the thyroid gland and the severities of hematopoietic cell proliferation of the spleen generally increased with increasing exposure concentration. In the 4-methylimidazole studies, all animals survived to the end of the studies, and there were no significant differences in mean body weights, clinical findings, organ weights, or gross or microscopic lesions between exposed and control groups. Groups of 10 male and 10 female rats and mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2- or 4-methylimidazole (equivalent to average daily doses of approximately 40, 80, 160, 300, or 560 mg/kg 2- or 4-methylimidazole to rats; and 100, 165, 360, 780, or 1,740 mg/kg 2-methylimidazole or 100, 240, 440, 915, or 1,840 mg/kg 4-methylimidazole to male mice; and 90, 190, 400, 800, or 1,860 mg/kg 2-methylimidazole or 110, 240, 540, 1,130, or 3,180 mg/kg 4-methylimidazole to females) for 14 weeks. All animals survived to the end of the 14-week 2-methylimidazole studies. Compared to the controls, the mean body weights were significantly decreased in groups of male rats and mice exposed to 2,500 ppm or greater and in 5,000 and 10,000 ppm female rats and mice. In rats, 2-methylimidazole induced a transient erythrocytosis in females and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia. 2-Methylimidazole increased thyroid-stimulating hormone concentrations and decreased thyroxine and triiodothyronine concentrations of male and female rats in an exposure concentration-related manner. 2-Methylimidazole induced a mild to moderate, exposure concentration-related, macrocytic, hyperchromic, responsive anemia in mice. Triiodothyronine concentrations were increased in exposed male and female mice, and thyroxine concentrations were decreased in exposed females. Relative to the control groups, clinical chemistry evaluations on day 29 and at week 14 identified decreases in alanine aminotransferase concentrations and total protein and albumin concentrations of rats. In the 2-methylimidazole studies, absolute spleen weights were significantly increased in all exposed groups of male rats. The heart and liver weights were increased in all exposed groups of male mice, as were the spleen weights of female mice exposed to 2,500 ppm or greater. Spermatid heads per testis and mean spermatid count were significantly decreased in 10,000 ppm male rats. The estrous cycle of 10,000 ppm female rats was significantly increased. Gross pathology observations included enlarged thyroid glands, small uteri, and mottled spleen in 5,000 and 10,000 ppm mice. The incidences of diffuse follicular cell hyperplasia of the thyroid gland were significantly increased in male rats exposed to 1,250 ppm or greater and female rats exposed to 2,500 ppm or greater. The incidence of testicular degeneration was significantly increased in 10,000 ppm male rats, and two males in the 10,000 ppm group had follicular cell adenoma of the thyroid gland. In mice, there were generally significant increases in the incidences of follicular cell hypertrophy of the thyroid gland, hematopoietic cell proliferation of the spleen, and hemosiderin pigmentation of the renal tubule in males exposed to 1,250 ppm or greater and females exposed to 2,500 ppm or greater. In the 14-week 4-methylimidazole studies, one 10,000 ppm male mouse was found dead during week 4, and seven 10,000 ppm female mice were found dead during weeks 1 and 2. Mean body weights were significantly less than those of the controls for male rats exposed to 2,500 ppm or greater, 5,000 and 10,000 ppm female rats, male mice exposed to 1,250 ppm or greater, and all exposed groups of female mice. Reduced feed consumption was observed in 5,000 and 10,000 ppm male and female rats. Clinical findings included nasal/eye discharge, ruffled fur, thinness, ataxia, and abnormal breathing in rats, and ruffled fur and dull coats in female mice. On days 29 and 82, functional observations in 5,000 and 10,000 ppm rats included labored or increased respiration, mild tremors, walking on tiptoes, hunched posture, piloerection, crouching over, impaired coordination of movement, ataxia, and pupillary constriction. 4-Methylimidazole induced a transient erythrocytosis and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia in male and female rats. Clinical chemistry evaluations generally showed a cholestatic effect in exposed male and female rats. At week 14, there was a significant decrease in total protein and albumin concentrations of female rats exposed to 5,000 or 10,000 ppm. In mice, 4-methylimidazole induced a macrocytic, hyperchromic, responsive anemia and, particularly in males, increases in triiododthyronine concentrations and transient decreases in thyroxine concentrations. In the 4-methylimidazole studies, the liver weights of male rats exposed to 2,500 ppm or greater were significantly increased; spleen weights of female rats exposed to 2,500 ppm or greater were decreased. The absolute liver weight was decreased in 10,000 ppm male mice, and relative weights were significantly increased in all exposed groups of mice. In female mice, there was a significant decrease in the absolute weights and increase in the relative weights of the heart, right kidney, and liver in groups exposed to 2,500 ppm or greater. The epididymal spermatozoal concentration was significantly increased in 5,000 ppm male rats. Gross pathology observations included pale livers in male rats exposed to 2,500 ppm or greater and small testes and uteri in 10,000 ppm male and female rats. Microscopic analysis identified significantly increased incidences of cytoplasmic hepatocyte vacuolization of the liver of male rats exposed to 2,500 ppm or greater and 10,000 ppm female rats, hypospermia of the epididymis in 10,000 ppm male rats, atrophy and inflammation of the prostate gland in 10,000 ppm male rats, and degeneration of the testes in 5,000 and 10,000 ppm male rats. 2-Methylimidazole and 4-methylimidazole were negative in the S. typhimurium mutation assay when tested in strains TA97, TA98, TA100, and TA1535, with and without S9 activation enzymes. Testing of 2-methylimidazole in vivo for induction of chromosomal damage, as measured by micronucleated erythrocyte frequency, produced mixed results. When administered by intraperitoneal injection three times at 24-hour intervals, 2-methylimidazole produced negative results in bone marrow micronucleus tests in rats and mice. However, in the 14-week study of 2-methylimidazole, a significant exposure-related increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood of male and female mice. In vivo, 4-methylimidazole produced uniformly negative results in three-injection bone marrow micronucleus tests in rats and mice and in 14-week peripheral blood micronucleus tests in male and female mice.
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PMID:NTP technical report on the toxicity studies of 2- and 4-Methylimidazole (CAS No. 693-98-1 and 822-36-6) administered in feed to F344/N rats and B6C3F1 mice. 1514 14


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