2-甲基咪唑和4-甲基咪唑(CAS编号693-98-1和822-36-6)在饲料中对F344/N大鼠和B6C3F1小鼠的毒性研究技术报告。

Toxicity report series Pub Date : 2004-04-01
P C Chan
{"title":"2-甲基咪唑和4-甲基咪唑(CAS编号693-98-1和822-36-6)在饲料中对F344/N大鼠和B6C3F1小鼠的毒性研究技术报告。","authors":"P C Chan","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>[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.</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":" 67","pages":"1-G12"},"PeriodicalIF":0.0000,"publicationDate":"2004-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"P C Chan\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>[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.</p>\",\"PeriodicalId\":23116,\"journal\":{\"name\":\"Toxicity report series\",\"volume\":\" 67\",\"pages\":\"1-G12\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2004-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicity report series\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicity report series","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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[结构-见文本]2-甲基咪唑和4-甲基咪唑是制造药品、照相和光热成像化学品、染料和颜料、农业化学品和橡胶的中间/起始材料或组分;这些化学物质已被确定为几种食品中的不良副产品,并已在主流和侧流烟草烟雾中检测到。美国国家癌症研究所提名2-甲基咪唑和4-甲基咪唑作为毒性和致癌性研究的候选药物。对雄性和雌性F344/N大鼠和B6C3F1小鼠进行了毒性研究。动物在饲料中分别暴露2-甲基咪唑和4-甲基咪唑15天或14周;在14周的研究中,分别于第8天、第29天、第86天和第14周进行临床病理研究。对鼠伤寒沙门菌、大鼠和小鼠骨髓以及小鼠外周血进行了遗传毒性研究。每组5只雄性和5只雌性大鼠和小鼠喂食含有0、1200、3300或10000 ppm 2-甲基咪唑的饲料(相当于大鼠平均每日剂量约为115、290或770毫克2-甲基咪唑/公斤体重);雄性小鼠220、640或2100 mg/kg;300、800或2400(雌性老鼠),持续15天。每组5只雄性和5只雌性大鼠和小鼠喂食含有0、300、800或2500 ppm 4-甲基咪唑的饲料(相当于大鼠的平均日剂量约为30、80或220毫克/公斤,小鼠的平均日剂量为65、170或500毫克/公斤)15天。在为期15天的2-甲基咪唑研究中,所有动物均存活至研究结束。10,000 ppm的雄性大鼠和雌性小鼠的平均体重明显低于对照组。减少了10,000 ppm雄性和雌性大鼠的饲料消耗。在3,300 ppm和10,000 ppm的雄性和雌性大鼠中观察到甲状腺肿大。与对照相比,3,300和10,000 ppm的雄性和雌性大鼠甲状腺滤泡细胞弥漫性增生和3,300和10,000 ppm的雄性和10,000 ppm的雌性垂体远侧肥大的发生率增加。在雄性和雌性各暴露组小鼠中,甲状腺滤泡细胞肥大的发生率和严重程度以及脾脏造血细胞增殖的严重程度普遍随暴露浓度的增加而增加。在4-甲基咪唑研究中,所有动物都存活到研究结束,暴露组和对照组在平均体重、临床表现、器官重量或肉眼或显微镜下病变方面没有显著差异。每组10只雄性和10只雌性大鼠和小鼠喂食含有0、625、1,250、2,500、5,000或10,000 ppm 2-或4-甲基咪唑的饲料(相当于对大鼠的平均日剂量约为40、80、160、300或560毫克/公斤2-或4-甲基咪唑;以及100、165、360、780或1,740毫克/公斤的2-甲基咪唑或100、240、440、915或1,840毫克/公斤的4-甲基咪唑雄性小鼠;以及90、190、400、800或1,860毫克/公斤2-甲基咪唑或110、240、540、1,130或3,180毫克/公斤4-甲基咪唑(雌性),持续14周。所有动物都存活到14周的2-甲基咪唑研究结束。与对照组相比,暴露于2500 ppm或更高浓度的雄性大鼠和小鼠组以及暴露于5000 ppm和10000 ppm的雌性大鼠和小鼠组的平均体重显著下降。在大鼠中,2-甲基咪唑诱导雌性短暂性红细胞增多和与暴露浓度相关的轻微、小细胞、常色、无反应性贫血。2-甲基咪唑增加了雄性和雌性大鼠的促甲状腺激素浓度,降低了甲状腺素和三碘甲状腺原氨酸浓度,并呈暴露浓度相关。2-甲基咪唑诱导小鼠轻度至中度、暴露浓度相关、大细胞性、高色素、反应性贫血。雌性和雄性小鼠的三碘甲状腺原氨酸浓度升高,雌性小鼠的甲状腺素浓度降低。与对照组相比,第29天和第14周的临床化学评估发现,大鼠的丙氨酸转氨酶浓度、总蛋白和白蛋白浓度下降。在2-甲基咪唑研究中,所有暴露组雄性大鼠的脾脏绝对重量均显著增加。所有暴露组的雄性小鼠的心脏和肝脏重量都增加了,暴露于2500 ppm或更高浓度的雌性小鼠的脾脏重量也增加了。在10,000 ppm的雄性大鼠中,每个睾丸的精子数和平均精子数显著降低。10000 ppm雌性大鼠的发情周期明显增加。大体病理观察包括5,000和10,000 ppm小鼠甲状腺肿大,子宫小,脾脏斑驳。 暴露于1,250 ppm或更高浓度的雄性大鼠和暴露于2,500 ppm或更高浓度的雌性大鼠中,甲状腺弥漫性滤泡细胞增生的发生率显著增加。在10,000 ppm的雄性大鼠中,睾丸变性的发生率显著增加,并且10,000 ppm组中的两只雄性有甲状腺滤泡细胞腺瘤。在小鼠中,暴露于1,250 ppm或更高浓度的雄性小鼠和暴露于2,500 ppm或更高浓度的雌性小鼠中,甲状腺滤泡细胞肥大、脾脏造血细胞增殖和肾小管含铁血黄素色素沉着的发生率普遍显著增加。在为期14周的4-甲基咪唑研究中,发现一只10,000 ppm的雄性小鼠在第4周死亡,7只10,000 ppm的雌性小鼠在第1周和第2周死亡。暴露于2500 ppm或更高浓度的雄性大鼠、暴露于5000 ppm和10000 ppm的雌性大鼠、暴露于1250 ppm或更高浓度的雄性小鼠以及所有暴露于该浓度的雌性小鼠组的平均体重明显低于对照组。在5000 ppm和10000 ppm的雄性和雌性大鼠中观察到饲料消耗减少。临床表现包括大鼠鼻/眼分泌物、毛皱褶、消瘦、共济失调和呼吸异常,雌性小鼠毛皱褶和被毛暗沉。在第29天和第82天,对5000 ppm和10000 ppm大鼠的功能观察包括呼吸困难或呼吸增加、轻度震颤、踮起脚尖走路、驼背姿势、竖毛、蹲伏、运动协调受损、共济失调和瞳孔收缩。在雄性和雌性大鼠中,4-甲基咪唑诱导了短暂性红细胞增多和与暴露浓度相关的轻微、小细胞、常色、无反应性贫血。临床化学评价普遍显示暴露的雄性和雌性大鼠的胆汁淤积作用。在第14周,暴露于5,000或10,000 ppm的雌性大鼠的总蛋白和白蛋白浓度显著下降。在小鼠中,4-甲基咪唑引起大细胞性、高色素性、反应性贫血,特别是在雄性小鼠中,三碘甲状腺原氨酸浓度升高,甲状腺素浓度短暂降低。在4-甲基咪唑研究中,暴露于2500 ppm或更高浓度的雄性大鼠肝脏重量显著增加;暴露于2500ppm或更高浓度的雌性大鼠脾脏重量下降。1万ppm雄性小鼠肝脏绝对重量降低,各暴露组小鼠肝脏相对重量均显著增加。在雌性小鼠中,暴露于2500 ppm或更高浓度的组中,心脏、右肾和肝脏的绝对重量显著减少,相对重量显著增加。5000ppm的雄性大鼠附睾精子浓度显著升高。大体病理观察包括暴露在ppm浓度为2500或更高的雄性大鼠的肝脏苍白,暴露在ppm浓度为10000的雄性和雌性大鼠的睾丸和子宫变小。显微镜分析发现,暴露于2500 ppm或更高浓度和10000 ppm的雄性大鼠的肝脏细胞质肝细胞空泡化的发生率显著增加,10000 ppm的雄性大鼠的附睾低精子症,10000 ppm的雄性大鼠的前列腺萎缩和炎症,5000 ppm和10000 ppm的雄性大鼠的睾丸变性。在TA97、TA98、TA100和TA1535菌株中,2-甲基咪唑和4-甲基咪唑的鼠伤寒沙门氏菌突变试验均为阴性。2-甲基咪唑在体内诱导染色体损伤的测试,通过微核红细胞频率来测量,产生了不同的结果。2-甲基咪唑每隔24小时腹腔注射3次,大鼠和小鼠骨髓微核试验均呈阴性。然而,在为期14周的2-甲基咪唑研究中,发现雄性和雌性小鼠外周血中微核正染红细胞的频率显著增加。在体内,4-甲基咪唑在大鼠和小鼠的三次骨髓微核试验和雄性和雌性小鼠的14周外周血微核试验中均呈阴性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

[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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