NTP technical report on the toxicity studies of malachite green chloride and leucomalachite green (CAS Nos. 569-64-2 and 129-73-7) administered in feed to F344/N rats and B6C3F1 mice.

Toxicity report series Pub Date : 2004-06-01
Sandra J Culp
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Male and female F344/N Nctr BR rats and B6C3F1/Nctr BR (C57BL/6N x C3H/HeN MTV-) mice were exposed to malachite green chloride (95% pure) or leucomalachite green (99% pure) (male rats and female mice only) in feed for 28 days. Animals were evaluated for clinical pathology and histopathology. Genetic toxicity studies formalachite green chloride were conducted in vitro in Salmonella typhimurium and in vivo in rat bone marrow erythrocytes and in mouse peripheral blood erythrocytes. Genetic toxicity studies for leucomalachite green were conducted in vivo in mouse peripheral blood erythrocytes. Groups of eight male and eight female rats and mice were fed diets containing 0, 25, 100, 300, 600, or 1,200 ppm malachite green chloride for 28 days. Additional groups of eight male and eight female rats designated for thyroid hormone assays were fed diets containing 0 or 1,200 ppm malachite green chloride. Groups of eight male rats and eight female mice were fed diets containing 0, 290, 580, or 1,160 ppm leucomalachite green for 28 days. Additional groups of eight male rats designated for thyroid hormone assays were fed diets containing 0 or 1,160 ppm leucomalachite green. All rats and mice survived to the end of the studies. In the malachite green chloride study, the body weight gain of males rats in the 1,200 ppm group was significantly less than that of the controls. The final mean body weight of female rats and mice in the 1,200 ppm groups and the body weight gains of female rats and mice in the 600 (rats only) and 1,200 ppm groups were significantly less than those of the controls. In the leucomalachite green study, the final mean body weight of male rats and female mice in the 1,160 ppm groups and the mean body weight gains of male rats and female mice in the 580 and 1,160 ppm groups were significantly less than those of the control groups. In the malachite green chloride study, feed consumption by all exposed groups of male and female rats and mice was generally similar to that by the control groups. Exposure concentrations of 25, 100, 300, 600, and 1,200 ppm resulted in average daily doses of 3 to 190 mg malachite green chloride/kg body weight to male and female rats and 5 to 250 mg/kg to male and female mice. In the leucomalachite green study, feed consumption by all groups of exposed male rats was similar to that by the controls. Dietary concentrations of 290, 580, and 1,160 ppm resulted in average daily doses of approximately 30, 60, and 115 mg leucomalachite green/kg body weight to male rats and approximately 62, 110, and 220 mg/kg to female mice. In female rats exposed to malachite green chloride, there was a significant increases in gamma-glutamyltransferase activities with an activity in 1,200 ppm females seven times greater than that in the controls. Likewise, gamma-glutamyltransferase activity in male rats exposed to 1,160 ppm leucomalachite green was twice that in the controls. On days 4 and 21, the concentration of thyroxine was significantly decreased in male rats exposed to 1,160 ppm leucomalachite green and the concentration of thyroid-stimulating hormone was significantly increased. In the malachite green chloride study, the relative liver weights of 600 and 1,200 ppm male rats and the relative and absolute liver weights of 300 ppm or greater female rats were generally significantly greater than those of the controls. In the leucomalachite green study, the relative liver weights of 290 ppm or greater male rats were significantly greater than those of the control group. No gross lesions were observed in rats or mice and no microscopic lesions were observed in female mice that were attributed to malachite green chloride exposure. Microscopically, the incidences of hepatocyte cytoplasmic vacuolization were significantly increased in 1,200 ppm male and female rats exposed to malachite green chloride. No gross lesions were observed in rats or mice that could be attributed to leucomalachite green exposure. Microscopically, the incidences of hepatocyte cytoplasmic vacuolization were significantly increased in 580 and 1,160 ppm male rats. The incidence of multifocal apoptosis in the transitory epithelium of the urinary bladder was significantly increased in 1,160 ppm female mice exposed to leucomalachite green. Malachite green chloride, tested at concentrations of 0.1 to 10 mircrog/plate, was not mutagenic in any of several strains of Salmonella typhimurium, with or without S9 metabolic activation. Negative results were also obtained in two in vivo micronucleus tests, one that assessed induction of micronuclei in rat bone marrow erythrocytes after three intraperitoneal injections of malachite green chloride, and a second study that determined the level of micronuclei in circulating erythrocytes of male and female mice following 28 days of exposure to malachite green chloride via dosed feed. The frequency of micronucleated normochromatic erythrocytes in peripheral blood was significantly increased in female mice exposed to leucomalachite green in feed for 28 days; no significant increases in micronucleus frequencies were observed in the polychromatic erythrocyte population.</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":" 71","pages":"1-F10"},"PeriodicalIF":0.0000,"publicationDate":"2004-06-01","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}
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Abstract

Malachite green chloride is a triphenylmethane dye used in the fish and dye industries. Leucomalachite green is prepared by the reduction of malachite green chloride. Malachite green chloride was nominated for toxicity and carcinogenicity testing by the Food and Drug Administration and selected by the National Institutes of Environmental Health Sciences for carcinogenicity testing by the National Toxicology Program (NTP) due to the potential for significant worker and consumer exposure and lack of carcinogenicity data. The current 28-day studies were conducted as part of an overall effort by the NTP to determine the toxicity and carcinogenicity of malachite green chloride. Male and female F344/N Nctr BR rats and B6C3F1/Nctr BR (C57BL/6N x C3H/HeN MTV-) mice were exposed to malachite green chloride (95% pure) or leucomalachite green (99% pure) (male rats and female mice only) in feed for 28 days. Animals were evaluated for clinical pathology and histopathology. Genetic toxicity studies formalachite green chloride were conducted in vitro in Salmonella typhimurium and in vivo in rat bone marrow erythrocytes and in mouse peripheral blood erythrocytes. Genetic toxicity studies for leucomalachite green were conducted in vivo in mouse peripheral blood erythrocytes. Groups of eight male and eight female rats and mice were fed diets containing 0, 25, 100, 300, 600, or 1,200 ppm malachite green chloride for 28 days. Additional groups of eight male and eight female rats designated for thyroid hormone assays were fed diets containing 0 or 1,200 ppm malachite green chloride. Groups of eight male rats and eight female mice were fed diets containing 0, 290, 580, or 1,160 ppm leucomalachite green for 28 days. Additional groups of eight male rats designated for thyroid hormone assays were fed diets containing 0 or 1,160 ppm leucomalachite green. All rats and mice survived to the end of the studies. In the malachite green chloride study, the body weight gain of males rats in the 1,200 ppm group was significantly less than that of the controls. The final mean body weight of female rats and mice in the 1,200 ppm groups and the body weight gains of female rats and mice in the 600 (rats only) and 1,200 ppm groups were significantly less than those of the controls. In the leucomalachite green study, the final mean body weight of male rats and female mice in the 1,160 ppm groups and the mean body weight gains of male rats and female mice in the 580 and 1,160 ppm groups were significantly less than those of the control groups. In the malachite green chloride study, feed consumption by all exposed groups of male and female rats and mice was generally similar to that by the control groups. Exposure concentrations of 25, 100, 300, 600, and 1,200 ppm resulted in average daily doses of 3 to 190 mg malachite green chloride/kg body weight to male and female rats and 5 to 250 mg/kg to male and female mice. In the leucomalachite green study, feed consumption by all groups of exposed male rats was similar to that by the controls. Dietary concentrations of 290, 580, and 1,160 ppm resulted in average daily doses of approximately 30, 60, and 115 mg leucomalachite green/kg body weight to male rats and approximately 62, 110, and 220 mg/kg to female mice. In female rats exposed to malachite green chloride, there was a significant increases in gamma-glutamyltransferase activities with an activity in 1,200 ppm females seven times greater than that in the controls. Likewise, gamma-glutamyltransferase activity in male rats exposed to 1,160 ppm leucomalachite green was twice that in the controls. On days 4 and 21, the concentration of thyroxine was significantly decreased in male rats exposed to 1,160 ppm leucomalachite green and the concentration of thyroid-stimulating hormone was significantly increased. In the malachite green chloride study, the relative liver weights of 600 and 1,200 ppm male rats and the relative and absolute liver weights of 300 ppm or greater female rats were generally significantly greater than those of the controls. In the leucomalachite green study, the relative liver weights of 290 ppm or greater male rats were significantly greater than those of the control group. No gross lesions were observed in rats or mice and no microscopic lesions were observed in female mice that were attributed to malachite green chloride exposure. Microscopically, the incidences of hepatocyte cytoplasmic vacuolization were significantly increased in 1,200 ppm male and female rats exposed to malachite green chloride. No gross lesions were observed in rats or mice that could be attributed to leucomalachite green exposure. Microscopically, the incidences of hepatocyte cytoplasmic vacuolization were significantly increased in 580 and 1,160 ppm male rats. The incidence of multifocal apoptosis in the transitory epithelium of the urinary bladder was significantly increased in 1,160 ppm female mice exposed to leucomalachite green. Malachite green chloride, tested at concentrations of 0.1 to 10 mircrog/plate, was not mutagenic in any of several strains of Salmonella typhimurium, with or without S9 metabolic activation. Negative results were also obtained in two in vivo micronucleus tests, one that assessed induction of micronuclei in rat bone marrow erythrocytes after three intraperitoneal injections of malachite green chloride, and a second study that determined the level of micronuclei in circulating erythrocytes of male and female mice following 28 days of exposure to malachite green chloride via dosed feed. The frequency of micronucleated normochromatic erythrocytes in peripheral blood was significantly increased in female mice exposed to leucomalachite green in feed for 28 days; no significant increases in micronucleus frequencies were observed in the polychromatic erythrocyte population.

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国家毒理学规划关于在饲料中添加孔雀石绿氯化物和白垩孔雀石绿对F344/N大鼠和B6C3F1小鼠的毒性研究的技术报告(CAS编号569-64-2和129-73-7)。
氯化孔雀石绿是一种三苯甲烷染料,用于鱼类和染料工业。绿孔雀石绿是由氯化孔雀石绿还原而成。由于工人和消费者接触孔雀石绿的可能性很大,并且缺乏致癌性数据,因此,美国食品和药物管理局提名孔雀石绿氯进行毒性和致癌性测试,并由国家环境卫生科学研究所选择进行国家毒理学计划(NTP)的致癌性测试。目前进行的为期28天的研究是国家毒理学规划总体努力的一部分,目的是确定孔雀石绿氯化物的毒性和致癌性。将雄性和雌性F344/N Nctr BR大鼠和B6C3F1/Nctr BR (C57BL/6N × C3H/HeN MTV-)小鼠在饲料中分别暴露于孔雀石绿(95%纯)或白垩孔雀石绿(99%纯)28 d(仅雄性大鼠和雌性小鼠)。对动物进行临床病理和组织病理学评估。本文对鼠伤寒沙门菌进行了体外遗传毒性研究,对大鼠骨髓红细胞和小鼠外周血红细胞进行了体内遗传毒性研究。本文对白垩孔雀石绿在小鼠外周血中的遗传毒性进行了研究。每组8只雄性和8只雌性大鼠和小鼠被喂食含有0、25、100、300、600或1200 ppm孔雀石绿氯化物的饮食28天。另外一组8只雄性和8只雌性大鼠被指定用于甲状腺激素测定,喂食含有0或1200 ppm孔雀石绿氯化物的饲料。每组8只雄性大鼠和8只雌性小鼠分别被喂食含有0、290、580或1160 ppm白孔雀石绿的饲料28天。另外一组8只雄性大鼠被指定用于甲状腺激素测定,喂食含有0或1,160 ppm白孔雀石绿的饲料。所有的大鼠和小鼠都活到了研究结束。在孔雀石绿氯化物研究中,1200ppm组雄性大鼠的体重增加明显小于对照组。1200ppm组雌性大鼠和小鼠的最终平均体重以及600(仅大鼠)和1200ppm组雌性大鼠和小鼠的体重增加明显小于对照组。在白孔雀石绿研究中,1160 ppm组雄性大鼠和雌性小鼠的最终平均体重以及580和1160 ppm组雄性大鼠和雌性小鼠的平均体重增加明显小于对照组。在孔雀石绿氯化物研究中,所有暴露组的雄性和雌性大鼠和小鼠的饲料消耗量与对照组大致相似。25、100、300、600和1200 ppm的暴露浓度导致雄性和雌性大鼠的平均日剂量为3至190毫克/公斤体重,雄性和雌性小鼠的平均日剂量为5至250毫克/公斤体重。在白孔雀石绿研究中,所有暴露组的雄性大鼠的饲料消耗量与对照组相似。290、580和1160 ppm的膳食浓度导致雄性大鼠的平均日剂量约为30、60和115毫克/公斤体重,雌性小鼠的平均日剂量约为62、110和220毫克/公斤体重。在暴露于孔雀石绿氯的雌性大鼠中,γ -谷氨酰转移酶的活性显著增加,在1200ppm的浓度下,雌性大鼠的活性是对照组的7倍。同样,暴露于1,160 ppm白孔雀石绿的雄性大鼠的γ -谷氨酰转移酶活性是对照组的两倍。1,160 ppm白孔雀石绿暴露第4天和第21天,雄性大鼠甲状腺素浓度显著降低,促甲状腺激素浓度显著升高。在孔雀石绿氯化物研究中,600 ppm和1200 ppm雄性大鼠的相对肝脏重量以及300 ppm及以上雌性大鼠的相对肝脏重量和绝对肝脏重量普遍显著大于对照组。在白垩孔雀石绿研究中,290 ppm及以上雄性大鼠的相对肝脏重量明显大于对照组。在大鼠或小鼠中未观察到肉眼病变,在雌性小鼠中未观察到归因于孔雀石绿氯暴露的显微镜病变。在显微镜下,暴露于1200ppm孔雀石绿氯的雄性和雌性大鼠肝细胞细胞质空泡的发生率显著增加。在大鼠或小鼠中未观察到可归因于白垩孔雀石绿暴露的明显病变。显微镜下580 ppm和1160 ppm雄性大鼠肝细胞胞浆空泡的发生率显著增加。暴露于1,160 ppm白垩孔雀石绿的雌性小鼠膀胱短暂上皮多灶性细胞凋亡发生率显著增加。 孔雀石绿氯化物,在浓度为0.1至10微克/皿的情况下进行测试,对几种鼠伤寒沙门氏菌菌株都没有诱变作用,无论是否有S9代谢激活。两项体内微核试验也获得了阴性结果,一项是评估三次腹腔注射孔雀石绿氯后大鼠骨髓红细胞微核的诱导情况,另一项研究是确定通过加剂量饲料接触孔雀石绿氯28天后雄性和雌性小鼠循环红细胞微核水平。饲喂白孔雀石绿28 d后,雌性小鼠外周血微核正染色红细胞频率显著升高;微核频率在多染红细胞群中未见明显增加。
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