国家毒理学规划(NTP)关于饮用水和饲料中硫酸铜对F344/N大鼠和B6C3F1小鼠毒性研究的技术报告(CAS No. 7758-99-8)。

Toxicity report series Pub Date : 1993-07-01
Charles Hebert
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One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and mice of each sex; this lesion was more severe in rats than in mice. Inflammation of the liver, periportal to midzonal in distribution, occurred in rats in the 8000 and 16,000 ppm groups. Depletion of hematopoietic cells was evident in rats of each sex in the bone marrow (8000 and 16,000 ppm) and spleen (16,000 ppm). Kidneys of male and female rats in the 4000, 8000, and 16,000 ppm groups had an increased number and size of protein droplets in the epithelia of the renal cortical tubules. In the 13-week feed studies, groups of 10 rats per sex received diets containing 500 to 8000 ppm cupric sulfate, and groups of 10 mice per sex received diets containing 1000 to 16,000 ppm cupric sulfate for 92 days; estimates of cupric sulfate consumption ranged from 32 to 551 mg/kg per day for rats and 173 to 4157 mg/kg per day for mice. There were no chemical-related deaths in rats or mice, and no clinical signs of cupric sulfate toxicity were recorded. Final mean body weights were lower than those of the controls for animals of both species receiving doses of 4000 ppm cupric sulfate and greater. In mice in the 13-week studies, there was a dose-related decrease in liver weights. Hematologic, clinical chemistry, and urinalysis evaluations of rats in the 13-week study revealed variable chemical-related changes that were, for the most part, restricted to the 4000 and 8000 ppm groups. Increases in serum alanine aminotransferase and sorbitol dehydrogenase activities in both sexes were indicative of hepatocellular damage, as were increases in 5'-nucleotidase and bile salts in males. Decreases in mean cell volume, hematocrit, and hemoglobin indicated the development of a microcytic anemia, while increases in reticulocyte numbers at the same time points suggested a compensatory response to the anemia by the bone marrow. Increases in urinary glucose and N-acetyl-beta-D-glucosaminidase (a lysosomal enzyme) and aspartate aminotransferase (alpha-cytosolic enzyme) were suggestive of renal tubule epithelial damage. Dose-related increases in copper occurred in all male rat tissues examined (lissues examined (liver, kidney, plasma, and testis). These increases were accompanied by increases in zinc in the liver and kidney. Plasma calcium was significantly reduced in the 4000 and 8000 ppm groups, and there was a trend toward reductions in calcium in the kidney and testis as well. In the 8000 ppm group, plasma magnesium was significantly increased relative to the controls. Rats in the three highest dose groups had hyperplasia and hyperkeratosis of the forestomach, inflammation of the liver, and increases in the number and size of protein droplets in the epithelial cytoplasm and the lumina of the proximal convoluted tubules. These effects were similar to those seen in the 2-week feed study, and the incidence and severity of these lesions were dose related. Many of the droplets in male rat kidneys were large and had irregular crystalline shapes. These droplets stained strongly positive for protein but were negative by iron, PAS, and acid-fast (lipofuscin) staining methods. &alpha;-2-Microglobulin was present in the droplets of male rats, but there was no dose- related, qualitative difference in the content of this protein. In the 4000 and 8000 ppm groups, copper was distributed in a periportal to midzonal pattern in the liver and was restricted to the cytoplasm of the proximal convoluted tubule epithelium in the kidney. Copper was present in some, but not all, of the protein droplets. Transmission electron microscopy of the livers of rats of each sex revealed increases in the number of secondary lysosomes in hepatocytes in the periportal area. In mice of each sex receiving 4000 ppm cupric sulfate and higher in the 13-week study, there was a dose-related increase in hyperplasia with hyperkeratosis of the squamous mucosa on the limiting ridge of the forestomach. Minimal positive staining for copper was present in the liver and was limited to high-dose (16,000 ppm) male and female mice. Cupric sulfate produced no adverse effects on any of the reproductive parameters measured in rats or mice of either sex. In summary, administration of cupric sulfate to rats in feed or drinking water resulted in significant gastric changes and hepatic and renal damage. The primary lesion in rats was an increase in the size and number of proteinaceous droplets in the epithelial cytoplasm and lumen of the proximal convoluted tubule. For rats in the 13-week study, the no-observed-adverse-effect level (NOAEL) for evidence of histologic injury to the kidney was 1000 ppm for males and 500 ppm for females, while the NOAEL for liver inflammation was 1000 ppm for males and 2000 ppm for females. Hyperplasia with hyperkeratosis of the epithelium on the limiting ridge separating the forestomach from the glandular stomach was also seen in rats of each sex, and the NOAEL for this change was 1000-ppm cupric sulfate in the feed. Additionally, clinical pathology alterations noted in the 13-week study, along with histologic changes in bone marrow noted in the 2-week feed study, were indicative of a microcytic anemia with a compensatory bone marrow response. Mice appeared to be much more resistant to the toxic effects of cupric sulfate than rats. The primary target tissue in mice was the epithelium of the limiting ridge of the forestomach. The NOAEL for the hyperplasia and hyperkeratosis seen at this site in mice was 2000-ppm cupric sulfate in the feed. Synonyms: Chalcanthite; Copper sulfate; cupric sulfate pentahydrate; bluestone; blue vitriol; Roman vitriol; Salzburg vitriol. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":"29 ","pages":"1-D3"},"PeriodicalIF":0.0000,"publicationDate":"1993-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice.\",\"authors\":\"Charles Hebert\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. 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Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and mice of each sex; this lesion was more severe in rats than in mice. Inflammation of the liver, periportal to midzonal in distribution, occurred in rats in the 8000 and 16,000 ppm groups. Depletion of hematopoietic cells was evident in rats of each sex in the bone marrow (8000 and 16,000 ppm) and spleen (16,000 ppm). Kidneys of male and female rats in the 4000, 8000, and 16,000 ppm groups had an increased number and size of protein droplets in the epithelia of the renal cortical tubules. In the 13-week feed studies, groups of 10 rats per sex received diets containing 500 to 8000 ppm cupric sulfate, and groups of 10 mice per sex received diets containing 1000 to 16,000 ppm cupric sulfate for 92 days; estimates of cupric sulfate consumption ranged from 32 to 551 mg/kg per day for rats and 173 to 4157 mg/kg per day for mice. There were no chemical-related deaths in rats or mice, and no clinical signs of cupric sulfate toxicity were recorded. Final mean body weights were lower than those of the controls for animals of both species receiving doses of 4000 ppm cupric sulfate and greater. In mice in the 13-week studies, there was a dose-related decrease in liver weights. Hematologic, clinical chemistry, and urinalysis evaluations of rats in the 13-week study revealed variable chemical-related changes that were, for the most part, restricted to the 4000 and 8000 ppm groups. Increases in serum alanine aminotransferase and sorbitol dehydrogenase activities in both sexes were indicative of hepatocellular damage, as were increases in 5'-nucleotidase and bile salts in males. Decreases in mean cell volume, hematocrit, and hemoglobin indicated the development of a microcytic anemia, while increases in reticulocyte numbers at the same time points suggested a compensatory response to the anemia by the bone marrow. Increases in urinary glucose and N-acetyl-beta-D-glucosaminidase (a lysosomal enzyme) and aspartate aminotransferase (alpha-cytosolic enzyme) were suggestive of renal tubule epithelial damage. Dose-related increases in copper occurred in all male rat tissues examined (lissues examined (liver, kidney, plasma, and testis). These increases were accompanied by increases in zinc in the liver and kidney. Plasma calcium was significantly reduced in the 4000 and 8000 ppm groups, and there was a trend toward reductions in calcium in the kidney and testis as well. In the 8000 ppm group, plasma magnesium was significantly increased relative to the controls. Rats in the three highest dose groups had hyperplasia and hyperkeratosis of the forestomach, inflammation of the liver, and increases in the number and size of protein droplets in the epithelial cytoplasm and the lumina of the proximal convoluted tubules. These effects were similar to those seen in the 2-week feed study, and the incidence and severity of these lesions were dose related. Many of the droplets in male rat kidneys were large and had irregular crystalline shapes. These droplets stained strongly positive for protein but were negative by iron, PAS, and acid-fast (lipofuscin) staining methods. &alpha;-2-Microglobulin was present in the droplets of male rats, but there was no dose- related, qualitative difference in the content of this protein. In the 4000 and 8000 ppm groups, copper was distributed in a periportal to midzonal pattern in the liver and was restricted to the cytoplasm of the proximal convoluted tubule epithelium in the kidney. Copper was present in some, but not all, of the protein droplets. Transmission electron microscopy of the livers of rats of each sex revealed increases in the number of secondary lysosomes in hepatocytes in the periportal area. 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引用次数: 0

摘要

硫酸铜是一种无机盐,广泛应用于工业、农业和兽医学。其应用包括在饮用水中作为杀藻剂,在猪、羊和牛中作为饲料添加剂和治疗剂。由于在人类供水中发现了铜盐,因此通过饮用水(仅2周研究)和给药饲料途径(2周和13周研究)对雄性和雌性F344/N大鼠和B6C3F1小鼠进行了五水硫酸铜的毒性研究。对动物进行血液学、临床化学、尿液分析、生殖毒性、组织金属积累和组织病理学评估。在为期两周的饮用水研究中,每一组5只大鼠和5只小鼠连续15天接受浓度为300至30,000 ppm的硫酸铜。3000 ppm组的1只雌性大鼠、1只雄性小鼠和3只雌性小鼠,以及10000 ppm和30000 ppm组的所有大鼠和小鼠在研究结束前死亡。3000 ppm组中剩余的小鼠和大鼠体重几乎没有增加或减少。两个物种的三个最高剂量组的用水量减少了65%以上。在这些组中观察到的临床症状是在垂死动物中看到的典型症状,并归因于脱水。与硫酸铜毒性相关的唯一肉眼或显微镜变化是300和1000 ppm组雄性大鼠肾近曲小管上皮内细胞质蛋白滴的大小和数量增加。在为期两周的饲料研究中,每性别5只大鼠和5只小鼠被喂食含有1000至16000 ppm硫酸铜的饲料。任何剂量组均未发生与化学品相关的死亡。与对照组相比,两个最高剂量组的大鼠和小鼠体重增加减少,这是由于饲料消耗量减少。大鼠、小鼠均见前胃限定脊鳞状上皮增生伴角化过度;这种损伤在大鼠中比在小鼠中更严重。8000 ppm组和16000 ppm组的大鼠肝脏出现门静脉周围至中区分布的炎症。在骨髓(8000 ppm和16000 ppm)和脾脏(16000 ppm)中,各性别大鼠的造血细胞明显减少。4000ppm、8000 ppm和16000 ppm组的雄性和雌性大鼠肾皮质小管上皮蛋白滴的数量和大小都有所增加。在为期13周的饲料研究中,每性别10只大鼠每组接受含有500至8000 ppm硫酸铜的饲料,每性别10只小鼠每组接受含有1000至16000 ppm硫酸铜的饲料,为期92天;估计大鼠每天的硫酸铜消耗量为32至551毫克/公斤,小鼠为173至4157毫克/公斤。在大鼠或小鼠中没有与化学物质相关的死亡,也没有记录硫酸铜毒性的临床症状。接受4000 ppm及以上硫酸铜剂量的两种动物的最终平均体重低于对照组。在为期13周的研究中,小鼠的肝脏重量出现了剂量相关的下降。在为期13周的研究中,对大鼠的血液学、临床化学和尿液分析评估显示,在大多数情况下,4000和8000 ppm组的化学相关变化是可变的。两性血清丙氨酸转氨酶和山梨醇脱氢酶活性的增加表明肝细胞损伤,男性5'-核苷酸酶和胆盐的增加也是如此。平均细胞体积、红细胞压积和血红蛋白的减少表明发生了小细胞性贫血,而在同一时间点网织红细胞数量的增加表明骨髓对贫血的代偿反应。尿葡萄糖、n -乙酰- β - d -氨基葡萄糖酶(一种溶酶体酶)和天冬氨酸转氨酶(α -胞质酶)升高提示肾小管上皮损伤。铜的剂量相关增加发生在所有被检查的雄性大鼠组织(检查的器官(肝脏、肾脏、血浆和睾丸))。这些增加伴随着肝脏和肾脏中锌的增加。在4000ppm和8000ppm组中,血浆钙明显减少,肾脏和睾丸中的钙也有减少的趋势。在8000ppm组中,血浆镁相对于对照组显著增加。三个最高剂量组大鼠出现前胃增生和角化过度,肝脏炎症,上皮细胞质和近曲小管腔内蛋白滴数量和大小增加。这些影响与在2周饲料研究中看到的相似,并且这些病变的发生率和严重程度与剂量有关。雄性大鼠肾脏中的许多液滴很大,呈不规则的结晶形状。 这些液滴对蛋白质染色呈强烈阳性,但对铁、PAS和抗酸(脂褐素)染色呈阴性。-2-微球蛋白存在于雄性大鼠的滴液中,但该蛋白的含量没有剂量相关的定性差异。在4000ppm和8000ppm组中,铜在肝脏呈门静脉周围到中区分布,仅限于肾近曲小管上皮的细胞质。铜存在于部分(但不是全部)蛋白质液滴中。通过透射电镜观察,雌雄大鼠肝脏门静脉周围区肝细胞次级溶酶体数量均有增加。在为期13周的研究中,在接受4000 ppm硫酸铜或更高剂量的小鼠中,前胃限制脊上的鳞状黏膜过度角化增生与剂量相关。肝脏中存在微量的铜阳性染色,仅限于高剂量(16,000 ppm)的雄性和雌性小鼠。硫酸铜对大鼠或小鼠的任何生殖参数均无不良影响。综上所述,在饲料或饮用水中给予硫酸铜可导致大鼠胃发生明显变化,并造成肝、肾损害。大鼠的原发性病变是近曲小管上皮细胞质和管腔内蛋白滴的大小和数量增加。在为期13周的研究中,大鼠肾脏组织学损伤证据的未观察到不良反应水平(NOAEL)雄性为1000 ppm,雌性为500 ppm,而肝脏炎症的NOAEL为1000 ppm,雌性为2000 ppm。各性别大鼠均见前胃与腺胃交界脊处上皮增生伴角化过度,该变化的NOAEL为饲料中硫酸铜含量为1000-ppm。此外,在13周的研究中发现的临床病理改变,以及在2周的饲料研究中发现的骨髓组织学变化,表明小细胞性贫血具有代偿性骨髓反应。小鼠似乎比大鼠更能抵抗硫酸铜的毒性作用。小鼠的主要靶组织是前胃限制脊的上皮。小鼠该部位增生和角化过度的NOAEL为饲料中2000 ppm硫酸铜。同义词:胆矾;硫酸铜;五水硫酸铜;青石;蓝矾;罗马硫酸盐;萨尔茨堡硫酸盐。(注:这些研究的部分资金来自《综合环境反应、赔偿和责任法案》信托基金(超级基金),并与美国公共卫生服务局有毒物质和疾病登记处达成了机构间协议。)
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NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice.

Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. Its applications include use as an algicide in potable waters and as a feed additive and therapeutic agent in swine, sheep, and cattle. Because copper salts are found in human water supplies, toxicity studies of cupric sulfate pentahydrate were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and dosed feed routes (2-week and 13-week studies). Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, tissue metal accumulation, and histopathology. In the 2-week drinking water studies, groups of five rats and five mice per sex received cupric sulfate at concentrations of 300 to 30,000 ppm for 15 days. One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and mice of each sex; this lesion was more severe in rats than in mice. Inflammation of the liver, periportal to midzonal in distribution, occurred in rats in the 8000 and 16,000 ppm groups. Depletion of hematopoietic cells was evident in rats of each sex in the bone marrow (8000 and 16,000 ppm) and spleen (16,000 ppm). Kidneys of male and female rats in the 4000, 8000, and 16,000 ppm groups had an increased number and size of protein droplets in the epithelia of the renal cortical tubules. In the 13-week feed studies, groups of 10 rats per sex received diets containing 500 to 8000 ppm cupric sulfate, and groups of 10 mice per sex received diets containing 1000 to 16,000 ppm cupric sulfate for 92 days; estimates of cupric sulfate consumption ranged from 32 to 551 mg/kg per day for rats and 173 to 4157 mg/kg per day for mice. There were no chemical-related deaths in rats or mice, and no clinical signs of cupric sulfate toxicity were recorded. Final mean body weights were lower than those of the controls for animals of both species receiving doses of 4000 ppm cupric sulfate and greater. In mice in the 13-week studies, there was a dose-related decrease in liver weights. Hematologic, clinical chemistry, and urinalysis evaluations of rats in the 13-week study revealed variable chemical-related changes that were, for the most part, restricted to the 4000 and 8000 ppm groups. Increases in serum alanine aminotransferase and sorbitol dehydrogenase activities in both sexes were indicative of hepatocellular damage, as were increases in 5'-nucleotidase and bile salts in males. Decreases in mean cell volume, hematocrit, and hemoglobin indicated the development of a microcytic anemia, while increases in reticulocyte numbers at the same time points suggested a compensatory response to the anemia by the bone marrow. Increases in urinary glucose and N-acetyl-beta-D-glucosaminidase (a lysosomal enzyme) and aspartate aminotransferase (alpha-cytosolic enzyme) were suggestive of renal tubule epithelial damage. Dose-related increases in copper occurred in all male rat tissues examined (lissues examined (liver, kidney, plasma, and testis). These increases were accompanied by increases in zinc in the liver and kidney. Plasma calcium was significantly reduced in the 4000 and 8000 ppm groups, and there was a trend toward reductions in calcium in the kidney and testis as well. In the 8000 ppm group, plasma magnesium was significantly increased relative to the controls. Rats in the three highest dose groups had hyperplasia and hyperkeratosis of the forestomach, inflammation of the liver, and increases in the number and size of protein droplets in the epithelial cytoplasm and the lumina of the proximal convoluted tubules. These effects were similar to those seen in the 2-week feed study, and the incidence and severity of these lesions were dose related. Many of the droplets in male rat kidneys were large and had irregular crystalline shapes. These droplets stained strongly positive for protein but were negative by iron, PAS, and acid-fast (lipofuscin) staining methods. α-2-Microglobulin was present in the droplets of male rats, but there was no dose- related, qualitative difference in the content of this protein. In the 4000 and 8000 ppm groups, copper was distributed in a periportal to midzonal pattern in the liver and was restricted to the cytoplasm of the proximal convoluted tubule epithelium in the kidney. Copper was present in some, but not all, of the protein droplets. Transmission electron microscopy of the livers of rats of each sex revealed increases in the number of secondary lysosomes in hepatocytes in the periportal area. In mice of each sex receiving 4000 ppm cupric sulfate and higher in the 13-week study, there was a dose-related increase in hyperplasia with hyperkeratosis of the squamous mucosa on the limiting ridge of the forestomach. Minimal positive staining for copper was present in the liver and was limited to high-dose (16,000 ppm) male and female mice. Cupric sulfate produced no adverse effects on any of the reproductive parameters measured in rats or mice of either sex. In summary, administration of cupric sulfate to rats in feed or drinking water resulted in significant gastric changes and hepatic and renal damage. The primary lesion in rats was an increase in the size and number of proteinaceous droplets in the epithelial cytoplasm and lumen of the proximal convoluted tubule. For rats in the 13-week study, the no-observed-adverse-effect level (NOAEL) for evidence of histologic injury to the kidney was 1000 ppm for males and 500 ppm for females, while the NOAEL for liver inflammation was 1000 ppm for males and 2000 ppm for females. Hyperplasia with hyperkeratosis of the epithelium on the limiting ridge separating the forestomach from the glandular stomach was also seen in rats of each sex, and the NOAEL for this change was 1000-ppm cupric sulfate in the feed. Additionally, clinical pathology alterations noted in the 13-week study, along with histologic changes in bone marrow noted in the 2-week feed study, were indicative of a microcytic anemia with a compensatory bone marrow response. Mice appeared to be much more resistant to the toxic effects of cupric sulfate than rats. The primary target tissue in mice was the epithelium of the limiting ridge of the forestomach. The NOAEL for the hyperplasia and hyperkeratosis seen at this site in mice was 2000-ppm cupric sulfate in the feed. Synonyms: Chalcanthite; Copper sulfate; cupric sulfate pentahydrate; bluestone; blue vitriol; Roman vitriol; Salzburg vitriol. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)

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