NTP technical report on the toxicity studies of Trinitrofluorenone (Cas No. 129-79-3) Administered by Dermal Application and Dosed Feed to F344/N Rats and B6C3F1 Mice.

Toxicity report series Pub Date : 1992-07-01
Frank Kari
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In disposition and metabolism studies, excretion patterns following oral administration of radiolabeled TNF (in doses ranging between 1 and 100 mg/kg body weight) were similar; 20% and 70% of the administered dose appeared in urine and feces, respectively, during the first 72 hours. Residual radiolabel in tissues comprised less than 1% of the dose. The appearance in the feces of 60-70% of a 1 mg/kg i.v. dose provided evidence for substantial biliary excretion of TNF; studies of the radiolabeled materials extracted from urine and feces suggested that glucuronidation is a major biotransfomation of TNF and its metabolites. In the dermal exposure studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were administered TNF in acetone by topical application once a day, 5 days per week, for 14 days. Doses were 0, 7.5, 15, 30, 60, or 120 mg/kg body weight for rats and 0, 12.5, 25, 50, 100, or 200 mg/kg for mice. There were no deaths, no adverse clinical signs, and no gross or microscopic changes related to treatment in either species, except for discoloration of skin at the site of application. Disposition studies with female rats showed that less than 10% of a dermal dose of 47 mg and less than 3% of a dermal dose of 400 mg were available systemically. In contrast, toxicity was observed in the 14-day feeding studies with TNF. Groups of 5 rats and 5 mice of each sex were fed diets containing TNF at concentrations of 0, 500, 1600, 5000, 16000, or 50000 ppm. There were no deaths of rats or mice, but body weight gains of rats receiving 50000 ppm were reduced by as much as 45%. Animals receiving diets with 5000 ppm or higher TNF had a black discoloration of the skin and hair and enlarged and/or dark thyroid glands. Mild follicular cell hypertrophy and pigmentation of the epithelium and colloid were noted in the thyroid gland. Among mice, the brain and gallbladder were dark; the spleen of females was dark and also enlarged by hematopoiesis. Thymic lymphoid depletion and atrophy of the seminal vesicles were present in top-dose male rats (50000 ppm). In 13-week studies, groups of 10 animals of each sex received diets containing TNF at concentrations of 0, 1000, 2000, 4000, 8000, or 16000 ppm for rats, and 0, 3125, 6250, 12500, 25000, or 50000 ppm for mice. No rats died, but the deaths of several mice in the 50000 ppm groups indicated a possible relation to TNF ingestion. Body weight gains of dosed rats were lower than controls and were dose-related. Top-dose male mice gained markedly less weight than controls. A mild macrocytic anemia and increase in methemoglobin was present in dosed rats at the end of the study. In both species, there was a widespread occurrence of a dark brown pigment in dosed animals, with little evidence of toxicity related to the pigment accumulation. Other treatment- related effects in male rats included mesenteric vascular inflammation, renal inflammation, testicular degeneration with reduced sperm count and motility, splenic hematopoiesis, and oval cell hyperplasia, cytoplasmic alteration, and mixed cell foci in the liver. Top-dose female rats had centrilobular hepatocyte cytoplasmic alteration and splenic hematopoiesis. Dosed mice of both sexes showed cystic degeneration of the thyroid gland, liver hypertrophy, and splenic hematopoiesis. In summary, TNF caused a variety of lesions in oral feeding studies. The no-observed-adverse-effect-level (NOAEL) for microscopic ced-adverse-effect-level (NOAEL) for microscopic changes other than pigment accumulation was 1000 ppm for rats. A NOAEL could not be determined for mice from this study. Limited dermal absorption likely would prevent significant systemic toxicity resulting from contact of TNF with the skin. Synonyms: TNF; 2,4,7-trinitro-9H-fluoren-9-one.</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":"13 ","pages":"1-D4"},"PeriodicalIF":0.0000,"publicationDate":"1992-07-01","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

Trinitrofluorenone (TNF) is a major component of a toning formulation that at one time was used widely in certain photocopy processes. Because the principal route of exposure of humans to TNF probably would be dermal, studies were conducted to compare chemical absorption, distribution, excretion, and tissue retention, as well as toxicity in 14-day studies, by oral and dermal routes of exposure. Further, 13-week toxicity studies were carried out with TNF incorporated into the feed of rats and mice of both sexes. In genetic toxicity evaluations, TNF was found to be mutagenic in Salmonella typhimurium, with and without metabolic activation. In disposition and metabolism studies, excretion patterns following oral administration of radiolabeled TNF (in doses ranging between 1 and 100 mg/kg body weight) were similar; 20% and 70% of the administered dose appeared in urine and feces, respectively, during the first 72 hours. Residual radiolabel in tissues comprised less than 1% of the dose. The appearance in the feces of 60-70% of a 1 mg/kg i.v. dose provided evidence for substantial biliary excretion of TNF; studies of the radiolabeled materials extracted from urine and feces suggested that glucuronidation is a major biotransfomation of TNF and its metabolites. In the dermal exposure studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were administered TNF in acetone by topical application once a day, 5 days per week, for 14 days. Doses were 0, 7.5, 15, 30, 60, or 120 mg/kg body weight for rats and 0, 12.5, 25, 50, 100, or 200 mg/kg for mice. There were no deaths, no adverse clinical signs, and no gross or microscopic changes related to treatment in either species, except for discoloration of skin at the site of application. Disposition studies with female rats showed that less than 10% of a dermal dose of 47 mg and less than 3% of a dermal dose of 400 mg were available systemically. In contrast, toxicity was observed in the 14-day feeding studies with TNF. Groups of 5 rats and 5 mice of each sex were fed diets containing TNF at concentrations of 0, 500, 1600, 5000, 16000, or 50000 ppm. There were no deaths of rats or mice, but body weight gains of rats receiving 50000 ppm were reduced by as much as 45%. Animals receiving diets with 5000 ppm or higher TNF had a black discoloration of the skin and hair and enlarged and/or dark thyroid glands. Mild follicular cell hypertrophy and pigmentation of the epithelium and colloid were noted in the thyroid gland. Among mice, the brain and gallbladder were dark; the spleen of females was dark and also enlarged by hematopoiesis. Thymic lymphoid depletion and atrophy of the seminal vesicles were present in top-dose male rats (50000 ppm). In 13-week studies, groups of 10 animals of each sex received diets containing TNF at concentrations of 0, 1000, 2000, 4000, 8000, or 16000 ppm for rats, and 0, 3125, 6250, 12500, 25000, or 50000 ppm for mice. No rats died, but the deaths of several mice in the 50000 ppm groups indicated a possible relation to TNF ingestion. Body weight gains of dosed rats were lower than controls and were dose-related. Top-dose male mice gained markedly less weight than controls. A mild macrocytic anemia and increase in methemoglobin was present in dosed rats at the end of the study. In both species, there was a widespread occurrence of a dark brown pigment in dosed animals, with little evidence of toxicity related to the pigment accumulation. Other treatment- related effects in male rats included mesenteric vascular inflammation, renal inflammation, testicular degeneration with reduced sperm count and motility, splenic hematopoiesis, and oval cell hyperplasia, cytoplasmic alteration, and mixed cell foci in the liver. Top-dose female rats had centrilobular hepatocyte cytoplasmic alteration and splenic hematopoiesis. Dosed mice of both sexes showed cystic degeneration of the thyroid gland, liver hypertrophy, and splenic hematopoiesis. In summary, TNF caused a variety of lesions in oral feeding studies. The no-observed-adverse-effect-level (NOAEL) for microscopic ced-adverse-effect-level (NOAEL) for microscopic changes other than pigment accumulation was 1000 ppm for rats. A NOAEL could not be determined for mice from this study. Limited dermal absorption likely would prevent significant systemic toxicity resulting from contact of TNF with the skin. Synonyms: TNF; 2,4,7-trinitro-9H-fluoren-9-one.

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国家毒理学规划(NTP)关于三硝基氟芴酮(Cas No. 129-79-3)对F344/N大鼠和B6C3F1小鼠皮肤给药和给药的毒性研究的技术报告。
三硝基芴酮(TNF)是调色配方的主要成分,曾在某些影印工艺中广泛使用。由于人类接触肿瘤坏死因子的主要途径可能是皮肤,因此在为期14天的研究中,通过口服和皮肤接触途径比较了化学物质的吸收、分布、排泄和组织保留,以及毒性。此外,将TNF加入大鼠和小鼠的饲料中进行了为期13周的毒性研究。在遗传毒性评估中,发现TNF在鼠伤寒沙门氏菌中具有诱变性,无论是否具有代谢激活。在处置和代谢研究中,口服放射性标记TNF(剂量范围为1至100 mg/kg体重)后的排泄模式相似;在最初的72小时内,20%和70%的给药剂量分别出现在尿液和粪便中。组织中残留的放射性标签占剂量的不到1%。1 mg/kg静脉注射剂量的60-70%出现在粪便中,提供了大量TNF胆汁排泄的证据;从尿液和粪便中提取的放射性标记物质的研究表明,葡萄糖醛酸化是TNF及其代谢物的主要生物转化。在皮肤暴露研究中,每组5只F344/N大鼠和5只B6C3F1小鼠,每周5天,每天1次局部应用TNF -丙酮,连续14天。大鼠的剂量为0、7.5、15、30、60或120 mg/kg体重,小鼠的剂量为0、12.5、25、50、100或200 mg/kg体重。除施用部位皮肤变色外,两种物种均无死亡,无不良临床症状,无与治疗相关的肉眼或显微镜变化。对雌性大鼠的处置研究表明,皮下剂量47毫克和皮下剂量400毫克的全身可用性分别不到10%和3%。相比之下,TNF在14天的饲养研究中观察到毒性。每组5只大鼠和5只小鼠分别饲喂TNF浓度为0、500、1600、5000、16000或50000 ppm的饲料。没有大鼠或小鼠死亡,但接受50000 ppm的大鼠体重增加减少了45%之多。饲料中TNF含量为5000ppm或更高时,动物的皮肤和毛发出现黑色变色,甲状腺增大和/或变黑。甲状腺可见轻度滤泡细胞肥大、上皮及胶体色素沉着。小鼠的大脑和胆囊是黑色的;雌性的脾脏颜色较暗,也因造血而增大。最高剂量雄性大鼠(50000 ppm)出现胸腺淋巴细胞减少和精囊萎缩。在为期13周的研究中,每组10只雌雄动物分别接受TNF浓度为0,1000,2000,4000,8000或16000 ppm(大鼠)和0,3125,6250,12500,25000或50000 ppm(小鼠)的饮食。没有大鼠死亡,但50000 ppm组中几只小鼠的死亡表明可能与TNF摄入有关。给药大鼠的体重增加低于对照组,且与剂量有关。剂量最大的雄性小鼠体重的增加明显少于对照组。在研究结束时,给药大鼠出现轻度大细胞性贫血和高铁血红蛋白升高。在这两个物种中,在给药的动物中广泛出现深棕色色素,几乎没有证据表明与色素积累有关的毒性。在雄性大鼠中,其他与治疗相关的影响包括肠系膜血管炎症、肾脏炎症、睾丸变性、精子数量和活力减少、脾造血、卵圆细胞增生、细胞质改变和肝脏混合细胞灶。高剂量雌性大鼠小叶中心肝细胞细胞质改变,脾脏造血。给药后雌雄小鼠均出现甲状腺囊性变性、肝脏肥厚和脾造血。总之,TNF在口服喂养研究中引起多种病变。大鼠除色素积累外的其他微观变化的无观察到不良效应水平(NOAEL)为1000 ppm。本研究无法确定小鼠的NOAEL。有限的皮肤吸收可能会防止因TNF与皮肤接触而引起的重大全身毒性。同义词:肿瘤坏死因子;2、4、7-trinitro-9H-fluoren-9-one。
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