NTP technical report on the toxicity studies of Toxicity Studies of Antimony Potassium Tartrate (CAS No. 28300-74-5) in F344/N Rats And B6C3F1 Mice (Drinking Water and Intraperitoneal Injection Studies).

Toxicity report series Pub Date : 1992-03-01
M Dieter
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Abstract

Antimony potassium tartrate (APT) is a complex salt that until recently was used worldwide as an anti-schistosomal drug. APT was efficacious in humans only if administered intravenously at a near-lethal total dose of 36 mg/kg. Because unconfirmed epidemiologic studies suggested a possible association between APT treatment and bladder cancer, prechronic toxicity studies were initiated with APT to select a route of administration and appropriate doses in the event chronic studies were needed. To determine the most appropriate route for longer-term studies, toxicity and concentrations of tissue antimony were compared in F344/N rats and B6C3F1 mice that were administered APT in drinking water or by i.p. injection for 14 or 16 days. The animals were assigned to dose groups, 5/sex/species. Drinking water doses, estimated by water consumption, were 0, 16, 28, 59, 94, or 168 mg/kg in rats and 0, 59, 98, 174, 273, or 407 mg/kg in mice; i.p. doses were 0, 1.5, 3, 6, 11, or 22 mg/kg in rats and 0, 6, 13, 25, 50, or 100 mg/kg in mice. APT was poorly absorbed and relatively nontoxic when given orally. There was no mortality or histopathological lesions in rats or mice receiving doses of APT as high as 168 or 273 mg/kg, respectively. One mouse in the highest dose group (407 mg/kg) died, and there were treatment-related lesions in the liver and forestomach of most mice in this dose group. In contrast, i.p. administration of the drug was much more toxic, resulting in the deaths of rats administered 22 mg/kg; kidney and liver lesions were found in these rats. In mice, i.p. administration of APT caused deaths and liver lesions at dose levels one-fourth of those that caused similar effects by oral administration. All male and female mice injected with 100 mg/kg APT died; half of the female mice given 50 mg/kg APT died; additional deaths occurred with doses as low as 6 mg/kg. Hepatocellular necrosis and inflammation of the liver capsule were present in both sexes of mice in the 50 mg/kg dose groups. As a result of these findings, an i.p. dose regimen was selected for subsequent studies. Groups of ten male and female F344/N rats and B6C3F1 mice were given 0, 1.5, 3, 6, 12, or 24 mg/kg doses of APT 3 times per week for 13 weeks by i.p. injection. Rats were more sensitive than mice to the toxic effects of APT, exhibiting dose-related mortality and reduction in body weight. Four male rats in the 24 mg/kg dose died; body weights in both sexes of rats from this dose group and in male rats from the 12 mg/kg dose group were 10-20% below controls. No clinical signs of toxicity in the mice, nor gross or microscopic lesions, could be attributed to APT. Increased concentrations of antimony, considered to be dose-related, were detected in the blood, liver, kidney, spleen, and heart of rats, and in the liver and spleen of mice. In rats, hepatocellular degeneration and necrosis were associated with dose-related elevations in activities of the liver-specific serum enzymes, sorbitol dehydrogenase and alanine aminotransferase. By alternating the site of abdominal injection and the days of treatment, mesenteric inflammation at the site of administration was minimized in the rats and mice, indicating that the i.p. route would be suitable for chronic studies. Hepatotoxicity in rats occurred in dose groups where there was little evidence of renal toxicity and no cardiac toxicity; thus, serial measurement of liver-specific serum enzyme activities may be useful to monitor the presence and progression of hepatocellular degeneration in longer-term exposures. Synonyms: APT; Tartar emetic; tartrated antimony; tartarized antimony; potassium antimonyltartrate; Bis [μ-[2,3-dihydroxy- butanedioato(4-)-O1, O2:O3, O4]]-diantimonate dipotassium trihydrate (stereoisomer).

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酒石酸锑钾对F344/N大鼠和B6C3F1小鼠(饮水和腹腔注射研究)毒性研究技术报告(中科院28300-74-5号)。
酒石酸锑钾(APT)是一种复合盐,直到最近才在世界范围内用作抗血吸虫药物。APT只有在静脉注射接近致死总剂量36mg /kg时才有效。由于未经证实的流行病学研究表明APT治疗与膀胱癌之间可能存在关联,因此开始了APT的慢性前毒性研究,以便在需要进行慢性研究时选择给药途径和适当剂量。为了确定长期研究的最合适途径,我们比较了F344/N大鼠和B6C3F1小鼠饮水或腹腔注射APT 14或16天的毒性和组织锑浓度。动物被分配到剂量组,每性别/种5只。根据饮水量估算,大鼠的饮水剂量分别为0、16、28、59、94或168 mg/kg,小鼠为0、59、98、174、273或407 mg/kg;大鼠的I.p.剂量为0、1.5、3、6、11或22 mg/kg,小鼠的I.p.剂量为0、6、13、25、50或100 mg/kg。口服时,APT吸收不良,相对无毒。大鼠和小鼠分别接受168和273 mg/kg高剂量的APT治疗,未见死亡和组织病理学损伤。最高剂量组(407 mg/kg) 1只小鼠死亡,该剂量组多数小鼠肝脏和前胃出现治疗相关病变。相比之下,口服给药的毒性要大得多,给药22 mg/kg的大鼠死亡;在这些大鼠中发现肾脏和肝脏病变。在小鼠中,口服给药引起的死亡和肝脏损伤的剂量水平是口服给药的四分之一。注射100 mg/kg APT后,雌雄小鼠均死亡;给药50 mg/kg的雌性小鼠有一半死亡;当剂量低至6毫克/公斤时,发生了额外的死亡。50 mg/kg剂量组男女小鼠均出现肝细胞坏死和肝包膜炎症。由于这些发现,在随后的研究中选择了一种i.p.剂量方案。每组10只雄性、雌性F344/N大鼠和B6C3F1小鼠分别给予0、1.5、3、6、12、24 mg/kg剂量的APT,每周3次,连续注射13周。大鼠对APT的毒性作用比小鼠更敏感,表现出剂量相关的死亡率和体重下降。24 mg/kg剂量下雄性大鼠死亡4只;该剂量组雌雄大鼠和12 mg/kg剂量组雄性大鼠的体重比对照组低10-20%。小鼠没有临床毒性症状,也没有肉眼或显微镜下的病变可归因于APT。在大鼠的血液、肝脏、肾脏、脾脏和心脏以及小鼠的肝脏和脾脏中检测到锑的浓度增加,认为与剂量有关。在大鼠中,肝细胞变性和坏死与肝脏特异性血清酶、山梨醇脱氢酶和丙氨酸转氨酶活性的剂量相关升高有关。通过交替腹腔注射部位和治疗天数,大鼠和小鼠给药部位的肠系膜炎症最小,表明腹腔注射途径适用于慢性研究。大鼠肝毒性发生在几乎没有肾毒性和无心脏毒性证据的剂量组;因此,连续测量肝脏特异性血清酶活性可能有助于监测长期暴露的肝细胞变性的存在和进展。同义词:恰当的;吐酒石;含酒石的锑;tartarized锑;antimonyltartrate钾;双[μ-[2,3-二羟基-丁二酸(4-)- o1, O2:O3, O4]]-三水合二锑酸二钾(立体异构体)。
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