Natl Toxicol Program Tech Rep Ser. 2002 Dec(503):1-218.
[structure: see text] Chloral hydrate is used medically as a sedative or hypnotic and as a rubefacient in topical preparations, and it is often given to children as a sedative during dental and other medical procedures. Chloral hydrate is used as a central nervous system depressant and sedative in veterinary medicine and as a general anesthetic in cattle and horses. It is a byproduct of the chlorination of water and has been detected in plant effluent after the bleaching of softwood pulp. Chloral, the anhydrous form of chloral hydrate, is used as a synthetic intermediate in the production of insecticides and herbicides. Chloral hydrate was nominated for study by the Food and Drug Administration based upon widespread human exposure and its potential hepatotoxicity and the toxicity of related chemicals. A dietary control component was incorporated in response to concerns within the regulatory community relating to increased background neoplasm incidences in rodent strains used for toxicity testing and to the proposed use of dietary restriction to control background neoplasm incidence in rodent cancer studies. Male B6C3F1 mice (ad libitum-fed or dietary-controlled) received chloral hydrate (99% pure) by gavage for 2 years. 2-YEAR STUDY IN MALE MICE: Groups of 120 male mice received chloral hydrate in distilled water by gavage at doses of 0, 25, 50, or 100 mg/kg 5 days per week for 104 to 105 weeks. Each dose group was divided into two dietary groups of 60 mice. The ad libitum-fed mice had free access to feed, and the dietary-controlled mice received feed in measured daily amounts calculated to maintain body weight on a previously computed idealized body weight curve. Twelve mice from each diet and dose group were evaluated at 15 months.
SURVIVAL, FEED CONSUMPTION, AND BODY WEIGHTS: Survival of dosed groups of ad libitum-fed and dietary-controlled mice was similar to that of the corresponding vehicle controls. When compared to the ad libitum-fed groups, dietary control significantly increased survival in the vehicle controls and 25 and 50 mg/kg groups. Mean body weights of all dosed groups were similar to those of the vehicle control groups throughout the study. The dietary-controlled mice were successfully maintained at or near their target idealized body weights. There was less individual variation in body weights in the dietary-controlled groups than in the corresponding ad libitum-fed groups. Feed consumption by 25 and 50 mg/kg ad libitum-fed mice was generally similar to that by the vehicle controls throughout the study. Feed consumption by 100 mg/kg ad libitum-fed mice was slightly less than that by the vehicle controls throughout the study.
Chloral hydrate did not significantly induce either lauric acid 4-hydroxylase activity or CYP4A immunoreactive protein in any of the dosed groups of ad libitum-fed mice. However, 100 mg/kg did significantly induce both lauric acid 4-hydroxylase activity and CYP4A immunoreactive protein in the dietary-controlled mice. Moreover, the induction response profile of CYP4A was similar to the increase in the incidence of liver neoplasms at 2 years in the dietary-controlled mice with the major effect occurring in the 100 mg/kg group. The serum enzymes alanine aminotransferase, amylase, aspartate aminotransferase, and lactate dehydrogenase were also assayed at 2 years. In the ad libitum-fed groups there was a significant increase in aspartate aminotransferase activity in the 50 mg/kg group. There were no other significant effects in any dosed group, but in general the dietary-controlled groups exhibited lower values than the corresponding ad libitum-fed groups.
The heart weight of ad libitum-fed male mice administered 100 mg/kg and the kidney weights of 50 and 100 mg/kg ad libitum-fed mice were significantly less than those of the vehicle controls at 2 years. The liver weights of all dosed groups of ad libitum-fed and dietary-controlled mice were greater than those of the vehicle control groups at 2 years, but the increases were not statistically significant. The incidence of hepatocellular adenoma or carcinoma (combined) in ad libitum-fed mice administered 25 mg/kg was significantly greater than that in the vehicle controls at 2 years. The incidences of hepatocellular carcinoma and of hepatocellular adenoma or carcinoma (combined) occurred with positive trends in dietary-controlled male mice at 2 years, and the incidence of hepatocellular carcinoma in 100 mg/kg dietary-controlled mice was significantly increased.
Under the conditions used in this 2-year gavage study, there was some evidence of carcinogenic activity of chloral hydrate in male B6C3F1 mice based on increased incidences of hepatocellular adenoma or carcinoma (combined) in ad libitum-fed mice and on increased incidences of hepatocellular carcinoma in dietary-controlled mice. In the dietary-controlled mice, induction of enzymes associated with peroxisome proliferation was observed at higher doses.
[结构：见正文]水合氯醛在医学上用作镇静剂或催眠剂，在局部制剂中用作发红剂，并且在牙科和其他医疗程序中常作为镇静剂给儿童使用。水合氯醛在兽医学中用作中枢神经系统抑制剂和镇静剂，在牛和马中用作全身麻醉剂。它是水氯化的副产物，在软木纸浆漂白后的植物废水中已被检测到。水合氯醛的无水形式氯醛用作生产杀虫剂和除草剂的合成中间体。基于广泛的人体暴露及其潜在的肝毒性以及相关化学品的毒性，美国食品药品监督管理局提名对水合氯醛进行研究。为回应监管界对用于毒性测试的啮齿动物品系背景肿瘤发生率增加以及在啮齿动物癌症研究中提议使用饮食限制来控制背景肿瘤发生率的担忧，纳入了饮食控制成分。雄性B6C3F1小鼠（随意进食或饮食控制）通过灌胃给予水合氯醛（99%纯），持续2年。
每组120只雄性小鼠，每周5天，以0、25、50或100mg/kg的剂量通过灌胃给予蒸馏水中的水合氯醛，持续104至105周。每个剂量组分为两个饮食组，每组60只小鼠。随意进食的小鼠可自由获取食物，饮食控制的小鼠按计算好的每日定量进食，以维持其体重符合先前计算的理想体重曲线。在15个月时，对每个饮食和剂量组的12只小鼠进行评估。
存活、饲料消耗和体重：随意进食和饮食控制的给药组小鼠的存活率与相应的溶剂对照组相似。与随意进食组相比，饮食控制显著提高了溶剂对照组以及25和50mg/kg组的存活率。在整个研究过程中，所有给药组的平均体重与溶剂对照组相似。饮食控制的小鼠成功维持在或接近其目标理想体重。饮食控制组的体重个体差异小于相应的随意进食组。在整个研究过程中，25和50mg/kg随意进食组小鼠的饲料消耗量通常与溶剂对照组相似。在整个研究过程中，100mg/kg随意进食组小鼠的饲料消耗量略低于溶剂对照组。
在随意进食的给药组小鼠中，水合氯醛在任何剂量组均未显著诱导月桂酸4 - 羟化酶活性或CYP4A免疫反应蛋白。然而，100mg/kg剂量在饮食控制的小鼠中显著诱导了月桂酸4 - 羟化酶活性和CYP4A免疫反应蛋白。此外，CYP4A的诱导反应谱与饮食控制的小鼠在2年时肝脏肿瘤发生率的增加相似，主要影响发生在100mg/kg组。在2年时还检测了血清酶丙氨酸氨基转移酶、淀粉酶、天冬氨酸氨基转移酶和乳酸脱氢酶。在随意进食组中，50mg/kg组的天冬氨酸氨基转移酶活性显著增加。在任何给药组中均无其他显著影响，但总体而言，饮食控制组的值低于相应的随意进食组。
在2年时，给予100mg/kg的随意进食雄性小鼠的心脏重量以及给予50和100mg/kg的随意进食小鼠的肾脏重量显著低于溶剂对照组。在2年时，随意进食和饮食控制的所有给药组小鼠的肝脏重量均大于溶剂对照组，但增加幅度无统计学意义。在2年时，给予25mg/kg的随意进食小鼠的肝细胞腺瘤或癌（合并）发生率显著高于溶剂对照组。在2年时，饮食控制的雄性小鼠中肝细胞癌以及肝细胞腺瘤或癌（合并）的发生率呈阳性趋势，且100mg/kg饮食控制小鼠的肝细胞癌发生率显著增加。
在本为期2年的灌胃研究中所采用的条件下，基于随意进食小鼠中肝细胞腺瘤或癌（合并）发生率增加以及饮食控制小鼠中肝细胞癌发生率增加，有一些证据表明水合氯醛在雄性B6C3F1小鼠中具有致癌活性。在饮食控制的小鼠中，可以观察到在较高剂量下与过氧化物酶体增殖相关的酶的诱导。
