卤代乙腈的毒理学

Toxicology of haloacetonitriles.

作者信息

Hayes J R, Condie L W, Borzelleca J F

出版信息

Environ Health Perspect. 1986 Nov;69:183-202. doi: 10.1289/ehp.8669183.

DOI:10.1289/ehp.8669183

PMID:3816722

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1474335/

Abstract

Haloacetonitriles are by-products of water chlorination and may form in vivo from the reaction of residual chlorine with endogenous compounds such as amino acids. Dibromoacetonitrile (DBAN) was negative in selected mutagenic assays; dichloroacetonitrile (DCAN) was mutagenic in S. typhimurium, but not in S. cerevisiae. Both DBAN and DCAN may be carcinogenic. There is a paucity of basic toxicological data for these compounds. The studies described were conducted to determine the acute, subacute, and subchronic toxicity of DBAN and DCAN. The acute oral LD50 values (mg/kg) in mice and rats are: DBAN, mice: 289 (M), 303 (F); DBAN, rats: 245 (M), 361 (F); DCAN, mice: 270 (M), 279 (F); DCAN, rats: 339 (M), 330 (F). Death was preceded by slowed respiration, depressed activity, prostration, and coma. There were no apparent compound-related gross pathological effects. DBAN (in corn oil) was administered by gavage to male and female CD rats for 14 or 90 days at levels of 23, 45, 90, and 180 mg/kg/day or 6, 23, and 45 mg/kg/day, respectively. Mortality was 100% at 180 mg/kg and 40% (M) and 20% (F) at 90 mg/kg/day. Compound-related mortality was 10% (M) and 5% (F) at 45 mg/kg and 0% (M) and 10% (F) at 23 mg/kg during the 90-day study. No consistent, significant, adverse compound-related effects on any of the parameters evaluated were evident. Possible target organs might be spleen, thymus, and liver. The no-observed adverse-effect level (NOAEL) for 14 days was 45 mg/kg/day and for 90 days was 23 mg/kg/day. DCAN (in corn oil) was administered by gavage to male and female CD rats for 14 or 90 days at levels of 12, 23, 45, and 90 mg/kg/day or 8, 33, and 65 mg/kg/day, respectively. There were no deaths during the 14-day study. Compound-related mortality was 50% (M) and 25% (F) at 65 mg/kg, 10% (M) and 5% (F) at 33 mg/kg, and 5% (M) and 0% (F) at 8 mg/kg during the 90-day study. Body weights were significantly lower at 90 and 65 mg/kg/day; weight and ratios of spleen and gonads and cholesterol levels were significantly lower at 90 mg/kg/day. No consistent, significant adverse compound-related effects on any of the parameters evaluated were evident. The NOAEL for 14 days was 45 mg/kg/day and for 90 days was 8 mg/kg/day.

摘要

卤代乙腈是水氯化过程中的副产物，可能在体内由残留氯与内源性化合物（如氨基酸）反应形成。二溴乙腈（DBAN）在特定的诱变试验中呈阴性；二氯乙腈（DCAN）在鼠伤寒沙门氏菌中具有致突变性，但在酿酒酵母中无致突变性。DBAN和DCAN都可能具有致癌性。关于这些化合物的基础毒理学数据匮乏。所描述的研究旨在确定DBAN和DCAN的急性、亚急性和亚慢性毒性。小鼠和大鼠的急性经口半数致死剂量（mg/kg）如下：DBAN，小鼠：289（雄性），303（雌性）；DBAN，大鼠：245（雄性），361（雌性）；DCAN，小鼠：270（雄性），279（雌性）；DCAN，大鼠：339（雄性），330（雌性）。死亡前会出现呼吸减慢、活动减少、虚脱和昏迷。未观察到明显的与化合物相关的大体病理效应。将DBAN（溶于玉米油）分别以23、45、90和180 mg/kg/天或6、23和45 mg/kg/天的剂量经口灌胃给予雄性和雌性CD大鼠14天或90天。在180 mg/kg时死亡率为100%，在90 mg/kg/天时雄性死亡率为40%，雌性死亡率为20%。在90天的研究中，45 mg/kg时与化合物相关的死亡率雄性为10%，雌性为5%；23 mg/kg时雄性为0%，雌性为10%。在所评估的任何参数上，均未观察到一致的、显著的、与化合物相关的不良影响。可能的靶器官可能是脾脏、胸腺和肝脏。14天的未观察到不良作用水平（NOAEL）为45 mg/kg/天，90天的NOAEL为23 mg/kg/天。将DCAN（溶于玉米油）分别以12、23、45和90 mg/kg/天或8、33和65 mg/kg/天的剂量经口灌胃给予雄性和雌性CD大鼠14天或90天。在14天的研究中无死亡发生。在90天的研究中，65 mg/kg时与化合物相关的死亡率雄性为50%，雌性为25%；33 mg/kg时雄性为10%，雌性为5%；8 mg/kg时雄性为5%，雌性为0%。在90和65 mg/kg/天时体重显著降低；在90 mg/kg/天时脾脏、性腺重量及比值和胆固醇水平显著降低。在所评估的任何参数上，均未观察到一致的、显著的、与化合物相关的不良影响。14天的NOAEL为45 mg/kg/天，90天的NOAEL为8 mg/kg/天。