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NTP对F344/N大鼠和B6C3F1小鼠进行的叔丁醇(化学物质登记号:75-65-0)毒理学和致癌性研究(饮用水研究)

NTP Toxicology and Carcinogenesis Studies of t -Butyl Alcohol (CAS No. 75-65-0) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

出版信息

Natl Toxicol Program Tech Rep Ser. 1995 May;436:1-305.

Abstract

t -Butyl alcohol is widely used in the manufacture of perfumes and a variety of cosmetics. It is also used as a raw material in the production of isobutylene, which may be used to produce methyl tertiary butyl ether, a common gasoline additive, or to produce butyl elastomers used in the production of automobile tires. Male and female F344/N rats and B6C3F1 mice were given t -butyl alcohol (greater than 99% pure) in drinking water for 13 weeks or 2 years. The genetic toxicity of t -butyl alcohol was assessed by testing the ability of the chemical to induce mutations in various strains of Salmonella typhimurium and in L5178Y mouse lymphoma cells, sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, and by measuring the frequency of micronucleated erythrocytes in mouse peripheral blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 2.5, 5, 10, 20, or 40 mg/mL t -butyl alcohol in drinking water for 13 weeks. All males and six females given 40 mg/mL died during the study. Final mean body weights of 10 and 20 mg/mL males and of 40 mg/mL females were 12%, 17%, or 21% less than those of the corresponding controls, respectively. Serum sorbitol dehydrogenase activities in 10 and 20 mg/mL males were greater than that in the controls after 13 weeks. Serum alanine aminotransferase activity in 40 mg/mL females was greater than that in the controls after 2 weeks and greater in all exposed females after 13 weeks. Urine volumes of 10, 20, and 40 mg/mL males and females decreased, and urine specific gravity values increased. Transitional epithelial hyperplasia and inflammation of the urinary bladder were observed in 20 and 40 mg/mL males and 40 mg/mL females. Absolute and relative liver weights of all exposed groups of females and relative liver weights of 5, 10, and 20 mg/mL males were significantly greater than those of the controls. Absolute and relative kidney weights of all exposed groups of males and females were significantly greater than those of the controls. Incidences of mineralization of the kidney were significantly increased in 10, 20, and 40 mg/mL males. The severity of nephropathy in 2.5, 5, 10, and 20 mg/mL males was significantly greater than that of the controls as was the accumulation of hyaline droplets in the kidney of 5, 10, and 20 mg/mL males. The incidences of nephropathy in 10, 20, and 40 mg/mL females were significantly greater than that of the controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 2.5, 5, 10, 20, or 40 mg/mL t -butyl alcohol in drinking water for 13 weeks. The deaths of two males and one female in the 40 mg/mL group were attributed to exposure to t -butyl alcohol. The final mean body weights of 20 and 40 mg/mL males and 40 mg/mL females were significantly lower than those of the controls. There were no biologically significant differences in hematology parameters of exposed and control groups of mice. Transitional epithelial hyperplasia and inflammation were observed in the urinary bladder of 20 and 40 mg/mL males and 40 mg/mL females. 2-YEAR STUDY IN RATS: Groups of 60 F344/N rats were given 0, 1.25, 2.5, or 5 mg/mL t -butyl alcohol (males) or 0, 2.5, 5, or 10 mg/mL t -butyl alcohol (females) in drinking water for 2 years. These correspond to average daily doses of approximately 90, 200, or 420 mg t -butyl alcohol/kg body weight for males and approximately 180, 330, or 650 mg t -butyl alcohol/kg body weight for females. Ten rats per group were evaluated after 15 months of chemical administration. Survival, Body Weights, and Water Consumption: Survival rates of 5 mg/mL males and 10 mg/mL females were significantly lower than those of the controls. The final mean body weights of exposed groups of males were 15% to 24% lower than that of the controls, and the final mean body weight of 10 mg/mL females was 21% lower than that of the controls. Water consumption by males increased with dose; water consumption by females decreased with dose. Hematology and Urinalysis: At the 15-month inte. Hematology and Urinalysis: At the 15-month interim evaluation, there were no significant differences in hematology parameters in males and females, and there were no significant differences in urinalysis parameters in males. Females given 5 or 10 mg/mL had increased urine specific gravities and decreased urine volumes. Pathology Findings: At the 15-month interim evaluation, relative kidney weights of 2.5 and 5 mg/mL males and absolute and relative kidney weights of 2.5, 5, and 10 mg/mL females were significantly greater than those of the controls. At 2 years, the incidence of mineralization in the kidney increased with dose and that of 5 mg/mL males was significantly greater than that of the controls. In the standard evaluation at the end of the study, the incidences of focal renal tubule hyperplasia and of adenoma were increased in exposed males and a carcinoma was observed in one 5 mg/mL male. Renal tubule hyperplasia occurred in one 10 mg/mL female. An extended evaluation of the kidney identified additional male rats with hyperplasia (control, 11/50; 1.25 mg/mL, 13/50; 2.5 mg/mL, 11/50; 5 mg/mL, 19/50) and renal tubule adenoma (7/50, 8/50, 15/50, 10/50); renal tubule carcinomas were identified in two 1.25 mg/mL males and in one 2.5 mg/mL male. Renal tubule adenoma was identified in one 5 mg/mL male from the 15-month extended evaluation. In the standard and extended evaluations combined, there were dose-related increased incidences of hyperplasia and adenoma. The severity of nephropathy and the incidence and severity of transitional cell hyperplasia of the kidney were increased in exposed male and female rats. Linear foci of mineralization were present in the renal papilla of exposed males. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were given 0, 5, 10, or 20 mg/mL t -butyl alcohol in drinking water for 2 years. Exposure levels of 5, 10, or 20 mg/mL delivered average daily doses of approximately 540, 1,040, or 2,070 mg t -butyl alcohol/kg body weight to males and approximately 510, 1,020, or 2,110 mg/kg to females. Survival, Body Weights, and Water Consumption: Survival of 20 mg/mL males was significantly lower than that of the controls. The final mean body weights of exposed groups of males were similar to those of the controls. The mean body weights of females given 20 mg/mL were 10% to 15% lower than those of the controls from week 13 to the end of the study. Water consumption by exposed groups of males and females was similar to that by the controls. Pathology Findings: Incidences of thyroid gland follicular cell hyperplasia were significantly increased in all exposed groups of males and in 10 and 20 mg/mL females. The incidence of follicular cell adenoma or carcinoma (combined) was marginally increased in 10 mg/mL males (0 mg/mL, 1/60; 5 mg/mL, 0/59; 10 mg/mL, 4/59; 20 mg/mL, 2/57). The incidence of follicular cell adenoma was significantly increased in 20 mg/mL females (2/58, 3/60, 2/59, 9/59). The incidences of chronic inflammation and transitional epithelial hyperplasia of the urinary bladder were increased in 20 mg/mL males and to a lesser extent in 20 mg/mL females. GENETIC TOXICOLOGY: t -Butyl alcohol was tested for induction of genetic damage in vitro and in vivo, and all results were negative. In vitro, t -butyl alcohol was negative in Salmonella typhimurium and mouse lymphoma cell mutation tests, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro studies were conducted with and without metabolic activation (S9). In vivo, no increase in micronucleated erythrocytes was observed in peripheral blood samples from mice administered t -butyl alcohol in drinking water for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was some evidence of carcinogenic activity of t -butyl alcohol in male F344/N rats based on increased incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity in female F344/N rats receiving 2.5, 5, or 10 mg/mL t -butyl alcohol. There was equivocal evidence of carcinogenic activity of t -butyl alcohol in male B6C3F1 mice based on the marginally increased incidences of follicular cell adenoma or carcinoma (combined) of the thyroid gland. There was some evidence of carcinogenic activity of t -butyl alcohol in female B6C3F1 mice based on increased incidences of follicular cell adenoma of the thyroid gland. Exposure to t -butyl alcohol was associated with mineralization and renal tubule hyperplasia in male rats, transitional epithelial hyperplasia and increased severity of nephropathy of the kidney in male and female rats, follicular cell hyperplasia of the thyroid gland in male and female mice, and chronic inflammation and hyperplasia of the urinary bladder in male mice and to a lesser extent in female mice. Synonyms: 2-Methyl-2-propanol, 2-methylpropan-2-ol, TBA, t -butanol, tertiary butyl alcohol, t -butyl hydroxide, trimethyl carbinol, trimethyl methanol

摘要

叔丁醇广泛应用于香水及各类化妆品的制造。它还用作生产异丁烯的原料,而异丁烯可用于生产甲基叔丁基醚(一种常见的汽油添加剂)或用于生产汽车轮胎用的丁基弹性体。将雄性和雌性F344/N大鼠以及B6C3F1小鼠置于含叔丁醇(纯度大于99%)的饮用水中,喂养13周或2年。通过检测该化学物质在各种鼠伤寒沙门氏菌菌株和L5178Y小鼠淋巴瘤细胞中诱导突变的能力、培养的中国仓鼠卵巢细胞中的姐妹染色单体交换和染色体畸变,以及测量小鼠外周血中微核红细胞的频率,来评估叔丁醇的遗传毒性。

大鼠13周研究:将10只雄性和10只雌性F344/N大鼠分为几组,分别给予饮用水中浓度为0、2.5、5、10、20或40mg/mL的叔丁醇,持续13周。所有给予40mg/mL叔丁醇的雄性大鼠以及6只雌性大鼠在研究期间死亡。给予10mg/mL和20mg/mL叔丁醇的雄性大鼠以及给予40mg/mL叔丁醇的雌性大鼠的最终平均体重分别比相应对照组低12%、17%或21%。13周后,给予10mg/mL和20mg/mL叔丁醇的雄性大鼠血清山梨醇脱氢酶活性高于对照组。给予40mg/mL叔丁醇的雌性大鼠在2周后血清丙氨酸转氨酶活性高于对照组,13周后所有暴露雌性大鼠的该酶活性均更高。给予10mg/mL、20mg/mL和40mg/mL叔丁醇的雄性和雌性大鼠尿量减少,尿比重值增加。在给予20mg/mL和40mg/mL叔丁醇的雄性大鼠以及给予40mg/mL叔丁醇的雌性大鼠中观察到膀胱移行上皮增生和炎症。所有暴露组雌性大鼠肝脏的绝对重量和相对重量以及给予5mg/mL、10mg/mL和20mg/mL叔丁醇的雄性大鼠肝脏的相对重量均显著高于对照组。所有暴露组雄性和雌性大鼠肾脏的绝对重量和相对重量均显著高于对照组。给予10mg/mL、20mg/mL和40mg/mL叔丁醇的雄性大鼠肾脏矿化发生率显著增加。给予2.5mg/mL、5mg/mL、10mg/mL和20mg/mL叔丁醇的雄性大鼠肾病严重程度显著高于对照组,给予5mg/mL、10mg/mL和20mg/mL叔丁醇的雄性大鼠肾脏透明滴积累情况也更严重。给予10mg/mL、20mg/mL和40mg/mL叔丁醇的雌性大鼠肾病发生率显著高于对照组。

小鼠13周研究:将10只雄性和10只雌性B6C3F1小鼠分为几组,分别给予饮用水中浓度为0、2.5、5、10、20或40mg/mL的叔丁醇,持续13周。40mg/mL组中有两只雄性和一只雌性小鼠死亡,归因于叔丁醇暴露。给予20mg/mL和40mg/mL叔丁醇的雄性大鼠以及给予40mg/mL叔丁醇的雌性大鼠的最终平均体重显著低于对照组。暴露组和对照组小鼠的血液学参数无生物学显著差异。在给予20mg/mL和40mg/mL叔丁醇的雄性大鼠以及给予40mg/mL叔丁醇的雌性大鼠膀胱中观察到移行上皮增生和炎症。

大鼠2年研究:将60只F344/N大鼠分为几组,分别给予饮用水中浓度为0、1.25、2.5或5mg/mL的叔丁醇(雄性)或0、2.5、5或10mg/mL的叔丁醇(雌性),持续2年。这些剂量分别对应雄性大鼠约90、200或420mg叔丁醇/千克体重的平均每日剂量以及雌性大鼠约180、330或650mg叔丁醇/千克体重的平均每日剂量。给药15个月后,每组评估10只大鼠。

存活、体重和饮水量:给予5mg/mL叔丁醇的雄性大鼠和给予10mg/mL叔丁醇的雌性大鼠存活率显著低于对照组。暴露组雄性大鼠的最终平均体重比对照组低15%至24%,给予10mg/mL叔丁醇的雌性大鼠最终平均体重比对照组低21%。雄性大鼠饮水量随剂量增加;雌性大鼠饮水量随剂量减少。

血液学和尿液分析

在15个月的中期评估中,雄性和雌性大鼠的血液学参数无显著差异,雄性大鼠的尿液分析参数也无显著差异。给予5mg/mL或10mg/mL叔丁醇的雌性大鼠尿比重增加,尿量减少。

病理学发现

在15个月的中期评估中,给予2.5mg/mL和5mg/mL叔丁醇的雄性大鼠肾脏相对重量以及给予2.5mg/mL、5mg/mL和10mg/mL叔丁醇的雌性大鼠肾脏绝对重量和相对重量均显著高于对照组。2年后,肾脏矿化发生率随剂量增加,给予5mg/mL叔丁醇的雄性大鼠矿化发生率显著高于对照组。在研究结束时的标准评估中,暴露雄性大鼠局灶性肾小管增生和腺瘤发生率增加,在一只给予5mg/mL叔丁醇的雄性大鼠中观察到癌。一只给予10mg/mL叔丁醇的雌性大鼠出现肾小管增生。对肾脏的扩展评估发现更多雄性大鼠出现增生(对照组,11/50;1.25mg/mL,13/50;2.5mg/mL,11/50;5mg/mL,19/50)和肾小管腺瘤(7/50,8/50,15/50,10/50);在两只给予1.25mg/mL叔丁醇的雄性大鼠和一只给予2.5mg/mL叔丁醇的雄性大鼠中发现肾小管癌。在15个月的扩展评估中,一只给予5mg/mL叔丁醇的雄性大鼠中发现肾小管腺瘤。在标准评估和扩展评估综合结果中,增生和腺瘤的发生率呈剂量相关增加。暴露的雄性和雌性大鼠肾病严重程度以及肾脏移行细胞增生的发生率和严重程度均增加。暴露雄性大鼠肾乳头出现线性矿化灶。

小鼠2年研究:将60只雄性和60只雌性B6C3F1小鼠分为几组,分别给予饮用水中浓度为0、5、10或20mg/mL的叔丁醇,持续2年。5mg/mL、10mg/mL或20mg/mL的暴露水平分别给予雄性大鼠约540、1040或2070mg叔丁醇/千克体重的平均每日剂量以及雌性大鼠约510、1020或2110mg/千克体重的平均每日剂量。

存活、体重和饮水量:给予20mg/mL叔丁醇的雄性大鼠存活率显著低于对照组。暴露组雄性大鼠的最终平均体重与对照组相似。从第13周直至研究结束,给予20mg/mL叔丁醇的雌性大鼠平均体重比对照组低10%至15%。暴露组雄性和雌性大鼠的饮水量与对照组相似。

病理学发现

所有暴露组雄性大鼠以及给予10mg/mL和20mg/mL叔丁醇的雌性大鼠甲状腺滤泡细胞增生发生率显著增加。给予10mg/mL叔丁醇的雄性大鼠滤泡细胞腺瘤或癌(合并)发生率略有增加(0mg/mL,1/60;5mg/mL,0/59;10mg/mL,4/59;20mg/mL,2/57)。给予20mg/mL叔丁醇的雌性大鼠滤泡细胞腺瘤发生率显著增加(2/58,3/60,2/59,9/59)。给予20mg/mL叔丁醇的雄性大鼠膀胱慢性炎症和移行上皮增生发生率增加,给予20mg/mL叔丁醇的雌性大鼠中该情况程度较轻。

遗传毒理学

对叔丁醇进行了体外和体内遗传损伤诱导测试,所有结果均为阴性。在体外,叔丁醇在鼠伤寒沙门氏菌和小鼠淋巴瘤细胞突变试验中呈阴性,并且在培养的中国仓鼠卵巢细胞中未诱导姐妹染色单体交换或染色体畸变。这些体外研究在有和没有代谢活化(S9)的情况下进行。在体内,对饮用含叔丁醇的水13周的小鼠外周血样本进行检测,未观察到微核红细胞增加。

结论

在这些为期2年的饮用水研究条件下,基于肾小管腺瘤或癌(合并)发生率增加,有一些证据表明叔丁醇对雄性F344/N大鼠具有致癌活性。接受2.5mg/mL、5mg/mL或10mg/mL叔丁醇的雌性F344/N大鼠没有致癌活性的证据。基于甲状腺滤泡细胞腺瘤或癌(合并)发生率略有增加,有不确定的证据表明叔丁醇对雄性B6C3F1小鼠具有致癌活性。基于甲状腺滤泡细胞腺瘤发生率增加,有一些证据表明叔丁醇对雌性B6C3F1小鼠具有致癌活性。暴露于叔丁醇与雄性大鼠的矿化和肾小管增生、雄性和雌性大鼠肾脏的移行上皮增生和肾病严重程度增加、雄性和雌性小鼠甲状腺滤泡细胞增生以及雄性小鼠膀胱慢性炎症和增生以及雌性小鼠较轻程度的上述情况有关。

同义词

2 - 甲基 - 2 - 丙醇、2 - 甲基丙 - 2 - 醇、TBA、叔丁醇、叔丁基醇、叔丁基氢氧化物、三甲基甲醇、三甲基 carbinol

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