2-羟基-4-甲氧基二苯甲酮(CAS No. 131-57-7)对F344/N大鼠和B6C3F1小鼠外用和给药的毒性研究技术报告。

Toxicity report series Pub Date : 1992-10-01
J.E. French
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引用次数: 0

摘要

2-羟基-4-甲氧基二苯甲酮(HMB)天然存在于花色素中,被合成用于防晒霜、各种化妆品中的紫外线稳定剂、塑料表面涂层和聚合物中。在F344/N大鼠和B6C3F1小鼠中进行了HMB的毒性研究,分别在饲料中给药和外用HMB,研究时间为2周(5只动物/性别、剂量和物种)和13周(10只动物/性别、剂量和物种)。评估包括血液学、临床化学、尿液分析、生殖毒性和组织病理学评估。在2周和13周的剂量饲料研究中,大鼠喂食含有0、3125、6250、12500、25000或50000 ppm HMB的饲料。1只高剂量雌性大鼠在2周的研究中死亡。在为期13周的研究中,高剂量雄性和雌性大鼠的体重增加都有所减少。在两项研究中,给药大鼠的肝脏和肾脏重量均有所增加。在为期2周的研究中,大鼠的肝脏增大与肝细胞细胞质空泡化显著相关,这些大鼠的饮食中含有6250 ppm或更高的HMB浓度;肾损害主要发生在高剂量大鼠,包括肾小管扩张和肾小管上皮细胞再生。在为期13周的研究中,肾脏病变进展为乳头状变性、坏死和炎症,而肝脏病变似乎有所消退;血清中肝酶保持升高。在13周的研究结束时,喂食50000 ppm HMB的大鼠显示附睾精子密度明显降低,发情周期长度增加。在为期2周的皮肤研究中,大鼠在丙酮或洗剂载体中局部应用1.25至20 mg HMB。唯一注意到的影响是肝脏和肾脏重量的小而可变的增加,主要在高剂量组达到统计学意义。在为期13周的研究中,大鼠接受12.5至200 mg/kg HMB丙酮外用剂量。给药组雌性大鼠肾脏重量升高。没有其他发现归因于HMB治疗。在2周和13周的剂量饲料研究中,小鼠接受含有0、3125、6250、12500、25000或50000 ppm HMB的饲料。在为期2周的研究中,小鼠肝脏重量的剂量相关性增加与肝细胞细胞质空泡化有关。在为期13周的研究中,小鼠体重增加的减少与剂量有关;在给药的雌雄小鼠中,肝脏重量都有轻微的增加。在给药的女性中,肾脏重量有不同程度的增加。显微镜下的病变只出现在接受50000 ppm HMB的男性肾脏中;这些包括扩张的肾小管中的嗜酸性蛋白铸型和与扩张的小管相关的轻度炎症。高剂量组小鼠附睾精子密度降低,发情周期延长。在为期2周的皮肤研究中,小鼠在丙酮或洗剂载体中局部应用0.5至8 mg HMB。唯一注意到的影响是肝脏和肾脏重量的微小、可变的增加,主要是在高剂量组。在为期13周的研究中,小鼠接受22.75至364 mg/kg的丙酮局部剂量。给药雄性小鼠的肾脏重量有不同程度的增加。在所有3种剂量水平(22.75、91和200 mg/kg)下,附睾精子密度均降低。鼠伤寒沙门菌致突变性研究、中国仓鼠卵巢细胞(CHO)细胞遗传学研究以及13周小鼠外周血涂片微核红细胞评价均对HMB的遗传毒性进行了评价。HMB在代谢激活的沙门氏菌中具有弱诱变作用,在代谢激活系统存在的情况下诱导CHO细胞的姐妹染色单体交换和染色体畸变。接受HMB治疗的小鼠血液中微核红细胞的频率没有增加。总之,HMB对大鼠和小鼠外用和口服后产生的效果大致相似。一致的发现包括附睾精子密度降低,发情周期延长,肝脏和肾脏重量增加。小鼠在剂量饲料研究中表现出肾脏的微观变化,包括嗜酸性蛋白铸型的小管扩张。大鼠肾脏出现扩张、肾小管再生、乳头变性和炎症;肝损伤包括明显可逆的肝细胞细胞质空泡化发生在大鼠和小鼠。在大鼠和小鼠的饮食中,显微镜下病变的未观察到的不良反应水平(NOAEL)为6250 ppm HMB。在13周的小鼠皮肤研究中,没有达到降低附睾精子密度的NOAEL (<23 mg/kg/天)。同义词:氧苯酮;4-Methoxy-2-hydroxy-benzophenone;Cyasorb紫外线;Uvinul m40;(2-hydroxy-4-methoxyphenyl) phenyl-methanone;nsc - 7778;Spectra-sorb紫外线;Syntase 62;佛罗里达大学3;美国空军CY-9;NCI-C60957。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NTP technical report on the toxicity studies of 2-Hydroxy-4-methoxybenzophenone (CAS No. 131-57-7) Adminstered Topically and in Dosed Feed to F344/N Rats and B6C3F1 Mice.

2-Hydroxy-4-methoxybenzophenone (HMB) occurs naturally in flower pigments and is synthesized for use in sunscreens, as a UV stabilizer in various cosmetic products, and in plastic surface coatings and polymers. Toxicity studies of HMB were performed in F344/N rats and B6C3F1 mice, by administering HMB in feed and by topical application, in studies of 2 weeks' (5 animals/sex, dose and species) and 13 weeks' (10 animals/sex, dose and species) duration. Assessments included hematology, clinical chemistry, urinalysis, reproductive toxicity, and histopathologic evaluations. In both 2- and 13-week dosed feed studies, rats received diets containing 0, 3125, 6250, 12500, 25000, or 50000 ppm HMB. One high-dose female rat died during the 2-week study. Body weight gains of high-dose male and female rats were reduced in the 13-week study. Liver and kidney weights were increased in dosed rats in both studies. In the 2-week studies, enlarged livers were associated with a marked hepatocyte cytoplasmic vacuolization in rats receiving diets containing concentrations of 6250 ppm HMB or higher; renal lesions, consisting of dilated tubules and regeneration of tubular epithelial cells, were found primarily in high-dose rats. In the 13-week studies, kidney lesions progressed to include papillary degeneration, or necrosis, and inflammation, while the liver lesion appeared to regress; liver enzymes in serum remained elevated. Rats receiving a diet with 50000 ppm HMB showed markedly lower epididymal sperm density and an increase in the length of the estrous cycle at the end of the 13-week studies. In 2-week dermal studies, rats received topical applications of 1.25 to 20 mg of HMB in an acetone or lotion vehicle. The only effects noted were small and variable increases in liver and kidney weights, reaching statistical significance primarily in the higher dose groups. In 13-week studies, rats received topical doses from 12.5 to 200 mg/kg HMB in acetone. Kidney weights were elevated in dosed groups of female rats. No other findings were attributed to HMB treatment. In 2- and 13-week dosed feed studies, mice received feed containing 0, 3125, 6250, 12500, 25000, or 50000 ppm HMB. A dose- related increase in liver weight associated with hepatocyte cytoplasmic vacuolization was the only finding in mice in the 2- week studies. Decreased body weight gains were dose-related in mice in the 13-week studies; mild increases in liver weights were seen in dosed mice of both sexes. Kidney weights were increased variably in dosed females. Microscopic lesions were noted only in the kidneys of males receiving 50000 ppm HMB; these included eosinophilic protein casts in dilated renal tubules and a mild inflammation associated with the dilated tubules. Mice in the highest dose group exhibited a decrease in epididymal sperm density and an increase in length of the estrous cycle. In 2-week dermal studies, mice received topical applications from 0.5 to 8 mg HMB in an acetone or lotion vehicle. The only effects noted were minimal, variable increases in liver and kidney weights, primarily in the higher dose groups. In 13-week studies, mice received topical doses of 22.75 to 364 mg/kg in acetone. Kidney weights were increased variably in dosed male mice. Epididymal sperm density was decreased at all 3 dose levels evaluated (22.75, 91, and 200 mg/kg). The genetic toxicity of HMB also was evaluated in mutagenicity studies with Salmonella typhimurium, in cytogenetic studies with Chinese hamster ovary (CHO) cells, and by evaluation of micronucleated erythrocytes in peripheral blood smears from mice in the 13-week studies. HMB was weakly mutagenic in Salmonella with metabolic activation, and induced sister-chromatid exchanges and chromosomal aberrations in CHO cells in the presence of a metabolic activation system. There was no increase in the frequency of micronucleated erythrocytes in the blood of mice receiving HMB. In summary, HMB produced generally similar effects following topical and oral administration to rats and mice. Consistent findings included decreases in epididymal sperm density, lengthened estrous cycle, and increased liver and kidney weights. Mice in the dosed feed studies exhibited microscopic changes in the kidneys, comprising tubular dilatation with eosinophilic protein casts. Dilatation, tubular regeneration, papillary degeneration, and inflammation were noted in the kidneys of rats; and liver lesions consisting of an apparently reversible hepatocyte cytoplasmic vacuolization occurred in both rats and mice. A no-observed-adverse-effect level (NOAEL) for microscopic lesions was 6250 ppm HMB in the diet for rats and mice. A NOAEL was not reached for decreased epididymal sperm density in the 13- week dermal study in mice (<23 mg/kg/day). Synonyms: Oxybenzone; 4-Methoxy-2-hydroxy-benzophenone; Cyasorb UV; Uvinul M 40; (2-hydroxy-4-methoxyphenyl)phenyl-methanone; NSC-7778; Spectra-sorb UV; Syntase 62; UF 3; USAF CY-9; NCI-C60957.

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