Toxicity studies of WY-14,643 (CAS No. 50892-23-4) administered in feed to male Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters.

Toxicity report series Pub Date : 2007-10-01
Michael L Cunningham
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Genetic toxicology studies were conducted in vivo in Tg.AC mouse peripheral blood erythrocytes. In the 2-week studies, groups of five mice were fed diets containing 0, 10, 50, 100, 500, or 1,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 2 to 184 mg Wy-14,643/kg body weight). Groups of five hamsters were fed diets containing 0, 10, 100, 500, 1,000, or 5,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 1 to 550 mg/kg). All animals survived to the end of the studies. The mean body weight gain of 500 ppm mice was significantly less than that of the controls; hamsters exposed to 100 ppm or greater lost weight during the study. Feed consumption by 500 ppm mice was greater than that by the controls. Liver weights of all exposed groups of mice and hamsters were generally significantly increased. In the 2-week studies, an increase in peroxisomal enzyme activity occurred in 10 ppm mice; increases in peroxisomal $-oxidation, carnitine acetyltransferase, catalase, and acyl CoA oxidase occurred in all exposed mice compared to controls. Significantly increased BrdU-labeled hepatocyte percentages occurred in 100 and 1,000 ppm mice and 500 and 5,000 ppm hamsters; peroxisomal $-oxidation of lipids was increased in all exposed groups of mice and hamsters. Gross lesions in the 2-week studies included liver foci in one 500 ppm mouse and one 1,000 ppm hamster and enlarged livers in one hamster in each of the 100 and 500 ppm groups and two 5,000 ppm hamsters. All 500 and 1,000 ppm mice had hepatocyte hypertrophy of the liver, and 1,000 ppm mice also had widespread individual cell necrosis. Minimal to mild multifocal vacuolation of the liver occurred in hamsters exposed to 500 ppm or greater. In the 3-month core studies, groups of 10 male rats, mice, or hamsters were fed diets containing 0, 5, 10, 50, 100, or 500 ppm Wy-14,643 (equivalent to average daily doses of approximately 0.3 to 34 mg/kg for rats, 0.9 to 135 mg/kg for mice, and 0.4 to 42 mg/kg for hamsters). Groups of 15 male rats, mice, or hamsters designated for special studies received the same concentrations of Wy-14,643 for up to 13 weeks. Groups of six male rats, 36 male mice, or 12 male hamsters designated for plasma concentration studies were fed diets containing 50, 100, or 500 ppm Wy-14,643 for up to 9 weeks. All core study animals survived to the end of the studies. Mean body weights were significantly decreased in all exposed groups except the 5 ppm groups and 10 ppm mice; hamsters in the 100 and 500 ppm groups lost weight during the study. Feed consumption by exposed rats and mice was generally similar to that by the controls; during week 14, hamsters exposed to 50 ppm or greater consumed slightly less feed than did the controls. The only clinical finding of toxicity was thinness of two 50 ppm and five 500 ppm hamsters. At all time points, the liver weights of exposed groups of core and special study rats, mice, and hamsters were generally significantly greater than those of the controls. Testis weights were significantly decreased in 500 ppm hamsters on day 34, in hamsters exposed to 5 ppm or greater at week 13 (special study), and in 100 and 500 ppm core study hamsters at the end of the study. In the sperm motility evaluation, the cauda epididymis weight of 500 ppm rats, epididymis weights of 100 and 500 ppm rats and mice, and the testis weight of 500 ppm mice were significantly less than those of the controls. For hamsters, cauda epididymis, epididymis, and testis weights; spermatid heads per testis; and spermatid counts were significantly decreased in all exposed groups evaluated for sperm motility. Epididymal spermatozoal motility and concentration in the 100 and 500 ppm groups and spermatid heads per gram testis in the 500 ppm group were also significantly decreased. Serum concentrations of estradiol were significantly decreased in all exposed groups of hamsters, and concentrations of testosterone and luteinizing hormone were decreased in groups exposed to 50 ppm or greater. At necropsy in the 3-month studies, liver foci were observed in three special study mice, including one 100 ppm mouse and one 500 ppm mouse on day 34 and one 100 ppm mouse at week 13. Liver discoloration and small testes were noted in 500 ppm hamsters on day 34, and hamsters exposed to 50 ppm or greater had enlarged livers and/or small testes at week 13 (special study) and at 3 months (core study). The incidences of cytoplasmic alteration in the liver were significantly increased in all exposed core groups of rats, mice, and hamsters; the severity of this lesion increased with increasing exposure concentration. The incidences of mitotic alteration of the liver in mice exposed to 50 ppm or greater and of liver pigmentation and oval cell hyperplasia in 500 ppm mice were significantly increased. Minimal regeneration of the corticomedullary junction of the renal tubule occurred in all exposed groups of rats. Significantly increased incidences of atrophy of the prostate gland, seminal vesicle, and testis occurred in 100 and 500 ppm hamsters. Degenerative myopathy of skeletal muscle was observed in the lumbar area and thigh of rats, mice, and hamsters and the lower leg of mice, primarily at 500 ppm. Following single-dose gavage exposure to Wy-14,643, plasma concentrations were generally higher in mice than in rats, which in turn were higher than those in hamsters. This pattern of plasma concentrations was usually attributed to high bioavailability in mice, medium bioavailability in rats, and low bioavailabilty in hamsters following an oral exposure to Wy-14,643. No increase in the frequency of micronucleated normochromatic erythrocytes was observed in the peripheral blood of male or female Tg.AC mice exposed to Wy-14,643 in feed or via dermal application for 6 months. Synonyms: [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid.</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":" 62","pages":"1-136"},"PeriodicalIF":0.0000,"publicationDate":"2007-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicity report series","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Wy-14,643 was selected for inclusion in a series of studies on peroxisome proliferators because it is known to produce considerable peroxisome proliferation and hepatocarcinogenicity in rats. Male Sprague-Dawley rats were exposed to Wy-14,643 (greater than 98% pure) in feed for up to 3 months; male B6C3F1 mice and male Syrian hamsters were exposed to Wy-14,643 in feed for 2 weeks or up to 3 months. Animals were evaluated for clinical pathology, plasma concentrations of Wy-14,643, reproductive system effects, cell proliferation and peroxisomal enzyme analyses, and histopathology. Single and multiple-dose toxicokinetic studies of Wy-14,643 were conducted in additional groups of male Sprague-Dawley and Wistar Furth rats, B6C3F1 mice, and Syrian hamsters. Genetic toxicology studies were conducted in vivo in Tg.AC mouse peripheral blood erythrocytes. In the 2-week studies, groups of five mice were fed diets containing 0, 10, 50, 100, 500, or 1,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 2 to 184 mg Wy-14,643/kg body weight). Groups of five hamsters were fed diets containing 0, 10, 100, 500, 1,000, or 5,000 ppm Wy-14,643 (equivalent to average daily doses of approximately 1 to 550 mg/kg). All animals survived to the end of the studies. The mean body weight gain of 500 ppm mice was significantly less than that of the controls; hamsters exposed to 100 ppm or greater lost weight during the study. Feed consumption by 500 ppm mice was greater than that by the controls. Liver weights of all exposed groups of mice and hamsters were generally significantly increased. In the 2-week studies, an increase in peroxisomal enzyme activity occurred in 10 ppm mice; increases in peroxisomal $-oxidation, carnitine acetyltransferase, catalase, and acyl CoA oxidase occurred in all exposed mice compared to controls. Significantly increased BrdU-labeled hepatocyte percentages occurred in 100 and 1,000 ppm mice and 500 and 5,000 ppm hamsters; peroxisomal $-oxidation of lipids was increased in all exposed groups of mice and hamsters. Gross lesions in the 2-week studies included liver foci in one 500 ppm mouse and one 1,000 ppm hamster and enlarged livers in one hamster in each of the 100 and 500 ppm groups and two 5,000 ppm hamsters. All 500 and 1,000 ppm mice had hepatocyte hypertrophy of the liver, and 1,000 ppm mice also had widespread individual cell necrosis. Minimal to mild multifocal vacuolation of the liver occurred in hamsters exposed to 500 ppm or greater. In the 3-month core studies, groups of 10 male rats, mice, or hamsters were fed diets containing 0, 5, 10, 50, 100, or 500 ppm Wy-14,643 (equivalent to average daily doses of approximately 0.3 to 34 mg/kg for rats, 0.9 to 135 mg/kg for mice, and 0.4 to 42 mg/kg for hamsters). Groups of 15 male rats, mice, or hamsters designated for special studies received the same concentrations of Wy-14,643 for up to 13 weeks. Groups of six male rats, 36 male mice, or 12 male hamsters designated for plasma concentration studies were fed diets containing 50, 100, or 500 ppm Wy-14,643 for up to 9 weeks. All core study animals survived to the end of the studies. Mean body weights were significantly decreased in all exposed groups except the 5 ppm groups and 10 ppm mice; hamsters in the 100 and 500 ppm groups lost weight during the study. Feed consumption by exposed rats and mice was generally similar to that by the controls; during week 14, hamsters exposed to 50 ppm or greater consumed slightly less feed than did the controls. The only clinical finding of toxicity was thinness of two 50 ppm and five 500 ppm hamsters. At all time points, the liver weights of exposed groups of core and special study rats, mice, and hamsters were generally significantly greater than those of the controls. Testis weights were significantly decreased in 500 ppm hamsters on day 34, in hamsters exposed to 5 ppm or greater at week 13 (special study), and in 100 and 500 ppm core study hamsters at the end of the study. In the sperm motility evaluation, the cauda epididymis weight of 500 ppm rats, epididymis weights of 100 and 500 ppm rats and mice, and the testis weight of 500 ppm mice were significantly less than those of the controls. For hamsters, cauda epididymis, epididymis, and testis weights; spermatid heads per testis; and spermatid counts were significantly decreased in all exposed groups evaluated for sperm motility. Epididymal spermatozoal motility and concentration in the 100 and 500 ppm groups and spermatid heads per gram testis in the 500 ppm group were also significantly decreased. Serum concentrations of estradiol were significantly decreased in all exposed groups of hamsters, and concentrations of testosterone and luteinizing hormone were decreased in groups exposed to 50 ppm or greater. At necropsy in the 3-month studies, liver foci were observed in three special study mice, including one 100 ppm mouse and one 500 ppm mouse on day 34 and one 100 ppm mouse at week 13. Liver discoloration and small testes were noted in 500 ppm hamsters on day 34, and hamsters exposed to 50 ppm or greater had enlarged livers and/or small testes at week 13 (special study) and at 3 months (core study). The incidences of cytoplasmic alteration in the liver were significantly increased in all exposed core groups of rats, mice, and hamsters; the severity of this lesion increased with increasing exposure concentration. The incidences of mitotic alteration of the liver in mice exposed to 50 ppm or greater and of liver pigmentation and oval cell hyperplasia in 500 ppm mice were significantly increased. Minimal regeneration of the corticomedullary junction of the renal tubule occurred in all exposed groups of rats. Significantly increased incidences of atrophy of the prostate gland, seminal vesicle, and testis occurred in 100 and 500 ppm hamsters. Degenerative myopathy of skeletal muscle was observed in the lumbar area and thigh of rats, mice, and hamsters and the lower leg of mice, primarily at 500 ppm. Following single-dose gavage exposure to Wy-14,643, plasma concentrations were generally higher in mice than in rats, which in turn were higher than those in hamsters. This pattern of plasma concentrations was usually attributed to high bioavailability in mice, medium bioavailability in rats, and low bioavailabilty in hamsters following an oral exposure to Wy-14,643. No increase in the frequency of micronucleated normochromatic erythrocytes was observed in the peripheral blood of male or female Tg.AC mice exposed to Wy-14,643 in feed or via dermal application for 6 months. Synonyms: [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid.

wy - 14643 (CAS No. 50892-23-4)作为饲料对雄性Sprague-Dawley大鼠、B6C3F1小鼠和叙利亚仓鼠的毒性研究。
之所以选择wy - 14643作为过氧化物酶体增殖剂的一系列研究对象,是因为已知它能在大鼠中产生相当大的过氧化物酶体增殖和肝癌致癌性。雄性Sprague-Dawley大鼠暴露于饲料中的wy - 14643(纯度大于98%)长达3个月;雄性B6C3F1小鼠和雄性叙利亚仓鼠暴露于饲料中的wy - 14643 2周或最长3个月。对动物进行临床病理、wy - 14643血药浓度、生殖系统影响、细胞增殖和过氧化物酶体酶分析以及组织病理学评估。在另外几组雄性Sprague-Dawley和Wistar Furth大鼠、B6C3F1小鼠和叙利亚仓鼠中进行了wy - 14643的单剂量和多剂量毒性动力学研究。对Tg进行了体内遗传毒理学研究。AC小鼠外周血红细胞。在为期两周的研究中,每组5只小鼠被喂食含有0、10、50、100、500或1,000 ppm的wey - 14643(相当于平均每日剂量约为2至184毫克/公斤体重)的饲料。每组5只仓鼠喂食含有0、10、100、500、1000或5000 ppm way - 14643的饲粮(相当于平均日剂量约为1至550毫克/公斤)。所有的动物都活到了研究结束。500ppm小鼠的平均体重增加显著小于对照组;在研究期间,暴露于100ppm或更高浓度的仓鼠体重减轻。500ppm小鼠的饲料消耗量大于对照组。各暴露组小鼠和仓鼠肝脏重量普遍显著增加。在为期2周的研究中,10 ppm小鼠的过氧化物酶体酶活性增加;与对照组相比,所有暴露小鼠的过氧化物酶体氧化、肉毒碱乙酰转移酶、过氧化氢酶和酰基辅酶a氧化酶均有所增加。100ppm和1000ppm小鼠以及500ppm和5000 ppm仓鼠中brdu标记的肝细胞百分比显著增加;在所有暴露组的小鼠和仓鼠中,脂质过氧化物酶体氧化增加。在为期两周的研究中,肉眼病变包括一只ppm浓度为500的小鼠和一只ppm浓度为1000的仓鼠肝脏病灶,100和500 ppm浓度组和两只ppm浓度为5000的仓鼠各有一只仓鼠肝脏肿大。500ppm和1000ppm的小鼠都有肝细胞肥大,1000ppm的小鼠也有广泛的单个细胞坏死。暴露于500ppm或更高浓度的仓鼠肝脏出现轻微至轻度多灶空泡。在为期3个月的核心研究中,每组10只雄性大鼠、小鼠或仓鼠被喂食含有0、5、10、50、100或500 ppm的wey - 14643(相当于大鼠的平均日剂量约为0.3至34毫克/公斤,小鼠为0.9至135毫克/公斤,仓鼠为0.4至42毫克/公斤)。每组15只雄性大鼠、小鼠或仓鼠被指定用于特殊研究,在长达13周的时间里接受相同浓度的wy - 14643。每组6只雄性大鼠、36只雄性小鼠或12只雄性仓鼠被指定用于血浆浓度研究,分别饲喂含有50、100或500 ppm way - 14643的饲料长达9周。所有核心研究动物都存活到研究结束。除5ppm组和10ppm组外,所有暴露组小鼠的平均体重均显著降低;100 PPM和500 PPM组的仓鼠在研究期间体重减轻。暴露的大鼠和小鼠的饲料消耗量与对照组大致相似;在第14周,暴露于50ppm或更高浓度的仓鼠消耗的饲料略少于对照组。唯一的临床毒性发现是两只50 ppm和五只500 ppm的仓鼠变瘦。在所有时间点,暴露组核心和特殊研究大鼠、小鼠和仓鼠的肝脏重量普遍显著大于对照组。在第34天,500 ppm的仓鼠睾丸重量显著下降,在第13周暴露于5 ppm或更高浓度的仓鼠(特殊研究),在研究结束时,100和500 ppm的核心研究仓鼠睾丸重量显著下降。在精子活力评价中,500ppm大鼠的附睾尾部重量、100ppm和500ppm大鼠和小鼠的附睾重量以及500ppm小鼠的睾丸重量均显著低于对照组。对仓鼠,测定附睾尾、附睾和睾丸重量;每个睾丸的精子头;在精子活力评估的所有暴露组中,精子数量都显著减少。100和500 ppm组附睾精子活力和浓度以及500 ppm组每克睾丸精子头数也显著降低。所有暴露组的仓鼠血清雌二醇浓度均显著降低,暴露于50ppm或更高浓度组的睾酮和黄体生成素浓度均降低。在为期3个月的研究尸检中,在3只特殊研究小鼠中观察到肝灶,其中包括一只ppm为100的小鼠和一只ppm为500的小鼠在第34天,一只ppm为100的小鼠在第13周。 500ppm的仓鼠在第34天观察到肝脏变色和小睾丸,暴露于50ppm或更高浓度的仓鼠在第13周(特殊研究)和3个月(核心研究)时肝脏和/或小睾丸变大。在所有暴露的核心组大鼠、小鼠和仓鼠中,肝脏细胞质改变的发生率显著增加;这种损伤的严重程度随着暴露浓度的增加而增加。暴露于50ppm或更高浓度的小鼠肝脏有丝分裂改变的发生率以及500ppm小鼠肝脏色素沉着和卵圆细胞增生的发生率显著增加。所有暴露组的大鼠肾小管皮质-髓质连接处都出现了最小程度的再生。在100ppm和500ppm的仓鼠中,前列腺、精囊和睾丸萎缩的发生率显著增加。在500ppm浓度下,在大鼠、小鼠和仓鼠的腰椎和大腿以及小鼠的小腿观察到骨骼肌退行性肌病。单剂量灌胃暴露于wy - 14643后,小鼠的血浆浓度普遍高于大鼠,而大鼠又高于仓鼠。这种血浆浓度模式通常归因于口服接触wy - 14643后小鼠的高生物利用度、大鼠的中等生物利用度和仓鼠的低生物利用度。男女Tg外周血微核正染红细胞的频率均未见增加。交流小鼠在饲料或皮肤中暴露于wy - 14643 6个月。[4-氯-6-(2,3-木基苯基)-2-嘧啶基硫]醋酸。
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