Toxicology and carcinogenesis study of styrene-acrylonitrile trimer in F344/N rats (perinatal and postnatal feed studies).

Q4 Medicine National Toxicology Program technical report series Pub Date : 2012-07-01
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In June 1998, due to community concerns about the toxicity of SAN Trimer, it was nominated to the NTP for carcinogenicity testing by a member of Congress. Male and female F344/N rats were exposed to SAN Trimer in feed in perinatal and postnatal studies for 7 weeks, 18 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, and in rat reticulocytes, leukocytes, liver cells, and brain cells. In vivo comet and micronucleus assays were performed in the juvenile rats. 7-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm SAN Trimer (equivalent to average daily doses of approximately 50, 90, 175, 270, or 410 mg SAN Trimer/kg body weight to males and 45, 90, 185, 295, or 430 mg/kg to females) for 2 weeks postweaning; the dams of these rats were fed the same concentrations of SAN Trimer from gestation day 7 until the pups were weaned. One 4,000 ppm male rat died 3 days after weaning; all other rats that started the postweaning phase survived to the end of the study. Mean body weights of 1,000, 2,000, and 4,000 ppm males and 2,000 and 4,000 ppm females were significantly less than those of the controls; weaning mean body weights were reduced in 4,000 ppm males and females and in 2,000 ppm females. Feed consumption by 2,000 and 4,000 ppm males and females was less than that by the control groups. Thinness in 4,000 ppm male rats was the only clinical finding related to SAN Trimer exposure. Nonneoplastic lesions were observed in the brain, thymus, spleen, liver, kidney, and reproductive organs of males and females and were considered due to overt toxicity. 18-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets of 0, 100, 200, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of 10, 20, 40, 80, or 150 mg/kg to males and females) for 3 months postweaning; the dams of these rats were fed the same concentrations from gestation day 7 until the pups were weaned. All rats survived to the end of the study. Mean body weights of 1,600 ppm males and females exposed to 200 ppm or greater were significantly less than those of the controls. At termination, brown staining of the urogenital fur was observed in females exposed to 200 ppm or greater. The liver weights of all exposed groups of males and the spleen weights of 800 and 1,600 ppm males and 1,600 ppm females were significantly greater than those of the controls. There were no significant differences in sperm parameters of male rats or the estrous cyclicity of female rats administered 400, 800, or 1,600 ppm in the diet when compared to the control groups. No exposure-related histopathologic lesions were observed. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female core study rats were fed diets of 0, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of approximately 20, 40, or 75 mg/kg to males and 20, 40, or 85 mg/kg to females) for 2 years. Special study groups of 20 males and 20 females were fed the same exposure concentrations and were evaluated at 27, 52, and 78 weeks for hematology and clinical chemistry or at 26, 51, and 77 weeks for urinalysis. The dams of core and special study rats were fed the same concentrations from gestation day 7 until the pups were weaned. Mean body weights of 1,600 ppm males were less than 90% of the controls after week 1; mean body weights of 800 and 1,600 ppm females were less than 90% of the controls after weeks 41 and 13, respectively. Feed consumption by exposed groups of males and females was generally similar to that by the control groups. Brown staining of the urogenital fur was observed in all exposed groups, and the number of animals affected increased with increasing exposure concentration. Rare neoplasms were present in the central nervous system of male and female rats. In the original evaluation, the 800 and 1,600 ppm groups of male rats each had one astrocytoma and one granular cell tumor in the brain. Also in the brain, one 400 ppm female had a granular cell tumor and one control, one 400 ppm, and one 800 ppm female had a mixed cell glioma. In the spinal cord, one astrocytoma was noted in a 1,600 ppm male in the original evaluation. In the expanded review of the spinal cord, one granular cell tumor was found in a 400 ppm male and one meningioma was found in an 800 ppm female. There were statistically significant increases in the incidence of spinal nerve root degeneration in 1,600 ppm males and the incidences of sciatic nerve degeneration in 800 and 1,600 ppm females. More importantly, there were increases in the severities of both nerve lesions in males and in the severity of spinal nerve root degeneration in females. The incidences of bone marrow hyperplasia were significantly increased in 1,600 ppm males and females and 800 ppm females. Incidences of bone marrow granulomatous inflammation were increased in 1,600 ppm males and 800 and 1,600 ppm females, and the increase in the 800 ppm females was significant. Because this lesion is very rare and did not occur in control animals, it should be considered biologically significant. In the liver, the incidence of eosinophilic focus was significantly increased in 1,600 ppm males and the incidences of mixed cell focus were significantly increased in 400 and 1,600 ppm males. Incidences of mixed cell focus were increased in the liver of all exposed groups of females, and the increase was significant in the 1,600 ppm group. The incidence of transitional epithelial hyperplasia of the urinary bladder in 1,600 ppm females was significantly greater than that in the controls. There were significant decreases in the incidences of pituitary gland pars distalis adenoma in 1,600 ppm males and females, and the incidences in both sexes occurred with negative trends. The incidences of mammary gland fibroadenoma occurred in females with a negative trend, and the incidences in 800 and 1,600 ppm females were significantly less than that in the control group. The incidences of mononuclear cell leukemia in all exposed groups of males and females were significantly less than those in the controls.</p><p><strong>Genetic toxicology: </strong>SAN Trimer (Batch 3) was not mutagenic in Salmonella typhimurium strains TA98 or TA100 or in Escherichia coli strain WP2 uvrA/pKM101 in tests conducted with and without exogenous metabolic activation. In vivo, however, results of a comet assay indicated significantly increased levels of DNA damage in brain cells of male and female juvenile rats following administration of SAN Trimer (Batch 3) by oral gavage. Dose-related increases in DNA damage in liver cells of these rats were also observed, but the increases were smaller than those observed in brain cells and were judged to be equivocal in both males and females. Indications of DNA damage following exposure to SAN Trimer were also seen in leukocytes of male and female rats. Increases in male rats were significant, but in females, observed levels of DNA damage did not correlate with dose. Therefore, the results were judged to be positive in males and equivocal in females. In addition to the positive comet assay results, significant increases in the frequencies of micronucleated reticulocytes were observed in peripheral blood of male and female juvenile rats dosed with SAN Trimer.</p><p><strong>Conclusions: </strong>Under the conditions of this 2-year feed study preceded by perinatal exposure, there was no evidence of carcinogenic activity of SAN Trimer in male and female F344/N rats given feed containing 400, 800, or 1,600 ppm SAN Trimer. Exposure to SAN Trimer resulted in increased incidences and/or severities of peripheral nerve degeneration in male and female F344/N rats, increased incidences of nonneoplastic lesions of the bone marrow and liver in male and female F344/N rats, and of nonneoplastic urinary bladder lesions in female F344/N rats. The incidences of pituitary gland adenoma and mononuclear cell leukemia in male and female F344/N rats and mammary gland fibroadenoma in female F344/N rats were decreased.</p>","PeriodicalId":19036,"journal":{"name":"National Toxicology Program technical report series","volume":" 573","pages":"1-155"},"PeriodicalIF":0.0000,"publicationDate":"2012-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"National Toxicology Program technical report series","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Medicine","Score":null,"Total":0}
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Abstract

Unlabelled: Styrene-acrylonitrile trimer (SAN Trimer) is a mixture of isomers formed by the condensation of two moles of acrylonitrile and one mole of styrene and has a molecular weight of 210. The mixture is composed of two structural forms: 4-cyano-1,2,3,4-tetrahydro-a-methyl-1-naphthaleneacetonitrile (THNA, CAS No. 57964-39-3) and 4-cyano-1,2,3,4-tetrahydro-1-naphthalenepropionitrile (THNP, CAS No. 57964-40-6). The THNA form consists of four stereoisomers. [Structure:see text]. The THNP form consists of two stereoisomers. [Structure:see text]. SAN Trimer is a by-product of the production of acrylonitrile styrene plastics and is created in specific manufacturing processes for polymers of acrylonitrile and styrene. In June 1998, due to community concerns about the toxicity of SAN Trimer, it was nominated to the NTP for carcinogenicity testing by a member of Congress. Male and female F344/N rats were exposed to SAN Trimer in feed in perinatal and postnatal studies for 7 weeks, 18 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, and in rat reticulocytes, leukocytes, liver cells, and brain cells. In vivo comet and micronucleus assays were performed in the juvenile rats. 7-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm SAN Trimer (equivalent to average daily doses of approximately 50, 90, 175, 270, or 410 mg SAN Trimer/kg body weight to males and 45, 90, 185, 295, or 430 mg/kg to females) for 2 weeks postweaning; the dams of these rats were fed the same concentrations of SAN Trimer from gestation day 7 until the pups were weaned. One 4,000 ppm male rat died 3 days after weaning; all other rats that started the postweaning phase survived to the end of the study. Mean body weights of 1,000, 2,000, and 4,000 ppm males and 2,000 and 4,000 ppm females were significantly less than those of the controls; weaning mean body weights were reduced in 4,000 ppm males and females and in 2,000 ppm females. Feed consumption by 2,000 and 4,000 ppm males and females was less than that by the control groups. Thinness in 4,000 ppm male rats was the only clinical finding related to SAN Trimer exposure. Nonneoplastic lesions were observed in the brain, thymus, spleen, liver, kidney, and reproductive organs of males and females and were considered due to overt toxicity. 18-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets of 0, 100, 200, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of 10, 20, 40, 80, or 150 mg/kg to males and females) for 3 months postweaning; the dams of these rats were fed the same concentrations from gestation day 7 until the pups were weaned. All rats survived to the end of the study. Mean body weights of 1,600 ppm males and females exposed to 200 ppm or greater were significantly less than those of the controls. At termination, brown staining of the urogenital fur was observed in females exposed to 200 ppm or greater. The liver weights of all exposed groups of males and the spleen weights of 800 and 1,600 ppm males and 1,600 ppm females were significantly greater than those of the controls. There were no significant differences in sperm parameters of male rats or the estrous cyclicity of female rats administered 400, 800, or 1,600 ppm in the diet when compared to the control groups. No exposure-related histopathologic lesions were observed. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female core study rats were fed diets of 0, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of approximately 20, 40, or 75 mg/kg to males and 20, 40, or 85 mg/kg to females) for 2 years. Special study groups of 20 males and 20 females were fed the same exposure concentrations and were evaluated at 27, 52, and 78 weeks for hematology and clinical chemistry or at 26, 51, and 77 weeks for urinalysis. The dams of core and special study rats were fed the same concentrations from gestation day 7 until the pups were weaned. Mean body weights of 1,600 ppm males were less than 90% of the controls after week 1; mean body weights of 800 and 1,600 ppm females were less than 90% of the controls after weeks 41 and 13, respectively. Feed consumption by exposed groups of males and females was generally similar to that by the control groups. Brown staining of the urogenital fur was observed in all exposed groups, and the number of animals affected increased with increasing exposure concentration. Rare neoplasms were present in the central nervous system of male and female rats. In the original evaluation, the 800 and 1,600 ppm groups of male rats each had one astrocytoma and one granular cell tumor in the brain. Also in the brain, one 400 ppm female had a granular cell tumor and one control, one 400 ppm, and one 800 ppm female had a mixed cell glioma. In the spinal cord, one astrocytoma was noted in a 1,600 ppm male in the original evaluation. In the expanded review of the spinal cord, one granular cell tumor was found in a 400 ppm male and one meningioma was found in an 800 ppm female. There were statistically significant increases in the incidence of spinal nerve root degeneration in 1,600 ppm males and the incidences of sciatic nerve degeneration in 800 and 1,600 ppm females. More importantly, there were increases in the severities of both nerve lesions in males and in the severity of spinal nerve root degeneration in females. The incidences of bone marrow hyperplasia were significantly increased in 1,600 ppm males and females and 800 ppm females. Incidences of bone marrow granulomatous inflammation were increased in 1,600 ppm males and 800 and 1,600 ppm females, and the increase in the 800 ppm females was significant. Because this lesion is very rare and did not occur in control animals, it should be considered biologically significant. In the liver, the incidence of eosinophilic focus was significantly increased in 1,600 ppm males and the incidences of mixed cell focus were significantly increased in 400 and 1,600 ppm males. Incidences of mixed cell focus were increased in the liver of all exposed groups of females, and the increase was significant in the 1,600 ppm group. The incidence of transitional epithelial hyperplasia of the urinary bladder in 1,600 ppm females was significantly greater than that in the controls. There were significant decreases in the incidences of pituitary gland pars distalis adenoma in 1,600 ppm males and females, and the incidences in both sexes occurred with negative trends. The incidences of mammary gland fibroadenoma occurred in females with a negative trend, and the incidences in 800 and 1,600 ppm females were significantly less than that in the control group. The incidences of mononuclear cell leukemia in all exposed groups of males and females were significantly less than those in the controls.

Genetic toxicology: SAN Trimer (Batch 3) was not mutagenic in Salmonella typhimurium strains TA98 or TA100 or in Escherichia coli strain WP2 uvrA/pKM101 in tests conducted with and without exogenous metabolic activation. In vivo, however, results of a comet assay indicated significantly increased levels of DNA damage in brain cells of male and female juvenile rats following administration of SAN Trimer (Batch 3) by oral gavage. Dose-related increases in DNA damage in liver cells of these rats were also observed, but the increases were smaller than those observed in brain cells and were judged to be equivocal in both males and females. Indications of DNA damage following exposure to SAN Trimer were also seen in leukocytes of male and female rats. Increases in male rats were significant, but in females, observed levels of DNA damage did not correlate with dose. Therefore, the results were judged to be positive in males and equivocal in females. In addition to the positive comet assay results, significant increases in the frequencies of micronucleated reticulocytes were observed in peripheral blood of male and female juvenile rats dosed with SAN Trimer.

Conclusions: Under the conditions of this 2-year feed study preceded by perinatal exposure, there was no evidence of carcinogenic activity of SAN Trimer in male and female F344/N rats given feed containing 400, 800, or 1,600 ppm SAN Trimer. Exposure to SAN Trimer resulted in increased incidences and/or severities of peripheral nerve degeneration in male and female F344/N rats, increased incidences of nonneoplastic lesions of the bone marrow and liver in male and female F344/N rats, and of nonneoplastic urinary bladder lesions in female F344/N rats. The incidences of pituitary gland adenoma and mononuclear cell leukemia in male and female F344/N rats and mammary gland fibroadenoma in female F344/N rats were decreased.

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苯乙烯-丙烯腈三聚体对F344/N大鼠的毒理学和致癌作用研究(围产期和产后饲料研究)。
未标注:苯乙烯-丙烯腈三聚体(SAN三聚体)是由2摩尔丙烯腈和1摩尔苯乙烯缩合而成的异构体混合物,分子量为210。混合物由两种结构形式组成:4-氰-1,2,3,4-四氢-1-甲基-1-萘乙腈(THNA, CAS号57964-39-3)和4-氰-1,2,3,4-四氢-1-萘丙腈(THNP, CAS号57964-40-6)。THNA由四种立体异构体组成。结构:看到文本。THNP形式由两个立体异构体组成。结构:看到文本。SAN三聚体是生产丙烯腈-苯乙烯塑料的副产品,是在丙烯腈和苯乙烯聚合物的特定制造工艺中产生的。1998年6月,由于社区对SAN Trimer毒性的关注,一名国会议员将其提名到国家毒理学规划进行致癌性测试。在围产期和产后研究中,雄性和雌性F344/N大鼠分别在饲料中暴露于SAN Trimer 7周、18周或2年。遗传毒理学研究在鼠伤寒沙门氏菌、大肠杆菌、大鼠网状细胞、白细胞、肝细胞和脑细胞中进行。对幼年大鼠进行了体内彗星和微核测定。在大鼠中进行为期7周的研究:断奶后2周,每组10只雄性大鼠和10只雌性大鼠分别饲喂含有0,250,500,1,000,2,000或4,000 ppm SAN Trimer的饲料(相当于雄性平均日剂量约为50,90,175,270或410 mg SAN Trimer/kg体重,雌性平均日剂量为45,90,185,295或430 mg/kg);这些大鼠的母鼠从妊娠第7天开始直到幼崽断奶,喂食相同浓度的SAN Trimer。一只4000ppm的雄性大鼠在断奶后3天死亡;所有其他开始断奶后阶段的大鼠都存活到研究结束。ppm含量为1,000、2,000和4,000 ppm的男性和ppm含量为2,000和4,000 ppm的女性的平均体重显著低于对照组;断奶时平均体重减少了4000 PPM的雄性和雌性以及2000 PPM的雌性。ppm为2000和4000ppm的雄性和雌性的饲料消耗量低于对照组。4000ppm的雄性大鼠变瘦是与SAN Trimer暴露有关的唯一临床发现。在男性和女性的大脑、胸腺、脾脏、肝脏、肾脏和生殖器官中观察到非肿瘤性病变,并认为是由于明显的毒性。18周大鼠研究:断奶后3个月,每组10只雄性和10只雌性大鼠分别饲喂0、100、200、400、800或1600 ppm三聚氰胺(相当于雄性和雌性的平均日剂量为10、20、40、80或150 mg/kg);这些大鼠的母鼠从妊娠第7天开始饲喂相同浓度的饲料,直到幼崽断奶。所有的老鼠都活到了研究结束。1600 ppm的男性和200 ppm或更高浓度的女性的平均体重明显低于对照组。在终止时,在暴露于200ppm或更高浓度的雌性中观察到泌尿生殖毛的棕色染色。各暴露组男性肝脏重量、800、1600 ppm男性和1600 ppm女性脾脏重量均显著大于对照组。与对照组相比,在400ppm、800ppm或1600ppm的饮食中,雄性大鼠的精子参数和雌性大鼠的发情周期没有显著差异。未观察到与暴露相关的组织病理学病变。对大鼠进行为期2年的研究:每组50只雄性和50只雌性核心研究大鼠分别饲喂0、400、800或1600 ppm三聚氰胺(相当于雄性的平均日剂量约为20、40或75 mg/kg,雌性为20、40或85 mg/kg) 2年。特殊研究组由20名男性和20名女性组成,给予相同的暴露浓度,并在第27、52和78周进行血液学和临床化学评估,或在第26、51和77周进行尿液分析。核心大鼠和特殊研究大鼠从妊娠第7天开始饲喂相同浓度的饲料,直至幼崽断奶。1周后,平均体重为1,600 ppm的男性低于对照组的90%;在41周和13周后,800 PPM和1600 PPM的雌性小鼠的平均体重分别低于对照组的90%。暴露组雄性和雌性的饲料消耗量与对照组大致相似。所有暴露组泌尿生殖毛均呈棕色,且受感染动物数量随暴露浓度的增加而增加。雌雄大鼠中枢神经系统均有罕见肿瘤。在最初的评估中,800 ppm和1600 ppm的雄性大鼠在大脑中各有一个星形细胞瘤和一个颗粒细胞瘤。同样在大脑中,一名400 ppm的女性患有颗粒细胞瘤,一名对照,一名400 ppm和一名800 ppm的女性患有混合细胞胶质瘤。在脊髓中,在最初的评估中,在1600 ppm的男性中发现了一个星形细胞瘤。 在脊髓的扩大检查中,400 ppm的男性中发现了一个颗粒细胞瘤,800 ppm的女性中发现了一个脑膜瘤。在1600 ppm的男性中,脊神经根变性的发生率有统计学意义的增加,而在800和1600 ppm的女性中,坐骨神经变性的发生率有统计学意义的增加。更重要的是,男性神经病变的严重程度和女性脊神经根变性的严重程度都有所增加。在ppm浓度为1600的男性和女性以及ppm浓度为800的女性中,骨髓增生的发生率显著增加。骨髓肉芽肿性炎症的发病率在浓度为1600 ppm的男性、800 ppm和1600 ppm的女性中均有所增加,其中浓度为800 ppm的女性的增加尤为显著。由于这种病变非常罕见,并且没有在对照动物中发生,因此应认为具有重要的生物学意义。在肝脏中,1600 ppm雄性嗜酸性灶的发生率显著增加,400和1600 ppm雄性混合细胞灶的发生率显著增加。所有暴露组的女性肝脏中混合细胞灶的发生率均增加,且在1,600 ppm组中增加显著。1,600 ppm的女性膀胱移行上皮增生的发生率明显高于对照组。在1600 ppm浓度下,男性和女性垂体远端部腺瘤的发病率均显著下降,两性发病率均呈负相关趋势。女性乳腺纤维腺瘤的发病率呈负相关趋势,800 ppm和1600 ppm女性的发病率明显低于对照组。在所有暴露组中,男性和女性的单核细胞白血病发病率明显低于对照组。遗传毒理学:在有和没有外源性代谢激活的情况下进行的试验中,SAN三聚体(第3批)对鼠伤寒沙门氏菌TA98或TA100或大肠杆菌WP2 uvrA/pKM101均无致突变性。然而,在体内,彗星试验的结果表明,通过灌胃给药SAN Trimer(第3批)后,雄性和雌性幼年大鼠的脑细胞DNA损伤水平显著增加。在这些大鼠的肝细胞中也观察到与剂量相关的DNA损伤增加,但增加比在脑细胞中观察到的要小,并且在雄性和雌性中都被认为是模棱两可的。在雄性和雌性大鼠的白细胞中也发现了暴露于SAN三聚体后DNA损伤的迹象。雄性大鼠的DNA损伤水平显著增加,但在雌性大鼠中,观察到的DNA损伤水平与剂量无关。因此,结果判断为阳性的男性和模棱两可的女性。除了阳性的彗星试验结果外,在服用SAN Trimer的雄性和雌性幼鼠外周血中观察到微核网状细胞的频率显著增加。结论:在围产期暴露前进行的为期2年的饲料研究条件下,没有证据表明在饲喂含有400ppm、800ppm或1600ppm SAN Trimer的饲料的雄性和雌性F344/N大鼠中SAN Trimer具有致癌活性。暴露于SAN Trimer导致雄性和雌性F344/N大鼠周围神经变性的发生率和/或严重程度增加,雄性和雌性F344/N大鼠骨髓和肝脏非肿瘤性病变的发生率增加,雌性F344/N大鼠非肿瘤性膀胱病变的发生率增加。雌、雄性F344/N大鼠垂体腺瘤、单核细胞白血病及雌性F344/N大鼠乳腺纤维腺瘤的发生率均降低。
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Toxicology and carcinogenesis study of triclosan administered dermally to B6C3F1/N mice. Toxicology and carcinogenesis studies of black cohosh root extract (CASRN 84776-26-1) administered by gavage to Sprague Dawley (Hsd:Sprague Dawley SD) rats and female B6C3F1/N mice. Toxicology and carcinogenesis studies of an isomeric mixture of tris(chloropropyl) phosphate administered in feed to Sprague Dawley (Hsd:Sprague Dawley SD) rats and B6C3F1/N mice. Toxicology and carcinogenesis studies of di(2-ethylhexyl) phthalate administered in feed to Sprague Dawley (Hsd:Sprague Dawley SD) rats. Toxicology and carcinogenesis studies of sodium tungstate dihydrate in Sprague Dawley (Hsd:Sprague Dawley SD) rats and B6C3F1/N mice (drinking water studies).
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