2,4-己二烯二醛(89%反式,反式异构体)毒理学和致癌性研究,CAS No. 142-83-6;11%顺式,反式异构体)(灌胃研究)。

Q4 Medicine
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Male and female F344/N rats and B6C3F1 mice received 2,4-hexadienal (89% trans,trans; 11% cis,trans) in corn oil by gavage for 16 days, 14 weeks, or 2 years. Tissues and plasma from dosed rats were examined for malondialdehyde and glutathione concentrations, and DNA adducts were characterized in liver and forestomach samples from dosed rats and mice. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 3, 9, 27, 80, or 240 mg 2,4-hexadienal/kg body weight in corn oil by gavage, 5 days per week, for 16 days. Three male and three female 240 mg/kg rats died before the end of the study. Mean body weight gains of 240 mg/kg rats were significantly less than those of the vehicle controls. Clinical findings included diarrhea, ataxia, lethargy, and nasal/eye discharge in males, and lethargy, paleness, and abnormal breathing in females in the 240 mg/kg groups. Liver weights of 240 mg/kg females were significantly greater than those of the vehicle controls. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in most 240 mg/kg rats, and forestomach epithelial hyperplasia was microscopically evident in most 80 mg/kg rats. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 3, 9, 27, 80, or 240 mg/kg, 5 days per week, for 16 days. Chemical-related deaths occurred in one male and one female in the 240 mg/kg groups. Female mice in the 240 mg/kg group lost weight during the study. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in all 240 mg/kg mice, and forestomach epithelial hyperplasia and hyperkeratosis were microscopically evident in 80 mg/kg mice. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. All rats survived to the end of the study. Mean body weights of 30, 60, and 120 mg/kg males were significantly less than those of the vehicle controls. The only clinical finding attributed to 2,4-hexadienal administration was hypersalivation in 30 and 120 mg/kg males and females. The incidences of forestomach hyperplasia and nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg rats. Nasal lesions occurred in most 120 mg/kg male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. No deaths were attributed to administration of 2,4-hexadienal. Mean body weights of males and females were similar to those of the vehicle controls throughout the study. Clinical findings included salivation and anal wetness in males and females. Kidney weights of 60 and 120 mg/kg males and liver weights of 60 mg/kg males and females were significantly greater than those of the vehicle controls. The incidences of forestomach hyperplasia and/or nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 2,4-hexministered 2,4-hexadienal in corn oil by gavage at doses of 0, 22.5, 45, or 90 mg/kg, 5 days per week, for up to 105 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control groups. The mean body weights of 90 mg/kg males were generally less than those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female rats. This neoplasm was found in 58% of males and 34% of females in the 90 mg/kg groups. In the forestomach of male rats, papilloma multiplicity was increased in the 90 mg/kg group, and squamous cell carcinomas were found in one 45 mg/kg male and two 90 mg/kg males. Epithelial hyperplasia of the forestomach occurred in most 45 and 90 mg/kg rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 30, 60, or 120 mg/kg, 5 days per week, for up to 105 weeks. Survival of dosed mice was similar to that of the vehicle controls. The mean body weights of all dosed groups were generally similar to those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female mice; squamous cell carcinomas were present in 120 mg/kg males and females. Epithelial hyperplasia of the forestomach occurred in many 120 mg/kg mice. Two 120 mg/kg males had uncommon squamous cell carcinoma of the oral cavity (tongue).</p><p><strong>Genetic toxicology: </strong>2,4-Hexadienal was mutagenic in S. typhimurium strain TA100 with and without induced hamster or rat liver enzymes; no mutagenic activity was detected with strains TA1535 or TA98, with or without S9. Results of bone marrow tests in male rats and male mice given intraperitoneal injections of 2,4-hexadienal showed a small increase in the induction of micronucleated erythrocytes. However, neither test was repeated, and the test results were judged to be inconclusive. Results of peripheral blood micronucleus tests in male and female mice treated with 2,4-hexadienal by gavage for 14 weeks were negative.</p><p><strong>Conclusions: </strong>Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity* of 2,4-hexadienal in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of squamous cell neoplasms of the forestomach. The occurrence of squamous cell carcinoma of the oral cavity (tongue) in male B6C3F1 mice may have been related to the administration of 2,4-hexadienal. Hyperplasia of the forestomach in male and female rats and mice was associated with administration of 2,4-hexadienal. Synonyms: Hexa-2,4-dienal; 2,4-hexadienal; 2,4-hexadien-1-al; 2,4-Hx; 1,3-pentadiene-1-carboxaldehyde; 2-propylene acrolein; sorbaldehyde; sorbic aldehyde</p>","PeriodicalId":19036,"journal":{"name":"National Toxicology Program technical report series","volume":" 509","pages":"1-290"},"PeriodicalIF":0.0000,"publicationDate":"2003-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NTP toxicology and carcinogensis Studies of 2,4-hexadienal (89% trans,trans isomer, CAS No. 142-83-6; 11% cis,trans isomer) (Gavage Studies).\",\"authors\":\"\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Unlabelled: </strong>2,4-Hexadienal, a colorless to yellow liquid with a pungent \\\"green\\\" or citrus odor, is used as a food additive for flavor enhancement, as a fragrance agent, as a starting material or intermediate in synthetic reactions in the chemical and pharmaceutical industries, as a fumigant, and as a corrosion inhibitor for steel. 2,4-Hexadienal was nominated for study by the National Cancer Institute because of the potential for carcinogenicity based on its alpha,beta-unsaturated aldehyde structure and the potential link between exposure to lipid peroxidation products in the diet and human malignancies. The commercial product is a mixture containing chiefly trans,trans-2,4-hexadienal in equilibrium with cis,trans-2,4-hexadienal. Male and female F344/N rats and B6C3F1 mice received 2,4-hexadienal (89% trans,trans; 11% cis,trans) in corn oil by gavage for 16 days, 14 weeks, or 2 years. Tissues and plasma from dosed rats were examined for malondialdehyde and glutathione concentrations, and DNA adducts were characterized in liver and forestomach samples from dosed rats and mice. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 3, 9, 27, 80, or 240 mg 2,4-hexadienal/kg body weight in corn oil by gavage, 5 days per week, for 16 days. Three male and three female 240 mg/kg rats died before the end of the study. Mean body weight gains of 240 mg/kg rats were significantly less than those of the vehicle controls. Clinical findings included diarrhea, ataxia, lethargy, and nasal/eye discharge in males, and lethargy, paleness, and abnormal breathing in females in the 240 mg/kg groups. Liver weights of 240 mg/kg females were significantly greater than those of the vehicle controls. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in most 240 mg/kg rats, and forestomach epithelial hyperplasia was microscopically evident in most 80 mg/kg rats. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 3, 9, 27, 80, or 240 mg/kg, 5 days per week, for 16 days. Chemical-related deaths occurred in one male and one female in the 240 mg/kg groups. Female mice in the 240 mg/kg group lost weight during the study. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in all 240 mg/kg mice, and forestomach epithelial hyperplasia and hyperkeratosis were microscopically evident in 80 mg/kg mice. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. All rats survived to the end of the study. Mean body weights of 30, 60, and 120 mg/kg males were significantly less than those of the vehicle controls. The only clinical finding attributed to 2,4-hexadienal administration was hypersalivation in 30 and 120 mg/kg males and females. The incidences of forestomach hyperplasia and nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg rats. 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Survival of all dosed groups of rats was similar to that of the vehicle control groups. The mean body weights of 90 mg/kg males were generally less than those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female rats. This neoplasm was found in 58% of males and 34% of females in the 90 mg/kg groups. In the forestomach of male rats, papilloma multiplicity was increased in the 90 mg/kg group, and squamous cell carcinomas were found in one 45 mg/kg male and two 90 mg/kg males. Epithelial hyperplasia of the forestomach occurred in most 45 and 90 mg/kg rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 30, 60, or 120 mg/kg, 5 days per week, for up to 105 weeks. Survival of dosed mice was similar to that of the vehicle controls. The mean body weights of all dosed groups were generally similar to those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female mice; squamous cell carcinomas were present in 120 mg/kg males and females. Epithelial hyperplasia of the forestomach occurred in many 120 mg/kg mice. Two 120 mg/kg males had uncommon squamous cell carcinoma of the oral cavity (tongue).</p><p><strong>Genetic toxicology: </strong>2,4-Hexadienal was mutagenic in S. typhimurium strain TA100 with and without induced hamster or rat liver enzymes; no mutagenic activity was detected with strains TA1535 or TA98, with or without S9. Results of bone marrow tests in male rats and male mice given intraperitoneal injections of 2,4-hexadienal showed a small increase in the induction of micronucleated erythrocytes. However, neither test was repeated, and the test results were judged to be inconclusive. 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引用次数: 0

摘要

未标示:2,4-己二烯二醛是一种无色至黄色的液体,带有刺鼻的“绿色”或柑橘气味,用作增强风味的食品添加剂、香料剂、化学和制药工业合成反应的起始材料或中间体、熏蒸剂和钢铁的缓蚀剂。2,4-己二醛被提名为国家癌症研究所的研究对象,因为基于其α, β -不饱和醛结构的潜在致癌性,以及饮食中脂质过氧化产物暴露与人类恶性肿瘤之间的潜在联系。商业产品主要含有反式、反式-2,4-六烯二醛与顺式、反式-2,4-六烯二醛平衡的混合物。雄性和雌性F344/N大鼠和B6C3F1小鼠接受2,4-六二烯二醛(89%反式,反式;玉米油中的11%顺式,反式)灌胃16天,14周,或2年。检测了给药大鼠的组织和血浆中丙二醛和谷胱甘肽的浓度,并在给药大鼠和小鼠的肝脏和前胃样本中检测了DNA加合物的特征。鼠伤寒沙门菌、大鼠和小鼠骨髓细胞以及小鼠外周血红细胞进行了遗传毒理学研究。16天的大鼠研究:每组5只雄性大鼠和5只雌性大鼠分别以0、3、9、27、80或240 mg /kg体重的玉米油灌胃,每周5天,连续16天。240 mg/kg大鼠雄性和雌性各3只,在研究结束前死亡。240 mg/kg大鼠的平均体重增加明显小于对照组。在240 mg/kg组中,男性出现腹泻、共济失调、嗜睡和鼻/眼分泌物,女性出现嗜睡、苍白和呼吸异常。240 mg/kg雌鼠肝脏重量显著高于对照。240 mg/kg大鼠镜下大体可见前胃坏死和溃疡,80 mg/kg大鼠镜下可见前胃上皮增生。小鼠16天研究:每组5只雄性和5只雌性小鼠,以0、3、9、27、80或240 mg/kg的剂量灌胃玉米油中的2,4-己二烯二醛,每周5天,持续16天。在240毫克/公斤组中,有一名男性和一名女性发生与化学品有关的死亡。240 mg/kg组的雌性小鼠在研究期间体重减轻。240mg /kg小鼠肉眼和显微镜下均可见前胃坏死和溃疡病变,80mg /kg小鼠显微镜下可见前胃上皮增生和角化过度。大鼠14周研究:每组10只雄性大鼠和10只雌性大鼠分别以0、7.5、15、30、60或120 mg/kg的剂量灌胃玉米油中的2,4-己二烯二醛,每周5天,持续14周。所有的老鼠都活到了研究结束。30mg /kg、60mg /kg和120mg /kg雄性小鼠的平均体重显著低于对照组。唯一归因于2,4-六二烯二醛给药的临床发现是男性和女性在30和120 mg/kg时唾液过多。120 mg/kg剂量组大鼠前胃增生、鼻嗅觉萎缩或坏死发生率显著升高。大多数120 mg/kg雄性大鼠出现鼻腔病变。小鼠14周研究:每组10只雄性和10只雌性小鼠,以0、7.5、15、30、60或120 mg/kg的剂量灌胃玉米油中的2,4-己二烯二醛,每周5天,持续14周。没有死亡归因于2,4-己二醛的施用。在整个研究过程中,男性和女性的平均体重与车辆对照组相似。临床表现包括男性和女性流涎和肛门湿润。60、120 mg/kg雄鼠肾脏重量及60 mg/kg雄鼠和雌鼠肝脏重量均显著高于对照。120 mg/kg小鼠前胃增生和/或鼻嗅觉萎缩或坏死的发生率显著增加。在大鼠中进行为期2年的研究:每组50只雄性和50只雌性大鼠分别以0、22.5、45或90 mg/kg的剂量灌胃玉米油中2,4-己二醛,每周5天,持续105周。各给药组大鼠的存活率与载药对照组相似。在整个研究过程中,90 mg/kg雄性小鼠的平均体重普遍低于车辆对照组。雌雄大鼠前胃鳞状细胞乳头状瘤的发生率均呈阳性趋势。在90mg /kg组中,58%的男性和34%的女性发现了这种肿瘤。在雄性大鼠的前胃中,90 mg/kg组乳头状瘤的多样性增加,1只45 mg/kg雄性和2只90 mg/kg雄性中发现鳞状细胞癌。45和90 mg/kg大鼠前胃上皮增生。 小鼠2年研究:每组50只雄性和50只雌性小鼠,以0、30、60或120 mg/kg的剂量灌胃玉米油中的2,4-己二烯二醛,每周5天,持续105周。给药小鼠的存活率与对照组相似。在整个研究过程中,所有给药组的平均体重与车辆对照组的体重大致相似。雌雄小鼠前胃鳞状细胞乳头状瘤的发生率均呈阳性趋势;鳞状细胞癌存在于120 mg/kg的男性和女性。120 mg/kg小鼠前胃上皮增生。2例120 mg/kg男性有罕见的口腔(舌)鳞状细胞癌。遗传毒理学:2,4-己二烯二醛对鼠伤寒沙门氏菌TA100有诱变作用;菌株TA1535和TA98在添加或不添加S9时均未检测到致突变活性。雄性大鼠和雄性小鼠腹腔注射2,4-己二烯二醛后,骨髓试验结果显示微核红细胞诱导量有小幅增加。然而,两项测试都没有重复,测试结果被认为是不确定的。灌胃2,4-己二醛14周后,雌雄小鼠外周血微核试验结果均为阴性。结论:在为期2年的灌胃研究条件下,2,4-己二烯二醛在雄性和雌性F344/N大鼠和雄性和雌性B6C3F1小鼠中具有明显的致癌活性*,其基础是前胃鳞状细胞肿瘤的发病率增加。雄性B6C3F1小鼠口腔(舌)鳞状细胞癌的发生可能与2,4-己二醛的使用有关。雄性和雌性大鼠和小鼠的前胃增生与2,4-己二醛的使用有关。同义词:Hexa-2 4-dienal;2、4-hexadienal;2、4-hexadien-1-al;2、4-Hx;1、3-pentadiene-1-carboxaldehyde;和丙烯醛;sorbaldehyde;己二烯醛
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NTP toxicology and carcinogensis Studies of 2,4-hexadienal (89% trans,trans isomer, CAS No. 142-83-6; 11% cis,trans isomer) (Gavage Studies).

Unlabelled: 2,4-Hexadienal, a colorless to yellow liquid with a pungent "green" or citrus odor, is used as a food additive for flavor enhancement, as a fragrance agent, as a starting material or intermediate in synthetic reactions in the chemical and pharmaceutical industries, as a fumigant, and as a corrosion inhibitor for steel. 2,4-Hexadienal was nominated for study by the National Cancer Institute because of the potential for carcinogenicity based on its alpha,beta-unsaturated aldehyde structure and the potential link between exposure to lipid peroxidation products in the diet and human malignancies. The commercial product is a mixture containing chiefly trans,trans-2,4-hexadienal in equilibrium with cis,trans-2,4-hexadienal. Male and female F344/N rats and B6C3F1 mice received 2,4-hexadienal (89% trans,trans; 11% cis,trans) in corn oil by gavage for 16 days, 14 weeks, or 2 years. Tissues and plasma from dosed rats were examined for malondialdehyde and glutathione concentrations, and DNA adducts were characterized in liver and forestomach samples from dosed rats and mice. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 3, 9, 27, 80, or 240 mg 2,4-hexadienal/kg body weight in corn oil by gavage, 5 days per week, for 16 days. Three male and three female 240 mg/kg rats died before the end of the study. Mean body weight gains of 240 mg/kg rats were significantly less than those of the vehicle controls. Clinical findings included diarrhea, ataxia, lethargy, and nasal/eye discharge in males, and lethargy, paleness, and abnormal breathing in females in the 240 mg/kg groups. Liver weights of 240 mg/kg females were significantly greater than those of the vehicle controls. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in most 240 mg/kg rats, and forestomach epithelial hyperplasia was microscopically evident in most 80 mg/kg rats. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 3, 9, 27, 80, or 240 mg/kg, 5 days per week, for 16 days. Chemical-related deaths occurred in one male and one female in the 240 mg/kg groups. Female mice in the 240 mg/kg group lost weight during the study. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in all 240 mg/kg mice, and forestomach epithelial hyperplasia and hyperkeratosis were microscopically evident in 80 mg/kg mice. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. All rats survived to the end of the study. Mean body weights of 30, 60, and 120 mg/kg males were significantly less than those of the vehicle controls. The only clinical finding attributed to 2,4-hexadienal administration was hypersalivation in 30 and 120 mg/kg males and females. The incidences of forestomach hyperplasia and nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg rats. Nasal lesions occurred in most 120 mg/kg male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. No deaths were attributed to administration of 2,4-hexadienal. Mean body weights of males and females were similar to those of the vehicle controls throughout the study. Clinical findings included salivation and anal wetness in males and females. Kidney weights of 60 and 120 mg/kg males and liver weights of 60 mg/kg males and females were significantly greater than those of the vehicle controls. The incidences of forestomach hyperplasia and/or nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 2,4-hexministered 2,4-hexadienal in corn oil by gavage at doses of 0, 22.5, 45, or 90 mg/kg, 5 days per week, for up to 105 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control groups. The mean body weights of 90 mg/kg males were generally less than those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female rats. This neoplasm was found in 58% of males and 34% of females in the 90 mg/kg groups. In the forestomach of male rats, papilloma multiplicity was increased in the 90 mg/kg group, and squamous cell carcinomas were found in one 45 mg/kg male and two 90 mg/kg males. Epithelial hyperplasia of the forestomach occurred in most 45 and 90 mg/kg rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 30, 60, or 120 mg/kg, 5 days per week, for up to 105 weeks. Survival of dosed mice was similar to that of the vehicle controls. The mean body weights of all dosed groups were generally similar to those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female mice; squamous cell carcinomas were present in 120 mg/kg males and females. Epithelial hyperplasia of the forestomach occurred in many 120 mg/kg mice. Two 120 mg/kg males had uncommon squamous cell carcinoma of the oral cavity (tongue).

Genetic toxicology: 2,4-Hexadienal was mutagenic in S. typhimurium strain TA100 with and without induced hamster or rat liver enzymes; no mutagenic activity was detected with strains TA1535 or TA98, with or without S9. Results of bone marrow tests in male rats and male mice given intraperitoneal injections of 2,4-hexadienal showed a small increase in the induction of micronucleated erythrocytes. However, neither test was repeated, and the test results were judged to be inconclusive. Results of peripheral blood micronucleus tests in male and female mice treated with 2,4-hexadienal by gavage for 14 weeks were negative.

Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity* of 2,4-hexadienal in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of squamous cell neoplasms of the forestomach. The occurrence of squamous cell carcinoma of the oral cavity (tongue) in male B6C3F1 mice may have been related to the administration of 2,4-hexadienal. Hyperplasia of the forestomach in male and female rats and mice was associated with administration of 2,4-hexadienal. Synonyms: Hexa-2,4-dienal; 2,4-hexadienal; 2,4-hexadien-1-al; 2,4-Hx; 1,3-pentadiene-1-carboxaldehyde; 2-propylene acrolein; sorbaldehyde; sorbic aldehyde

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