过氧化甲基乙酮(CAS No. 1338-23-4)在邻苯二甲酸二甲酯(CAS No. 131-11-3)(45:55)中局部给药F344/N大鼠和B6C3F1小鼠的毒性研究的NTP技术报告。

Toxicity report series Pub Date : 1993-02-01
Errol Zeiger
{"title":"过氧化甲基乙酮(CAS No. 1338-23-4)在邻苯二甲酸二甲酯(CAS No. 131-11-3)(45:55)中局部给药F344/N大鼠和B6C3F1小鼠的毒性研究的NTP技术报告。","authors":"Errol Zeiger","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>Methyl ethyl ketone peroxide (MEKP) is an unstable organic peroxide used in the manufacture of acrylic resins, as a hardening agent for fiberglass-reinforced plastics, and as a curing agent for unsaturated polyester resins. It is commercially available as a 40% to 60% solution in dimethyl phthalate (DMP). Because exposure to MEKP is typically through dermal contact, 2-week and 13-week toxicity studies were conducted by topical application of MEKP in DMP (45:55 w/w) to the clipped dorsal region of male and female Fischer 344/N rats and mice. Animals were evaluated for histopathology and for reproductive endpoints. In vitro genetic toxicity studies of MEKP included assessments of mutagenicity in Salmonella typhimurium and in mouse lymphoma L5178Y cells and analysis of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. In addition, the peripheral blood of mice from the 13-week study was evaluated in the micronucleus assay. In the 2-week studies, groups of 5 animals of each species and sex were administered MEKP in DMP for 5 days per week at doses of 50.6, 101.3, 202.5, 405, and 810 mg/kg body weight per day for rats and 112.5, 225, 450, 900, and 1800 mg/kg body weight per day for mice. Control groups received DMP or no treatment. No rats died during the studies, but at least 1 mouse in each group receiving MEKP died. Body weight gains of rats decreased with increasing doses of MEKP; body weight gains of mice were not affected by treatment. The primary effects of topical administration of MEKP in both rats and mice were an extensive coagulative necrosis of the epidermis and dermis, variable degrees of inflammation of the adnexa, and epidermal regeneration and hyperplasia at the application site. Lesions considered secondary to the dermal lesions included increased hematopoiesis in the spleen in rats and mice and increased myeloid hyperplasia of the bone marrow in mice, primarily at the higher doses. Mice showed a marked, dose-related increase in liver weight. In the 13-week dermal studies, groups of 10 rats and 10 mice of each sex were administered MEKP in DMP for 5 days per week at doses of 1.07, 3.57, 10.7, 35.7, and 107 mg/rat and 0.357, 1.19, 3.57, 11.9, and 35.7 mg/mouse. All high-dose mice, 3 high-dose female rats, and 1 female mouse in the 11.9 mg/animal group died or were sacrificed during the first week of the studies. Skin lesions similar to those seen in the 2-week studies were judged of sufficient severity to warrant early termination of surviving rats and mice in the 2 highest dose groups. All rats and mice in the remaining dose groups survived to the end of the studies, and weight gains were generally lower with increasing doses of MEKP. Skin lesions at the application site for the remaining animals (rats and mice) in the 10.7 mg/rat and 3.57 mg/mouse dose groups involved a spectrum of necrosis, inflammation, and acanthosis (epidermal hyperplasia). Lesions in the lower dose groups were limited to acanthosis and hyperkeratosis in rats (1.07 and 3.57 mg/rat) and acanthosis in mice (0.357 and 1.19 mg/mouse). While splenic and bone marrow lesions similar to those described in the 2-week studies were seen in animals that died early in the 13-week studies and in the rats and mice that showed ulcerative or necrotic injury, no other systemic changes were noted in animals that did not show ulcerative skin lesions. In genetic toxicity studies, MEKP in DMP (45:55 w/w) was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without S9activation. A positive response was obtained in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9. In cytogenetic tests with Chinese hamster ovary cells, MEKP induced sister chromatid exchanges and chromosomal aberrations, with and without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples obtained from male and female mice at the termination of the 13-week toxicity study. In summary, topical administration of MEKP in DM of MEKP in DMP resulted in a spectrum of necrotic, inflammatory, and regenerative skin lesions limited to the application site. Histopathologic changes in the spleen and bone marrow were also seen in rats and mice with ulcerative skin lesions, and were considered a secondary response. A no-observed-adverse-effect level (NOAEL) for histopathologic skin lesions could not be determined from these studies, as lesions were observed with administration of daily doses as low as 1.07 mg for rats and 0.357 mg for mice. Methyl Ethyl Ketone Peroxide Synonyms: 2-Butanone Peroxide. Dimethyl Phthalate Synonyms: 1,2-Benzenedicarboxylic acid dimethyl ester; phthalic acid dimethyl ester; methyl phthalate; dimethyl 1,2-benzene- dicarboxylate; DMP</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":"18 ","pages":"1-C10"},"PeriodicalIF":0.0000,"publicationDate":"1993-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NTP technical report on the toxicity studies of Methyl Ethyl Ketone Peroxide (CAS No. 1338-23-4) in Dimethyl Phthalate (CAS No. 131-11-3) (45:55) Administered Topically in F344/N Rats and B6C3F1 Mice.\",\"authors\":\"Errol Zeiger\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Methyl ethyl ketone peroxide (MEKP) is an unstable organic peroxide used in the manufacture of acrylic resins, as a hardening agent for fiberglass-reinforced plastics, and as a curing agent for unsaturated polyester resins. It is commercially available as a 40% to 60% solution in dimethyl phthalate (DMP). Because exposure to MEKP is typically through dermal contact, 2-week and 13-week toxicity studies were conducted by topical application of MEKP in DMP (45:55 w/w) to the clipped dorsal region of male and female Fischer 344/N rats and mice. Animals were evaluated for histopathology and for reproductive endpoints. In vitro genetic toxicity studies of MEKP included assessments of mutagenicity in Salmonella typhimurium and in mouse lymphoma L5178Y cells and analysis of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. In addition, the peripheral blood of mice from the 13-week study was evaluated in the micronucleus assay. In the 2-week studies, groups of 5 animals of each species and sex were administered MEKP in DMP for 5 days per week at doses of 50.6, 101.3, 202.5, 405, and 810 mg/kg body weight per day for rats and 112.5, 225, 450, 900, and 1800 mg/kg body weight per day for mice. Control groups received DMP or no treatment. No rats died during the studies, but at least 1 mouse in each group receiving MEKP died. Body weight gains of rats decreased with increasing doses of MEKP; body weight gains of mice were not affected by treatment. The primary effects of topical administration of MEKP in both rats and mice were an extensive coagulative necrosis of the epidermis and dermis, variable degrees of inflammation of the adnexa, and epidermal regeneration and hyperplasia at the application site. Lesions considered secondary to the dermal lesions included increased hematopoiesis in the spleen in rats and mice and increased myeloid hyperplasia of the bone marrow in mice, primarily at the higher doses. Mice showed a marked, dose-related increase in liver weight. In the 13-week dermal studies, groups of 10 rats and 10 mice of each sex were administered MEKP in DMP for 5 days per week at doses of 1.07, 3.57, 10.7, 35.7, and 107 mg/rat and 0.357, 1.19, 3.57, 11.9, and 35.7 mg/mouse. All high-dose mice, 3 high-dose female rats, and 1 female mouse in the 11.9 mg/animal group died or were sacrificed during the first week of the studies. Skin lesions similar to those seen in the 2-week studies were judged of sufficient severity to warrant early termination of surviving rats and mice in the 2 highest dose groups. All rats and mice in the remaining dose groups survived to the end of the studies, and weight gains were generally lower with increasing doses of MEKP. Skin lesions at the application site for the remaining animals (rats and mice) in the 10.7 mg/rat and 3.57 mg/mouse dose groups involved a spectrum of necrosis, inflammation, and acanthosis (epidermal hyperplasia). Lesions in the lower dose groups were limited to acanthosis and hyperkeratosis in rats (1.07 and 3.57 mg/rat) and acanthosis in mice (0.357 and 1.19 mg/mouse). While splenic and bone marrow lesions similar to those described in the 2-week studies were seen in animals that died early in the 13-week studies and in the rats and mice that showed ulcerative or necrotic injury, no other systemic changes were noted in animals that did not show ulcerative skin lesions. In genetic toxicity studies, MEKP in DMP (45:55 w/w) was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without S9activation. A positive response was obtained in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9. In cytogenetic tests with Chinese hamster ovary cells, MEKP induced sister chromatid exchanges and chromosomal aberrations, with and without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples obtained from male and female mice at the termination of the 13-week toxicity study. In summary, topical administration of MEKP in DM of MEKP in DMP resulted in a spectrum of necrotic, inflammatory, and regenerative skin lesions limited to the application site. Histopathologic changes in the spleen and bone marrow were also seen in rats and mice with ulcerative skin lesions, and were considered a secondary response. A no-observed-adverse-effect level (NOAEL) for histopathologic skin lesions could not be determined from these studies, as lesions were observed with administration of daily doses as low as 1.07 mg for rats and 0.357 mg for mice. Methyl Ethyl Ketone Peroxide Synonyms: 2-Butanone Peroxide. Dimethyl Phthalate Synonyms: 1,2-Benzenedicarboxylic acid dimethyl ester; phthalic acid dimethyl ester; methyl phthalate; dimethyl 1,2-benzene- dicarboxylate; DMP</p>\",\"PeriodicalId\":23116,\"journal\":{\"name\":\"Toxicity report series\",\"volume\":\"18 \",\"pages\":\"1-C10\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1993-02-01\",\"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}","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

摘要

甲基乙基酮过氧化物(MEKP)是一种不稳定的有机过氧化物,用于制造丙烯酸树脂,作为玻璃纤维增强塑料的硬化剂,以及作为不饱和聚酯树脂的固化剂。它在商业上以40%至60%的邻苯二甲酸二甲酯(DMP)溶液出售。由于MEKP的暴露通常是通过皮肤接触,因此将MEKP在DMP中(45:55 w/w)局部应用于雄性和雌性Fischer 344/N大鼠和小鼠的剪短背区,进行了2周和13周的毒性研究。评估动物的组织病理学和生殖终点。MEKP的体外遗传毒性研究包括鼠伤寒沙门菌和小鼠淋巴瘤L5178Y细胞的诱变性评估以及中国仓鼠卵巢细胞的染色体畸变和姐妹染色单体交换分析。此外,在13周的研究中,用微核测定法评估小鼠外周血。在为期2周的研究中,每组5只动物,每个物种和性别,在DMP中按50.6、101.3、202.5、405和810 mg/kg体重每天给药大鼠,112.5、225、450、900和1800 mg/kg体重每天给药小鼠,每周5天。对照组给予DMP或不给予治疗。研究期间没有大鼠死亡,但每组至少有1只小鼠死亡。大鼠体重增加随MEKP剂量的增加而减少;治疗对小鼠的体重增加没有影响。在大鼠和小鼠中,外用MEKP的主要作用是表皮和真皮的广泛凝固性坏死,附件的不同程度的炎症,以及表皮再生和增生。被认为继发于皮肤病变的病变包括大鼠和小鼠脾脏造血功能增加,小鼠骨髓骨髓增生增加,主要是在较高剂量下。小鼠的肝脏重量表现出明显的剂量相关性增加。在为期13周的皮肤研究中,每组10只大鼠和10只小鼠,每组10只,按1.07、3.57、10.7、35.7和107 mg/只大鼠和0.357、1.19、3.57、11.9和35.7 mg/只小鼠的剂量,每周给药5天。11.9 mg/动物组的所有高剂量小鼠、3只高剂量雌性大鼠和1只雌性小鼠在研究的第一周死亡或牺牲。与2周研究中类似的皮肤损伤被判断为足够严重,可以保证在2个最高剂量组中存活的大鼠和小鼠的早期终止。其余剂量组的所有大鼠和小鼠都存活到研究结束,并且随着MEKP剂量的增加,体重增加通常较低。在10.7 mg/大鼠和3.57 mg/小鼠剂量组中,其余动物(大鼠和小鼠)的应用部位皮肤病变包括一系列坏死、炎症和棘层增生(表皮增生)。低剂量组的病变仅限于大鼠棘层增生和角化过度(1.07和3.57 mg/只)和小鼠棘层增生(0.357和1.19 mg/只)。虽然在13周研究中早期死亡的动物以及出现溃疡性或坏死性损伤的大鼠和小鼠中发现了与2周研究中描述的相似的脾和骨髓病变,但在没有出现溃疡性皮肤病变的动物中没有发现其他全身性变化。在遗传毒性研究中,无论是否激活s9, DMP中的MEKP (45:55 w/w)对鼠伤寒沙门氏菌菌株TA100、TA1535、TA1537或TA98都没有诱变作用。在小鼠淋巴瘤试验中,对不含S9的L5178Y细胞诱导三氟胸苷耐药获得了阳性反应。在中国仓鼠卵巢细胞的细胞遗传学试验中,MEKP诱导姐妹染色单体交换和染色体畸变,不论有无S9。在13周的毒性研究结束时,雄性和雌性小鼠的外周血样本中微核红细胞的频率未见增加。综上所述,外用MEKP于DM或MEKP于DMP可导致局限于应用部位的一系列坏死、炎症和再生皮肤病变。在溃疡性皮肤损伤的大鼠和小鼠中,脾脏和骨髓的组织病理学改变也被观察到,被认为是继发性反应。从这些研究中无法确定组织病理学皮肤病变的无观察到的不良反应水平(NOAEL),因为观察到病变时,大鼠的日剂量低至1.07毫克,小鼠为0.357毫克。过氧化甲基乙基酮同义词:过氧化2-丁酮。邻苯二甲酸二甲酯同义词:1,2-苯二甲酸二甲酯;邻苯二甲酸二甲酯;邻苯二甲酸二甲酯;1,2-苯二羧酸二甲基;DMP
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 Methyl Ethyl Ketone Peroxide (CAS No. 1338-23-4) in Dimethyl Phthalate (CAS No. 131-11-3) (45:55) Administered Topically in F344/N Rats and B6C3F1 Mice.

Methyl ethyl ketone peroxide (MEKP) is an unstable organic peroxide used in the manufacture of acrylic resins, as a hardening agent for fiberglass-reinforced plastics, and as a curing agent for unsaturated polyester resins. It is commercially available as a 40% to 60% solution in dimethyl phthalate (DMP). Because exposure to MEKP is typically through dermal contact, 2-week and 13-week toxicity studies were conducted by topical application of MEKP in DMP (45:55 w/w) to the clipped dorsal region of male and female Fischer 344/N rats and mice. Animals were evaluated for histopathology and for reproductive endpoints. In vitro genetic toxicity studies of MEKP included assessments of mutagenicity in Salmonella typhimurium and in mouse lymphoma L5178Y cells and analysis of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. In addition, the peripheral blood of mice from the 13-week study was evaluated in the micronucleus assay. In the 2-week studies, groups of 5 animals of each species and sex were administered MEKP in DMP for 5 days per week at doses of 50.6, 101.3, 202.5, 405, and 810 mg/kg body weight per day for rats and 112.5, 225, 450, 900, and 1800 mg/kg body weight per day for mice. Control groups received DMP or no treatment. No rats died during the studies, but at least 1 mouse in each group receiving MEKP died. Body weight gains of rats decreased with increasing doses of MEKP; body weight gains of mice were not affected by treatment. The primary effects of topical administration of MEKP in both rats and mice were an extensive coagulative necrosis of the epidermis and dermis, variable degrees of inflammation of the adnexa, and epidermal regeneration and hyperplasia at the application site. Lesions considered secondary to the dermal lesions included increased hematopoiesis in the spleen in rats and mice and increased myeloid hyperplasia of the bone marrow in mice, primarily at the higher doses. Mice showed a marked, dose-related increase in liver weight. In the 13-week dermal studies, groups of 10 rats and 10 mice of each sex were administered MEKP in DMP for 5 days per week at doses of 1.07, 3.57, 10.7, 35.7, and 107 mg/rat and 0.357, 1.19, 3.57, 11.9, and 35.7 mg/mouse. All high-dose mice, 3 high-dose female rats, and 1 female mouse in the 11.9 mg/animal group died or were sacrificed during the first week of the studies. Skin lesions similar to those seen in the 2-week studies were judged of sufficient severity to warrant early termination of surviving rats and mice in the 2 highest dose groups. All rats and mice in the remaining dose groups survived to the end of the studies, and weight gains were generally lower with increasing doses of MEKP. Skin lesions at the application site for the remaining animals (rats and mice) in the 10.7 mg/rat and 3.57 mg/mouse dose groups involved a spectrum of necrosis, inflammation, and acanthosis (epidermal hyperplasia). Lesions in the lower dose groups were limited to acanthosis and hyperkeratosis in rats (1.07 and 3.57 mg/rat) and acanthosis in mice (0.357 and 1.19 mg/mouse). While splenic and bone marrow lesions similar to those described in the 2-week studies were seen in animals that died early in the 13-week studies and in the rats and mice that showed ulcerative or necrotic injury, no other systemic changes were noted in animals that did not show ulcerative skin lesions. In genetic toxicity studies, MEKP in DMP (45:55 w/w) was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without S9activation. A positive response was obtained in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9. In cytogenetic tests with Chinese hamster ovary cells, MEKP induced sister chromatid exchanges and chromosomal aberrations, with and without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples obtained from male and female mice at the termination of the 13-week toxicity study. In summary, topical administration of MEKP in DM of MEKP in DMP resulted in a spectrum of necrotic, inflammatory, and regenerative skin lesions limited to the application site. Histopathologic changes in the spleen and bone marrow were also seen in rats and mice with ulcerative skin lesions, and were considered a secondary response. A no-observed-adverse-effect level (NOAEL) for histopathologic skin lesions could not be determined from these studies, as lesions were observed with administration of daily doses as low as 1.07 mg for rats and 0.357 mg for mice. Methyl Ethyl Ketone Peroxide Synonyms: 2-Butanone Peroxide. Dimethyl Phthalate Synonyms: 1,2-Benzenedicarboxylic acid dimethyl ester; phthalic acid dimethyl ester; methyl phthalate; dimethyl 1,2-benzene- dicarboxylate; DMP

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信