{"title":"国家毒理学计划(NTP)对F344/N大鼠和B6C3F1小鼠灌胃给予过苯甲酸丁酯(CAS No. 614-45-9)毒性研究的技术报告。","authors":"H.B. Matthews","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>t-Butyl perbenzoate (t-BP) is a relatively stable, lipid-soluble, organic peroxide widely used in the polymer industry. Studies were designed to determine the stability of t-BP in various biological media, its dermal absorption and distribution in intact animals, and the toxicity of t-BP when administered orally to both sexes of rats and mice for 14 days or 13 weeks. In genetic toxicity studies, t-BP was found to be mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98, with and without metabolic activation. t-BP-induced sister-chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells in vitro but did not induce formation of micronuclei in peripheral blood in mice in the 13-week studies. Stability studies indicated t-BP was sufficiently stable in dose formulations to permit administration by gavage, intravenous injection, or dermally. However, t-BP degraded rapidly in blood, stomach contents, and liver homogenates, or in the presence of glutathione. Initial degradation products of t-BP are benzoic acid and t-butanol. Studies of t-BP disposition determined that approximately 16% of dermal doses administered to rats was absorbed and rapidly eliminated without tissue accumulation. Similarly, t-BP given intravenously was rapidly degraded and eliminated, primarily in urine, with no apparent accumulation in any tissue. Because dermal absorption was considered insufficient to administer a toxic dose, studies of t-BP toxicity were performed using gavage administration. Results of 14-day toxicity studies with 5 animals of each sex of rats and mice indicated that t-PB, administered by gavage in corn oil in doses ranging from 70 to 1112 mg/kg, produced no marked signs of systemic toxicity. Toxicity in mice, attributable to t- BP, was limited largely to increased stomach weights in males and females receiving the highest doses. This toxicity was characterized by forestomach epithelial hyperplasia, ulceration, and acute inflammation. Equimolar doses of the degradation products of t-BP (t-butanol and benzoic acid) also were administered in the 14-day studies to determine if t-BP toxicity could be attributed to the parent compound or products of its chemical degradation and/or metabolism. Results of these studies indicated that equimolar doses of t-butanol were not toxic in either sex or species. Some systemic toxicity of benzoic acid was observed in both sexes of mice, but not rats, receiving the highest dose (642 mg/kg). Toxicity was evidenced by the poor condition of dosed animals and in several deaths during the first week of the study. No lesions were observed microscopically, and it is speculated that this toxicity may have been due to acidosis. In the 13-week studies, t-BP was administered by gavage in water to 10 rats and 10 mice of each sex, at doses up to 500 mg/kg. The doses resulted in depressed body-weight gains in the highest dose groups and in dose-dependent increases in forestomach weights. Hyperplasia of the forestomach mucosa was observed in most groups of dosed rats and increased in severity with dose. Hyperplasia was characterized by increased cellularity and basophilia of the squamous epithelium with variable degrees of hyperkeratosis. t-BP toxicity observed in mice was limited to increased forestomach weight in most dose groups and to less dramatic increases in glandular stomach weight in mice receiving the highest doses. Forestomach toxicity was characterized by dose-dependent increases in hyperplasia of the squamous epithelium in all mice except those in the low dose group. Based on the results presented in this report, it is concluded that the no-observed-adverse-effect-level (NOAEL) for t-BP to induce forestomach lesions in rats and mice is approximately 30 mg/kg. Systemic toxicity was not observed in either species with oral doses as high as 1112 mg/kg. Synonyms: Benzenecarboperoxoic acid; 1,1-dimethylester; Esperox 10; Trigonox C; t-BP.</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":"15 ","pages":"1-B7"},"PeriodicalIF":0.0000,"publicationDate":"1992-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NTP technical report on the toxicity studies of t-Butyl Perbenzoate (CAS No. 614-45-9) Administered By Gavage To F344/N Rats And B6C3F1 Mice.\",\"authors\":\"H.B. Matthews\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>t-Butyl perbenzoate (t-BP) is a relatively stable, lipid-soluble, organic peroxide widely used in the polymer industry. Studies were designed to determine the stability of t-BP in various biological media, its dermal absorption and distribution in intact animals, and the toxicity of t-BP when administered orally to both sexes of rats and mice for 14 days or 13 weeks. In genetic toxicity studies, t-BP was found to be mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98, with and without metabolic activation. t-BP-induced sister-chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells in vitro but did not induce formation of micronuclei in peripheral blood in mice in the 13-week studies. Stability studies indicated t-BP was sufficiently stable in dose formulations to permit administration by gavage, intravenous injection, or dermally. However, t-BP degraded rapidly in blood, stomach contents, and liver homogenates, or in the presence of glutathione. Initial degradation products of t-BP are benzoic acid and t-butanol. Studies of t-BP disposition determined that approximately 16% of dermal doses administered to rats was absorbed and rapidly eliminated without tissue accumulation. Similarly, t-BP given intravenously was rapidly degraded and eliminated, primarily in urine, with no apparent accumulation in any tissue. Because dermal absorption was considered insufficient to administer a toxic dose, studies of t-BP toxicity were performed using gavage administration. Results of 14-day toxicity studies with 5 animals of each sex of rats and mice indicated that t-PB, administered by gavage in corn oil in doses ranging from 70 to 1112 mg/kg, produced no marked signs of systemic toxicity. Toxicity in mice, attributable to t- BP, was limited largely to increased stomach weights in males and females receiving the highest doses. This toxicity was characterized by forestomach epithelial hyperplasia, ulceration, and acute inflammation. Equimolar doses of the degradation products of t-BP (t-butanol and benzoic acid) also were administered in the 14-day studies to determine if t-BP toxicity could be attributed to the parent compound or products of its chemical degradation and/or metabolism. Results of these studies indicated that equimolar doses of t-butanol were not toxic in either sex or species. Some systemic toxicity of benzoic acid was observed in both sexes of mice, but not rats, receiving the highest dose (642 mg/kg). Toxicity was evidenced by the poor condition of dosed animals and in several deaths during the first week of the study. No lesions were observed microscopically, and it is speculated that this toxicity may have been due to acidosis. In the 13-week studies, t-BP was administered by gavage in water to 10 rats and 10 mice of each sex, at doses up to 500 mg/kg. The doses resulted in depressed body-weight gains in the highest dose groups and in dose-dependent increases in forestomach weights. Hyperplasia of the forestomach mucosa was observed in most groups of dosed rats and increased in severity with dose. Hyperplasia was characterized by increased cellularity and basophilia of the squamous epithelium with variable degrees of hyperkeratosis. t-BP toxicity observed in mice was limited to increased forestomach weight in most dose groups and to less dramatic increases in glandular stomach weight in mice receiving the highest doses. Forestomach toxicity was characterized by dose-dependent increases in hyperplasia of the squamous epithelium in all mice except those in the low dose group. Based on the results presented in this report, it is concluded that the no-observed-adverse-effect-level (NOAEL) for t-BP to induce forestomach lesions in rats and mice is approximately 30 mg/kg. Systemic toxicity was not observed in either species with oral doses as high as 1112 mg/kg. Synonyms: Benzenecarboperoxoic acid; 1,1-dimethylester; Esperox 10; Trigonox C; t-BP.</p>\",\"PeriodicalId\":23116,\"journal\":{\"name\":\"Toxicity report series\",\"volume\":\"15 \",\"pages\":\"1-B7\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1992-07-01\",\"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}
NTP technical report on the toxicity studies of t-Butyl Perbenzoate (CAS No. 614-45-9) Administered By Gavage To F344/N Rats And B6C3F1 Mice.
t-Butyl perbenzoate (t-BP) is a relatively stable, lipid-soluble, organic peroxide widely used in the polymer industry. Studies were designed to determine the stability of t-BP in various biological media, its dermal absorption and distribution in intact animals, and the toxicity of t-BP when administered orally to both sexes of rats and mice for 14 days or 13 weeks. In genetic toxicity studies, t-BP was found to be mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98, with and without metabolic activation. t-BP-induced sister-chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells in vitro but did not induce formation of micronuclei in peripheral blood in mice in the 13-week studies. Stability studies indicated t-BP was sufficiently stable in dose formulations to permit administration by gavage, intravenous injection, or dermally. However, t-BP degraded rapidly in blood, stomach contents, and liver homogenates, or in the presence of glutathione. Initial degradation products of t-BP are benzoic acid and t-butanol. Studies of t-BP disposition determined that approximately 16% of dermal doses administered to rats was absorbed and rapidly eliminated without tissue accumulation. Similarly, t-BP given intravenously was rapidly degraded and eliminated, primarily in urine, with no apparent accumulation in any tissue. Because dermal absorption was considered insufficient to administer a toxic dose, studies of t-BP toxicity were performed using gavage administration. Results of 14-day toxicity studies with 5 animals of each sex of rats and mice indicated that t-PB, administered by gavage in corn oil in doses ranging from 70 to 1112 mg/kg, produced no marked signs of systemic toxicity. Toxicity in mice, attributable to t- BP, was limited largely to increased stomach weights in males and females receiving the highest doses. This toxicity was characterized by forestomach epithelial hyperplasia, ulceration, and acute inflammation. Equimolar doses of the degradation products of t-BP (t-butanol and benzoic acid) also were administered in the 14-day studies to determine if t-BP toxicity could be attributed to the parent compound or products of its chemical degradation and/or metabolism. Results of these studies indicated that equimolar doses of t-butanol were not toxic in either sex or species. Some systemic toxicity of benzoic acid was observed in both sexes of mice, but not rats, receiving the highest dose (642 mg/kg). Toxicity was evidenced by the poor condition of dosed animals and in several deaths during the first week of the study. No lesions were observed microscopically, and it is speculated that this toxicity may have been due to acidosis. In the 13-week studies, t-BP was administered by gavage in water to 10 rats and 10 mice of each sex, at doses up to 500 mg/kg. The doses resulted in depressed body-weight gains in the highest dose groups and in dose-dependent increases in forestomach weights. Hyperplasia of the forestomach mucosa was observed in most groups of dosed rats and increased in severity with dose. Hyperplasia was characterized by increased cellularity and basophilia of the squamous epithelium with variable degrees of hyperkeratosis. t-BP toxicity observed in mice was limited to increased forestomach weight in most dose groups and to less dramatic increases in glandular stomach weight in mice receiving the highest doses. Forestomach toxicity was characterized by dose-dependent increases in hyperplasia of the squamous epithelium in all mice except those in the low dose group. Based on the results presented in this report, it is concluded that the no-observed-adverse-effect-level (NOAEL) for t-BP to induce forestomach lesions in rats and mice is approximately 30 mg/kg. Systemic toxicity was not observed in either species with oral doses as high as 1112 mg/kg. Synonyms: Benzenecarboperoxoic acid; 1,1-dimethylester; Esperox 10; Trigonox C; t-BP.