NTP technical report on the toxicology studies of a pentabromodiphenyl ether mixture [DE-71 (Technical grade)] (CASRN 32534-81-9) in F344/N rats and B6C3F1/N mice and toxicology and carcinogenesis studies of a pentabromodiphenyl ether mixture [DE-71 (Technical grade)] in Wistar Han [Crl:WI(Han)] rats and B6C3F1/N mice (Gavage studies)
CONCLUSIONS: Under the conditions of these 2-year oral gavage studies, there was clear evidence of carcinogenic activity (see Explanation of Levels of Evidence of Carcinogenic Activity; see a summary of the Peer Review Panel comments and the public discussion on this Technical Report in Appendix O)...
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| Format: | eBook |
| Language: | English |
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Research Triangle Park, North Carolina, USA
National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services
2016, February 2016
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| Series: | NTP TR
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| Collection: | National Center for Biotechnology Information - Collection details see MPG.ReNa |
| Summary: | CONCLUSIONS: Under the conditions of these 2-year oral gavage studies, there was clear evidence of carcinogenic activity (see Explanation of Levels of Evidence of Carcinogenic Activity; see a summary of the Peer Review Panel comments and the public discussion on this Technical Report in Appendix O) of DE-71 in male Wistar Han rats based on increased incidences of hepatocholangioma, hepatocellular adenoma, or hepatocellular carcinoma (combined). Increased incidences of thyroid gland follicular cell adenoma and increased incidences of pituitary gland (pars distalis) adenoma were also considered to be related to exposure. There was clear evidence of carcinogenic activity of DE-71 in female Wistar Han rats based on increased incidences of hepatocholangioma, hepatocellular adenoma, and hepatocellular carcinoma. The occurrence of cholangiocarcinoma of the liver was also considered related to treatment. In males and females administered 5\smg/kg or greater, the concentrations of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), and 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153) in adipose and liver increased with increasing dose on day\s25 and at week\s14. The concentrations in adipose were higher than in liver suggesting preferential accumulation in the adipose. BDE-47 and BDE-99 concentrations in adipose were similar and were higher than the BDE-153 concentrations in both sexes; however, BDE-47, BDE-99, and BDE-153 concentrations were similar in the liver. Although there were no differences in BDE-153 concentrations on day\s25 or at week\s14 in the liver, BDE-47 and BDE-99 concentrations at week\s14 were lower than on day\s25, suggesting that BDE-47 and BDE-99 induce their own metabolism. On day 25, acetanilide-4-hydroxylase (A4H) activities were significantly increased in male rats administered 50\smg/kg or greater and in female rats administered 5\smg/kg or greater. At week\s14, significant dose-related increases were observed in both male and female rats administered 5\smg/kg or greater. 7-Pentoxyresorufin-O-dealkylase (PROD) activities were increased in male and female rats administered 5\smg/kg or greater on day\s25 and at week\s14. In the liver, there were significantly increased incidences of hepatocyte hypertrophy in males and females administered 5\smg/kg or greater. The incidences of cytoplasmic vacuolization of the hepatocytes were significantly increased in 50\smg/kg males and 100 and 500\smg/kg males and females. There were significantly increased incidences of thyroid gland follicle hypertrophy in females administered 50\smg/kg or greater and in 500\smg/kg males. THREE-MONTH STUDY IN F344/N RATS: Groups of 10 male and 10 female rats were administered 0, 0.01, 5, 50, 100, or 500 mg DE-71/kg body weight in corn oil by gavage 5 days per week for 14\sweeks. Groups of 10 male and 10 female special study rats were administered the same doses for 25\sdays. All rats survived to the end of the study. Mean body weights of 500\smg/kg males and females and 100\smg/kg females were significantly less than those of the vehicle controls. Dose-related decreases in serum thyroxine (T4) concentration occurred on days 4, 25, and 93 in males and females administered 5\smg/kg or greater. The decreases in T4 were accompanied by increases in serum thyroid stimulating hormone concentrations, which occurred most consistently in the 100 and 500\smg/kg groups at 14\sweeks. In the 500\smg/kg groups, there were significantly increased incidences of epididymis hypospermia and glandular stomach erosion in males and thymus atrophy in females. Epididymis and cauda epididymis weights were significantly decreased in 500\smg/kg males. The 500\smg/kg group also exhibited significantly decreased sperm per cauda and sperm per gram of cauda. In general, dosed males exhibited fewer total spermatids per testis and sperm per gram of testis were significantly decreased in the 100 and 500\smg/kg groups. Sperm motility was significantly decreased in the 500\smg/kg group. All 500\smg/kg females failed to cycle and remained in persistent diestrus throughout the examination period. Based on these findings, DE-71 exhibits the potential to be a reproductive toxicant in both male and female rats. The incidences of stromal polyp or stromal sarcoma (combined) of the uterus may have been related to treatment. There was clear evidence of carcinogenic activity of DE-71 in male B6C3F1/N mice based on increased incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma. There was clear evidence of carcinogenic activity of DE-71 in female B6C3F1/N mice based on increased incidences of hepatocellular adenoma and hepatocellular carcinoma. Administration of DE-71 resulted in increased incidences of nonneoplastic lesions in the liver, thyroid gland, kidney, parotid salivary gland, prostate gland, preputial gland, thymus, and forestomach of male rats; liver, thyroid gland, uterus, cervix, kidney, and adrenal cortex of female rats; liver, thyroid gland, forestomach, adrenal cortex, and testes of male mice; and liver, thyroid gland, forestomach, and adrenal cortex of female mice Serum cholesterol concentrations demonstrated dose-related increases at all time points in males and females administered 50\smg/kg or greater; the 0.01 and 5\smg/kg groups demonstrated an increase in cholesterol concentration at one or more time points. At\sweek\s14, a small decrease in the circulating red cell mass, evidenced by decreases in hematocrit values and hemoglobin concentrations, occurred in 100 and 500\smg/kg males and females. Absolute and relative liver weights of males and females administered 5\smg/kg or greater were significantly increased. Absolute and relative kidney weights were significantly greater than those of the vehicle controls in the 50, 100, and 500\smg/kg male groups. In females, absolute kidney weights were significantly increased in the groups administered 5\smg/kg or greater. Relative kidney weights were significantly greater than those of the vehicle control in all dosed groups of females. The absolute thymus weight in 500\smg/kg males and absolute and relative thymus weights in females administered 50\smg/kg or greater were significantly decreased. In the liver, uridine diphosphate glucuronosyl transferase (UDPGT) activities were significantly increased in male rats administered\s0.01\smg/kg on day\s25 and in male and female rats administered 5\smg/kg or greater on day\s25 and at week\s14. 7-Ethoxyresorufin-O-deethylase (EROD) activities on day\s25 displayed generally dose-related increases and significant increases were observed in males and females administered 5\smg/kg or greater. By week\s14, EROD activity in 500\smg/kg males was induced approximately 105-fold, while in 500\smg/kg females, it was induced approximately 209-fold. Significant but smaller increases were observed in 50 and 100\smg/kg males and females administered 5\smg/kg or greater. |
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| Physical Description: | 1 PDF file (various pagings) illustrations |