title: Toxicologic effects of 28-day dietary exposure to the flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)-cyclohexane (TBECH) in F344 rats.
abstract: The brominated flame retardant TBECH is used as an additive to delay ignition and inhibit fires in construction materials and consumer goods. Trends in human exposure are not clear, although humans may be exposed to TBECH via indoor dust and air. In birds and fish there is some evidence of disruption in endocrine and reproductive parameters due to TBECH. In vitro studies indicate that TBECH is an androgen receptor agonist. In this study rats were exposed to 0, 10, 50, 250, 1250 or 5000mg/kg technical TBECH for 28days in diet, corresponding to 0, 0.9, 4.2, 21.3, 98.0 or 328.9mg TBECH/kg bw/d in males and 0, 0.8, 3.9, 19.4, 91.7 or 321.4mg TBECH/kg bw/d in females. Dose-dependent increases in α- and β- TBECH were detected in serum, liver and adipose. Rats in the 5000mg/kg group lost weight rapidly and were euthanized after 15-18days. At study termination rats displayed dose-dependent clinical and histopathological changes consistent with mild hepatic and renal inflammation. In male rats, evidence of gender-specific alpha2u-globulin nephropathy was not considered predictive of renal toxicity in humans. Frank immunosuppression or inappropriate immunostimulation were not apparent, nor was there a primary effect of TBECH on adaptive immunity. Some evidence of hormone disruption was observed, including changes in serum testosterone levels in males and changes in serum T3 and T4 levels in females. Apparent increases in thyroid follicular cell hypertrophy and hyperplasia in male and female rats were not statistically significant. Benchmark dose (BMD) modelling indicated that clinical changes indicative of mild nephrotoxicity and increased blood monocyte numbers indicative of inflammation and tissue damage were the most sensitive outcomes of TBECH exposure that could be modelled. Preliminary evidence of hormone disruption supports the need for rodent studies using more sensitive models of growth, development and reproduction.
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada. Electronic address: Ivan.Curran@Canada.ca.
authors.forename: Ivan H A
authors.initials: IH
authors.lastname: Curran
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Virginia
authors.initials: V
authors.lastname: Liston
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Andrée
authors.initials: A
authors.lastname: Nunnikhoven
authors.affiliation: Scientific Services Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Don
authors.initials: D
authors.lastname: Caldwell
authors.affiliation: Ontario Food Laboratory, Laboratories Directorate, Regulatory Operations and Regions Branch, Health Canada, 2301 Midland Avenue, Toronto, ON, M1P 4R7, Canada.
authors.forename: Matthew J S
authors.initials: MJ
authors.lastname: Scuby
authors.affiliation: Ontario Food Laboratory, Laboratories Directorate, Regulatory Operations and Regions Branch, Health Canada, 2301 Midland Avenue, Toronto, ON, M1P 4R7, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Pantazopoulos
authors.affiliation: Food Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Dorothea F K
authors.initials: DF
authors.lastname: Rawn
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Laurie
authors.initials: L
authors.lastname: Coady
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Armstrong
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Lefebvre
authors.affiliation: Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON, K1A 0K9, Canada.
authors.forename: Genevieve S
authors.initials: GS
authors.lastname: Bondy
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D004032:Diet / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005411:Flame Retardants / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D003510:Cyclohexanes; D005411:Flame Retardants; C517232:1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane
keywords: 1,2-dibromo-4-(1,2-dibromoethyl)-cyclohexane; Endocrine; Kidney; Rat; TBECH