Abstract  The endocrine-disrupting activities of bisphenol A (BPA) and 19 related compounds were comparatively examined by means of different in vitro and in vivo reporter assays. BPA and some related compounds exhibited estrogenic activity in human breast cancer cell line MCF-7, but there were remarkable differences in activity. Tetrachlorobisphenol A (TCBPA) showed the highest activity, followed by bisphenol B, BPA, and tetramethylbisphenol A (TMBPA); 2,2-bis(4-hydroxyphenyl)-1-propanol, 1,1-bis(4-hydroxyphenyl)propionic acid and 2,2-diphenylpropane showed little or no activity. Anti-estrogenic activity against 17beta-estradiol was observed with TMBPA and tetrabromobisphenol A (TBBPA). TCBPA, TBBPA, and BPA gave positive responses in the in vivo uterotrophic assay using ovariectomized mice. In contrast, BPA and some related compounds showed significant inhibitory effects on the androgenic activity of 5alpha-dihydrotestosterone in mouse fibroblast cell line NIH3T3. TMBPA showed the highest antagonistic activity, followed by bisphenol AF, bisphenol AD, bisphenol B, and BPA. However, TBBPA, TCBPA, and 2,2-diphenylpropane were inactive. TBBPA, TCBPA, TMBPA, and 3,3'-dimethylbisphenol A exhibited significant thyroid hormonal activity towards rat pituitary cell line GH3, which releases growth hormone in a thyroid hormone-dependent manner. However, BPA and other derivatives did not show such activity. The results suggest that the 4-hydroxyl group of the A-phenyl ring and the B-phenyl ring of BPA derivatives are required for these hormonal activities, and substituents at the 3,5-positions of the phenyl rings and the bridging alkyl moiety markedly influence the activities.

Abstract  25637-99-4

Abstract  Bromine has been added to cis,trans,trans-1,5,9-cyclododecatriene under various reaction conditions. All expected direct addition products have been isolated, and their structures have been determined by microanalysis, NMR and X-ray crystallography. Advanced NMR techniques were used to determine solution conformations of several of the compounds, enabling comparison with the solid-state conformations obtained by crystallography.

Abstract  This chapter illustrates the thermal rearrangement of Hexabromocyclododecane (HBCD) and pure isomers. It was found that all isomers thermally rearrange to give the same final isomer distribution. During this rearrangement no evidence was found for “bromine dancing” on the ring. No side reaction was detected. The longer the time and the higher the temperature the greater thermal degradation of the HBCD occurred. Thermal equilibrium consists of 78 % isomer 3, 13 % isomer 2 and 9 % isomer 1.

Abstract  The chemicals targeted by the Stockholm Convention are listed in the annexes of the convention text.

Abstract  A method of estimating the bioconcentration factor of organic chemicals in fathead minnows (Pimephales promelas) is described. Water at 25 °C was intermittently dosed with the chemical at a nontoxic concentration in a flow-through aquarium. Thirty minnows are placed in the aquarium, and composite samples of five fish are removed for analysis after 2, 4, 8, 16, 24, and 32 d of exposure. The bioconcentration process is summarized by using the first-order uptake model, and the steady-state bioconcentration factor is calculated from the 32-d exposure. A structure-activity correlation between the bioconcentration factor (BCF) and the n-octanol/water partition coefficient (P) of individual chemicals is summarized by the equation log BCF = 0.85 log P − 0.70, which permits the estimation of the bioconcentration factor of chemicals to within 60% before laboratory testing. The facilities and resources for testing need be used only for those chemicals that are likely to result in substantial bioconcentration in organisms. The bioconcentration factors derived from tests of mixtures of chemicals are shown to be the same as those derived from tests with the chemicals individually. Key words: bioconcentration factor, bioaccumulation, structure-activity, bioassay

Abstract  The objective of this consultation document and the corresponding 60 day electronic public comment period is to solicit feedback from stakeholders and the public regarding the proposed risk management measure for hexabromocyclododecane (HBCD). Comments received will help to inform the development of the proposed risk management measure for publication in Canada Gazette, Part I.

Abstract  This report provides information on hexabromocyclododecane (HBCD; CASRN 25637-99-4; 3194-55-6) used as a flame retardant in polystyrene building insulation, possible substitutes, and alternative materials. The report was developed by the U.S. Environmental Protection Agency (EPA) with input from a partnership of stakeholders from business, government, academia, and environmental organizations. According to technical experts on the Partnership, between 2011 and 2014 there were only three viable flame retardant alternatives to HBCD for use in expanded and extruded polystyrene foam (EPS and XPS) insulation under current manufacturing processes. Alternative materials are also available as substitutes to HBCD-containing insulation. These alternatives may require additive flame retardants or other treatment to meet fire safety requirements. This report: 1) Identifies viable and non-viable flame retardant alternatives for HBCD in polystyrene building insulation foam; 2) Describes uses and provides an overview of end-of-life scenarios and exposure to HBCD; 3) Provides hazard profiles for HBCD and the three chemical alternatives; and 4) Provides an overview of relevant alternative materials. Based on DfE AA criteria and guidance, the hazard profile of the butadiene styrene brominated copolymer (CASRN 1195978-93-8) shows that this chemical is anticipated to be safer than HBCD for multiple endpoints. Due to its large size, lack of low molecular weight (MW) components, and un-reactive functional groups, human health and ecotoxicity hazard for this polymer are measured or predicted to be low, although experimental data were not available for all endpoints. In general the exposure potential to the butadiene styrene brominated copolymer is expected to be lower than the other chemicals in this assessment because it is a large polymer and is unlikely to be released from the polystyrene. However, this alternative is inherently persistent and its long-term behavior in the environment is not currently known. Chemical suppliers have commercialized this polymer, and polystyrene manufacturers are testing it in their products to ensure that the polystyrene will meet all performance standards. The hazard designations for this alternative are based upon high MW formulations of the polymer, where all components have a MW >1,000. The polymer is regulated with a Significant New Use Rule that was finalized in June 2013. Manufacture (or import) of the polymer requires notification to EPA except in these cases: (1) the MW of the polymer is in the range of 1,000 to 10,000 daltons, or (2) the MW of the polymer is ≥10,000 daltons and less than 5 percent of the particles are in the respirable range of 10 microns or less (U.S. EPA 2013). The hazard profiles of the tetrabromobisphenol A (TBBPA)-bis brominated ether derivative (CASRN 97416-84-7) and TBBPA bis(2,3-dibromopropyl) ether (CASRN 21850-44-2) show that these chemicals have limited data sets for human health endpoints and hazard designations show a potential for toxicity. These two chemicals are also anticipated to have High potential for bioaccumulation.

Abstract  Client: Saytech inc.

Abstract  Client: Saytech Inc.

Abstract  The present study investigates chemical thyroid hormone disruption at the level of thyroid hormone receptor (TR) functioning. To this end the (ant)agonistic action of a series of xenobiotics was tested in the newly developed T-screen. This assay makes use of a GH3 rat pituitary cell line, that specifically proliferates when exposed to 3,3',5-triiodo-L-thyronine (T3). The growth stimulatory effect is mediated via T3-receptors. (Ant)agonistic and potentiating action of compounds was studied in absence and presence of T3 at its EC50 level (0.25 nM). The compounds tested included the specific TR-antagonist amiodarone, as well as a series of brominated diphenyl ethers (BDEs), including specifically synthesized BDEs with a structural resemblance to 3,5-diiodo-L-thyronine (T2), T3 and T4 (3,3',5,5'-tetraiodo-L-thyronine). The results obtained reveal that only BDE206 and amiodarone are specific antagonists. Interestingly some compounds which did not respond in the T-screen in absence of T3, potentiated effects when tested in combination with T3. This points at possibilities for disruption at the TR in vivo, where exposure generally occurs in presence of T3. Altogether the results of the present study show that the newly developed T-screen can be used as a valuable tool for identification and quantification of compounds active in disturbing thyroid hormone homeostasis at the level of TR-functioning.

Abstract  The T-Screen represents an in vitro bioassay based on thyroid hormone dependent cell proliferation of a rat pituitary tumor cell line (GH3) in serum-free medium. It can be used to study interference of compds. with thyroid hormone at the cellular level, thus bridging the gap between limitations of assays using either isolated mols. (enzymes, transport proteins) or complex in vivo expts. with all the complex feedback mechanisms present. Compds. are tested both in the absence and presence of thyroid hormone (EC50 concn. of T3) to test for both agonistic and antagonistic potency. Thyroid hormones (3,3'-5-triiodothyronine: T3 and 3,3',5,5'-tetraiodothyroxine: T4) and compds. resembling the structure of thyroid hormones (3,3'-5-triiodothyroacetic acid: Triac; 3,3',5,5'-tetraiodothyroacetic acid: Tetrac) induced cell growth, with the rank order Triac > T3 > Tetrac > T4 (relative potency = 1.35>1 > 0.29>0.07), which is identical to published affinities of these compds. for nuclear thyroid hormone receptors. Exposure to 5,5'-diphenylhydantoin (DPH) in the presence of 0.25 nM T3 resulted in up to 60% decreased cell growth at 200 ?M DPH. No effect of DPH on basal metabolic activity of GH3 cells was obsd. at this concn. Fentinchloride (IC50 = 21 nM) decreased cell growth induced by 0.25 nM T3, whereas parallel exposure to these concns. in the absence of T3 did not alter basal metabolic activities of GH3 cells. Apolar sediment exts. from the Dommel (34%) and Terneuzen (14%) decreased cell growth in the presence of 0.25 nM T3, whereas the ext. from Hoogeveen increased cell growth (26%) and the ext. from North Sea Channel had no effect. The T-Screen proved to be a fast and functional assay for assessing thyroid hormone receptor active potencies of pure chems. or environmental mixts.

Abstract  The aim of this study was to present an overview of the use of flame-retardant substances in the UK and, in particular, to identify substances that might require detailed consideration in terms of their possible impact on the environment.

Abstract  100% Reactive liquid bromine based flame retardant that can be used by itself or in combination with phosphorus and nitrogen based flame retardants

Abstract  A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabromocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at the lower 95% one-sided confidence bound (BMDL) at predefined critical effect sizes (CESs) of 10-20%. The most remarkable findings were dose-related effects on the thyroid hormone axis, that is, decreased total thyroxin (TT4, BMDL 55.5 mkd at CES--10%), increased pituitary weight (29 mkd at 10%) and increased immunostaining of TSH in the pituitary, increased thyroid weight (1.6 mkd at 10%), and thyroid follicle cell activation. These effects were restricted to females. Female rats also showed increased absolute liver weights (22.9 mkd at 20%) and induction of T4-glucuronyl transferase (4.1 mkd at 10%), suggesting that aberrant metabolization of T4 triggers feedback activation of the thyroid hormone system. These effects were accompanied by possibly secondary effects, including increased cholesterol (7.4 mkd at 10%), increased tibial bone mineral density (> 49 mkd at 10%), both in females, and decreased splenocyte counts (0.3-6.3 mkd at 20%; only evaluated in males). Overall, female rats appeared to be more sensitive to HBCD than male rats, and an overall BMDL is proposed at 1.6 mkd, based on a 10% increase of the thyroid weight, which was the most sensitive parameter in the sequence of events.

Abstract  To evaluate the developmental immunotoxicity of brominated flame retardant, hexabromocyclododecane (HBCD) , maternal Sprague-Dawley rats were given HBCD at dietary concentrations of 0, 100, 1000, 10000 ppm from gestational day 10 to postnatal day 21 (postnatal week 3, PNW3). At PNW3 and PNW11, lymphocytes in the spleen, thymus, and peripheral blood of male pups were subjected to flow cytometric analyses for expression of surface markers (CD3, CD4, CD8a, CD25, CD45RA, CD71, and CD161 (NKRP1A)). The spleen and thymus weights, and number of white blood cells of two organs did not change between HBCD-exposed and control groups at PNW3 and PNW11. A significant decrease in thyroid hormone T3 and increase in serum albumin concentration were observed at PNW3 and lasted until PNW11. By flow cytometric analysis, the dramatic change was not observed in the population of the splenic and thymic T/B lymphocyte between the HBCD treated groups and control group. In the peripheral blood of BNW3 rats, the population of activated T cells was decreased and that of inactivated B cells was increased. And the population of NK cells in the spleen was decreased. All of these changes were mild in degree, and returned to the normal levels by PNW11. Production of anti-KLH IgG antibody after KLH immunization was reduced by the 10000 ppm HBCD treatment. These results suggest that developmental exposure to the highest dose of HBCD had a weak immunomodulatory effect at PNW3, and most of the immunomodulatory effect had recovered to normal levels by PNW11.

Abstract  Pursuant to section 74 and 68(b) of the Canadian Environmental Protection Act, 1999 (CEPA 1999), the Ministers of the Environment and of Health have conducted a screening assessment of hexabromocyclododecane (HBCD). HBCD having Chemical Abstracts Service Registry Number 3194­55-6 was one of the substances on the Domestic Substances List (DSL) selected for a pilot project for screening assessments. During the categorization of the DSL, the substance was identified as a high priority for screening assessment as it met the criteria for persistence, bioaccumulation and inherent toxicity to aquatic life. It is recognized that the Chemical Abstracts Service (CAS) registry contains more than one number for HBCD (e.g., CAS RN 25637-99-4 refers to HBCD where the bromine substituents are not numbered). In this assessment, all available relevant data and studies that are of reliable quality were considered equally, and thus the assessment findings and scope apply to HBCD in general and are irrespective of the Chemical Abstracts Service Registry Number (CAS RN). The primary application of HBCD is as a flame retardant in polystyrene foams that are used as thermal insulation materials in the construction industry. A second application is the flame retarding of textiles for usage in residential and commercial upholstered furniture, transportation seating, wall coverings and draperies. Minor uses include addition to latex binders, adhesives, and paints and to high-impact polystyrene and styrene-acrylontrile resins for electrical and electronic equipment. For the years and continents having available data since 2000, increases in the demand for HBCD have been reported. Global demand for HBCD was estimated at 16 700 tonnes in 2001, representing 8.2% of total demand for brominated flame retardants that year. Results from a section 71 Notice with Respect to Certain Substances on the Domestic Substances List (DSL) conducted for the year 2000 indicated that HBCD was not manufactured in Canada at that time. Amounts imported into the country in that year were in the range of 100 000 to 1 000 000 kg.