2,2',6,6'-Tetrachlor-4,4'-isopropylidendiphenol

LC50; Species: Pimephales promelas (Fathead Minnow) age 31 days, length 19.3 mm, weight 0.078 g; Conditions: freshwater, flow through, 25.1 °C, pH 7.9, hardness 44.8 mg/L CaCO3, alkalinity 44.8 mg/L CaCO3, dissolved oxygen 7.1 mg/L; Concentration: 1330 ug/L for 96 hr (95% confidence interval: 1220-1450 ug/L) /98% purity/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6X10+5(SRC), determined from a structure estimation method(2), indicates that 2,2',6,6'-tetrachlorobisphenol A is expected to be immobile in soil(SRC). The estimated pKa of 2,2',6,6'-tetrachlorobisphenol A is 6.91(3), indicating that this compound will exist partially in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of 2,2',6,6'-tetrachlorobisphenol A from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.8X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(2). 2,2',6,6'-Tetrachlorobisphenol A is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6X10+5(SRC), determined from a structure estimation method(2), indicates that 2,2',6,6'-tetrachlorobisphenol A is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.8X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 5900(SRC), from an estimated log Kow of 6.22(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). 2,2',6,6'-Tetrachlorobisphenol A is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Phenols can undergo sensitized photo-oxidation in surface waters exposed to sunlight via reaction with hydroxyl and peroxy radicals with half-lives on the order of days to weeks at the water surface(5); therefore, photo-oxidation may have some importance as a fate process for 2,2',6,6'-tetrachlorobisphenol A in natural water(SRC). 2,2',6,6'-Tetrachlorobisphenol A has been shown to undergo anaerobic biodegradation in estuarine sediment with the formation of a persistent dichlorinated bisphenol A isomer(6).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,2',6,6'-tetrachlorobisphenol A, which has an estimated vapor pressure of 3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 2,2',6,6'-tetrachlorobisphenol A is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3.5 days(SRC), calculated from its rate constant of 3.5X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase 2,2',6,6'-tetrachlorobisphenol A may be removed from the air by wet and dry deposition(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 2,2',6,6'-tetrachlorobisphenol A can be estimated to be 6X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2,2',6,6'-tetrachlorobisphenol A is expected to be immobile mobility in soil. The estimated pKa of 2,2',6,6'-tetrachlorobisphenol A is 6.91(3), indicating that this compound will exist partially in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/ALTERNATIVE and IN VITRO TESTS/ The capability of the flame retardants tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) to activate peroxysome proliferator-activated receptors (PPARs) alpha, beta, and gamma and estrogen receptors (ERs) alpha and beta has been recently investigated, but the activity of their biotransformation products and of their lower molecular weight analogues formed in the environment remains unexplored. The aim of this study was to investigate the relationship between the degree of halogenation of BPA analogues and their affinity and activity towards human PPARgamma and ERs and to characterize active metabolites of major marketed halogenated bisphenols. The biological activity of all compounds was studied using reporter cell lines expressing these nuclear receptors (NRs). /The researchers/ used NR-based affinity columns to rapidly evaluate the binding affinity of halogenated bisphenols for PPARgamma and ERs and to trap active metabolites of TBBPA and TCBPA formed in HepG2 cells. The agonistic potential of BPA analogs highly depends on their halogenation degree: the bulkier halogenated BPA analogs, the greater their capability to activate PPARgamma. In addition, PPARgamma-based affinity column, HGELN-PPARgamma reporter cell line and crystallographic analysis clearly demonstrate that the sulfation pathway, usually considered as a detoxification process, leads for TBBPA and TCBPA, to the formation of sulfate conjugates which possess a residual PPARgamma-binding activity. /The researchers/ results highlight the effectiveness NR-based affinity columns to trap and characterize biologically active compounds from complex matrices. Polyhalogenated bisphenols, but also some of their metabolites, are potential disrupters of PPARgamma activity.

ANAEROBIC: The anaerobic biotransformation of 2,2',6,6'-tetrachlorobisphenol A was examined in estuarine sediments(1); dehalogenation of 2,2',6,6'-tetrachlorobisphenol A occurred under both methanogenic and sulfate-reducing conditions with an accumulation of a persistent dichlorinated bisphenol A isomer and no formation of bisphenol A(1).

An estimated BCF of 5900 was calculated in fish for 2,2',6,6'-tetrachlorobisphenol A(SRC), using an estimated log Kow of 6.22(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for 2,2',6,6'-tetrachlorobisphenol A is estimated as 2.8X10-12 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 2,2',6,6'-tetrachlorobisphenol A is expected to be essentially nonvolatile from water surfaces(2). 2,2',6,6'-Tetrachlorobisphenol A's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). 2,2',6,6'-Tetrachlorobisphenol A is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3X10-8 mm Hg(SRC), determined from a fragment constant method(1).

/ENDOCRINE MODULATION/ Some phenols have been suspected to modulate the endocrine systems of wildlife and humans, but less is known about their interactions with different types of nuclear receptors. In this study, the ability of 2-tert-butylphenol, 2-isopropylphenol, 4-tert-octylphenol (4-t-OP), 2,4-dichlorophenol (2,4-DCP), 3,4-dichlorophenol (3,4-DCP), pentachlorophenol (PCP), bisphenols A (BPA), tetrabromobisphenol A (TBBPA), tetrachlorobisphenol A (TCBPA) and 4-phenylphenol to activate estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR) and estrogen-related receptor (ERR) were determined using a set of recombined yeast strains. It was found that 4-t-OP, 3,4-DCP, PCP, BPA, TBBPA, TCBPA and 4-phenylphenol were ERalpha agonists, while 4-t-OP, PCP and 4-phenylphenol showed ERalpha antagonistic activities. 2-tert-Butylphenol, 4-t-OP, 2-isopropylphenol, 2,4-DCP, 3,4-DCP, BPA, TCBPA and 4-phenylphenol were antagonists for AR, whereas none of the compounds studied were found to be an AR agonist. TCBPA, TBBPA and PCP were PR antagonists, and 2-tert-butylphenol, 3,4-DCP, 4-t-OP, 4-phenylphenol and 2-isopropylphenol were weak inhibitors on expression under control of the PR. None of the phenols were PR agonists. 2-tert-Butylphenol, 4-t-OP and PCP were ERRgamma inverse agonists, while 2,4-DCP, 3,4-DCP, PCP, BPA, TBBPA and TCBPA exhibited the ability to reverse the ERR inhibition induced by 4-hydroxytamoxifen. Based on the functional agonistic or antagonistic receptor-mediated effects, we further discussed the possible action mechanisms of these phenols as endocrine disrupting chemicals.

/ENDOCRINE MODULATION/ Previously, /the researchers/ transiently transfected Gal4-fused thyroid hormone receptor (TR) expressing vector and the Gal4 response reporter structure pUAS-tk-luc into HepG2 cell, developed a TR beta-1 mediated reporter gene assay to screen for compounds that acted on the TR signaling pathway. In this study, /the researchers/ improved the test efficiency by changing the transfected cell line into CV-1 cell. Triiodothyronine (T3) and thyroxine (T4) induced higher luciferase expression, with the median effective concentration (EC(50)) of 1.16 x 10(-8) and 1.36 x 10(-7)M, respectively. Bisphenol A (BPA) was selected as a positive antagonist, exhibiting weak anti-thyroid hormone activity with the median inhibitory concentration (IC(50)) of 1.64 x 10(-5)M. The assay showed acceptable repeatability to T3 with inter coefficient of variability (CV) of 27.5% and intra CV of 18.6%. Two flame retardants, tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA), were tested for their agonist and antagonist activities. As a result, /the researchers/ found that both of them possessed TR antagonist activity and neither of them showed agonist activity. These results suggested that TBBPA and TCBPA could act as TH antagonists. This assay provided a useful tool for the assessment of environmental chemicals as thyroid system disruptors.

/ENDOCRINE MODULATION/ The thyroid hormonal-disrupting activity of the flame retardants tetrabromobisphenol A and tetrachlorobisphenol A was examined and compared with that of bisphenol A, a typical estrogenic xenobiotic. Tetrabromobisphenol A and tetrachlorobisphenol A, halogenated derivatives of bisphenol A, markedly inhibited the binding of triiodothyronine (T(3); 1 x 10(-10) M) to thyroid hormone receptor in the concentration range of 1 x 10(-6) to 1 x 10(-4) M, but bisphenol A did not. The thyroid hormonal activity of tetrabromobisphenol A and tetrachlorobisphenol A was also examined using rat pituitary cell line GH3 cells, which grow and release growth hormone (GH) depending on thyroid hormone. Tetrabromobisphenol A and tetrachlorobisphenol A enhanced the proliferation of GH3 cells and stimulated their production of GH in the concentration range of 1 x 10(-6) to 1 x 10(-4) M, while bisphenol A was inactive. Tetrabromobisphenol A, tetrachlorobisphenol A, and bisphenol A did not show antagonistic action, i.e., these compounds did not inhibit the hormonal activity of T(3) to induce growth and GH production of GH3 cells. Tetrabromobisphenol A and tetrachlorobisphenol A, as well as bisphenol A, enhanced the proliferation of MtT/E-2 cells, whose growth is estrogen-dependent. These results suggest that tetrabromobisphenol A and tetrachlorobisphenol A act as thyroid hormone agonists, as well as estrogens.

/ENDOCRINE MODULATION/ 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.

For more Non-Human Toxicity Excerpts (Complete) data for 2,2',6,6'-TETRACHLOROBISPHENOL A (10 total), please visit the HSDB record page.

The rate constant for the vapor-phase reaction of 2,2',6,6'-tetrachlorobisphenol A with photochemically-produced hydroxyl radicals has been estimated as 3.5X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3.5 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 2,2',6,6'-Tetrachlorobisphenol A is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Phenols can undergo sensitized photo-oxidation in surface waters exposed to sunlight via reaction with hydroxyl and peroxy (RO2) radicals with half-lives on the order of days to weeks at the water surface(3); therefore, photo-oxidation may have some importance as a fate process for 2,2',6,6'-tetrachlorobisphenol A in natural water(SRC).

Occupational exposure to 2,2',6,6'-tetrachlorobisphenol A may occur through dermal contact with this compound at workplaces where 2,2',6,6'-tetrachlorobisphenol A is produced or used. Use data indicate that the general population may be exposed to 2,2',6,6'-tetrachlorobisphenol A via dermal contact with consumer products containing 2,2',6,6'-tetrachlorobisphenol A. (SRC)