2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) (CASRN 5436-43-1)
view QuickView

You will need Adobe Reader to view some of the files on this page. See EPA's PDF page to learn more.
Note: A TOXICOLOGICAL REVIEW is available for this chemical in Adobe PDF Format (xx pp, xx Kb). Similar documents can be found in the List of Available IRIS Toxicological Reviews.
Links to specific pages in the toxicological review are available throughout this summary. To utilize this feature, your Web browser and Adobe program must be configured properly so the PDF displays within the browser window. If your browser and Adobe program need configuration, please go to EPA's PDF page for instructions.
1010
2,2',4,4'-Tetrabromodiphenyl ether (BDE-47); CASRN 5436-43-1; 00/00/0000
This U.S. EPA IRIS summary is based on the U.S. Government-sponsored technical review of the "Health Implications of Perchlorate Ingestion" by the National Research Council of the National Academies (NRC, 2005). The NRC perchlorate committee took into consideration presentations at the committee's public meetings, submitted public comments, and the comments made by technical experts on the draft NRC perchlorate report. The conclusions, recommendations and final content of the NRC (2005) report rest entirely with the committee. The NRC review follows two external draft toxicological reviews of perchlorate prepared by EPA (1998, 2002) that were also subject to public comment and independent external peer review. The IRIS summary has undergone review by EPA health scientists from several program offices, regional offices, and the Office of Research and Development. Sections I (Chronic Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the positions that were reached during the review process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website at http://www.epa.gov/ncea/iris/backgr-d.htm.
STATUS OF DATA FOR 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47)
File First On-Line 00/00/0000
Category (section) |
Status |
Last Revised |
---|---|---|
Chronic Oral RfD Assessment (I.A.) | On-line | 00/00/0000 |
Chronic Inhalation RfC Assessment (I.B.) | Discussion | 00/00/0000 |
Carcinogenicity Assessment (II.) | Discussion | 00/00/0000 |
_I. Health Hazard Assessments for Noncarcinogenic Effects
The congener 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) has not been previously assessed in IRIS. A health assessment of the tetrabromodiphenyl ether homolog group (CASRN 40088-47-9) was previously entered on IRIS 08/01/1990. Information was not available to derive an RfD or RfC or to assess the carcinogenic potential of the tetrabromodiphenyl ether homolog group.
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47)
CASRN — 5436-43-1
Section I.A. Last Revised — 00/00/0000
The RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The RfD is intended for use in risk assessments for health effects known or assumed to be produced through a nonlinear (possibly threshold) mode of action. It is expressed in units of mg/kg-day. Please refer to the guidance documents at http://www.epa.gov/ncea/iris/backgr d.htm for an elaboration of these concepts. Because RfDs can be derived for the noncarcinogenic health effects of substances that are also carcinogens, it is essential to refer to other sources of information concerning the carcinogenicity of this chemical substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation will be contained in Section II of this file.
__I.A.1. Chronic Oral RfD Summary
Critical Effect |
Point of Departure* |
UF |
Chronic RfD |
---|---|---|---|
Neurobehavioral effects | BMDL1SD: 0.35 mg/kg | 3000 | 0.0001 mg/kg-day |
Single dose gavage study in mice | BMDL1SD: 0.47 mg/kg | ||
Eriksson et al., 2001 |
* Conversion Factors and Assumptions - BMDL1SD = 95% lower confidence limit on the maximum likelihood estimate of the dose corresponding to a change in the mean equal to one SD of the control mean. BMD1SD = maximum likelihood estimate of the dose corresponding to a change in the mean equal to one SD of the control mean.
__I.A.2. Principal and Supporting Studies
The only study suitable for dose-response assessment is the neurobehavioral study of Eriksson et al. (2001). In this study, male NMRI mice were administered on postnatal day (PND) 10 single oral doses of 0, 0.7, or 10.5 mg/kg of BDE-47 (>98% purity) in a fat emulsion. Spontaneous motor behavior was tested at ages 2 and 4 months in groups of eight male mice, randomly selected from three to four different litters, and the mice were tested once only. Spontaneous motor behavior was tested for a 60-minute period, divided into three 20-minute periods. Locomotion (horizontal movement), rearing (vertical movement), and total activity (all types of vibration within the test cage [i.e., those caused by mouse movement, shaking/tremors, and grooming]) were measured. In order to study time-dependent changes in habituation (2 month-old vs. 4-month-old mice), data from the spontaneous motor behavior tests were used. A habituation ratio was calculated between the performance periods 40—60 minutes and 0—20 minutes for each of the three different variables: locomotion, rearing, and total activity. The habituation ratio was used to analyze alteration in habituation of 2-month-old and 4-month-old treated mice, within each treatment group, in comparison with their respective controls. Swim-maze performance, a measure of learning and memory ability, was tested in groups of 16—18 mice randomly selected from three to four different litters at age 5 months, given the high dose of BDE-47 (10.5 mg/kg). There were no clinical signs of dysfunction in the treated mice throughout the experimental period nor were there any significant deviations in body-weight gain in the BDE-47 treated mice compared with the vehicle-treated mice.
Control mice showed habituation (i.e., a decrease in locomotion, rearing, and total activity) in response to the diminishing novelty of the test chamber over the three 20-minute test periods. Data for the three spontaneous behavior variables (horizontal movement, vertical movement, and total activity) are only available in graphic form and could not be used for quantitative assessment (attempts to obtain numerical values and other information on the data from the authors were not successful). Numerical values, suitable for dose-response assessment, are only available for the habituation ratio. For all three spontaneous motor behavior variables (locomotion, rearing, and total activity), 2-month-old mice receiving 10.5 mg/kg BDE-47 displayed significantly less activity than controls during the first 20-minute period (hypoactivity) but were significantly more active than controls during the third 20-minute period (hyperactivity). The aberrations in spontaneous motor behavior were more pronounced in 4-month-old mice than in 2-month-old mice, indicating worsening with increasing age. In mice given 10.5 mg/kg BDE-47, the habituation capability was significantly reduced in 4-month-old mice compared with 2-month-old mice for all three variables (locomotion, rearing, and total activity). Performance of 5-month-old mice in the swim-maze learning/memory test, presented in graphic form only, was not affected at any dose. The no-observed-adverse-effect level (NOAEL) in this study was 0.7 mg/kg and the lowest-observed-adverse-effect level (LOAEL) was 10.5 mg/kg for changes in spontaneous motor behavior and decreased habituation capability in adult male mice, worsening with increasing age.
The RfD for BDE-47 was derived by applying the benchmark dose (BMD) approach to the data on habituation response to BDE-47 exposure collected by Eriksson et al. (2001). In the case of motor activity, there is no specific change that is generally regarded as indicative of an adverse response. In the absence of some idea of the level of response to consider adverse, the benchmark response (BMR) selected was a change in the mean equal to one SD from the control mean. Habituation ratios (based on the spontaneous behaviors of locomotion, rearing, and total activity) were modeled as continuous variables by fitting the linear, polynomial, and power models. Habituation ratios for total activity in 2- and 4-month-old male mice were the most suitable endpoints for developing a point of departure (POD).
Of the BMDs and the BMD lower confidence limits (BMDLs) estimated from the continuous models that provided an adequate fit, the lowest BMD and BMDL were obtained by fitting a linear model to habituation ratios based on decreased total activity habituation in 4-month-old mice. The estimated BMD1SD is 0.47 mg/kg, and the BMDL1SD is 0.35 mg/kg.
__I.A.3. Uncertainty Factors
UF = 3000
A total uncertainty factor (UF) of 3000 was applied: 10 for extrapolating animal data to humans (UFA interspecies variability), 10 for susceptible human subpopulation (UFH interhuman variability), 3 for extrapolating from a single-dose duration to a chronic exposure duration (UFS), and 10 to account for a deficient database (UFD).
A default interspecies UFA of 10 was applied because the data were insufficient to characterize toxicokinetic and toxicodynamic differences between rodents and humans.
A default intraspecies UFH of 10 was applied to account for variations in susceptibility within the human population (or interhuman variability). This factor accounts for humans who may be more sensitive than the general population to exposure to BDE-47.
A UFS of 3 was used for extrapolating effects seen in a single-exposure neurodevelopmental study to a lifetime exposure. Exposure on PND 10 occurred during a period of rapid brain development in mice. Brain development does not continue at an equivalent rate across the lifespan and is more quiescent during adult life stages. There are a wide variety of brain structures that have very limited critical windows during development, particularly in early life. These critical windows translate to susceptible periods of exposure that are very short in duration. Toxicokinetic data suggest that a mouse urinary protein becomes functional at some time between PNDs 28 and 40, leading to a dramatic increase in BDE-47 urinary excretion, especially in males. This reduces the total body burden, including the levels of radiolabel reaching the brain 24 hours after dosing in older mice compared to young mice. These data suggest that neurodevelopmental risk in neonatal mice may be greater than at later ages because of the postnatal brain-growth spurt and coincident increased retention of BDE-47 and/or its metabolites. Thus, it is not necessary to make a 10-fold adjustment for exposure duration.
A UFD of 10 was used to account for database uncertainty. The available oral database for BDE-47 lacks prenatal developmental neurotoxicity studies, reproductive toxicity studies, and standard chronic or subchronic studies of systemic toxicity.
Application of a total uncertainty factor of 3000 to the BMDL1SD of 0.35 mg/kg results in a reference dose for BDE-47 of 0.0001 mg/kg-day.
__I.A.4. Additional Studies/Comments
Gee and Moser (2007) administered a single dose (in corn oil) of 1, 10, or 30 mg/kg BDE-47 (purity >99%) to groups of 18-21 male pups (of C57BL/6 dams) per dose, on PND 10. Neurobehavioral testing included developmental/observational testing on PND 12, 14, 16, 18, 32, and 88 and motor activity testing on PNDs 57 and 120. An increase in body weight was observed in all treated animals from PND 47 throughout the remainder of the study. The male pups treated with 30 and 10 mg/kg (on most weighing days) showed significant body weight changes, while those administered 1 mg/kg only exhibited a significant change on two weighing days. Significant delays in motor coordination were observed in treated mice. On PND 14, 16% of the mice in the each of the 1 and 10 mg/kg dose groups were observed wobbling during walking. Grip time was reduced in all of the treated animals. The group means for rearing were greater in treated animals at 1, 2, and 4 months. Although rearing was observed at a greater incidence in treated animals (with a trend toward significant dose-by-interval interaction), only the 1 mg/kg mice were statistically significantly different from controls.
At 2 months (PND 57), mice in the 30 mg/kg dose group exhibited horizontal motor activity levels that were significantly greater than the 1 and 10 mg/kg mice, although none of the treated animals were significantly different from the controls. All treated mice tended to have higher levels of vertical motor activity than controls, but there were no statistically significant differences. However, at 4 months (PND 120), the vertical motor activity was increased (hyperactivity) in all of the treated dose groups compared with controls, with an overall significant dose effect. The hyperactivity was statistically significant in the 1 and 10 mg/kg dose groups, compared with controls. An increase in horizontal motor activity was noted in the 1 and 30 mg/kg mice at the 60-minute timepoint of the testing session and throughout the testing 20-, 40-, and 60-minute sessions in the 10 mg/kg mice (statistically significant). The authors concluded that shifts in patterns of normal ontogeny in neuromotor development and hyperactivity, noted at 2 and 4 months of age (worsening with age), indicate that exposure to BDE-47 during early development results in subtle changes in neuromotor activity that may affect behavior in mice as adults.
Three short-term studies are available to determine the effect of BDE-47 on thyroid hormone levels. In the study of Hallgren et al. (2001), the ability of BDE-47 to alter thyroid hormone and vitamin A levels as well as microsomal enzyme activities in mice was compared with that of the commercial pentaBDE Bromkal and polychlorinated biphenyls (PCBs). Groups of 8—10 female C57BL/6 mice were administered BDE-47 dissolved in corn oil, once a day by gavage at 0 or 18 mg/kg-day for 14 days. Body-weight gains were not affected and no overt signs of toxic effects were seen in the study. The liver to body weight ratio was significantly increased over control values, but no statistically significant differences were found for thymus or spleen somatic indices. BDE-47 significantly decreased plasma free and total thyroxine (T4) levels. The effects were more pronounced for free T4, believed to be the most direct indicator of thyroid status. In contrast to T4 levels, plasma thyroid stimulating hormone (TSH) was not significantly changed, which could be due to the short-term nature of the study. The decrease in concentration of T4 was highest for PCBs, followed by BDE-47 and the commercial pentaBDE Bromkal. Hepatic vitamin A levels were not significantly changed, which could be due to the short-term nature of the study. Vitamin A was included in the assessment because it is transported by the same protein complex as T4.
Induction of microsomal phase I enzymes was measured as ethoxy-, methoxy-, and pentoxyresorufin O-dealkylase (EROD, MROD, PROD) activities in the study by Hallgren et al. (2001). EROD and MROD activities were highest after exposure to PCBs, followed by Bromkal, but were also significantly increased in the BDE-47-treated group; PROD activity was significantly induced by PCBs but not by BDE-47 or Bromkal treatment. The phase II enzyme uridine diphosphoglucuronyl transferase (UDPGT) activity that glucuronidates T4 for excretion in bile was not significantly induced by any of the compounds tested.
The effects of BDE-47 on thyroid hormone levels were examined in rats (Hallgren and Darnerud, 2002). Female Sprague-Dawley rats were administered gavage doses of 0, 1, 6, or 18 mg/kg-day BDE-47 (>98% purity) in corn oil for 14 days. Plasma total and free T4 and TSH were measured at the end of the study. In order to test possible mechanisms for the alterations of thyroid hormones, the induction of UDPGT activity, morphological effects on the thyroid epithelia, and ex vivo binding of 125I-thyroxine to the plasma thyroid hormone transporter transthyretin (TTR) were studied. In addition, microsomal phase I enzyme activities were also assayed (EROD, MROD, and PROD). No signs of clinical toxicity were seen in the study, and liver or thyroid somatic indices and body-weight gains were unaffected. No effects were seen on thyroid morphology at any dose. Plasma levels of free T4 showed a decreasing trend that was significant only at 18 mg/kg-day (61% of control). Plasma levels of total T4 showed the same pattern of reduction as the free hormone, but the effects were less pronounced and not significant at any dose.
In contrast to T4 levels, plasma levels of TSH were not changed at any dose. The ex vivo binding of 125I-T4 to TTR was significantly reduced at 18 mg/kg-day. EROD activity was significantly induced at 6 and 18 mg/kg-day but not in a dose-dependent manner. MROD and PROD activities showed dose-dependent increases, statistically significant at 6 and 18 mg/kg-day. Treatment with BDE-47 resulted in a moderate dose-dependent induction of UDPGT activity, significant only at 18 mg/kg-day, but the increase in UDPGT activity did not correlate well with the decrease in T4 level.
As a possible mechanism behind the thyroid hormone effects, the authors noted that the observed degree of thyroid hormone reduction after BDE-47 exposure coincided with a decrease in the ex vivo binding of 125I-T4 to the plasma thyroid hormone transport protein TTR and with induction of the microsomal phase I enzymes EROD, MROD, and PROD. These observed effects match the hypothesis that the T4 decrease is chiefly due to disturbances in serum transport, caused by binding of in vivo formed BDE-47 metabolites to TTR. It is hypothesized that the lack of response of serum TSH levels to the reduction in T4 levels is due to BDE-47 and/or its metabolites mimicking thyroid hormones and possibly binding to thyroid hormone receptors in the pituitary, thereby blocking TSH release (Hallgren and Darnerud, 2002). Free T4 was found to be the most sensitive indicator of imbalance in thyroid hormone status in this study.
Richardson et al. (2007) administered a single oral gavage (in corn oil) dose of 3, 10, or 100 mg/kg-day BDE-47 (purity >98%) to female C57BL/6 mice for 4 days. Serum T4 was decreased (approx. 43%) in the 100 mg/kg-day dose group compared with the controls. There were no effects on liver weight and serum T4 at the two lower doses of BDE-47. In examining UGT induction, the authors showed increases in UGT1A1, UGT2B5, and UGT1A7 expression, respectively, at 100 mg/kg-day. UGT1A7 expression was increased at 10 mg/kg-day. The changes in UGT isoform expression correlated with the observed T4 decreases. However, in contrast to the observed changes in UGT mRNA expression, BDE-47 treatment did not change hepatic T4-UGT enzyme activity. The authors suggested that the T4-UGT enzyme assay was not adequately sensitive to measure changes in activity of individual UGT isoforms.
Significant correlations were observed between decreases in T4 and increased PROD activity (R2=0.57, p<0.0001) and T4 and increased CYP-2B10 expression (R2=0.44, p<0.005). A significant increase (47%) in the expression of a major glucuronide transporter, hepatic MRP3 mRNA at 100 mg/kg-day BDE-47 was significantly correlated with T4 decreases (R2=0.46, p<0.001). Significant, dose-dependent decreases in hepatic MDR 1A (but not MDR 1B), a transporter for glucuronides and thyroid hormones, were observed at all doses of BDE-47; however, these decreases did not correlate with the decreases in T4 (R2=0.17, p=0.08). A thyroid hormone uptake transporter, MCT8, was significantly decreased (0.8-fold) at 100 mg/kg-day. The authors suggested that MCT8 may play a role in thyroid hormone changes, although the decrease in MCT8 mRNA expression did not correlate with T4 decreases (R2=0.02, p=0.56). A major rodent transport protein in the serum, transthyretin, was significantly decreased at 100 mg/kg-day and correlated with the decrease in T4 (R2=0.61, p<0.0001). Richardson et al. (2007) noted that the parallel decreases in transthyretin and T4 support the hypothesis that BDE-47 interferes with transthyretin transport of T4.
In a postnatal exposure study, Gee et al. (2007) administered a single oral gavage dose (in corn oil) of 1, 10, or 30 mg/kg of BDE-47 (purity >99%) to male C57BL/6 mice pups (23-32 pups per dose group) on PND 10. Pups were sacrificed 1, 5, or 10 days after treatment (i.e., on PNDs 11, 15, or 20). Bound and free total thyroxine (T4) and triiodothyronine (T3) were measured to examine the effects of BDE-47 on the levels of circulating hormones. There was a significant increase in total T4 levels on PND15, although the study authors indicated that this was not treatment-related. No other changes were noted in the circulating levels of either T3 or T4 in the male pups. These results are in contrast to those reported for BDE-47 (Hallgren and Darnerud, 2002; and Hallgren et al., 2001), in which thyroid hormone levels in rodents were affected by treatments. The authors proposed several reasons for these different results: 1) a function of differing study designs, 2) stored T3 and T4 from the thyroid gland masking altered circulating hormone levels, 3) only total T3 and T4 were measured, not tissue concentrations or free levels, and/or 4) many of the previous studies were performed in rats (as opposed to mice) and species differences (i.e., excretion rate) may exist.
Despite the possibility of thyroid hormone involvement in the neurodevelopmental impact of BDE-47 on the habituation response in male mice exposed to a single dose on PND 10, there are no mode-of-action data that link thyroid hormones to the observations of Eriksson et al. (2001). Thyroid hormone levels and behavioral activity were not comeasured in the study in mice of Eriksson et al. (2001).
For more detail on Susceptible Populations, exit to the toxicological review, Section 4.X (PDF).
__I.A.5. Confidence in the Chronic Oral RfD
Study -- Low
Data Base -- Low
RfD -- Low
Confidence in the principal study is low because the study was conducted in male mice only, the protocol was unique and did not conform to health effects test guidelines for neurotoxicity, the dosing regimen did not include gestation and lactation exposure, several pups per litter were used for the behavioral testing, and only single doses were given. Confidence in the database is low because it lacks prenatal developmental neurotoxicity studies, reproductive toxicity studies, and standard chronic or subchronic studies of systemic toxicity. As a result, the overall confidence in the RfD assessment is low.
For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF).
__I.A.6. EPA Documentation and Review of the Chronic Oral RfD
Source Document — U.S. EPA (2007).
This assessment was peer reviewed by a group of external scientists. Comments from the peer reviewers were evaluated carefully and considered by the Agency during the finalization of this assessment. A record of these comments is included in Appendix A of the Toxicological Review of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) (U.S. EPA, 2007). To review this appendix, exit to the toxicological review, Appendix XXX, Summary of and Response to External Peer Review Comments (PDF)
Agency Completion Date -- __/__/__
__I.A.7. EPA Contacts
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email address).
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47)
CASRN — 5436-43-1
Last Revised — 00/00/0000
The RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The RfC considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral to the respiratory system (extrarespiratory effects). The inhalation RfC (generally expressed in units of mg/m3) is analogous to the oral RfD and is similarly intended for use in risk assessments for health effects known or assumed to be produced through a nonlinear (possibly threshold) mode of action.
Inhalation RfCs are derived according to Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994). Because RfCs can also be derived for the noncarcinogenic health effects of substances that are carcinogens, it is essential to refer to other sources of information concerning the carcinogenicity of this chemical substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation will be contained in Section II of this file.
__I.B.1. Chronic Inhalation RfC Summary
No data are available for deriving a reference concentration for BDE-47.
__I.B.2. Principal and Supporting Studies
Not applicable.
__I.B.3. Uncertainty Factors
Not applicable.
__I.B.4. Additional Studies/Comments
Not applicable.
__I.B.5. Confidence in the Chronic Inhalation RfC
Not applicable.
__I.B.6. EPA Documentation and Review of the Chronic Inhalation RfC
Source Document -- U.S. EPA (2007)
This assessment was peer reviewed by a group of external scientists. Comments from the peer reviewers were evaluated carefully and considered by the Agency during the finalization of this assessment. A record of these comments is included in Appendix A of the Toxicological Review of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) (U.S. EPA, 2007).
Agency Completion Date -- __/__/__
__I.B.7. EPA Contacts
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email address).
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name — 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47)
CASRN — 5436-43-1
Section II. Last Revised — 00/00/0000
This section provides information on three aspects of the carcinogenic assessment for the substance in question: the weight-of-evidence judgment of the likelihood that the substance is a human carcinogen, and quantitative estimates of risk from oral and inhalation exposure. Users are referred to Section I of this file for information on long-term toxic effects other than carcinogenicity.
The rationale and methods used to develop the carcinogenicity information in IRIS are described in the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) and the Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (U.S. EPA, 2005b). The quantitative risk estimates are derived from the application of a low-dose extrapolation procedure, and are presented in two ways to better facilitate their use. First, route-specific risk values are presented. The "oral slope factor" is an upper bound on the estimate of risk per mg/kg-day of oral exposure. Similarly, a "unit risk" is an upper bound on the estimate of risk per unit of concentration, either per µg/L drinking water (see Section II.B.1.) or per µg/m3 air breathed (see Section II.C.1.). Second, the estimated concentration of the chemical substance in drinking water or air when associated with cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000 is also provided.
_II.A. Evidence for Human Carcinogenicity
Epidemiological studies of exposure to BDE-47 and cancer occurrence in humans are not available. Animal chronic toxicity/carcinogenicity studies have not been conducted with BDE 47.
__II.A.1. Weight-of-Evidence Characterization
Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a,b), there is inadequate information to assess the carcinogenic potential of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47).
For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF).
For more detail on Susceptible Populations, exit to the toxicological review, Section 4.X (PDF).
__II.A.2. Human Carcinogenicity Data
Not applicable.
__II.A.3. Animal Carcinogenicity Data
Not applicable.
__II.A.4. Supporting Data for Carcinogenicity
BDE-47 demonstrated low or no recombinogenic potential in two in vitro Chinese hamster cell assays. Helleday et al. (1999) examined the effects of BDE-47 at concentrations of 0 to 40 µg/mL in two in vitro V79 Chinese hamster cell-line assays, Sp5 and SDP8, for intragenic recombination at an endogenous locus in mammalian cells. Results from this study indicate that BDE-47 is weakly recombinogenic in the SPD8 cell line assay with up to a 1.8-fold increase at 40 µg/mL but not recombinogenic in the Sp5 cell line. This difference in assay results may be due to different levels of sensitivity and mechanisms among the Sp5 and SPD8 cell lines. Based on these results, BDE-47 appears to be weakly mutagenic at best in mammalian cells.
_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
Not applicable.
__II.B.1. Summary of Risk Estimates
Not applicable.
__II.B.2. Dose-Response Data
Not applicable.
__II.B.3. Additional Comments
Not applicable.
__II.B.4. Discussion of Confidence
Not applicable.
_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
__II.C.1. Summary of Risk Estimates
Not applicable.
__II.C.2. Dose-Response Data
Not applicable.
__II.C.3. Additional Comments
Not applicable.
__II.C.4. Discussion of Confidence
Not applicable.
_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)
__II.D.1. EPA Documentation
Source Document -- U.S. EPA (2007)
This assessment was peer reviewed by a group of external scientists. Comments from the peer reviewers were evaluated carefully and considered by the Agency during the finalization of this assessment. A record of these comments is included in Appendix A of the Toxicological Review of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) (U.S. EPA, 2007). To review this appendix, exit to the toxicological review, Appendix X, Summary of and Response to External Peer Review Comments (PDF).
__II.D.2. EPA Review
Agency Completion Date -- __/__/__
__II.D.3. EPA Contacts
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email address).
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_VI. Bibliography
Substance Name — 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47)
CASRN — 5436-43-1
Section VI. Last Revised — 00/00/0000
_VI.A. Oral RfD References
Eriksson, P; Jakobsson, E; Fredriksson, A. (2001) Brominated flame retardants: a novel class of developmental neurotoxicants in our environment? Environ Health Perspect 109(9):903—908.
Gee, JR; Hedge, JM; Moser, VC. (2007) Lack of alterations in thyroid hormones following exposures to polybrominated diphenyl ether 47 during a period of rapid brain development in mice. Drug and Chem Toxicol (in press).
Gee, JR; Moser, VC. (2007) Acute postnatal exposure to brominated diphenylether 47 delays neuromotor ontogeny and alters motor activity in mice. Neurotoxicol and Teratol (in press).
Hallgren, S; Darnerud, PO. (2002) Polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and chlorinated paraffins (CPs) in rats—testing interactions and mechanisms for thyroid hormone effects. Toxicology 177(2—3):227—243.
Hallgren, S; Sinjari, T; Hakansson, H; et al. (2001) Effects of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) on thyroid hormone and vitamin A levels in rats and mice. Arch Toxicol 75(4):200—208.
Richardson, VM; Staskal, DF; Diliberto, JJ; et al. (2007) Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener. Toxicol Appl Pharm (in press).
U.S. EPA (Environmental Protection Agency). (2007) Toxicological Review of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) in Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. Available online at http://www.epa.gov/ncea/iris.
_VI.B. Inhalation RfC References
U.S. EPA. (2007) Toxicological Review of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) in Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. Available online at http://www.epa.gov/ncea/iris.
U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH; EPA/600/8-90/066F. Available from the National Technical Information Service, Springfield, VA, PB2000-500023, and online at http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=71993.
_VI.C. Carcinogenicity Assessment References
Helleday, T; Tuominen, KL; Bergman, A; et al. (1999) Brominated flame retardants induce intragenic recombination in mammalian cells. Mutat Res 439:137—147.
U.S. EPA. (2007) Toxicological Review of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) in Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. Available online at http://www.epa.gov/ncea/iris.
U.S. EPA. (2005a) Guidelines for carcinogen risk assessment. Federal Register 70(66):17765—18717. Available online at http://www.epa.gov/cancerguidelines.
U.S. EPA. (2005b) Supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. Risk Assessment Forum, Washington, DC; EPA/630/R-03/003F. Available online at http://www.epa.gov/cancerguidelines.
_VII. Revision History
Substance Name — 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47)
CASRN — 5436-43-1
File First On-Line __/__/__
Date |
Section |
Description |
---|---|---|
00/00/0000 | I., II. | RfD, RfC, and cancer assessment first on line__ |
_VIII. Synonyms
Substance Name — 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47)
CASRN — 5436-43-1
Section VIII. Last Revised — 00/00/0000
- Benzene, 1,1'-oxybis(2,4-dibromo-
- 2,2',4,4'-Tetrabromodiphenyl ether
- PBDE 47
- BDE-47