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EC number: 201-236-9 | CAS number: 79-94-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 9th August 2001 - 26th December 2001
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP study; conducted according to standardized guidelines; no analytical verification of test compound concentrations
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 006
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 000
- Reference Type:
- review article or handbook
- Title:
- Unnamed
- Year:
- 1 996
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Details on test material:
- - Name of test material (as cited in study report): Tetrabromobisphenol-A
- Molecular formula (if other than submission substance): N/A
- Molecular weight (if other than submission substance): N/A
- Smiles notation (if other than submission substance): N/A
- InChl (if other than submission substance): N/A
- Structural formula attached as image file (if other than submission substance): see Fig. N/A
- Substance type: Monoconstituent
- Physical state: Solid, white powder
- Analytical purity: 98.71 to 98.87%
- Impurities (identity and concentrations):
Tetrabromobisphenol-A: 98.71% (pre-study)
o,p-Tetrabromobisphenol-A: 0.04%
2,4,6-Tribromobisphenol: N.D.
Tribromobisphenol-A: 1.25%
- Composition of test material, percentage of components: See above
- Isomers composition: See above
- Purity test date: 15 November 2001 and 11 January 2002
- Lot/batch No.: 5381A
- Expiration date of the lot/batch: Not reported
- Radiochemical purity (if radiolabelling): N/A
- Specific activity (if radiolabelling): N/A
- Locations of the label (if radiolabelling): N/A
- Expiration date of radiochemical substance (if radiolabelling): N/A
- Stability under test conditions: Stable in corn oil for at least 14 days when refrigerated
- Storage condition of test material: At room temperature, in a dry, well-ventilated area
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Portage, Mich. USA
- Age at study initiation: 8 weeks
- Weight at study initiation: Males- 128 to 156g; Females- 110 to 151g
- Fasting period before study:
- Housing: Individually in cages
- Diet (e.g. ad libitum): Diet Certified Rodent Diet #5002, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 15 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 to 24C
- Humidity (%): 28 and 70%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours light: 12 hours dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Corn oil, for gavage
- Storage temperature of food: Refrigerated
VEHICLE
- Justification for use and choice of vehicle (if other than water): None
- Concentration in vehicle: Sufficient to give dose levels of 100, 300, and 1000 mg/kg/day
- Amount of vehicle (if gavage): 5 mL/kg/day - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC analysis with the following:
Column: Phenomex Luna C18 (250 mm x 4.6mm)
Mobile Phase: A. 10 mM Phosphate buffer; B. Acetonitrile
Flow rate: 1.25 mL per minute
Injection volume: 20uL
Expected retention time: ~12 minutes - Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Daily gavage treatments
Doses / concentrations
- Remarks:
- Doses / Concentrations:
100, 300, 1000 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 15 males/15 females each in control and 1000 mg/kg/day exposure
10 males/10 females each in 100 and 300 mg/kg/day exposures - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on available data from previous studies
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: Randomized prior to study
- Post-exposure recovery period in satellite groups: 6-week recovery period - Positive control:
- N/A
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day/ seven days a week
- Cage side observations checked: Morbidity, mortality, signs of injury, availability of food and water
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, calculated as g food/animal/day
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: At test initiation and termination
- Dose groups that were examined: All
HAEMATOLOGY: Yes / No / No data
- Time schedule for collection of blood: At test termination and at end of 6-week recovery period
- Anaesthetic used for blood collection: Yes, CO2
- Animals fasted: Yes, overnight
- How many animals: Only main study rats
- Parameters checked: TSH, T3, T4, serum
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Weekly
- Dose groups that were examined: all
- Battery of functions tested: activity, gait and posture, reactivity to handling or sensory stimuli, altered strength, and stereotypes or bizarre behavior
OTHER: Functional Observation Battery (FOB), at test initiation and at week 12 - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes- cavity analysis, organ weights
HISTOPATHOLOGY: Yes-
- Adrenal (2)*#
- Aorta*
- Bone with marrow (femur)*
- Bone with marrow (stemum)*
- Bone marrow smear'*
- Brain (cerebrum, midbrain, cerebellum, medulla/pons) *#
- Eye including optic nerve and retina (2)*
- Gastrointestinal tract:
--esophagus*
--stomach (glandular and nonglandular)*
--duodenum*
--jejunum*
--ileum*
--cecum*
--colon*
--rectum *
- Gonads:
--ovary (2)*#
--testis (2)*# with epididymis (2)*#
- Gross Lesions*
- Harderian gland (2)
- Heart*#
- Kidney (2)*#
- Lacrimal gland, exorbital (2)
- Larynx*
- Liver (3 sections collected, 2 examined)*#
- Lung with mainstem bronchi (2 sections examined)*
- Lymph nodes: mandibular (2 collected, lexamined)*, mesenteric*, and regional lymph node*
- Mammary gland (females only)*
- Nose (4 sections examined)*
- Pancreas*
- Pharynx*
- Pituitary*
- Prostate* and seminal vesicle (2)*
- Salivary gland, mandibular (2 collected, i examined)*
- Sciatic nerve*
- Skeletal muscle, biceps femoris*
- Skin*
- Spinal cord (cervical, thoracic, and lumbar)*
- Spleen*#
- Thymus*#
- Thyroid/parathyroid (2)*#
- Tissue Masses*
- Tongue
- Trachea*
- Urinary bladder*
- Uterus (both) - Statistics:
- See table below
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- All mortality due to dosing injuries
- Mortality:
- no mortality observed
- Description (incidence):
- All mortality due to dosing injuries
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See table below
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL CHEMISTRY: significant reduction in T4 levels (see table below)
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects obsreved even at 1000mg/kg test substance (highest dose tested).
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Mean TSH and T3 levels were statistically comparable between control and treated animals at all time points (Day 33, Day 90, and Recovery Sacrifice). (See table below). Mean T4 blood levels in male and female rats were statistically lower than their respective control means on Day 33 in the 100, 300 and 1000 mg/kg/d groups. Mean T4 levels were statistcally lower in all male groups on Day 90 compared to the control mean. Mean T4 levels were statistically comparable to the control mean on Day 90 in all female groups. At recovery euthanasia, mean T4 levels were comparable in the control and 1000 mg/kg/d male and female groups. The change in T4 levels was reversible on recovery.
Table 1: Male and female T4 levels (ng/dL)
Treatment |
Sex |
Mean T4 concentrations (Day 33) |
Terminal T4 level |
Control |
Male |
4.96±0.84 |
5.09± 0.80 |
100 mg/kg/day |
Male |
3.66± 0.88* |
3.27± 0.67* |
300 mg/kg/day |
Male |
3.42±0.71* |
2.61± 0.87* |
1000 mg/kg/day |
Male |
3.39± 0.55* |
3.09± 0.91* |
Control |
Female |
4.27± 0.96 |
5.41± 1.04 |
100 mg/kg/day |
Female |
3.31± 1.08* |
5.22± 1.23 |
300 mg/kg/day |
Female |
3.24± 0.85* |
4.95± 1.32 |
1000 mg/kg/day |
Female |
3.33±0.84* |
4.95± 1.11 |
* Significantly different from control; (p < 0. 01)
The decrease in serum T4 levels was considered a possible effect of test article administration. TBBPA has been shown to competitively displace T4 from transthyretin (TTR), a major serum T4 -binding protein in the rat, in vitro (Meerts et al. 2000). That portion of serum T4 displaced from its serum binding site would be available for metabolism and elimiantion, thereby leading to a decrease in serum levels. The half-life of T4 in the rat is short due to its transport by TBBP, and thus this species is sensitive to perturbations in T4 levels. For example, the plasma T4 half-life in rats is 12 -24 hours while the human half-life is 5 -9 days (Capen C 1996). In humans, circulating T4 is bound primarily to thyroxin binding globulin, but htis high affinity binding protein is not present in
rodents. This mechanism, displacement of T4 from TTR by TBBPA, may have accounted for the decreased mean T4 levels in treated animals. However, as shown by Schauer et al. (2006), TBBPA has a low systemic bioavailability in rats (and humans) and undergoes extensive first-pass hepatic metabolism to sulfate and glucuronide conjugates. Hepatic induction of glucuronidation could result in a decreased half-life of T4 in the rat. Because the derease in T4 levels was not of sufficient magnitude to alter mean serum TSH or T3 levels, thyroid histopathology, thyroid weight, or other parameters indicative of thyroid pathology (e.g. body weigth, tec.), the decrease in serum T4 levels was not considered adverse. The reduction in serum T4 levels was not accompanied by evidence of toxicity or adverse effects, and the animals were clinically normal.
Applicant's summary and conclusion
- Conclusions:
- The 90 D No Observed Adverse Effect Level (NOAEL) in the rat was 1000 mg/kg/day, the highest dose tested.
- Executive summary:
This study was conducted using a composite of the commercial products produced by Albemarle Corporation, Dead Sea Bromine Group, and Great Lakes Chemical Corporation. It was performed according to Good Laboratory Practices and according to US EPA OPPTS and OECD guidelines.
This study was conducted to evaluate the subchronic toxicity of TBBPA in CD® [Crl: CD® (SD) IGS BR] rats. The study consisted of three treatment groups and one vehicle (corn oil) control group (ten rats/sex/group). Recovery animals (five rats/sex) were
included in the control and high-dose group and evaluated over a 6-week post-treatment period. TBBPA was administered orally by gavage daily for 13 weeks at dose levels of 0, 100,300, and 1000 mg/kg/day at a constant volume of 5 mL/kg/day. The control animals received the vehicle at the same volume and dosing regimen as the treated groups. Animals were observed daily cage side for survivability, injury, and availability of feed and water. Other observations conducted weekly during the study included detailed physical and neurobehavioral evaluations, and measurements of body weights and food consumption. A Functional Observational Battery (FOB) was conducted pretest and at Week 12. Motor activity (MA) was also evaluated during Week 12. Ophthalmoscopic examinations were conducted pretest, study termination, and following recovery .Other evaluations conducted at termination and following recovery included: hematology, clinical chemistry , urinalysis, organ weights, and pathological examinations (macroscopic and microscopic). Thyroid hormone levels [Thyroid Stimulating Hormone (TSH), T3 (3,5,3' -triiodothyronine), and T4 (thyroxine
or 3,5,3'5'-tetraiodothyronine)] were evaluated of animals at 33 days and at termination. These same hormone levels were evaluated following recovery. Homogeneity of the dosing suspensions at the low and high concentration levels was determined on mixes used the first week of study. Mean concentration recoveries from the periodic analyses of dosing suspensions used on study were 102.5%, 110.2%, and 106.8% of nominal for the l00, 300, and 1000 mg/kg/day groups, respectively.
A total of six females (two control and four in the 1000 mg/kg/day group) died or were euthanized in extremis.The mortality/moribundity seen in these groups was considered related to dosing injury and not treatment related.
No effect of treatment was seen in clinical or neurobehavioral evaluations, body weights, food consumption, ophthalmological examinations, MA, FOB evaluations, hematology or urinalysis evaluations. Likewise, no effect of treatment was evident from organ weights, or from the macroscopic or microscopic examinations. After 90 days of dosing, total bilirubin values were statistically higher than the control means (males: 0.14 ± 0.05; females: 0.13 ± 0.05) in males in the 1000 mg/kg/day dose (0.34 ± 0.024) (p<0.01) group and in females in the 300 (0.19 ± 0.03) (p<0.05) and 1000 mg/kg/day (0.2 ± 0.06) groups (p<0.01 ). Mean serum alkaline
phosphatase (ALP) levels after 90 days of dosing in the female 1000 mg/kg/day (98.9 ± 49.47) group was statistically higher than that of the control mean (58.4 ± 28.46) (p<0.05). A slight increase, but non-statistically different, was also observed in males. Although these differences were considered possibly due to test article administration, neither of these changes was of sufficient magnitude as to be biologically or toxicologically meaningful or adverse. Serum bilirubin and ALP levels in control and treated groups of both sexes were comparable after the end of the recovery period. With respect to serum hormone levels, mean TSH and T3 levels were statistically comparable between control and treated animals at all time points (Day 33, terminal and recovery euthanasia). Mean T4 levels were statistically lower than the control mean (Day 33: 4.96 ± 0.84; terminal: 5.09 ± 0.80) in the 100 (Day 33: 3.66 ± 0.88; terminal: 3.27 ± 0.67), 300 (Day 33: 3.42 ± 0.71; terminal: 2.61 ± 0.87) and 1000 (Day 33: 3.39 ± 0.55; terminal: 3.09 ± 0.91) mg/kg/day male dose groups at days 33 and 90 (p<0.01). Mean T4 1evels were also statistically lower than the control mean (4.27 ± 0.96) in females in the l00 (3.31 ± 1.08), 300 (3.24 ± 0.85) and 1000 (3.33 ± 0.84) mg/kg/day dose groups at Day 33 (p<0.05). Mean T4 1evels in all female dose groups were statistically comparable to the control mean at Day 90. At the recovery euthanasia, mean T4 1evels were comparable in the control and 1000 mg/kg/day male and female groups. The change in T41evels seen in the 1000 mg/kg/day group was reversible and levels comparable to control were seen following recovery. The decrease in serum T 4 levels was considered a possible effect of test article administration. TBBPA has been shown to competitively displace T4 from transthyretin (TTR), a major serum T4-binding protein in the rat,in vitro(Meerts et al. 2000. Toxicological Sciences, 56,95-104). That portion of serum T4 displaced from its binding site would be available for metabolism and elimination, thereby leading to a decrease in serum levels. The half-life of T4 in the rat is short due to its transport by TTR, and thus this species is sensitive to perturbations in T4 levels. For example, the plasma T4 half-life in rats is 12-24 hours while T4's half-life in humans is 5-9 days (Capen, C. 1996. Chapter 21. Toxic Responses of the Endocrine System. In: Casarett & Doull's Toxicology, The Basic Science of Poisons. Fifth Edition. Ed. Curtis Klaassen. McGraw-Hill, New York. 474-006). In humans circulating T4 is bound primarily to thyroxin binding globulin, but this high affinity binding protein is not present in rodents.
This mechanism, displacement of T4 from TTR-binding by TBBPA with subsequent metabolism and elimination in the liver, may account for the decreased mean serum T4 levels in treated animals. Because the decrease in T4 1evels was not of sufficient magnitude to alter mean serum TSH or T3 levels, thyroid histopathology, thyroid weight, or other parameters indicative of thyroid pathology (e.g. body weight, etc.), the decrease in serum T4 1evels was not considered adverse. The reduction in serum T4 1evels was not accompanied by evidence of toxicity or adverse effects, and the animals were clinically normal.
Thus, in this rat 90-day oral toxicity study with TBBP A, the No Observed Adverse Effect Level (NOAEL) was 1000 mg/kg/day, the highest dose tested. No effect on mortality, clinical signs, body or organ weights, histopathology, urinalysis, ophthalmology, FOB, MA, serum TSH, serum T3 or serum chemistries was observed. Differences were observed for bilirubin and ALP, but neither of these changes were found to be biologically or toxicologically meaningful or adverse. Serum T4 levels were decreased in treated animals, but the decrease was not of sufficient magnitude to induce adverse effects.
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