Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26th January 2001 - 20th September 2001
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted according to standardized OECD/EPA guidelines, with analytical verification of test compound concentrations administered

Data source

Referenceopen allclose all

Reference Type:
study report
Report Date:
Reference Type:
EU risk assessment: United Kingdom (TBBPA)
Bibliographic source:
Environment Agency Chemicals Assessment Section United Kingdom
Report Date:

Materials and methods

Test guidelineopen allclose all
according to
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
according to
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Limit test:

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: 98.91%
- Impurities (identity and concentrations):
Tetrabromobisphenol-A: 98.91%
o,p- tetrabromobisphenol-A: 0.05%
2,4,6-Tribromophenol: <0.01%
Tribromobisphenol-A: 1.04%
- Composition of test material, percentage of components: See Above
- Isomers composition: Not reported
- Purity test date: 4 and 5 January and 9 May 2001
- Lot/batch No.: 5381
- 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: Not reported
- Storage condition of test material: Room temperature, dessiccated, in a dry well-ventilated area

Test animals

Details on test animals and environmental conditions:
- Source: Charles River Laboratories, Portgage MI USA
- Age at study initiation: 10 weeks old at study initiation
- Weight at study initiation: 203 to 274 g
- Fasting period before study: Not reported
- Housing: Individually in hanging wire cages
- Diet (e.g. ad libitum): Rodent Chow #5002, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks prior to mating

- Temperature (°C): 18 to 26C
- Humidity (%): 38 to 63%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours light: 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Measured weights of TBBPA added pre-determined quantities of corn oil

- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Corn oil, for gavage
- Storage temperature of food: Refrigerated

- Justification for use and choice of vehicle (if other than water): Not given, standard vehicle
- Concentration in vehicle: Sufficient to give 100, 300, and 1000 mg/kg/day
- Amount of vehicle (if gavage): 5mL per kg
- Lot/batch no. (if required): PU0041, PO0173
- Purity: Not reported
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Prior to initiation oftest article administration, test batches ofthe test article suspensions at the low and high concentrations used in the study (20 and 200 mg/mL, respectively) were prepared to assess the homogeneity of the test preparations employing the same method and batch size to be used during the study.
Validation was performed by HPLC with UV detection, with an internal standard operating procedure. LLOQ = 0.0100 mg/mL
Column: Phenomenex Luna C i 8, (250 mm x 4.6 mm), 5 urn
Guard Column: 0.45 urn ¡nline filter canridge
Column Temp: Ambient
Mobile Phase: A: 10 mM Phosphate buffer (pH = 4) B: Acetonitrle

Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Not reported
- Further matings after two unsuccessful attempts: Not reported
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy Not reported, referred to as day 0 of pregnancy
- Any other deviations from standard protocol: None reported
Duration of treatment / exposure:
Exposed to 100, 300, and 1000 mg/kg/day from Day 0 of gestation to Day 19
Frequency of treatment:
Duration of test:
20 days
Doses / concentrations
Doses / Concentrations:
100, 300, 1000 mg/kg/day
actual ingested
No. of animals per sex per dose:
25 females per dose plus control
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


Maternal examinations:
- Time schedule: Twice daily, seven days a week for morbidity, mortality, and signs of injury

- Time schedule: Daily

- Time schedule for examinations: On Days 0, 3,6, 9, 12, 15, 18, and 20 of gestation.

- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

- Sacrifice on gestation day #20
- Organs examined: uterus, placenta, standard gross necropsy on maternal rats, fetal examinations

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Group Pair-Wise Comparisons; Fisher's Exact Test; Arcsin-Square-Root transformation; Covariate analysis; Descriptive
Fertility indices
Historical control data:
See table below

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
One mortality determined to be result of dosing injury; salivation effects determined to be sporadic and not related to dose

Effect levels (maternal animals)

open allclose all
Dose descriptor:
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The few external findings (malformations and variations) seen in the treated groups occurred with low incidence on both a per fetus and per litter basis and were considered unrelated to treatment. The litter incidences for these findings for the treated groups did not differ statistically from controls.

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

In this oral developmental toxicity study in rats with Tetrabromobisphenol A, the NOAEL (No Observable Adverse Effect Level) for maternal and developmental toxicity was 1000 mg/kg/day, the highest dose level evaluated.
Executive summary:

The objective of this study was to provide general information concerning the effects of oral treatment of the pregnant rat with Tetrabromobisphenol A (TBBP A) on the developing organism. This included death, structural abnormalities or altered growth, and assessment of maternal effects. Female CD rats were mated in-house and received the TBBPA at dose levels of 0, 100, 300, and 1000 mg/kg/day at a constant volume of 5 mL/kg. The test article was administered orally by gavage as a single daily dose.

Observations of the dams included clinical signs, gestational body weights, and food consumption. Females were euthanized on Day 20 of gestation and given a postmortem macroscopic examination. All fetuses were given a gross external examination for malformations and variations. Approximately one-half of the fetuses in each litter were fixed in Bouin's solution, and the remaining fetuses were skinned and preserved in alcohol.

Pretest analyses confirmed that the suspensions as prepared were homogeneous and stable for at least 14 days when stored refrgerated. Periodic analysis of dosing suspensions used on study ranged from 88 to 113% of nominal and confirmed that animals were receiving the appropriate dose levels.

No treatment-related mortality was seen. The death of 1 animal in the 300 mg/kg/day group on Gestation Day 5 was attributed to an intubation injury. All other animals survived to scheduled euthanasia.

Salivation was seen among the TBBPA-treated animals, occurring most frequently at the 300 and 1000 mg/kg/day dose levels, Because of its sporadic occurrence, this was not considered to represent a direct effect of treatment with TBBPA, but more likely was in response to the taste of residual amounts oftest article on the dosing catheter. No other effects of treatment were seen from the clinical examinations, and no effect of treatment was evident from gestational parameters (body weight, body weight gain, or food consumption), uterine implantation data, liver weights, or necropsy findings, Likewise, no effect of treatment was evident from fetal body weights, fetal sex distribution, or from fetal external, visceral, or skeletal examinations.

Thus, in this oral developmental toxicity study in rats with TBBPA, the NOAEL (No Observable Adverse Effect Level) for maternal and developmental toxicity was 1000 mg/kg/day, the highest dose level evaluated.