Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28th October 1977 - 16th February 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP data; methodology predates or was not conducted according to standardized guidelines; no analytical verification of test compound concentrations

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Tetrabromobisphenol-A was applied to the shaved skin of male and female rabbits 5 days a week for three weeks at dose levels of 100, 500, and 2500 mg/kg/day.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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: Not reported
- Impurities (identity and concentrations): Not reported
- Composition of test material, percentage of components: Not reported
- Isomers composition: Not reported
- Purity test date: Not reported
- Lot/batch No.: 1021-85, received from Velsicol Chemical Corp.
- 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: Not reported

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sweetwater Farms, Hillsboro, Ohio USA
- Age at study initiation: Not reported
- Weight at study initiation: Male- 1886 to 2284g; Female- 2030 to 2311g
- Fasting period before study: Not reported
- Housing: Individually in hanging wire mesh cages
- Diet (e.g. ad libitum): Purina Rabbit Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled, not specified
- Humidity (%): Controlled, not specified
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Controlled, not specified

Administration / exposure

Type of coverage:
open
Vehicle:
other: 0.9% physiological saline to form paste
Details on exposure:
TEST SITE
- Area of exposure: Dorsal area
- % coverage: 10% of body area
- Type of wrap if used: N/A
- Time intervals for shavings or clipplings: "As necessary"

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Area wiped clean
- Time after start of exposure: Approx 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100, 500, 2500 mg/kg/day
- Concentration (if solution): 100, 500, 2500 mg/kg/day
- Constant volume or concentration used: yes/no
- For solids, paste formed: Yes
VEHICLE
- Justification for use and choice of vehicle (if other than water): Saline (physiological)
- Amount(s) applied (volume or weight with unit): 1.5 mL/kg
- Concentration (if solution): 100, 500, 2500 mg/kg/day

USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes, collars
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not performed
Duration of treatment / exposure:
15 exposures of 6 hours each
Frequency of treatment:
5 days a week for three weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 500, and 2500
Basis:
nominal per unit body weight
No. of animals per sex per dose:
4 males and 4 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Increase of 5x
- Rationale for animal assignment (if not random): Random
- Section schedule rationale (if not random): Random
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations: signs of overt toxicity, moribundity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At time 0 and at week 3

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: After each 6-hour exposure

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At time 0 and at week 3
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes, overnight
- How many animals: All
- Parameters examined: hemoglobin, hematocrit, erythrocyte count, leucocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At time 0 and at week 3
- Animals fasted:Yes, overnight
- How many animals: all
- Parameters examined: Blood urea nitrogen, fasting glucose, serum alkalie phosphatase, serum glutamic oxalacetic transaminase, serum glutamin pyruvic transaminase, calcium, inorganic phosphorus, total protein and albumin.

URINALYSIS: Yes
- Time schedule for collection of urine: at time 0 and week 3
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes
- Parameters examined: specific gravity, color and appearance, pH , and qualitative tests for albumin, glucose, ketones, occult blood and bilirubin

Sacrifice and pathology:
GROSS PATHOLOGY: Yes- spleen, liver, adrenals, testes/ovaries, thyroid/ parathyroid, brain, and kidneys
HISTOPATHOLOGY: Yes (see table)
Statistics:
One-way ANOVA, Bartlett's test, Dunnett's

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
See table below
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
See explanation below
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
ORGAN WEIGHTS: There was a statistically significant increase in mean absolute brain weight for males in the 500-mg/kg/day group. The biological significance of this variation is not known.

Effect levels

Dose descriptor:
NOAEL
Effect level:
2 500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Mortality

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table: description of dermal effects observed in rabbits exposed to TBBPA

Treatment level

Effect

Degree

Number affected

Duration

100 mg/kg/day

Erythema

Very slight

2

Short –term, not specified

500 mg/kg/day

Erythema

Very slight

8

1 to 3 days

2500 mg/kg/day

Erythema

Very slight

6

3+ days

Applicant's summary and conclusion

Conclusions:
There was no mortality in any group. The animals did not show any signs of systemic toxicity or unusual behavior. Very slight erythema was observed in all exposures. No compound induced gross lesions were observed in any of the rabbits at the terminal sacrifice. There were no compound-related microscopic alterations observed in any of the tissues examined.
Executive summary:

TBBPA was administered to the backs of New Zealand White rabbits,at dosage levels of 100, 500 and 2500 mg/kg/day, 5 days a week, for 3 weeks. Four male and four females rabbits were used at each dosage level and also in a control group. The control rabbits were administered 1.5 ml/kg of 0.9% physiological saline on the same regimen as treated rabbits. The compound was mixed with 0.9% physiological saline to form a paste which was applied. The rabbits were observed daily for signs of overt toxicity, dermal irritation, moribundity and mortality . Body weights were recorded weekly. Hematologic and biochemical studies and urinalyses were conducted during the pretest period and at 3 weeks of study. There was no mortality and no sign of overt toxicity or unusual behavior for the rabbits in any group.

The application of TBBA

on the skin of rabbits at a dosage of 100 mg/kg/day occasionally elicited very slight erythema. The dosage of 500 and 2500 mg/kg/day evoked very slight erythema for almost all rabbits for varying lengths of time. There were no other signs of skin irritation or any signs of toxicity. No changes considered to be related to compound were seen in body weights, hematologic and biochemical parameters and urinalysis. There were no compound induced gross or microscopic lesions in any of the tissues examined. No compound-related organ weight variations occurred.