2,2',6,6'-tetrabromo-4,4'-isopropylidenediphenol

Repeated dose toxicity: dermal

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

Test material information

Constituent 1

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 or test system 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.