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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Remarks:
This study does not meet the detail requirements for current guidelines, but the study design was adequate to produce results that are acceptable for assessment. The design included three doses, abraded and unabraded skin, sufficient males and females, monitoring of weight, hematology, blood chemistry, urinalysis, and gross and microscopic pathology.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1977
Report Date:
1977

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Young adult male and female albino rabbits had the hair on their backs removed with clippers, and were allowed to recover for 24 hours. The animals were divided into groups of 4 of each sex per dose, and 2 additionally had their skin abraded after hair removal (as deep as the stratum corneum) with the tip of a needle prior to application of the test compound. The hair was clipped again at least once per week, and if applicable, the skin re-abraded twice per week. The rabbits were fitted with flexible plastic collars to prevent oral ingestion of the test compound from their unoccluded skin. The test compound was applied to the skin surface 5 days per week for 4 weeks at doses of 100, 300, and 1000 mg/kg, and the dose was distributed over 5-20% of the body surface of the animal. The test compound was not removed by washing or rinsing. Control animals received applications of 1% w/v aqueous methylcellulose vehicle.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: granular
Specific details on test material used for the study:
Lot number: 3106

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female

Administration / exposure

Type of coverage:
open
Vehicle:
other: aqueous methyl cellulose
Details on exposure:
TEST SITE
- Area of exposure: skin of the back
- % coverage: the clipped area was 30% of the total body surfacer; 5-20% of the body surface was contacted during the dermal application of test compound; clipping was reeated at least once per week, or more often if necessary; a 24-hour recovery period was allowed prior to application so skin could recover from the slight distrubance of the stratum corneum
- Time intervals for shavings or clipplings: Animals were clipped at least once per week

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: The study was conducted for four weeks, and the test compound was not removed during that time. The animals were unable to clean themselves because of a plastic collar to prevent ingestion of test compound, so they also did not remove the compound from the skin surface.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): the 100 mg/kg dose was applied in 0.2 ml/kg; the 300 mg/kg dose was applied in 0.6 ml/kg; the 1000 mg/kg dose was applied in 2.0 ml/kg.
- Concentration (if solution): 50% w/v
- Constant volume or concentration used: constant concentration
- For solids, paste formed: as a 'suspension'

VEHICLE
- Justification for use and choice of vehicle (if other than water): aqueous methylcellulose
- Amount(s) applied (volume or weight with unit): 1% (w/v)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 days per week for 4 weeks; no removal of test compound between dosing
Frequency of treatment:
5 times per week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
4 animals per sex per dose; 2 from each group had hair clipped from skin, while the remaining 2 had hair clipped and additional abrasion by a needle
Control animals:
yes, concurrent vehicle
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: after 1-3, 4, 9, 10-11, 16, 18, and 20th applications

BODY WEIGHT: Yes
- Time schedule for examinations: weekly, starting two weeks before dosing

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day -6 and Day 28
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 32 total
- Parameters checked in table [No.?] were examined: total leukocyte count, erythrocyte concentration, hemoglobin concentration, hematocrit value, differential leukocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day -6 and Day 28
- Animals fasted: Yes
- How many animals: 32
- Parameters checked in table [No.?] were examined: fasting blood glucose concentration, blood urea nitrogen concentration, serum alkaline phosphatase activity, serum glutamic pyruvic transaminase activity, serum glutamic oxalecetic transaminase activity

URINALYSIS: Yes
- Time schedule for collection of urine: Day -6 and Day 28
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table [No.?] were examined: protein, glucose, ketones, occult blood, bilirubin, bile pigments, pH, RBC, WBC, crystals, casts, epithelial cells, specific gravity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (including organ weights)
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
one rabbit died at 21 days, but cause of death was not evident from tissues examined
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
slightly irritating
Mortality:
no mortality observed
Description (incidence):
one rabbit died at 21 days, but cause of death was not evident from tissues examined
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
epithelial acanthoses with hyperkeratosis (skin)
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related effects other than slight skin irritation reflected in epithelial acanthoses with hyperkeratosis.

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 pharmacotoxic symptoms were observed at any time during the study. Treatment-related lesions were noted on the test skin sites of all animals.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In this adequate 28-day dermal study, 2,4,6-tribromophenol was found to be slightly irritating to the skin, and no other indications of toxicity were found.
The NOAEL for subacute dermal toxicity of 2,4,6 -tribromophenol is 1000 mg/kg based on a lack of toxic effects at the highest dose tested in this study.