Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: WTP-64
Deviations:
yes
Remarks:
Please see details below.
Principles of method if other than guideline:
Species: New Zealand White rabbit
Exposure: A single 2000 mg/kg dose was applied to intact or abraded skin sites of fourteen rabbits (8 male and 6 female).
Examinations: Mortalities, irritancy, sublethal effects and necropsy

1. Observations for clinical signs of toxicity were not recorded on the afternoon of day 5.
2. The original protocol required 32 rabbits to be used. Only 26 were considered sufficiently healthy for testing. The animals were originally randomly assigned to treatment groups by the Datatox weight stratification program. The allocation was then edited on a non-preselected basis to insure 4 males and 3 females for the groups receiving the test material. Of the females available for use as controls, three were assigned to the abraded group and two were assigned to the intact group. Subsequently, animal no. 64-27 originally allocated as an intact female control, was inadvertently abraded.
3. The original protocol specified 30 March 1981 as day 0. The date for day 0 should have been listed as 31 March 1981.

The deviations encountered did not materially affect the outcome or validity of the study.
GLP compliance:
no
Test type:
other:
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Camm Research Institute, Wayne, New Jersey
- Age at study initiation: No data.
- Weight at study initiation: Males: 2725.3 +/- 109.1 g; females: 2848.9 +/- 127.3 g
- Fasting period before study: No data.
- Housing: No data.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 28 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Average temperature 19.4 (l5.6-21.1)°C
- Humidity (%): Average relative humidity 46.4 (29-58)%.
- Air changes (per hr): No data.
- Photoperiod (hrs dark / hrs light): A light cycle of 12 hours on (6 a.m. - 6 p.m.) and 12 hours off.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
other: normal saline
Details on dermal exposure:
TEST SITE
- Area of exposure: back/trunk region
- Type of wrap if used: 4 x 4 inch surgical gauze patch secured in place with tape and covered with impervious plastic wrap (Saran Wrap) and an overwrap of an elastic Ace bandage to immobilize the patch.

REMOVAL OF TEST SUBSTANCE
Following a 24-hour exposure period, the dressings were removed and any remaining material removed with a moist towel.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg, approximately 50% aqueous paste using 0.9% NaCl (normal saline).
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.9% NaCl (normal saline)
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
8 males and 6 females (fourteen animals in total)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortalities and clinical signs of toxicity were made at 1, 2, 4, and 6 hours following application, at 24 hours and twice daily (a.m. and p.m.) thereafter until termination of the study on day 14. Body weights were determined on days -1, 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights,
Statistics:
Statistical analysis for significance of body weight changes included the calculation of the mean (x) and standard error (S.E.). Determination of the significance of body weight changes on day 7 and 14 compared to controls was made using an independent T-test. A probability level of 0.05 was used as criterion for significance.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
One lethality occurred in the group of rabbits treated with the test material. No other mortalities occured.
Clinical signs:
No clinical signs of toxicity were observed in the rabbit that died until day 7 when a mucoid stool was observed. The following day the animal had diarrhea and decreased food consumption. From day 8 until the animal died on day 12 (am), the only clinical signs observed were no observable feces, decreased food consumption and hypoactivity (at one observation period - day 8). The clinical signs observed in the rabbit that died were not dissimilar from those exhibited by control and the other test animals.

No other abnormalities were observed.
Body weight:
No significant reduction in body weight gain occurred in the test animals on either day 7 or 14 as compared to the control group.
Gross pathology:
The rabbits were subjected to gross necropsy as soon as possible after spontaneous death or after euthanasia on day 14 of the study. Each of the remarkabLe
findings in the rabbits was considered to be incidental and not related to treatment with Crude Catalyst 32899. The renal paleness was a post-mortem
artifact. A fully accurate assessment of the internal viscera in rabbit 64-23 was precluded by generalized autolysis.

Remarkable findings were considered to be incidental and not related to treatment. Necropsy of the one rabbit that died on day 12 (No. 64-23) was not informative because of the generalized autolytic condition of the carcass.

Any other information on results incl. tables

Skin Irritant Effects

The scores reflect only a slight to minimal skin irritant effect that was equivalent in both the test and control animals. Based on these results the test material would not be considered as having a skin irritant effect.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test results indicate the LD50 of the test material is in excess of 2000 mg/kg. Based on these results the test material would not be considered as having a skin irritant effect.
Executive summary:

An acute dermal toxicity study was conducted in the rabbit on Crude catalyst 32899 (WRC Tox. Sample No. 14200-124-1E). The 2000 mg/kg dose of the test material was applied as a 50% paste, prepared using 0.9% normal saline under an occlusive wrapping to intact or abraded skin sites of 8 male and 6 female rabbits. Seven male and five female rabbits were used as controls. Skin irritation effects observed in the test animals following removal of the wrappings at 24 hours were comparable to controls. No skin irritant effects were evident at 14 days. No treatment-related Clinical signs of toxicity occurred in the study. One lethality (1/14) occurred in the test group on day 12. Clinical signs observed in the rabbit that died included a lack of appetite and hypoactivity, diarrhea and/or no observable feces for four days prior to death. Necropsy of this rabbit was not remarkable because of generalized autolysis. Necropsy of surviving rabbits was not remarkable and included only incidental effects not related to treatment. The test results indicate the LD50 of the test material is in excess of 2000 mg/kg.