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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:
supporting study
Study period:
From 02 to 30 March 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is primarily a Comedogenic study and so is conducted at low doses and investigations focussed on dermal reactions. While well run is not considered suitable to address this endpoint in isolation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study method is as FDA (21 CFR Part 58) and FDRL Standard Operating Procedures.
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Batch No.: 87-0071
Purity: 2% w/v suspension in distilled water

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Inc.
- Age at study initiation: Young adult.
- Weight at study initiation: 2-3 kg
- Fasting period before study:
- Housing: Individually housed in wire-mesh cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): Fresh tap water was provided ad libitum.
- Acclimation period: At least 5 days prior to study initiation.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):

IN-LIFE DATES: From: 2 March 1987 To: 30 March 1987

Administration / exposure

Type of coverage:
open
Vehicle:
other: distilled water
Details on exposure:
A volume of 0.5 mL of the test substance or positive control was applied to the external left ear canal of the appropriate group, 5 days a week for 4 consecutive weeks. Dosing was done at approximately the same time daily. Each dose was evenly distributed over the treatment site using a clean glass stirring rod. The right ear of each animal served as an untreated control.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 days a week for 4 consecutive weeks
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5 mL of a 2% aqueous suspension: equivalent to ca. 3-5 mg/kg bw/d
Basis:
nominal per unit area
No. of animals per sex per dose:
Six males were assigned to the test group and three to the positive control group.
Control animals:
yes
Details on study design:
Terminal studies:
All animals were sacrificed on day 29 by intracardiac injection of sodium pentobarbital. Treated and control sites were excised, fixed in 10% neutral buffered formalin, embedded in paraffin, cut in cross section to 5 μm thickness and stained with hematoxylin and eosin. Treated and untreated sites were examined microscopically. Each tissue was assigned a comedogenic grade based on the degree of follicular hyperkeratosis and other morphological changes in the pilosebaceous units according to the system of Morris and Kwan (1983).
A group mean comedogenic grade was then calculated for the test article and positive control materials and the degree of comedogenic activity of each assessed.
Positive control:
Concurrent positive control group animals were treated with 1% coal tar in Polylan.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were observed daily for signs of toxicity, behavioral abnormalities and general health. Mortality checks were conducted twice daily, at least 5 hours apart.

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Treated and untreated ears were examined daily and the condition and gross appearance of each was noted. This examination was conducted prior to dosing on application days.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on days 1 and 29.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: No data
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, ear canal
HISTOPATHOLOGY: Yes, ear canal
Other examinations:
None stated
Statistics:
None stated

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical signs and Mortality:
All test animals appeared normal throughout the study. One control animal exhibited soft stools on study days 5, 6, 7 and 16. This finding is common among stock laboratory rabbits and is not considered to be of toxicological significance.

Body weight:
Body weights were increased in both groups at day 29.

Dermal irritation:
Treatment with the test substance produced dermal irritation characterized by redness, dryness and flaking.

Pathology:
A comedogenic response was observed at the test site in one of six rabbits used in the test group.
Based on the scoring system used in this study, the group of animals treated with the test substance had a mean comedogenic grade of 0.5. One of six test animals received a comedogenic grade of 3.

Effect levels

Dose descriptor:
NOAEL
Basis for effect level:
other: The purpose of this test is to determine a mean comedogenic grade.
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Study is primarily a Comedogenic study and so is conducted at low doses and investigations focussed on dermal reactions. While well run is not considered suitable to address this endpoint in isolation. Under the conditions of the study, in which a mean comedogenic grade of ≥ 2.0 in rabbits is considered to indicate potential comedogenesis in humans the test substance is not expected to be comedogenic in humans.