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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
Study period:
11.07.1988 to 12.03.1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
Limited haematology
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles Rivers Breeding Laboratories, Portage, Michigan
- Age at study initiation: 'young'
- Weight at study initiation: males: 259-286 g; females: 215-263 g
- Fasting period before study: No data
- Housing: Individually in standard stainless steel wire mesh cages of conventional design
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Seven days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±3
- Humidity (%): 30-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To:

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: Dorsal area
- % coverage: approx. 10%
- Type of wrap if used: Occluded with plastic wrap
- Time intervals for shavings or clippings: as needed


REMOVAL OF TEST SUBSTANCE
- Washing (if done): No

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): No data
- Constant volume or concentration used: No data


USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily for 6 hr/day, 7d/week, for 28 days
Doses / concentrationsopen allclose all
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
800 mg/kg bw/day (actual dose received)
Dose / conc.:
1 600 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 per sex in main study groups, 5 per sex in the 2 satellite groups.
Control animals:
other: occluded with plastic wrap, but without test material
Details on study design:
- Dose selection rationale: No data
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: reversibility of adverse effects (control and 1600 mg/kg bw/day groups)
- Post-exposure recovery period in satellite groups: 28 days
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily for all groups

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes
- Time schedule for examinations: study initiation, weekly throughout the study and at termination, including the post-exposure rest period.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


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

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: study initiation and termination
- Dose groups that were examined: control and high dose group animal

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: Yes (ketamine HCl)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At study termination
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined


URINALYSIS: Yes
- Time schedule for collection of urine: At study termination
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 1 were examined.


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Other examinations:
None
Statistics:
Body weight, food consumption, hematology, clinical chemistry, urinalysis, organ weights analysed by 1-way ANOVA.
Group means compared with controls using Dunnett's multiple T-test or non-parametric analysis of variance by ranks
where appropriate.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
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:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
• Body weight: No significant differences were found.
• Food/water consumption: No significant differences were found.
• Description, severity, time of onset and duration of clinical signs: No significant clinical observations or
behavioural changes were reported.
• Ophthalmologic findings incidence and severity: No adverse effects observed.
• Hematological findings incidence and severity: No significant changes were reported.
• Clinical biochemistry findings incidence and severity: No significant changes were reported for clinical chemistry or
urinalysis results.
• Mortality and time to death: No unscheduled early deaths occurred during this study.
• Gross pathology incidence and severity: There were no apparent treatment-related effects noted at gross necropsy.
• Organ weight changes: No significant changes were reported
• Histopathology incidence and severity: No significant dose-related findings were reported for either terminal or
recovery group sacrifices.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No systemic effects observed.
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No local effects observed.

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Dermal administration of undiluted D5 under occlusive conditions over a 28-day period at doses up to and including 1600 mg/kg bw/day resulted in no adverse effects on survival, body weight, food consumption, clinical observations, clinical pathology, hematology, ophthalmoscopy, organ weights, or gross or microscopic pathology (study reliability score 1).