Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, comparable to guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
no
Principles of method if other than guideline:
In a 21-day dermal toxicity study 5 male and 5 female rabbits were treated with 0, 125, 500 or 2000 mg Santocur/kg/day (5 days/weeks) on intact and abraded skin. The animals were observed for mortality, clinical signs, body weight gain and dermal irritation. A gross pathology and microscopic examination was performed at the end of the study.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: Santocure CBS

Test animals

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

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
Route of Administration: dermal
Duration of treatment / exposure:
21 d
Frequency of treatment:
Daily (5 days per week).
Doses / concentrations
Remarks:
Doses / Concentrations:
125, 500 or 2000 mg/kg bw/d
Basis:

No. of animals per sex per dose:
Ten per dose and sex (5 per dose and sex intact skin, 5 per dose and sex abraded skin).
Control animals:
yes
Details on study design:
Post-exposure period: no data
Positive control:
None.

Examinations

Observations and examinations performed and frequency:
Mortality, general observations, body weight gain, dermal irritation .
Sacrifice and pathology:
Gross pathology and microscopic examination.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No test article-related signs were noted for any animal in the test groups; a few rabbits in the 125 and 500 mg/kg bw test groups exhibited some signs of occular irritation such as injected iris, corneal opacity and conjunctivial redness and swelling. None of the animals in the 2000 mg/kg group were noted for ocular irritation.
Dermal irritation:
no effects observed
Description (incidence and severity):
The majority of the rabbits in both control and test groups (abraded and intact skin) exhibited no dermal irritation during the study period; however during the study period a few rabbits in each CBS dose groups exhibited very slight to slight erythema on the application area of the skin, which was reversible within day 21 of the study; the incidence of very slight to slight desquamation was increased in test compound treated groups; but a dose-response relationship was not noticed.
Mortality:
no mortality observed
Description (incidence):
No test substance related mortality.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No statistically significant differences were seen.
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:
effects observed, treatment-related
Haematological findings:
no effects observed
Description (incidence and severity):
No changes considered to be related to CBS were seen in the hematologic studies and biochemical studies.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No changes considered to be related to CBS were seen in the hematologic studies and biochemical studies.
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The body weight means of the different test groups and most of the mean organ weights were simular to the control groups.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No findings related to the test substance were observed.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The main microscopic findings in the skin were slight hyperkeratosis abd acanthosis in the epidermis and infiltration of inflammatory infiltrate in the dermis. These changes were present in control animals and CBS treated animals and were considered as unrelated to the application of CBS.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No major signs of local or systemic toxicity noted in rabbits treated with CBS at dosage of 125, 500, or 2000 mg/kg bw/day

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

No test article-related signs were noted for any animal in the test groups; a few rabbits in the 125 and 500 mg/kg bw test groups exhibited some signs of occular irritation such as injected iris, corneal opacity and conjunctivial redness and swelling. None of the animals in the 2000 mg/kg group were noted for ocular irritation.

mortality: control 1/10 males (on day 12); 1/10 males 2000 mg/kg (on day 13)

mortality not test substance related

Dermal Irritation:

the majority of the rabbits in both control and test groups (abraded and intact skin) exhibited no dermal irritation during the study period; however during the study period a few rabbits in each CBS dose groups exhibited very slight to slight erythema on the application area of the skin, which was reversible within day 21 of the study; the incidence of very slight to slight desquamation was increased in test compound treated groups; but a dose-response relationship was not noticed.

Body weight: no statistically significant differences were seen.

Clinical laboratory tests:

No changes considered to be related to CBS were seen in the hematologic studies and biochemical studies.

Gross pathology: No findings related to the test substance were observed.

Organ weights: the body weight means of the different test groups and most of the mean organ weights were simular to the control groups.

Histopathology: the main microscopic findings in the skin were slight hyperkeratosis abd acanthosis in the epidermis and infiltration of inflammatory infiltrate in the dermis. These changes were present in control animals and CBS treated animals and were considered as unrelated to the application of CBS.

Findings on the internal organs were consistent with the usual spontaneous lesions found in this strain of rabbits

No evidence of toxicity related to test material administration.

Applicant's summary and conclusion

Conclusions:
No evidence of toxicity related to test material administration.
Executive summary:

In a dermal 21-day toxicity study comparable to OECD TG 100 CBS was applied daily to the intact and abraded skin in doses of 125, 500 and 2000 mg/kg bw and day to each of the male and female adult New New Zealand white rabbits for a period of 3 weeks. Saline was used as negative control. Ground CBS was applied onto the skin moistened and covered with occlusive dressing. No data were available indicating the administered concentrations or surface area doses of CBS. The exposure time was 6 hours per day for a 5-day per week basis, for a period of 21 consecutive days. Two rabbits died during the course of study. One male control rabbit was found dead on day 12 and one male treated with 2000 mg/kg bw and day on day 13, respectively. Neither death was attributed to treatment with CBS. No dose dependent effects were noted for general appearance, behaviour, body weight, haematology, blood biochemistry, gross pathology, absolute and relative organ weights and histopathology. During the study period a few rabbits in each of the CBS dose groups exhibited very slight to slight erythema on the application area of the skin, which was reversible within day 21 of the study. The incidence of very slight to slight desquamation seen as slight scaling was increased in animals of the CBS-dose groups when compared to controls. But a dose-response relationship was not noticed. At microscopy of the skin slight hyperkeratosis and acanthosis in the epidermis and infiltration of inflammatory infiltrate in the dermis were observed. These findings were present in both CBS-treated animals and those of controls. Their incidence and severity did not distinguish CBS-treated rabbits from controls. Therefore, the NOAEL for systemic effects and local effects in rabbits after repeated dermal exposure was 2000 mg/kg bw and day (Monsanto Co.1981).