Registration Dossier

Toxicological information

Repeated dose toxicity: dermal

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Standard method, GLP-compliant, adequate experimental details for assessment

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985

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:
substance applied 3 times per instead of 5 or 7 times per week
Principles of method if other than guideline:
Subacute dermal toxicity test as described. Micropathology limited to control and high-dose animals
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Clear liquid

Test animals

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

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
Method of administration:
6hr topical application under occlusion, 3x weekly for 4 weeks
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Duration of exposure per day: 6 hours
3 times per week
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Male: 5 animals at 2000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 2000 mg/kg bw/day
Control animals:
yes, sham-exposed

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
See details on results
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
See details on results
Mortality:
mortality observed, treatment-related
Description (incidence):
See details on results
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
See details on results
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 examined
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:
effects observed, treatment-related
Description (incidence and severity):
See details on results
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
skin consisted of dry, scaly or thickened skin (treatment related)
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
skin changes - no reported changes to any other tissues examined
Histopathological findings: neoplastic:
not examined
Details on results:
Clinical observations:
[1] There was one incidental death in an animal receiving
200 mg/kg, on day 12. There was no evidence of systemic
toxicity other than reduced body weight gain in high dose
animals (see below). Treatment-related dermal changes were
noted in all groups (except controls), consisting of erythma
and oedema, cracked, flaky and/or leathery skin which was
assessed as moderate at 2000 mg/kg, slight to moderate at
1000 mg/kg and minimal at 200 mg/kg.

[2] Body weight changes.

Both males amd females receiving 2000 mg/kg lost weight in
the first week of study, resulting in overall statistically
lower body weight gain compared with controls over the
entire study. Body weight gain over the last 3 weeks of the
study was however normal, as were body weights and body
weight gain in the 2 lower dose groups. The effects on body
weight are attributed to the stress of the dosing procedure
during Week 1.

Laboratory findings:
No significant changes in blood chemistry or haematology.

Effects in organs:
Absolute and relative kidney weights were significantly
increased in males receiving 2000 mg/kg, while relative
kidney weight was decreased in females at this dose level.
Relative adrenal weights were increased in both males and
females at this dose level and in females at 200 mg/kg
(within historical control range and considered unlikely to
be related to treatment) and relative brain weight was also
increased in females at 2000 mg/kg (also unlikely to be
related to treatment). No microscopic findings were reported
that could be related to treatment, other than
histopathological effects in the skin and increased
granulopoiesis/cellularity of the bone marrow in 4 high-dose
males and 5 high-dose females. The histopathological
changes in the skin consisted of epidermal hyperplasia and
hyperkeratosis accompanied by inflammatory changes in the
dermis. No histopathological examination was carried out on
the skin of animals receiving 200 or 1000 mg/kg.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day
Basis for effect level:
other: Local effect -skin irritation

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Reproductive toxicity: no adverse findings recorded during microscopic examination.

Applicant's summary and conclusion