Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
other information
Study period:
27. April 1976 to 21. July 1976
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well reported study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1977
Report Date:
1977

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
10 rabbits (5/sex) were treated dermally once daily over 5 hours with 1% (w/w) (0, 5 and 25 mg/kghydrocortisone-21-acetate 7 days/week over a period of 12 weeks.
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): hydrocortisone-21-acetate (ZK9152)
- Lot/batch No.: 14606583

Test animals

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

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
other: one-phase fat cream
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
5 hours 7 days/week over period of 12 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
5 and 25 mg/kg
Basis:

No. of animals per sex per dose:
5/sex/dose
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:
NOEL
Effect level:
< 5 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: reduced body weight gain

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Reduced body weight gain (females) and reduced thickness of skin fold (atrophy) including reduction of inflammation cells in corium infiltate at 5 and 25 mg/kg bw. Hematology showed reduced hemoglobin, HK, erythrocytes, lymphocytes, eosinophiles in the high dose group. Erythrocyte sedimentation rate, neutrophiles, glucose, total protein, lipids, phosphatide, trigyceride, cholsterol, fibrinogen, GOT and GPT were increased in animals treated with 25 mg/kg hydrocortisone-acetate. Organ weight was increased in liver and kidneys and decreased in adrenal glands, spleen and sceletal muscles (females). Histopathology showed lipid infiltration, swelling and focal necroses of liver cells, increase in kidney protein cylinders, enlargement of tubuli in Bowman capsule, lipid infiltration in medulla of kidney, haemosideroses in spleen, atrophy of zona fasciculata in adrenal gland and inflated cells in zona fasciculata and reticularis, thymus involution, atrophy of lymphatic tissue in lymph nodes. In pancreas ductus proliferation, degranulation, hypertrophy and hyperplasia of the B-cells were observed. Testes developed tubuli atrophy. Reduction in reaction of inflammation cells in liver.

Applicant's summary and conclusion

Conclusions:
NOEL below 5 mg/kg
Executive summary:

Dermal application of hydrocortisone-21 -acetate (0, 5 and 25 mg/kg, 5 h/day 7 times/week) to rabbits (5/sex/group)over 12 weeks results in reduced body weight gain (females) and reduced thickness of skin fold (atrophy) including reduction of inflammation cells in corium infiltate. Hematology showed reduced hemoglobin, HK, erythrocytes, lymphocytes, eosinophiles. Erythrocyte sedimentation rate, neutrophiles, glucose, total protein, lipids, phosphatide, trigyceride, cholsterol, fibrinogen, GOT and GPT were increased. Organ weight was increased in liver and kidneys and decreased in adrenal glands, spleen and sceletal muscles (females). Histopathology showed lipid infiltration, swelling and focal necroses of liver cells, increase in kidney protein cylinders, enlargement of tubuli in Bowman capsule, lipid infiltration in medulla of kidney, haemosideroses in spleen, atrophy of zona fasciculata in adrenal gland and inflated cells in zona fasciculata and reticularis, thymus involution, atrophy of lymphatic tissue in lymph nodes. In pancreas ductus proliferation, degranulation, hypertrophy and hyperplasia of the B-cells were observed. Testes developed tubuli atrophy. Reduction in reaction of inflammation cells in liver. NOEL below 5 mg/kg.