Hydrocortisone 21-acetate

Repeated dose toxicity: dermal

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

Test material information

Constituent 1

Reference substance name:

Hydrocortisone 21-acetate

EC Number:

200-004-4

EC Name:

Hydrocortisone 21-acetate

Cas Number:

50-03-3

Molecular formula:

C23H32O6

IUPAC Name:

11,17-dihydroxy-3,20-dioxopregn-4-en-21-yl acetate

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.