Pregna-1,4-diene-3,20-dione, 6-fluoro-11-hydroxy-16-methyl-21-[(1-oxopentyl)oxy]-, (6.alpha.,11.beta.,16.alpha.)-

Repeated dose toxicity: other routes

Administrative data

Endpoint:

sub-chronic toxicity: other route

Type of information:

experimental study

Adequacy of study:

other information

Study period:

9. Mar to 7. Apr 1971

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Rats (10/sex/dose) were treated daily subcutaneously with test substance over a period of 4-5 weeks and sacrificed afterwards. Different hematological and biochemical examinations were performed. Macroscopic and histological changes were recorded.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Fluocortolone

EC Number:

205-811-5

EC Name:

Fluocortolone

Cas Number:

152-97-6

Molecular formula:

C22H29FO4

IUPAC Name:

6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione

Details on test material:

- Name of test material (as cited in study report): fluocortolone (ZK 10445)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Züchter Mus Rattus AG.
- Weight at study initiation: 150-245 g
- Housing: individually in macrolon type II cages
- Diet (e.g. ad libitum): Altromin ad libitum
- Water (e.g. ad libitum): Tap Water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Humidity (%): 45-65
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

not specified

Details on exposure:

The application volume was 0.1 mL/100 g, control animals received the vehicle in the same manner.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

7 days/week for 4 to 5 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.002 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

0.02 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

0.2 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10/sex/dose

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Mortality:

no mortality observed

Effect levels

Dose descriptor:

LOAEL

Effect level:

>= 0.002 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: increased lipid concentration in zona fasciculata in adrenal gland (m and f), reduced gamma-globulin fraction in females

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Starting at low dose animals developed increased lipid concentration in zona fasciculata in adrenal gland and reduced gamma-globulin fraction in electrophoresis. At higher dose (0.02 mg/kg) rats developed reduced body weight gain, increased sodium excretion. At 0.2 mg/kg additionally increased chlorid excretion, reduced absolute thymus, lymph node and adrenal gland (also relative) weights, follicle atrophy and reduced lymphocytes in spleen, also involution of thymus with pyknosis of thymocytes and atrophy in adrenal gland and increased erythropoesis were noted. In addition haemorrhages around the location of application were detected.

Applicant's summary and conclusion

Conclusions:

LOAEL: 0.002 mg/kg bw; NOAEL could not be identified.


Rats (10/sex/group) were treated subcutaneously with fluocortolone at a dose level of 0, 0.002, 0.02, or 0.2 mg/kg once daily for 4-5 weeks. Findings were mainly reduced body weight gain, effects on thymus, adrenal gland and spleen. In addition
haemorrhages around the location of application were detected.

Executive summary:

In a repeated dose toxicity study (conducted prior to implementation of OECD test guidelines) male and female Wistar rats (10/group) were administered Fluocortolon subcutaneously in concentrations of 0, 0.002, 0.02, and 0.2 mg/kg bw over a period of 4-5 weeks, 7 days a week. Findings were mainly reduced body weight gain, effects on thymus, adrenal gland and spleen. In addition haemorrhages around the location of application were detected. Based on the observed increased lipid concentration in the zona fasciculata (adrenal gland) and a reduced gamma-globulin fraction in female rats starting already at a dose of 0.002 mg/kg bw the LOAEL was set to 0.002 mg/kg bw, a NOAEL could not be identified.