Fluocortolone

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1969

Report date:

1969

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

not applicable

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:

(1S,2R,3aS,3bS,5S,9aR,9bS,10S,11aS)-5-fluoro-10-hydroxy-1-(2-hydroxyacetyl)-2,9a,11a-trimethyl-1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-7-one

Details on test material:

- Name of test material (as cited in study report): 6-alpha-fluoro-16-alpha-methyl-delta-1,4-pregnadiene-11ß, 21-diol-3, 20-dione (ZK10445)
- Lot/batch No.: 1008

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: cornstarch

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The dosage was administered in gelatin capsules six days per week. All animals were dosed in the morning about one and one-half hours after feeding. Dogs receiving the test item were given a dilution of one part of test compound to 49 parts of cornstarch. The cornstarch was mixed with a weighed quantity of compound and sieved several times. The appropriate amount of cornstarch was then added and the mixture was blended in a Twin Shell Blender for 10 minutes. Control dogs received 50 mg/kg of cornstarch six days per week.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

56 weeks

Frequency of treatment:

daily, 6 days/week

Doses / concentrations

Dose / conc.:

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

No. of animals per sex per dose:

3/sex

Control animals:

yes, concurrent vehicle

other: positive control: 9 mg/kg prednisolone

Results and discussion

Effect levels

Key result

Dose descriptor:

LOAEL

Effect level:

>= 1 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Occasionally dryness of the skin, polydipsia, slight hair loss, slow response to neurological stimulus and a slight increase in serum alkaline phosphatase was detected. Enlarged livers with increased glycogen content and pigmented Kupffer cells. Atrophy of adrenal cortex and slight irregularity and reduced activity of proliferating cartilage occurred in the bone marrow.

All animals of control and test substance group survived until termination. Three animals of positiv control were sacrificed in moibund condition during weeks 40, 41 and 48. two females died during week 44 and 56.

Applicant's summary and conclusion

Conclusions:

LOAEL: 1 mg/kg bw; NOAEL was not identified.
Fluocortolone is classified according to the Directive 67/548 EEC: Xn, R48/21/22
According to Regulation (EC) 1272/2008 (CLP) fluocortolone is classified as Cat 1 .

Executive summary:

In a study conducted comparable to OECD test guideline 452 (study performed prior to implementation of OECD guidelines) female and male Beagle dogs (3 males and 3 females per group) received fluocortolone orally at dose levels of 0, 1.0 mg/kg body weight once daily for 56 weeks; 6 days/week. Mortality was not observed at the 1.0 mg/kg bw dose group.

Effects seen in the fluorocotolon dose groups were predominantly mild and of transient character. Occasionally dryness of the skin, polydipsia, slight hair loss, slow response to neurological stimulus and a slight increase in serum alkaline phosphatase was detected. The enlarged livers showed an increased glycogen content and pigmented Kupffer cells. Atrophy was detected in the adrenal cortex and slight irregularity and reduced activity of proliferating cartilage occurred in the bone marrow.

The LOAEL was determined at > 1.0 mg/kg body weight, a NOAEL could not be determined.