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: 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:

1966

Report date:

1966

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:

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): 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: capsule

Vehicle:

other: cornstarch

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: capsules

DIET PREPARATION
The dosage was administered in gelatin capsules, six days per week, with the high level animals receiving half their dosage in the morning and half in the afternoon about four and one-half hours apart.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

54 weeks

Frequency of treatment:

daily, 6 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

No. of animals per sex per dose:

4/sex/dose

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Mortality:

mortality observed, treatment-related

Description (incidence):

All of the dogs on
the 50 mg/kg dosage level of SH 742 died or were sacrificed in moribund condition within 16 weeks. Except for dog No. 4448 M in the partial sacrifice at 15 weeks, all of the dogs on the 9.0 mg/kg dosage level died or were sacrificed in moribund condition within 43 weeks. Dogs 4451 M and 4499 F on the 3.0 mg/kg dosage level were in the partial sacrifice at 15 weeks. Dogs 4395 M and 4555 M on this low level died during weeks 32 and 54, respectively. The other four dogs on the 3.0 mg/kg level survived until termination of the experiment.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

All of the animals on the 50 mg/kg dosage level ofthe test compound lost from 1.2 to 6.1 kilograms of bodyweight be fore being autopsied. Two of the males and three of the females on the 9.0 mg/kg level lost from 0.9 to 4.0 kilograms of body weight before being autopsied. Dog No. 4395 M on the 3.0,mg/kg level lost 1.4 kilograms and dog NO. 4555 M lost 0.6 kilogram prior to death. Each of the four 3.0 mg/kg animals that survived gained at least 1.0 kilogram of body weight more than any of the controls.

Effect levels

Key result

Dose descriptor:

LOAEL

Effect level:

>= 3 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

All dogs of the highest and of the medium dose level died or were sacrificed in moribund condition within 43 weeks (medium dose group) respectively 16 weeks (highest dose group). Two dogs of the low dose group died in weeks 32 and 54.

Toxic effects were seen after 3 weeks (high dose) or later (17-29 weeks for the low dose) with a distinct dose dependency. Increased mortality, decreased body weight and food consumption, slight to moderate polyuria and polydipsia, swollen neck lymph nodes, fat deposition in the subcutis, alopecia, (bloody) diarrhoea, vomiting, neurological effects, lowering of the body temperature, dehydration, head muscle degeneration and disturbance of the electrolyte balance occurred.

Atrophy of the lymphoreticular tissue was predominant with a concurrent decrease in blood leukocyte count and haemoglobin concentration and bone marrow hypocellularity. Serum alkaline phosphatase values were elevated proportional to dose.

Increased liver weight was correlated with an increased deposition of glycogen and pigment. The kidney, the adrenal glands, and the cartilages were likewise affected by degenerative and atrophic changes.

Applicant's summary and conclusion

Conclusions:

Dogs (4 males and 4 females per group) received fluocortolone orally at dose levels of 0, 3.0, 9.0 or 50 mg/kg body weight once daily for 54 weeks. All dogs of the highest and of the medium dose level died or were sacrificed in moribund condition within 43 weeks (medium dose group) respectively 16 weeks (highest dose group). Two dogs of the low dose group died in weeks 32 and 54.
Toxic effects were seen after 3 weeks (high dose) or later (17-29 weeks for the low dose) with a distinct dose dependency.
The LOAEL was determined at 3.0 mg/kg body weight, a NOAEL was not determined.

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 (4 males and 4 females per group) received fluocortolone orally at dose levels of 0, 3.0, 9.0 or 50 mg/kg body weight once daily for 54 weeks; 6 days/week. All dogs of the highest and of the medium dose level died or were sacrificed in moribund condition within 43 weeks (medium dose group) respectively 16 weeks (highest dose group). Two dogs of the low dose group died in weeks 32 and 54.

Toxic effects were seen after 3 weeks (high dose) or later (17-29 weeks for the low dose) with a distinct dose dependency. Increased mortality, decreased body weight and food consumption, slight to moderate polyuria and polydipsia, swollen neck lymph nodes, fat deposition in the subcutis, alopecia, (bloody) diarrhoea, vomiting, neurological effects, lowering of the body temperature, dehydration, head muscle degeneration and disturbance of the electrolyte balance occurred.

Atrophy of the lymphoreticular tissue was predominant with a concurrent decrease in blood leukocyte count and haemoglobin concentration and bone marrow hypocellularity. Serum alkaline phosphatase values were elevated proportional to dose.

Increased liver weight was correlated with an increased deposition of glycogen and pigment. The kidney, the adrenal glands, and the cartilages were likewise affected by degenerative and atrophic changes.

The LOAEL was determined at 3.0 mg/kg body weight, a NOAEL could not be determined.