6 alpha-Fluoro-16 alpha-methyl-21-valeryloxy-1,4,9(11)-pregnatriene-3,20-dione

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

other information

Study period:

25. June to 17. July 1969

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1969

Report date:

1969

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Male mice received a single dose of test substance subcutaneously and were sacrificed after observation period of 23 days.

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 (ZK10445)

Test animals

Species:

mouse

Strain:

NMRI

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. Spiegel, no further information
- Weight at study initiation: 18-24 g
- Fasting period before study: 19 h
- Housing: conventional in groups of 5 animals in Macrolon cages type II
- Diet (e.g. ad libitum): Altromin R, ad libitum
- Water (e.g. ad libitum): Tap Water, ad libitum
- Acclimation period: 12 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 55-65
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

Preparation of suspension: Microcrystalsuspension made of 0.5 g carboxymethylcellulose in Aqua dest. as vehicle and 4g of test item
Applied volume:
360 mg/kg = 0.18 mL/20 g
500 mg/kg = 0.25 mL/20 g
720 mg/kg = 0.36 mL/20 g
1000 mg/kg = 0.5 mL/20 g
1440 mg/kg = 0.72 mL/20 g
2000 mg/kg = 1.0 mL/20 g

Doses:

360, 500, 720 1000, 1440 and 2000 mg/kg bw

No. of animals per sex per dose:

10/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 23 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, other: Gross pathology

Statistics:

Probit analysis

Results and discussion

Effect levels

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 811 mg/kg bw

Based on:

test mat.

95% CL:

>= 689 - <= 953

Remarks on result:

other: Probit analysis

Mortality:

Mortality occurred at animals of the 500 mg/kg dose group (1 animal at day 4) and increased with increasing dosage. 720 mg/kg group: 2 animals after 15 and 18 days; 1000 mg/kg group: 2 animals on day 10, 2 animals on day 11, 3 animals on day 12, 1 animal at day 17.
1440 mg/kg group: 3 animals on day 3; 2 animals on day 4; 1 animals on day 5; 2 animals on day 7; 2 animals on day 12.
2000 mg/kg group: 7 animals on day 3; 2 animals on day 4 and 1 animal on day 11.

Clinical signs:

The most prominent clinical sign was apathy in different degrees of strengths.

Body weight:

not reported

Gross pathology:

Prematurely died animals: Substance residues in the subcutis in the application area; thickening of the cutaneous lining of the stomach; bleeding in the lining of the glandular stomach; discoloration, decrease in consistency, bleeding and submilar gray-white foci in the liver.

Sacrificed animals: Substance residues, bleeding and abscess formation in the subcutis at the application area; scabbed areas of skin inside and outside the application area; discoloration, reduced consistency and miliary gray-white foci in the liver.

Any other information on results incl. tables

After application apathy was found in the animals starting in low dose group. At autopsy, a part of the test substance remained in the subcutis at the application side, also bleeding and abscesses in the subcutis were detected. In the gastrointestinal tract, changes such as ulcers and bleeding in the gastric mucous membrane were noted. Furthermore discoloration, bleeding and grey-white foci in the liver were observed. Animals of dose group 500 mg/kg and above died between 3 and 18 days after application.

Number of death animals per dose group:

Dose [mg/kg]	No of death animals/ all animals per group
360	0/10
500	3/10
720	5/10
1000	7/10
1440	7/10
2000	9/10

Applicant's summary and conclusion

Conclusions:

The acute subcutanous toxicity (LD50) of fluocortolone in male mice is 811 mg/kg bw. After single subcutaneous administration of fluocortolone in the doses of 360, 500, 720 1000, 1440 and 2000 mg/kg bw to male mice (10/group) apathy was found as clinical sign. At autopsy, a part of the test substance remained in the subcutis at the application side, also bleeding and abscesses in the subcutis were detected. In the gastrointestinal tract, changes such as ulcers and bleeding in the gastric mucous membrane were noted. Furthermore discoloration, bleeding and grey-white foci in the liver were observed. Animals of dose group 500 mg/kg and above died between 3 and 18 days after application.

Executive summary:

In an acute oral toxicity study, groups of fasted, NRMI mice (10 males/group) were given a single subcutaneous dose of Fluocortolon in CMC at a doses of 360, 500, 720 1000, 1440 and 2000 mg/kg bw and were observed for 23 days.

The LD50 value was determined by Probit-analysis: 811 mg/kg bw (95% C.I.: 689 – 953 mg/kg bw)

 

After single subcutaneous administration of fluocortolone in the doses of 360, 500, 720 1000, 1440 and 2000 mg/kg bw to male mice (10/group) apathy was found as clinical sign. At autopsy, a part of the test substance remained in the subcutis at the application side, also bleeding and abscesses in the subcutis were detected. In the gastrointestinal tract, changes such as ulcers and bleeding in the gastric mucous membrane were noted. Furthermore discoloration, bleeding and grey-white foci in the liver were observed. Animals of dose group 500 mg/kg and above died between 3 and 18 days after application.

Fluocortolon cannot be classified based on the results presented here due to the application site chosen. However, the results are useful as supporting information.