Fluocortolone

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1965

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:

1965

Report date:

1965

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not applicable

Remarks:

pre-guideline study

Principles of method if other than guideline:

- Principle of test: The test item was once orally applied to male and female Wistar rats in doses of 45 mg/kg, 125 mg/kg, 180 mg/kg, 250 mg/kg, 360 mg/kg, 500 mg/kg, 720 mg/kg, and 2000 mg/kg. The animals were observed for further 8 days. At the end of the observation period the animals were sacrificed if no premature death occurred and the exterior and interior appearance was recorded regardless wheter the animals died before the end of the observaqtion period or not.

GLP compliance:

no

Remarks:

study conducted prior to implementation of the respective OECD test guideline

Test type:

standard acute method

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): 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: Tierzüchter Wulf (not further specified)
- Weight at study initiation: 80-110 g
- Fasting period before study: 16- 18 hours
- Housing: conventional (1 animal per cage) in macrolon cages
- Diet (ad libitum): Altromin R, ad libitum
- Water (ad libitum): tap water, ad libitum
- Acclimation period: 4-5 days

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: gummi arabicum ad aqua dest.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 620mg, 2.5g and 10g in 100 mL
- Amount of vehicle (if gavage): dependent on concentration, for 45 mg/kg : 0.72 mL/100g bw; for 125 mg/kg: 0.5 mL/100 g bw; for 180 mg/kg: 0.72 mL/100 g bw; for 250 mg/kg: 1.0 mL/100g bw; for 360 mg/kg: 1.4 mL/100 g bw; for 500 mg/kg: 2.0 mL/100 g bw; for 720 mg/kg: 2.8 mL/100 g bw; for 2.0 g/kg: 2.0 mL/100 g bw.


DOSAGE PREPARATION (if unusual): suspension

Doses:

45, 125, 180, 250, 360, 500, 720 and 2000 mg/kg bw

No. of animals per sex per dose:

5/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 8 days
- kind of observations: clinical signs, mortality
- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, gross pathology

Statistics:

The LD50 was determined by the method of Litchfied and Wilcoxon.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

245 mg/kg bw

Based on:

test mat.

95% CL:

>= 173 - <= 347

Mortality:

Animals of the dose level of 125 mg/kg bw and above died between 2 and 8 days after application (details see table 1).

Clinical signs:

other: After single oral administration animals developed apathy from 125 mg/kg upwards.

Gross pathology:

At autopsy, hydrops ascites and fibrinous peritonitis, changes in the gastrointestinal tract such as ulcers, erosions and thickening of the gastric mucous membrane were observed. Also haemorrhagic mesenteric lymph nodes, necrobiosis of the liver, abscesses and subacute pneumonia in the lungs were noted. Adhesions of organs contained in the abdominal cavity were found.

Any other information on results incl. tables

Table 1: Number of dead animals per dose group after single oral application of fluocortolone (ZK 10445) to rats (males and females combined):

 

Dose [mg/kg]	No of dead animals/ No of treated animals
50	0/10
125	3/10
180	5/10
250	7/10
360	7/10
500	8/10
720	8/10
2000	9/10

 

 

Calculation of LD50 (Litchfield and Wilcoxon)
Dose (mg/kg)	T/E	%W	%E	D	Chi²	t
45	0/10	0	3	2.0	0.013	-----
125	3/10	30	23	7.0	0.025	5-7d
180	5/10	50	37	13.0	0.072	3-7d
250	7/10	70	51	19.0	0.140	4-8d
360	7/10	70	67	3.0	0.004	4-8d
500	8/10	80	79	1.0	-----	3-7d
720	8/10	80	88	8.0	0.060	4-7d
2000	10/10	100	99.1	0.6	0.004	2-5d

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The acute oral toxicity (LD50) of fluocortolone in male and female rats was determined to be 245 mg/kg.
From 125 mg / kg onwards sporadically, and in higher doses more accumulated, partly considerable apathy observed. The death occurred between 2 and 8 days after application. In those animals that prematurely died or were killed at 125 mg / kg miliary gray-white foci found in the liver at autopsy.
In higher doses severe gastrointestinal alterations (ulcers, bleeding, hyperemia, bloody infiltration of the mesenterial lymph nodes) and liver dystrophies) (color and consistency changes, multiple gray-white foci) were observed. As consequences hydrops ascites and fibrinous peritonitis was observed. The pathological anatomical findings primarily point to the damaging effects of the substance in the gastrointestinal tract and suggest that secondary diseases and autointoxications are a major contributor to the cause of death. This considerably limits the informative value of the LD50 p.o. as indicator for the actual lethal effect of the substance. However, based on the calculation according to Litchfield and Wilcoxon the oral LD50 for rats is 245 mg/kg bw (173 – 347 mg/kg bw).

Executive summary:

In an acute oral toxicity study similar to OECD test guideline 401 (the study was conducted prior to implementation of this guideline), groups of fasted, Wistar rats (5/sex) were given a single oral dose of  Fluocortolon in 5% gummi arabicum at doses of  45, 125, 180, 250, 360, 500, 720 and 2000 mg/kg bw and observed for 8 days.

Oral LD50 Females/Males = 245 mg/kg bw (95% C.I. 173 – 347 mg/kg)

 

After single oral administration of fluocortolone in doses of 45, 125, 180, 250, 360, 500, 720 and 2000 mg/kg bw to male and female rats (5/sex/group) apathy was found as clinical sign. At autopsy, hydrops ascites and fibrinous peritonitis were observed. Furthermore, changes in the gastrointestinal tract such as ulcers, erosions and thickening of the gastric mucous membrane were detected. Haemorrhagic mesenteric lymph nodes, necrobiosis of the liver, abscesses and subacute pneumonia in the lungs were noted. Adhesions of organs contained in the abdominal cavity were found. Animals of the dose level of 125 mg/kg bw and above died between 2 and 8 days after application.

Fluocortolon is of MODERATE Toxicity based on the LD50 in female and male Wistar rats, thus, Fluocortolon is classified in Category 3 for acute oral toxicity according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).