Fluocortolone

Endpoint summary

Description of key information

Study report: Acute oral toxicity in Wistar rats (OECD 401); results; LD50 = 245 mg/kg bw [Günzel, 1965]
Study reports: Acute oral toxicity in NRMI mice, male and female (similar to OECD 401); results:LD50 males: 1500 mg/kg bw, LD50 females: 1300mg/kg bw [Günzel, 1969]
Study reports: Acute oral toxicity in beagle dogs, male and female (similar to OECD 401); results: In both studies the LD50 value could not be determined because no adverase erffects occurred, Highest dose tested was 100 mg/kg bw in the first study and 200 mg/kg bw in the second study. [Günzel, 1965 and 1971]

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

20. Nov to 10. Dec 1970

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

no guideline available

Principles of method if other than guideline:

Single oral administration of 200 mg/kg bw fluocortolone was applied to 3 male and 1 female dogs. Dogs were observed for 21 days and clinical signs were recorded. The animals were not sacrificed after end of study.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

dog

Strain:

other: Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG
- Weight at study initiation: 9.5-13.0 kg
- Fasting period before study: The feed was withdrawn from the animals 21 hours before application. Approx. 30 minutes before application, 100 g feed / animal were administered. After application, the animals remained without food and Water for another 24 hours in the metabolism cage. From the 2nd to the 21st day after application, the animals received food and water ad libitum.
- Housing: Single box
- Diet (e.g. ad libitum): Altromin R, ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: n/a

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Doses:

200 mg/kg bw

No. of animals per sex per dose:

3 male and 1 female dogs

Control animals:

no

Details on study design:

- Duration of observation period following administration: 21days
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs

Key result

Sex:

male/female

Effect level:

> 200 mg/kg bw

Based on:

test mat.

Mortality:

No mortality observed

Clinical signs:

other: One dogs vomited during the observation period (approx. 6-20 h) after application

Gross pathology:

Not performed

One of four animals vomited the test substance between 6 and 20 hours after application. No clinical sings were found and no animal died.

200 mg/kg bw; 3 male and 1 female beagle dog
Time	Signs	No. of dogs with signs/total no. of dogs	diagnosis
immediately after application	n/a	4/4	without pathological findings
ca. 6-20h	n/a	1/4	vomiting
	n/a	3/4	without pathological findings
2.-21. d	n/a	4/4	without pathological findings

Interpretation of results:

study cannot be used for classification

Remarks:

no severe adverse effects were observed at the dose tested.

Conclusions:

The acute oral toxicity (LD50) of fluocortolone in male and female dogs is > 200 mg/kg. Single oral administration of 200 mg/kg bw fluocortolone was applied to 3 male and 1 female dogs. One of four animals vomited the test substance between 6 and 20 hours after application. No clinical sings were found and no animal died. The animals were not sacrificed. The acute oral toxicity (LD50) of fluocortolone in male and female dogs is > 200 mg/kg.

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, beagle dogs (3 male and 1 female) were given a single oral dose of Fluocortolon as capsule at a dose of 200 mg/kg bw and were observed for 21 days.

A LD50 value could not be established due to the absence of severe adverse effects

 

After single oral administration of fluocortolone in a dose of 200 mg/kg bw to fasted female and male beagle dogs (1/3) one of the four animals vomited the test substance between 6 and 20 hours after application. No clinical sings were found. No animal died.

Fluocortolon is of LOW Toxicity based on the results in female and male beagle dogs, however, Fluocortolon cannot be classified based on the results presented here due to the absence of severe adverse effects at only one dose tested.

 

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

Fasted male and female dogs (3/sex/group ) were administered a single oral dose of 100 mg/kg bw fluocortolone. Animals were then observed for 1 day.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

dog

Strain:

other: Beagle

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

other: gummi arabicum 5% ad 100 mL Aqua dest.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 1 g in 100 mL
- Amount of vehicle (if gavage): 10 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

100 mg/kg bw applied to group of fed and group of fasted dogs

No. of animals per sex per dose:

3/sex/group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 1 day
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 100 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was reported

Clinical signs:

other: except for two dogs, one in each group that vomited after application of the substance no further signs were observed.

Gross pathology:

not performed

One of three animals of the fasted group and one of three animals of the fed group vomited the test substance between 1.5 and 2 hours after application. No clinical sings were found. no animal died.

100 mg/kg; 3 fasted dogs
Time of observation	Signs	No. of dogs with signs/total no. of dogs	diagnosis
1.5 h	n/a	3/3	without pathological findings
2 h	n/a	1/3	vomiting
		2/3	without pathological findings
4 h	n/a	3/3	without pathological findings
24 h	n/a	3/3	without pathological findings
100 mg/kg; 3 fed dogs
1.5 h	n/a	1/3	vomiting
		2/3	without pathological findings
2 h	n/a	3/3	without pathological findings
4 h	n/a	3/3	without pathological findings
24 h	n/a	3/3	without pathological findings

Interpretation of results:

study cannot be used for classification

Remarks:

no severe adverse effects were observed at the dose tested.

Conclusions:

The acute oral toxicity (LD50) of fluocortolone in male and female dogs is >100 mg/kg. Single oral administration of 100 mg/kg bw fluocortolone to fed and fasted male and female dogs (3/sex/group ) was applied. One of three animals of the fasted group and one of three animals of the fed group vomited the test substance between 1.5 and 2 hours after application. No clinical sings were found. no animal died. The acute oral toxicity (LD50) of fluocortolone in male and female dogs is >100 mg/kg.

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, beagle dogs (3/sex) were given a single oral dose of Fluocortolon in 5% gummi arabicum at a dose of 100 mg/kg bw and were observed for 1 day.

A LD50 value could not be established due to the absence of severe adverse effects

 

After single oral administration of fluocortolone in a dose of 100 mg/kg bw to fed and fasted female and male beagle dogs (3/sex) one of three animals of the fasted group and one of three animals of the fed group vomited the test substance between 1.5 and 2 hours after application. No clinical sings were found. No animal died.

Fluocortolon is of LOW Toxicity based on the results in female and male beagle dogs, however, Fluocortolon cannot be classified based on the results presented here due to the absence of severe adverse effects at only one dose tested.                                                                          

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

16. May to 11. June 1969

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not applicable

Remarks:

, pre-guideline

Principles of method if other than guideline:

- Principle of test: Female NMRI mice (10/per group) were once orally exposed to the test item at 360; 500; 720; 100; 1440; 2000 mg/kg and observed for 26 d. At the end of the observation period the animals were sacrificed and the LD 50 value was determined with a Probit-analysis

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

NMRI

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. Spiegel (not further specified)
- Weight at study initiation: 16-22 g
- Fasting period before study: 19 h
- Housing: in Groups of five animals in macrolon type II cages
- Diet (e.g. ad libitum): Altromin R, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 7 d

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

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 4 g in 100 mL
- Amount of vehicle (if gavage): 0.18 mL/20 g; 0.25 mL/20g, 0.36 mL/20 g; 0.5 mL/20 g; 0.72 mL/20 g; 1.0 mL/20g

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: 26 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, other: gross pathology

Statistics:

Probit-analysis

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 1 300 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 100 - <= 1 700

Remarks on result:

other: Probit analysis

Mortality:

Mortality occurred from 720 mg/kg bw onwards. The animals died between 3h and 26 d.

Clinical signs:

other: The most predominant clinical sign was apathy followed by clonic convulsions

Gross pathology:

The main changes were observed in the GI-tract, liver ovary and lung

After application apathy and convulsion were found in the animals starting at low dose. At autopsy, changes in the gastrointestinal tract such as ulcers, internal bleeding and enteritis were detected. Furthermore grey-white or grey-reddish foci in the liver were noted. Animals of dose group 720 mg/kg bw and above died between 3 hours and 12 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	0/10
720	2/10
1000	2/10
1440	3/10
2000	9/10

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

harmful if swallowed

Conclusions:

The acute oral toxicity (LD50) of fluocortolone in female mice is 1300 mg/kg. The main effects observed beside a premature death were: Stomach overload; Substance residues in the stomach; Ulcers and bleeding in the stomach lining; catarrhal enteritis; gray-reddish or gray-white foci in the liver. In animals that were sacrificed the following effects were observed: Ulcers in the cutaneous lining of the stomach; gray-reddish or gray-white foci in the liver.

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, NMRI mice (10 females/dose) were given a single oral dose of Fluocortolon in CMC at doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw and observed for 26 days.

Oral LD50 Males = 1300 mg/kg bw (95% C.I 1100 – 1700 mg/kg)

 

After single oral administration of fluocortolone in doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw to female NMRI mice (10/ group) apathy and convulsion were found as predominant clinical sign. At autopsy, changes in the gastrointestinal tract such as ulcers, internal bleeding and enteritis were detected. Furthermore, thickening of the gastric mucous membrane, grey-yellowish foci in the kidneys, grey-reddish discoloration of the liver were noted. Animals of dose group 720 mg/kg bw and above died between 3 hours and 26 days after application.

Fluocortolon is of MODERATE Toxicity based on the LD50 in female NMRI mice, thus, Fluocortolon is classified in Category 4 for acute oral toxicity according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).                                                                          

 

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

15. May to 9. June 1969

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not applicable

Remarks:

pre-guideline

Principles of method if other than guideline:

- Principle of test: The study was conducted prior to implementation of the respective OECD test guideline. NMRI mice (male) were orally exposed to 0.36; 0.5; 0.72; 1.0; 1.44; 2 g/kg of the test item and were observed for 25 days. The LD50 value was determined via Probit analysis.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

NMRI

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. Spiegel (not further specified)
- Weight at study initiation: 18-25 g
- Fasting period before study: 18 h
- Housing: housed in groups of five animals in macrolon cages of type II
- Diet (e.g. ad libitum): Altromin R, ad libitum
- Water (e.g. ad libitum): Tap water; ad libitum
- Acclimation period: 7 d

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

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5 g ad 100 mL Aqua dest.

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 4 g in 100 mL
- Amount of vehicle (if gavage): 0.18 mL/20 g bw; 0.25 mL/20g bw ; 0.3 mL/20 g bw; 0.5 mL/20 g bw; 0.72 mL/20 g bw; 1.0 mL/20 g bw

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

Doses:

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

No. of animals per sex per dose:

10/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 25 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, other: gross necropsy

Statistics:

Probit analysis

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 1 500 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 300 - <= 2 100

Remarks on result:

other: Probit analysis

Mortality:

Premature death occured from 720 mg/kg bw onwards after 3h to 12 d. In the 2000 mg/kg bw group 8 animals out of 10 died within the first 3 h.

Clinical signs:

other: The most predominant symptoms were apathy and clonic seizures.

Gross pathology:

GI-tract: In almost every treatment doses grous: Overload; Cutaneous mucous membrane thickened with numerous ulcers the size of millet grains. catarrhal enteritis.
Alterations in kidney, liver and lung with increasing treatment doses

After application apathy and convulsion were found starting at low dose group. At autopsy, changes in the gastrointestinal tract such as ulcers, internal bleeding and enteritis were detected. Furthermore, thickening of the gastric mucous membrane, grey-yellowish foci in the kidneys, grey-reddish discoloration of the liver, adhesion of liver and diaphragm, and abscesses in the kidneys were noted. Animals of dose group 720 mg/kg bw and above died between 3 hours and 15 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	0/10
720	1/10
1000	1/10
1440	2/10
2000	9/10

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

harmful if swallowed

Conclusions:

The acute oral toxicity (LD50) of fluocortolone in male mice is 1500 mg/kg bw.
Effects reported in prematurely died animals and in killed animals were gastric overload; Thickening and ulceration of the cutaneous gastric mucosa; submiliary bleeding catarrhal in the gastric mucosa Enteritis; grayish-yellow foci in the kidney. In killed animals: Thickening and ulcers of the cutaneous gastric mucosa; grayish reddish discoloration of the liver; adhesion between the liver and diaphragm; Kidney abscess.

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, NMRI mice (10 males/dose) were given a single oral dose of Fluocortolon in CMC at doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw and observed for 25 days.

Oral LD50 Males = 1500 mg/kg bw (95% C.I 1300 – 2100 mg/kg)

 

After single oral administration of fluocortolone in doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw to male NMRI mice (10/ group) apathy and convulsion were found as predominant clinical sign. At autopsy, changes in the gastrointestinal tract such as ulcers, internal bleeding and enteritis were detected. Furthermore, thickening of the gastric mucous membrane, grey-yellowish foci in the kidneys, grey-reddish discoloration of the liver, adhesion of liver and diaphragm, and abscesses in the kidneys were noted. Animals of dose group 720 mg/kg bw and above died between 3 hours and 15 days after application.

Fluocortolon is of MODERATE Toxicity based on the LD50 in male NMRI mice, thus, Fluocortolon is classified in Category 4 for acute oral toxicity according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).                                                                          

Reference 5

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

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

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

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.

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.

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

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).                                                                          

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

245 mg/kg bw

Quality of whole database:

The study is of sufficient quality (Klimisch score = 2)

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

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.                                                 

Additionally, 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, NMRI mice (10 males/dose) were given a single oral dose of Fluocortolon in CMC at doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw and observed for 25 days.

Oral LD50 Males = 1500 mg/kg bw (95% C.I 1300 – 2100 mg/kg)

After single oral administration of fluocortolone in doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw to male NMRI mice (10/ group) apathy and convulsion were found as predominant clinical sign. At autopsy, changes in the gastrointestinal tract such as ulcers, internal bleeding and enteritis were detected. Furthermore, thickening of the gastric mucous membrane, grey-yellowish foci in the kidneys, grey-reddish discoloration of the liver, adhesion of liver and diaphragm, and abscesses in the kidneys were noted. Animals of dose group 720 mg/kg bw and above died between 3 hours and 15 days after application.

The described experiment was repeated with female NRMI mice. Groups of fasted, NMRI mice (10 females/dose) were given a single oral dose of Fluocortolon in CMC at doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw and observed for 26 days.

Oral LD50 Males = 1300 mg/kg bw (95% C.I 1100 – 1700 mg/kg)

After single oral administration of fluocortolone in doses of 360, 500, 720, 1000, 1440, and 2000 mg/kg bw to female NMRI mice (10/ group) apathy and convulsion were found as predominant clinical sign. At autopsy, changes in the gastrointestinal tract such as ulcers, internal bleeding and enteritis were detected. Furthermore, thickening of the gastric mucous membrane, grey-yellowish foci in the kidneys, grey-reddish discoloration of the liver were noted. Animals of dose group 720 mg/kg bw and above died between 3 hours and 26 days after application.

Similar to the studies conducted with rats and mice the acute oral toxicity was also determined in beagle dogs.

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, beagle dogs (3/sex) were given a single oral dose of Fluocortolon in 5% gummi arabicum at a dose of 100 mg/kg bw and were observed for 1 day.

A LD50 value could not be established due to the absence of severe adverse effects

After single oral administration of fluocortolone in a dose of 100 mg/kg bw to fed and fasted female and male beagle dogs (3/sex) one of three animals of the fasted group and one of three animals of the fed group vomited the test substance between 1.5 and 2 hours after application. No clinical sings were found. No animal died.

 

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, beagle dogs (3 male and 1 female) were given a single oral dose of Fluocortolon as capsule at a dose of 200 mg/kg bw and were observed for 21 days.

A LD50 value could not be established due to the absence of severe adverse effects

After single oral administration of fluocortolone in a dose of 200 mg/kg bw to fasted female and male beagle dogs (1/3) one of the four animals vomited the test substance between 6 and 20 hours after application. No clinical sings were found. No animal died.

 

Justification for classification or non-classification

Based on the study results (oral LD50 in rats: 245 mg/kg bw) a classification with Acute Toxicity Cat. 3 (H301: Toxic if swallowed) is required according to Regulation (EC) No. 1272/2008 (CLP).