Pregn-4-ene-3,20-dione, 21-(acetyloxy)-6-fluoro-11-hydroxy-16-methyl-, (6.alpha.,11.beta.,16.alpha.)-

Endpoint summary

Description of key information

Fluocortolone-A-acetate is not irritating to the skin of rats (Stark and Wick, 1998) and slightly irritating to the eyes of rabbits (Stark, 1998).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July 1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

17 July 1992

Deviations:

yes

Remarks:

exposure time 24 hrs instead of 4 hrs, 6 animals instead of 3, few details in test description and reporting

Principles of method if other than guideline:

A combined study on acute dermal toxicity and on local tolerance was used to assess skin irritation/corrosion (comparable to OECD TG 402 and 404). The study design and reporting deviates from the current OECD TG 404, however, the study is considered sufficient for assessment of this endpoint. As described in ATP 96/54/EC ANNEX IV A, PART B: METHODS FOR THE DETERMINATION OF TOXICITY AND OTHER HEALTH EFFECTS, a strategy of testing for irritancy allows the non-performance of a test if an acute toxicity study by the dermal route has been conducted at the limit test dose with the substance (method B.3), and no skin irritation was observed, further testing for skin irritation (method B.4) may be unnecessary.

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Schering AG
- Weight at study initiation: males: 278-282 g; females: 204-207g
- Housing: individually under conventional conditions
- Diet (e.g. ad libitum): ad libitum pell. Altromin® R
- Water (e.g. ad libitum): ad libitum demineralized acidified water, pH 2-3
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 64-66
- Photoperiod (hrs dark / hrs light):12/12

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

other: liquid paraffin

Controls:

other: the untreated skin served as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 556-564 mg/male animal or 408-414 mg/female animal


VEHICLE
- Amount(s) applied (volume or weight with unit): 556 and 564 mg + 0.6 ml vehicle
556 mg + 0.5 ml vehicle
408-414mg + 0.5 ml vehicle

Duration of treatment / exposure:

24 hours

Observation period:

14 days

Number of animals:

3 males and 3 females

Details on study design:

TEST SITE
- Area of exposure: not reported

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not reported


OBSERVATION TIME POINTS
day 1, 7 and 14

SCORING SYSTEM:
According to Annex I no. 1 of "Gefahrstoffverordnung, Verordnung zum Schutz vor gefährlichen Stoffen ( Gefahrstoffverordnung- GefStoffV), 6. Aufl., Stand Aug. 96

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Other effects:

none

Interpretation of results:

GHS criteria not met

Conclusions:

A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg bw (556-564 mg/male and 408 -414 mg/female applied as a paste) was tolerated without any local irritations. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0. Therefore, local application of ZK 47525 (fluocortolone-A-acetate) was tolerated without irritation of the skin.

Executive summary:

In a primary dermal irritation study equivalent to OECD test guideline 404, young adult Wistar rats (3/sex) were dermally exposed to 556 and 564 mg + 0.6 mL vehicle, 556 mg + 0.5 mL vehicle, 408-414mg + 0.5 mL vehicle of Fluocortolone acetate (100% a.i.) in liquid paraffin for 24. Animals then were observed for 14 days.  Irritation was done according to the system recommended in Directive 67/548/EEC.

 

A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg bw (556-564 mg/male and 408 -414 mg/female applied as a paste) was tolerated without any local irritations. The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Oct 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

24 February 1987

Deviations:

yes

Remarks:

4 instead of 3 animals

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River, Kisslegg
- Weight at study initiation: males: 3.3 - 4.1 kg; females: 3.7 - 3.9 kg
- Housing: individually in metal cages under conventional conditions
- Diet (e.g. ad libitum): pell. Altromin® K ad libitum
- Water (e.g. ad libitum): demineralized water ad libitum
- Acclimation period: > 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 60-62
- Photoperiod (hrs dark / hrs light):12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: the right eye, which remained untreated, served as control.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL corresponding to 39.3 - 42.6 mg

Duration of treatment / exposure:

test substance remained in the eye (eye was not rinsed)

Observation period (in vivo):

4 days

Number of animals or in vitro replicates:

2 males and 2 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing

SCORING SYSTEM: according to guideline

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Chemosis score was not determined, reddening and swelling was only investigated for the iris

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Remarks:

reddening

Basis:

mean

Time point:

24/48/72 h

Score:

0.37

Max. score:

3

Reversibility:

fully reversible within: 4 days

Irritation parameter:

conjunctivae score

Remarks:

swelling

Basis:

mean

Time point:

24/48/72 h

Score:

0.08

Max. score:

4

Reversibility:

fully reversible within: 3 days

Table 1: Results of the study

		Irritant effects (score)
Animal no. (sex)	Irritation parameter	24 h	48 h	72 h	Mean scores
1 (M)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	1	1	0	0.67
	Conjunctiva (swelling)	0	0	0	0.0
2 (M)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	0	0	0	0.0
	Conjunctiva (swelling)	0	0	0	0.0
3 (F)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	1	0	0	0.33
	Conjunctiva (swelling)	0	0	0	0.0
4 (F)	Cornea	0	0	0	0.0
	Iris	0	0	0	0.0
	Conjunctiva (reddening)	1	0	0	0.33
	Conjunctiva (swelling)	1	0	0	0.33

The control eyes were without findings.

The single application of 0.1 mL ZK 47525 (corresponding to 39.3 - 42.6 mg) into the conjunctival sac of the left eye led to slight to moderate reddening and slight to severe swelling of the conjunctivae on the administration day 1. On days 2 and 3 only slight reddening and/or swelling was observed. On day 4 (72 h after end of exposure) all animals were without findings.

Interpretation of results:

GHS criteria not met

Conclusions:

In a local tolerance test on the rabbit eye according to OECD TG 405 a single application of the test substance into the conjunctival sac provoked slight conjunctival reddening and/or swelling on study days 2 and 3. On day 4 (72 h after end of exposure) all animals were without findings. The mean values of findings relevant for classification at the time-points 24, 48 and 72 hours after application were 0.0 for the parameters cornea and iris, 0.37 for conjunctival reddening as well as 0.08 for conjunctival swelling. According to EU classification criteria ZK 47525 (fluocortolone-A-acetate) need not be labelled as an eye irritant.

Executive summary:

In a primary eye irritation study according to OECD test guideline 405 (1987), 0.1mL Fluocortolone acetate (100% a.i.) was instilled into the conjunctival sac of the left eye of young adult New Zealand White rabbits (2/sex). Animals then were observed for 4 days.  Irritation was scored by the method recommended by the guideline.

 

The single administration of 0.1 ml Fluocortolone acetate (= 39.3 - 42.6 mg) into the conjunctival sac of the left eye led to slight to moderate reddening and slight to severe swelling of the conjunctivae on the administration day. On days 2 and 3, only slight reddening and/or swelling was observed. On day 4, all animals were without finding. According to the system of evaluation recommended for EU (1), the mean values of findings relevant for classification at the time-points 24, 48 and 72 hours after administration were 0 tor the cornea and iris, 0.33 for conjunctival reddening and 0.08 for the conjunctival swelling., thus, Fluocortolone acetate does not need to be classified according to Regulation 1272/2008 (CLP) with regard to eye irritation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A single dermal administration of the test substance for 24 hours to male and female rats at a dose of 2000 mg/kg bw (556-564 mg/male and 408 -414 mg/female applied as a paste) was tolerated without any local irritations (Stark and Wick, 1998). The mean values of findings relevant for classification (reddening, scab formation and swelling of the skin) at the time-points 24, 48 and 72 hours after the end of administration were 0. Therefore, local application of fluocortolone-A-acetate was tolerated without irritation of the skin.

In a local tolerance test on the rabbit eye according to OECD TG 405 a single application of the test substance into the conjunctival sac provoked slight conjunctival reddening and/or swelling on study days 2 and 3 (Stark, 1998). On day 4 (72 h after end of exposure) all animals were without findings.The mean values of findings relevant for classification at the time-points 24, 48 and 72 hours after application were 0.0 for the parameters cornea and iris, 0.37 for conjunctival reddening as well as 0.08 for conjunctival swelling. According to EU classification criteria fluocortolone-A-acetate need not be labelled as an eye irritant.

Justification for classification or non-classification

Based on the study results a classification according to Regulation (EC) No. 1272/2008 (CLP) is not required.