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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data available.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information
No effects on the development of the offspring were recorded in teratogenicity studies with fluocortolone in rats but cleft palate was observed in mice after subcutaneous administration (Poggel et al., 1973). In rabbits at a low dose high incidence in embryolethality was observed after dermal application (Korte, 1975).
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
16. Jan 1975 to 09. Apr 1975
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: breeder Scheele, Büderich
- Weight at study initiation: 2.4 - 4.4 kg
- Housing: The animals were kept for the whole period of the study in cages with perforated bottoms
- Diet (e.g. ad libitum): ad libitum, Ssniff
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 50-60
- Photoperiod (hrs dark / hrs light):12/12

Route of administration:
dermal
Vehicle:
other: ointment
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: no data
- Length of cohabitation: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
on the gestation days 6 -18 (13 days)
Frequency of treatment:
once daily
Duration of test:
until day 28 of pregnancy. Termination by caesarean section.
Dose / conc.:
2 500 mg/kg bw/day
Remarks:
as ointment with a concentration of 0.5%, corresponding to 12.5 mg/kg bw of the test item
Dose / conc.:
500 mg/kg bw/day
Remarks:
as ointment with a concentration of 0.5%, corresponding to 2.5 mg/kg bw of the test item
Dose / conc.:
50 mg/kg bw/day
Remarks:
as ointment with a concentration of 0.5%, corresponding to 0.25 mg/kg bw of the test item
No. of animals per sex per dose:
13 to 15 females/group
Control animals:
yes, concurrent vehicle
Key result
Dose descriptor:
NOAEL
Effect level:
>= 0.25 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: Embryolethality
Key result
Dose descriptor:
LOAEL
Effect level:
>= 0.25 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Reduced body weight gain in dams at the two higher dose levels. Marked treatment-related embryotoxicity at all dose levels. Embryolethality of 50% at 0.25 mg/kg bw, increasing up to 100% at high dose. no teratogenic effects.

Conclusions:
no teratogenicity effects on fetuses were observed.

Dermal application of an ointment containing 0.5 % fluocortolone was done at doses of 0.25, 2.5 or 12.5 mg/kg bw fluocortolone to the clipped and scarified skin of rabbits (13 to 15 females/group) once daily on the gestation days 6 -18. Maternal toxicity was observed as reduced body weight gain at the two higher dose levels. The NOAEL for maternal toxicity was determined at 0.25 mg/kg bw. A marked treatment-related embryotoxicity was seen at all dose levels. Even the lowest dose level led to an embryolethality of 50% which increased with increasing dose up to 100%. Teratogenic effects were not observed.
Executive summary:

In a developmental toxicity study conducted similar to OECD test guideline 414 but prior to implementation of OECD guidelines Fluocortolone (0.5% a.i. in ointment) was administered dermally to 13 to 15 female New Zealand White rabbits/dose at dose levels of 0, 50, 500, or 2500 mg ointment/kg bw/day corresponding to 0, 0.25, 2.5 and 12.5 mg test item/kg bw/day from days 6 through 18 of gestation.


 


In does a reduced body weight gain was observed at the two higher dose levels. A marked treatment-related embryotoxicity was noted at all dose levels. Embryolethality of 50% occurred at 0.25 mg/kg bw, increasing up to 100% at high dose. Teratogenic effects were not observed. The maternal NOAEL is> 0.25 mg/kg bw/day, based on reduced body weight gain in does. The developmental LOAEL is> 0.25 mg/kg bw/day, based on embryolethality.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
04. Jul 1974 to 13. Aug 1974
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Breeder W. Gassner, Sulzfeld
- Weight at study initiation: males: 360-565 g, females: 170-265 g
- Housing: cohousing in a ratio of 1:4
- Diet (e.g. ad libitum): ad libitum, Snniff
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 50-60
- Photoperiod (hrs dark / hrs light):12/12
Route of administration:
dermal
Vehicle:
other: ointment
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:4
- Length of cohabitation: over night
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
10 days (on gestation days 6 to 15)
Frequency of treatment:
once daily
Duration of test:
until day 19 of pregnancy. Termination by caesarean section.
Dose / conc.:
2 500 mg/kg bw/day
Remarks:
dose refers to ointment with a concentration 0.5%, thus corresponding to 12.5 mg test item/kg bw
Dose / conc.:
500 mg/kg bw/day
Remarks:
dose refers to ointment with a concentration 0.5%, thus corresponding to 2.5 mg test item/kg bw
Dose / conc.:
50 mg/kg bw/day
Remarks:
dose refers to ointment with a concentration 0.5%, thus corresponding to 0.25 mg test item/kg bw
No. of animals per sex per dose:
21 or 23 pregnant females/dose
Control animals:
yes, concurrent vehicle
Key result
Dose descriptor:
NOAEL
Effect level:
>= 0.25 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

The dermal application led to a dose-related reduction of body weight gain in dams at doses of 2.5 and 12.5 mg/kg. No effect on embryos as well as on fetal viability. A relatively high incidence of skeletal variations in fetuses of all groups including controls. Although the nature of these skeletal variations is known from the control group and from earlier control groups, the frequency with which this variation occurs in the dose groups may be an indication of a possible teratogenic effect of the administered substance.

Conclusions:
no proven treatment-related effects on fetuses were observed.
Dermal application of an ointment containing 0.5 % fluocortolone was done at doses of 0.25, 2.5 or 12.5 mg/kg bw fluocortolone to the clipped and scarified skin of rabbits (13 to 15 females/group) once daily on the gestation days 6 -18. Maternal toxicity was observed as reduced body weight gain at the two higher dose levels. The NOAEL for maternal toxicity was determined at 0.25 mg/kg bw. A marked treatment-related embryotoxicity was seen at all dose levels. Even the lowest dose level led to an embryolethality of 50% which increased with increasing dose up to 100%. Teratogenic effects which could be exclusively related to treatment were not observed.
Executive summary:

In a developmental toxicity study conducted equivalent to OECD test guideline 414 Fluocortolon (100% a.i.) was dermally administered to 21 or 23 of female Sprague Dawley rats/dose as ointment (concentration 0.5%) at dose levels of 0.25, 2.5 and 12.5 mg/kg bw/day from days 6 through 15 of gestation.


After application of 2.5 mg/kg or 12.5 mg/kg of the test item, the effect in dams was a strong dose-dependent reduction in the average body weight gain during the treatment period. The maternal NOAEL is considered to be > 0.25 mg/kg bw/day, based on reduced body weight gain.


After treatment with 0.25, 2.5 and 12.5 mg/kg bw in 12, 14, and 14 fetuses of each group which were examined for skeletal malformations some variations were observed. These variations consisted mainly of rip deformations which are known to occur also in control groups but based on the increased frequency of these variations in the treatment groups a teratological effect cannot be excluded. Moreover, an embryotoxicity was observed in every dose group. However, an effect level for developmental toxicity could not be derived.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
no guideline available
Principles of method if other than guideline:
For dose level determination in main study preliminary study was conducted with following doses: 5, 10, 20, 35 and 50 mg/kg with 7-10 animals (rats or mice) /group. Pregnant animals reveived test substance from gestation day 7 to 13. Termination by caesarean section on day 21 (rat) or 18 (mouse).

Teratogenicity study: 15 dams/group were exposed to fluocortolone (5 or 10 mg/kg for rats; 5 or 20 mg/kg for mice) on gestation day 7 to 13. Termination by caesarean section on day 21 (rat) or 18 (mouse).

Postnatal study: 5 dams/group were exposed to fluocortolone (5 or 10 mg/kg for rats; 5 or 20 mg/kg for mice) on gestation day 7 to 13. Dams remained for spontanous delivery. Termination of study on day 21 post partum.
GLP compliance:
no
Limit test:
no
Species:
other: rats and mice
Strain:
other: Rat: SD-JCL strain; Mouse: ICR-JCl strain
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Nippon-Clare, Osaka
- Age at study initiation: rats: 10-13 weeks, mice 8-10 weeks
- Housing: cohoused over night
- Diet (e.g. ad libitum): ad libitum, solid food CA-1 supplied by.Nippon-Clare
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 50-60
Route of administration:
subcutaneous
Vehicle:
castor oil
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: over night
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
7 days (on gestation days 7 to 13)
Frequency of treatment:
once daily
Duration of test:
15 rats/group until day 21 of pregnancy. Termination by caesarean section.
5 dams remained for spontanous delivery. Termination of study on day 21 post partum
15 mice/group until day 18 of pregnancy. Termination by caesarean section.
5 dams remained for spontanous delivery. Termination of study on day 21 post partum
Dose / conc.:
20 mg/kg bw/day
Remarks:
mice high dose, main experiment
Dose / conc.:
10 mg/kg bw/day
Remarks:
high dose rats, main experiment
Dose / conc.:
5 mg/kg bw/day
Remarks:
mice and rats, low dose, main experiment
Dose / conc.:
50 mg/kg bw/day
Remarks:
preliminary study
Dose / conc.:
35 mg/kg bw/day
Remarks:
preliminary study
Dose / conc.:
20 mg/kg bw/day
Remarks:
preliminary study
Dose / conc.:
10 mg/kg bw/day
Remarks:
preliminary study
Dose / conc.:
5 mg/kg bw/day
Remarks:
preliminary study
No. of animals per sex per dose:
20 pregnant females/dose
Control animals:
yes, concurrent vehicle
Key result
Dose descriptor:
NOAEL
Remarks:
mouse
Effect level:
>= 5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
>= 10 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: cleft palate in mice
Key result
Dose descriptor:
NOAEL
Remarks:
mouse
Effect level:
>= 5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Effect level:
>= 5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Key result
Dose descriptor:
LOAEL
Remarks:
mouse
Effect level:
>= 5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Preliminary dose selection study: Rats: at >20 mg/kg almost all rat fetuses and at 10 mg/kg ca. half fetuses were resorbed or dead. The number of death in dams were 8/10 at 50 mg/kg, 10/10 at 35 mg/kg, 7/10 at 20 mg/kg and 1/8 in 10 mg/kg.


Mice: at >35 mg/kg almost all fetuses and at 20 mg/kg ca. half fetuses were resorbed or dead. In high dose group (50 mg/kg) 1/10 mouse died.


 


Teratogenicity study: Reduced body weight gain in mouse dams. Increase in embryomortality in mice and rats. Dose dependent occurrence of cleft palate in mice.


 


Post natal study: no substance-related effects observed.

Conclusions:
Teratogenic effects in mice were observed.
Rats and mice (20 female/group) were treated subcutanously with fluocortolone at dose levels of 0, 5 or 10 mg/kg for (rats) and 0, 5 or 20 mg/kg (mouse) once daily on gestation days 7 -13. 15 dams per species were sacrificed via ceasarean section on day 18 (mouse) or 21 (rat) of pregnancy. 5 dams per species were kept for spontanous delivery. Study was terminated on day 21 post partum. Maternal toxicity was seen as a treatment-related reduction of body weight gain in mice at 20 mg/kg bw. The NOAEL for maternal toxicity was 5 mg/kg bw. Embryo lethal effects could be observed in mice and rats at high dose (NOAEL: 5 mg/kg for rats ans mice). No treatment-related teratogenic effects occurred in rats, but dose dependence occurrence of cleft palate was observed in mice. Substance related effects in offsprings did not occur.
Executive summary:

In a developmental/teratogenicity study conducted prior to implementation of OECD guidelines Fluocortolone (100 % a.i.) was administered subcutaneously to 20 female SD-JCL rats or ICR-JCL mice/dose in castor oil at dose levels of 0, 5 and 10 or 5 and 20 mg/kg bw/day, respectively, from days 7 through 13 of gestation.


In the preliminary study in rats at the dose of 20 mg/kg bw and 10 mg/kg bw respectively almost all rat fetuses were resorbed or dead and half of the rat fetuses were resorbed or dead. The number of dead animals in dams were 8/10 at 50 mg/kg, 10/10 at 35 mg/kg, 7/10 at 20 mg/kg and 1/8 in 10 mg/kg. In mice almost all fetuses were resorbed or dead at 35 mg/kg bw and at 20 mg/kg bw approximately half of the fetuses were resorbed or dead. In the high dose group (50 mg/kg bw) one mouse died.


In the main study a reduced body weight was determined in mouse dams at 20 mg/kg bw. Embryo lethality was observed in the high dose groups in both rats and mice. Cleft palate was observed in both high dose groups in rats and mice although there was only one case in rats and 4 cases in mice. However, cleft palate was also detected in the low dose group in mice (2 cases) and in the high dose group one case of the higher dosage group showed costal fusion and 1 of the lover dosage group sternal fusion as the symptom of skeletal malformation. The maternal NOAEL is > 10 mg/kg bw/day in rats and > 5 mg/kg bw in mice.


The growth in offspring of rats was not affected by the drug. No abnormalties were found. Both the treated groups and the control presented no external, thoracic and abdominal and skeletal malformations. Similar findings were made for the mice offspring. The drug exhibited no effecton the growth of offsprings. At the 21st day after birth, the skin, the auditory system and the behaviour in general were all normal. No external, thoracic and abdominal, and skeletal malformations were observed in both the treated groups and the control. The developmental LOAEL is > 5mg/kg bw/day in mice , based on on the increased incidence of cleft palate. The developmental NOAEL is > 5 mg/kg bw/day in both species based on the embryotoxicity that increased also fetal mortality in the high dose groups.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
07. Jul 1971 to 04. Oct 1971
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Breeder Gassner
- Weight at study initiation: females: 175-225 g
- Housing: during acclimation in groups, for treatment cohoused in a ratio of 1:4
- Diet (e.g. ad libitum): ad libitum, Altromin R
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 50-70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
physiological saline
Remarks:
microcrystal suspension
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 3 mg ad 100 mL, 10 mg ad 100 mL

VEHICLE
- Amount of vehicle (if gavage): 1 mL/100 g bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:4
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
10 days (on gestation days 6 to 15)
Frequency of treatment:
once daily
Duration of test:
until day 19 of pregnancy. Termination by caesarean section.
Dose / conc.:
1 mg/kg bw/day
Dose / conc.:
0.3 mg/kg bw/day
No. of animals per sex per dose:
20 pregnant females/dose
Control animals:
yes, concurrent vehicle
Key result
Dose descriptor:
NOAEL
Effect level:
>= 0.3 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal toxicity: dose-related reduction of body weight gain from 1 mg/kg bw.

No toxic effects on embryos or fetuses and no treatment-related teratogenic effects.

Conclusions:
No effects on fetuses with clear treatment-relationship were observed.

Rats (20 female/group) were treated orally with fluocortolone at dose levels of 0, 0.3 or 1.0 mg/kg bw once daily on the gestation days 6 -15. Maternal toxicity was seen as a treatment-related reduction of body weight gain at 1 mg/kg bw. The NOAEL for maternal toxicity was 0.3 mg/kg bw. No toxic effects on embryos or fetuses and no treatment-related teratogenic effects occurred.

Isolated malformations were seen in treated and in control animals without a clear treatment relationship.
Executive summary:

In a developmental toxicity study conducted equivalent to OECD test guideline 414 Fluocortolon (100% a.i.) was administered to 20 of female Sprague Dawley rats/dose in 0.9% NaCl by gavage at dose levels of 0.3 and 1.0 mg/kg bw/day from days 6 through 15 of gestation.


After application of 0.3 mg/kg or 1.0 mg/kg of the test item, the only statistically verified (p = 0.05) substance-related effect in the dams was a dose-dependent reduction in the average body weight gain during the treatment period in the 1.0 mg/kg bw group females. The maternal NOAEL is considered to be > 0.3 mg/kg bw/day, based on reduced body weight gain.


No other substance-related changes were observed in either the dams or the fetuses. Thus, no effect level could be determined for developmental toxicity.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
17. Sep 1969 to 10. Oct 1969
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Breeder Gassner
- Weight at study initiation: males: 280-496 g; females: 184-288 g
- Housing: cohoused in a ratio of 1:4
- Diet (e.g. ad libitum): ad libitum, Altromin R
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light):12/12

Route of administration:
oral: gavage
Vehicle:
physiological saline
Remarks:
0.85 g Myrj 52 + 9 g NaCl. in 1000 mL Aqua dest.
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: microcrystal suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.85 g Myrj 52 + 9 g NaCl in 1000 mL Aqua dest.
- Concentration in vehicle:
I 3 mg in 100 mL
II 10 mg in 100 mL
- Amount of vehicle (if gavage): 1 mL/100 g bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:4
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
10 days (on gestation days 6 to 15)
Frequency of treatment:
once daily
Duration of test:
until day 19 of pregnancy. Termination by caesarean section.
Dose / conc.:
1 mg/kg bw/day
Dose / conc.:
0.3 mg/kg bw/day
No. of animals per sex per dose:
20 pregnant females/dose
Control animals:
yes, concurrent vehicle
Key result
Dose descriptor:
LOAEL
Effect level:
>= 0.3 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal toxicity: dose-related reduction of body weight gain from 0.3 mg/kg bw.

No toxic effects on embryos or fetuses and no treatment-related teratogenic effects.

Isolated malformations were seen in treated and in control animals without a clear treatment relationship.

Conclusions:
No effects on fetuses with clear treatment-relationship were observed
Executive summary:

In a developmental toxicity study conducted equivalent to OECD test guideline 414 Fluocortolon (100% a.i.) was administered to 20 of female Sprague Dawley rats/dose in 0,85 g Myrj 52 + 9 g NaCl in 1000 mL Aqua dest.by gavage at dose levels of 0.3 and 1.0 mg/kg bw/day from days 6 through 15 of gestation.


After application of 0.3 mg/kg or 12.0 mg/kg of the test item, the only statistically verified (p = 0.05) substance-related effect in the dams was a dose-dependent reduction in the average body weight gain during the treatment period. The maternal LOAEL is considered to be > 0.3 mg/kg bw/day, based on reduced body weight gain.


A correlation between the anomaly observed after application of 0.3 mg/kg of the test item (anophthalmia on both sides and malformation of the brain) and the application of the substance seems unlikely, since the anomaly occurred only once and was not dose-dependent. However, a connection cannot be excluded. All other anomalies observed (deviations in the ossification of the vertebral bodies and the occipital bone, tail aplasia) are known in terms of type and frequency as spontaneous malformations in untreated animals of the rat strain used. Thus, no effect level could be determined for developmental toxicity.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Study period:
11. Dec 1968 to 6. Jan 1969
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: breeder Gassner
- Weight at study initiation: males: 238-313 g; females: 183-240 g
- Housing: cohousing in a ratio of 1:4
- Diet (e.g. ad libitum): ad libitum, Altromin R
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23
- Humidity (%): 55-65
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
physiological saline
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: microcrystal suspension

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0,85 g Myrj 52 + 9 g NaCl in 1000 mL Aqua dest.
- Concentration in vehicle:
I = 3 mg in 100 mL
II = 10 mg in 100 mL
- Amount of vehicle (if gavage): 1 mL/100 g bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:4
- Length of cohabitation: no data
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
10 or 11 days (on gestation days 6 to 15/16)
Frequency of treatment:
once daily
Duration of test:
until day 19 of pregnancy. Termination by caesarean section.
Dose / conc.:
2 mg/kg bw/day (nominal)
Dose / conc.:
0.2 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20 pregnant females/dose
Control animals:
yes, concurrent vehicle
Key result
Dose descriptor:
LOAEL
Effect level:
>= 0.2 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal toxicity was seen as a dose-related reduction of body weight gain from 0.2 mg/kg bw. No toxic effects on embryos or fetuses and no treatment-related teratogenic effects occurred. Isolated malformations were seen in treated and in con­trol animals without a clear treatment-relationship.

Conclusions:
no effects on fetuses with clear treatment-relationship were observed
Executive summary:

 


In a developmental toxicity study conducted equivalent to OECD test guideline 414 Fluocortolon (100% a.i.) was administered to 20 of female Sprague Dawley rats/dose in 0,85 g Myrj 52 + 9 g NaCl in 1000 mL Aqua dest.by gavage at dose levels of 0, 0.2 and 2.0 mg/kg bw/day from days 6 through 15-16 of gestation.


After application of 0.2 mg/kg or 2.0 mg/kg of the test item, the only statistically verified (p = 0.05) substance-related effect in the dams was a dose-dependent reduction in the average body weight gain during the treatment period. The maternal LOAEL is considered to be > 0.2 mg/kg bw/day, based on body weight loss.


Some of the anomalies found in the fetuses (delayed ossification of the 19th vertebral body, two foci of ossification in the 20th, vertebral bodies, two foci of ossification in the 18th and 19th vertebral bodies, umbilical hernia) occurred sporadically and are known to be spontaneous malformations of the type found in untreated animals of the rat strain used. The following anomalies were found after application of the test item that have not yet been observed in control animals:



  1. Subcutaneous and intermuscular hemorrhage dorsally in the area of thoracic vertebrae 2 - 3 (0.2 mg/kg and 2.0 mg/kg).

  2. Tail aplasia, anatresia, dislocation of the uterus and absence of ovaries and adrenal glands (2.0 mg/kg).

  3. Heavily blood-filled atria (2.0 mg/kg).


A correlation between the anomalies and the substance application cannot be excluded.


The subcutaneous and intermuscular hemorrhages, as well as the heavy accumulation of blood in the atria of the heart, however, can also be a consequence of mechanical manipulation after the fetuses have been obtained by caesarean section. Thus, no effect level could be determined for developmental toxicity.


 

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
0.25 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Additional information

Maternal toxicity was seen as a dose-related reduction of body weight gain from 0.2 mg/kg bw. No toxic effects on embryos or fetuses and no treatment-related teratogenic effects occurred. Isolated malformations were seen in treated and in control animals without a clear treatment- relationship (Korte, 1969).


 


Rats (20 females/group) were treated orally with fluocortolone at dose levels of 0, 0.3 or 1.0 mg/kg bw once daily on the gestation days 6 -15. Maternal toxicity was seen as a dose-related reduction of body weight gain from 0.3 mg/kg bw. No toxic effects on embryos or fetuses and no treatment-related teratogenic effects occurred. Isolated malformations were seen in treated and in control animals without a clear treatment relationship (Korte, 1970).


 


Rats (20 female/group) were treated orally with fluocortolone at dose levels of 0, 0.3 or 1.0 mg/kg bw once daily on the gestation days 6 -15. Maternal toxicity was seen as a treatment-related reduction of body weight gain at 1 mg/kg bw. The NOAEL for maternal toxicity was 0.3 mg/kg bw. No toxic effects on embryos or fetuses and no treatment-related teratogenic effects occurred.


Isolated malformations were seen in treated and in control animals without a clear treatment relationship (Korte, 1971).


 


Pregnant rats and mice (20 female/group) were treated subcutanously with fluocortolone at dose levels of 0, 5 or 10 mg/kg for (rats) and 0, 5 or 20 mg/kg (mouse) once daily on gestation days 7 -13. 15 dams per species were sacrificed via ceasarean section on day 18 (mouse) or 21 (rat) of pregnancy. 5 dams per species were kept for spontanous delivery. Study was terminated on day 21 post partum. Maternal toxicity was seen as a treatment-related reduction of body weight gain in mice at 20 mg/kg bw. The NOAEL for maternal toxicity was 5 mg/kg bw. Embryo lethal effects could be observed in mice and rats at high dose (NOAEL: 5 mg/kg for rats ans mice). No treatment-related teratogenic effects occurred in rats, but dose dependence occurrence of cleft palate was observed in mice. Substance-related effects in offsprings did not occur (Poggel et al., 1973).


 


Dermal application of an ointment containing 0.5 % fluocortolone was done at doses of 0, 0.25, 2.5 or 12.5 mg/kg bw fluocortolone to the clipped and scarified skin of rats (20 to 23 females/group) once daily on the gestation days 6 -15. The dermal application led to a dose-related reduction of body weight gain in dams at doses of 2.5 and 12.5 mg/kg bw fluocortolone. Therefore the maternal NOAEL was determined at 0.25 mg/kg bw. The treatment had no effect on embryos as well as on fetal viability. A relatively high incidence of skeletal variations was seen in fetuses of all groups including controls, but there was no treatment relationship evident (Poggel, 1975).


 


Dermal application of an ointment containing 0.5 % fluocortolone was done at doses of 0.25, 2.5 or 12.5 mg/kg bw fluocortolone to the clipped and scarified skin of rabbits (13 to 15 females/group) once daily on the gestation days 6 -18. Maternal toxicity was observed as reduced body weight gain at the two higher dose levels. The NOAEL for maternal toxicity was determined at 0.25 mg/kg bw. A marked treatment-related embryotoxicity was seen at all dose levels. Even the lowest dose level led to an embryolethality of 50% which increased with increasing dose up to 100%. Teratogenic effects were not observed (Korte, 1975).


 


Additionally results of developmental toxicity studies with fluocortolone are cited in RTECS database (Jun 2010):


 


Subcutaneous daily application to rabbits on gestation day 6 to 15 results post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants), TDLo: 2500 ug/kg (6-15D preg) [AMI-Berichte. (, Fed. Rep.) No. 1-2, 1978-82. v. (1), p. 127, 1988 (AMBED4).]


 


Daily subcutaneous administration of fluocortolone to rabbits on gestation day 7 to 18 results effects on fetotoxicity (except fetal death), developmental abnormalities of the central nervous system and of craniofacial abnormalities (including nose and tongue); TDLo: 30 mg/kg (7-18D preg) [ Yakubutsu Ryoho. Medicinal Treatment. (,) V.1-14, 1968-81.Suspended. v. 10, p. 151, 1977 (YKRYAH)]


 


Oral single application to mice on gestation day 12 results in fetotoxicity at TDLo: 20 mg/kg (12D preg) and in fetal death at TDLo: 70 mg/kg (12D preg) [Yakubutsu Ryoho. Medicinal Treatment. (Tokyo, Japan) V.1-14, 1968-81.Suspended. v. 9, p. 1623, 1976 (YKRYAH)]


 


Oral and subcutaneous single administration to mice on gestation day 13 results in craniofecial developmental abnormalities (including nose and tongue); TDLo: 70 mg/kg (13D preg) [Yakubutsu Ryoho. Medicinal Treatment. (Tokyo, Japan) V.1-14, 1968-81.Suspended. v. 9, p. 1623, 1976 (YKRYAH)]


 


In summary, no effects on the development of the offspring were recorded in teratogenicity studies with fluocortolone in rats but cleft palate was observed in mice. This effect can be considered as indication for possible teratogenic effects. In rabbits treated with a low dose a high incidence in embryo lethality was observed.


Thus, it can be considered that if exposure is sufficiently high, embryolethal and/or teratogenic effects can be induced with glucocorticoids in suitable test systems in animal experiments.


However, epidemiological studies in humans have so far not yielded an evidence for embryotoxic or teratogenic effects from systemic glucocorticoid therapy. On the other hand, the occurrence of low birthweights and low placental weights after long-term therapy with glucocorticoids in humans was judged to be an embryotoxic effect and thus glucocorticoids are classified as RD: Cat: 1A. For precautionary reasons also a classification as RF: Cat. 2 was used because glucocorticoids in unphysiologically high concentrations are expected to negatively influence fertility via the pituitary-gonadal axis. (see also German technical guidelines for hazardous substances [TRGS 905 latest version 13.03.2020] which are based on the German regulation for hazardous substances [GefStoffV, latest amended version 21.07.2021])


Based on the available information Fluocortolone is classified according to Regulation (EU) No. 1272/2008 (CLP) and German regulation for hazardous substances [GefStoffV, latest amended version 21.07.2021] as toxic to reproduction RD: 1A and RF: 2.


 

Toxicity to reproduction: other studies

Description of key information

No data available.

Justification for classification or non-classification

Regarding toxicity to reproduction the following self classification of fluocortolone is required according to Regulation (EC) No.1272/2008 (CLP) :


Repr. 1A (H360Df: May damage the unborn child. Suspected of damaging fertility).


 


The classification is in accordance with German legislation for classification of glucocorticoides. The German Committee on Hazardous Substances (AGS) recommended for glucocorticoides classification as Repr. Cat. 2 for effects on fertility and Repr. Cat. 1A for developmental toxicity each according to criteria of CLP Regulation, Annex I.


(see Technical Rule for Hazardous Substances 905; elaborated by the German Committee on Hazardous Substances (AGS) and published by the German Federal Ministry of Labour and Social Affairs, version: 13.03.2020, only available in German, URL http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Begruendungen- 905-906.html).


The associated documentation and justification for grouping steroid hormones and their classification was published in Sep. 1999. Fluocortolone is mentioned in attachment 2 on page 15.

Additional information