Fluocortolone

Developmental toxicity / teratogenicity

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

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:

(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): Fluocortolon (ZK 10445)

Test animals

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

Administration / exposure

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.

Doses / concentrations

Doses / concentrations 1

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

Doses / concentrations 2

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

Doses / concentrations 3

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

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

>= 0.25 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects. Remark: Embryolethality

Effect levels (fetuses)

Key result

Dose descriptor:

LOAEL

Effect level:

>= 0.25 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.