6 alpha-Fluoro-16 alpha-methyl-21-valeryloxy-1,4,9(11)-pregnatriene-3,20-dione

Developmental toxicity / teratogenicity

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1973

Materials and methods

Test guideline

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

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:

6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione

Details on test material:

- Name of test material (as cited in study report): Fluocortolone (ZK 10445)

Test animals

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

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 mg/kg bw/day

Remarks:

mice high dose, main experiment

Doses / concentrations 2

Dose / conc.:

10 mg/kg bw/day

Remarks:

high dose rats, main experiment

Doses / concentrations 3

Dose / conc.:

5 mg/kg bw/day

Remarks:

mice and rats, low dose, main experiment

Doses / concentrations 4

Dose / conc.:

50 mg/kg bw/day

Remarks:

preliminary study

Doses / concentrations 5

Dose / conc.:

35 mg/kg bw/day

Remarks:

preliminary study

Doses / concentrations 6

Dose / conc.:

20 mg/kg bw/day

Remarks:

preliminary study

Doses / concentrations 7

Dose / conc.:

10 mg/kg bw/day

Remarks:

preliminary study

Doses / concentrations 8

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

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

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

2

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

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: cleft palate in mice

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Remarks:

mouse

Effect level:

>= 5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

2

Key result

Dose descriptor:

NOAEL

Remarks:

rat

Effect level:

>= 5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

3

Key result

Dose descriptor:

LOAEL

Remarks:

mouse

Effect level:

>= 5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.