Betamethasone

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non-guideline study, some restrictions in design and/or reporting but otherwise adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Disproportionate growth of organs and body weight following glucocorticoid treatment of the rat fetus

Author:

Mosier, H.D. Jr; Dearden, L.C.; Jansons, R.A.; Roberts, R.C.; Biggs, C.S.

Year:

1982

Bibliographic source:

Dev. Pharmacol. Ther. 1982, 4, 89-105.

Materials and methods

Principles of method if other than guideline:

A mixture of betamethasone sodium phosphate and betamethasone acetate suspension (commercial dosage form) was administerd to Long-Evans rats during the first pregnancy, in a dose of 0.18 or 0.42 mg/injection, by subcutaneous injection on days 12 and 13 of gestation. All rats were weighed on day 12 of gestation prior to injections and again on day 21. Rats were sorted into experimental and control grups on the basis of body weight in order to provide similar means and variances of body weight between groups.
Control rats were injected with physiological saline.
Fetuses were removed on day 21 of gestatiojn under ether anesthesia, bled from the neck, weighed and examined for gross malformations. In fetuses used for organ weight determinations the abdiminal cavities were opened to enhance fixation and the fetuses were placed in 10% phosphate-buffered neutral formalin. Brain, heart, liver, adrenals, and kidneys were removed from the formalin-fixed fetuses, dissected free of surrounding tissues, blotted, and weighed on a semi-micro balance.
Statistical significance was determined by a one-tailed Student's t test or by calculation of the chi square statistic.

GLP compliance:

not specified

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Betamethasone sodium phosphate

IUPAC Name:

Betamethasone sodium phosphate

Constituent 2

Reference substance name:

Betamethasone acetate

IUPAC Name:

Betamethasone acetate

Details on test material:

- Name of test material (as cited in study report): mixture of betamethasone sodium phosphate and betamethasone acetate suspension

Test animals

Species:

rat

Strain:

Long-Evans

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Labs (Gilroy, California)
- Housing: Except during breeding, all animals were housed individually in stainless steel cages (hanging type) 7x7x10 inches in size
- Diet: ad libitum
- Water: tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 - 23.9°C
- Photoperiod (hrs dark / hrs light): 10/14 hrs
- Animal handling was carried out by the same attendant

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

other: water; dibasic sodium phosphate; monobasic sodium phosphate; edetate disodium; and benzalkonium chloride.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 days, on day 12 and 13 of gestation

Frequency of treatment:

daily

Duration of test:

From the day of appearance of vaginal plug, that was designed as day 1 of gestation, to day 21.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.18 mg/injection
Basis:
nominal conc.
corresponding to ca. 0.38 mg/kg bw at day 12 of pregnancy

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.42 mg/injection
Basis:
nominal conc.
corresponding to ca. 0.89 mg/kg bw at day 12 of pregnancy

No. of animals per sex per dose:

5 rats for 0.18 mg/injection
5 rats for 0.42 mg/injection

Control animals:

other: yes, injected with physiological saline

Statistics:

Statistical significance was determined by a one-tailed Student's t test or by calculation of the chi square statistic.

Results and discussion

Any other information on results incl. tables

	Control	Betamethasone 0.18 mg	Betamethasone 0.42 mg
RATS N.	6	5	5
Weight (g) on day 12	283.7 ± 7.2	285.8 ± 8.3	289.2 ± 12.8
Weight (g) on day 21	369.2 ± 6.6	337.0 ± 10.4 (p<0.025)	305.6 ± 17.6 (p<0.005)
Litters, N.	16	14	17
N. fetuses/litter	10.19 ± 0.44	10.00 ± 0.47	9.82 ± 0.71
Incidence of cleft palate	0/154	n.a.	3/47 (p<0.0017)
Incidence of omphalocele	0/348	8/127 (p<0.0001)	13/140 (p<0.0001)
Body weight, g (N. of fetuses)	4.03 ± 0.04 (178)	3.85 ± 0.05 (54) (p<0.01)	2.75 ± 0.13 (36) (p<0.005)
Brain weight, mg (N. of fetuses)	203.3 ± 1.66 (178)	216.9 ± 1.79 (53) (p<0.05)	203.4 ± 0.66 (36)
Heart weight, mg (N. of fetuses)	24.73 ± 0.35 (177)	23.50 ± 0.41 (54) (p<0.05)	19.44 ± 0.66 (36) (p<0.005)
Liver weight, mg (N. of fetuses)	359.5 ± 3.48 (176)	287.2 ± 5.69 (54) (p<0.005)	157.6 ± 11.9 (35) (p<0.005)
Adrenals weight, mg (N. of fetuses)	2.31 ± 0.03 (172)	2.09 ± 0.04 (54) (p<0.005)	1.62 ± 0.07 (35) (p<0.005)
Kidneys, mg (N. of fetuses)	32.07 ± 0.42 (175)	29.72 ± 0.66 (53) (p<0.005)	19.09 ± 1.02 (36) (p<0.005)

Applicant's summary and conclusion

Conclusions:

The marked differences in organ weight ratio with control, as well as organ weight / body weight ratio, suggest that betamethasone interfere with the proportionate growth controls in the fetus or the response of the organs to these controls. Marked differences that are relevant for this assessment are related not only to the fetal weight, but also to liver and kidneys weight in comparison with the control. Thus, it can be shown specific toxicity for these two organs.