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Key value for chemical safety assessment

Effects on fertility

Description of key information
Evidence of toxicity to specific organs is reported.
A classification related to FDA pregnanci category available in an handbook is reported.

Effects on developmental toxicity

Description of key information
Evidence of cleft palate induced by betamethasone in more animal species has been found in the corresponding reference.
The use of betamethasone in the first trimester of pregnancy is therefore not considered to be free from possible adverse effects.
Additional information

Pregnant Holtzman rats were injected subcutaneously with anti-inflammatory drugs from day 12 to15 of gestation. Cleft palate was induced by betamethasone even by daily doses ranging from 0.05 to 0.3 mg (from 0.26 to 1.1 mg/kg bw). The possible significance of these experiments in relation to testing potential teratogens and to the mechanism of palate closure is discussed in the article.

This work underscore as the teratogenic action of a glucocorticoid is unpredictable between species. If this hypotesis is true it becames pointless to rest for teratogenicity of drugs in rodents, since the only purpose of such testing is to extrapolate to man. Such extrapolation is very provisional at best. Thus, more genetic backgrounds are required to evaluate the teratogenic potential of a drug. (Walker, B.E. 1971)

Pregnant A/J mice were injected subcutaneously with betamethasone from days 11 -14 of gestation. Cleft palate was induced by betamethasone at doses below 0.2 mg. The possible significance of these experiments in relation to testing potential teratogens and to the mechanism of palate closure is discussed in the article. (Walker, B.E. 1971)

Teratological data in the Pika treated subcutaneously with betamethasone has been compared with previously reported data in the rat, mouse, and rabbit.

The Pika appears to be more sensitive than the rat and mouse to the embryolethal effect of betamethasone. Rat, mouse, and rabbit reproductive hazards of betamethasone were reviewed in this publication as reference (Walker, B.E. 1971 (rat, mouse)). However, is difficult to compare the teratological susceptibility between these species because the occurrence of malformations in the Pika did not seem dose-dependent.

It is noteworthy that the Pika is much less sensitive than the rabbit to the teratogenicity and embryolethality of this chemical.

Embryolethality and teratogenicity, with indications of developmental anomalies, were reported about rat, mouse, and rabbit, taking into accout the administration during the organogenesis of embryos. (Nishimura, H. et al. 1986)

Intramuscular injections of betamethasone to New Zeland White rabbits were carried out to investigate the induction of cleft palate. Betamethasone was administered at doses from 1 to 4 mg /day from day 13 to 16 of gestation. Betamethasone is able to produce cleft palate in rabbit. However, can not be underestimated the ability of betamethasone to lead to a resorption of litter in 87.5% of cases. (Walker, B.E. 1967)

The QSAR study, performed with the Developmental Toxicity classification model - version 1.0.0.12 available with CAESAR software, predicts betamethasone as developmental toxicant. Because of the predicted substance is into the Application domain of the model, the prediction should be considered as reliable as supporting study for REACH purpose. (In silico QSAR)

Prenatal treatment with betamethasone may result in decreased endogenous levels of testosteronein male pups, which are crucial for brain sexual differentiation, with conseguent drop of testosterone production in adulthood, in association with damaged semen parameters. (Piffer, R.C et al. 2009)

Toxicity to reproduction: other studies

Additional information

All dose levels of betamethasone, 0.18 and 0.42 mg, resulted in a significant reduction of body weight, respectively of 18% and 31.8%.

The reduction of body weight is very significant and consequently many organs have marked reductions in weight. Moreover, organ weight in comparison with the controls shows 56.2% of weight reduction in the case of the liver and 68% in the case of kidneys. Thus, it can be shown specific toxicity for these two organs in accordance with the ratio organ weight / body weight to the detriment of the organ. The other organs described, does not have a ratio organ weight / body weight that indicate a specific organ toxicity. (Mosier, H.D. Jr; et al. 1982)

Betamethasone was classified in the FDA pregnancy category C. Risk factor D if used in the 1st trimester. (Briggs, G.G. et al. 2008)

Justification for classification or non-classification

Based on the available reported reference about animal studies, where adverse effects on the fetus (teratogenic or embryocidal or other) have been reported, betamethasone is classified in accordance with Directive 67/548/EEC and Regulation 1272/2008/EC.

Adverse effects relarted to specific organs were also reported, thus a classification for STOT RE is required in accordance with Directive 67/548/EEC and Regulation 1272/2008/EC.