Pregna-1,4-diene-3,20-dione, 9-bromo-6-fluoro-11-hydroxy-16-methyl-21-[(1-oxopentyl)oxy]-, (6.alpha.,11.beta.,16.alpha.)-

Endpoint summary

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 data available.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Description of key information

No data available.

Justification for classification or non-classification

There is no reproductive toxicity study with bromhydrin-valerate (CAS No. 54605-02-6) available. However, due to its chemical structure bromhydrin-valerate belongs to the group of steroids characterised by an hydroxyl group on C11 and a carboxyl ester on C21 which is typical for glucocorticoids. Therefore, it is assumed that for glucocorticoids typical toxicological properties occur.

 

In animal experiments glucocorticoids have embryolethal and teratogenic effects. However, since there are no clear signs of such effects following therapeutic use in humans, pregnancy is not regarded as a contraindication to the use of glucocorticoids. Higher levels during pregnancy could, however, lead to a risk of an embryotoxic effect. Following long-term systemic therapy with glucocorticoids such as prednisone and beclomethasone proprionate for asthmatic and other chronic diseases reduced birth weight and placental weight were reported, which are supposed to be an indication for a reversible fetotoxic effect. Similar effects might be expected at high levels of bromhydrin-valerate. Long-term exposure to glucocorticoids can impair fertility (due to a negative influence on the hypophyseal-gonadal axis).

 

For effects on fertility the findings of DFV on the male and female reproductive tracts, in particular on the gonads, can be evaluated on the basis of the data from repeated dose toxicity studies. According to the results from acute, subchronic and chronic systemic tolerance studies which were conducted with repeated daily administration of DFV over a wide range of dosages including doses which exerted massive systemic toxic effects, no adverse effects on the gonads or other organs of the male and female reproductive tract have to be expected as a consequence of exposure to the glucocorticoid. 

DFV was examined in a series of developmental toxicity studies with regard to embryotoxicity in mice, rats and rabbits. DFV exerted developmental toxic effects typical for glucocorticoids to conceptuses. Regarding systemic effects of DFV in adult animals, reduced food consumption and/ or decreased body weight gain was observed at least in the high-dose groups. The changes on the developmental appeared in general at or close to maternal toxic dose levels and manifestations included increased prenatal loss, decreased fetal weights and teratogenicity (mainly cleft palate) at sufficiently high doses. Although the available epidemiological data on the therapeutic use of pharmacodynamically effective glucocorticoid doses does not indicate an embryotoxic/teratogenic potential in humans, such effects cannot be excluded for higher doses. 

In the mouse embryotoxicity study, daily s.c. DFV-doses of 1 µg/kg on gestation days 7 through 13 exerted no adverse effects on the dams and their offspring. At doses of 10 and 100 µg/kg/day, slight maternal toxicity as indicated by a reduced body weight gain was observed. Prenatal survival of fetuses and fetal weights were unaffected up to the highest tested dose of 100 µg/kg/day. Fetal external examinations revealed however a compound-related, dose-dependent increased incidence of cleft palates from 10 µg/kg/day onwards. In the delivery subgroup at the high dose level (100 µg/kg/day), perinatal mortality and postnatal loss were increased, one case of cleft palate was observed and vaginal opening was delayed in the F1-offspring. Changes in anogenital distance were not considered treatment related. The cleft palate induction study in the mouse showed the expected, glucocorticoid-typical effects of single high doses given at the critical stage of development. Single DFV doses of 1000 µg/kg given on days 12 or 13 of gestation induced cleft palates in about 24 or 38% of the fetuses. Similar results were obtained with Betamethasone valerate (28% cleft palates after day 12. dosing; 22% cleft palates after dosing on day 13) at the dose of 3300 µg/kg. The latter drug is less potent in terms of glucocorticoid effects as compared to DFV. 

In the s.c. rat embryotoxicity study, the low dose of 10 µg/kg/day given on gestation days 7 through 13 exerted no adverse effects. At the high dose of 100 µg/kg/day, maternal toxicity as indicated by a decreased food consumption and reduced body weight gain was observed in conjunction with an increase in prenatal loss, reduced fetal weights and an increased incidence of malformations (omphalocele and one cleft palate). Accordingly, a reduction in litter size and decreased birth weights were recorded in the delivery subgroups. The anogenital distance in male fetuses was significantly shortened, but without a significant difference in the anogenital distance/body weight ratio. Thus, the latter is considered to be due to the reduced fetal body weight.  

DFV was administered as an ointment formulation at dosages of 5, 50, 500 and 2500 µg/kg/day on days 6 through 15 of gestation in the dermal rat embryotoxicity study. At the low dose, no compound-related effects were observed. The lower intermediate dose of 50 µg/kg/day exerted slight maternal effects in the form of a reduction in body weight gain without any developmental toxic effects. Maternal toxicity at 500 and 2500 µg/kg/day were manifested as a loss in body weights. In addition, the incidences of skeletal variations and minor anomalies were increased. There were 5 malformed fetuses in the upper intermediate dose group and 21 in the high-dose group (11 x cleft palate). At the high dose, the developmental toxic effects of DFV were indicated by slightly increased prenatal loss and by reduced fetal weights in addition to the structural changes which were already mentioned. 

Evaluation of the data from the s.c. embryotoxicity study in the rabbit revealed no indications of maternal toxicity at the tested dose levels of 2, 10 and 50 µg/kg/day given on days 6 through 18 of gestation. In the low and high-dose group, fetal weights were reduced and a low incidence of cleft palates (about 7 to 8% of fetuses) was recorded. In addition, prenatal loss was increased at the dose of 50 µg/kg/day. DFV was administered as an ointment at dosages of 5,50,500 and 2500 µg/kg/day on gestation days 6 through 18 in the dermal rabbit embryotoxicity study. No compound-related effects were observed at the low dose. At 50 and 500 µg/kg/day, prenatal lass was increased. At the high dose of 2500 µg/kg/day, embryolethal effects were accompanied by reduced fetal weights and an increased incidence of malformations (7 fetuses) which included 3 cleft palates. Maternal body weight gain at the high dose was decreased for the postdosing period between days 18 and 28, which could either have been related to the observed embryotoxicity (reduced litter sizes and fetal weights), to a direct systemic effect of DFV on the maternal organism or to a combination thereof. 

 

Based on animal experiments and human experience with glucocorticoids the following self classification of bromhydrin-valerate is recommended 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: 19.04.2016, 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.