Registration Dossier
Registration Dossier
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EC number: 200-186-5 | CAS number: 53-86-1
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Additional information
Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAID) and is used as such in human anti-inflammatory therapy. Its mode of action is based on reversible inhibition of prostaglandin synthesis (inhibition of cyclooxygenase I and II).
In-house reproductive toxicity studies for indomethacin are restricted to studies with indomethacin as a comparator for acemetacin.
Published data from the Physisicians Desk Reference describe no effect on fertility in a two generation reproduction study in mice or a two litter reproduction study in rats at dose levels up to 0.5 mg/kg/day.
A reproduction study with Acemetacin (a pro-drug of indomethacin) in rats showed at ulcerogenic doses of 6 mg/kg a reduced number of corpora lutea and implantations but no other effects on estrus cycle or fertility nor anomalies in the fetuses. Maternal mortality occurred at the 8 mg/kg dose.
In other in-house/published (RTECS inventory) experimental studies in rats and rabbits anti-implantation and anti-ovulation (luteinized non-ovulated follicles) activity of indomethacin was considered to be mediated by its prostaglandin-synthesis inhibiting properties.
Effects on developmental toxicity
Additional information
Prevailing number of publications (RTECS inventory) on structural developmental effects in experimental animals are refering to alterations related to the prostaglandin-synthesis inhibiting properties of the drug (persistent ductus arteriosus, changes in pulmonary vasculature, oligohydramnion). Early developmental toxicity study in mice (Kusanagi et al. 1977) with maternally toxic doses (7.5 mg/kg) revealed increased incidence of skeletal malformations (at cervical and thoracic vertebra, ribs) after administration from day 7 -15 of gestation or when using high single doses (10 mg/kg bw) on day 7 of gestation. In studies performed by Persaud et al. (1974) in mice and rats increased number of resorptions, fetal death and fetal malformations/abnormalities were observed.
The main number of studies published on indomethacin did however not show a teratogenic potential in experimental animals (rodents and rabbits) and humans.
Teratogenic effects were not seen in studies for regulatory purposes (dose level 0.5 -1.0 -2.0 and 4.0 mg/kg bw/day) up to 4 mg/kg bw/day in mice and rats while fetal weights were reduced and fetal ossification retarded at the latter dose (Physicicans Desk reference), which evidently should have been a maternally toxic dose.
Indomethacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
As indomethacin only crosses the placenta at minimal amounts during the period of organogenesis in rodents and since maternal mortality precludes use of higher doses in rodents, existing studies may not have fully explored the teratogenic hazard of the test substance.
Toxicity to reproduction: other studies
Additional information
Indomethacin is used therapeutically in obstetric practise for tocolysis, treatment of fetal polyhydramnions, and closure of patent ductus arteriosus in newborns. Adverse effects have been described after therapeutic use in pregnancy and neonates and included premature (i.e. intrauterine) closure of ductus arteriosus, oligohydramnion, pulmonary hypertension, myocardial degenerative changes, tricuspid valve insufficiency, reduced renal perfusion and reduced fetal urine production, renal dysfunction or failure, platelet dysfunction with resultant bleeding, intracranial bleeding, gastrointestinal bleeding or ulceration and oligohydramnion. These findings are most probably due to the pharmacological properties (prostaglandin-synthesis inhibition) of the drug.
Indomethacion-related effects on peri- and postnatal development in rats comprised dystocia, increased gestation length and impaired lactation behaviour at 3.5 mg/kg. Reduced number of implantation sites, decreased number of. live pups, increased number of dead pups and decreased pup survival until day 7 p.p. were as well observed at 3.5 mg/kg. Fertility testing of the F1 generation showed no adverse effects and no relevant effects on the F2 progeny. (Aoki et al. 1981)
Indomethacin is excreted in the milk of nursing mothers. Indomethacin is not recommended for use in nursing mothers.
Justification for classification or non-classification
Indomethacin is not classified according to the German legislation (TRGS-905).
According to Directive 67/548/EEC Indomethacin is classified as
Category 2; R60 - may impair fertility
Category 2; R61 - may cause harm to the unborn child
According to Regulation (EC) 1272/2008 (CLP) Indomethacin is classified as
Category 1 A; H360
Additional information
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