Indometacin

Endpoint summary

Description of key information

Repeated dose toxicity studies with indomethacin were performed by oral dosing (gavage, capsule, feed) in different species (rat, dog, monkey) for different time frames (from 21 days to 52 weeks). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

Study duration:

subchronic

Species:

rat

Additional information

After repeated exposure to Indomethacin typical effects for NSAIDs (non-steroidal anti-inflammatory drugs) related to its pharmacological mode of action (inhibition of prostaglandin synthesis) are observed. Prominent findings in animal experiments comprised gastrointestinal alterations (e.g. gastrointestinal ulcers, ascites, peritonitis) and effects on the kidneys (papillary necrosis in rats). Sequelae presented as clinical symptoms, impaired body weight gain, anemia, extramedullary hematopoiesis, increased spleen/adrenal and liver weight, impaired hematology and clinical chemistry parameters and mortality. Daily doses of 3.4 mg/kg bw and above were lethal in rats (subchronic feeding study). In dogs no relevant adverse effects were seen at subchronic dosing of 1 mg/kg bw.

As therapeutic doses in humans 75 - 150 mg/day divided in 3 -4 doses for a duration of 7 -14 days are quoted. Adverse reactions at therapeutic doses and seen at an incidence of greater than 1% are nausea with or without vomiting, dyspepsia, diarrhea, abdominal distress or pain, constipation, headache, dizziness, vertigo, somnolence, depression, fatigue and tinnitus.

Side effects of therapy with NSAIDs may be cardiovascular thrombotic events, hypertension (onset or worsening), congestive heart failure and edema, gastrointestinal effects (ulceration, bleeding, perforation), renal toxicity, anaphylactic/anaphylactoid reactions, skin reactions (e.g. exfoliative dermatitis, Steven-Johnson syndrome, toxic epidermal necrolysis), ocular effects (after prolonged therapy), central nervous effects (aggravate depression, psychiatric disturbances, epilepsy, and parkinsonism), elevation of liver enzymes (rare cases of fatal fulminant hepatitis), anemia, may aggravate pre-existing asthma; when given at the end of pregnancy: premature closure of ductus arteriosus.

(cited from Physicians Desk Reference 2010 for Indocin(R) - www.pdrel.com)

Justification for classification or non-classification

Classification according to Directive 67/548/EEC and Regulation (EC) 1272/2008 (CLP) is not required as findings are triggered by the mode of action which is covered by classification of acute toxicity.