Indometacin

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1977

Report date:

1980

Materials and methods

Principles of method if other than guideline:

Male and female rats were treated with indomethacin in powdered diet for 8 weeks. Indomethacin was investigated in order to determine the level showing minimal toxicity, for use as a positive control in a long term study for a related test substance.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Indometacin

EC Number:

200-186-5

EC Name:

Indometacin

Cas Number:

53-86-1

Molecular formula:

C19H16ClNO4

IUPAC Name:

2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid

Test animals

Species:

rat

Strain:

other: (CFY (derived fromSprague-Dawley strain) from Anglia Laboratory Animals, Alconbury,England)

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

8 weeks

Frequency of treatment:

daily (continously via feed)

Doses / concentrations

Remarks:

Doses / Concentrations:
3.4-5.2-6.9 and 8.6 mg/kg bw/day
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Results and discussion

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Endpoint	Findings	Sex	at Dose [mg/kg]
Mortality	- 2 M, 4 F died at 5.2 mg/kg bw/day; all animals died at ≥ 6.9 mg/kg bw/day (mainly during the first 3 weeks of treatment)	M, F	≥ 5.2
Clinical signs	- yellow brown staining of fur in urogenital region - swelling of abdomen - poor general condition before death/sacrifice in extremis	M, F	≥ 5.2
Food consumption	- reduced towards controls (only marginal in F of the 3.4 mg/kg dose group) - inferior efficiency of food utilisation	M, F   M, F	≥ 3.4   8.6
Body weight	- slight to marked depression of body weight gain   (decedents: partly body weight loss)	M F	≥ 5.2 ≥ 3.4
Necropsy	- decedents: fibrous adhesion between all levels of the GI tract, sometimes involving other viscera and abdominal wall, enlargement and pallor of spleen, copious serous fluid in abdominal cavity (ascites) - animals surviving up to completion of study: moderate intestinal adhesion and enlargement of spleen (one F at 3.4 mg/kg)	M, F         M F	≥ 5.2         ≥ 5.2 ≥ 3.4
Organ weights	- higher absolute weight and organ-to-body weight ratio of spleen	M, F	5.2
	- higher absolute weight and organ-to-body weight ratio of liver	F	5.2
	- higher absolute weight and organ-to-body weight ratio of adrenals	M F	≥ 3.4 5.2
M: Males; F: Females; GI tract: gastrointestinal tract

Applicant's summary and conclusion

Executive summary:

Male and female rats were treated with indomethacin in powdered diet for 8 weeks at dose levels of 3.4-5.2-6.9 and 8.6 mg/kg bw/day . Indomethacin was investigated in order to determine the level showing minimal toxicity, for use as a positive control in a long term study for a related test substance. In both gender dosing at 5.2 mg/kg and above caused clinical symptoms (yellow brown staining of fur, swollen abdomen), mortality, impaired body weight gain (in females already at 3.4 mg/kg), gross pathological lesions (fluid and adhesions in peritonal cavity indicating peritonitis, enlarged spleen in one female already at 3.4 mg/kg) and increased absolute and relative organ weights (spleen, liver, adrenals (in males already at 3.4 mg/kg)).