Indometacin

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: (female fertility study)

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Data source

Reference

Reference Type:

publication

Title:

Collaborative work on evaluation of ovarian toxicity - 12) Effects of 2- or 4-week repeated dose studies and fertility study of indomethacin in female rats

Author:

Tsubota K et al.

Year:

2009

Bibliographic source:

Journal of Toxicological Science (Special Issue I): SP 129 - SP 136

Materials and methods

Principles of method if other than guideline:

Ten females/group were treated daily by gavage with indomethacin, for 2 weeks before mating, during mating with untreated males and until day 7 of pregnancy. Timing of estrus phase was determined during the 2-week premating treatment phase. Necropsies were performed on day 14 of gestation and females examined for reproductive parameters.

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

Details on test material:

supplied by Sigma-Aldrich, St. Louis, MO, USA; suspended in 0.5% methylcellulose suspension

Test animals

Species:

rat

Strain:

other: (Crl:CD(Sprague-Dawley)

Sex:

female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: (0.5% methylcellulose solution; Metlose(R) SM-400)

Duration of treatment / exposure:

females were treated 2 weeks before the mating period, through mating and until day 7 of pregnancy

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0 - 0.4 - 1.3 - 4 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

10 females/dose

Control animals:

yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1.3 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: systemic and reproductive effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

At 4 mg/kg females showed clinical signs, impaired body weight development, mortality and gross pathological lesions (gastrointestinal ulcers, peritonitis). Three animals of the 4 mg/kg group showed prolonged diestrus (> 3 days) most probably as the result of their poor condition exacerbated by gastrointestinal damage. The reproductive outcome at 0.4 mg/kg and 1.3 mg/kg was not significantly different from those in the control. Numeric values were not analyzed at the 4 mg/kg dose level due to high maternal mortality.

Dose (mg/kg bw/day)	0	0.4	1.3	4
Finding in Females
Clinical signs	-	-	-	decreased spontaneous motility, moist fur around urethal orifice, prone position and soiled fur aorund the nose
No. that died/sacrificed moribund	-	-	-	8 (six during the premating period and 2 during mating)
BW gain (g) (day 1-15)	19	20	14	5**
Mean No. Estrus phase/15 days	3.7	3.8	3.7	3.8
Irregular estrus cycle (diestrus persists for 3 days or longer)	0	1	2	3
No. of animals mated	10	10	10	3
No. of animals copulated (inseminated)	10	10	10	3
No. of pregnant animals	10	10	10	2
Necropsy findings	-	-	-	Intestinal ulcers, peritonitis, adhesion of various celiac organs
Mean no. of Corpora lutea	14.9	15.8	14.4	12.5
Mean no. of implantations	14.0	14.6	13.4	10.0
Mean % preimplantation loss	5.5	7.1	7.2	19.8
Mean no. live embryos	13.1	13.9	12.4	9.5
Mean no. dead embyos	0.9	0.7	1.0	0.5
Mean % postimplantation loss	6.5	4.9	7.4	5.6
BW: body weight; ** : statistically significant difference to control with p < 0.01

Applicant's summary and conclusion

Executive summary:

Ten females/group were treated daily by gavage with indomethacin, for 2 weeks before mating, during mating with untreated males and until day 7 of pregnancy with doses of 0, 0.4, 1.3 and 4 mg/kg bw.. Timing of estrus phase was determined during the 2-week premating treatment phase. Necropsies were performed on day 14 of gestation and females examined for reproductive parameters.

At 4 mg/kg females showed clinical signs, impaired body weight development, mortality and gross pathological lesions (gastrointestinal ulcers, peritonitis). Three animals of the 4 mg/kg group showed prolonged diestrus (> 3 days) most probably as the result of their poor general condition exacerbated by gastrointestinal damage. The reproductive outcome at 0.4 mg/kg and 1.3 mg/kg was not significantly different from those in the control. Numeric values were not analyzed at the 4 mg/kg dose level due to high maternal mortality. The NOAEL was established in this study at 1.3 mg/kg bw/day.