Indometacin

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: summary of published data

Data source

Reference

Reference 1

Reference Type:

publication

Title:

The effects of an inhibitor of prostaglandin synthesis (indomethacin) on ovulation, pregnancy, and pseudopregnancy in the rabbit

Author:

O'Grady P et al.

Year:

1972

Bibliographic source:

Prostaglandins, 1 (2): 97 - 106

Reference 2

Reference Type:

publication

Title:

Nonteratogenicity of indomethacin in mice

Author:

Kalter H

Year:

1973

Bibliographic source:

Teratology, 7, A19

Reference 3

Reference Type:

publication

Title:

Prolongation of pregnancy and abnormal fetal development in rats treated with indomethacin

Author:

Persaud TVN

Year:

1975

Bibliographic source:

IRCS Med. Sci. Libr. Compend. 3: 300

Reference 4

Reference Type:

publication

Title:

Indomethacin - Placental transfer, cytotoxicity, and teratology in the rat

Author:

Klein, KL et al.

Year:

1981

Bibliographic source:

Am. J. Obstet. Gynecol., 141: 448 - 452

Reference 5

Reference Type:

publication

Title:

effect of indomethacin on alcohol-induced morphological anomalies in mice

Author:

Randall, CL et al.

Year:

1987

Bibliographic source:

Life Sciences, 41: 361 - 369

Reference 6

Reference Type:

review article or handbook

Title:

Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits

Author:

Cook JC et al.

Year:

2003

Bibliographic source:

Birth Defects Research (Part B), 68: 5 - 26

Reference 7

Reference Type:

publication

Title:

teratogenic effects of non-steroidal anti-inflammatory agents in mice

Author:

Kusanagi T et al

Year:

1977

Bibliographic source:

Congenital Anomalies, 17: 177 - 185

Reference 8

Reference Type:

study report

Title:

Unnamed

Year:

1986

Reference 9

Reference Type:

review article or handbook

Title:

Teratogen Update: Fetal effects of indomethacin adminsitration during pregnancy

Author:

Norton ME

Year:

1997

Bibliographic source:

Teratology 56: 282 -292

Reference 10

Reference Type:

publication

Title:

Absence of teratogenicity of indomethacin in ovarian hyperstimulation syndrome

Author:

Katz Z

Year:

1984

Bibliographic source:

Int. J. Fertil. 29 (3): 186 - 188

Materials and methods

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

Results and discussion

Results (fetuses)

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Species (Strain)/ Group size	Dosing	Findings	Conclusion	References
Rabbits (White) n = 2-5 /group	0, 8, 16 mg/kg bw from day of mating	Resorption of fetuses (laparotomy after 21-28 days of pregnancy) - 16 mg/kg: resorption of 46/47 implants - 8 mg/kg: resorption 23/28 implants No data on maternal findings	Interference with pregnancy	O’Grady et al. 1972
Mouse (different strains: A, BALB/c; C3H, C57BL) n = not given	Single and multiple doses, p.o.,, i.m. day 9-15 of gestation	- 7.5 mg/kg (single dose) killed 28/34 pregnant females within few days, surviving females had 28 apparently normal fetuses and 14 resorptions - 0.5 – 7 mg/kg (single dose): no maternal mortality, 1 litter with total resorption, 19 litters with 144 apparently normal fetuses and 28 resorptions - 5-9 mg/kg (multiple dose): killed 5/8 females, surviving females had 19 apparently normal fetuses and 6 resorptions	Without teratogenic effect	Kalter 1973
Rat (Sprague-Dawley) n = 6 (control) n = 11 (indomethacin)	By drinking water 13.4 mg/animal/ day (range: 11.1 – 13.9 mg) Given from day 0 of gestation until parturition	Animals killed a onset of parturition - Control group: length of pregnancy 21.5 ± 0 days, 82 implantations, 1 resorption, 1 dead fetus, 80 alive fetuses, no abnormal fetuses - Indomethacin group: length of pregnancy 22.8 ± 0.2 days 133 implantations, 13 resorptions, 6 dead fetuses, 114 alive fetuses, 43 abnormal fetuses	No maternal findings, prolongation of pregnancy, increased incidence of resorptions, fetal deaths and malformed fetuses (type of malformations not described)	Persaud 1975
Mouse	7.5 mg/kg bw 10 mg/kg bw	Dosing from day 7-15 of gestation Result: increased incidence of skeletal malformations (cervical and thoracic vertebrae, ribs) in the offspring at a maternally toxic dose (7 out of 26 females died during treatment) Single dosing on day 6, 7, 8 or 9 of gestation Result: increased incidence of external and skeletal malformations when given on day 7 of gestation	Teratogenic effects	Kusanagi et al. 1977
Rats (Haffkine strain) n = 10	4 mg/kg bw p.o. from days 10 – 16 of gestation	Number of implantation sites counted on day 10 of gestation (surgical observation), size of litters at term was recorded, pups born were observed for one month p.p. for gross abnormalities   Indomethacin group: 5 females died during treatment, none of surviving females delivered, one female showed vaginal bleeding indicating abortion on day 16 of gestation, bw loss, reduced feed intake	Maternal toxicity and total resorptions of surviving females	Yegnanarayan et al. 1978
Rat (Wistar derived strain - Royalheart) n = 10/group	4 mg/kg bw from day 10-12 of gestation Suspension in 0.3% CMC	Cesarean section on day 20 of gestation Mortality of dams 3/10 No increase in resorptions, malformations, no effects on fetal weights Investigation on placental transfer of indomethacin on day 11 and 21 of gestation: - day 11 no indomethacin (only analyzed for parent compound) found in embryonic tissue - day 21: indomethacin found in maternal and fetal plasma Radiolabeled compound (no differentiation of indomethacin and major metabolites N-deschloro-benzoyl-indomethacin and O-desmethyl-indomethacin): - day 11: maternal plasma levels 37 – 66 fold greater than corresponding embryonic tissue levels - day 21: maternal plasma levels 3 – 4 fold greater than fetal plasma levels	Maternal toxicity, no teratogenic effects, no relevant placental transfer during time of organogenesis	Klein et al. 1981
Human woman with ovarian hyperstimulation syndrome (OHSS) N = 8 pregnancies	Therapeutic use of total doses 700 -1200 mg over 3 to 8 days given 2-7 days after human chorionic gonadotropin administration	Mild hypospadia in one baby, no congenital malformations in other newborns	Absence of teratogenicity	Katz et al. 1984
Mouse (Strain: B10.A) N = 6 (control) or 5 litters (indomethacin)	1 mg/kg Indomethacin,from day 11-14 of gestation, Control: DMSO	Cesarean section on day 18, measurement of anogenital distance (AGD), fetal weight and fetal sex determined Control: Mean Fetal weight: 1.06 ± 0.12 g Mean AGD:  M: 1.70 ± 0.14 mm (n = 19)  F:  0.92 ± 0.17 mm (n = 21)   Indomethacin: Mean Fetal weight: 1.05 ± 0.10 g Mean AGD:  M: 1.43 ± 0.14 mm (n = 20)  F:  0.87 ± 0.11 mm (n = 21)	Anti-masculinizing effect probably mediated by inhibition of arachidonic acid cascade which is involved in masculinizing action of testosteron	Gupta et al. 1986
Mouse (Strain C57BL/6J) n = 19 - 27 plugged females/group (resulting in 6-11 litters with viable fetuses/group)	0, 5, 10, 20 mg/kg bw, in 0.1 M sodium phosphate buffer, pH 8, dose volume 0.02mL/gram; given s.c. once on day 10 of gestation (day of vaginal plug = day 1) one hour before oral administration of saline/sucrose solution	Cesarean section on day 19 of gestation - 20 mg/kg: mortality of dams 10/27, full-term pregnancy: 6 of surviving females (average pregnancy rate 52 %) - reduced litter weights at 10 and 20 mg/kg - no effects on fetal morphology - placental transfer of radiolabeled drug on day 10 of gestation: ratio embryo:plasma was 0.012 – 0.013 – 0.015 for the respective doses	Maternal mortality, reduced fertility at 20 mg/kg Reduced litter weight at ≥ 10 mg/kg No teratogenic effects	Randall et al. 1987
Human	Indomethacin – first trimester use	Literature analysis of data available on first trimester exposure One congenital defect in 50 pregnancies One of nine live babies with mild hypospadia (700-1200 mg over 3 – 8 days Of 229101 pregnancies from 1985 – 1992, 114 newborns were exposed to indomethacin during first trimester, 7 (6.9%) had major birth defects (5 expected), 2 of which were cardiovascular (1 expected); no anomalies in 5 other categories	Suggestion that the drug does not produce malformations	Norton 1997
Rat, rabbit	Indoles (Indomethacin: 2 - 6 mg/kg bw/day , Indomethacin farnesyl: 5 – 500 mg/kg bw/day Acemetacin: 2 - 8 mg/kg bw/day	Literature analysis of experimental studies (of different experimental design and quality) for indoles: 6 studies in rats, 2 studies in rabbits (+ 10 supporting studies)	No diaphragmatic hernia, no midline defects, no ventricular septal defects in the 8 studies ; no definitive determination for presence or absence of teratogenicity of NSAID was made	Cook et al. 2003
Bw: body weight,: subcutaneous; p.o.: per os, i.m.: intrasmuscular, p.p.: post partum; CMC: carboxymethylcellulose, M : mol NSAID: non-steroidal anti-inflammatory drug