Indometacin

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP status not indicated

Data source

Reference

Reference Type:

publication

Title:

Acemetacin (k-708) Reproduction Studies with Acemetacin (K-708). Perinatal and postnatal Study in Rats

Author:

Aoki Y et al

Year:

1981

Bibliographic source:

Pharmacometrics 22 (6): 777-786

Materials and methods

Principles of method if other than guideline:

Indomethacin was administered to inseminated female rats in the perinatal and lactation period (from day 17 of gestation until day 21 of lactation). Examinations were performed on general tolerance of the test compound by the F0 females, as well as on its effects on peri- and postnatal development and reproduction of the F1 generation (including effects on the F2 progeny).

Type of method:

in vivo

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 Sumitom chemical Industries, Co. LTd, Japan

Test animals

Species:

rat

Strain:

other: (Slc:Sprague Dawley)

Sex:

female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

(0.5%)

Duration of treatment / exposure:

F0-females: from day 17 of gestation until day 21 of lactation

Frequency of treatment:

once daily

Duration of test:

FO females: from day 0 of gestation to end of lactation (day 21 p.p.)
F1 pups: until week 6 after birth
F1 animals used for fertility testing: F1 males until after mating; F1 females until day 21 of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
0-1.8-3.5 mg/kg bw/day
Basis:
nominal conc.
(dose volume: 2 mL/kg bw)

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

<= 1.8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: maternal effects (mortality)

Remarks on result:

not determinable

Remarks:

no NOAEL identified

2

Dose descriptor:

NOAEL

Effect level:

<= 1.8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: dystocia

Remarks on result:

not determinable

Remarks:

no NOAEL identified

3

Dose descriptor:

LOAEL

Effect level:

>= 3.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: increased gestation lenght, reduced number of implantation sites, impaired lactation behaviour, decreased survival of F1 pups

4

Dose descriptor:

NOAEL

Effect level:

ca. 1.8 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: peri/postnatal development of the F1 generation including late effects on F2 progeny

Any other information on results incl. tables

At 1.8 mg/kg and above systemic effects characterized by mortality, clinical symptoms and gross pathological findings (ulcers in cecum, atrophy of thymus) were seen in F0 females together with slightly impaired body weight gain at 3.5 mg/kg.. With respect to reproductive parameters dystocia occurred at 1.8 mg/kg and above together with increased gestation length and impaired lactation behaviour at 3.5 mg/kg. At 3.5 mg/kg reduced number of implantation sites, decreased number of. live F1 pups, increased number of dead F1 pups and decreased survival until day 7 p.p. was observed. Further rearing of the F1 generation revealed no treatment-related effect. Postnatal physical and functional development including open field examination, water-multiple-maze test, moving performance, visceral and skeletal examination and sexual maturation revealed no treatment related effects. One F1 pup of the 1.8 mg/kg group showed a short 13th rib. Fertility testing of the F1 generation revealed neither adverse effects and nor relevant late effects on the F2 progeny.

The available results are given in the following table:

Parameter	0 mg/kg bw/day	1.8 mg/kg bw/day	3.5 mg/kg bw/day
Numbers of females used	20	20	20
F0 generation
Mortality	-	1 (day 25)	6 (day 24-27)
Clinical signs (coarse, lusterless fur, blood around anus)	-	Lusterless, rough fur, piloerection, in some animals snout and perianal area stained with blood, dystocia	Lusterless, rough fur, piloerection, in some animals snout and perianal area stained with blood dystocia
Body weight (g)            Day 0 pc            Day 21 pc Gain Day 0-21 pc	215 ± 22 317 ± 28 100 ± 13	224 ± 21 329 ± 20 104 ± 7	220 ± 19 317 ± 25 97 ± 18
Anatomical findings
Ulcers in cecum	-	Present	Present
Atrophy of thymus	-	Present	Present
Died animals	-	Ulcer in cecum, peritonitis, adhesions of intestinal tract, thymus atrophy, externl genitalia stained with blood, obstetric canal obstructed with a fetus	Ulcer in cecum, peritonitis, adhesions of intestinal tract, thymus atrophy, externl genitalia stained with blood, obstetric canal obstructed with a fetus
Duration of gestation (days) (extended in died animals)	22.0 ± 0.2	22.1 ± 0.5	22.6 ± 0.6**
Delivery	20	19	14
Prolonged parturition	0	3	8
Lack of care for offspring	0	0	8 (cannibalism, incomplete removal of fetal membranes/placenta, lack of lactation behaviour, returned to normal few days after parturition)
No. of implants     Mean ± S.D.	265 13.3 ± 2.0	253 13. ± 2.3	124 8.9 ± 4.3**
No. of newborns Alive  Mean ± SD Dead	249 12.5 ± 2.1 1	230 12.1 ± 2.0 2	124 8.9 ± 4.3** 54**
Delivery rate (%)	94.2 ± 5.3	92.2 ± 7.5	91.5 ± 10.9
Rearing
Number of females used	20	20	20
No of fostering dams	20	19	6
No of live offspring after birth on day 0	249	230	124
On day 7	240	223	65
Day7 (male/female)	225 (107/118)	210 (113/97)	62 (35/27)
Day 14 (male/female)	223 (106/117)	210 (113/97)	62 (35/27)
Day 21 (male/female)	223 (106/117)	210 (113/97)	62 (35/27)
Day 42 (male/female)	223 (106/117)	210 (113/97)	62 (35/27)
Survival rate (%)	96.6 ± 5.7	97.0 ± 4.8	45.7 ± 51.4**
Fostering rate (%)	99.2 ± 2.4	100.0 ± 0.0	98.6 ± 3.4
F1 generation – Postnatal development
No. of offspring on day 3 p.p.	241	226	65
Pinnae detachment (%)	220 (91.39	223 (98.7)	65 (100.0)
No. of offspring examined on day 14 p.p.	223	210	62
Separation of eye lids (%)	16 (7.1)	62 (29.5)	7 (11.3)
On day 15 p.p.	84 (37.5)	145 (69.0)	43 (69.4)
No of offspring examined on day 28 p.p.	106	113	35
Descent of testis (%)	101 (95.3)	113 (100.0)	34 (97.1)
No. of offspring examined on day 35 p.p.	117	97	26
Vaginal opening	18 (15.4)	36 (37.1)	9 (34.6)
On day 36	29 (24.8)	50 (51.59	11 (42.3)
On day 37	51 (43.6)	61 (62.9)	12 (46.2)
On day 38	57 (48.7)	71 (73.2)	15 (57.7)
F1 pups – Emotional and Functional tests
Open field	No relevant treatment related findings in males and females
Water multiple maze test	No relevant treatment related findings in males and females
Moving performance	No relevant treatment related findings in males and females
Visceral examination of F1 pups after end of rearing
No. of offspring examined	88	82	22
Anomalies (%)
Atrophy of testis	1 (1.1)	-	-
Hydronephrosis  with dilated ureter	-	1 (1.2)	-
Skeletal examination of F1 pups after end of rearing
No. of offspring examined	105	99	30
Malformations (%)	0	0	0
Variations (%)	0	1 (1.0) (13^thrib short, right)	0
No. of caudal vertebrae (mean ± SD)	28.0 ± 0.5	27.5 ± 0.8*	28.0 ± 0.3
F1 generation – Fertility testing
No. of male rats	10	10	3
No. of fertilizable males	9	10	3
No. of female rats	20	20	6
No. of copulated females	20	20	6
Pregnancy rate (%)	100	100.0	100.0
Body weight of F1 generation during gestation
Day 0	227 ± 26	227 ± 29	219 ± 38
Day 21	339 ± 31	348 ± 35	334 ± 58
Gains (g)	111 ± 12	121 ± 20	115 ± 26
Cesarean sction of F1 females and effects on F2 progeny
Cesarean section data (uterine weight, no. of C.L./implants/dead+ resorbed fetuses/no. and sex ratio of surviving fetuses, body weight and crown-rump length of surviving F2 fetuses, placental weight	No anomalies observed
External deformations/ immature F2 fetus	No anomalies observed
Visceral findings of F2 fetuses	Expansion of renal pelvis in control and experimental groups
Skeletal findings of F2 fetuses	Asymmetry of sternal nucleus, shorter cervical ribs and 13^thribs occurred sporadically in control and experimental groups Mean number of ossified phalanx, sacro-coccygeal vertebrae and ossified calcanei was increased in the 1.8 mg/kg group No indication of retarded ossification
pc: post coitus; p.p.: post partum; BW: body weight; * p < 0.05; ** p < 0.01; C.L.: corpora lutea

Applicant's summary and conclusion

Executive summary:

Indomethacin was administered to inseminated female rats in the perinatal and lactation period (from day 17 of gestation until day 21 of lactation) at dose levels of 1.8 and 3.5 mg/kg bw/day. Examinations were performed on general tolerance of the test compound by the F0 females, as well as on its effects on peri- and postnatal development and reproduction of the F1 generation (including effects on the F2 progeny).

At 1.8 mg/kg and above systemic effects characterized by mortality, clinical symptoms and gross pathological findings (ulcers in cecum, atrophy of thymus) were seen in F0 females together with slightly impaired body weight gain at 3.5 mg/kg.. With respect to reproductive parameters dystocia occurred at 1.8 mg/kg and above together with increased gestation length and impaired lactation behaviour at 3.5 mg/kg. Reduced number of implantation sites, decreased number of. live F1 pups, increased number of dead F1 pups and decreased survival until day 7 p.p. was as well observed at 3.5 mg/kg. Further rearing of the F1 generation revealed no treatment-related effects. Postnatal physical and functional development including open field examination, water-multiple-maze test, moving performance, visceral and skeletal examination and sexual maturation revealed no anomalies except of one F1 pup of the 1.8 mg/kg group with a short 13th rib. Fertility testing of the F1 generation showed neither adverse effects and nor relevant late effects on the F2 progeny.