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EC number: 200-186-5 | CAS number: 53-86-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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:
- 1 981
- 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
- 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
Constituent 1
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
open allclose all
- 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
- 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
- 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
- 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) (13thrib 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 13thribs 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.
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