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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
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
Referenceopen allclose all
- 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:
- 1 972
- Bibliographic source:
- Prostaglandins, 1 (2): 97 - 106
- Reference Type:
- publication
- Title:
- Nonteratogenicity of indomethacin in mice
- Author:
- Kalter H
- Year:
- 1 973
- Bibliographic source:
- Teratology, 7, A19
- Reference Type:
- publication
- Title:
- Prolongation of pregnancy and abnormal fetal development in rats treated with indomethacin
- Author:
- Persaud TVN
- Year:
- 1 975
- Bibliographic source:
- IRCS Med. Sci. Libr. Compend. 3: 300
- Reference Type:
- publication
- Title:
- Indomethacin - Placental transfer, cytotoxicity, and teratology in the rat
- Author:
- Klein, KL et al.
- Year:
- 1 981
- Bibliographic source:
- Am. J. Obstet. Gynecol., 141: 448 - 452
- Reference Type:
- publication
- Title:
- effect of indomethacin on alcohol-induced morphological anomalies in mice
- Author:
- Randall, CL et al.
- Year:
- 1 987
- Bibliographic source:
- Life Sciences, 41: 361 - 369
- 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:
- 2 003
- Bibliographic source:
- Birth Defects Research (Part B), 68: 5 - 26
- Reference Type:
- publication
- Title:
- teratogenic effects of non-steroidal anti-inflammatory agents in mice
- Author:
- Kusanagi T et al
- Year:
- 1 977
- Bibliographic source:
- Congenital Anomalies, 17: 177 - 185
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 986
- Reference Type:
- review article or handbook
- Title:
- Teratogen Update: Fetal effects of indomethacin adminsitration during pregnancy
- Author:
- Norton ME
- Year:
- 1 997
- Bibliographic source:
- Teratology 56: 282 -292
- Reference Type:
- publication
- Title:
- Absence of teratogenicity of indomethacin in ovarian hyperstimulation syndrome
- Author:
- Katz Z
- Year:
- 1 984
- Bibliographic source:
- Int. J. Fertil. 29 (3): 186 - 188
Materials and methods
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
Constituent 1
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
- 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
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
|
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 |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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