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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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- other: does not meet important criteria of today standard method (insufficent number of animals, lack of positive controls/historical control data)
Data source
Reference
- Reference Type:
- publication
- Title:
- Evaluation of the anti-inflammatory drug indomethacin, for its genotoxicity in mice.
- Author:
- Shoba Devi, P et al.
- Year:
- 1 987
- Bibliographic source:
- Mutation Research 188, 343 - 347
Materials and methods
- Principles of method if other than guideline:
- Micronucleus test in bone marrow cells, sperm head abnormality (SHA) assay and analysis of meiotic chromosomes in sperm cells was performed in Swiss male mice after oral and intraperitoneal administration of Indomethacin at increasing doses.
- GLP compliance:
- not specified
- Type of assay:
- micronucleus assay
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:
- pure form, supplied by Merck Sharp and Dohme Ltd., Bombay, India
suspended in 4% gum acacia for administration
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- Swiss
- Sex:
- male
Administration / exposure
- Route of administration:
- other: (oral and i.p.)
- Duration of treatment / exposure:
- Micronucleus test: 1 day
SHA (sperm head analysis): for 5 consecutive days
Meiotic chromosome analysis: for 7, 15 or 30 consecutive days - Frequency of treatment:
- Micronucleus test: two times (at 0 and 24 hours) by gavage or i.p.
SHA analysis: once daily by gavage or i.p.
Meiotic chromosome analysis: once daily by gavage - Post exposure period:
- Micronucleus test: 6 hours after the 2nd administration
SHA analysis: 30 days after the last administration
Meiotic chromosome analysis: 24 hours after the final treatment
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
12 - 24 - 36 mg/kg bw/day
Basis:
nominal conc.
(for oral adminstration)
- Remarks:
- Doses / Concentrations:
8 - 16 - 24 mg/kg bw/day
Basis:
nominal conc.
(for i.p. administration)
- No. of animals per sex per dose:
- Micronucleus test: 6
SHA analysis: 6
Meiotic chromosome analysis: data not given (probably 6) - Control animals:
- yes, concurrent vehicle
Examinations
- Tissues and cell types examined:
- Micronucleus test: femoral bone marrow cells (smears)
SHA analysis: sperms from cauda epidymidis
Meiotic chromosome analysis: metaphase chromosomes of spermatocytes of testicular cells
Results and discussion
Test resultsopen allclose all
- Sex:
- male
- Genotoxicity:
- positive
- Remarks:
- (weak effects in micronucleus test at highest dose)
- Toxicity:
- not specified
- Remarks:
- (doses used correspond to 25%, 50% and 75% of LD50 values)
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- not examined
- Sex:
- male
- Genotoxicity:
- positive
- Remarks:
- (SAH analysis: abnormal sperm starting at the oral lowest dose)
- Toxicity:
- not specified
- Remarks:
- (doses used correspond to 25%, 50% and 75% of LD50 values)
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- not examined
- Sex:
- male
- Genotoxicity:
- positive
- Remarks:
- (increased percentage of chromosomal aberrations in spermatocytes starting at the lowest dose)
- Toxicity:
- yes
- Remarks:
- (lethality/toxic effects at medium and high dose after 15 days of treatment)
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- not examined
Any other information on results incl. tables
Micronucleus assay:
After oral dosing percentages of micronuclei in polyerthrocytes (P) were 0.31%, 0.41% and 0.55% at 12, 24 and 36 mg/kg compared to 0.21% in vehicle controls with statistical significance at the 36 mg/kg dose level. In normochromic erythrocytes (N) micronuclei were 0.07%, 0.09% and 0.08 % compared to 0.06% in vehicle controls. P/N ratio was 0.94, 0.88 and 0.73 compared to 0.94 in controls.
After i.p. dosing percentages of micronuclei in polyerthrocytes (P) were 0.39%, 0.41% and 0.63% at 8, 16 and 24 mg/kg compared to 0.26% in vehicle controls with statistical significance at the 24 mg/kg dose level. In normochromic erythrocytes (N) micronuclei were 0.08 % at all dose levels compared to 0.04% in controls. P/N ratio was 0.94, 0.86 and 0.76 compared to 0.94 in controls.
SHA analysis:
Results are given per group (data summarized for all males in the respective groups) in the following table:
Route of Administration |
Dose [mg/kg bw] |
Total sperm counted |
Abnormal sperm N % |
|
|
|
|
|
|
Oral |
0 |
10820 |
302 |
2.79 |
|
12 |
12028 |
433 |
3.60* |
|
24 |
11933 |
465 |
3.90* |
|
36 |
11652 |
501 |
4.30* |
|
|
|
|
|
i.p. |
0 |
11052 |
364 |
3.29 |
|
8 |
11599 |
452 |
3.94 |
|
12a |
13001 |
559 |
4.30* |
|
24 |
12211 |
602 |
4.93* |
|
|
|
|
|
* significant compared to controls (p < 0.01; Chi- square test) a dose given in the table in the publication, according to the method section it should be 16 mg/kg bw There was no animal-to-animal variation |
Meiotic chromosome analysis:
Indomethacin was toxic/lethal when given for more than 15 days at doses of 24 mg/kg bw and higher. Animals were sluggish and unhealthy looking.
Incidence of chromosomal aberrations in spermatocytes was increased at all dose levels tested with statistical significance:
Total percentage of anomalies were 14.63%, 15.11% and 17.10% compared to 10.35% in the control after 7 days of oral treatment; 16.92%, 16.31% and 18.61% compared to 12.10% after 15 days of treatment at doses of 12, 24 and 36 mg/kg bw/day and 17.83% at the 12 mg/kg dose compared to 13.62% in the control after 30 days of treatment (only males of the 12 mg/kg group survived until evaluation).
Applicant's summary and conclusion
- Executive summary:
Micronucleus test in bone marrow cells, sperm head abnormality (SHA) assay and analysis of meiotic chromosomes in sperm cells were performed in Swiss male mice after oral and intraperitoneal administration of Indomethacin at increasing doses (12, 24, 36 mg/kg bw were given by gavage once daily and in relation to the test employed up to 30 consecutive days and 8, 16 and 24 mg/kg bw were given i.p. once daily up to 5 consecutive days). Micronucleus test was positive at the respective p.o. and i.p. highest doses (36 and 24 mg/kg bw, respectively). Frequency of abnormal sperm and number of total chromosomal aberrations was increased at doses of 12 mg/kg and higher. Doses used in this study induced mortality after multiple administration (none of the animals of the 24 and 36 mg/kg doses survived when adminstered p.o. for > 15 days).
Testing protocol was inadequate (e.g. lack of positive controls/historical control data, insufficent number of animals, only positive at one dose level) so that the study can not be used for hazard and risk assessment.
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