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EC number: 205-592-6 | CAS number: 143-22-6
- 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:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- supporting study
- Study period:
- 1984
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well documented publication which meets basic scientific principles and provides strong evidence to support the mode of action for the hypothesis that developmental effects seen in developmental toxicity studies are secondary to maternal toxicity.
Data source
Reference
- Reference Type:
- publication
- Title:
- Diflunisal-induced maternal anemia as a cause of teratogenicity in rabbits
- Author:
- Clark, R.L., Robertson, R.T., Minsker, D.H., Cohen, S.M., Tocco, D.J., Allen, H.L., James, M.L., and Bokelman, D.L.
- Year:
- 1 984
- Bibliographic source:
- Teratology 30, 319-332.
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The study followed the basic principles of a developmental toxicity study but used a single dose on GD 5. This was designed to produce an anaemia that would be much more persistent than the drug itself, which is cleared quite rapidly from the animals' system. The study is therefore designed to see if hypoxia is the secondary cause of the developmental toxicity seen with the drug rather than it being a direct acting developmental toxicant.
- GLP compliance:
- not specified
- Type of method:
- in vivo
Test material
- Reference substance name:
- Diflunisal
- EC Number:
- 245-034-9
- EC Name:
- Diflunisal
- Cas Number:
- 22494-42-4
- IUPAC Name:
- 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid
- Reference substance name:
- 5-(2,4-Difluorophenyl)salicylic acid
- IUPAC Name:
- 5-(2,4-Difluorophenyl)salicylic acid
- Details on test material:
- Source: Merck Sharp & Dohme Research Laboratories, West Point, PA
Molecular Formula C13H8F2O3
Molecular Weight 250.20
CAS Registry Number 22494-42-4
EINECS 245-034-9
Constituent 1
Constituent 2
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, WIlmington MA
Administration / exposure
- Route of administration:
- oral: unspecified
- Vehicle:
- not specified
- Details on exposure:
- To test the possible causality between the teratogenic effects and anemia induced by diflunisal, a single dose of 180 mg/kg diflunisal was administered to rabbits on gestation day 5.
- Analytical verification of doses or concentrations:
- not specified
- Frequency of treatment:
- Single dose on GD 5.
- Duration of test:
- to GD 20
Doses / concentrations
- Remarks:
- Doses / Concentrations:
180mg/kg
Basis:
actual ingested
- No. of animals per sex per dose:
- 4
- Control animals:
- yes
- Details on study design:
- To test the possible causality between the teratogenic effects and anemia induced by diflunisal, a single dose of 180 mg/kg diflunisal was administered to rabbits on gestation day 5. This treatment produced an anemia that persisted through gestation day 15 in addition to causing the characteristic axial skeletal defects. Since diflunisal was cleared from maternal blood before gestation day 9, the critical day for induction of similar axial skeletal defects by hypoxia, the skeletal malformations probably resulted from maternal hypoxia secondary to anemia and not from a direct and specific effect of the drug on the embryo.
Results and discussion
Effect levels
- Dose descriptor:
- NOAEC
- Effect level:
- < 180 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Qualitative nature of result and mode of action are more important than actual NOAEC.
Observed effects
Any other information on results incl. tables
Effects were attributed to maternal anemia rather than a direct effect of diflunisal, because diflunisal is highly protein bound in maternal blood (greater than 98 %); thus, there are only low concentrations of diflunisal in rabbit embryos. Furthermore, rats, which are resistant to diflunisal-induced maternal anemia, do not demonstrate embryo/fetal effects, despite reaching approximately equivalent doses of diflunisal in rat embryos. Furthermore, there is little accumulation of diflunisal in embryos, which is likely a reflection of its low placental transfer. This study provides strong evidence that the embryo/fetal effects (similar to those seen with 2-(2-(2-butoxyethoxy)ethoxy)ethanol) were secondary to maternal anemia.
Applicant's summary and conclusion
- Conclusions:
- Anaemina causes embrotoxicity and fetal toxicity. The results provide strong support to the hypothesis that similar effects seen in studies with 2-(2-(2-butoxyethoxy)ethoxy)ethanol are secondary to anaemia
- Executive summary:
In a developmental toxicity study designed to establish the mechanism of toxicity of the anti-inflammatory drug, diflunisal, pregnant rabbits were given a single 100mg/kg dose of the drug on GD5. The known metabolism of the drug meant that it would be cleared from the bloodstream by GD9, which is known to be the critical day for the induction of axial skeletal defects by hypoxia. Diflunisal also causes anaemia, which is persistent to GD15 and the study produced the same axial skeletal defects that were seen in a conventional developmental toxicity study. The results provided strong support for the hypothesis that, for this drug, the developmental toxicity was primarily caused by anaemia rather than directly by the drug itself.
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