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EC number: 202-777-3 | CAS number: 99-66-1
- 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:
- weight of evidence
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Well-documented publication of experiments with test procedures in accordance with generally accepted scientific standards and described in sufficient details.
Data source
Reference
- Reference Type:
- publication
- Title:
- Valproic Acid Developmental Toxicity and Pharmacokinetics in the Rhesus Monkey: An Interspecies Comparison
- Author:
- A.G. Hendrickx, H. Nau, P. Binkerd, J.M. Rowland, J.R. Rowland, M.J. Cukierski, and M.A. Curieski
- Year:
- 1 988
- Bibliographic source:
- Teratology 38:329-345 (1988)
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The present study was undertaken to
1) evaluate the teratogenic potential of VPA administered to rhesus monkeys during organogenesis,
2) determine the maternal disposition of VPA on the first and last days of treatment,
3) determine embryo concentrations of VPA during early organogenesis, and
4) correlate these teratogenic and pharmacokinetic findings in rhesus monkeys and compare them with similar data in other species. - GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Valproic acid (VPA)
- IUPAC Name:
- Valproic acid (VPA)
- Reference substance name:
- 2-propylvaleric acid
- EC Number:
- 202-777-3
- EC Name:
- 2-propylvaleric acid
- Cas Number:
- 99-66-1
- Molecular formula:
- C8H16O2
- IUPAC Name:
- 2-propylpentanoic acid
- Details on test material:
- Valproic acid (VPA) was supplied by Sigma Chemical Co., St Louis, MO. The VPA was neutralized with an equimolar amount of aqueous sodium hydroxide. (See "any other information on material and method")
Constituent 1
Constituent 2
Test animals
- Species:
- monkey
- Strain:
- other: Macaca mulatta
Administration / exposure
- Route of administration:
- other: Nasogastric intubation
- Vehicle:
- other: aqueous sodium hydroxide
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: females mated with a fertile male on menstrual cycle days 11, 13, and 15 or 11 and 13.
- Mating occurred during a limited period of 2 hours per day with day 13 designated as day zero (0) of pregnancy.
- Proof of pregnancy: pregnancy was detected by radioreceptorassay or a radioimmunoassay (RIA) between gestational days (GD) 18 and 20. - Duration of treatment / exposure:
- GD 21 - GD 50: 20, 75, 100, 150, 200 mg/kg/day doses.
GD 20- GD 23: 450 and 600 mg/kg/day dose. - Frequency of treatment:
- daily
- No. of animals per sex per dose:
- 1 female for 450 mg/kg/day,
3 females for each of the doses of 20, 75, 150 mg/kg/day,
6 females for 600 mg/kg/day,
7 females for 100 mg/kg/day,
10 females for 200 mg/kg/day. - Control animals:
- yes, concurrent vehicle
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: minimal effects and not dose-dependant
Effect levels (maternal animals)
- Key result
- Remarks on result:
- not measured/tested
Maternal abnormalities
- Key result
- Abnormalities:
- effects observed, non-treatment-related
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Effect levels (fetuses)
- Key result
- Remarks on result:
- not measured/tested
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- external: cranium
- external: face
- skeletal: skull
- skeletal: rib
- skeletal: vertebra
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
The following important observations were made:
- Dose-dependent developmental toxicity (increased embryo/fetal mortality), intrauterine growth retardation, and craniofacial and skeletal defects.
- Biphasic plasma elimination curves for total and free VPA on the first and last days of treatment at both 100 and 200 mg/kg/day
- Dose-independent elimination kinetics at the plasma concentrations
- No significant change in pharmacokinetic parameters between the first and last days of treatment at either dose level.
- Placental transfer studies: apparently embryos were exposed to half the free VPA concentrations present in maternal plasma.
Applicant's summary and conclusion
- Conclusions:
- The authors point to the necessity of evaluating both teratogenic and pharmacokinetic endpoints to explain species differences and the limitations of estimating human developmental hazards from experimental data.
In the conditions of the study, embryotoxic and teratogenic effects were observed. Craniofacial and skeletal defects were the most significant findings in this study.
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