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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
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1976
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Report date:
- 1999
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Deviations:
- yes
- GLP compliance:
- no
Test material
- Reference substance name:
- valproic acid
- IUPAC Name:
- valproic acid
- Details on test material:
- Name of Active Ingredient: Valproic Acid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: CD albino
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on mating procedure:
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Males: 60 days prior to mating through day 20 of mating period
Females: 14 days prior to mating to day 21 post partum - Frequency of treatment:
- Daily
- Details on study schedule:
- One half of the females from each group were sacrificed on day 13 of gestation for evaluation. The others were allowed to deliver spontaneously
Day of sacrifice of females: day 13 of gestation (n = 10) and 21 days post-partum (n = 10)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 65 mg/kg bw/day
- Dose / conc.:
- 150 mg/kg bw/day
- Dose / conc.:
- 350 mg/kg bw/day
- No. of animals per sex per dose:
- 10 animals/sex/dose
- Control animals:
- yes, concurrent vehicle
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose-related delay in parturition
Effect levels (P0)
- Key result
- Dose descriptor:
- other:
- Remarks on result:
- not measured/tested
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- At 350 mg/kg/d, reduction of number neonates per litter and prematurely death of neonates
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Slight reduction of body weight gain of neonates at 65 and 150 mg/kg/d
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Effect levels (F1)
- Key result
- Dose descriptor:
- other:
- Remarks on result:
- not measured/tested
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
The reproductive capacity of males and females of either group was not altered by valproic acid administration.
The main observations were as follows:
- at 65 and 150 mg/kg/day: the bodyweight gain of neonates was very slightly lower than that of contro
ls,
- at 150 and 350 mg/kg/day: reduction in the number of implantation sites. This decrease was due to
high pre-implantation loss,
- at 350 mg/kg/day :
. reduction of the mean number of neonates per lifter,
. all neonates issued from dams of this group died very shortly after birth.
Dosage (mg/Kg/day expressed in valproic acid) |
0 |
65 |
150 |
350 |
|
parents |
Females with sperm |
/10 |
/10 |
/10 |
/10 |
Pregnant females |
8 |
8 |
10 |
9 |
|
Female with delivery |
8 |
8 |
10 |
9 |
|
Mean duration of gestation (days) |
22 |
22 |
22 |
23 |
|
Litter means |
Live births |
10.9 |
12.3 |
12.6 |
9.3 |
Stillbirths |
0 |
0 |
0 |
0.4 |
|
Survivors days 4 pp |
7.4 |
9.5 |
8 |
0 |
|
Weight at birth (g) |
6.5 |
6.4 |
6.3 |
6.0 |
Applicant's summary and conclusion
- Conclusions:
- The results of these studies show the toxic effect of valproic acid at 350 mg/kg/day with reduced number of pregnant females and delayed parturition. The loss of approximately 30% of neonates very shortly after birth, indicates the existence of pre- and peri-natal toxicity. Moreover, the low survival index and marked retardation of body weight gain in neonates can be attributed to post-natal toxicity.
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