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EC number: 212-714-1 | CAS number: 853-23-6
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- initiated February 2003 - end date unknown
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Principles of method if other than guideline:
- A one year study of dehydroepiandrosterone (DHEA) was conducted in male and female Cynomolgus monkeys in support of a New Drug Application (NDA) of DHEA submitted to the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe dyspareunia in menopausal women. DHEA suspended in 0.4% aqueous methylcellulose was administered daily to male and female monkeys by nasogastric intubation at doses of 0, 2 and 10 mg/kg/day (4/sex/group). An additional group received 10 mg/kg DHEA and 0.3 mg/kg estradiol, while another group received 10 mg/kg DHEA, 0.3 mg/kg estradiol and a selective estrogen modulator (EM 652 HCl; SCH 57068 HCl; Acolbifene). Observations included mortality, clinical signs, body weights, food consumption, ophthalmoscopy, hematology, clinical chemistry, urinalysis, gross pathology, organ weights and histopathology.
- GLP compliance:
- yes
Test material
- Reference substance name:
- Prasterone
- EC Number:
- 200-175-5
- EC Name:
- Prasterone
- Cas Number:
- 53-43-0
- Molecular formula:
- C19H28O2
- IUPAC Name:
- (3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one
- Test material form:
- solid
- Details on test material:
- white solid
Constituent 1
- Specific details on test material used for the study:
- IDENTITY: Dehydroepiandrosterone (DHEA); EM-760
- Lot: EM-760-13
- CAS Registry Number: 53-43-0
- Generic Name: Prasterone
- Molecular Weight: 288.4
SOURCE OF TEST MATERIAL
- Source of test material: no data
- Purity: 99.7%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Not specified
- Stability of the test substance in the solvent/vehicle: Not specified
FORM AS APPLIED IN THE TEST
- Suspension
Test animals
- Species:
- monkey
- Strain:
- other: Cynomolgus
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Not specified
- Age: Young adult, males 4-6 years, females 6-18 years.
- Weight: 2.9 to 7.1 kg
- Housing: Not specified
- Diet: Not specified
- Water: Not specified
ENVIRONMENTAL CONDITIONS
- Temperature: Not specified
- Humidity (%): Not specified
- Photoperiod (hrs dark / hrs light): Not specified
Administration / exposure
- Route of administration:
- other: Nasogastric intubation
- Details on route of administration:
- Method: Oral by nasogastric intubation.
Frequency: The test substance was administered once daily - Vehicle:
- methylcellulose
- Remarks:
- 0.4% aqueous
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- DHEA was prepared as a suspension in 0.4% aqueous methylcellulose.
VEHICLE
- Concentration DHEA in vehicle: 0 mg/mL (group 1); 1 mg/mL (group 2); 5 mg/mL (group 3); 5 mg/mL (group 4); 5 mg/mL (group 5)
- Amount of vehicle (if gavage): 2 mL/kg body weight - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 1 year
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Group 1 (vehicle control)
- Dose / conc.:
- 2 mg/kg bw/day (actual dose received)
- Remarks:
- Group 2 (DHEA low dose)
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Remarks:
- Group 3 (DHEA high dose)
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Remarks:
- Group 4 (DHEA high dose and 0.3 mg/kg estradiol)
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Remarks:
- Group 5 (DHEA high dose, 0.3 mg/kg estradiol and 40 mg/kg EM-652-HCl)
- No. of animals per sex per dose:
- 4 animals/sex/group
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- - In-life observations included mortality, clinical signs, body weights, food consumption, ophthalmoscopy, and urinalysis. Schedule and frequency of observations were not specified.
- Observations included hematology and clinical chemistry. Blood was collected on days 1, 184 and 359 - Sacrifice and pathology:
- - Observations included gross pathology, organ weights and histopathology.
ORGAN WEIGHTS
- Female monkeys: Organ weights were conducted on the following tissues: Adrenals, ovaries, pituitary, thyroid/parathyroids, uterus, vagina.
- Male monkeys: Organ weights were conducted on the following tissues: Adrenals, epididymides, pituitary, prostate, seminal vesicles, testes, thyroid/parathyroids.
HISTOPATHOLOGY
- Female Rats: Histopathologic examinations were conducted on the following tissues: Mammary gland, ovary, oviduct, pituitary, uterus, vagina.
- Male Rats: Histopathologic examinations were conducted on the following tissues: epididymis, mammary gland, pituitary, prostate, seminal vesicle, skin/subcutis (dorsal), spleen, testis, thymus. - Other examinations:
- - Toxicokinetics parameters (Days 1, 184 and 359): AUC(0-24 hr) in ng*hr/mL for DHEA and DHEA sulfate
- Statistics:
- No data
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- - No signs with DHEA alone.
- Estrogen related signs were observed in monkeys receiving both DHEA and estradiol. - Mortality:
- no mortality observed
- Description (incidence):
- No deaths occurred
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Slight decrease observed with estradiol and DHEA.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No adverse effects
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - No drug related changes were observed in females.
- Only changes were observed in males that received estradiol with DHEA. - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No changes with DHEA alone.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No changes
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - Changes in endocrine organ weights (ovary, uterus, vagina, pituitary in females and epididymis, testis, spleen and thymus in males) all attributed to estrogenic effects.
- Thyroid weight was also increased. This was presumably the result of estrogenic stimulation of SHBG and possible TBG resulting in reduced feedback and increased TSH. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No DHEA only effects
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No changes with DHEA alone.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Assumes that the effects on endocrine organ weights are pharmacologic.
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
Toxicokinetics:
Female monkeys given 2 and 10 mg/kg DHEA orally for 184 days had serum AUC's0-24h of 281 and 418 ng.h/ml and males had AUC's of 392 and 684 ng.h/ml. Women given 0.5% (6.5mg) DHEA intravaginally for 7 days had a mean serum AUC0 -24h of 56 ng.h/ml. Exposur margins are 5 and 7x for females and 7 and 12x for males.
Applicant's summary and conclusion
- Conclusions:
- In a one year monkey oral toxicology study, DHEA produced no adverse effects in male and female monkeys up to 10 mg/kg/day. Changes in endocrine organ weights (ovary, uterus, vagina, pituitary in females and epididymis, testis, spleen and thymus in males) were attributed to estrogenic/androgenic effects that were assumed to be pharmacologic in nature. A NOAEL of 10 mg/kg was identified for male and female monkeys.
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