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EC number: 207-383-5 | CAS number: 466-99-9
- 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:
- supporting study
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- documentation insufficient for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Evaluation of the teratogenic potential of hydromorphone administered via a miniature implantable pump in mice
- Author:
- Behm MC, Stout-Caputi MV, Mahalik MP and Gautieri RF
- Year:
- 1 985
- Bibliographic source:
- Research Communications in Substance Abuse 6 (3) 165 - 177
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Single injections (5 mg/kg) and continuous infusion of the test material were administered by microosmotic pump to gravid mice and the maternal and foetal effects assessed.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Hydromorphone
- EC Number:
- 207-383-5
- EC Name:
- Hydromorphone
- Cas Number:
- 466-99-9
- Molecular formula:
- C17H19NO3
- IUPAC Name:
- (1S,5R,13R,17R)-10-hydroxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-trien-14-one
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- CF-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: At least 22 g.
- Housing: Females were placed in aggregate cages, each holding 10 animals. Males were placed in individual cages (12.5 x 15 x 10 cm) possessing wire mesh fronts and floors.
- Diet: All animals were maintained on laboratory food ad libitum.
- Water: All animals were maintained on water ad libitum.
Administration / exposure
- Route of administration:
- subcutaneous
- Vehicle:
- water
- Remarks:
- Double distilled
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The solutions of the test material were prepared every two weeks in concentrations of 31.25, 15.625 and 7.8125 mg/mL, using double distilled water. All solutions were filtered prior to filling the micro-osmotic pumps used to administer the test material.
The gravid mice were randomly assigned to one of 17 experimental categories. The treatments included groups of 3.125, 1.625 and 0.78125 % test material, an untreated control category and saline control treatment groups on Days 7 through 10 of gestation. - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- Not reported in reference but citation to Mahalik et. al, 1980 which reports the breeding procedure implemented in the study to achieve timed pregnancies.
Gestation Day 0 is the day of the vaginal plug appearance. - Duration of treatment / exposure:
- day 7 through day 10 of gestation
- Frequency of treatment:
- continuous
- Duration of test:
- The gravid mice were sacrificed by cervical dislocation on Day 18 (one day prior to term).
Doses / concentrationsopen allclose all
- Dose / conc.:
- 7.812 other: mgc/mcL
- Dose / conc.:
- 15.625 other: mgc/mcL
- Dose / conc.:
- 31.25 other: mgc/mcL
- No. of animals per sex per dose:
- 6 pregnant mice per group.
- Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The pilot study evaluating the teratogenic effects of the test material administered subcutaneously utilised a dose of 5 mg/kg. Using the weight of an average mouse (25 g) and considering that the pump delivers 1 µL/h for 7 days, it was determined that a 12.5 % solution of the test material would be required to administer 5 mg/kg of the test material (the dose given subcutaneously) every hour for 7 days. The 12.5 % concentration administered was evaluated for maternal effect in a preliminary study. In addition, two other concentrations (6.25 % and 3.125 %) were tested to provide dose-response representation.
The preliminary investigation showed that both the 12.5 and 6.25 % concentration of the test material administered produced marked maternal toxicity (approximately 50 % fatalities prior to term). The 3.125 % (31.25 mcg/mcL) concentration produced minimal maternal toxicity and was therefore chosen as the high dose. To provide additional dose-response evaluations, lower test material concentrations of 1.5625 % (15.625 mcg/mcL) and 0.78125 % (7.8125 mcg/mcL) were included in the experiment.
Examinations
- Maternal examinations:
- Behaviour and maternal weight gain.
- Ovaries and uterine content:
- Incisions along the linea alba as well as two diagonal cuts in the pelvic region formed flaps which were reflected back to expose foetal swellings and resorption sites.
- Fetal examinations:
- The foetuses were removed, blotted dry and examined for viability (reflex movement to mechanical stimulation), position within the uterine horns, gross abnormalities and gender. The foetuses were weighed to the nearest 0.01 g and alternately distributed to respective solutions for subsequent skeletal and soft tissue analysis.
- Statistics:
- The data generated was evaluated using Student’s “t” test and the uncorrected Chi^2 test for binomial populations.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- The only abnormal behaviour observed in animals completely recovered from the ether anaesthesia following impantation of the pump, was mild scratching and biting directed dorsally. This was transient and did not result in any deterimental effects to the mother. Post-laparotomy examination of the subcutaneous pocket (implantation site) revealed no infections or septic condition in any of the treated mice.
The only appreciable maternal response observed was straub tail, indicative of CNS stimulation and was obseved only occassionally and almost exclusively in mice receiving 3.125 % test material solution. These minimal maternal effects were anticipated because of the method of dose selection. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a significant decrease observed in maternal weight gain in mice administered the 3.125 % concentration of the test material on Day 10 of gestation when compared to the saline control.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not examined
Effect levels (maternal animals)
- Remarks on result:
- not measured/tested
Maternal abnormalities
- Abnormalities:
- not specified
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- A significant decrease in mean foetal weight occurred in the 3.125 % test material group on Days 7 and 8 of gestation when compared with the saline controls. In addition, significant increases in soft tissue defects (1.5625 % test material on Days 9 and 10; 3.125 % test material on Day 9 and skeletal abnormalities (1.5625 % test material on Day 7; 3.125 % test material on Days 7 and 8) were also observed.
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not examined
- External malformations:
- not specified
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Skeletal malformations observed at significant levels included: Split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws, and ectopic ossification sites.
Other skeletal abnormalities observed, but not in statistically significant proportions, included:
Split xiphoid, extra sternebrae, missing parietal, frontal, premaxillary, nasal mandibular, maxillary, sternebrae and xiphoid; delayed ossification of the supraoccipital parietal and nasal processes, split occipital and parietal bones; extra and fused ribs, fractured ribs, fused sternebrae and hypoplasia of the premaxillary, nasal and mandibular processes. - Visceral malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Cryptorchidism was the only soft tissue anomally observed at significant levels. Other soft tissue defects occurring but not significantly, included intestinal, thoracic, renal and pleural haemorrhage, cleft palate, malformed ventricles and retina, hypoplastic kidney, ectopic tissue formation, hydronephrosis and thoraco-intestinal schists.
- Other effects:
- not examined
Effect levels (fetuses)
- Remarks on result:
- not measured/tested
Fetal abnormalities
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: Skeletal and body weight
Overall developmental toxicity
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 7.812 other: mgc/mcL
- Treatment related:
- yes
- Relation to maternal toxicity:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Any other information on results incl. tables
Comparison of untreated controls with foetuses born to mothers with implanted pumps and administered saline revealed no significant differences.
Applicant's summary and conclusion
- Conclusions:
- Subcutaneous injections of the test material to maternal rats resulted in significant skeletal and tissue anomalies to their foetuses.
- Executive summary:
The test material was administered as a single injection of 5 mg/kg subcutaneously on only one day of gestation from days 7 through 12. The test material was found to produce significant numbers of both skeletal and soft tissue anomalies, although its teratogenic potential did not predominate on any particular day of treatment. The foetal malformations observed did, however, parallel the period of ontogenesis for those structures developing during that specific treatment period.
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