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EC number: 206-076-3 | CAS number: 299-29-6
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- Date of study initiation: August 5, 2000
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- Study is reported by US-FDA in the drug approval process for the product Ferinject (NDA 22-054 Ferinject) as iron replacement product indicated for the treatment of iron deficiency anemia, the original study report is not available but study and test item summaries can be accessed via: Drug Approval Package NJECTAFER (ferric carboxymaltose) Injection Company: Luitpold Pharmaceuticals, Inc. Application No.: 203565 Approval Date: 07/25/2013 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203565Orig1s000TOC.cfm Pharmacology Review(s), Chemistry Review(s) and Other Review(s)
Data source
Referenceopen allclose all
- Reference Type:
- secondary source
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- not specified
- Principles of method if other than guideline:
- To study the potential teratogenic effects of VIT-45 in pregnant rabbits, VIT-45 was given by intravenous infusion to rabbits (22/group) at 0, 4.5, 9, 13.5, and 18 mg/kg/day from gestation days 6 to 19.
Study is reported by US-FDA in the drug approval process for the product Ferinject (NDA 22-054 Ferinject) as iron replacement product indicated for the treatment of iron deficiency anemia, the original study report is not available but study and test item summaries can be accessed via: Drug Approval Package NJECTAFER (ferric carboxymaltose) Injection Company: Luitpold Pharmaceuticals, Inc. Application No.: 203565 Approval Date: 07/25/2013 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203565Orig1s000TOC.cfm
Pharmacology Review(s), Chemistry Review(s) and Other Review(s) - GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 9007-72-1
- Cas Number:
- 9007-72-1
- IUPAC Name:
- 9007-72-1
- Reference substance name:
- Ferric Carboxymaltose
- IUPAC Name:
- Ferric Carboxymaltose
- Test material form:
- other: Aqueous solution of dark brown colour (intended for intravenous use)
- Details on test material:
- - Molecular formula (as other than submission substance): [FeOx(OH)y(H2O)z]n [{C6H10O5)m(C6H12O7)}l]k where n=~10³, m=~8, l=~11 and k=~4
- Molecular weight (as other than submission substance): ca. 150'000 g/mol
- Physical state: The pure test item is a brown amorphous powder ( Chemistry Review(s), Reference ID: 3142758, page 9 of 74, i.e. p 26 of 45 of the PDF document)
- Lot/batch No.: 894209B
Constituent 1
Constituent 2
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: no data
- Age at study initiation: 19-27 weeks
- Weight at study initiation: 3.45 - 5.55 kg
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
Study initiation date: 2000-08-05
Administration / exposure
- Route of administration:
- intravenous
- Vehicle:
- other: watery solution of sodium chloride 0.9 %
- Details on exposure:
- no data
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- no data
- Details on mating procedure:
- no data
- Duration of treatment / exposure:
- treatment from gestation day 6 to 19
- Frequency of treatment:
- once daily i.v.
- No. of animals per sex per dose:
- 22 female rabbits/group, for dose group 18 only 10 animals/group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- no data
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: no data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: daily
FOOD CONSUMPTION ): Yes , daily
WATER CONSUMPTION: No data
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: no data
- Organs examined: yes, corpora lutea, gravid uterus - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes
- Head examinations: Yes: all per litter - Statistics:
- no data
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Two dams per dose group died or were sacrificed. One dam in dose group 4.5, 9 and 18 mg/kg and two dams of group 13.5 mg/kg aborted. Prior to death/sacrifice dams in group 13.5 and 18 mg/kg had weight loss and reduced food intake. Most of these dose groups dams had liver tinged orange with accenturated lobular pattern. Brown/dark pinna was noted in the rabbits at 9 and 13.5 mg/kg and orange/brown eyelids in rabbits at 18 mg/kg. At necropsy orange/brown discoloration in various organs were noted it dams of group 9, 13.5 and 18 mg/kg/day. Preimplantation loss was marked in high dose group (33%) compared to control (18%).
Effect levels (maternal animals)
- Dose descriptor:
- LOAEL
- Effect level:
- 4.5 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes. Remark: at maternal toxic dose
Details on embryotoxic / teratogenic effects:
Three fetuses at high dose and two fetuses in 13.5 mg/kg group had marked domed craniums. Both 13.5 mg fetuses had additionally internal hydrocephaly or suspected hydrocephaly (major malformations). One fetus in 9 mg group had moderately domed cranium (minor malformation). The domed cranium was in incidence and severity dose related.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 4.5 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: Basis for effect level / Remarks: head malformation
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Litter value – group value
Live young |
Resorption |
Implantation Loss % |
||||||||||
Group |
No. pregnant dams |
|
Corpora lutea |
Implant-ations |
Males |
Females |
Total |
Early |
Late |
Total |
Pre- |
Post- |
1(control) |
22 |
Means/ |
12.5/3.4 |
10.1/2.9 |
4.1/1.7 |
4.1/2.29 |
8.2/2.3 |
0.9/0.9 |
1.0/1.0 |
1.9/1.3 |
18.1 |
17.4 |
2(4.5 mg/kg) |
16 |
Means/ |
13.1/1.9 |
11.5/2.8 |
4.9/1.7 |
4.7/1.8 |
9.6/2.5 |
0.5/0.7 |
1.4/1.2 |
1.9/1.3 |
13.1 |
15.0 |
3(9 mg/kg) |
19 |
Means/ |
11.6/2.0 |
9.6/3.1 |
3.9/2.0 |
4.4/2.1 |
8.3/3.5 |
0.6/0.8 |
0.7/0.9 |
1.3/1.1 |
16.3 |
14.0 |
5(13.5mg/kg) |
16 |
Means/ |
12.1/2.0 |
10.6/2.7 |
4.1/2.2 |
5.1/2.4 |
9.2/2.7 |
0.7/0.8 |
0.8/1.1 |
1.4/1.5 |
12.2 |
13.7 |
4(18 mg/kg) |
7 |
Means/ |
12.1/1.9 |
8.4/3.4 |
3.1/2.8 |
3.7/2.2 |
6.9/3.1 |
0.1/0.4 |
1.4/1.2 |
1.6/1.3 |
32.7 |
17.0 |
Table 2: Fetal examination – major abnormalities – group incidences
Gross Observation |
||||||||
Fetus |
Litters |
|||||||
Group |
1 |
2 |
3 |
5 |
1 |
2 |
3 |
5 |
Dose (mg Fe/kg/day) |
0 |
4.5 |
9 |
13.5 |
0 |
4.5 |
9 |
13.5 |
Number examined |
181# |
154 |
158 |
147 |
22 |
16 |
19 |
16 |
Number affected |
2 |
1 |
2 |
3 |
2 |
1 |
2 |
3 |
Malformations |
||||||||
Marked internal hydrocephaly/suspected, marked domed cranium |
- |
- |
- |
2 |
- |
- |
- |
2 |
Partially fused bilateral frontal, small left orbital socket |
1 |
- |
- |
- |
1 |
- |
- |
- |
Fused bilateral parietal to interparietal, partially fused bilateral frontal, dilated pulmonary trunk, narrow ascending aorta, retroesophageal aortic arch, large/small atria, misshapen ventricle |
- |
1 |
- |
- |
- |
1 |
- |
- |
Palatine irregularity, protruding tongue, incompletely ossified cranial bones and vertebral elements, irregularly ossified, kinked and medially thickened ribs, irregularly ossified long bones |
- |
- |
- |
1 |
- |
- |
- |
1 |
Dilated ascending aorta and aortic arch, transposition of ascending aorta and dorsally displaced pulmonary trunk, displaced ductus arteriosus, ventricular septal defect |
- |
- |
1 |
- |
- |
- |
1 |
- |
Lumbar scoliosis |
- |
- |
1 |
- |
- |
- |
1 |
- |
Lumbosacral vertebral irregularities |
1 |
- |
- |
- |
1 |
- |
- |
- |
# Includes 1 early birth
Table 3: Fetal examinations – placental abnormalities – group incidences
Gross Observation |
||||||||
Fetus |
Litters |
|||||||
Group |
1 |
2 |
3 |
5 |
1 |
2 |
3 |
5 |
Dose (mg Fe/kg/day) |
0 |
4.5 |
9 |
13.5 |
0 |
4.5 |
9 |
13.5 |
Number examined |
181# |
154 |
158 |
147 |
22 |
16 |
19 |
16 |
Malformations |
||||||||
Amniotic sac, milky fluid in |
1 |
- |
- |
- |
1 |
- |
- |
- |
Amniotic sac, tinged orange |
- |
- |
- |
55 |
- |
- |
- |
6 |
Placenta, milky fluid around |
1 |
1 |
- |
- |
1 |
1 |
- |
- |
Placenta, maternal potion tinged orange |
- |
- |
- |
95 |
- |
- |
- |
10 |
Placenta, pale and swollen |
- |
- |
- |
9 |
- |
- |
- |
1 |
Number of fetuses affected |
1 |
1 |
- |
122 |
1 |
1 |
- |
13 |
# Includes 1 early birth
Applicant's summary and conclusion
- Conclusions:
- The test substance does only show fetal effects at maternal toxic dose. Therefore, it is not considered as teratogenic.
- Executive summary:
Pregnant rabbits were treated intravenously with ferric carboxymaltose (CAS 9007-72-1) at the doses of 4.5, 9, 13.5 and 18 mg Fe/kg /day from day 6 to 19 of pregnancy. After sacrifice or premature death section was performed on dams and fetuses.
Two dams per dose group died or were sacrificed. Prior to death/sacrifice dams in group 13.5 and 18 mg/kg suffered from weight loss and reduced food intake and showed a liver tinged orange with accentuated lobular pattern. Orange/brown discoloration in variuos organs were noted it dose group 9 mg/kg upwards. Several dams starting at dose group 4.5 mg/kg onwards aborted. Preimplantation loss was marked in high dose group (33 %) compared to control (18 %).
Three fetuses at high dose and two fetuses in 13.5 mg/kg developed marked domed craniums. Both 13.5 mg fetuses had additionally internal hydrocephaly or suspected hydrocephaly (major malformations). One fetus in 9 mg group had moderately domed cranium (minor malformation). The domed cranium was in incidence and severity dose related. All fetal effects appeared at maternal toxic dose. Therefore, ferric carboxymaltose is assumed to be not teratogenic under the conditions of this test.
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