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EC number: 235-049-9 | CAS number: 12062-81-6
- 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
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Remarks:
- Bioaccessibility
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- June 2021 - July 2021
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods
- Qualifier:
- according to guideline
- Guideline:
- other:
- Version / remarks:
- OECD Series on Testing and Assessment No. 29 (23-Jul-2001): Guidance document on transformation/dissolution of metals and metal compounds in aqueous media
- Principles of method if other than guideline:
- An internationally agreed guideline does not exist for this test (e.g. OECD). However, similar tests have been conducted with several metal compounds in previous risk assessments (completed under Regulation (EEC) No 793/93) and in recent preparation for REACH regulation (EC) No 1907/2006. The test was conducted on the basis of the guidance for OECD-Series on testing and assessment Number 29 and according to the bioaccessibility test protocol provided by the study monitor. The test media were artificial physiological media: gastric fluid (GST), phosphate-buffered saline (PBS), artificial lysosomal fluid(ALF) and Gamble's solution (GMB).
- GLP compliance:
- yes (incl. QA statement)
- Radiolabelling:
- no
- Species:
- other: in vitro (simulated human body fluids)
- Details on test animals or test system and environmental conditions:
- Test principle in brief:
- four different artificial physiological media,
- single loading of test substance of 100 mg/L,
- GST and PBS media: samples taken after 2 and 24 hours agitation (100 rpm) at 37 ± 2 °C
- ALF and GMB media: samples taken after 2, 24 and 168 hours agitation (100 rpm) at 37 ± 2 °C
- the study was performed in triplicate
- three vessels with test item and two blanks per medium (measurement in duplicate)
- analysis of two fractions (0.2 µm filtered and 0.2 µm + 3 kDa filtration)
The aim of this test was to assess the dissolution of Iron manganese trioxide (Bayferrox® 645 T) in four artificial physiological media: Phosphate buffered saline (PBS, pH 7.2-7.4), Artificial gastric fluid (GST, 1.5-1.6), Artificial lysosomal fluid (ALF, pH 4.5) and Gamble’s solution (GMB, pH 7.4). The test media were selected to simulate relevant human-chemical interactions (as far as practical), e.g. a substance entering the human body by ingestion into the gastro-intestinal tract (GST). - Duration and frequency of treatment / exposure:
- Manganese and Iron concentrations were determined after 2 and 24 hours of incubation in GST, PBS, ALF and GMB. In GMB and ALF media, manganese and iron concentrations were additionally determined after 168 h.
- Dose / conc.:
- 100 other:
- Remarks:
- mg of test item/L artificial media
- Details on study design:
- Test setup
Three replicate flasks (500 mL glass flasks) per test medium (PBS, GST, ALF, GMB) were prepared with a loading of 100 mg/L. The test item was weighed into flasks, adjusted to volume with the respective artificial physiological medium and agitated at 100 rpm in the dark at 37 °C ± 1 °C. Furthermore, the test with GMB was performed in a 5% CO2 atmosphere. Samples of GST/ PBS medium were taken after 2 h and 24 h and ALF/GMB samples after 2 h, 24 h and 168 h (7 d). Manganese and iron concentrations were determined after filtration (Syringe Filter w / 0.2 μm, polyethersulfon membrane, DIA Nielsen, Dueren, Germany) and centrifugal filtration (i.e., 0.2 μm filtration and Vivaspin 3kDa centrifugal filtration, Sartorius, Göttingen, Germany) via ICP-OES.
Sample fortification:
In addition, samples of the artificial physiological media were fortified with a known amount of manganese and iron (by standard addition of commercial standards) to determine the standard recovery. For detailed information please refer to "Any other information on materials and methods incl. tables".
Manganese and Iron analysis:
- Standards for metal analysis: Commercially available single element standards were mixed accordingly to prepare a stock solution and subsequent calibration solutions for the ICP-OES measurements. The following single element standards were used for manganese and iron: Merck HC86803426, Merck HC01344369
- Certified reference materials: As quality control standards, certified aqueous reference materials TMDA-52.4 (lot no. 1219) and TMDA-64.3 (lot no. 1219) obtained from Environment Canada and a multi-element standard (Carl Roth ICP standard 100 mg/L, lot no. 723218; Karlsruhe, Germany) were analysed for total dissolved manganese and iron by ICP-OES. - Type:
- other: Bioaccessibility GST, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 78.9 µg Fe/L (dissolved)
- Type:
- other: Bioaccessibility GST, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 735 µg Fe/L (dissolved)
- Type:
- other: Bioaccessibility PBS, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- < LOD (0.586 µg Fe/L) (dissolved)
- Type:
- other: Bioaccessibility PBS, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- < LOD (0.586 µg Fe/L) (dissolved)
- Type:
- other: Bioaccessibility GMB, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- < LOQ (1.38 µg Fe/L) (dissolved)
- Type:
- other: Bioaccessibility GMB, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 1.20 µg Fe/L (dissolved)
- Type:
- other: Bioaccessibility GMB, 168h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 0.954 µg Fe/L (dissolved)
- Type:
- other: Bioaccessibility ALF, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 71.5 µg Fe/L (dissolved)
- Type:
- other: Bioaccessibility ALF, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 352 µg Fe/L (dissolved)
- Type:
- other: Bioaccessibility ALF, 168h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 1866 µg Fe/L (dissolved)
- Type:
- other: Bioaccessibility GST, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 361 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility GST, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 1388 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility PBS, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 32.0 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility PBS, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 79.3 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility GMB, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 29.7 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility GMB, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 33.6 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility GMB, 168h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 16.7 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility ALF, 2h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 708 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility ALF, 24h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 1440 µg Mn/L (dissolved)
- Type:
- other: Bioaccessibility ALF, 168h @ 37 °C (100 mg/L loading, 0.2 µm + 3 kDa filtration for phase separation)
- Results:
- 2908 µg Mn/L (dissolved)
- Bioaccessibility (or Bioavailability) testing results:
- Please refer to "any other information on results incl. tables" below.
- Conclusions:
- The bioaccessibility of iron manganese trioxide (Bayferrox® 645 T) was determined in vitro by examining dissolution in artificial body fluids at 37°C. At a loading of 100 mg test item/L, dissolved manganese concentrations (operationally defined as the dissolved Mn fraction after 0.2 µm filtration and centrifugal filtration (~2.1 nm, < 3 kDa)) were determined with 361 and 1388 µg Mn/L after 2 and 24 h in artificial gastric fluid (GST, pH = 1.5), respectively. With mean manganese concentrations of 708, 1440 and 2908 µg/L, dissolution of iron manganese trioxide was maximal in artificial lysosomal fluid (ALF, pH = 4.5) after 2, 24, and 168 hours of incubation, respectively. Accordingly, dissolved iron concentrations (operationally defined as the dissolved Fe fraction after 0.2 µm filtration and centrifugal filtration (~2.1 nm, < 3 kDa)) were determined with 78.9 and 735 µg/L after 2 and 24 h in artificial gastric fluid (GST, pH = 1.5), respectively. With mean iron concentrations of 71.5, 352 and 1866 µg/L, the iron release of iron manganese trioxide was maximal in artificial lysosomal fluid (ALF, pH = 4.5) after 2, 24, and 168 hours of incubation, respectively. With maximum Fe and Mn concentrations of 1.20 µg/L Fe and 79.3 µg/L Mn, iron and manganese release was low in phosphate buffered saline (PBS, pH = 7.2 - 7.4) and Gamble’s solution (GMB, pH 7.4) at a loading of 100 mg/L. In sum, iron manganese trioxide (Bayferrox® 645 T) can be considered poorly soluble in artificial body fluids.
Reference
Manganese and iron concentrations in simulated artificial body fluids
All data presented are corrected for background when feasible, i.e. when background manganese or iron concentrations in blank media are > LOQ.
The bioaccessibility of iron manganese trioxide (Bayferrox® 645 T) was determined in vitro by simulating dissolution under physiological conditions considered to mimic artificial body fluids with a loading of 100 mg test item/L. Dissolved manganese and iron concentrations were operationally defined as the dissolved elemental fraction after 0.2 µm filtration and centrifugal filtration (~2.1 nm, see table 2 and 3). In addition, dissolved/dispersed mean iron and manganese concentrations (operationally defined as the dissolved elemental fraction after 0.2 µm filtration) are summarized in table 4 and 5.
Tables 2 -5 are provided as an Attachment to this entry.
Solution pH
During the study, the pH of all media incl. blanks remained stable (see Table 6 -9)
Table 6: pH – GST. Target pH = 1.5, n.d. = not determined
Sample name | pH prior to the test | pH after 2 h | pH after 24 h |
GST 1 | 1.501 | n.d. | 1.5 |
GST 2 | 1.507 | n.d. | 1.517 |
GST 3 | 1.501 | n.d. | 1.517 |
GST 4 | 1.506 | 1.47 | 1.497 |
GST blank vessel 1 | 1.501 | 1.513 | 1.521 |
GST blank vessel 2 | 1.5 | 1.504 | 1.516 |
Table 7: pH – PBS. Target pH = 7.2 - 7.4, N.d. = not determined
Sample name | pH prior to the test | pH after 2 h | pH after 24 h |
PBS 1 | 7.304 | n.d. | 7.321 |
PBS 2 | 7.308 | n.d. | 7.327 |
PBS 3 | 7.309 | n.d. | 7.329 |
PBS 4 | 7.31 | 7.293 | 7.31 |
PBS blank vessel 1 | 7.315 | 7.351 | 7.36 |
PBS blank vessel 2 | 7.314 | 7.337 | 7.354 |
Table 8: pH – GMB. Target pH = 7.4, N.d. = not determined
Sample name | pH prior to the test | pH after 2 h | pH after 24 h | pH after 7 d |
GMB 1 | 7.403 | n.d. | n.d. | 7.545 |
GMB 2 | 7.38 | n.d. | n.d. | 7.53 |
GMB 3 | 7.399 | n.d. | n.d. | 7.548 |
GMB 4 | 7.41 | 7.486 | 7.522 | 7.548 |
GMB blank vessel 1 | 7.399 | 7.486 | 7.472 | 7.465 |
GMB blank vessel 2 | 7.41 | 7.497 | 7.509 | 7.466 |
Table 9: pH – ALF. Target pH = 4.5, N.d. = not determined
Sample name | pH prior to the test | pH after 2 h | pH after 24 h | pH after 7 d |
ALF 1 | 4.497 | n.d. | n.d. | 4.49 |
ALF 2 | 4.501 | n.d. | n.d. | 4.498 |
ALF 3 | 4.506 | n.d. | n.d. | 4.484 |
ALF 4 | 4.98 | 4.452 | 4.467 | 4.58 |
ALF blank vessel 1 | 4.507 | 4.529 | 4.532 | 4.515 |
ALF blank vessel 2 | 4.501 | 4.508 | 4.531 | 4.5 |
Temperature
The temperature in the thermostatically controlled incubation cabinet was within the limit of 37 °C ± 1 °C to simulate the human body temperature.
Method validation summary (ICP-MS)
Limits of detection (LODs), limits of quantification (LOQs) and correlation coefficients (r)
Manganese:
Limits of detection (LOD) within all measurement series: < 0.281 µg Mn/L.
Limits of quantification (LOQ) within all measurement series: < 0.844 µg Mn/L.
Iron:
Limits of detection (LOD) within all measurement series: < 1.70 µg Fe/L.
Limits of quantification (LOQ) within all measurement series: < 5.10 µg Fe/L.
Fe and Mn correlation coefficients (r) within all measurement series: >0.9998
Recovery data
Recovery of fortified samples, certified reference materials and quality control standards for both Fe and Mn were in the range of 87.7 – 106 % for all media.
Description of key information
A category approach justification for the iron oxides - Fe2O3, Fe3O4, FeOOH, (Fe,Mn)2O3, (Fe,Mn)3O4, ZnFe2O4 - was developed.
In the updated category approach justification, the category was extended and includes additional information on nano- and/or powder material to justify that the category covers nano- and micro-sized materials.
The members of the category are insoluble, inert particles. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs after inhalation was not observed in repeated dose toxicity studies (see endpoint summary repeated dose toxicity; Pauluhn, 2005). Due to its structure and physicochemical properties (insoluble in water and organic solvents) absorption and bioaccumulation is negligible if no overload effect of the lung occurs – see Category Approach Justification - Iron oxides.
Data on the dissolution behaviour of iron oxides in physiological media is available from bioaccessibility testing: The dissolution of iron manganese trioxide (Bayferrox® 645 T) was examined in artificial physiological media selected to simulate relevant human-chemical interactions (as far as practical), i.e. for a substance entering the human body by inhalation or by ingestion. The manganese and iron release was assessed in bioaccessibility tests with a test item loading of 100 mg/L at 37°C after 2 h, 24 h and 168 h (GMB and ALF only) applying the following four media:
- Artificial gastric fluid (GST, pH 1.5) mimics the very harsh digestion milieu of high acidity in the stomach.
- Phosphate-buffered saline (PBS, pH 7.4) is a standard physiological solution that mimics the ionic strength of human blood serum. It is widely used in research and medical health care as reference test solution for comparison with data from simulated physiological conditions.
- Gamble’s solution (GMB, pH 7.4) mimics interstitial fluid within the deep lung under normal health conditions.
- Artificial lysosomal fluid (ALF, pH 4.5)simulates intracellular conditions in lung cells occurring with phagocytosis and represents relatively harsh conditions.
In artificial gastric fluid, phosphate buffered saline, Gamble´s solution and artificial lysosomal fluid, maximum dissolved manganese and iron concentrations (operationally defined as the dissolved metal fraction after 0.2 µm filtration and centrifugal filtration (~2.1 nm, < 3 kDa)) at a loading of 100 mg test item/L were determined in ALF media with 2908 µg/L Mn and 1866 µg/L Fe after 168h. With maximum Mn and Fe concentrations of 79.3 µg/L Mn and 1.20 µg/L Fe, very low manganese and iron release was detected in phosphate buffered saline (PBS, pH = 7.2 - 7.4) and Gamble’s solution (GMB, pH 7.4) at a loading of 100 mg/L. Thus, the extent to which iron manganese trioxide (Bayferrox® 645 T) can produce soluble available ionic and other manganese and iron-bearing species in artificial body fluids is limited.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
As demonstrated in the category approach justification, in regard to structure, physicochemical properties, environmental fate characteristics, ecotoxicity and toxicity, the grouping of Fe2O3 (diiron trioxide), Fe3O4 (triiron tetraoxide), FeOOH (iron hydroxide oxide), (Fe,Mn)2O3 (iron manganese trioxide), (Fe,Mn)3O4 (manganese ferrite), and ZnFe2O4 (zinc ferrite) in the "Iron Oxides Category" is justified.
In the updated category approach justification , the category was extended to nano- and/or powder material. Comprehensive and sufficient data are available to conclude that nano- and micro-sized category member behave similar and no further testing is necessary.
Notably, from the results of repeated dose inhalation studies with FeOOH, Fe2O3 or Fe3O4 any size dependent increased translocation of iron outside the lung did not occur. Therefore no systemic toxicity for nano- and powder material of the iron oxides exists.
These repeated dose toxicity studies demonstrated, that the occupational limit value for nano- and powder material is identical.
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