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EC number: 215-168-2 | CAS number: 1309-37-1
- 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
Endpoint summary
Administrative data
Description of key information
A subacute inhalation toxicity study for Fe3O4, Fe2O3 and FeOOH and a subchronic inhalation study for Fe3O4 are available. Additionally, a short-term (5-day) inhalation study with two different grades of nanomaterials was conducted. Rats were exposed to 10 and 30 mg/m³ of smaller nano-sized Fe2O3 and 30 mg/m³ of larger nano-sized Fe2O3.
Based on the information from a 90-day repeated dose oral toxicity study in rats (according to OECD 408, GLP) it is concluded that the Fe3O4 does not show any adverse effects up to the highest dose level of 1000 m/kg bw/day.
For dermal toxicity no reliable repeated dose toxicity studies are available for the iron oxide category
Details on the category justification are given in the read-across document attached in IUCLID section 13.2.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- not specified
- Remarks:
- not specified in the publication
- Specific details on test material used for the study:
- Hydrodynamic size: 117.9 (in distilled water) and 140.4 (0.05% carboxylmethyl cellulose)
Zeta potential: 13.6 mV (pH6 suspension) - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- daily
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12 per group
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- The changes of serum biochemical parameters in the Fe2O3 nanoparticle groups were sporadic and were of a small magnitude, indicating that these differences were not considered dose-related adverse effects of the nanoparticle treatments.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: no adverse effects observed
- Key result
- Critical effects observed:
- no
- Conclusions:
- In the current repeated dose toxicity study, iron oxide red in water was administered via gavage to groups of 12 female Sprague-Dawley rats at dose levels of 250, 500, and 1000 mg/kg bw/day. The administration occurred daily for a 13-week period.
Fe2O3 nanoparticles had no significant effects on body weight, mean daily food and water consumption, when compared with control groups. There were no treatment-related changes in haematological, serum biochemical parameters or histopathological observations. Some changes in organ weights were observed: decreases in weight of pituitary gland and liver and increases in weight of adrenal gland and testis. According to the authors, ‘these changes were sporadic without dose-dependent trends, indicating that they were not considered toxicologically relevant’. In blood and all tissues tested, including liver, kidney, spleen, lung and brain, the concentration of Fe showed no dose-associated response in comparison to the control groups. Iron concentrations in the urine of Fe2O3 nanoparticle-treated rats showed no significant differences compared to those of control animals. Although not statistically significant, the concentrations of Fe in the faeces of treated animals were found to be higher than those of the control groups. The authors stated that the subchronic oral dosing with Fe2O3 nanoparticles showed no systemic toxicity to rats. The NOAEL was established to be greater than 1000 mg/kg bw/day, the highest dose tested in rats receiving Fe2O3 nanoparticles by gavage.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study - very well documented, study was performed with Fe3O4 as a representative for the iron oxide group - see Category approach for Fe2O3, Fe3O4, FeOOH, (Fe,Mn)2O3, (Fe,Mn)3O4, ZnFe2O4
- Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Route of administration:
- inhalation
- Type of inhalation exposure:
- nose only
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: MMAD was 1.3 µm, GDS ~2
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 6 hours/day 5 days/week
- Remarks:
- Doses / Concentrations:
4.7, 16.6, 52.1 mg/m³
Basis:
analytical conc. - No. of animals per sex per dose:
- 20
- Control animals:
- yes
- Dose descriptor:
- NOAEC
- Effect level:
- 4.7 mg/m³ air
- Sex:
- male/female
- Basis for effect level:
- other: see "Remarks"
- Critical effects observed:
- not specified
- Executive summary:
- Rats exposed subchronically to three different concentrations of Fe3O4 revealed findings clearly consistent with and typical for a poorly soluble particle. The retention kinetics of inhaled Fe3O4 particles revealed neither analytical nor toxicological evidence that free, biosoluble iron was liberated from the inhaled dust to any appreciable extend. Also in this study no evidence of extrapulmonary toxicity existed. The results of this study support the view, that the NOAEL of Fe3O4 is 4.7 mg/m³.
Reference
Rats exposed subchronically to three different concentrations of Fe3O4 revealed findings clearly consistent with and typical for a poorly soluble particle. Congruent with previous studies addressing the retention kinetics of inhaled Fe3O4 particles, neither analytical nor toxicological evidence existed that free, biosoluble iron was liberated from the inhaled dust to any appreciable extend. Also in this study no evidence of extrapulmonary toxicity existed. With regard to indices considered to be adverse, viz. increased counts of cells and especially PMNs in BAL, elevated LDH as marker of cytotoxicity, and ß-NAG as marker of increased lysosomal activities 4.7 mg/m³ constitute an exposure level without evidence of adversity. These findings match those observed by histopathology.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- GLP guideline study according OECD #413 (Subchronic Inhalation Toxicity: 90-Day)
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study - very well documented, study was performed with Fe3O4 as a representative for the iron oxide group - see Category approach for Fe2O3, Fe3O4, FeOOH, (Fe,Mn)2O3, (Fe,Mn)3O4, ZnFe2O4
- Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Route of administration:
- inhalation
- Type of inhalation exposure:
- nose only
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: MMAD was 1.3 µm, GDS ~2
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 6 hours/day 5 days/week
- Remarks:
- Doses / Concentrations:
4.7, 16.6, 52.1 mg/m³
Basis:
analytical conc. - No. of animals per sex per dose:
- 20
- Control animals:
- yes
- Dose descriptor:
- NOAEC
- Effect level:
- 4.7 mg/m³ air
- Sex:
- male/female
- Basis for effect level:
- other: see "Remarks"
- Critical effects observed:
- not specified
- Executive summary:
- Rats exposed subchronically to three different concentrations of Fe3O4 revealed findings clearly consistent with and typical for a poorly soluble particle. The retention kinetics of inhaled Fe3O4 particles revealed neither analytical nor toxicological evidence that free, biosoluble iron was liberated from the inhaled dust to any appreciable extend. Also in this study no evidence of extrapulmonary toxicity existed. The results of this study support the view, that the NOAEL of Fe3O4 is 4.7 mg/m³.
Reference
Rats exposed subchronically to three different concentrations of Fe3O4 revealed findings clearly consistent with and typical for a poorly soluble particle. Congruent with previous studies addressing the retention kinetics of inhaled Fe3O4 particles, neither analytical nor toxicological evidence existed that free, biosoluble iron was liberated from the inhaled dust to any appreciable extend. Also in this study no evidence of extrapulmonary toxicity existed. With regard to indices considered to be adverse, viz. increased counts of cells and especially PMNs in BAL, elevated LDH as marker of cytotoxicity, and ß-NAG as marker of increased lysosomal activities 4.7 mg/m³ constitute an exposure level without evidence of adversity. These findings match those observed by histopathology.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 4.7 mg/m³
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- GLP guideline study according OECD #413 (Subchronic Inhalation Toxicity: 90-Day)
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: dermal
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Introductory remark on read-across:
The predominant characteristic of the iron oxide category substances is the inertness being a cause of their chemical stability and very poor reactivity. This is shown by a very low dissolution in water and artificial physiological fluids as well as a very low in vivo bioavailability after oral administration. This very low reactivity, solubility and bioavailability leads to a complete lack of systemic toxicity after acute, sub-acute or sub-chronic oral or inhalation exposure up to the limit dose of the maximum tolerated concentration of the respective test. Similarly, a lack of systemic effects for the endpoints mutagenicity and reproductive toxicity are anticipated. Further information on the read-across approach is given in the report attached to IUCLID section 13.2.
Repeated dose toxicity: oral
A subchronic toxicity study of various orally administered nanoparticles including red iron oxide (Fe2O3, 60-118 nm) was performed by Yun et al. (2015) according to the OECD Test Guideline (TG) 408 (OECD, 1998). Sprague-Dawley rats received daily doses of 250, 500 or 1000 mg/kg bw/day for 13 weeks by gavage. Fe2O3 nanoparticles had no significant effects on body weight, mean daily food and water consumption, when compared with control groups. There were no treatment-related changes in haematological, serum biochemical parameters or histopathological observations. Some changes in organ weights were observed: decreases in weight of pituitary gland and liver and increases in weight of adrenal gland and testis. According to the authors, ‘these changes were sporadic without dose-dependent trends, indicating that they were not considered toxicologically relevant’. In blood and all tissues tested, including liver, kidney, spleen, lung and brain, the concentration of Fe showed no dose-associated response in comparison to the control groups. Iron concentrations in the urine of Fe2O3 nanoparticle-treated rats showed no significant differences compared to those of control animals. Although not statistically significant, the concentrations of Fe in the faeces of treated animals were found to be higher than those of the control groups. The authors stated that the subchronic oral dosing with Fe2O3 nanoparticles showed no systemic toxicity to rats. The NOAEL was established at 1000 mg/kg bw/day, the highest dose tested in rats receiving Fe2O3 nanoparticles by gavage.
Twenty-eight days repeated dose oral toxicity studies were conducted on Fe2O3-30 nanomaterial (29.75± 1.87 nm) and its counterpart Fe2O3-powder (<5 µm) on female rats by dividing them into 4 groups (10 rats in each group); control, low dose (30 mg/kg/day), medium dose (300 mg/kg/day), and high dose (1000 mg/kg/day) (Kumari, 2012). High dose treated rats showed toxic signs and symptoms but no mortality. Inhibition was observed in total, Na+, K+, Mg2+ and Ca2+ATPases in brain of exposed rats and increased aspartate amino transferase, alanine amino transferase and lactate dehydrogenase in serum and liver, whereas, these enzymes were decreased in kidney. Increased levels of these enzymes in liver as well as in serum might be an adaptive mechanism due to the stress of iron particles.
Repeated dose toxicity: inhalation
In a subacute inhalation toxicity study, 48 male rats per group were exposed to three different aerosolized iron oxide powders (Fe2O3, Fe3O4 and FeOOH). Exposure was 6-hours/day on five days/week for two consecutive weeks. The rats were exposed to mean actual concentrations of 185.6 mg/m³ Fe3O4, 210.2 mg/m³ Fe2O3 and 195.7 mg/m³ FeOOH (Pauluhn, 2005). The repeated exposure to the aerosolized iron oxides was not associated with any specific clinical signs, changes in body temperature or body weights. Histopathological evaluation of rat lungs exposed to the different iron oxides revealed findings consistent with a 'poorly soluble particle' effect after the 2-week exposure period, including the 3-month postexposure period. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs was not observed (Pauluhn, 2005). This supports the conclusion, that Fe3O4 can serve as a surrogate for FeOOH and Fe2O3.
For Fe3O4 valid subacute and subchronic inhalation studies are available (Pauluhn, 2006a; Pauluhn, 2006b). In the subacute inhalation toxicity study 30 male rats were exposed to 10.1, 19.4, 45.6 and 95.8 mg/m³ Fe3O4 for 6 hours/day, 5 days/week for 4 weeks and serially sacrificed 1, 8, 24 weeks after the 4 weeks exposure period. Clinical signs were recorded daily before and after exposure or once per week during the postexposure period. At each serial sacrifice, inflammatory endpoints were determined in bronchoalveolar lavage (BAL). Rats were subjected to gross pathological examination and histopathology (nasal passages, trachea, lung, liver, spleen, kidneys, testes and thymus). The repeated 4-week exposure to the aerosolized dry powder was not associated with specific clinical signs or consistent changes in body weights. Changes in organ weights occurred and consisted of increased lung and lung-associated lymph nodes (LALN) weight at 45.6 mg/m³ and above. Histopathological evaluation of rat lungs exposed to Fe3O4 revealed finding consistent with a poorly soluble particle effect. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs to any appreciable extent was not found. Extrapulmonary effects causally linked to the exposure of Fe3O4 were not found at any exposure concentration and time point (Pauluhn, 2006b). In the subchronic inhalation toxicity study in rats (20 male and 20 female rats per group) the animals were exposed 6 hours/day, 5 days/week for 13 weeks to 4.7, 16.6 and 52.1 mg/m³ Fe3O4. During the study, the body weights were determined twice weekly and clinical signs were recorded daily before and after exposure. At sacrifice, inflammatory endpoints were determined in BAL. Histopathology focused on the entire respiratory tract (nasal passages, trachea, lung, lung associated lymph nodes) and included all extrapulmonary organs as suggested by OECD 413. At sacrifice biological specimens were collected for hematology, clinical pathology and urinalysis (Pauluhn, 2006a). The repeated exposure of rats during a study period of 13 weeks was not associated with any specific clinical signs. Hematology, clinical pathology and urinalysis were unobtrusive. Neither analytical nor toxicological evidence existed that free, biosoluble iron was liberated from the inhaled dust to any appreciable extent. However, the neutrophils in male rats and some biochemical markers were elevated at 4.7 mg/m³ and above (Pauluhn, 2006a). The NOAECs for Fe3O4 are 10.1 mg/m³ for the subacute exposure and 4.7 mg/m³ for subchronic exposure in rats (Pauluhn, 2006a; Pauluhn, 2006b).
A histopathological evaluation of rat lungs exposed to three different iron oxides revealed findings consistent with a 'poorly soluble particle' effect after the 2- week exposure period, including the 3-month postexposure period. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs was not observed. Extrapulmonary effects causally linked to the high-level exposure of iron oxides were not be detected at any time point. At the end of the 3-month postexposure period the findings causally linked to the high-level exposure to iron oxides (e.g. focal inflammatory infiltrates, bronchioloalveolar hypercellularity) showed a decrease in incidence and/or severity. The comparative assessment of the three different iron oxides revealed the same quality and time course of responses, i.e., marked differences of any toxicological significance between the test specimens were not observed. Nonetheless, there was a consistent trend that the rats exposed to Fe3O4 displayed minimally more pronounced changes when compared to Fe2O3 and FeOOH. This supports the conclusion that from a scientific point of view further testing of Fe2O3 and Fe3O4 does not appear to be justified and that future studies with Fe3O4 can serve as conservative proxy for Fe2O3 and FeOOH (Pauluhn, 2005).
In a short-term (5-day) inhalation study (BASF SE 2015), 8 male Wistar rats (5 animals in the main group and 3 animals in the recovery group) were exposed to 10 and 30 mg/m³ of smaller nano-sized Fe2O3 and 30 mg/m³ of larger nano-sized Fe2O3. Dust Inhalation exposure of rats to 10 and 30 mg/m³ test item 1 and 30 mg/m³ of test item 2 on 5 consecutive days did not cause any adverse effect in the respiratory tract, which was examined by broncho-alveolar lavage and histopathology. There were no changes of hematology and clinical chemistry parameters. A slightly decreased mean body weight and intermittently reduced body weight change were observed during exposure and post-exposure period of the test group with micro-sized Fe2O3. However, the deviations to the control group were not biologically relevant. Thus, under current study conditions, the NOAEC was 30 mg/m³ for both nano-sized samples. No relevant differences between the smaller nano-sized and the larger nano-sized Fe2O3 were observed.
Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
study with the longest application duration (subchronic) is used
Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
study with the longest application duration (subchronic) is used
Justification for classification or non-classification
Repeated dose toxicity, oral:
In one guideline compliant study, iron oxide red did not show any effects on rats when administered up to the limit dose of 1000 mg/kg bw/day. In conclusion, based on the data observed for the substance in 90 day repeated dose oral toxicity study in rats, the classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and the no observed adverse effect level (NOAEL) via oral application is above the guidance value for a Category 1 classification of 10 mg/kg bw/day and above the guidance value for a Category 2 classification of 100 mg/kg bw/day. For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, oral is required.
Repeated dose toxicity, inhalation:
The NOAECs for Fe3O4 are 10.1 mg/m³ for the subacute exposure and 4.7 mg/m³ for subchronic exposure in rats.
A classification is therefore not justified.
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