Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Starting point:

The members of the iron oxide category (diiron trioxide Fe2O3, triiron tetraoxide Fe3O4, iron hydroxide oxide FeOOH, iron manganese trioxide (Fe,Mn)2O3, manganese ferrite (Fe,Mn)3O4, zinc ferrite ZnFe2O4 are insoluble, inert particles with no systemic toxicity.

In consideration of the available data no acute or chronic oral or dermal effects of the members of the category are expected. From mutagenicity studies and despite the widespread use and ubiquitous occurrence of the category members no mutagenic or carcinogenic potential of the group members has been detected in real life.

The only critical exposure pathway to humans is the inhalation of the dust of the compounds of the group members. Therefore it is only necessary to consider this route of exposure as a threshold mode of action for workers.

In principle two modus operandi are possible to derive no-effect levels for the hazard assessment of workers.

• One approach based on the data collection of available information and toxicological studies to set dose descriptors (e.g. NOAELs) and derivation of DNELs by dividing the NOAELs with appropriate assessment factors.

• The other method is the use of existing occupational limits (OELs). For insoluble and inert dusts the general dust limit values for dusts is applicable to prevent unspecific effects of dusts (e.g. overloading effects) on the respiratory organs.

The use of the general dust limit as OEL is regarded as valid, if the available data from repeated dose studies generate DNELs equivalent to the general dust limit.

Derivation of DNELs based on dose descriptors (e.g. NOAECs) by dividing them with appropriate AF (assessment factors):

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.

Due to the same physico-chemical properties and the absence of systemic effects of all group members, Fe3O4 has been chosen as a representative for the whole group and the results of the inhalations studies are significant for all group members (Schlecker 2015).

For Fe3O4 valid subacute and subchronic inhalation studies (according OECD) are available (Pauluhn, 2006a; Pauluhn, 2006b). The NOAECs are 10.1 mg/m³ from the 28 days study (Pauluhn, 2006b) and 4.7 mg/m³ from the 90 days study (Pauluhn, 2006a) with LOAECs of 19.7 mg/m³and 16.6 mg/m³, respectively.

In the subchronic inhalation study rats were exposure for 6 hours/day, 5 days/week for 13 weeks to mean actual concentrations (i. e. breathing zone volumes) of highly respirable aerosol of 4.7 +/- 0.6, 16.6 +/- 3.0 and 52.1 +/- 6.4 mg/m³, respectively. The repeated exposure was not associated with any specific clinical signs. Hematology, clinical pathology and urinalysis were unobtrusive. No evidence of extrapulmonary toxicity existed (Pauluhn, 2006a).

With regard to the most sensitive parameters considered to be adverse, viz. increased counts of cells and especially PMNs in BAL (Polymorphonuclear cells in bronchoalveolar lavage, elevated LDH (Lactate dehydrogenase) as markers of cytotoxicity, and ß-NAG (ß-N-Acetyl-glucosamidase) as marker of increased lysosomal activities 4.7 mg/m³ constitute an exposure level without evidence of adversity (Pauluhn, 2006a).

The NOAEC of Fe3O4 as a surrogate for the whole group is 4.7 mg/m³ for respirable dust. Non-specific toxicity consistent with a ‘poorly soluble particle’ and no specific toxicity were observed at higher concentrations at the port of entry (respiratory tract) only (Pauluhn, 2006a). Therefore the group can be treated as dust without specific toxicity.

According to the ECETOC Technical Report No. 122 (Poorly soluble particles/lung overload) from December 2013, (http://www.ecetoc.org/technical-reports) there is substantial evidence that poorly soluble particles of low toxicity, whether nano- or micro-sized, exert toxicologically relevant adverse effects via a threshold mode of action. Hence, the derivation of DNELs based on NOAELs/NOAECs as derived in animal inhalation studies, adjusted for human equivalent concentrations by appropriate dosimetry modelling, is toxicologically justified. Due to the higher sensitivity of the rat compared to humans with regard to lung overload driven effects, an overall assessment factor of 1 for intra- as well as interspecies differences is considered suitable and sufficient. The need of an AF for exposure duration extrapolation is regarded as questionable. In the 13 weeks study with Fe3O4 a NOAEC of 4.7 mg/m³ was found. If the default AF = 2 for time extrapolation from subchronic to chronic exposure is used a toxicological threshold of approx. 2.5 mg/m³ Fe3O4 is calculated for respirable dust.

Derivation of DNELs based on the general dust limit:

According to ECHA Guidance Document R.8 the general dust limits might be considered as DNEL for non-soluble inert dusts. “The general dust limits of 10 mg m3 for the inhalable airborne fraction and 3 mg m3 for the respirable airborne fraction used in setting Occupational Exposure Limits in many countries should be considered in combination with nature of the dust". (ECHA Guidance Document R.8; Version 2.1, November 2012; page 48).

The value above for the respirable fraction is in accordance with the recently modified general dust limit for the respirable fraction in Germany. Based on an evaluation of available data for biopersistent granular dusts by the “German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area” (MAK 2012) a calculation for a legally binding health based general dust limit for the respirable airborne fraction of non-soluble inert dusts is derived by multiplying 0.5 mg/m³ (limit for dust with the dust-density of 1 g/cm3) with the compound specific dust density (TRGS 900. 2014). By applying the dust-density value for iron oxides (ca. 5 g/cm3) a general dust limit for the respirable airborne fraction of 2.5 mg/m3 can be calculated as a health based general dust limit for the iron oxides based on the TRGS 900 guidance.

As also indicated in the ECHA Guidance Document R.8 “Note that DNELs derived based on substance specific data can never be adjusted upwards based on the general dust limits and that the dust limits cannot be used as a surrogate DNEL when there is no data to set a substance-specific DNEL.” (ECHA Guidance Document R.8;Version 2.1, November 2012; page 48).

In the case of the iron oxides the general dust limits as mentioned in the ECHA Guidance Document are supported by comprehensive experimental data. Based on the data of the 13-week inhalation toxicity study it was demonstrated that the effects after inhalation are attributable to the particle per se rather than a substance specific toxicity; therefore the use of the general dust limit value as DNEL is confirmed by experimental data. The NOAEC for repeated inhalation in the 13 week study for the respirable dust is higher than the respective general dust limit and therefore in accordance with the general dust limit of 10 mg/m³ for the inhalable airborne fraction and 3 mg/m³ for the respirable airborne fraction as a health based DNEL for the iron oxides.

A time-weighted average Threshold Limit Value (TWA-TLV) of 5 mg/m³ iron oxide (respirable fraction) is set as the limit dose by the American Conference of Governmental Industrial Hygienists (ACGIH; 2006).

Additional literature concerning DNEL estimation of poorly soluble micro- and/or nano-sized particles:

The setting of a health based DNEL or OEL for poorly soluble particles (PSP) like iron oxides was thoroughly investigated. Several research articles were published in the scientific literature concerning DNEL estimation of poorly soluble particles (e. g. iron oxides):

1) Based on the above mentioned sub-chronic 13 weeks study with Fe3O4 the empirical no-observed-adverse-effect level and the lower bound 95% confidence limit on the benchmark concentration (BMCL) obtained by benchmark analysis was 4.7 and 4.4 mg/m³, respectively and support an OEL (time-adjusted chronic occupational exposure level) of 2 mg/m³ (alveolar fraction), (Pauluhn , 2012).

2) Published evidence suggests that repeated exposure inhalation studies on rats represent the most sensitive bioassays in regard to granular biopersistent particulate matter. This analysis suggests that the prevention of any overload-like condition may also prevent adverse effects to occur from secondary inflammatory responses or long-term sequelae. This conclusion matches the deliberations of expert groups convened to address PM (particulate matter)-related chronic toxicity (ILSI Risk Science Institute, 2000). http://www.ncbi.nlm.nih.gov/pubmed/10715616

3) A volume based generic concentration of 0.54µl PMresp/m³ (PMresp = particulate matter respirable), is considered to represent a defensible OEL based on both generic theoretical considerations as well as empirical evidence. Related mass concentrations can readily be calculated by multiplication of the volume concentration with the PM-agglomerate density (ρ) (mass concentration-mg/m3 = 0.54µl PMresp/m³ ×ρ). In this analysis a volume-based generic mass concentration of 0.5µl PMrespirable/ m³ ×agglomerate density, independent on nano- or micro-sized properties, is derived as a generic NOEC in both rats and humans (Pauluhn, 2011a). The iron oxides of the iron oxide group have a relative density (ρ) of approximately 5.0 mg/µl. Therefore, a generic OEL of approximately 2.7 mg/m³ can be derived for nano- and micro-sized iron oxides.

4) In a mechanistic study, the two poorly soluble iron containing solid aerosols of siderite (FeCO3) and magnetite (Fe3O4) were compared in a 4-week inhalation study on rats at similar particle mass concentrations of approximately 30 or 100 mg/m³ (Pauluhn, 2011b). The particle size distributions were essentially identical (MMAD ≈1.4 μm). The iron-based concentrations were 12 or 38 and 22 or 66 mg Fe/m³ for FeCO3 and Fe3O4, respectively. Modeled and empirically determined iron lung burdens were compared with endpoints suggestive of pulmonary inflammation by determinations in bronchoalveolar lavage (BAL) and oxidative stress in lung tissue during a post-exposure period of 3 months. The objective of the study was to identify the most germane exposure metrics, i.e. the concentration of elemental iron (mg Fe/m³), total particle mass (mg PM/m³) or particle volume (μl PM/m³) and their associations with the effects observed. From this analysis it was apparent that the intensity of pulmonary inflammation was clearly dependent on the concentration of particle-mass or -volume and not of the iron content. Despite its lower iron content, the exposure to FeCO3 caused a more pronounced and sustained inflammation as compared to Fe3O4. Similarly, borderline evidence of increased oxidative stress and inflammation occurred especially following exposure to FeCO3 at moderate lung overload levels. The in situ analysis of 8-oxoguanine in epithelial cells of alveolar and bronchiolar regions supports the conclusion that both FeCO3 and Fe3O4 particles are effectively endocytosed by macrophages as opposed to epithelial cells. Evidence of intracellular or nuclear sources of redox-active iron did not exist. In summary, this mechanistic study supports previous conclusions, namely that the repeated inhalation exposure of rats to highly respirable pigment-type iron oxides cause nonspecific pulmonary inflammation which shows a clear dependence on the particle volume-dependent lung overload rather than any increased dissolution and/or bioavailability of redox-active iron.

5) A further evaluation, demonstrated the applicability of a general OEL for nano- and micro-sized iron oxides. For this purpose the results of repeated dose studies of Fe3O4 and FeOOH were compared (Pauluhn , 2014).

Goethite fulfills the currently applied generic definition of nano-sized materials with ≤ 0.1 μm in at least one dimension. Despite this characteristic ‘nano-goethite’ was equal-to-less inflammogenic upon repeated inhalation exposure of rats than magnetite under otherwise dosimetrically adjusted similar exposure conditions. The time-course changes of the ‘nano-goethite’ inflammogenicity were typical of nano-/micro-sized poorly soluble, low toxicity particles. The apparent faster clearance of ‘nano-goethite’ is considered to be confounded by pulmonary inflammogenicity as endogenous inflammation-related iron’ which cannot be distinguished from particle related iron. Therefore, the impact of facilitated dissolution and of goethite relative to magnetite cannot be judged. Translocation of iron is a typical occurrence and sequel of pulmonary inflammation; however any nano-size-dependent increased translocation did not occur. Accordingly, a read-across from magnetite is considered to be implicitly conservative and scientifically justified based on the generic, overload dependent effects observed. Based on the generic relationship, an OEL of 2 mg/m³ (TWA) is considered to be applicable also to goethite.

In conclusion, the effects of micro- and nano-sized iron oxides are thoroughly investigated and the results were published. There is clear evidence that the effects observed, are caused by an overload effect of the lungs caused by poorly soluble particles. The pulmonary toxicity is determined by the poorly soluble particle and not the iron content. No health based difference in the OEL (DNEL) for nano- and micro-sized material is applicable. The derived OEL for inhalable iron oxide dust is in the range of 2 to 3 mg/m³.

The use of the general dust limit as OEL is regarded as valid, because the available data from repeated dose studies generate DNELs equivalent to the general dust limit.

Overall, based on

• the substance-specific data on the mode of action of iron oxide after inhalation,

• the available repeated dose inhalation toxicity studies with Fe2O3, Fe3O4 and FeOOH and

• the ECHA Guidance Document R8A general dust limit of 10 mg/m3 for the inhalable airborne fraction and 3 mg/m3 for the respirable airborne fraction is considered appropriate as a health based DNEL for the iron oxides. 

References:

ACGIH. 2006. United States Department of labor: https://www.osha.gov/dts/chemicalsampling/data/CH_247400.html

BASF SE (2015), Short-term (5-day) inhalation lung toxicity study in male Wistar rats dust exposure with 3 week recovery period, BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany, Report No. 34I0772/05I048

ECHA Guidance Document R.8; Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version: 2.November 2012; http://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf

ILSI Risk Science Institute, The relevance of the rat lung response to particle overload for human risk assessment: a workshop consensus report, Inhal Toxicol. 2000 Jan-Feb;12(1-2):1-17 http://www.ncbi.nlm.nih.gov/pubmed/10715616

MAK 2012. "German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area". General threshold limit value for dust. http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb0230stwe5314/pdf

Pauluhn J (2006a), Iron Oxide 'Black', Subacute inhalation Toxicity in Rats (Exposure 6 hours/day, 5 days/week for 4 weeks followed by a postexposure period of 6 months), Bayer HealthCare AG Departments: PH·R&D T MST Inhalation, Report-No.: AT02853, 2006-03-06

Pauluhn J (2006b), Magnetite (Fe3O4, Iron Oxide ‘Black'), Subchronic inhalation Toxicity in Rats (Exposure 6 hours/day, 5 days/week for 13 weeks), Bayer HealthCare AG, PH-GDD-T Molecular & Special Toxicology, Report-No.: AT03159, 2006-07-04

Pauluhn J (2011a), Poorly soluble particulates: Searching for a unifying denominator of nanoparticles and fine particles for DNEL estimation, Toxicology 2011, 279, 176-188

Pauluhn J (2011b), Siderite (FeCO3) and magnetite (Fe3O4) overload-dependent pulmonary toxicity is determined by the poorly soluble particle not the iron content, Inhalation Toxicology 2011, 23, 763-783

Pauluhn J (2012), Subchronic inhalation toxicity of iron oxide (magnetite, Fe3O4) in rats: pulmonary toxicity is determined by the particle kinetics typical of poorly soluble particles, J. Appl. Toxicol. 2012; 32: 488–504

Pauluhn (2014) Expert opinion Goethite (FeOOH) - Derivation of OEL based on Read Across with Magnetite, Bayer Pharma AG, Experimental Toxicology - Inhalation, D-42096 Wuppertal, Germany)

Schlecker H (2015), Updated Category Approach Justification-Iron Oxides- Fe2O3,Fe3O4, FeOOH, (Fe,Mn)2O3, (Fe,Mn)3O4), ZnFe2O4 - Lanxess Deutschland GmbH D-51369 Leverkusen-Compiled and evaluated by Dr. Hans Allmendinger and Dr. Harald Schlecker

TRGS 900. 2014. Begründung zum Allgemeinen Staubgrenzwert (2014/2001) in TRGS 900. http://www.baua.de/cae/servlet/contentblob/664342/publicationFile/47939/900-allgemeiner-staubgrenzwert.pdf

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

The only critical exposure pathway to humans is the inhalation of the dust of the compounds of the group members. Therefore it is only necessary to consider this route of exposure as a threshold mode of action for workers and the general population. However, consumers are not exposed via inhalation as the substance is bound physically in the matrix of an article. Therefore, no relevant exposure via inhalation is expected for consumers