Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

50 µg/m³

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/m³

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/kg bw/day

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/kg bw/day

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/cm²

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/cm²

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

low hazard (no threshold derived)

The substance is a multi-constituent substance and no toxicological data is available for the substance itself. Data is presented for one of the major constituents, hematite (Fe2O3), and for the lead impurity.

For Iron Oxides:

In consideration of the available data no acute or chronic oral or dermal effects of the members of the iron oxides category are expected. From mutagenicity studies (Bayer, 1982e; Moriya et al., 1983; Bevan and Manger, 1985; Fujita et al., 1994; Bayer 1990, Bayer 2008 a, b, c) and despite the widespread use and ubiquitous occurrence of the category members no carcinogenic potential of the group members is identified (Steinhoff, Mohr, and Hahnemann, 1991).

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 way of exposure as a threshold mode of action for workers and the general population.

Due to the same physicochemical 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.

For Fe3O4 valid subacute and subchronic inhalation studies (according OECD) are available (Bayer, 2006a; Bayer, 2006b).

The NOAECs are 10.1 mg/m³ from the 28 days study (Bayer, 2006b) and 4.7 mg/m³ from the 90 days study ( Bayer, 2006a) with LOAECs of 19.7 mg/m³and 16.6 mg/m³, respectively. In the subchronic inhalation study in rats exposure was 6 hours/day, 5 days/week for 13 weeks.

In the 13 weeks study the rats were exposed 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. Haematology, clinical pathology and urinalysis were unobtrusive. No evidence of extra-pulmonary toxicity existed (Bayer, 2006a).

With regard to the most sensitive parameters 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 (Bayer, 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 (Bayer, 2006a). There is no evidence of systemic toxicity, genotoxicity or carcinogenicity. Therefore the group can be treated as dust without specific toxicity and the general dust limit applies.

Derivation of DNEL:

According to ECHA Guidance Document R.8; Appendix R 8-13 a national Occupational Exposure Limit (OEL) can be used in place of a DNEL under certain circumstances. For general dust in Germany the current binding national Occupational Exposure Limit is 10 mg/m3 for inhalable and 3 mg/m3 for respirable dust (TRGS900; http://www.baua.de/cae/servlet/contentblob/666764/publicationFile/55580/TRGS-900.doc), whereas the German MAK commission has published a value of 4 mg/m3 for inhalable and 1.5 mg/m3 for respirable dust (DFG, 2009).

The use of the official national German value for general dust is in line with the proposal in ECHA Guidance document R8 from May 2008. Here it is stated that 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. It is stated in the ECHA Guidance document that for non-soluble inert dusts if the derived DNEL for inhalation is above these dust limits, the general dust limits should apply for exposure scenarios with exposure to dust (see chapter 8.7.1, page 54 of ECHA guidance document R.8 from May 2008).

In the case of the ferrous oxides covered by this assessment 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 does not argue against that approach.

Overall, based on

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

• the available 90 day inhalation toxicity study and

• the ECHA guidance how to select the critical DNEL in case of inert dusts

the current binding national Occupational Exposure Limit in Germany for dust of 10 mg/m3 for inhalable and 3 mg/m3 for respirable dust (TRGS900) will be used as DNEL for long term exposure to iron oxides.

For the lead impurity:

NOAEL’s were used to derive DNEL’s with the following rationale being applied to interpretation of the health effects data.

1. Correction of dose descriptors is not needed since data are based upon a systemic measure of exposure (lead in blood) in humans that eliminates the need for route to route extrapolations or other corrections to the dose descriptors. The toxicity of systemic lead is mediated by the lead cation and is independent of the original speciation of the lead compound to which exposure occurred. For inorganic lead and its' compounds, toxicity indexed to internal blood lead can generally be evaluated independent of the speciation of the compound to which exposure originally occurred.

2. The NOAEL’s were identified from multiple (in some case in excess of 100) scientific studies of human populations. This has permitted detailed evaluation of issues such as age, gender, ethnicity, intensity of exposure and duration of exposure that can be sources of uncertainty in effects assessment. Given that extrapolations are not made from animal studies and that specific NOAEL’s have been derived for susceptible subpopulations there is no need to correct for inter-species variability with Assessment Factors. Separate

3. NOAEL’s have been developed for sensitive subpopulations and accommodate intra-species variability that might otherwise require the use of an Assessment factor. NOAEL’s derived for different health endpoints are shown in the following table. Those NOAEL’s that are the lowest for a given subpopulation are shown in bold text. From this table it can be seen that NOAEL’s have been proposed for the most sensitive subsets of the population and define blood lead levels protective against subtle effects. Whereas NOAEL’s indexed to endpoints that constitute a material impairment of health might merit consideration of an Assessment Factor greater than “1”, the NOAEL’s derived in this assessment protect against preclinical effects that precede material health impairment.

NOAEL’s and proposed blood lead levels for different exposed populations

Health effects endpoint	NOAEL	Exposed population
Renal system effects	60 μg/dL	Adult
Haematological effects	50 μg/dL	Adults
Reproductive effects (male)	45 μg/dL	Male Adults
Nervous system effects (adult)	40 μg/dL	Adults
Reproductive effects (female)	30 μg/dL	Women of child-bearing capacity
Nervous system effects (foetal effects) during pregnancy	10 μg/dL	Pregnant women/women of child-bearing capacity

4. The most sensitive NOAEL’s in adults protect against effects known to be reversible if exposure is reduced.

5. The dose response for lead toxicity is steep and increases the precision with which NOAEL’s can be identified. For example, although sub-clinical manifestations of neurotoxicity may be manifested in adults in the range of 40 – 50μg/dL, significant cognitive impairment would be expected to result from a doubling of blood lead.

6. Consideration was given to whether Assessment Factors might be needed to guard against more significant health effects that might occur at higher blood lead levels. This consideration was primarily relevant to the occupational setting but was considered unnecessary since blood lead levels in the occupational setting are routinely monitored – risk management protocols already in place should preclude significant exceeding of the NOAEL’s. Furthermore, the NOAEL’s are indexed to blood lead and not to external measures of exposure. The toxicokinetics of lead are highly non-linear – particularly in the exposure ranges that characterise the workplace. Simulations from a physiologically based model of lead determined that a doubling of occupational blood lead in the workplace would require a disproportionately higher increase in external exposure. The toxicokinetics of lead are such that Assessment Factors are not need afford protection against exposures that might exceed NOAEL’s for more significant health effects since in the increase in external exposure required would be large and prevented by medical surveillance and biological monitoring programs.

Combined, the preceding indicated that the NOAEL’s derived here are both conservative and protective of health. The majority of NOAEL’s can thus be converted to DNEL’s with an Assessment Factor of “1”.

Separate DNEL’s indexed to acute toxicity are not needed. Animal testing indicates that lead is not acutely toxic. Moreover, the DNEL’s for repeated dose toxicity are far lower than those that might be considered under acute exposure circumstances.

No DNEL/DMEL has been proposed for mutagenicity. In vitro doses required to produce effects (via what are believed to be indirect, threshold mechanisms) are far higher than those that possess physiological relevance and in vivo testing via physiologically relevant administration routes is considered to be negative.

No DNEL/DMEL has been proposed for cancer. Lead induces tumours (generally of the kidney) via what is believed to be an indirect mechanism that is likely non-genotoxic and a multi-step process involving sustained renal toxicity accompanied by prolonged forced cell proliferation. The generally negative genotoxicity profile of lead is consistent with this rationale, as are the generally negative epidemiology studies of workers occupationally exposed to lead. If kidney cancer were to be induced in humans it would likely proceed via a threshold non-genotoxic mechanisms that requires exposures higher than those that produce significant renal damage. A DNEL/DMEL for cancer, if derived, would be higher than the NOAEL’s that have been derived for neurological function in adults.

The DNEL’s derived for different sub-sets of the population in accordance with the preceding are summarised below in terms of lead in blood concentrations.

DNEL’s Used for Occupational Exposure Assessment

Subpopulation	DNEL	Health Basis of DNEL
Pregnant Woman	10 ug/dL	Developmental toxicity affecting cognitive development
All Other Adults	40 ug/dL	Neuropsychological function

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/m³

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/m³

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/m³

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/m³

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/kg bw/day

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/kg bw/day

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/cm²

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/cm²

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/kg bw/day

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

100 µg/kg bw/day

Justification:

Default value, will be changed in the complete dossier update.

Hazard assessment conclusion:

low hazard (no threshold derived)

The substance is a multi-constituent substance and no toxicological data is available for the Substance itself. Data is presented for one of the major constituents, hematite (Fe2O3), and for the lead impurity.

For the Iron Oxides:

The only critical exposure pathway to humans is the inhalation of the dust. Therefore it is only necessary to consider this way 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. For LEAD:

NOAEL’s were used to derive DNEL’s with the following rationale being applied to interpretation of the health effects data.

1. Correction of dose descriptors is not needed since data are based upon a systemic measure of exposure (lead in blood) in humans that eliminates the need for route to route extrapolations or other corrections to the dose descriptors.

2. The NOAEL’s were identified from multiple (in some case in excess of 100) scientific studies of human populations. This has permitted detailed evaluation of issues such as age, gender, ethnicity, intensity of exposure and duration of exposure that can be sources of uncertainty in effects assessment. Given that extrapolations are not made from animal studies and that specific NOAEL’s have been derived for susceptible subpopulations there is no need to correct for inter-species variability with Assessment Factors. Separate NOAEL’s have been developed for sensitive subpopulations and accommodate intra-species variability that might otherwise require the use of an Assessment factor.

3. NOAEL’s derived for different health endpoints are shown in the following table. Those NOAEL’s that are the lowest for a given subpopulation are shown in bold text. From this table it can be seen that NOAEL’s have been proposed for the most sensitive subsets of the population and define blood lead levels protective against subtle effects. Whereas NOAEL’s indexed to endpoints that constitute a material impairment of health might merit consideration of an Assessment Factor greater than “1”, the NOAEL’s derived in this assessment protect against preclinical effects that precede material health impairment.

NOAEL’s and proposed blood lead levels for different exposed populations

Health effects endpoint

NOAEL

Exposed population

Renal system effects

60 μg/dL

25 µg/dL

Adults

Child

Haematological effects

50 μg/dL

40 µg/dL

Adults

Child

Reproductive effects (male)

45 μg/dL

Male Adults

Nervous system effects (adult)

40 μg/dL

Adults

Reproductive effects (female)

30 μg/dL

Women of child-bearing capacity

Nervous system effects (child)

10 μg/dL

Individual Child

Nervous system effects (child)

5 µg/dL

Population Based Child Limit

Nervous system effects (foetal effects) during pregnancy

10 μg/dL

Pregnant women/women of child-bearing capacity

4. The most sensitive NOAEL’s in adults protect against effects known to be reversible if exposure is reduced.

5. The dose response for lead toxicity is steep and increases the precision with which NOAEL’s can be identified. For example, although sub-clinical manifestations of neurotoxicity may be manifested in adults in the range of 40 – 50μg/dL, significant cognitive impairment would be expected to result from a doubling of blood lead.

6. The effects that are the basis of the NOAEL’s applicable to the general population lack functional or clinical significance for the individual and cannot be detected at the level of the individual. Protection is thus being offered against effects which, by many definitions, would not be considered as adverse.

7. In the specific instance of the effect of low-level lead exposure upon IQ development in children, consideration was given to the fact that no threshold has yet to be identified for the effects of lead upon IQ. A NOAEL of 10μg/dL was set as an exposure level that would not produce adverse effects detectable at the level of the individual. This NOAEL does not preclude potential “societal impacts” resulting from subtle effects of lead upon large numbers of individuals. However, virtually all neurotoxicants are regarded to have a threshold and an “epistemic” threshold was identified for lead (5μg/dL). This level of lead in blood, set as a target for the general population average, would both mitigate against potential societal effects of lead at blood lead levels less than 10μg/dL and guards against exceeding of the NOAEL of 10 μg/dL set to prevent subtle effects detectable at the level of the individual. This tiered strategy for managing the blood lead levels of children eliminates the need to consider arbitrary Assessment Factors that might be proposed in light of possible population effects of lead at low blood lead levels.

8. Combined, the preceding indicated that the NOAEL’s derived here are both conservative and protective of health. The majority of NOAEL’s can thus be converted to DNEL’s with an Assessment Factor of “1”.

9. As assessment factor of 2 will be applied to the NOAEL of 40 μg/dL for adult neurological function since adults in the general population will not be under medical surveillance. Note that, due to non-linearities in the toxicokinetics of lead, an Assessment Factor of 2 is actually equivalent to an approximate five-fold reduction in external exposure.

Separate DNEL’s indexed to acute toxicity are not needed. Animal testing indicates that lead is not acutely toxic. Moreover, the DNEL’s for repeated dose toxicity are far lower than those that might be considered under acute exposure circumstances.

No DNEL/DMEL has been proposed for mutagenicity. In vitro doses required to produce effects (via what are believed to be indirect, threshold mechanisms) are far higher than those that possess physiological relevance and in vivo testing via physiologically relevant administration routes is considered to be negative.

DNEL/DMEL has been proposed for cancer. Lead induces tumours (generally of the kidney) via what is believed to be an indirect mechanism that is likely non-genotoxic and a multi-step process involving sustained renal toxicity accompanied by prolonged forced cell proliferation. The generally negative genotoxicity profile of lead is consistent with this rationale, as are the generally negative epidemiology studies of workers occupationally exposed to lead. If kidney cancer were to be induced in humans it would likely proceed via a threshold non-genotoxic mechanisms that requires exposures higher than those that produce significant renal damage. A DNEL/DMEL for cancer, if derived, would be higher than the NOAEL’s that have been derived for neurological function in adults.

The DNEL’s derived for different sub-sets of the population in accordance with the preceding are summarised below in terms of lead in blood concentrations.

DNEL’s Used for General Population Exposure Assessment

Subpopulation	DNEL	Health Basis of DNEL
Individual Child	10 ug/dL	Impaired cognitive development
Large Population of Children	5 ug/dL	Societal impact of indeterminate nature
Pregnant Woman	10 ug/dL	Developmental toxicity affecting cognitive development
Adult	20 ug/dL	Neuropsychological function

Registration Dossier

Registration Dossier

Diss Factsheets

Feldspar minerals, hematite and quartz, calcination products of copper mining residues

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population