Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Read-across approach for lead containing glass, oxide, chemicals:

The test item is covered under the definition "glass". In this context, “glass" is defined as an amorphous, inorganic, transparent, translucent or opaque substance formed by variouspowdery substances (mostly oxides) which are not present as such in the final glass: they are fully integrated into the glass matrix through the melting process and they lose their original characteristics. Thus, the available analytical information is only of quantitative nature without any indication as to elemental composition or structural purposes. Based on the definition under Regulation (EC) No 1907/2006, the test item fulfils the criteria for UVCB substances.

Substance-specific information for the test item glass, oxide, chemicals (water solubility < 100 mg/L) are not available. For this reason, read-across is anticipated to lead monoxide as a moderately soluble lead substance.

This read-across is considered justified and also conservative since lead monoxide (water solubility approx. 700 mg/L at 20°C) is one of the major starting materials (content ranging from approx. 30-80%) for the test item manufacture, and also represents the component of major toxicological concern.

For the substantiation of read-across, solubility tests (T/D and bioaccessibility) were performed with the test item in order to determine the release of lead from the “glass” matrix for a comparison to the solubility of the selected read-across substance.

The following lead concentrations were measured in two T/D tests with the test item with variable lead monoxide concentrations (starting material concentration):

Test material with a PbO content of 38.4%:

After 7 days, the dissolution of Pb ranged from 17.0 ± 1.99 µg/L (pH 8) to 18.7 ± 2.08 µg/L (pH 6).

After 28 days, the dissolution of Pb ranged from 37.8 ± 3.64 µg/L (pH 8) to 60.1 ± 17.2 µg/L (pH 6).

Based on the nominal test item amount, the maximum dissolution of Pb at pH 6 from the test item corresponded to 6.01% (w/w); based on contained lead 5.95% (w/w).

At pH 8, the maximum dissolution of Pb after 24 h based on contained Pb was 3.68 µg/L (1.03% (w/w)).

Test material with a PbO content of 78.0%:

After 7 days, the dissolution of Pb ranged from 53.8 ± 8.53 µg/L (pH 8) to 562 ± 86.1 µg/L (pH 6).

After 28 days, the dissolution of Pb ranged from 110 ± 8.28 µg/L (pH 8) to 684 ± 22.8 µg/L (pH 6).

At pH 6, the maximum dissolution of Pb from the test item was 68.4% (w/w) based on nominal test item loading. Based on contained Pb, the dissolution corresponded to 94.3 % (w/w).

At pH 8, the maximum dissolution of Pb after 24 h based on contained Pb was 29.4 µg/L (4.06 % (w/w)).

In comparison, a water solubility of lead monoxide (saturation solubility, OECD 105; Heintze 2005) of is given with 70.2 mg/L in the REACH registration dossier and in the "Voluntary Risk Assessment for Lead and Lead Compounds"; a T/D screening test at pH = 8 with a 100 mg/L loading revealed an average (+- SD) dissolved Pb concentration after 24 hours of 101 (+-0.003) µg/L.

Based on the above data, the release of Pb fromthe test item glass, oxide, chemicals is substantial, but eithersimilar or lower compared to pure PbO. Thus, read-across to lead monoxide can be considered scientifically justified and sufficiently conservative.

Discussion:

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 exceedence 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, threshholded 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 nongenotoxic 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 threshholded 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

 

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

Read-across approach for lead containing glass, oxide, chemicals:

The test item is covered under the definition "glass". Glass" is defined as an amorphous, inorganic, transparent, translucent or opaque substance formed by variouspowdery substances (mostly oxides) which are not present as such in the final glass: they are fully integrated into the glass matrix through the melting process and they lose their original characteristics. Thus, reliable analytical information are only of quantitative nature without any hints on element distribution or structural purposes. Based on the definition under Regulation (EC) No 1907/2006, the test item fulfils the criteria for UVCB substances.

Substance-specific information for the test item glass, oxide, chemicals (water solubility < 100 mg/L) are not available. For this reason, read-across is made to lead monoxide as a moderately soluble lead substance.

This read-across is considered justified and also conservative since lead monoxide (water solubility < 100 mg/L at 20°C) is one of the starting materials for the test item manufacture, and also represents the component of highest toxicological concern.

Discussion:

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 exceedence 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, threshholded 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 nongenotoxic 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 threshholded 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