Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

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

Workers - Hazard via dermal route

Systemic effects

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

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

All DNELs are based upon systemic biomarkers of internal exposure (lead in blood) and not upon external exposure. Potential toxicity is thus assessed independent of the exposure route and systemic DNELs derived.

NOAELs were used to derive DNELs 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 NOAELs 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 NOAELs have been derived for susceptible subpopulations there is no need to correct for inter-species variability with Assessment Factors. Separate NOAELs have been developed for sensitive subpopulations and accommodate intra-species variability that might otherwise require the use of an Assessment factor.

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

NOAELs 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

Nervous system effects (foetal effects) during pregnancy

10 μg/dL

Pregnant women/women of child-bearing capacity

 

4.   The most sensitive NOAELs 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 NOAELs 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 exceedance of the NOAELs. Furthermore, the NOAELs 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 NOAELs 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 NOAELs derived here are both conservative and protective of health. The majority of NOAELs can thus be converted to DNELs with an Assessment Factor of “1”.

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

DNELs(blood lead)Used for Occupational Exposure Assessment

Subpopulation

DNEL (blood lead)

Health basis of DNEL

Pregnant woman

10 µg/dL

Developmental toxicity affecting cognitive development

All other adults

40 µg/dL

Neuropsychological function

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

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

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

All DNELs are based upon systemic biomarkers of internal exposure (lead in blood) and not upon external exposure. Potential toxicity is thus assessed independent of the exposure route and systemic DNELs derived.

NOAELs were used to derive DNELs 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 NOAELs 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 NOAELs have been derived for susceptible subpopulations there is no need to correct for inter-species variability with Assessment Factors. Separate NOAELs have been developed for sensitive subpopulations and accommodate intra-species variability that might otherwise require the use of an Assessment factor.

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

NOAELs 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

Nervous system effects (child)

5 μg/dL

 

Individual Child

Nervous system effects (child)

2 µg/dL

Population Based Child Limit

Nervous system effects (foetal effects) during pregnancy

5 μg/dL

 

Pregnant women/women of child-bearing capacity

 

4. The most sensitive NOAELs 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 NOAELs 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 NOAELs 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 5μg/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 (2μg/dL). A DNEL of 2μg/dL is put forward as a benchmark that the average blood lead in a large population should not exceed. Applying a population benchmark of 2μg/dL helps reduces that the risk of an individual child having a blood lead in excess of 5μg/dL.

8. Combined, the preceding indicated that the NOAELs derived here are both conservative and protective of health. The majority of NOAELs can thus be converted to DNELs 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 and the NOAEL of 10μg/dL for nervous system effects on the foetus during pregnancy since adults in the general population will not be under medical surveillance as is the case for worker populations. 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 DNELs indexed to acute toxicity are not needed. Animal testing indicates that lead is not acutely toxic. Moreover, the DNELs for repeated dose toxicity are far lower than those that might be considered under acute exposure circumstances.

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

DNELs(blood lead) Used for General Population Exposure Assessment

Subpopulation

DNEL (blood lead)

Health Basis of DNEL

Large Population of Children

2 μg/dL

Societal impact of indeterminate nature

Pregnant Woman

5 μg/dL

Developmental toxicity affecting cognitive development

Adult

20 μg/dL

Neuropsychological function