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EC number: 208-908-0 | CAS number: 546-67-8
- 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
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- 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
Key value for chemical safety assessment
Additional information
The genotoxic profile of lead is mixed. Bacterial mutagenesis assays produce negative results while conflicting (positive and negative) observations have been made in mammalian cell mutagenesis systems. In the absence of confirmation that lead was in fact taken up by bacteria, negative results in bacterial systems will not be assigned significance in a weight of evidence evaluation.
With few exceptions, in vitro studies of lead’s effects upon eukaryotic cellsin vitrohave employed high concentrations of soluble lead compounds producing significant levels of cytotoxicity and only weak genotoxic responses. A central issue that requires resolution is whether mechanisms for in vitro genotoxicity possess physiological relevance, by virtue of the mechanisms involved or the concentrations required to produce effects. For example, induction of genotoxic effects in cultured cells at lead concentrations in the µM or mM range would have limited relevance to in vivo exposures wherein the concentration of lead available for transfer to the soft tissues is in the nM range or lower. Extrapolation of the effects of soluble lead compounds to the compounds that are the subject of this risk assessment is further complicated by the sparingly soluble nature of the metal and its’ compounds. The compounds, while largely untested for mutagenicityin vitro, will not undergo dissolution in neutral aqueous media to an extent that will yield lead ion concentrations adequate to induce the weak effects reported for soluble compounds.In vitromutagenicity assay results would thus be expected to be negative if tests were conducted using sparingly soluble compounds but the lead cation itself appears to have weak genotoxic potential. This activity does not appear to entail direct interaction with DNA – instead indirect mechanisms have been proposed to mediate genotoxicity.
Multiple indirect mechanisms have been proposed for lead genotoxicity in vitro but not all are concordant with the genotoxicity response profiles observed. For example, although some studies have suggested that noncytotoxic lead concentrations can interfere with the mitotic spindle and induce aneuploidy that manifests as micronucleus induction, the concentrations required to disrupt spindle formation are higher than those that induce micronuclei. Conversely, interference with spindle formation would not be expected to produce the DNA damage or point mutations that have been reported to accompany micronucleus induction in other studies. There is thus inconsistency between the dose responses for genotoxic effects observed and some of the underlying mechanisms that have been proposed to produce them. Although lead may be capable of inducing genotoxicity by multiple mechanisms, it is not yet possible to ascertain which mechanism, or group of mechanisms, is of greatest importance and/or of physiological relevance in producing the spectrum of changes suggested byin vitrostudies.
In vivo studies using experimental animals are similarly characterised by conflicting results for endpoints such as DNA damage, chromosome aberrations, micronuclei and sister chromatid exchange induction. In most studies responses have occurred after lead compounds were administered via exposure routes (e.g. i.v., i.p. or s.c. injection) that have limited relevance to normal exposure routes and/or that are difficult to compare on a dosimetric basis to lead administered via ingestion. Furthermore, in many instances, only single doses have been studied and dose response relationships that help to validate the significance of a positive finding cannot be evaluated. When multiple doses have been evaluated, especially in injection studies, the dose response for genotoxic effects has either been weak, non-existent or inverse. Poor dose dependency under such circumstances is likely an indication of systemic or tissue toxicity that limits response. Injection routes of administration bypass the normal toxicokinetic processes responsible for the uptake and distribution of lead – 99% of the lead taken up into the blood following oral or inhalation exposure is bound within the red blood cell and only a small fraction (~1%) of lead in the blood is available for transfer to the soft tissues. Studies have not documented the free or biologically available lead in blood concentrations that result from i.p. or i.v. administration routes but the concentrations are likely far higher, perhaps by three orders of magnitude, than those that can be achieved via physiological routes of administration prior to the onset of lethality or other severe manifestations of systemic toxicity. For this reason, the dosimetry for genotoxic effects from injection studies is difficult to compare to other effects of concern such as carcinogenicity. Studies evaluating the comparative toxicokinetics of lead after oral and i.v. administration are ongoing and should assist in resolving this issue.
Given the preceding concerns regarding dosimetry for effects and the induction of indirect mechanisms with physiological relevance, studies conducted using physiologically relevant routes of exposure are especially important. Oral or inhalation exposure to high levels of soluble lead compounds produce negative or equivocal responses in all but one study. Assays for chromosome damage are either negative or report effects (e.g. weak induction of chromosome gaps) that are not now believed to be true indicators of a mutagenic response. Induction of weak positive responses can also require non-standard test conditions (e.g. extreme calcium deficiency) that make results difficult to interpret. A single study reported aberrations in bone marrow cells and spermatocytes, but the levels of Pb administration were high and cytotoxicity was not monitored. Lack of information regarding systemic lead levels precludes comparison of the study results from studies with similar dosing levels but negative findings. In this instance, the weight of evidence derived from four negative studies of high and comparable study quality would indicate that chromosomal aberrations are not induced by oral lead administration.
Several findings of micronucleus induction were reported but are difficult to interpret. One observed a low level response in polychromatic ethrythrocytes after prolonged exposure to high levels of lead – the response observed may have been an artifactual positive produced by anaemia. Other studies observed micronuclei following the administration of high levels of lead but did not adequately control for cytotoxicity. Only one germ cell mutagenesis assay was found reported in the literature, but although the administration of lead in drinking water did not produce a response in the dominant lethal assay, the dose administered only produced a modest elevation of blood lead.
When studies are ranked by overall study quality, negative response are generally seen in the higher quality studies and suggestions of effects generally are relegated to low quality studies. Responses in so-called indicator assays (SCE induction or the Comet assay) have been reported as positive with greater frequency but are difficult to interpret in light of the mostly negative findings from true mutagenicity assays and a failure if indicator assay studies to adequately monitor apoptosis and, in most instances, cytotoxicity.
This inconsistent response profile extends to observational studies in humans where endpoints such as chromosome aberrations, micronuclei and sister chromatid exchange induction have been evaluated. Both positive and negative studies exist, but even positive studies are characterised by weak or non-existent dose responses and small effect sizes. Furthermore, almost without exception, studies in humans have failed to monitor potential impacts of lead upon apoptosis or cellular toxicity and measurements are generally lacking of co-exposures to other substances in the workplace that may have genotoxic potential. The lack of a cohesive response profile, combined with technical inadequacies in most studies, does not support the presence of significant in vivo genotoxic activity in humans.
Short description of key information:
Although lead genotoxicity can be induced in vitro, responses appear to be induced by indirect mechanisms and at very high concentrations that lack physiological relevance.
Endpoint Conclusion: No adverse effect observed (negative)
Justification for classification or non-classification
While it is not possible to ascribe genotoxic activity to lead in vivo, soluble lead compounds appear to have weak genotoxic activity in vitro. Effects observed usually, but not always, require treatment with highly soluble compounds at cytotoxic concentrations several orders of magnitude higher than that which could reasonably be expected to occur in vivo. There is further general agreement that if lead produces genotoxicity it likely occurs via indirect mechanisms. The ability to directly damage DNA appears to be lacking. Rather, a diverse range of indirect mechanisms have been proposed such as increased production of oxygen radicals, depletion of glutathione, impaired DNA repair and interference with components of the mitotic apparatus during cell division. Which, if any, of these hypothesised mechanisms explains lead’s effectsin vitrocannot be determined at this time. However, indirect mechanisms imply potential non-linear dose response and the presence of apparent thresholds below which effects will not be observed. There is as yet little evidence suggesting that the indirect effects suspected of mediating lead genotoxicity occur at lead concentrations that can be reasonably maintained in experimental animals or humans without rapid lethality. On both a mechanistic and a dosimetric basis, the results of most in vitro studies cannot be readily extrapolated to in vivo exposure scenarios.
Based upon this weight of evidence evaluation, genotoxicity is not an endpoint appropriate for use in Risk Characterization nor are the data sufficient as the basis for Classification on the basis of Mutagenicity.
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