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EC number: 235-252-2 | CAS number: 12141-20-7
- 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
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- Nanomaterial pour density
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- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
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- 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
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Additional information
The data on mutagenicity of lead is inconsistent. 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, studies of lead’s effects upon eukaryotic cells in vitro have 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. Lead oxide, while largely untested for mutagenicity in 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 vitro mutagenicity assay results would thus be expected to be negative if tests were conducted using lead oxide 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 by in vitro studies.
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.
Given the preceding concerns regarding dosimetry for effects and the induction of indirect mechanisms with physiological relevance, studies conducted in animals 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 in animal studies but are difficult to interpret. One observed a low-level response in polychromatic erythrocytes 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 animal studies are ranked by overall study quality, negative responses 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 of 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, until recent years, 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. A number of recent studies have now documented that apoptosis and necrosis, as well as co-exposure to known genotoxicants, accompanies the increase in blood lead and increased induction of micronuclei and/or increased comet assay responses. Appropriate correction for these factors remains problematic and may contribute to the inverse dose-responses or other inconsistencies that continue to complicate study interpretation. The lack of a cohesive response profile and technical uncertainties preclude a determination that lead poses significant genotoxic risk for exposure humans. Garcia-Leston et al. (2010) has recently reviewed many of these same studies and similarly concluded lead genotoxicity is mediated via indirect mechanisms that is expressed under situations highly dependent upon the experimental variables. Although their analysis suggests there is evidence of a genetic risk, they concur that there are still conflicting data on the conditions under which genotoxicity becomes apparent.
The most recent genotoxicity studies in occupational groups published since the Garcia-Leston et al. (2010) review corroborate indirect mechanisms for the genotoxicity for lead. Many of these studies incorporate comet, micronucleus, and chromosomal aberration assays in peripheral blood lymphocytes of workers exposed to lead in the workplace. Studies that measure oxidative stress and/or damage and impairment of DNA repair capacity are typical of these more recent studies. Finally, study techniques incorporate specific cellular signaling pathway methods that also suggest lead is not directly genotoxic. The ToxTracker assay utilizes a comprehensive panel of protein reporters to discriminate between different primary reactivities of substances such as lead, including their ability to react with DNA and block DNA replication, induce oxidative stress, activate the unfolded protein response, or cause a general P53-dependent cellular stress response. By incorporating these various toxic responses in a single assay, the ToxTracker assay discriminates between direct DNA damage, oxidative stress, and protein damage as primary toxic responses.
In summary, 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 effects in vitro cannot 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. It is on this basis that the observation that induction of genotoxicity in experimental animals occurs predominantly after non-physiological routes of lead administration becomes particularly significant. The exposure conditions conducive to genotoxicity in vitro appear to be difficult (if not impossible) to achieve under physiological routes of exposure. Although there has been an increase in the number of studies suggesting increases in endpoints such as micronucleus induction and the Comet assay, the lead exposure conditions that produce these responses are being increasingly associated with apoptosis and necrosis which complicate data interpretation. Co-exposures clearly cloud the interpretation of a number of recent studies, as do observations of inverse dose-response relationships with lead exposure. To appropriately evaluate genotoxicity of lead on workers without the confounding impact of co-exposures, as well as the influence of historically higher exposures that are generally absent in the modern workplace, prospective studies (i.e., following a group over time) would be required in workers with blood lead levels consistently in the lower blood lead range of 10 to 30 μg/dL. Such studies have not been conducted to date.
However, based upon this weight-of-evidence evaluation of existing studies and data, this substance is not expected to be directly genotoxic under normal use and handling conditions.
Short description of key information:
Studies using in vitro tests with mammalian cell systems show a proportion of studies reporting positive test results for genotoxicity. Inconsistency of responses in similar test systems is observed, and when positive responses are observed, they tend to be weak and require high concentrations of soluble lead compounds, producing significant levels of cytotoxicity. The central issue 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. Solubility is a further complicating issue in that lead oxide, largely untested for mutagenicity in 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, such as lead acetate. In vitro mutagenicity assay results would thus be expected to be negative if tests were conducted using lead oxide, 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.
Compound-specific information pertaining to the effects of individual lead compounds is generally lacking for sparingly soluble lead compounds: most scientific literature has been generated by the study of soluble lead salts easily taken up into the body of organisms and/or humans. The application of read-across to Lead REACH Consortium substances is discussed in detail in the document ‘Use of read-across in Lead REACH Consortium dossiers’ appended to this CSR (see IUCLID section 13).
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 effects in vitro cannot 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. It is on this basis that the observation that induction of genotoxicity in experimental animals occurs predominantly after non-physiological routes of lead administration becomes particularly significant. The exposure conditions conducive to genotoxicity in vitro appear to be difficult (if not impossible) to achieve under physiological routes of exposure. Although there has been an increase in the number of studies suggesting increases in endpoints such as micronucleus induction and the Comet assay, the lead exposure conditions that produce these responses are being increasingly associated with apoptosis and necrosis which complicate data interpretation. Co-exposures clearly cloud the interpretation of a number of recent studies, as do observations of inverse dose-response relationships with lead exposure. To appropriately evaluate genotoxicity of lead on workers without the confounding impact of co-exposures, as well as the influence of historically higher exposures that are generally absent in the modern workplace, prospective studies (i.e., following a group over time) would be required in workers with blood lead levels consistently in the lower blood lead range of 10 to 30 μg/dL. Such studies have not been conducted to date.
However, based upon this weight-of-evidence evaluation of existing studies and data, this substance is not expected to be directly genotoxic under normal use and handling conditions.
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