Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Human evidence is available to demonstrate that transfer of lead from a nursing mother to the infant can occur and in exceptional circumstances could result in an exceedance of the the FAO/WHO acceptable level of 16 μg/l .

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
adverse effect observed
Additional information

Animal studies serve primarily to validate mechanistic inferences drawn from studies in humans - a number of which are described in section 7.10.2. The following conclusions have been drawn from observational studies in humans.

1.     The available data indicate that extremely high lead exposure can have a marked adverse impact upon semen quality. Aberrant sperm morphology, decreased sperm count and decreased sperm density have all been demonstrated in heavily exposed individuals. However, it is difficult to precisely define the levels of exposure at which these effects will be exerted. The recently completed Asclepios Project (Bonde et al., 1999, 2002) was of sufficient size to model dose-effect relationships and indicted a threshold for an effect of concurrent blood lead upon semen quality of 45 µg/dL. Significant changes in semen quality that may adversely impact reproductive function of the individual require exposures in excess of 50 µg/dL. In the range of 50 – 60 µg/dL lead in blood, alterations in semen quality are relatively mild, but could be significant for individuals who (for other reasons) are already of marginal fertility. Lead exposure might thus be hypothesised to increase the difficulty such individuals experience in achieving conception, but such as effect has not yet been documented in association with lead exposure. Decrements in semen quality that would unambiguously impact upon fertility have been only inconsistently reported and are associated with exposure levels (e.g. require occupational exposures that produce blood lead levels of 70 µg/dL or higher) associated with clinical lead intoxication.

2.     A NOAEL of 45 µg/dL is indicated for effects upon male semen quality and thus for effects upon male fertility. At exposure levels moderately in excess of the NOAEL effects upon actual fertility will be modest.

3.     Effects upon female human fertility have been documented in the historical literature but their dosimetry is uncertain. Given that other reproductive impacts will manifest at lower doses (e.g. developmental effects), the exposure levels that may impair female fertility will be secondary to other reproductive endpoints in quantitative risk assessment. Data in females are not adequate to estimate a NOAEL for fertility, but any effects will likely manifest as secondary impacts of systemic toxicity associated with clinicallead intoxication at blood lead levels in excess of 70 µg/dL .


Short description of key information:
Although a number of studies have been conducted of male reproductive function in workers occupationally exposed to lead, definitive statements regarding the impact of lead upon male reproductive potential are difficult to make. Alterations in semen quality are the most commonly observed effects in the occupational setting and can be documented with precision, but such changes are not synonymous with impacts upon fertility. Natural and extreme variability in semen quality (e.g. sperm count and motility) is evident among fertile individuals and modest impacts upon semen quality(e.g. in blood lead ranges of 50 – 60 µg/dL) would not be expected to have a significant impact upon actual fertility. Higher blood lead levels would have greater impacts upon semen quality – the decrements associated with high blood lead levels would be expected to have an impact upon the fertility of normal, healthy individuals. The dosimetry for impacts upon female fertility is uncertain but appears to entail general systemic toxicity induced at blood lead levels in excess of 70 µg/dL.

Effects on developmental toxicity

Description of key information

The existing data indicate that lead exposure will not lead to increased frequency of congenital abnormalities in humans. Data relating prenatal blood levels to preterm delivery, gestational age and/or birth weight are mixed and provide uncertain results. Weight of evidence evaluation indicates that effects do not occur at blood lead levels up to 30 µg/dL, but are not adequate to determine the extent of the higher exposure levels that would be required to produce effects. A NOAEL of 30 µg/dL is recommended for pregnancy outcome on a precautionary basis.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Additional information

Effects on preterm delivery, gestational age and birth weight

High doses of lead have been reported to cause spontaneous abortion in women. Data relating maternal blood lead to increased incidence of preterm delivery, gestational age and/or reduced birth weight have provided conflicting results but weight of evidence suggests that such effects are not likely below blood lead levels of 30 µg/dL.

Prenatal Effects

Effects of prenatal lead exposure upon neurobehavioural performance measures have been demonstrated in studies of experimental animals and presumably will occur in humans. However, available data are inadequate to establish the dose-effect relationships that characterize this endpoint. While effects have been observed upon early measures of mental and physical development, attenuation of effects typically occurs over time and, in most studies, are not associated with impacts upon measures such as IQ. However, effects of prenatal lead exposure upon IQ can be difficult to dissociate from those of postnatal exposure. An effect of pre-natal lead exposure has been suggested by two of nine longitudinal studies and has only been reported to persist in one. Effects observed are secondary in magnitude to those produced by exposures after birth, but blood lead levels above 10 µg/dL have been suggested to exert an effect. Although the effects under consideration would not constitute material impairment of an individual child born to a woman with a blood lead level in the range of 10 – 20 µg/dL, maintenance of the blood lead levels of pregnant women at or below 10µg/dL is advised. .

Neurological Effects in Children

The impacts of post-natal lead exposure upon the development of children have been studied and multiple endpoints evaluated using psychometric testing tools. Confounding factors that influence complex behavioural endpoints are imperfectly understood, and quantitative assessment of impacts at low blood lead levels is highly imprecise. Given the inherent difficulty of assessing effects upon behavioural endpoints, intelligence (IQ) is the endpoint for which the most robust measurement tools are available and for which confounder correction can be most comprehensively implemented. The underlying mechanisms for lead-induced IQ decrements is not known, nor have epidemiology studies identified a specific “syndrome” of neuropsychological deficits that would permit more precise quantitation of low-level lead effects independent of residual confounding and other sources of uncertainty in effects assessment.

The effects of lead upon IQ in children are thus summarised as follows:

1.     Meta-analyses of human observational epidemiology data show a statistical association between post-natal blood lead and IQ that is small and most likely between a one to three IQ point deficit for a change in mean blood lead level from 10 µg/dL to 20 µg/dL. Meta-analyses performed by Pocock et al. (1994) and IPCS (1995) serve as the basis for this estimate of effect size.

2. Characterisation of the dose response for effects under 10 µg/dL has proved to be more difficult. Crump et al (2013) confirmed earlier conclusions by Lanphear et al (2005) that non-linear models provide better fits to the overall data base than linear models and concluded that statisticall significant effects of lead on cognitative performance of children in IQ test are apparant down to concurrent blood lead levels of 5 µg/dL and peak blood level of 7 µg/dL.

3. IQ decrements less than 5 are smaller than the standard error of measurements in IQ tests. As such they cannot be detected at the level of the individual and have no known functional significance and cannot be regarded as "adverse". Thus a NOAEL for effects of lead on IQ can be regarded as 5 µg Pb /dL blood.

Toxicity to reproduction: other studies

Additional information

Effect of Lead on Lactation

According to the CLP criteria classification for lactation is recommended when “absorption, metabolism, distribution and excretion studies indicate the likelihood that the substance is present at toxic levels in breast milk.” Although levels of lead in breast milk are generally low, they can influence infant blood lead levels over and above the influence of maternal blood to which the infant was exposed in utero. In a large-scale study of breast milk and infant blood lead levels, milk lead was found to account for 10% of the variance in 6-month blood lead and there was a linear dose–response relationship between breast milk lead and infant blood lead at age 6 months (Rabinowitz et al. 1985). In another study, breast milk lead accounted for 12% of the variance of infant blood lead levels at 1 month of age and levels of breast milk lead were significantly correlated with infant blood lead (Ettinger et al. 2004). Evidence also suggests that the breast milk lead to maternal blood lead ratio may increase in a nonlinear fashion when maternal blood lead concentrations exceed about 40 μg/dL.

Justification for classification or non-classification

Lead compounds not otherwise specified are included in Annex VI to CLP, designated as:

Repro. 1A: (H360Df)

Studies in humans and experimental animals have evaluated impacts of lead upon sexual maturation and semen quality, pregnancy outcome, and neurobehavioural effects of pre and post-natal lead exposure upon child development.If reported neurological effects on children are determined to represent evidence of developmental toxicity then there is clear evidence that the human data support designation of lead monoxide as a category Repr. 1A reproductive toxicant. Moreover,given that aberrant sperm morphology, decreased sperm count and decreased sperm density have all been demonstrated in workers exposed to high levels of lead in the workplace there is justification that lead compounds also meet the criteria for classification as Repro 1A for fertility effects.

In exceptional circumstances it is possible that potentially harmful levels of lead may be transmitted in breast milk of mothers exposed to lead/lead compounds to nursing infants. It is therefore proposed that the hazard statement “May cause harm to breast fed children” be applied. However it should be pointed out that the US Centres for Disease Control recommends that initiation of breastfeeding should be encouraged for all mothers with blood lead levels ≤40 µg/dL per the 2010 CDC document, https://www.cdc.gov/nceh/lead/publications/leadandpregnancy2010.pdf (page 97; 3rd bullet) (last checked 25 October 2017).

It is therefore proposed that a classification of Repr. 1A – H360DF and as Lact. – H362 is more appropriate than the current harmonised CLP classification of Repro. 1A: (H360Df).