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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
0.09 mg/m³
Additional information

Effects on fertility and sex organs have been noted in experimental studies at high doses of cadmium which generally caused other manifestations of toxicity (e.g. changes in body or organ weights and/or lethality). The lowest NOAELs correspond to 1 mg Cd/kg bw/d via the oral route and ca. 0.09 mg Cd/m3 after inhalatory exposure. Only a few publications on the effects on human fertility were found. Overall, epidemiological evidence does not speak for an association between exposure to cadmium and relevant effects on fertility or sex organs.


Short description of key information:
Effects of cadmium treatment on male and female reproductive organs have been observed after oral administration of cadmium compounds in rats and mice. In several studies, effects were detected at dose levels which caused also general toxicity. In male rats and mice, acute exposure to cadmium compounds at doses higher than 50 mg/kg bw was shown to cause testicular atrophy and necrosis and concomitant decreased fertility. In females, effects on length of oestrous cycle after administration of cadmium compounds by gavage were observed at a dose of 40 mg/kg bw/d. Fertility was however reported to be affected at doses of 10 mg/kg bw/d. Overall, the lowest concentration (LOAEL) of cadmium reported to affect fertility in male and female rats upon oral administration was 10 mg Cd/kg bw/d (Sutou et al., 1980).

In male rats exposed by inhalation to 1 mg CdO/m3 for 13 weeks (Dunnick, 1995), the number of spermatids per testis, as evaluated at necropsy, was reduced compared to controls. No histopathological changes of the reproductive system were observed (reproductive LOAEL: 1 mg CdO/m3 ca. 0.9 mg Cd/m3). This effect on the number of spermatids was not observed in mice (Dunnick, 1995). Exposure to cadmium oxide at a concentration of 1 mg/m3 (for more than 10 weeks) has been associated with an increase in oestrous cycle length in rats in two studies. It has been suggested that the effects on the oestrous cycle occur only when other signs of cadmium intoxication are present and might be related to other cadmium-induced effects such as hormonal changes; however, current data do not allow to definitely draw this conclusion. The reproductive LOAEL for inhalation is therefore considered to be 1 mg CdO/m3 (ca. 0.9 mg Cd/m3), derived from the 13-week rat study. The corresponding NOAEL is 0.1 mg CdO/m³ (ca. 0.09 mg Cd/m³).

Effects on developmental toxicity

Description of key information
Oral route
Cadmium compounds have been reported to induce reduced bodyweight and malformations (primarily of the skeleton) in offspring of animals exposed via gavage or diet at doses that produced maternal toxicity. In some studies, information on maternal toxicity is lacking, but cross-reading with studies that provide this information indicates that the reported developmental effects occur at doses levels expected to cause maternal toxicity (overall > 5 ppm or ca. 0.6 mg CdCl2/kg bw/d) ( Sorell and Graziano, 1990; Baranski, 1985; ECB, 2007).
Neurobehavioral effects or changes in electrophysiological parameters were reported to occur at doses that did not induce maternal toxicity. The lowest dose reported to generate behavioural changes in pups was 0.04 mg Cd/kg bw/day (LOAEL) (Baranski et al., 1983). The significance of these changes and underlying mechanisms for the observed effects on behavioural endpoints are not completely elucidated yet; some authors suggested that the toxic effects might be mediated by placental toxicity or by interference with the normal foetal metabolism of zinc and/or copper. Several other mechanisms of action (e.g. neurotransporters or ions channels) were suggested to explain the neurobehavioral changes in the pups of exposed dams. There is a need for further studies to better describe the effects of cadmium on the developing brain.
Inhalation route
Decreased foetal weight and a significant increase in retarded ossification frequency were reported in offsprings of rats and mice exposed to CdO by inhalation at levels that produced maternal toxicity (0.5 and 2 mg CdO/m3 in mouse and rat, respectively) (Dunnick, 1995).
Neurobehavioural changes were reported in young rats from dams exposed to CdO (0.02 mg Cd/m3) in a single experiment (Baranski, 1984) but observations should be confirmed in an independent study (ECB, 2007).
Taken together, these results indicate a potential for developmental toxicity.
Additional information

In studies with mouse and rat, effects on development were observed after oral and inhalatory exposure to cadmium compounds. Neurobehavioural changes were reported in the absence of maternal toxicity but the robustness of these observations was not sufficient to derive an appropriate NOAEL. It is suggested that further studies are needed to better document the possible effects of cadmium on the developing brain (ECB, 2007). No clear evidence indicates that cadmium has adverse effects on the development of offprings from women exposed indirectly via the environment or occupationally. Effects on birth weight, motor and perceptual abilities of offsprings have been reported by some authors. However, these studies suffer from drawbacks either in the definition of the study postulation, the definition of the effects, or in the assessment of exposure. Moreover, it is not clear whether the effects on psychomotor development were related to cadmium or to a simultaneous exposure to other substances such as lead. This aspect is not considered to have received enough attention in humans and follow-up with a well designed epidemiology study has been proposed (ECB, 2007).

Justification for classification or non-classification

Water-soluble cadmium chloride and sulphate are currently classified as Repr. Cat. 2; R60-61(May impair fertility, may cause damage to unborn child) in Annex I of Directive 67/548 (the corresponding GHS-CLP classification would beReproduction category 1B; H360). By analogy, a similar classification for cadmium nitrate could be considered.

Slightly soluble cadmium metal and oxide have been granted the classification Repr. Cat. 3; R62-63(Possible risk of impaired fertility, possible harm to unborn child) in Annex I of Directive 67/548 (the corresponding GHS-CLP classification would be Reproduction category 2; H361). Other cadmium compounds in this solubility class (e.g. cadmium hydroxide and carbonate) may warrant this classification as well.

Apart from cadmium sulphide, none of the insoluble cadmium compounds (e.g. cadmium sulfoselenide, cadmium zinc sulphide or cadmium telluride), not expected to penetrate easily into the organisms, are classified for reproductive toxicity. Cadmium sulphide is an exception. As there is no data to support itsRepr. Cat. 3; R62-63classification, a revision of the classification may be appropriate based on solubility properties.